Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist ‘CJ-17,493’

Abstract A novel central nervous system (CNS) selective neurokinin-1 (NK 1 ) receptor antagonist, (2 S ,3 S )-3-[(1 R )-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine ‘CJ-17,493’ (compound (+)- 1 ), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)- 1 displayed high and selective affinity ( K i  = 0.2 nM) for the human NK 1 receptor in IM-9 cells, potent activity in the [Sar 9 , Met(O 2 ) 11 ]SP-induced gerbil tapping model (ED 50  = 0.04 mg/kg, sc) and in the ferret cisplatin (10 mg/kg, ip)-induced anti-emetic activity model (vomiting: ED 90  = 0.07 mg/kg, sc), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result provides a potential solution for the clinical issue observed with CP-122,721.