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Antitumor N-methyl-3,5-diarylmethylene-4-piperidone and quaternary ammonium derivatives thereof

A technology of diarylmethylene and methoxybenzylidene is applied in the field of N-methyl-3, achieving the effects of great application prospect, avoiding genotoxicity and novel structure

Active Publication Date: 2015-05-06
BINZHOU MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, studies have also found that such compounds can avoid multidrug resistance by reversing P-glycoprotein, so it is possible to find effective MDR reversal agents from them

Method used

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  • Antitumor N-methyl-3,5-diarylmethylene-4-piperidone and quaternary ammonium derivatives thereof
  • Antitumor N-methyl-3,5-diarylmethylene-4-piperidone and quaternary ammonium derivatives thereof
  • Antitumor N-methyl-3,5-diarylmethylene-4-piperidone and quaternary ammonium derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Synthesis of N-methyl-3,5-bis(4-trifluoromethylbenzylidene)-4-piperidone intermediate 3a

[0035] Mix 0.005 mol of N-methyl-4-piperidone and 0.01 mol of 4-trifluoromethylbenzaldehyde in 12.5 mL of glacial acetic acid, feed dry HCl gas for 45 min at room temperature, and stir for 7-24 h. The reaction endpoint was determined by TLC thin layer chromatography thin layer analysis. After the reaction was completed, suction filtered, and the obtained precipitate was added with 12.5 mL of 10% sodium hydroxide solution, stirred at room temperature for 0.5 h, suction filtered, and recrystallized with methanol to obtain N-methyl-3,5-bis(4- Trifluoromethylbenzylidene)-4-piperidone 2.82g, yield 48%, melting point 122-126°C.

[0036] UVλmax(logε) 316(0.848), 214(2.102)nm.IR(KBr Pellet cm-1): 2785(w), 1415(m), 3347(m), 696(m), 1614(s), 1583 (m), 2360(m), 2332(m), 1325(s), 1277(s), 1171(s), 825(m), 924(m), 1117(s), 1070(s).1H NMR (400MHz, DMSO, 25°C, TMS, ppm): δ=3.01(s, 3H, NCH3), ...

Embodiment 2

[0038] Synthesis of N-methyl-N-(4-fluorobenzyl)-3,5-bis(4-trifluoromethylbenzylidene)-4-piperidone bromide salt 3b

[0039] Mix 0.001mol of intermediate 3a and 1.5mL of N,N-dimethylformamide solution in a 25ml two-neck flask, stir and heat at 80°C until intermediate 3a dissolves, then add 0.0015mol of p-fluorobenzyl bromide solution dropwise, and use TLC Detect the progress of the reaction, in the TLC detection, the developer dichloromethane:methanol is 15:1, after the reaction is completed, wash with ether 2-3 times until the precipitation is complete, collect the precipitate by suction filtration, and then carry out the recrystallization operation with methanol, 0.315 g of N-methyl-N-(4-fluorobenzyl)-3,5-bis(4-trifluoromethylbenzylidene)-4-piperidone bromide was obtained, with a yield of 59.0% , melting point 184-189°C.

[0040] UVλmax(logε)308(0.436), 220(0.360)nm.IR(KBr Pellet cm-1): 3400(w), 1415(m), 1514(m), 600.99(m), 696(m), 854 (m), 1612(s), 1327(s), 1174(s), 1070(s...

Embodiment 3

[0042] Synthesis of N-methyl-N-benzyl-3,5-bis(4-trifluoromethylbenzylidene)-4-piperidone bromide salt 3c

[0043] Add 1.5 mL of N,N-dimethylformamide solution to 0.001 mol of intermediate 3a, heat and stir in an oil bath at 80°C until intermediate 3a dissolves, then add 0.0015 mol of benzyl bromide dropwise, and use TLC to detect the progress of the reaction. In the TLC detection, the developer dichloromethane:methanol was 20:1. After the reaction was completed, it was washed 2-3 times with ether until the precipitation was complete. The precipitate was collected by suction filtration, and then recrystallized with acetone, and vacuum-dried at 30°C for two hours, N-methyl-N-benzyl-3,5-bis(4-trifluoromethylbenzylidene)-4-piperidone bromide salt 0.39g, yield 75.6%, melting point 194 -196°C.

[0044] UVλmax(logε) 423(0.001), 306(0.278), 220(0.251), 208(0.183)nm.IR(KBr Pellet cm-1): 2995(w), 1415(m), 1475(m), 3429 (m), 611(m), 708(m), 854(m), 1614(s), 1329(s), 1167(s), 1070(s).1H...

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Abstract

The invention relates to antitumor drugs and particularly relates to an anti-tumor N-methyl-3,5-diarylmethylene-4-piperidone and quaternary ammonium derivatives thereof. The preparation method comprises the following steps of carrying out Claisen-Schmidt condensation reaction on N-methyl-4-piperidinone and an aryl formaldehyde derivative to obtain an intermediate and carrying out quaternization reaction on the intermediate and benzyl halide to obtain the N-methyl-3,5-diarylmethylene-4-piperidone quaternary ammonium derivatives. N-methyl-3,5-diarylmethylene-4-piperidone and the quaternary ammonium derivatives thereof are novel in structures and have the advantages of both multi-molecular target binding and multi-drug resistance reversal activity and the genotoxicity of the currently used anticancer drugs can be avoided. N-methyl-3,5-diarylmethylene-4-piperidone and quaternary ammonium derivatives thereof have greater toxicity to tumor cells compared to normal cells in anti-tumor activity and have very great application prospects in the field of anticancer drugs.

Description

technical field [0001] The invention relates to an antitumor drug, in particular to an antitumor N-methyl-3,5-diarylmethylene-4-piperidone and a quaternary ammonium salt derivative thereof. Background technique [0002] 3,5-diaryl methylene-4-piperidone derivatives are a class of compounds combining cyclic α, β unsaturated ketones and β amino ketones. There are many α, β unsaturated ketone compounds, which are very important intermediates in organic synthesis, and are widely used in the fields of medicine, chemical industry and spices. Studies by Dimmock et al. have shown that many α and β unsaturated ketones show cytotoxicity and anti-tumor activity. The mode of action of these compounds is quite unique. They have significant affinity for sulfhydryl groups that do not exist in nucleic acids, but for amino groups that exist in nucleic acids. It has little or no affinity with hydroxyl, so it can avoid the genotoxicity of many anticancer drugs currently used; in addition, bec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/74A61P35/00A61P35/02
CPCC07D213/68
Inventor 孙居锋王春华侯桂革李珂珂丛蔚刘文帅
Owner BINZHOU MEDICAL COLLEGE
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