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Oxa- or thio-evodiamine anti-tumor derivatives and preparation method thereof

A technology of heteroevodial and derivatives, which is applied in the field of oxa or thiaevodipine antitumor derivatives and their preparation, and can solve the problems of poor water solubility, high toxicity and the like

Active Publication Date: 2014-08-20
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the lactone structure necessary for the activity of this type of compound is hydrolyzed too quickly in the human body into an inactive carboxylate, and has poor water solubility and high toxicity

Method used

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  • Oxa- or thio-evodiamine anti-tumor derivatives and preparation method thereof
  • Oxa- or thio-evodiamine anti-tumor derivatives and preparation method thereof
  • Oxa- or thio-evodiamine anti-tumor derivatives and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Embodiment 1: the synthesis of 15-oxa evodiamine

[0074] A. Preparation of N-formyltryptamine

[0075] In a 50mL three-necked bottle, add 8g (50mmol) tryptamine and 25g ethyl formate, and reflux at 80°C for 12 hours. After the reaction, evaporate the solvent to obtain a brown oily substance, which is left at room temperature for 2-3 days, and crystals slowly appear. Suction filtration obtained 7.3 g of the product with a yield of 87.1%.

[0076] B. Preparation of 3,4-dihydro-β-carboline

[0077] In a 100mL three-necked flask, add 50mL of dichloromethane, add 5g (26mmol) of N-formyltryptamine under stirring conditions, cool to about 5°C in an ice-water bath, then slowly add 12.5mL of phosphorus oxychloride, ice React in the bath for 2 hours, and then react at room temperature for 2 hours. After the reaction, dichloromethane and unreacted phosphorus oxychloride were recovered by distillation under reduced pressure, and the residual solid was extracted three times with ...

Embodiment 2

[0082] Example 2: Synthesis of 13-(4-chlorobenzoyl chloride)-15-oxaevodiamine

[0083] Take 0.30g (1.0mmol) of 15-oxaevodiamine, dissolve it in 15mL of DMF, add 0.04g (1.7mmol) of NaH, stir in ice bath for 10min, add 0.35g (2.0mmol) of p-chlorobenzoyl chloride, and react for 1h Afterwards, the reaction was processed, purified by column chromatography, and the eluent was petroleum ether: ethyl acetate=5:1 to obtain 0.30 g of 13-(4-chlorobenzoyl chloride)-15-oxaevodiamine with a yield of 69.3 %.

Embodiment 3

[0084] Example 3: Synthesis of 10-chloro-15-oxaevodiamine

[0085] Referring to Example 1, the starting material is 5-chlorotryptamine. In step D, 3,4-dihydro-6-chloro-β-carboline and o-hydroxybenzoyl chloride were reacted in dichloromethane at room temperature for 5 h, 0.72 g of 10-chloro-15-oxaevodiamine was obtained with a total yield of 46.4%.

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PUM

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Abstract

The invention relates to the technical field of medicines and in particular relates to oxa- or thio-evodiamine anti-tumor derivatives as well as a preparation method of the derivatives and application of the derivatives in preparation of topoisomerase inhibitors and anti-tumor drugs. The oxa- or thio-evodiamine anti-tumor derivatives are newly discovered topoisomerase I inhibitors with brand-new structures and have remarkable anti-tumor activity, and the structure of a compound is as shown in a general formula I.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of oxa or thia evodiamine antitumor derivatives and a preparation method thereof. Background technique [0002] DNA topoisomerase I (topoisomerase I, TopoI) is an essential enzyme for cell DNA replication, transcription, recombination and repair, and the content of TopoI in tumor cells, especially colon cancer, cervical cancer, ovarian cancer, etc. is much higher than that in normal tissues , Drugs that selectively inhibit TopoI can have higher selectivity for tumor cells. Inhibitors of this enzyme have been listed as one of the six major categories of anti-tumor drugs by the US NCI. [0003] Camptothecin is a classic topoisomerase I inhibitor. At present, three camptothecin compounds have entered clinical use, namely Irinotecan, Topotecan and Belotecan. . However, the lactone structure necessary for the activity of this type of compound is hydrolyzed too quickly in t...

Claims

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Application Information

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IPC IPC(8): C07D498/14C07D513/14A61K31/5365A61K31/542A61P35/00
CPCC07D498/14C07D513/14
Inventor 盛春泉张万年王胜正方堃董国强缪震元姚建忠李振钢何世鹏陈伟蒋琰
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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