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3, 4-dihydroisoquinoline antitumor compounds as well as preparation method and application thereof

A technology of dihydroisoquinoline and dimethoxyisoquinoline, applied in the field of medicine

Inactive Publication Date: 2013-11-20
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

[0006] There is no literature report on a compound that can simultaneously promote tubulin polymerization and inhibit VEGFR-2

Method used

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  • 3, 4-dihydroisoquinoline antitumor compounds as well as preparation method and application thereof
  • 3, 4-dihydroisoquinoline antitumor compounds as well as preparation method and application thereof
  • 3, 4-dihydroisoquinoline antitumor compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1: 4-(4-nitrobenzyl)-N-(3-chlorophenyl)-3,4-dihydro-6,7-dimethoxyisoquinolin-1-amine (H- 1) Preparation

[0073] A. Preparation of (Z) 2-(3,4-dimethoxyphenyl)-3-(4-nitrophenyl)acrylonitrile

[0074] Weigh 1.77g of 3,4-dimethoxyphenylacetonitrile (0.010mol) into a 250ml round bottom flask, then add 1.81g of p-nitrophenylacetonitrile (0.012mol) and 40ml of ethanol, there is a large amount of insoluble matter, then add 0.40g (0.010mol) sodium hydroxide, stirred under ice bath, completely dissolved after 1min. After 30 min, a large amount of yellow powder was precipitated, the reaction was stopped, the reaction solution was filtered, the solid was washed with ethanol three times, and then crystallized with ethyl acetate as a solvent to obtain 2.73 g of yellow crystals with a yield of 88.1%. The melting point is 134°C to 135°C. 1 H NMR (300MHz, CDCl 3 )δ8.46–8.26(m,2H),8.16–7.97(m,2H),7.48(s,1H),7.31(m,1H),7.17(d,J=2.3Hz,1H),6.95(d ,J=8.5Hz,1H),3.98(s,3H),3.96(s...

Embodiment 2

[0084] Embodiment 2: the preparation of 4-(4-aminobenzyl)-N-(3-chlorophenyl)-3,4-dihydro-6,7-dimethoxyisoquinolin-1-amine (H -2) Preparation

[0085]In a 100ml round bottom flask, add 40ml of methanol, 1.10g (0.0024mol) of compound H-1, stir and dissolve at room temperature, then add 3ml of 85% hydrazine hydrate (0.045mol) and 0.2g of Raney nickel, and stir for 0.5h at room temperature. After the reaction, filter with a sand core funnel, react the filter residue with dilute acid until there is no air bubbles, put it into the waste liquid bucket, evaporate the filtrate to dryness under reduced pressure, and obtain a white solid H-21.01g, the yield is 98.4%, and it can be put into it without purification Next reaction.

[0086] The preparation methods of compounds H-13 and H-22 are the same as in Example 2.

Embodiment 3

[0087] Example 3: 1-(4-((1-(3-chlorophenylamino)-3,4-dihydro-6,7-dimethoxyisoquinolin-4-yl)methyl)phenyl )-3-(4-(trifluoromethyl)phenyl)urea (H-9) preparation

[0088] In a 50ml round bottom flask, add 10ml THF, 0.20g (0.00047mol) compound H-2, stir and dissolve at room temperature, then add 0.09g (0.00047mol) 4-trifluoromethylphenylisocyanate, and continue stirring for 24h. After the reaction, evaporate under reduced pressure until a small amount of solvent remains (less than 1ml), and separate by reverse-phase medium-pressure column chromatography with methanol / water as the mobile phase. After separation, 0.15 g of white solid H-9 is obtained, with a yield of 51.7%.

[0089] The preparation methods of compounds H-3~H-8, H-10~H-11, H-14~H-20 and H-23 are the same as in Example 3.

[0090] The chemical structure, physicochemical constants, 1 H NMR and ESI-MS data are shown in Table 1 and Table 2.

[0091] Table 1. Compound structure, physical and chemical constants, molecul...

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Abstract

The invention discloses 3, 4-dihydroisoquinoline antitumor compounds, a preparation method of the compounds, and an application of the compounds in preparation of antitumor medicines. The compounds have a structural formula (I) as shown in the specification. The compounds disclosed by the invention are structurally novel antitumor compounds which have the double mechanisms of inhibiting kinase VEGFR-2 (Vascular Endothelial Growth Factor Receptor-2) and promoting tubulin polymerization, and have good antitumor activity.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a new class of substituted 3,4-dihydroisoquinoline compounds and a preparation method thereof, as well as the application of the compounds in the preparation of drugs for preventing or treating tumors. Background technique [0002] Malignant tumor is one of the main diseases that seriously affect human health and threaten human life. [0003] Traditional antineoplastic drugs can be divided into: drugs targeting DNA, such as alkylating agents and antimetabolites; drugs targeting mitosis, such as paclitaxel that acts on tubulin, Vincristine, etc. Most of them treat tumors by directly inhibiting the growth and proliferation of tumor cells. In recent years, with the rapid development of life science research, many specific targets based on the mechanism of cancer cell occurrence and development have been identified, such as protein tyrosine kinase (PTK) involved in intr...

Claims

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Application Information

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IPC IPC(8): C07D217/22A61K31/472A61P35/00
Inventor 朱驹黄晶晶陈颖韩进松郑灿辉周有骏吕加国王重庆周浩田巍孙囡囡
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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