Document Report Card

ID: ALA1122844

Journal: J Med Chem

Title: Novel nonnarcotic analgesics with an improved therapeutic ratio. Structure-activity relationships of 8-(methylthio)- and 8-(acylthio)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines.

Authors: Hori M, Ban M, Imai E, Iwata N, Suzuki Y, Baba Y, Morita T, Fujimura H, Nozaki M, Niwa M.

Abstract: Conversion of the 8-phenolic 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines to the corresponding 8-thiophenolic analogues was achieved by three different routes. Diazotization of 8-amino-2,6-methano-3-benzazocine (2) followed by the reaction with CH3SNa afforded 8-(methylthio)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (3). Another route using Grewe cyclization was also examined for the synthesis of 3. As the most effective route, Newman-Kwart rearrangement of benzazocines was selected and closely investigated. 8-(N,N-Dimethylthiocarbamoyl)oxy derivatives (6a-e) rearranged to 8-(N,N-dimethylcarbamoyl)thio derivatives (7a-e) in good yields. Reductive cleavage of 7a-e and subsequent methylation or acylations gave the title compounds (3, 8-24). Although analgesic activities of sulfur-containing benzazocines decreased compared to the corresponding hydroxy compounds, the N-methyl derivative (S-metazocine, 8) showed potent analgesic activity.

CiteXplore: 2999399

DOI: 10.1021/jm00149a020