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

Abstract

A series of eight (-)-14-methoxymorphinan-6-ones was synthesized and biologically evaluated. The morphinanones 3-7 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 the 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 9 and 10 was accomplished by starting from 14-methoxy-7,8-dihydrocodeinone and involved a similar reaction sequence. The compounds 12-15 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, 9, 10, 14, and 15 exhibited high antinociceptive potency in the hot-plate assay in mice, after both subcutaneous 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 analogue oxymorphone (11). The 14-OCH3 series also exhibited a considerably higher affinity to opioid receptors in binding studies using [3H]naloxone as ligand when compared to their 14-OH analogues.

Peripheral versus Central Antinociceptive Actions of 6-Amino Acid-Substituted Derivatives of 14-O-Methyloxymorphone in Acute and Inflammatory Pain in the Rat

“…2). 14-O-Methyloxymorphone was synthesized as described previously (Schmidhammer et al, 1984;Fig. 1).…”

“…Efforts to eliminate or minimize the undesired side effects of morphine led to the synthesis of a significant large number of compounds (for reviews, see Schmidhammer, 1993;Fü rst et al, 1995). A derivative of oxymorphone, 14-Omethyloxymorphone, was developed by our group and reported to be about 400-and 40-fold more potent than morphine and oxymorphone, respectively, in the hot-plate test in mice (Schmidhammer et al, 1984;Fig. 1).…”

14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

“…The development of 14-alkyloxymorphinan analogues was first represented by the synthesis of 14-O-methyloxymorphone (Schmidhammer et al, 1984) followed by others (Spetea and Schmidhammer, 2012). Similar strategy was carried out for the synthesis of 14-O-methylmorphin-6-O-sulfate (Lacko et al, 2012) and here for 14-O-methylmorphine.…”

Synthesis and Biological Evaluation of 14‐Alkoxymorphinans Part 4 opioid agonists and partial opioid agonists in a series of N‐(cyclobutylmethyl)‐14‐methoxymorphinan‐6‐ones

“…Compounds 19, 20, and 21 were synthesized starting from 22 which is available from oxymorphone in six steps [2]. N-Demethylation was performed via the carbamate 23 which was cleaved reductively as described above for 14 [l].…”