The C-14, C-13, And N-15 Syntheses Of A Potent Vegfr-2 Kinase Inhibitor, Brivanib, And Its Prodrug, Brivanib Alaninate

The interruption of tyrosine kinase vascular endothelial growth factor receptor-2 (VEGFR-2) signaling by the binding of a small molecule inhibitor, for example, Brivanib, to VEGFR-2 kinase domain has been shown as an effective method of slowing angiogenesis and tumor progression. [C-14]Brivanib, 13 and its prodrug [C-14]Brivanib Alaninate, 15 were prepared to support preclinical and clinical studies. Their respective stable isotope-labeled versions, [(C3N2)-C-13-N-15]Brivanib, 21 and [(C3N2)-C-13-N-15]Brivanib Alaninate, 28, were also prepared to support bioanalytical LC-MS analyses of clinical samples. All of the four title compounds were synthetically derived from the respective isotopically labeled common pyrrolotriazinone intermediate, 6 or 16. This labeled central core pyrrolotriazinone was also conveniently used to synthesize other structurally related drug discovery candidates.