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4-position spliced ​​melphalan nitrogen mustard derivative of brefeldin a and its preparation method and application

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 lack of specificity of cell action and toxic side effects Large, unsatisfactory treatment effect and other problems

Active Publication Date: 2021-01-29
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • 4-position spliced ​​melphalan nitrogen mustard derivative of brefeldin a and its preparation method and application
  • 4-position spliced ​​melphalan nitrogen mustard derivative of brefeldin a and its preparation method and application
  • 4-position spliced ​​melphalan nitrogen mustard derivative of brefeldin a and its preparation method and application

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Experimental program
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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 relates to the fields of natural medicine and medicinal chemistry, and relates to a preparation method and application of a 4-position spliced ​​melphalan nitrogen mustard derivative of brefeldin A. It specifically relates to the preparation method of introducing DNA alkylating agent melphalan derivatives into the 4-OH site of brefeldin A and its application in the preparation of antitumor drugs. The structure of the 4-position melphalan nitrogen mustard derivative of brefeldin A according to the present invention and its pharmaceutically acceptable salt is shown in the general formula I, wherein, n is as in the claims and description mentioned.

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 Patents(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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