N-(4-fluorobenzyl)-3, 5-bis(4-trifluoromethyl benzylidene)-4-piperodone and preparation as well as application

A technology for trifluoromethylbenzylidene and trifluoromethylbenzaldehyde, which is applied in the field of chemical drugs, can solve problems such as weak selectivity, and achieve the effects of low acute toxicity in vivo and small toxic and negative effects

Inactive Publication Date: 2013-04-10
SHANGHAI NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The common disadvantage of chemotherapeutic drugs commonly used in clinical practice is that their selectivity is not strong, and they have almost the same killing effect on normal cells and tumor cells.

Method used

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  • N-(4-fluorobenzyl)-3, 5-bis(4-trifluoromethyl benzylidene)-4-piperodone and preparation as well as application
  • N-(4-fluorobenzyl)-3, 5-bis(4-trifluoromethyl benzylidene)-4-piperodone and preparation as well as application
  • N-(4-fluorobenzyl)-3, 5-bis(4-trifluoromethyl benzylidene)-4-piperodone and preparation as well as application

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Experimental program
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Embodiment 1

[0031] The preparation method of embodiment 1N-(4-fluorobenzyl)-3,5-bis(4-trifluoromethylbenzylidene)-4-piperidone

[0032] In an ice-water bath at 0°C, add 0.4 mol of methyl acrylate and 7 mL of methanol into a 100 mL three-neck flask, and after stirring for 30 min, slowly add 0.1 mol of 4-fluorobenzylamine and 10 mL of methanol dropwise to control the rate of addition. , so that the system temperature does not exceed 50°C (about 1 drop / second). After the dropwise addition was completed, stir at room temperature for 30 min, continue to raise the temperature to 65° C., reflux, and track the reaction progress by thin layer chromatography (TLC). After reacting for about 8 hours, the reaction was stopped, and methanol and unreacted methyl acrylate were recovered by distillation under reduced pressure to obtain light yellow oily liquid intermediate (b).

[0033] At room temperature, add 15mL of anhydrous toluene and 0.1mol of sodium metal (cut into blocks) into a 250mL dry three-...

Embodiment 2

[0039] Example 2 Compound ALB65 inhibits the proliferation of 12 leukemia cancer cell lines including leukemia K562 IC 50 the test

[0040] 1. Test reagents and equipment

[0041] Experimental drugs and reagents: self-made compound ALB65, dissolved in DMSO, added distilled water to the required concentration (DMSO concentration ≤ 1‰), sterilized and stored at 4°C. MTT (tetramethylazolazolium blue) reagent was purchased from Sigma. Human leukemia cells K562, Jarket, U937, THP-1, NB 4 BF, MM-6, HK-2, HL-60, ML-2, KG-1a, Molm-13, SP2 / 0 cell lines were purchased from Shanghai Chinese Academy of Sciences Cell Bank. 10% SDS reagent (Sino-American Biotechnology product), RPMI-1640 (GiBCo, USA) culture medium containing 20% ​​fetal bovine serum (FBS) was used, and other reagents were commercially available analytically pure. At 37°C, 5% CO 2 Subculture was carried out in an incubator with saturated humidity, and the cells were used for experiments when they were in the logarithmi...

Embodiment 3

[0050] Example 3 Compound ALB65 inhibits the proliferation of ovarian cancer, breast cancer, liver cancer and esophageal cancer cell lines IC 50 the test

[0051] 1. Test reagents and equipment

[0052] Experimental drugs and reagents: self-made compound ALB65, dissolved in DMSO, added distilled water to the required concentration (DMSO concentration ≤ 1‰), sterilized and stored at 4°C. MTT (tetramethylazolazolium blue) reagent was purchased from Sigma. Human leukemia cells, ovarian cancer HO-8910 cell line, breast cancer MCF-7 cell line, liver cancer SMMC-7721 cell line and esophageal cancer ECA-109 cell line were purchased from the Cell Bank of Shanghai Chinese Academy of Sciences. 10% SDS reagent (Sino-American Biotechnology product), RPMI-1640 (GiBCo, USA) culture medium containing 20% ​​fetal bovine serum (FBS) was used, and other reagents were commercially available analytically pure. At 37°C, 5% CO 2 Subculture was carried out in an incubator with saturated humidity...

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Abstract

The invention relates to the field of organic synthesis and medicines and discloses an N-(4-fluorobenzyl)-3, 5-bis(4-trifluoromethyl benzylidene)-4-piperodone. A preparation method comprises the steps of: sequentially carrying out Michael addition, Diecmann condensation, acidolysis and decarboxylation on 4-flunamine and methyl acrylate to obtain N-(4-fluorobenzyl)-4-piperodone, and carrying out aldol condensation reaction between N-(4-fluorobenzyl)-4-piperodone and 4-trifluoromethylbenzaldehyde to obtain the target compound N-(4-fluorobenzyl)-3, 5-bis(4-trifluoromethyl benzylidene)-4-piperodone. The target compound can be used for efficiently and selectively inhibiting proliferation of 12 leukemic cell lines, and the cell lines of ovarian cancers, breast cancers, liver cancers, esophageal cancers and the like and has lower toxicity on normal hematopoietic stem cells; and the activity of inhibiting the cancer cell line proliferation of the target compound is obviously higher than that of the traditional chemotherapeutics 5-fluorouracil.

Description

technical field [0001] The invention belongs to the field of chemical medicines, in particular to N-(4-fluorobenzyl)-3,5-bis(4-trifluoromethylbenzylidene)-4-piperidone, which can be used as a medicine for treating leukemia, ovarian cancer, Lead compounds for breast, liver and esophageal cancer drugs. Background technique [0002] Cancer is one of the diseases with the highest mortality rate in the world today, and it has caused extremely serious harm to human health. According to the epidemiological statistics released by my country, the incidence of leukemia in various regions of China ranks sixth among all kinds of tumors. At present, there are at least 4 million leukemia patients, and about 40,000 new cases are added every year. In recent years, due to the pollution caused by interior decoration, the number of patients with blood diseases has increased dramatically. Leukemia is a kind of malignant disease of hematopoietic cells, which is prone to occur in adolescents, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/74A61K31/45A61P35/00A61P35/02
Inventor 薛思佳肖笛李兴玉孙传文
Owner SHANGHAI NORMAL UNIVERSITY
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