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Brefeldin A derivative with melphalan-based chlormethine linked at site 4, preparation method and uses thereof

A technology of feldspar and its derivatives, which is applied in the field of brefeldin A 4-position spliced ​​melphalan nitrogen mustard derivatives and its preparation and application, which can solve the problem of unsatisfactory therapeutic effect and serious side effects , the lack of specificity of cell action, etc.

Active Publication Date: 2019-07-19
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of drug is widely used clinically, but its toxic and side effects are relatively large, and it lacks specificity for cell action, and with the occurrence of tumor drug resistance in recent years, the therapeutic effect is not satisfactory. Chemical modification, improving its curative effect has very important value

Method used

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  • Brefeldin A derivative with melphalan-based chlormethine linked at site 4, preparation method and uses thereof
  • Brefeldin A derivative with melphalan-based chlormethine linked at site 4, preparation method and uses thereof
  • Brefeldin A derivative with melphalan-based chlormethine linked at site 4, preparation method and uses thereof

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Embodiment 1

[0022]

[0023] Take brefeldin A intermediate 3 (32mg, 0.08mmol), dissolve in dichloromethane (2.5ml), add melphalan methyl butyric acid (34mg, 0.08mmol), EDCI (29mg, 0.15mmol) ) and a catalytic amount of DMAP, the reaction was stirred at room temperature, the reaction progress was monitored by TCL, and the reaction was terminated after 24 hours. The reaction solution was poured into 20ml of ice-water mixture, extracted with dichloromethane (30ml×3), washed with saturated saline solution, dried over anhydrous sodium sulfate, recovered dichloromethane, passed through a silica gel column (petroleum ether: ethyl acetate = 2: 1), separated to obtain intermediate 7, then dissolved 7 in anhydrous THF, removed the 7-position TBS protecting group with TBAF in THF solution, and separated through silica gel column (petroleum ether: ethyl acetate = 2:1) , to obtain yellow oil 8-1 with a yield of 21%. HRMS (ESI,M+Na + )m / z calcd for C 39 h 43 Cl 2 N 5 o 6 H:703.2523,found703.245...

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Abstract

The invention belongs to the field of natural medicine and medicinal chemistry, and relates to a preparation method and uses of a brefeldin A derivative with melphalan-based chlormethine linked at site 4, specifically to a preparation method for introducing a DNA alkylating agent melphalan derivative at the 4-OH site of brefeldin A, and applications in preparation of antitumor drugs. According tothe present invention, the brefeldin A derivative with melphalan-based chlormethine linked at site 4, and the pharmaceutically acceptable salt have a structure represented by a general formula I, wherein n is defined in the claim and specification.

Description

technical field [0001] The invention belongs to the field of natural medicine and medicinal chemistry, and relates to the preparation method and application of the 4-position melphalan nitrogen mustard derivative of brefeldin A, in particular to the 4-OH site of brefeldin A The modified derivatives relate to these brefeldin A derivatives substituted by DNA alkylating agent melphalan derivatives at the 4-OH position, its preparation method and its application in the preparation of antitumor drugs. Background technique [0002] Brefeldin A (brefeldin A, BFA) is a secondary metabolite of Ascomycetes (Ascomycetes), which belongs to macrolide antibiotics, also known as clinomycin or ascodiosporin. It was isolated from the fermentation broth of Penicillium decumbens by Singleton et al. in 1958. Brefeldin A, prismatic crystal, white, insoluble in petroleum ether, chloroform, water, easily soluble in ethyl acetate, acetone and methanol. Pharmacological studies have shown that bref...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D313/00A61K31/365A61P35/00A61P35/02
CPCC07D313/00Y02P20/55
Inventor 李达翃华会明李占林田康涛韩通孙艺珈蔡林璇
Owner SHENYANG PHARMA UNIVERSITY
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