Preparation method and application of a class of 7-position nitrogen mustard derivatives of brefeldin a

A technology of feldspar and its derivatives, which is applied in the fields of medicine, natural medicine and medicinal chemistry, and can solve problems such as unsatisfactory therapeutic effect, large toxic and side effects, and lack of specificity in cell action.

Active Publication Date: 2021-02-26
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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  • Preparation method and application of a class of 7-position nitrogen mustard derivatives of brefeldin a
  • Preparation method and application of a class of 7-position nitrogen mustard derivatives of brefeldin a
  • Preparation method and application of a class of 7-position nitrogen mustard derivatives of brefeldin a

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018]

[0019] Take brefeldin A 1 (32mg, 0.08mmol), dissolve it in dichloromethane (2.5ml), add benzoic acid mustard (21mg, 0.08mmol), EDCI (29mg, 0.15mmol) and catalytic amount of DMAP, the reaction was stirred at room temperature, the progress of the reaction 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 = 5: 1), the yellow oil 6a was obtained with a yield of 19%. HR-MS(ESI,M+H)m / z:calcd forC 39 h 46 Cl 2 N 4 o 4 H:524.1965,found524.1957. 1 H NMR (400MHz, DMSO-d 6 ): δ(ppm)7.68(2H,m,Ar-H),7.37(1H,m,C 3 -H),6.72(2H,m,Ar-H),5.74(1H,m,C 11 -H),5.54(1H,d,J=15.8Hz,C 2 -H),5.41(1H,m,OH),5.20-5.31(2H,m,C 10 -H,C 7 -H),4.73(1H,m,C 15 -H),4.08(1H,m,C 4 -H),3.48-3.81(8H,m,...

Embodiment 2

[0021]

[0022] Compound 3b was prepared according to the synthesis method of Example 1. Yellow oil, yield 19%. HR-MS(ESI,M+H)m / z: calcd for C 39 h 46 Cl 2 N 4 o 3 H:566.2435,found 566.2417. 1 H NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.76 (2H, d, J = 9.0Hz, Ar-H), 7.37 (1H, dd, J = 15.6, 3.0Hz, C 3 -H),6.84(2H,d,J=9.1Hz,Ar-H),5.71-5.78(2H,m,H-2,C 11 -H),5.20-5.26(3H,m,OH,C 10 -H,C 7 -H),4.72(1H,m,C 15 -H),4.05(1H,m,C 4 -H),3.76-3.81(8H,m,-NCH 2 CH 2 Cl),0.75-2.33(21H,m,-CH 2 CH 2 CH 2 -,C 5 ,2C 6 ,2C 8 ,C 9 ,2C 12 ,2C 13 ,2C 14 -H,CH 3 ). 13 C NMR (100MHz, DMSO-d 6 ): δ (ppm) 166.1, 165.7, 154.7, 150.7, 137.0, 131.5, 131.5, 130.6, 129.2, 117.0, 111.7, 111.7, 75.6, 74.5, 71.4, 56.5, 56.5, 52.8, 52.2, 52.2, 43.2, 4 41.3, 39.1, 33.9, 31.9, 30.5, 26.9, 21.2, 19.0.

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Abstract

The invention relates to the fields of natural medicine and medicinal chemistry, in particular to a preparation method and application of a 7-position spliced ​​nitrogen mustard derivative of brefeldin A with antitumor activity. The structure of the nitrogen mustard derivative at the 7-position of brefeldin A according to the present invention and its pharmaceutically acceptable salt is shown in the following general formula I, wherein, n is as described in the claims and description.

Description

technical field [0001] The invention belongs to the technical field of medicine, relates to the field of natural medicine and medicinal chemistry, and specifically relates to a preparation method and application of a 7-position nitrogen mustard derivative of brefeldin A with antitumor activity. The invention relates to these derivatives splicing DNA alkylating agent nitrogen mustard compounds at the 7-OH position of brefeldin A, their preparation methods and their 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 ha...

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王茗莹李昊楠焦润伟胡旭
Owner SHENYANG PHARMA UNIVERSITY
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