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Preparation method and uses of a class of brefeldin A derivative containing chlormethine linked at site 4 and site 7

A technology of feldsparin and derivatives, applied in the field of natural medicine and medicinal chemistry, can solve the problems of unsatisfactory treatment effect, large toxic and side effects, and lack of specificity of cell action.

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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  • Preparation method and uses of a class of brefeldin A derivative containing chlormethine linked at site 4 and site 7
  • Preparation method and uses of a class of brefeldin A derivative containing chlormethine linked at site 4 and site 7
  • Preparation method and uses of a class of brefeldin A derivative containing chlormethine linked at site 4 and site 7

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018]

[0019] Take Brefeldin A 1 (32mg, 0.08mmol), dissolve it in dichloromethane (2.5ml), add chlorambucil (21mg, 0.08mmol), EDCI (29mg, 0.15mmol) and catalytic amount of DMAP, the reaction was stirred at room temperature, TCL monitored the progress of the reaction, and the reaction was terminated after 24 hours. The reaction solution was poured into 20ml ice-water mixture, extracted with dichloromethane (30ml×3), washed with saturated aqueous salt solution, dried with anhydrous sodium sulfate, recovered dichloromethane, and passed through a silica gel column (petroleum ether: ethyl acetate = 5: 1) to obtain a yellow oil 3a with a yield of 35%. HR-MS(ESI,M+Na)m / z:calcd for C 32 H 32 Cl 2 N 4 O 3 Na:767.2183,found 767.2174. 1 H NMR(400MHz, DMSO-d 6 ): δ (ppm) 7.76 (4H, m, Ar-H), 7.39 (1H, dd, J = 15.7, 3.1 Hz, C 3 -H), 6.82 (4H, m, Ar-H), 5.83 (1H, m, C 11 -H), 5.58(1H,d,J=15.74Hz,C 2 -H),5.53(1H,d,J=10.17Hz,C 10 -H),5.23-5.33(2H,m,C 4 ,C 7 -H), 4.75(1H,m,C 15 -H),3.76-3.77(1...

Embodiment 2

[0021]

[0022] Referring to the synthesis method of Example 1, compound 3b was prepared. Yellow oil, yield 19%. HR-MS(ESI,M+H)m / z:calcd for C 33 H 34 Cl 2 N 4 O 3 H: 851.3122, found 851.3101. 1 H NMR(400MHz, DMSO-d 6 ):δ(ppm)7.27(1H,dd,J=15.8,3.2Hz,C 3 -H), 7.01 (4H, dd, J = 8.5, 3.0 Hz, Ar-H), 6.64 (4H, dd, J = 8.7, 3.1 Hz, Ar-H), 5.73-5.81 (1H, m, C 11 -H), 5.61(1H,d,J=15.66Hz,C 2 -H),5.32(1H,d,J=9.7Hz,C 10 -H), 5.20 (1H, dd, J = 15.2, 9.7 Hz, C 4 -H),5.04(1H,m,C 7 -H), 4.75(1H,m,C 15 -H), 3.69(16H,m,-NCH 2 CH 2 Cl),0.75-2.46(27H,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) 172.8, 172.3, 165.4, 149.0, 145.0, 145.0, 136.3, 131.1, 130.0, 129.8, 129.7, 129.7, 129.7, 129.7, 117.6, 112.4, 112.4, 112.3, 112.3, 76.1, 75.2, 71.8, 52.7, 52.7, 52.7, 52.7, 49.9, 42.9, 41.6, 41.6, 41.6, 41.6, 41.6, 41.6, 38.1, 33.9, 33.7, 33.7, 33.3, 31.8, 27.2, 27.1,26.8, 21.1.

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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 class of brefeldin A derivative containing chlormethine linked at site4 and site 7 and having antitumor activity, wherein the brefeldin A derivative containing chlormethine linked at site 4 and site 7, and the pharmaceutically acceptable salt have a structure represented by the following general formula I, and 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 a preparation method and application of a 4,7-position spliced ​​nitrogen mustard derivative of Brefeldin A with anti-tumor activity. Specifically, it relates to the derivatives of these nitrogen mustard compounds which are combined with the DNA alkylating agent at the 4-OH and 7-OH positions of Brefeldin A, and their preparation methods and applications in the preparation of antitumor drugs. Background technique [0002] Brefeldin A (BFA) is a secondary metabolite of Ascomycetes and belongs to the macrolide antibiotic, also known as reprodin or ascosporine. It was separated from the fermentation broth of Penicillium decumbens by Singleton et al. in 1958. Brefeldin A, crystals are prismatic, white, insoluble in petroleum ether, chloroform, water, and easily soluble in ethyl acetate, acetone and methanol. Pharmacological studies have shown that Brefeldin A has an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D313/00A61K31/365A61P35/00A61P35/02
CPCC07D313/00
Inventor 李达翃华会明李占林韩通胡旭杨剑锋袁紫琪
Owner SHENYANG PHARMA UNIVERSITY
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