RESUMEN
The preparation of the selective VEGF-R2 kinase inhibitor 10 (JNJ-17029259) is described in which the key precursor, 4-(5-isoxazolyl)benzonitrile, undergoes clean transformation to the corresponding cumylamine derivative with CeCl(3)-MeLi in THF. This high-yielding cerium mediated transformation is robust, reproducible, and readily scalable based on a requirement for the anhydrous CeCl(3) to be milled and subjected to ultrasound treatment prior to addition of methyllithium.
Asunto(s)
Cerio/química , Cesio/química , Cloruros/química , Compuestos de Litio/química , Nitrilos/química , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/síntesis química , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ultrasonido , Benceno/química , Estructura Molecular , Nitrilos/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Through an in vivo screening model, we developed the in vivo SAR of beta-alkylthio indolyl carbinols. Through these efforts we identified a compound with potent oral in vivo efficacy in both immature and mature rat prostate weight reduction models and in a murine xenograft prostate cancer model.