Synthesis, crystal structure and activity evaluation of novel 3,4-dihydro-1-benzoxepin-5(2H)-one derivatives as protein–tyrosine kinase (PTK) inhibitors

Abstract

Four new 3,4-dihydro-1-benzoxepin-5(2H)-one derivatives, namely (E)-4-(5-bromo-2-hydroxybenzylidene)-6,8-dimethoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, (7), (E)-4-[(E)-3-(5-bromo-2-hydroxyphenyl)allylidene]-6,8-dimethoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, (8), (E)-4-(5-bromo-2-hydroxybenzylidene)-6-hydroxy-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, C18H15BrO5, (9), and (E)-4-[(E)-3-(5-bromo-2-hydroxyphenyl)allylidene]-6-hydroxy-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one, (10), have been synthesized and characterized by FT–IR, NMR and MS. The structure of (9) was confirmed by single-crystal X-ray diffraction. Crystal structure analysis shows that molecules of (9) are connected into a one-dimensional chain in the [010] direction through classical hydrogen bonds and these chains are further extended into a three-dimensional network via C—H...O interactions. The inhibitory activities of these compounds against protein–tyrosine kinases (PTKs) show that 6-hydroxy-substituted compounds (9) and (10) are more effective for inhibiting ErbB1 and ErbB2 than are 6-methoxy-substituted compounds (7) and (8). This may be because (9) and (10) could effectively bind to the active pockets of the protein through intermolecular interactions.