1-Aryl-3-azabicyclo[3.1.0]hexanes, a new series of nonnarcotic analgesic agents

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.

Palladium-catalysed transannular C–H functionalization of alicyclic amines

“…Selective C–H functionalization reactions on complex molecular scaffolds provide valuable opportunities for streamlining analog generation and thereby accelerating structure activity relationship studies 5,6 . The bicyclo[3.1.0] scaffold appears in numerous pharmaceutical candidates, including the serotonin-norepinephrine-dopamine reuptake inhibitor amitifadine ( 7 ) 26,27 . As shown in Fig.…”

Molecular-biological problems of drug design and mechanism of drug action

“…This prompted searches for antidepressants and RT inhibitors among analgesics [3]. The structure of the known analgesic profadol, an arylpyrrolidine (XIV), served as the starting point for the synthesis and development of triple RT inhibitors among aryl-3-azabicyclo[3.1.0]hexanes [37,38] (Scheme 3).…”

Efficient and practical syntheses of a stable labelled form of the non‐narcotic analgesic, bicifadine and its metabolites

“…1 Some improvements of the synthesis of 1-aryl-3-aza-bicyclo[3.1.0]hexanes have recently been reported in patent literature. 6 Here we report a simple and effective synthesis of deuterium-labelled bicifadine, illustrated in Scheme 1.…”

“…It is effective in the treatment of acute dental pain 1,2 and postoperative bunionectomy pain. 3 It is also active in models of neuropathic pain, with no narcotic-like withdrawal symptoms.…”