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.

A variety of colchicine, demecolcine, and isocolchicine derivatives were examined for their potency in the lymphocytic leukemia P388 screen in mice, for their toxicity in mice, and for their binding to microtubule protein. A qualitatively direct correlation was found between in vivo potency and toxicity; potency appeared to be less well correlated with tubulin binding. The most potent compounds were N-acylated analogues of colchicine and demecolcine. Among the monophenols, only 3-demethylcolchicine showed an appreciable effect in vitro and in vivo and was less toxic than colchicine. Improved methods were found for the preparation of 3- and 2-demethylcolchicine, which involved the use of 85% phosphoric acid and concentrated sulfuric acid, respectively. Decoupling experiments with 1H NMR proved that the double bond of dehydro-7-deacetamidocolchiceine and its derived tropolonic methyl ethers 24 and 25 was in the 5,6 position, rather than the 6,7 position formerly tentatively assigned.

A series of natural and synthetic colchicine derivatives was examined for their potency in the lymphocytic leukemia P388 screen in mice, for their toxicity in mice, and for their binding to microtubule protein. The natural alkaloids cornigerine and colchifoline and several N,O-substituted analogues of colchifoline were found to be as potent and as toxic as colchicine in the P388 screen with good affinity for tubulin. The 1,2-(methylenedioxy)-substituted isomer of cornigerine was considerably less potent in vivo than could have been anticipated from the in vitro tubulin binding data. Several N-acyl and N-aroyl derivatives prepared from deacetylcolchicine showed high potency in the in vitro and in vivo screens. Colchicide was found to be highly potent in vivo, and N-carbethoxydeacetylcolchicine, a synthetic analogue of colchicine with a N-carbethoxy instead of an N-acetyl function, showed interesting biological properties.

No abstract

SummaryThe synthesis of several 14-hydroxymorphinans, using oxymorphone (= 3,14-dihydroxy-4,5-epoxy-N-methylmorphinan-6-one, 1) as starting material, is described. The antinociceptive potency of the N-methyl substituted 14-hydroxymorphinans was determined. Thus, in order of antinociceptive potency, 14-hydroxy-4-methoxy-N-methylmorphinan-6-one (5)>4,5-epoxy-14-hydroxy-N-methylmorphinan-6-one (3)> 4,14-dihydroxy-N-methylmorphinan-6-one (4) > 14-hydroxy-4-methoxy-N-methylmorphinan (1 1) z 4,14-dihydroxy-N-methylmorphinan (12). The most potent compound in this series, 14-hydroxy-4-methoxy-N-methylmorphinand-one (5), was found to have about six times the potency of morphine; it was equipotent with levorphanol.The high antinociceptive potency of 4-methoxy-N-methylmorphinan-6-one, prepared from 3-deoxydihydromorphine of the natural series of opioids [ 11, and 3,4-dimethoxy-N-methylmorphinan, prepared from natural thebaine [ 2 ] , was recently reported. This program was extended to include the preparation of congeners with N-substituents known to afford narcotic antagonists 131, and of highly potent morphinan-6-ones unsubstituted in the aromatic ring moiety [4]. The events leading to these developments were recently summarized [5] [6]. We now would like to report on the synthesis (s. Scheme) and biological properties of representative morphinans containing a 14-hydroxy substituent. This extension was stimulated by the proven clinical effectiveness of butorphanol as an analgesic [7], by the finding of oxilorphan as a strong narcotic antagonist [7], and by the discovery of long-acting opiate agonists and antagonists among 14-hydroxydihydromorphinone hydrazones [8].The tetrazolyloxy compound 22) was obtained from oxymorphone (1) by alkylation with 5-chloro-1-phenyl-1 H-tetrazole in DMF in the presence of K2C03 1) )To whom correspondence should be addressed. All new compounds were characterized by elemental analysis and show the expected spectroscopic features.