Agents for the Treatment of Overactive Detrusor. V. Synthesis and Inhibitory Activity on Detrusor Contraction of N-tert-Butyl-4,4-diphenyl-2-cyclopentenylamine.

N-tert-Butyl-4, 4-diphenyl-2-cyclopentenylamine ((±)-3) was designed to restrict the conformation of terodiline 1 and was synthesized in a 6-step approach starting with diphenylacetaldehyde (10) or in a 4-step approach starting with 2, 2-diphenyl-4-pentenoic acid (17). Using di-p-toluoyltartaric acid as a resolving agent, the synthetic (±)-3 was resolved into its optically pure forms, (-)- and (+)-3. The (-)-enantiomer (-)-3·HCl (FK584) showed about ten times more potent inhibitory acitivity on urinary bladder rhythmic contraction in rats (ED30 =0.18 mg/kg, i.v.)than terodiline (ED30=1.9 mg/kg, i.v), while the (+)-enantiomer (+)-3·HCl showed no inhibitory activity at 1.0 mg/kg i.v.Compound (-)-3·HCl (FK584) has pharmacological properties similar to those of terodiline, as evaluated by in vitro assay and is currently in clinical development for the treatment of overactive detrusor.