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Pyridino-miazines PLK1 (Polo-like kinase 1) inhibitor and application thereof

A technology of pyrimidine and dihydropyridine, applied in the field of medicinal chemistry, can solve the problems of apoptosis, formation of tumor cell bipolar spindle, growth inhibition, etc.

Inactive Publication Date: 2013-12-11
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Importantly, the work of many scholars has shown that knocking down PLK1 in tumor cells with antisense technology, siRNA technology or small molecule inhibitors can cause the formation of bipolar spindles in tumor cells to be blocked, growth inhibition, and even apoptosis

Method used

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  • Pyridino-miazines PLK1 (Polo-like kinase 1) inhibitor and application thereof
  • Pyridino-miazines PLK1 (Polo-like kinase 1) inhibitor and application thereof
  • Pyridino-miazines PLK1 (Polo-like kinase 1) inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] 4-[isopropyl(3-methoxy-3-oxopropyl)amino]-2-methylthiopyrimidine-5-carboxylic acid ethyl ester (M1)

[0070] Add 0.579g of the compound 3-methyl isopropylaminopropionate, 5 drops of DIPEA, and 12ml of n-butanol into a 25ml medium reaction flask, stir well and cool in an ice bath for 5min, slowly add 2-methyl-6-chloropyrimidine- 0.928 g of ethyl 5-formate, stirred in an ice bath for 10 min, and reacted at room temperature for 9 h. Evaporate the solvent under reduced pressure, add 10ml of water to the residue, extract with ethyl acetate (10ml×3), dry the organic phase with anhydrous magnesium sulfate, concentrate and column chromatography (PE:EA=30:1) to obtain a white solid 0.9g, yield 66.1%, MS [M+H] + 342.1.

Embodiment 2

[0072] 4-[Cyclopentyl(3-methoxy-3-oxopropyl)amino]-2-methylthiopyrimidine-5-carboxylic acid ethyl ester (M2)

[0073] The preparation method was similar to M1, and 1.2 g of the sample was obtained, with a yield of 61.5%, MS [M+H] + 368.2.

Embodiment 3

[0075] Methyl 8-isopropyl-2-methylthio-5-oxo-5,6,7,8-tetrahydropyridin[2,3-d]pyrimidine-6-carboxylate (M3)

[0076] Add 10.36g of compound M, 3ml of toluene, and a small amount of t-BuOK into a 25ml reaction bottle, and the reaction turns yellow immediately. After 2h, add 20ml of ice water, extract with DCM (15ml×3), evaporate the solvent under reduced pressure, and concentrate the column layer Analysis gave 0.14g of yellow crystals, yield 44.9%, MS[M+H] +296.1.

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Abstract

The invention relates to the field of medicinal chemistry, and particularly relates to pyridino-miazines compounds, preparation methods of the pyridino-miazines compounds, medicinal compositions containing the compounds, and medicinal applications of the pyridino-miazines compounds and the medicinal compositions, especially applications of the pyridino-miazines compounds and the medicinal compositions serving as Polo-like kinase 1 inhibitors.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to pyridopyrimidine derivatives, their preparation methods, pharmaceutical compositions containing these compounds and their medical applications, especially as Polo-like kinase 1 (Polo-like kinase1, PLK1) Use of Inhibitors. Background technique [0002] In recent years, tumors have surpassed cardiovascular diseases and become the world's leading cause of death. The research on anti-tumor drugs has important academic and practical significance. [0003] Studies have found that almost all tumors are related to uncontrolled cell growth, blocked differentiation, and abnormal apoptosis caused by the disorder of cell cycle regulation mechanism. The frequency of tumor cell division is faster than that of normal cells, and various proteins that regulate microtubule polymerization, centrosome duplication, spindle formation, and cytokinesis are often overexpressed and their activi...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/519A61K31/5377A61P35/00A61P35/02
Inventor 卢帅孙善亮张亮刘海春陈亚东陆涛
Owner CHINA PHARM UNIV
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