N4-(3-bromophenyl)-7-(substituted benzyl) pyrrolo23-dpyrimidines as Potent Multiple Receptor Tyrosine Kinase Inhibitors: Design Synthesis and In vivo Evaluation

摘要

With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized eleven N⁴-(3-bromophenyl)-7-(substitutedbenzyl) pyrrolo[2,3-d]pyrimidines >9a–19a. These compounds were obtained from the key intermediate N⁴-(3-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine >29. Various arylmethyl groups were regiospecifically attached at the N7 of >29 via sodium hydride induced alkylation with substituted arylmethyl halides. Compounds >11a and >19a were potent dual inhibitors of PDGFRβ and VEGFR-2. In a COLO-205, in vivo tumor mouse model >11a demonstrated inhibition of tumor growth, metastasis, and tumor angiogenesis that was better than or comparable to the standard compound TSU-68 (SU6668, >8).