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Compound of ADT-OH type H2S donor and evodiamine and preparation method thereof and application

A technology of ADT-OH and evodiamine, which is applied in the field of natural medicine and medicinal chemistry, can solve the problems of uncontrolled release, high toxicity, and inability to be directly applied to clinical research.

Active Publication Date: 2018-06-22
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its unsuitable release in the body and high toxicity, it cannot be directly used in clinical research.

Method used

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  • Compound of ADT-OH type H2S donor and evodiamine and preparation method thereof and application
  • Compound of ADT-OH type H2S donor and evodiamine and preparation method thereof and application
  • Compound of ADT-OH type H2S donor and evodiamine and preparation method thereof and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021]

[0022] Take evodiamine intermediate 3a (20mg, 0.05mmol), dissolve it in dichloromethane (5mL), and add nortrisulfide (4, 20mg, 0.08mmol), EDCI (45mg, 0.25mmol), DMAP (4mg , 0.02mmol), the reaction was stirred at room temperature, the progress of the reaction was monitored by TCL, and the reaction was terminated after 12h. The reaction solution was poured into 10 mL ice-water mixture, extracted with dichloromethane (10 mL×3), washed with saturated saline solution, dried over anhydrous sodium sulfate, recovered dichloromethane, and obtained crude product 5a, which was passed through a silica gel column (petroleum ether: acetic acid Ethyl ester=8:1), separated to obtain a brown-red solid with a yield of 70%. MS(ESI)m / z calcd for C 30 h 23 N 3 HO 3 S 3 [M+H] + 569.1, found 569.8. 1 H NMR (CDCl 3 ,400MHz)δ8.15(d,J=7.8Hz,1H,Ar-H),7.66(m,3H,Ar-H),7.52(m,2H,Ar-H),7.36(m,3H,Ar-H) -H),7.30(m,1H,Ar-H),7.25(m,1H,Ar-H),7.23(s,1H,4H-1,2-dithiole-3-thione),7.17(d,J =7.8...

Embodiment 2

[0024]

[0025] Compound 5b was prepared according to the synthesis method of Example 1. Brown-red solid, yield 30%. HRMS(ESI)m / zcalcd for C 32 h 27 N 3 NaO 3 S 3 [M+Na] + 620.1040, found 620.1107. 1 H NMR (CDCl 3 ,400MHz)δ8.14(dd,J=7.8,1.2Hz,1H,Ar-H),7.72(m,1H,Ar-H),7.61(d,J=8.5Hz,2H,Ar-H), 7.53(m,1H,Ar-H),7.50(m,1H,Ar-H),7.46(m,1H,Ar-H),7.38(s,1H,4H-1,2-dithiole-3-thione ),7.31(m,1H,Ar-H),7.21(m,2H,Ar-H),7.06(d,J=8.5Hz,2H,Ar-H),6.01(s,1H,N-CH- N),4.92(m,1H,N-CH 2 ),4.57(m,1H,13-N-CH 2 ),4.36(m,1H,13-N-CH 2 ),3.20(m,1H,N-CH 2 ),3.04(m,1H,-CH 2 ),2.91(m,1H,-CH 2 ),2.65(m,2H,-CH 2 ),2.41(s,3H,N-CH 3 ),2.30(m,2H,-CH 2 ). 13 C NMR (CDCl 3 ,100MHz)δ215.64,171.61,170.79,164.67,153.38,150.95,137.41,136.18,133.10,131.04,129.41,129.17,128.97,128.32(×2),125.96,124.50,123.30,123.11,122.82(×2),120.02 ,119.31,113.85,109.82,68.21,65.70,50.97,42.90,31.60,25.14,20.49.

Embodiment 3

[0027]

[0028]Compound 5c was prepared according to the synthesis method of Example 1. Brown-red solid, yield 46%. HRMS(ESI)m / zcalcd for C 33 h 29 N 3 NaO 3 S 3 [M+Na] + 634.1263, found 634.1219. 1 H NMR (CDCl 3 ,400MHz)δ8.14(dd,J=7.8,1.2Hz,1H,Ar-H),7.64(d,J=8.7Hz,2H,Ar-H),7.61(m,1H,Ar-H), 7.49(m,1H,Ar-H),7.40(m,1H,Ar-H),7.38(s,1H,4H-1,2-dithiole-3-thione),7.29(m,1H,Ar-H ),7.17–7.24(m,3H,Ar-H),7.13(d,J=8.7Hz,2H,Ar-H),5.99(s,1H,N-CH-N),4.91(m,1H, N-CH 2 ),4.45(m,1H,13-N-CH 2 ),4.28(m,1H,13-N-CH 2 ),3.20(m,1H,N-CH 2 ),3.03(m,1H,-CH 2 ),2.90(m,1H,-CH 2 ),2.62(m,2H,-CH 2 ),2.41(s,3H,N-CH 3 ),1.98(m,2H,-CH 2 ),1.82(m,2H,-CH 2 ). 13 C NMR (CDCl 3 ,100MHz)δ215.60,171.64,171.07,164.65,153.53,150.99,137.25,136.15,133.08,129.35,129.12,128.37,128.32(×2),125.92,124.46,124.25,123.25,122.89(×3),119.84,119.27 ,113.49,109.78,68.24,43.63,39.43,36.63,33.94,29.64,22.46,20.48.

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Abstract

The invention relates to the field of natural medicine and medicinal chemistry, in particular to a derivative for modifying an N-13 locus of evodiamine, especially the evodiamine derivative substituted by an N-13-locus ADT-OH type H2S donor and a preparation method thereof and application in preparation of medicine resistant to tumors. The evodiamine derivative substituted by the ADT-OH type H2S donor and a pharmaceutically acceptable salt structure of the derivative are shown as the formula I, wherein n is shown in the claims and the description. The formula I is shown in the description.

Description

technical field [0001] The present invention relates to the field of natural medicine and medicinal chemistry, relates to derivatives modified at the N-13 site of evodiamine, in particular to these N-13 ADT-OH derivatives 2 Evodiamine derivatives substituted by S donors, their preparation methods and their 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 apoptosis and necrosis, and enhances cell autophagy. It is a good topoisomerase inhibitor. Studies have shown that evodiamine has certain inhibitory...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61K31/519A61P35/00A61P35/02
CPCC07D471/14
Inventor 李达翃华会明李占林胡旭臧凌鹤廖嘉穗王悦婷
Owner SHENYANG PHARMA UNIVERSITY
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