Diaryldimethylpiperazine ligands with μ- and δ-opioid receptor affinity: Synthesis of (+)-4-[(α R)-α-(4-allyl-(2 S,5 S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]- N-ethyl- N-phenylbenzamide and (−)-4-[(α R)-α-(2 S,5 S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]- N-ethyl- N-phenylbenzamide

We have explored the synthesis of compounds that have good affinity for both μ- and δ-opioid receptors from the (α R,2 S,5 S) class of diaryldimethylpiperazines. These non-selective compounds were related to opioids that have been found to interact selectively with μ- or δ-opioid receptors as agonists or antagonists. In our initial survey, we found two compounds, (+)-4-[(α R)-α-(4-allyl-(2 S,5 S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]- N-ethyl- N-phenylbenzamide (14) and its N–H relative, (−)-4-[(α R)-α-(2 S,5 S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]- N-ethyl- N-phenylbenzamide ( 15), that interacted with δ-receptors with good affinity, and, as we hoped, with much higher affinity at μ-receptors than SNC80. The relative configuration of the benzylic position in (+)-4-[(α R)-α-(4-allyl-(2 S,5 S)-dimethyl-1-piperazinyl)-(3-methoxyphenyl)methyl]-benzyl alcohol (10) was determined by X-ray crystallographic analysis of a crystal that was an unresolved twin. The absolute stereochemistry of that benzylic stereogenic center was unequivocally derived by the X-ray crystallographic analysis from the two other centers of asymmetry in the molecule that were known. Those were established from the synthesis via a dipeptide cyclo- l-Ala- l-Ala in which the absolute stereochemistry was established. Graphic