Preparation method and application of a class of evodiamine and nitrogen mustard derivatives with antitumor activity

A technology of evodiamine and evodiamine hydroxyl, which is applied in the field of natural medicine and medicinal chemistry, and can solve the problems of lack of specificity in cell action, large toxic and side effects, and unsatisfactory therapeutic effect

Active Publication Date: 2019-10-25
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 evodiamine and nitrogen mustard derivatives with antitumor activity
  • Preparation method and application of a class of evodiamine and nitrogen mustard derivatives with antitumor activity
  • Preparation method and application of a class of evodiamine and nitrogen mustard derivatives with antitumor activity

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019]

[0020] Take evodiamine intermediate 2 (n is 2, m is 1), 65mg, 0.19mmol, dissolve in dichloromethane (15ml), add chlorambucil (60mg, 0.19mmol), EDCI (108mg, 0.56 mmol), DMAP (7mg, 0.06mmol), the reaction was stirred at room temperature, the reaction progress was monitored by TCL, and the reaction was terminated after 24h. 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 to obtain crude product 8a, passed through a silica gel column (petroleum ether: acetic acid Ethyl ester=5:1), separated to obtain a yellow oil with a yield of 66%. HR-MS(ESI,M+H)m / z calcdfor C 35 h 38 Cl 2 N 4 o 3 H:633.2394,found:633.2385. 1 H NMR (CDCl 3 ,400MHz), δ(ppm)8.15(1H,dd,J=7.8,1.4Hz,Ar-H),7.60(1H,d,J=7.9Hz,Ar-H),7.50(1H,td,J= 7.9,1.43Hz,Ar-H),7.43(1H,d,J=7.9Hz,Ar-H),7.30(1H,d,J=7.9Hz,Ar-H),7.27(1H,m,Ar-H H),7.23(1H,m,Ar-H)...

Embodiment 2

[0022]

[0023] Compound 8b was prepared according to the synthesis method of Example 1. Yellow oil, 80% yield. HR-MS(ESI,M+H)m / z: calcd for C 36 h 40 Cl 2 N 4 o 3 H:647.2550,found:647.2572. 1 H NMR (CDCl 3 ,400MHz),δ(ppm)8.14(1H,dd,J=7.8,1.0Hz,Ar-H),7.60(1H,d,J=7.8Hz,Ar-H),7.48(1H,m,Ar-H H),7.37(1H,d,J=8.2Hz,Ar-H),7.28(1H,m,Ar-H),7.24(1H,m,Ar-H),7.19(1H,m,Ar-H ),7.16(1H,m,Ar-H),7.02(2H,d,J=8.5Hz,Ar-H),6.62(2H,d,J=8.5Hz,Ar-H),5.96(1H,s ,NCH),4.02-4.53(4H,m,-CH 2 ),3.69(4H,m,NCH 2 CH 2 Cl),3.61(4H,m,NCH 2 CH 2 Cl),2.45-3.18(6H,m,-CH 2 ),2.39(3H,s,NCH 3 ),1.79-2.18(6H,m,-CH 2 ); 13 C NMR (CDCl 3 ,100MHz)δ(ppm)173.42,164.62,150.02,144.37,137.25,133.01,130.77,129.78(×2),129.14,128.45,125.97,124.49,124.34,123.26,122.92,119.90,119.27,113.53,112.48(× 2),109.63,68.09,61.64,53.80(×2),40.58(×2),39.39,36.54,34.07,33.56,29.82,29.33,26.69,20.46.

Embodiment 3

[0025]

[0026] Compound 8c was prepared according to the synthesis method of Example 1. Yellow oil, yield 34%. HR-MS(ESI,M+H)m / z: calcd for C 39 h 46 Cl 2 N 4 o 4 H:705.2969,found:705.2986. 1 H NMR (CDCl 3,400MHz), δ(ppm)8.12(1H,dd,J=7.8,1.0Hz,Ar-H),7.60(1H,d,J=7.8Hz,Ar-H),7.47(1H,m,Ar-H H),7.42(1H,d,J=8.2Hz,Ar-H),7.29(1H,m,Ar-H),7.22(1H,m,Ar-H),7.19(1H,m,Ar-H ),7.16(1H,m,Ar-H),7.07(2H,d,J=8.5Hz,Ar-H),6.64(2H,d,J=8.5Hz,Ar-H),5.99(1H,s ,NCH),3.99-4.90(6H,m,-CH 2 ),3.69(4H,m,NCH 2 CH 2 Cl),3.61(4H,m,NCH 2 CH 2 Cl),2.45-3.18(8H,m,-CH 2 ),2.40(3H,s,NCH 3 ),1.74-2.31(8H,m,-CH 2 ); 13 C NMR (CDCl 3 ,100MHz)δ(ppm)173.62,164.72,151.07,144.25,137.40,132.97,131.05,129.85(×2),129.04,128.67,125.84,124.23,124.19,123.16,122.72,119.71,119.09,113.22,112.53(× 2),109.93,68.00,67.69,67.44,61.52,53.85(×2),40.72,40.53(×2),39.44,36.44,34.15,33.76,30.34,29.12,26.90,20.52

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Abstract

The invention relates to the fields of natural drugs and medicinal chemistry, particularly a preparation method of evodiamine N-13 combined nitrogen mustard derivatives and application of the evodiamine N-13 combined nitrogen mustard derivatives in preparing antineoplastic drugs. The structure of the evodiamine combined nitrogen mustard derivatives and pharmaceutically acceptable salts thereof isdisclosed as a general formula I, wherein n, m and p are as described in the claims and specification. The evodiamine derivatives provided by the invention have better antineoplastic effects, and canbe used for further preparing antineoplastic drugs.

Description

technical field [0001] The invention relates to the fields of natural medicine and medicinal chemistry, and relates to a preparation method and application of a class of evodiamine and nitrogen mustard derivatives with antitumor activity. It specifically relates to the N-13 splicing nitrogen mustard derivative of evodiamine, and also relates to the preparation method of the N-13 splicing DNA alkylating agent nitrogen mustard derivative of evodiamine and its application in the preparation of antitumor drugs. Background technique [0002] Evodiamine is an indolequinazolone alkaloid compound isolated from Rutaceae Evodia plants. Evodiamine is a light yellow needle-like crystal, insoluble in water, easily soluble in dichloromethane, chloroform, soluble in methanol, ethyl acetate and other organic solvents. It has inhibitory effect on various tumor cells. Evodiamine has anti-tumor cell proliferation, inhibits the formation and invasion of tumor cell microtubules, induces tumor ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14A61P35/02A61P35/00
CPCC07D471/14
Inventor 李达翃华会明李占林胡旭季小艺李伟高明晨
Owner SHENYANG PHARMA UNIVERSITY
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