FK584[(-)-N-tert-butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride, (-)-4-HCl], a potential candidate for the treatment of overactive detrusor, was synthesized in a 4-step approach starting with Sharpless oxidation of cyclopentenol 6 (kinetic resolution). This epoxidation is a rare case in that the empirical rule does not work. Regio- and stereoselective introduction of tert-butylamine to the obtained epoxycyclopentanol 5 and subsequent conversion of the resulting diol to an olefin completed the synthesis. The absolute configuration of FK584 was determined to be S by X-ray crystallographic analysis of the salt of S-(+)-mandelic acid.

01 Jan 1996·Chemical and Pharmaceutical BulletinQ4 · MEDICINE

Agents for the Treatment of Overactive Detrusor. IX. Synthesis and Pharmacological Properties of Metabolites of N-tert-Butyl-4,4-diphenyl-2-cyclopentenylamine(FK584) in Human Urine.

Q4 · MEDICINE

Article

Author: Yamamoto, Takao ; Tsubaki, Kazunori ; Terai, Takao ; Yamano, Katsuhiro ; Miyao, Yasuhiro ; Taniguchi, Kiyoshi ; Kusunoki, Takahiro ; Shiokawa, Youichi

We synthesized the racemates of the five presumed metabolites (1b-f) of (S)-(--)-N-tert-butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride (FK584, S(--)-1a), a novel agent for the treatment of overactive detrusor syndrome, in order to confirm the structures of the metabolites and also to evaluate their inhibitory activity against detrusor contraction. (+/-)-N-tert-Butyl-4-(4-hydroxyphenyl)- and 4-(4-hydroxyphenyl)- and 4-phenyl-2-cyclopentenylamines (1b--e) were synthesized via 5-(4-methoxyphenyl)- and 5-(4-benzyloxy-3-methoxyphenyl)-5-phenyl-2-cyclopenten-1-one (9g, h), respectively. Compounds 1b-f prepared in this study were identical with the metabolites in human urine in gas chromatography-mass spectrometry and analytical HPLC. The inhibitory activity of compounds 1b-f against detrusor contraction in vitro induced by electrical field stimulation in guinea-pigs was less potent than that of FK584.

01 Jan 1996·Chemical and Pharmaceutical Bulletin

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

Article

Author: Okumura, Kazuo ; Terai, Takao ; Take, Kazuhiko ; Shiokawa, Youichi ; Taniguchi, Kiyoshi ; Tsubaki, Kazunori

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Pollakisuria	Phase 2	JP	Fujisawa Pharmaceutical Co., Ltd.	-
Urinary Bladder, Overactive	Phase 2	-	Astellas Pharma, Inc.	-

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