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Tetrahydropyridopyridone derivatives, preparation methods and applications thereof

A kind of technology of tetrahydropyridopyridone and tetrahydropyridine, which is applied in the field of tetrahydropyridopyridone derivatives and preparation thereof, and can solve the problems of lack of leading compounds and the like

Active Publication Date: 2015-12-09
SHANGHAI NORMAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, there is still a lack of new drugs or their lead compounds that can effectively inhibit the above diseases

Method used

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  • Tetrahydropyridopyridone derivatives, preparation methods and applications thereof
  • Tetrahydropyridopyridone derivatives, preparation methods and applications thereof
  • Tetrahydropyridopyridone derivatives, preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Preparation of 6-(4-fluorobenzyl)-4-(2-chlorophenyl)-8-(2-chlorobenzylidene)-3-cyano-1,2,5,6-tetra Hydropyrido[4,3-b]pyridin-2-one (Ia).

[0042]

[0043] At room temperature, add 0.16mol methyl acrylate and 7mL methanol into a 100mL three-necked flask, and slowly add a mixture of 0.04mol p-fluorobenzylamine and 4mL methanol into the three-necked flask while stirring, so that the temperature of the reaction system does not exceed 50°C . After the dropwise addition, heat to reflux for 8 hours. After the reaction is over, recover methanol and unreacted methyl acrylate, and distill under reduced pressure to obtain light yellow oily liquid N,N-bis(methoxycarbonylethyl)-p-fluorobenzylamine (b 1 ).

[0044] Add 15 mL of anhydrous toluene and 0.122 mol of sodium metal to a 250 mL dry three-necked flask, stir and heat to reflux, add 0.2 mL of anhydrous methanol, and then slowly add 0.04 mol of N, N-bis(methoxycarbonylethyl)-p-fluorobenzyl Amine (b 1 ) and 20m...

Embodiment 2

[0048] Example 2: Preparation of 6-(4-fluorobenzyl)-4-(4-methylphenyl)-8-(4-methylbenzylidene)-3-cyano-1,2,5,6-tetrahydro Pyrido[4,3-b]pyridin-2-one (Ib).

[0049]

[0050] Prepare N-p-fluorobenzyl-4-piperidone (d) in the same manner as in Example 1 1 ).

[0051] Add 0.005mol N-p-fluorobenzyl-4-piperidone (d 1 ) and 0.01mol p-tolualdehyde, add 15mL of absolute ethanol, stir and add 1mL of 10% NaOH (mass fraction), stir at room temperature for 30min, a yellow solid is precipitated, and the reaction progress is tracked by thin layer chromatography (TLC). After the reaction was finished, the solid was washed with ethanol, and recrystallized with ethyl acetate and petroleum ether to obtain N-(4-fluorobenzyl)-3,5-bis-p-methylbenzylidene piperidin-4-one (e 2 ).

[0052] Add N-(4-fluorobenzyl)-3,5-bis-p-methylbenzylidenepiperidin-4-one (e 2 ) (1mmol), malononitrile (1.5mmol, 99mg), ammonium acetate (1.5mmol) absolute ethanol (6mL) was heated under reflux for 8 hours, the refl...

Embodiment 3

[0054] Example 3: Preparation of 6-(4-fluorobenzyl)-4-(4-fluorophenyl)-8-(4-fluorobenzylidene)-3-cyano-1,2,5,6-tetra Hydropyrido[4,3-b]pyridin-2-one (Ic).

[0055]

[0056] Prepare N-p-fluorobenzyl-4-piperidone (d) in the same manner as in Example 1 1 ).

[0057] Add 0.005mol N-p-fluorobenzyl-4-piperidone (d 1 ) and 0.01mol p-fluorobenzaldehyde, add 15mL absolute ethanol, stir and add 1mL10% NaOH (mass fraction), stir at room temperature for 30min, a yellow solid is precipitated, and the reaction process is tracked by thin layer chromatography (TLC). After the reaction was finished, the solid was washed with ethanol, and recrystallized with ethyl acetate and petroleum ether to obtain N-(4-fluorobenzyl)-3,5-bis-p-fluorobenzylidene-4-piperidone (e 3 ).

[0058] Add N-(4-fluorobenzyl)-3,5-bis-p-fluorobenzylidenepiperidin-4-one (e 3 ) (1mmol), malononitrile (1.5mmol, 99mg), ammonium acetate (1.5mmol) absolute ethanol (6mL) was heated under reflux for 8 hours, the reflux te...

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Abstract

The invention provides a tetrahydropyridopyridone derivative as shown in a general formula (I), and a preparation method thereof. The method comprises the following steps of: preparing N,N-bi(methoxycarbonyl group) substituted benzylamine (b) by carrying out Michael addition on substituted benzylamine (a) and methyl acrylate, carrying out Dieckmann condensation on (b) under the action of sodium alcoholate, subsequently carrying out hydrolysis and decarboxylation under the action of acid so as to obtain N-substituted benzyl-4-piperidone (d), carrying out an aldol condensation reaction on (d) and bimolecular aromatic aldehyde so as to obtain N-substituted-3,5-bi(substituted benzylidene piperidine-4-ketone (e), and refluxing and heating (e) malononitrile and ammonium acetate in ethanol so as to obtain a final product as shown in the general formula (I). The tetrahydropyridopyridone derivative is simple in process and convenient to produce in scale, and the compound (I) has a good inhibition effect on multiplication of leukemia K562 cells, ovarian cancer HO-8910 cells and liver cancer SMMC-7721 cells. Therefore, the invention further provides an application of the compound as shown in the general formula (I) in preparing medicaments for preventing multiplication of the leukemia K562 cells, the ovarian cancer HO-8910 cells and the liver cancer SMMC-7721 cells.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to the chemical synthesis of anticancer drugs, and more specifically to a class of tetrahydropyridopyridones capable of effectively inhibiting the proliferation activity of leukemia K562 cells, ovarian cancer HO-8910 cells and liver cancer SMMC-7721 cells Derivatives and methods for their preparation. Background technique [0002] Among various diseases, cancer poses the greatest threat to human life and is the number one killer of patients. Among all kinds of cancers, leukemia, ovarian cancer and liver cancer are three common malignant tumors with a high incidence rate. Therefore, it is very useful to design and develop drugs that can effectively inhibit the proliferation of leukemia, ovarian cancer and liver cancer cells and make them rapidly apoptotic. significance. [0003] Leukemia is one of the diseases with the highest mortality rate in the world today, which has caused s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/4375A61P35/00A61P35/02
Inventor 孙传文张旺庚庞春成薛思佳
Owner SHANGHAI NORMAL UNIVERSITY
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