Synthesis and Anticholinesterase Activity of (-)-N1-Norphysostigmine, (-)-Eseramine, and Other N(1)-Substituted Analogues of (-)-Physostigmine

Article abstract of DOI:10.1021/jm00120a008

(-)-N¹-Benzylnorphysostigmine (4), prepared from synthetic (-)-O-methyl-N¹-noreseroline (1) by N-benzylation, ether cleavage, and reaction of (-)-N¹-benzylnoreseroline (3) with methyl isocyanate, was the intermediate used to prepare the title compounds.Catalytic debenzylation of (4) afforded (-)-N¹-norphysostigmine (5), and (-)-eseramine (6) was obtained by reaction of 5 with methyl isocyanate.Reductive N-methylation of 5 gave (-)-physostigmine (9) while reaction of 5 with allyl bromide and phenethyl bromide afforded carbamates 7 and 8, respectively.Data on the in vitro potencies (IC₅₀) and activities of certain of these compounds (4-8) as inhibitors of electric eel acetyl cholinesterase are reported. (-)-N¹-Norphysostigmine (5) was found to be similarly potent against AChE as (-)-physostigmine (9).