AntiNociception
Greenlighter
- Joined
- Apr 21, 2010
- Messages
- 6
The team led by B. Pelmont at H. La Roche that formed in 1949 to investigate the 14(R)-morphinans (incl. norlevorphanol derivs such as Ro4-1539 or furethylnormorphinan) were tasked with the tetracyclic "Grewe morphinans." Grewe's newfangled Bronsted-catalyzed morphinan cyclization was 'fresh-off-the-press.' the german pharma firms of this era, still partially under Allied control, who were doing a thorough job of gutting them of 'intellectual property war loot,' allowed for a brief window of time where Swiss firms were best equipped to investigate these new fully synthetic morphinans. The 4,5-epoxy bridged pentacycles had been thoroughly investigated by the earlier American NRC (later the COPDD) investigation from 1929-1941 (the key figures involved in this NRC effort were Lyndon F Small, Nathan B. Eddy, & Everette L. May). The NRC research elucidated the epoxymorphinan class w/ the hopes of finding analgesics with reduced physical dependence capacity (PDC). after investigating hundreds of compounds, they found only two candidates: metopon and desomorphine. According to NB Eddy (writing in his posthumously published memoirs "The National Research Council involvement in the opiate problem, 1928-1971") the two derivs were the only novel pentacyclic morphinans which demonstrated a statistically relevant separation of analgesia from dependence liability.
Janssen & Leysen confirmed in a pair of separate review articles, another was a chapter (can't recall the volume it was a part of, will update later when i search thru my notes) that N-phenethyl-nordesomorphine (approx 80 x morphine as analgesic) substituted equally well as N-(2-thienylethyl)-nordesomorphine when tested in SDS assays in animal subjects (morphine w/d suppression) -- both of the N-arylethyl derivs fully substituting for morphine in the SDS (morphine-habituated rodents).
I was frustrated by this reference, as it provides an analgesic estimate for the N-phenethyl deriv, but fails to mention any such analgesic estimate for the thienylethyl. Nor does it provide the mg/kg suppression dose for the the N-thienylethyl (or provide a citation whose full-text was electronically accessible at the time (it was over ten yrs ago, so perhaps they've digitized the publication) -->
quantitative comparison of the non-phenyl 2-arylethyl subsitututed N-nor-epoxymorphinans remains elusive. But I'm positive they are out there. I would check the work performed by Schmidhammer (spellling?) et al. he specializes in 14-hydroxymorphinans and the 6-keto derivs (morphin-6-ones) but he is among the few still conducting research in N-phenethyl epoxymorphinans. See "phenomorphone" or N-phenethyl-noroxymorphone
Another very interesting area of inquiry is that of the levorphanol 14(S)-epimers, so called 'isomorphinans' (M. Gates first elucidated and provided bioactivity data on the isolevorphanol series in a JACS article in 1958)
See the link below for detailed discussion of lewis acid-catalyzed cyclization of a novel 1-benzyloctahydroisoquinoline (OHiQ; an isomer of the common morphinan precursor octabase) with a shifted double bound, which, upon exposure to AlBr3 (lewis acid) cyclized to the corresponding 14(S)-isomorphinan -- the 14(S)-epimer of 14(R)-levorphanol configured morphinans
Some very unique stereochemistry, increased activity, and some fascinating work done by Marshall Gates (the same Gates who elucidated the formal synthesis of morphine in 1952).
14(S)-isomorphinans are accessible by a 'Grewe-analogous' cyclization mechanism initiated by heating with Lewis Acids (instead of the bronsted acid/H3PO4 in the conventional Grewe procedure). See the diagram below for additional insight involving cyclization of an appropriate substituted OHiQ with AlBr3
According to a 1964 article by Fry & May, the same type of benzomorphan epimer (beta-metazocine derivs) was achieved using AlCl3 -- Gates chose AlBr3 for his isolevorphanol and isocyclorphan syntheses (the specific isomorphinans that were the topic of his mechanism postulates) b/c of a recommendation by a colleague who he gives credit to in the text of his review (will have to look that one up in the actual print lit. as well--another reference not avail electronically)
Sincerely,
--Deandra
(aka: Oxycosmopolitan and DuchessVonD)
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