Synthesis and stereochemical assignment of 7‐arylidene and 7‐heteroarylidene morphinan‐6‐ones

A number of (E)-7-arylidenenaltrexones were synthesized by azeotropic distillation of water from a benzene solution of naltrexone and an aromatic aldehyde (benzaldehyde, 4-chloro- and 4-fluorobenzaldehyde, 3-and 4-pyridinecarboxaldehyde and 1-methyl-2-imidazolecarboxaldehyde) using piperidine as a catalyst. In addition, (E)-7-benzylidenenaloxone was prepared by the previously published Claisen-Schmidt condensation using sodium hydroxide in methanol. The stereochemistry of these arylidene derivatives 3–9 was determined to be (E) by means of nuclear Overhauser enhancement experiments. The 13C nmr spectra of (E)-3–9 are recorded in deuteriochloroform and those of the hydrochlorides in deuteriodimethyl sulfoxide.

[1]  R. Hartmann,et al.  Pyridyl-substituted tetrahydrocyclopropa[a]naphthalenes: highly active and selective inhibitors of P450 arom. , 1995, Journal of medicinal chemistry.

[2]  Michael P. Williamson,et al.  Searching Conformational Space in Flexible Molecules Using NOEs and Molecular Modeling , 1995 .

[3]  J. Flippen-Anderson,et al.  Probes for narcotic receptor-mediated phenomena. 20. Alteration of opioid receptor subtype selectivity of the 5-(3-hydroxyphenyl)morphans by application of the message-address concept: preparation of delta-opioid receptor ligands. , 1995, Journal of medicinal chemistry.

[4]  P. Portoghese,et al.  Electrophilic N-benzylnaltrindoles as delta opioid receptor-selective antagonists. , 1995, Journal of medicinal chemistry.

[5]  P. Portoghese,et al.  Monophenylation of Morphinan-6-ones with Diphenyliodonium Iodide , 1995 .

[6]  P. Portoghese,et al.  7'-Substituted amino acid conjugates of naltrindole. Hydrophilic groups as determinants of selective antagonism of delta 1 opioid receptor-mediated antinociception in mice. , 1995, Journal of medicinal chemistry.

[7]  W. L. Nelson,et al.  Synthesis and opioid receptor affinity of a series of aralkyl ethers of 6 alpha- and 6 beta-naltrexol. , 1994, Journal of medicinal chemistry.

[8]  W. L. Nelson,et al.  Formation of an 6α,14-epoxy-bridged isomorphinan, an unusual product from a substituted 6α,14-dihydroxymorphinan , 1994 .

[9]  R. Hartmann,et al.  Aromatase inhibitors. Syntheses and structure-activity studies of novel pyridyl-substituted indanones, indans, and tetralins. , 1994, Journal of medicinal chemistry.

[10]  P. Portoghese,et al.  Synthesis of naltrexone-derived delta-opioid antagonists. Role of conformation of the delta address moiety. , 1994, Journal of medicinal chemistry.

[11]  P. Portoghese,et al.  A selective delta 1 opioid receptor agonist derived from oxymorphone. Evidence for separate recognition sites for delta 1 opioid receptor agonists and antagonists. , 1993, Journal of medicinal chemistry.

[12]  G. Caldwell,et al.  Complete proton and carbon nuclear magnetic resonance spectral assignments of some morphinan‐6‐one alkaloids by two‐dimensional NMR techniques , 1993 .

[13]  K. Görlitzer,et al.  Zur Mannich‐Reaktion von Hydrocodon und Oxycodon , 1993 .

[14]  W. L. Nelson,et al.  O3-(2-carbomethoxyallyl) ethers of opioid ligands derived from oxymorphone, naltrexone, etorphine, diprenorphine, norbinaltorphimine, and naltrindole. Unexpected O3-dealkylation in the opioid radioligand displacement assay. , 1992, Journal of medicinal chemistry.

[15]  P. Portoghese,et al.  A highly selective δ1-opioid receptor antagonist : 7-benzylidenenaltrexone , 1992 .

[16]  P. Portoghese,et al.  Edward E. Smissman-Bristol-Myers Squibb Award Address. The role of concepts in structure-activity relationship studies of opioid ligands. , 1992, Journal of medicinal chemistry.

[17]  R. Hartmann,et al.  New aromatase inhibitors. Synthesis and biological activity of pyridyl-substituted tetralone derivatives. , 1991, Journal of medicinal chemistry.

[18]  D. L. Larson,et al.  Persistent binding of fatty acyl derivatives of naltrexamine to opioid receptors. , 1991, Journal of medicinal chemistry.

[19]  P. Portoghese.  An approach to the design of receptor-type-selective non-peptide antagonists of peptidergic receptors: delta opioid antagonists. , 1991, Journal of medicinal chemistry.

[20]  P. Portoghese,et al.  Role of spacer and address components in peptidomimetic delta opioid receptor antagonists related to naltrindole. , 1991, Journal of medicinal chemistry.

[21]  D. Taylor,et al.  Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 4. Effect of various side-chain substituents on therapeutic activity against anticholinesterase intoxication. , 1991, Journal of medicinal chemistry.

[22]  P. Portoghese,et al.  Role of the spacer in conferring kappa opioid receptor selectivity to bivalent ligands related to norbinaltorphimine. , 1991, Journal of medicinal chemistry.

[23]  D. Zimmerman,et al.  Selective opioid receptor agonists and antagonists: research tools and potential therapeutic agents. , 1990, Journal of medicinal chemistry.

[24]  P. Portoghese,et al.  The facility of formation of a .DELTA.6 bond in dihydromorphinone and related opiates , 1989 .

[25]  M. Noack,et al.  Indoxyl‐δ‐aminosäuren aus Hydromorphon und Hydrocodon , 1986 .

[26]  E. J. Simon,et al.  Opioid agonists and antagonists. 6-Desoxy-6-substituted lactone, epoxide, and glycidate ester derivatives of naltrexone and oxymorphone. , 1985, Journal of medicinal chemistry.

[27]  J. Polazzi,et al.  Analgesic narcotic antagonists. 8. 7 alpha-Alkyl-4,5 alpha-epoxymorphinan-6-ones. , 1981, Journal of medicinal chemistry.

[28]  J. Polazzi.  Mannich reaction product of dihydrocodeinone , 1981 .

[29]  F. Carroll,et al.  Ring C conformation of 6beta-naltrexol and 6alpha-naltrexol. Evidence from proton and carbon-13 nuclear magnetic resonance. , 1976, The Journal of organic chemistry.

[30]  F. Carroll,et al.  Carbon-13 nuclear magnetic resonance spectra of morphine alkaloids. , 1976, The Journal of organic chemistry.

[31]  P. Portoghese.  A new concept on the mode of interaction of narcotic analgesics with receptors. , 1965, Journal of medicinal chemistry.

[32]  L. Birkofer,et al.  Aldehydaddition an Enamine , 1962 .