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4,7-position melphalan-like nitrogen mustard derivative of brefeldin a, its preparation method and use

A technology of fideloidin and melphalan, which is applied to the 4,7-position of Brefeldin A splicing melphalan-like nitrogen mustard derivatives and the fields of their preparation and use, can solve the lack of specificity of cell action , large toxic side effects, unsatisfactory treatment effect, etc.

Active Publication Date: 2021-01-29
SHENYANG PHARMA UNIVERSITY
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  • 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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  • 4,7-position melphalan-like nitrogen mustard derivative of brefeldin a, its preparation method and use
  • 4,7-position melphalan-like nitrogen mustard derivative of brefeldin a, its preparation method and use
  • 4,7-position melphalan-like nitrogen mustard derivative of brefeldin a, its preparation method and use

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Embodiment 1

[0020]

[0021] Take brefeldin A1 (32mg, 0.08mmol), dissolve in dichloromethane (2.5ml), add melphalan methyl butyric acid (68mg, 0.16mmol), EDCI (29mg, 0.15mmol) and catalytic The amount of DMAP was stirred at room temperature for the reaction, the progress of the reaction was monitored by TCL, and the reaction was terminated after 24 h. 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 yellow oil 5-1 with a yield of 24%. HR-MS(ESI,M+H)m / z: calcd for C 43 h 51 Cl 2 N 5 o 7 H:1081.3661,found 1081.3552. 1 H NMR (400MHz, DMSO-d 6 ): δ(ppm)7.23(1H,dd,J=15.8,3.1Hz,C 3 -H),7.03(4H,d,J=8.5Hz,Ar-H),6.64(4H,d,J=8.4Hz,Ar-H),5.75(1H,m,C 11 -H),5.64(1H,dd,J=15.8,1.5Hz,C 2 -H),5.17-5.24(2H,m,C 4 ,C 10 -H),4.98(1H,m,C 7 -H)...

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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 and site 7, specifically to a preparation method for introducing DNA alkylating agent melphalan derivatives at the 4-OH site and the 7-OH site of brefeldin A, and applications in preparation of antitumor drugs. According to the present invention, the brefeldin A derivative with melphalan-based chlormethine linked at site 4 and site 7, 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 4,7-position melphalan nitrogen mustard derivatives of brefeldin A and its preparation method and application, in particular to the 4-position of brefeldin A Derivatives modified at OH and 7-OH sites relate to brefeldin A derivatives substituted by DNA alkylating agent melphalan derivatives at the 4-OH and 7-OH sites and their preparation methods and 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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D313/00A61K31/365A61P35/00A61P35/02
CPCC07D313/00
Inventor 李达翃华会明李占林田康涛韩通崔祎航廖嘉穗
Owner SHENYANG PHARMA UNIVERSITY
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