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Preparation method and application of evodiamine combined nitrogen mustard derivatives with antineoplastic activities

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 large toxic and side effects, unsatisfactory therapeutic effect, and lack of specificity in cell action

Active Publication Date: 2018-02-09
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 evodiamine combined nitrogen mustard derivatives with antineoplastic activities
  • Preparation method and application of evodiamine combined nitrogen mustard derivatives with antineoplastic activities
  • Preparation method and application of evodiamine combined nitrogen mustard derivatives with antineoplastic activities

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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, dissolved 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 progress of the reaction was monitored by TCL, and the reaction was terminated after 24h. The reaction solution was poured into 20ml ice-water mixture, extracted with dichloromethane (30ml×3), washed with saturated aqueous salt solution, dried over anhydrous sodium sulfate, and recovered dichloromethane to obtain crude product 8a, which was 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, 1.4 Hz, Ar-H), 7.60 (1H, d, J = 7.9 Hz, Ar-H), 7.50 (1H, td, J = 7.9, 1.43 Hz, Ar-H), 7.43 (1H, d, J = 7.9 Hz, Ar-H), 7.3...

Embodiment 2

[0022]

[0023] According to the synthesis method of Example 1, compound 8b was prepared. Yellow oil, yield 80%. 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, 1.0 Hz, Ar-H), 7.60 (1H, d, J = 7.8 Hz, Ar-H), 7.48 (1H, m, Ar- H), 7.37 (1H, d, J = 8.2 Hz, 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] Referring to the synthesis method of Example 1, compound 8c was prepared. 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, 1.0 Hz, Ar-H), 7.60 (1H, d, J = 7.8 Hz, Ar-H), 7.47 (1H, m, Ar- H), 7.42 (1H, d, J = 8.2 Hz, 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 = 8.5 Hz, Ar-H), 6.64 (2H, d, J = 8.5 Hz, 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 present invention relates to the fields of natural medicine and medicinal chemistry, and relates to a preparation method and application of a kind of evodia base and nitrogen mustard derivatives with anti-tumor activity. Specifically, it relates to the N-13-positioned spliced ​​nitrogen mustard derivatives of evodia, and also relates to the preparation method of the N-13-position spliced ​​DNA alkylating agent nitrogen mustard derivatives of evodia and the application in the preparation of anti-tumor drugs. Background technique [0002] Evodiamine is an indoloquinazolone alkaloid compound isolated from Euodia plants in the Rutaceae family. Evodia base is a kind of light yellow needle crystal, insoluble in water, soluble in dichloromethane, chloroform, and soluble in organic solvents such as methanol and ethyl acetate. It has inhibitory effect on a variety of tumor cells. Evodiline has anti-tumor cell proliferation, inhibits tumor cell microtubule form...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61P35/02A61P35/00
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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