1-Aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as potential inhibitors of VEGFR-2: synthesis and molecular modelling studies

Angiogenesis is a requirement for tumor growth and metastasis and occurs through several signalling pathways. One key pathway that initiates proliferation and migration of endothelial cells is signalling through the vascular endothelial growth factor receptor-2 (VEGFR-2).1 Therefore, small molecules that block this signalling pathway through inhibition of the VEGFR tyrosine kinase activity could potentially inhibit angiogenesis and tumour growth. Recently works describing thienopyrimidines2 and thienopyridine ureas3 as inhibitors of VEGFR-2 have appeared in the literature. Here we present the synthesis of new 1,3-diarylureas 2 starting by regioselective nucleophilic substitution of the 4-chlorothieno[3,2-d]pyrimidine with 4-aminophenol to obtain 4-(thieno[3,2-d]pyridin-4-yloxy)aniline 1 which reacts with different arylisocyanates