Evodiamine derivative as well as preparation and application thereof

A technology of evodiamine and its derivatives, which is applied in the field of medicine and can solve the problems of reducing the effect of evodiamine

Pending Publication Date: 2021-11-23
NANHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the modification of the N14 position is less
It has been reported that the methyl group at N14 is easily removed during metabolism in the body, thereby reducing the effect of evodiamine

Method used

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  • Evodiamine derivative as well as preparation and application thereof
  • Evodiamine derivative as well as preparation and application thereof
  • Evodiamine derivative as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] 10-methoxy-7,8,13,13b-tetrahydro-5H-benzo [5',6'] [1,3] thiazino[3',2':1,2] pyrido [3,4-b]indol -5-one (compound 6a)

[0045] The structural formula of compound 6a is:

[0046] (1) At room temperature, mix 2-(phenylamino)benzoic acid (compound 1-1, 1 mmol), tryptamine (1.2 mmol), 1-ethyl-(3-dimethylaminopropyl) carbonyl di Imine hydrochloride (1.2 mmol), triethylamine (3 mmol), 1-hydroxybenzotriazole (1.3 mmol), dissolved in 10 ml of dichloromethane, reacted for 5 hours, separated by extraction column chromatography to obtain the product N-(2-(1H-indol-3-yl)ethyl)-2-(phenylamino)benzamide (compound 1-2), the yield was 78%;

[0047] The structural formula of compound 1-1 is:

[0048] The structural formula of compound 1-2 is:

[0049] (2) N-(2-(1H-indol-3-yl)ethyl)-2-(phenylamino)benzamide (compound 1-2, 1 mmol), triethyl orthoformate (3 mmol) and boron trifluoride Diethyl ether (0.5 mmol) was added into a 25 mL round bottom flask, and N,N-dimethylformamide wa...

Embodiment 2

[0051] 14-(2-fluorophenyl)-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one (compound 6b)

[0052] The structural formula of compound 6b is:

[0053] Replace the raw material 2-(phenylamino)benzoic acid (compound 1-1) in step (1) of Example 1 with 2-((2-fluorophenyl)amino)benzoic acid (compound 2-1), and the rest of the steps are the same as in the example 1 prepared with a yield of 77%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.12 (s, 1H), 7.85 (dd, J = 7.8, 1.6 Hz,1H), 7.49 – 7.35 (m, 3H), 7.31 (dt, J = 8.1, 0.9 Hz, 1H), 7.28 – 7.21 (m,2H), 7.19 – 7.14 (m, 1H), 7.04 (m, 2H), 6.95 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H),6.87 (d, J = 8.2 Hz, 1H), 6.48 (s, 1H), 4.62 (dd, J = 13.0, 5.6 Hz, 1H), 3.36(m, 1H), 3.00 – 2.83 (m, 1H), 2.68 (dd, J = 15.5, 4.7 Hz, 1H). 13 C NMR (101MHz, DMSO) δ 165.03, 158.08 (d, J = 248.1 Hz), 145.62, 136.45, 133.68, 133.44(d, J = 10.8 Hz), 131.44, 129.52, 128.33, 128.14 (d, J = 8.0 Hz), 126.60,125.27 (d, J = 3.7 Hz), 1...

Embodiment 3

[0056] 14-(2-chlorophenyl)-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one (compound 6c)

[0057] The structural formula of compound 6c is:

[0058] Replace the raw material 2-(phenylamino)benzoic acid (compound 1-1) in step (1) of Example 1 with 2-((2-chlorophenyl)amino)benzoic acid (compound 3-1), and the rest of the steps are the same as in the example 1 prepared in a yield of 74%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.92 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H),7.56 – 7.22 (m, 7H), 7.00 (m, 3H), 6.67 (d, J = 8.2 Hz, 1H), 6.45 (s, 1H), 4.63 (dd, J = 13.0, 5.7 Hz, 1H), 3.32 (s, 1H), 3.03 – 2.92 (m, 1H), 2.70 (dd, J = 16.1, 4.9 Hz, 1H). 13 C NMR (101 MHz, DMSO) δ 165.12, 145.99, 142.56,136.46, 133.76, 132.30, 131.72, 131.09, 128.89, 128.50, 126.57, 122.19,119.26, 118.55, 112.21, 112.12, 71.06, 42.45, 19.71.

[0059] The structural formula of compound 3-1 is:

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Abstract

The invention provides an evodiamine derivative. The evodiamine derivative is prepared by taking an anthranilic acid compound and tryptamine as initial raw materials through a condensation reaction and a one-step ring closing reaction catalyzed by lewis acid. The evodiamine derivative prepared by the preparation method disclosed by the invention has dual inhibition effects on topoisomerase I/II, so a broad-spectrum anti-tumor effect is achieved. The derivative can induce apoptosis of cancer cells and retard proceeding to a G2/M period in a concentration-dependent manner, and has an effect of inhibiting invasion and migration of cancer cells in vitro. The derivative has a good tumor growth inhibition effect in a nude mouse transplantation tumor model, has no obvious toxicity at a cell level and an animal level, has good safety and can be applied to preparation of anti-tumor drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to the preparation of an evodiamine derivative; the invention also relates to the application of the evodiamine derivative in the preparation of antitumor drugs. Background technique [0002] Active ingredients in medicinal plants play an important role in the treatment of diseases by affecting the function of multiple targets. In Eastern medicine, Chinese herbal medicine has been widely used as an important medicine. In recent years, a variety of bioactive components have been isolated from these sources and have been shown to have anticancer activity in experimental and epidemiological studies. Therefore, Chinese herbal medicine has become an important resource for designing multi-target bioactive molecules. Evodia rutaecarpa is a well-known Chinese herbal medicine in China. It is widely used in traditional Chinese medicine. It has the effects of dispelling cold and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14A61P35/00A61P35/04
CPCC07D471/14A61P35/00A61P35/04
Inventor 王震张红花邓杰丹梁子怡雷芳石桃
Owner NANHUA UNIV
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