Diaryl ethyl diether compound and pharmaceutically acceptable hydrate or salt as well as synthetic method and anti-tumor application thereof

Abstract

The invention provides a diaryl ethyl diether compound and a pharmaceutically acceptable hydrate or salt as well as a synthetic method and anti-tumor application thereof. A structural general formulais as shown in the description. A preparation method comprises the following steps: dissolving 3-hydroxy-2 nitropyridine into DMF, adding 1,2-dibromoethane and potassium carbonate, and carrying out reaction, so that a compound e is obtained; dissolving the compound e into a solvent DMF, then adding a substance (as shown in the description) and potassium carbonate, then heating, and carrying out reaction, so that a compound d is obtained; reducing the compound d by virtue of iron powder, so that a compound c is obtained; dissolving the compound c into acetonitrile solution, and carrying out bromination reaction, so that a product b is obtained; adding the compound b and 1-(1-t-butyloxycarboryl piperidine-4-yl) pyrazole-4-boronic acid pinacol ester into DME, then adding Pd(dppf)Cl2 and Cs2CO3 aqueous solution, and carrying out reaction, so that a compound a is obtained; and adding the compound a into dichloromethane, dropwise adding 1,4-dioxane solution of hydrogen chloride under ice-bath condition, and carrying out reaction, so that the product is obtained. The compound provided by the invention is novel in structure, has the effect of resisting to non-small cell lung cancer and neuroblastoma and has the antitumor activity equivalent to or better than that of a positive control crizotinib.

Description

technical field [0001] The invention relates to a diaryl ethylene ether compound and its pharmaceutically acceptable salt or hydrate, its chemical preparation and antitumor application. Background technique [0002] Lung cancer is one of the most important diseases threatening human health. Anaplastic Lymphoma Kinase (Anaplastic Lymphoma Kinase, ALK) positive non-small cell lung cancer accounts for about 5% of the total number of lung cancer patients. Tyrosine kinase inhibitors targeting ALK are powerful means for the treatment of ALK-positive non-small cell lung cancer. Crizotinib is an oral tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer. Crizotinib is an ATP-competitive tyrosine kinase inhibitor that has inhibitory effects on tyrosine kinases c-Met, ALK and ROS1 (Segaliny AI et al., J Bone Oncol. 4:1-12, 2015). As the first-generation ALK inhibitor, crizotinib was approved by the US FDA in 2011 for the treatment of advanced ALK-po...

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Problems solved by technology

However, patients taking crizotinib often develop drug resistance within 1-2 years, and central nervous system recurrence is more common (Katayama R et al, P Natl Acad Sci USA.108:7535-7540, 2011)

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