Synthesis of (1',2'-trans)-3-phenyl-1-[2'-(N-pyrrolidinyl)cyclohexyl]pyrrolid -2-ones as kappa-selective opiates

(1',2'-trans)-3-Phenyl-1-[2'-(N-pyrrolidinyl)cyclohexyl]pyrrolid-2 -ones (1 and 2) and their 3,4-dichlorophenyl analogues (4 and 5) were synthesized as lactam analogues of U-50,488 (I; a kappa-opiate analgesic developed by Upjohn Company). Compounds 1 and 2 were found to be oxidized by air, in the presence of a strong base, to the 3-hydroxylated derivative 3. Compound 4 gave slightly higher kappa-affinity (Ki = 10 nM) than I, with about half the kappa-selectivity (mu/kappa = 23). Compounds 1 and 3 showed weaker kappa-binding (Ki = 400 nM), with about the same kappa-selectivity as 4. Compound 5, a diastereomer of 4, gave significantly weaker and less selective kappa-binding than 4; likewise, 2 is a weaker and less selective kappa-binder than 1. The binding data of intermediate compounds having the basic skeleton of I seem to reflect the importance of lipophilicity and the detrimental effects of bulky substituents on the amide nitrogen. It is likely that the binding conformation of I at the opiate receptors approaches that of the lactam analogue 4.