Chemical & Pharmaceutical Bulletin 1996-10-01

Agents for the treatment of overactive detrusor. V. Synthesis and inhibitory activity on detrusor contraction of N-tert-butyl-4,4-diphenyl-2-cyclopentenylamine.

K Take, K Okumura, K Tsubaki, K Taniguchi, T Terai, Y Shiokawa

Index: Chem. Pharm. Bull. 44(10) , 1858-64, (1996)

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Abstract

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 activity 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.