Analogs with C-methyl and Other Hydrocarbon Substituents in the Piperidine Ring

ANALOGS WITH C-METHYL (AND OTHER HYDROCARBON) SUBSTITUENTS IN THE PIPERIDINE RING 

Discussion of this group of variants, which includes such well-known analgesics as a- and / -prodine and promedol, is deferred to Chapter 7 because of the extent and complexity of the work involved. 

A study of heterocyclic ring contraction and expansion upon activity in reversed esters of pethidine has shown that analgesic properties are retained 

Azacycloheptan-4-one intermediates required for these studies were made by ring expansion of 4-piperidones with diazomethane N-substituted 3-pyrrolidones were made by the Dieckmann procedure from acyclic precursors of type 26.(70,74) 

Isoprodines (28), related to /3-pethidine, are inactive in mice in doses up to 100 mg/kg(76) the bicyclic analog 29 with the piperidine ring constrained to a boat conformation is about half as active as a-prodine in rats while its diastereoisomer is inactive/77 Results on /3-pethidine and isoprodine should be compared with data on 3-aryl-3-methylpiperidines that lack an oxygen substitutent in the piperidine ring but possess one in the aromatic moiety (p. 279). 

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