Stereochemistry of Long-lasting Opiates. 2. δ-Selective Opiate Antagonists and Their Agonist Analogues

We have discovered novel δ-selective opiate antagonists of a non-peptide nature. Our lead compound at the present time is the mixed azine between estrone and naloxone (16). In this work we describe syntheses and stereochemical determinations of several antagonist and agonist analogues of 16, all of which are mixed azines between steroids and opiates. For example, we have prepared the mixed azine between pregnenolone and naltrexone (17). A ¹³C NMR stereochemical analysis showed that 17 was formed as a mixture of two azine isomers: 20(steroid)anti-6(opiate)anti and 20(steroid)anti-6(opiate)syn, The X-ray structural analysis of pregnenolone hydrazone (8) (from which 17 was formed) showed 20 anti hydrazone. The X-ray analysis of a single crystal of 17 showed the 20(steroid)anti-6(opiate)anti azine. The C=N—N=C torsion angle was -123°, indicating gauche geometry of the azine bond.