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.
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.
mesh_terms: D000215:Acylation; D000698:Analgesia; D000818:Animals; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D008745:Methylation; D051379:Mice; D009019:Morphinans / Q000138:chemical synthesis / Q000378:metabolism; D009020:Morphine; D009270:Naloxone / Q000378:metabolism; D010100:Oxygen; D010620:Phenazocine / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship; D013455:Sulfur
chemical_list: D009019:Morphinans; D011957:Receptors, Opioid; D009270:Naloxone; D013455:Sulfur; D009020:Morphine; D010620:Phenazocine; D010100:Oxygen; C047238:metazocine