1. 1-Aryl-3-azabicyclo[3.1.0]hexanes, a new series of nonnarcotic analgesic agents
- Author
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Arnold C. Osterberg, F. M. Lovell, Thomas C. McKenzie, Herbert J. Brabander, Corris M. Hofmann, D. B. Cosulich, Epstein Joseph William, Sidney R. Safir, and William J. Fanshawe
- Subjects
Bridged-Ring Compounds ,Analgesics ,Crystallography ,Chemical Phenomena ,Chemistry ,Aryl ,Analgesic ,Absolute configuration ,Medicinal chemistry ,Rats ,Bridged Bicyclo Compounds ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Amide ,Drug Discovery ,medicine ,Animals ,Molecular Medicine ,Potency ,Enantiomer ,Ether cleavage ,Bicifadine ,medicine.drug - Abstract
A series of 1-aryl-3-azabicyclo[3.1.0]hexanes was synthesized by hydride reduction of 1-arylcyclopropanedicarboximides. Hydroxyphenyl analogues 20, 22, and 24 were prepared by EtSNa--DMF ether cleavage of the corresponding methoxyphenyl analogues 2m, 2n, and 23, respectively, with the secondary amines 20 and 22 going through the N-formyl intermediate 19 and 21. The p-ethoxy analogue 26 was obtained by O-ethylation of 19, followed by base hydrolysis of the amide 25. The greatest analgesic potency in mouse writhing and rat paw-pain assays was observed for para-substituted compounds. Bicifadine, 1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane (2b), was the most potent member of the series and is presently undergoing clinical trials in man. Analgesic activity of 2b is limited to the (+) enantiomer 2v, which has the 1R,5S absolute configuration as determined by single-crystal X-ray analysis. The N-methyl analogue (27d) of 2b showed significant analgesic potency, whereas the N-allyl (27a), N-(cyclopropylmethyl) (27b), and N-(n-hexyl) (27c) analogues were inactive. Bicifadine (2b) showed a nonnarcotic profile different from analogous azabicycloalkane and 3-phenylpyrrolidine analgesics.
- Published
- 1981