RESUMO
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.
Assuntos
Cério/química , Césio/química , Cloretos/química , Compostos de Lítio/química , Nitrilas/química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ultrassom , Benzeno/química , Estrutura Molecular , Nitrilas/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
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.