The Chemical Development of CHIR-258

Abstract

This paper is a case history of the early stage chemical development of CHIR-258 (4-amino-5-fluoro-3-[6(4-methyl-1-piperazinyl)-1H-benzimidazol-2-yl]-2(1H)-quinolinone, DL-lactate salt), a vascular endothelial growth factor (VEGF) kinase inhibitor for treatment of solid and hematologic cancers. The article covers various aspects of work in chemical development. In particular we discuss evaluation of the medicinal chemistry route, scale-up, salt preparation, process impurities, in-process control (IPC) method development, supply route development, technology transfer to contract manufacturing organization (CMO) and pilot plant production. Some interesting points regarding regulatory requirement for chemical development are also discussed.