Multi-targeted antitumor active evodiamine derivative and preparation and application thereof

A technology of evodiamine and methoxy evodiamine, which is applied in the field of medicine and can solve the problems of complex pharmacokinetic properties of drug-drug interactions and the like

Inactive Publication Date: 2016-04-27
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the clinical treatment of malignant tumors mainly adopts the combination drug method, but this method has many defects, such

Method used

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  • Multi-targeted antitumor active evodiamine derivative and preparation and application thereof
  • Multi-targeted antitumor active evodiamine derivative and preparation and application thereof
  • Multi-targeted antitumor active evodiamine derivative and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Example 1: Preparation of 13-(7-(hydroxyamino)-7-oxoheptyl) evodiamine (A1)

[0110] NaH (60% oil, 1.2 mmol) was added into a DMF solution (10 mL) containing evodiamine (0.2 g, 0.66 mmol), and stirred at room temperature for 15 min. Bromo-7-heptanoic acid methyl ester (0.176g, 0.79mmol) was added, and the temperature was raised to 80°C to continue the reaction for 24h. TLC spot plate monitoring. After the reaction was completed, it was diluted with 50 mL of water, and extracted three times with 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (CH 2 Cl 2 : MeOH=100:1) to obtain the pure compound intermediate 13-(7-(methoxy)-7-oxoheptyl)evodiamine (5) (0.21g, yield 77%). Dissolve hydroxylamine hydrochloride (2.33g, 34mmol) in 12mL of methanol and stir in an ice bath, add methanol (7mL) dissolved in potassium hydroxide (2.81g, 50mmol), keep stirring at 0°C for 15min, add Magnesium su...

Embodiment 2

[0113] Example 2: Preparation of 10-hydroxyl-13-(4-(hydroxycarbamoyl)benzyl)evodiamine (A12)

[0114] Referring to Example 1, the product 13-(4-(hydroxycarbamoyl)benzyl)-10-methoxyevodiamine A3 was prepared.

[0115] Dissolve A3 (0.2g, 0.414mmol) in 10mL of dichloromethane, add BBr at -78°C under nitrogen protection 3 (0.5 mL), stirred for 30 min, then gradually raised to room temperature to continue the reaction for 2 h, after the reaction was completed, the reaction solution was washed with 50 mL of saturated aqueous sodium bicarbonate solution. Dichloromethane 50mL was extracted three times, the organic layers were combined, and dried with anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by column chromatography (CH 2 Cl 2 : MeOH=100:10) to obtain the target product A12 (0.071g, yield 35%).

[0116] 1 H-NMR (300MHz, DMSO-d 6 ,TMS):δ=11.12(s,1H),8.98(s.1H),8.89(s,1H),7.87(d,J=7.5Hz,1H),6.19(d,J=7.5Hz,2H) ,7.50(t,J=7.5Hz,1H),7.10-7.28(m...

Embodiment 3

[0118] Example 3: Class B compound intermediate 7(6-methoxy-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(phenyl)methanol Preparation of ketones

[0119] Compound 3 (4g, 19.98mmol) was dissolved in 100mL methanol, stirred at 0°C, and NaBH was slowly added 4 (0.83g, 21.97mmol) was reacted for 2h, monitored by TLC, after the reaction solution was distilled under reduced pressure, dissolved in 200mL of water, adjusted to pH 7-8 with dilute hydrochloric acid, a yellow solid was precipitated, filtered with suction, washed with water, and dried to obtain the intermediate Compound 4 (3.8 g, yield 91.0%). Compound 2 (2.5g, 12.38mmol), benzoic acid (1.66g, 13.61mmol), HBTU (5.6g, 14.86mmol), triethylamine (3.75g, 37mmol), dissolved in DMF (100ml), stirred at room temperature 2 hours, TLC monitoring. After the reaction was completed, the reaction solution was poured into 500ml of cold water, extracted three times with 200ml of ethyl acetate, the organic layers were combined, and washed...

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Abstract

The invention relates to the field of a medical technology. The invention discloses a multi-targeted antitumor active evodiamine derivative with antitumor activity and preparation and application thereof. The general structural formula of the compound is as shown in A or B. In-vitro antitumor activity test of the compound shows strong in-vitro antitumor activity and broad spectrum antitumor characteristics. Top1, Top2 and HDAC1 inhibitory activity shows that most compounds have strong inhibiting effect on Top1, Top2 and HDAC1 and are Top1/Top2/HDAC1 three-target inhibitors. The compound of the invention can be used in treating malignant tumor and diseases related to differentiation and proliferation.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of evodiamine derivatives with multi-target anti-tumor activity and a preparation method and application thereof. Background technique [0002] At present, cancer has become a disease that seriously threatens human health and life. At present, combination drugs are mainly used in clinical treatment of malignant tumors, but this method has many defects, such as the need to confirm the rationality of drug compatibility, possible drug-drug interactions, and complex pharmacokinetic properties. Multi-target drugs act on multiple key links or sites in the tumor disease network to exert a synergistic anti-tumor effect, and their therapeutic effect on tumors is better than that of a single drug. In addition, multi-target drugs have relatively simple absorption, distribution, metabolism and excretion processes, reduce the occurrence of drug-drug interactions, have lower side eff...

Claims

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Application Information

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IPC IPC(8): C07D471/14C07D471/04A61P35/00A61P5/00A61P37/02A61P25/00
CPCC07D471/14C07D471/04
Inventor 盛春泉张万年董国强李振钢武善超陈树强刘娜缪震元姚建忠
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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