Oxilorphan and Butorphanol. Potent Narcotic Antagonists and Nonaddicting Analgesics in the 3,14-Dihydroxymorphinan Series. Part V

Abstract

. 53,3094 (1975). A series of 3,14-dihydroxymorphinans 8 was synthesized via a method of (a) acylation of 3-metho~y-A~~'~-morphinan 4a (6) stereospecific epoxidation of the resultant arnides to p-epoxides 5 (c) simultaneous reduction of amide and epoxide functions and (d) dernethylation of the resultant 3-methoxy-14-hydroxymorphinans 7. Alternatively deblocking of the m i n e function in 56 by hydrolysis followed by reduction of the resultant amino epoxide 5e afforded 14-hydroxy-3-methoxyrnorphinan 7e, which is readily alklyated and demethylated to give various 8. On a basis of interesting pharmacological profiles compounds I-8c (oxilorphan) and I-8d (butorphanol) were selected for clinical studies.

The Power of Visual Imagery in Drug Design. Isopavines as a New Class of Morphinomimetics and Their Human Opioid Receptor Binding Activity

“…In view of the nonspecific recognition of the opioid receptors, morphine and many of its congeners have serious side effects such as physical dependence, respiratory depression, and muscle rigidity. − Strategies that capitalize on different levels of agonist efficacy vis - à - vis these receptors have been advocated as a means of diminishing side effects . A large proportion of opioid ligands have centered around the 4,5-epoxymorphinan, dihydromorphone, and dihydromorphindole structures …”

“…14 A large proportion of opioid ligands have centered around the 4,5-epoxymorphinan, dihydromorphone, and dihydromorphindole structures. 32 Morphine, nalorphine, naltrexone, natrindole, oxymorphindole, and their variants are representative opioids that belong to these classes. Tricyclic structures have included morphinans, benzomorphans, aminotetralins, and cyclazocines, to mention a few.…”

Cyclization of ylidenemalononitriles. 9. Rearrangement of 2-cyano-3-(1-methylcyclopentyl)indenone to 4a-methyl-9-oxo-10-cyano-1,2,3,4,4a,9-hexahydrophenanthrene

“…A second ring enlargement involving a phenyl migration would produce the protonated hydrophenanthrene structure 4a, which by loss of a proton would give 4a-methyl-9-oxo-10-cyanol,2,3,4,4a,9-hexahydrophenanthrene (4). An alternative rearrangement of 3 involving migration of the methyl group in preference to a ring carbon to give the spiro compound 5 may also be possible (Scheme I). In this case, methyl migration in carbonium ion 3a followed by ring enlargement of the resulting carbonium ion 4b would lead to the spiro carbonium ion 5a, which could lose a porton to produce 2'-methyl-3'cyanospiro[cyclopentane-l,l,(4,/i)-naphthalen]-4'-one (5).…”

“…An alternative rearrangement of 3 involving migration of the methyl group in preference to a ring carbon to give the spiro compound 5 may also be possible (Scheme I). In this case, methyl migration in carbonium ion 3a followed by ring enlargement of the resulting carbonium ion 4b would lead to the spiro carbonium ion 5a, which could lose a porton to produce 2'-methyl-3'cyanospiro[cyclopentane-l,l,(4,/i)-naphthalen]-4'-one (5). Alternatively, 5a could undergo ring enlargement to the protonated hydrophenanthrene 5b, which by methyl migration would ultimately give the desired product 4.…”

“…5 °C; IR (KBr)3.40,4.50,6.25,6.70 Mm; NMR (CDClg) 1.7-2.5 (m, 8 H, cyclopentyl), 3.35 (s, 2 H, benzyl), 3.85 (s, 3 H, MeO), 6.43 (d, 2 H, J = 8 Hz, aryl ortho to MeO),6.88 (d, 2 H, J = 8 Hz, aryl ortho to C=C), 7.5-8.0 (m, 5 H, aryl).Anal. Caled for C23H22N20: C, 80.67; H, 6.47; N, 8.18; MW 342.…”