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Chlormethine fructus evodiamine derivatives, and preparation method and application thereof

A technology of evodiamine and nitrogen mustards, which is applied in the field of natural medicine and medicinal chemistry, can solve the problems of large toxic and side effects, unsatisfactory therapeutic effect, and lack of specificity of cell action, and achieve good pharmaceutical activity.

Active Publication Date: 2018-01-19
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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  • Chlormethine fructus evodiamine derivatives, and preparation method and application thereof
  • Chlormethine fructus evodiamine derivatives, and preparation method and application thereof
  • Chlormethine fructus evodiamine derivatives, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020]

[0021] Take evodiamine intermediate 2 (n is 2, m is 1), 65mg, 0.19mmol, dissolve in dichloromethane (15ml), add melphalan methyl butyric acid (85mg, 0.19mmol), EDCI (120mg , 0.60mmol), DMAP (6mg, 0.05mmol), 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 6a, passed through a silica gel column (petroleum ether: acetic acid Ethyl ester=2:1), separated to obtain a yellow oil with a yield of 24%. HRMS(ESI,M+H)m / zcalcd for C 39 h 43 Cl 2 N 5 o 6 H:748.2663,found:748.2684. 1 H NMR (CDCl 3 ,400MHz), δ(ppm)8.17(1H,d,J=7.7Hz,Ar-H),7.63(1H,d,J=7.8Hz,Ar-H),7.55(1H,m,Ar-H) ,7.49(1H,m,Ar-H),7.33(1H,d,J=7.4Hz,Ar-H),7.28(1H,d,J=7.4Hz,Ar-H),7.23(1H,m, Ar-H), 7....

Embodiment 2

[0023]

[0024] Compound 6b was prepared according to the synthesis method of Example 1. Yellow oil, yield 75%. HR-MS(ESI,M+H)m / z: calcd for C 40 h 45 Cl 2 N 5 o 6 H:762.2820,found:762.2811. 1 H NMR (CDCl 3 ,400MHz), δ(ppm)8.11(1H,d,J=7.8Hz,Ar-H),7.60(1H,d,J=7.8Hz,Ar-H),7.48(1H,m,Ar-H) ,7.40(1H,m,Ar-H),7.30(1H,m,Ar-H),7.21(2H,m,Ar-H),7.16(1H,m,Ar-H),6.97(2H,d ,J=8.2Hz,Ar-H),6.60(2H,d,J=8.2Hz,Ar-H),6.00(1H,m,NCH),5.96(1H,m,-NH),4.80(1H, m,-CH),4.05-4.54(4H,m,-CH 2 ),3.72(3H,d,-COOCH 3 ),3.68(4H,m,NCH 2 CH 2 Cl),3.60(4H,m,NCH 2 CH 2 Cl),2.47-3.20(6H,m,-CH 2 ),2.39(3H,s,NCH 3 ),1.65-2.36(6H,m,-CH 2 ); 13 C NMR (CDCl 3 ,100MHz)δ(ppm)172.72,172.16,170.74,164.66,150.99,145.12,137.25,133.07,133.04,130.70(×2),129.04,128.40,125.90,124.49,124.44,123.29,122.92,119.85,119.19,113.46 ,112.31(×2),109.70,68.06,62.12,62.09,53.63(×2),52.43,40.75,40.71(×2),40.45,39.39,36.80,30.59,29.24,29.05,20.44.

Embodiment 3

[0026]

[0027] Compound 6c was prepared according to the synthesis method of Example 1. Yellow oil, yield 64%. HR-MS(ESI,M+H)m / z: calcd for C 43 h 51 Cl 2 N 5 o 7 H:820.3238,found:820.3239. 1 H NMR (CDCl 3,400MHz), δ(ppm)8.11(1H,d,J=7.8Hz,Ar-H),7.60(1H,d,J=7.8Hz,Ar-H),7.47(1H,m,Ar-H) ,7.42(1H,m,Ar-H),7.29(1H,m,Ar-H),7.22(1H,m,Ar-H),7.19(1H,m,Ar-H),7.15(1H,m ,Ar-H),6.97(2H,d,J=8.5Hz,Ar-H),6.59(2H,d,J=8.5Hz,Ar-H),6.17(1H,m,-NH),5.99( 1H,s,NCH),4.55(1H,m,-CH),4.28(2H,m,-CH 2 ),4.06(2H,m,-CH 2 ),3.73(3H,s,-COOCH 3 ),3.69(4H,m,NCH 2 CH 2 Cl),3.60(4H,m,NCH 2 CH 2 Cl),2.90-3.37(6H,m,-CH 2 ),2.49-2.63(4H,m,-CH 2 ),2.39(3H,s,NCH 3 ),1.45-2.05(8H,m,-CH 2 ); 13 C NMR (CDCl 3 ,100MHz)δ(ppm)172.78,172.23,171.00,164.75,151.07,145.30,137.37,133.00,131.04,130.71(×2),129.01,128.97,125.86,124.71,124.21,123.16,122.72,119.70,119.09,113.16 ,112.17(×2),109.95,67.96,67.64,67.38,65.70,61.92,53.59(×2),53.43,52.43,40.70,40.53(×2),39.24,36.83,32.05,30.90,29.83,29.025,20. .

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Abstract

The invention relates to the fields of natural medicines and medicinal chemistry, and provides chlormethine fructus evodiamine derivatives, and a preparation method and application thereof. In particular, the invention relates to a preparation method for introducing DNA alkylating agent melphalan derivatives at N-13 site of evodiamine, and application to preparation of anti-tumor medicines. The structure of the evodiamine splicing melphalan derivatives and pharmaceutically acceptable salt is shown in a general formula I shown in the description, wherein n, m and p are described in the claims and the description.

Description

technical field [0001] The invention relates to the field of natural medicine and medicinal chemistry, a class of nitrogen mustard derivatives of evodiamine and their preparation methods and applications, in particular to derivatives modified at the N-13 site of evodiamine, and relate to these derivatives modified at the N-13 site An evodiamine derivative substituted by a DNA alkylating agent melphalan derivative, its preparation method 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 cell apoptosi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/22A61K31/519A61P35/00A61P35/02
Inventor 李达翃华会明李占林胡旭施泓俊张子涵李欣悦
Owner SHENYANG PHARMA UNIVERSITY
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