Phenolic Piperidines and Pyrrolidines

In an attempt to determine the conformational binding mode (ax- or e 7-4-arylpiperidine chair) some 3,6-dimethyl analogs were tested, and evidence 

There is evidence that 3-aryl-3-methylpiperidines closely related to the 4,4-disubstituted piperidines also mimic morphine in their associations with opiate receptors. Again all active derivatives of this type are phenols and some possess antagonist properties when carrying an allyl or CPM substituent at the basic center. N-Methyl derivatives are feeble analgesics but become more 

Many conformational options are open to such 3-arylpiperidines, and it is reasonable to believe that some may provide a similar spatial relationship between the charged nitrogen and aromatic features as obtains in the rigid system of morphine (see 60). Parahydroxyphenyl analogs of the N-allyl and N-CPM derivatives were much less potent antagonists/79 results that emphasize the importance of a m-hydroxyphenyl moiety for ligands that bind to opioid receptors. 

The key intermediate for synthesis of the diastereoisomers 59 (R = Me) is the tetrahydropyridine 61 obtained by hydrogenation of a cyanoketone a further reduction step using a Pd catalyst gave a separable mixture of isomers 62, which were converted to N-substituted phenolic analogs by standard methods/81 The configurations a c-2-Me, r-3-Ar and /3 f-2-Me, r-3-Ar were 

Profadol was first made by cyclizing the substituted succinic acid 67, 85) but a more versatile route to such derivatives is direct C-3 alkylation of the intermediate 68,(83) Some bridged profadol analogs that incorporate a ketal function have been studied of these, the ketal 69 bound to rat brain homogenates with an affinity similar to that of morphine.(88) 

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