Synthesis and biological evaluation of 14-alkoxymorphinans. 1. Highly potent opioid agonists in the series of (-)-14-methoxy-N-methylmorphinan-6-ones

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Abstract
A series of eight (-)-14-methoxymorphinan-6-ones was synthesized and biologically evaluated. The morphinanones 3-7 [-)-4,5-epoxy-14-methoxy-N-methylmorphinan-6-one (3),(-)-4-hydroxy-14-methoxy-N-methylmorphinan-6-one (4), (-)-4,14-dimethoxy-N-methylmorphinan-6-one (5), [1-14-methoxy-N-methyl-4-[(1-phenyl-1H-Tetrazol-5-yl)oxylmorphinan-6-one (6) and (-)-14-methoxy-N-methylmorphinan-6-one (7) were prepared from 3-desoxy-7,8-dihydro-14-hydroxymorphinone (1). The key step in this synthetic sequence, O-methylation in position 14, was accomplished with dimethyl sulfate. Hydrolysis followed by reductive opening of 4,5-oxygen bridge afforded the phenol 4, which was O-methylated to give 5. Removal of the 4-OH group yielded the aromatic unsubstituted morphinan 7. The synthesis of 10 [(-)-3,4,14-trimethoxy-N-methylmorphinan-6-one] was accomplished by starting from 14-methoxy-7,8-dihydrocodeinone and involved a similar reaction sequence. The compounds 13-15 [(-)-3-(benzyloxyl)-6,7-didehydro-6,14-dimethoxy-4,5-epoxy-N-methylmorphinan (13), (-)-3-(benzyloxy)-4,5-epoxy-14-methoxy-N-methylmorphinan-6-one hydrobromide (14) and (-)-4,5-epoxy-3-hydroxy 14-methoxy-N-methylmorphinan-6-one-hydrobromide] were synthesized from oxymorphone (11), which was 3-O-benzylated, 6,14-bis O-methylated with dimethyl sulfate hydrolyzed, and hydrogenated to yield the oxymorphone 14-O-methyl ether 15. The derivatives 3,4, 5, 7, 10, 14, and 15 exhibited high antinociceptive potency in the hot-plate assay in mice, after both s.c. and oral administration. The most potent derivative in this series (15) showed a potency (sc) about 400 times higher than that of morphine and about 40 times higher than its 14-OH analog (11). The 14-OCH3 series also exhibited a considerably higher affinity to mouse opioid receptors in binding studies using [3H] naloxone as ligand when compared to their 14-OH analogs.

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