1-aryl-3-(4-(7-methylthieno[3,2-d]pyrimidin-4-yloxy)phenyl)ureas: synthesis and molecular modelling studies using VEGFR-2

The development of anticancer drugs inhibiting angiogenesis has been an area of extensive research in the past decade. 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 VEGFR-2 tyrosine kinase activity could potentially inhibit angiogenesis and tumor growth. Recently works describing thienopyrimidine2 and thienopyrimidine 1,3-diarylureas3 as VEGFR-2 inhibitors have emerged in the literature. Here we present the synthesis of new 1-aryl-3-(4-(7-methylthieno[3,2-d]pyrimidin-4-yloxy)phenyl)ureas 2 in high yields by reaction of 4-[(7-methylthieno[3,2-d]pyridin-4-yl)oxy]aniline 1 with arylisocyanates. The former was prepared by regioselective nucleophilic substitution of 4-chloro-7-methylthieno[3,2-d]pyrimidine with 4-aminophenol