Structure-activity relations in analgesics based on 4-anilinopiperidine

The synthesis of some 1-alkyl and l-aralkyl-4-(N-phenylpropion-amido)piperidines and related derivatives is described and the hot-plate activities in mice of these compounds reported. Activity variations among 1-methyl, 1-benzyl, and 1-phenethyl derivatives resemble those of corresponding open-chain anilide rather than 4-phenyl-piperidine analgesics. Infrared and nmr data show the two nitrogen atoms of the 4-anilinopiperidine derivatives to be further apart than those of open-chain anilides in their respective preferred conformations; these results, together with the extreme potency difference between the N-phenethyl derivatives diampromide and fentanyl, show that the two classes are best regarded as mutually distinct types of analgesic.