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 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.
Take
K
K
New Drug Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.
Okumura
K
K
Tsubaki
K
K
Taniguchi
K
K
Terai
T
T
Shiokawa
Y
Y
D000588:Amines / Q000494:pharmacology; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D002082:Butylamines / Q000494:pharmacology; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009184:Mydriatics / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology; D011680:Pupil / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
D000588:Amines; D001559:Benzhydryl Compounds; D002082:Butylamines; D003517:Cyclopentanes; D018721:Muscarinic Agonists; D009184:Mydriatics; C102407:N-tert-butyl-4,4-diphenyl-2-cyclopentenylamine; D010276:Parasympatholytics; C092685:4,4-diphenyl-2-cyclopentenylamine; C010637:terodiline