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Imidazopyridine compound and preparation method and application thereof

A technology of imidazopyridines and compounds, applied in the field of compounds with skeleton structures, can solve problems such as less NEK2

Active Publication Date: 2015-11-04
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Up to now, there are very few drug research and development work using NEK2 as the target for the treatment of tumors, and no patents have been found. There are only three kinds of NEK2 inhibitors with skeleton structures reported in the literature [J.Med.Chem., 2010, 53, 7682-7698; J.Med .Chem., 2011, 54, 1626-1639; J.Med.Chem., 2012, 55, 3228-3241; J.Med.Chem., 2011, 54, 4133-4146]

Method used

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  • Imidazopyridine compound and preparation method and application thereof
  • Imidazopyridine compound and preparation method and application thereof
  • Imidazopyridine compound and preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0024] Synthesis of embodiment 1 formula (1) imidazopyridine compound

[0025] (1) Synthesis of Fragment I:

[0026] Synthesis of compound B: 5.0 g of A and 4.89 g of NaHCO3 were dissolved in 50 mL of ethanol solution, and 12 mL of chloroacetaldehyde (purity 40%) was added to the mixture. The mixture was heated to reflux for 6 hours. After the reaction, filter the reaction solution with diatomaceous earth, evaporate the organic solvent to dryness, then dilute the residue with 50 mL of ethyl acetate, wash the organic phase twice with 56 mL of water, and extract the obtained aqueous phase twice with 40 mL of ethyl acetate. The obtained organic phase was washed with saturated brine and dried over anhydrous Na2SO4. The dried organic phase was concentrated and then separated by silica gel column chromatography. The eluent was ethyl acetate:petroleum ether=1:1, and 4.44 g of white solid B was finally obtained with a yield of 78%.

[0027] 1 H NMR (400MHz, CDCl 3 )δ7.98(d, J=7.1...

Embodiment 2

[0045] The in vitro antitumor activity evaluation of embodiment 2 formula (1) imidazopyridine compound

[0046] The research at the cell level of the present invention shows that the imidazopyridine compound (MLWH-10151) of formula (1) can be used as a selective inhibitor of NEK2.

[0047] (1) Inhibitory effect of formula (1) imidazopyridine compound (MLWH-10151) on tumor cell proliferation

[0048] Experimental method: tumor cells in the logarithmic growth phase were inoculated into 96-well culture plates, and different concentrations of MLWH-10151 (0, 0.016, 0.08, 0.4, 2, 10, and 50 μM) were given after the cells adhered to the wall. °C, 5% CO 2 After culturing under the conditions for 72 hours, add 5 mg / mL MTT solution to continue culturing for 4 hours, and add triple solution (10% SDS-5% isobutanol-0.01mol / L HCl) in a CO2 incubator overnight. After the formazan is completely dissolved, measure its absorbance at 570nm with a microplate reader, and calculate the cell viabi...

Embodiment 3

[0051] Embodiment 3 Formula (1) in vivo tumor growth regulation experiment of imidazopyridine compound

[0052] Take PC3 cells in the logarithmic growth phase and inoculate them in the armpit of nude mice until the tumor grows to 100mm 3 At the same time, it was administered orally (50 mg / kg) and intravenously (15 mg / kg), and the body weight and tumor volume of the mice were regularly recorded. like image 3 (Inhibitory effect of MLWH-1015 on xenograft mouse model tumors) shows that the two administration methods can effectively inhibit tumor growth, and the tumor growth inhibition rates (TGI) of oral and intravenous injection groups are 57.1% and 92.9%, respectively. %.

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Abstract

The invention provides an imidazopyridine compound shown in the formula (1) and a preparation method and application thereof. The imidazopyridine compound shown in the formula (1) is obtained by taking 2-amidogen-4-hydroxypyridine, 4-bromine-2-methyl glyoxalidine hydroxybenzoate, dimethylethanolamine and 2-(trifluoromethyl)phenylethanol as the raw materials, taking alkali and metal catalysts as the catalysts and taking organic solvents as the solvents through multi-step reactions. The invention further provides the application of the imidazopyridine compound shown in the formula (1) which serves as an NEK2 inhibitor in regulating tumor cell growth.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis and chemical engineering, and specifically relates to a compound with an anticancer activity and a skeleton structure of imidazopyridine and its synthesis and application. Background technique [0002] The World Health Organization and its affiliated Cancer Research Institute (IARC) released a research report in 2012, stating that about 14 million new cancer cases were diagnosed worldwide. Half of the new cancer cases worldwide occur in Asia, most of them in China [http: / / china.caixin.com / 2014-02-08 / 100636253.html? cx_from=news.baidu.com]. According to the report, 20 years later, the number of new cancer cases worldwide will increase to 22 million each year. At the same time, the number of cancer deaths will increase from about 8.2 million people per year currently to about 13 million people per year. Essentially, tumors are caused by mutations in certain genes. Current researc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/625A61P35/00
CPCC07D471/04
Inventor 胡文浩马明亮席间备吕思莹王文科章雄文方艳芬
Owner EAST CHINA NORMAL UNIV
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