Stereochemical Studies on Medicinal Agents. 17. Synthesis, Absolute Configuration, and Analgetic Potency of Enantiomeric Diastereomers of 3-Ethyl and 3-Propyl Derivatives of 1-Methyl-4-phenyl-4-propionoxypiperidine

Kevin H. Bell, Philip S Portoghese

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

We recently have reported2on the relative stereochemistries of racemic diastereomers of 1 and have noted that, unlike the prodines 2, the α isomer is considerably more potent than the β isomer. The corresponding allyl racemates also were found to possess a qualitatively similar stereostructure-activity relationship; however, on a quantitative basis (±)-α-3 is 15 times more potent than morphine and 24 times that of (±)-α-1. A subsequent report3on the optical isomers of 3 revealed that α-3 possesses high enantiomeric stereoselectivity [potency ratio, (3R,4S)/(3S,4R) = 260], while the much less active β-3 exhibits an enantiomeric potency ratio of unity. This is in marked contrast to the stereochemical behavior of α-24where potency and enantiomeric stereoselectivity are one order of magnitude lower [(3R,4S)/(3S,4R) = 25] than α-3. Moreover, β-24also shows a striking difference (when compared to β-3) in that it possesses moderate enantiomeric stereoselectivity [(3S,4S)/(3R,4R) = 13].

Original languageEnglish (US)
Pages (from-to)129-131
Number of pages3
JournalJournal of Medicinal Chemistry
Volume17
Issue number1
DOIs
StatePublished - Jan 1 1974

Fingerprint

Alphaprodine
Morphine
4-propionyloxy-4-phenyl-N-methylpiperidine

Cite this

@article{a72976ac3fd1412bab0eb70c46460669,
title = "Stereochemical Studies on Medicinal Agents. 17. Synthesis, Absolute Configuration, and Analgetic Potency of Enantiomeric Diastereomers of 3-Ethyl and 3-Propyl Derivatives of 1-Methyl-4-phenyl-4-propionoxypiperidine",
abstract = "We recently have reported2on the relative stereochemistries of racemic diastereomers of 1 and have noted that, unlike the prodines 2, the α isomer is considerably more potent than the β isomer. The corresponding allyl racemates also were found to possess a qualitatively similar stereostructure-activity relationship; however, on a quantitative basis (±)-α-3 is 15 times more potent than morphine and 24 times that of (±)-α-1. A subsequent report3on the optical isomers of 3 revealed that α-3 possesses high enantiomeric stereoselectivity [potency ratio, (3R,4S)/(3S,4R) = 260], while the much less active β-3 exhibits an enantiomeric potency ratio of unity. This is in marked contrast to the stereochemical behavior of α-24where potency and enantiomeric stereoselectivity are one order of magnitude lower [(3R,4S)/(3S,4R) = 25] than α-3. Moreover, β-24also shows a striking difference (when compared to β-3) in that it possesses moderate enantiomeric stereoselectivity [(3S,4S)/(3R,4R) = 13].",
author = "Bell, {Kevin H.} and Portoghese, {Philip S}",
year = "1974",
month = "1",
day = "1",
doi = "10.1021/jm00247a024",
language = "English (US)",
volume = "17",
pages = "129--131",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "1",

}

TY - JOUR

T1 - Stereochemical Studies on Medicinal Agents. 17. Synthesis, Absolute Configuration, and Analgetic Potency of Enantiomeric Diastereomers of 3-Ethyl and 3-Propyl Derivatives of 1-Methyl-4-phenyl-4-propionoxypiperidine

AU - Bell, Kevin H.

AU - Portoghese, Philip S

PY - 1974/1/1

Y1 - 1974/1/1

N2 - We recently have reported2on the relative stereochemistries of racemic diastereomers of 1 and have noted that, unlike the prodines 2, the α isomer is considerably more potent than the β isomer. The corresponding allyl racemates also were found to possess a qualitatively similar stereostructure-activity relationship; however, on a quantitative basis (±)-α-3 is 15 times more potent than morphine and 24 times that of (±)-α-1. A subsequent report3on the optical isomers of 3 revealed that α-3 possesses high enantiomeric stereoselectivity [potency ratio, (3R,4S)/(3S,4R) = 260], while the much less active β-3 exhibits an enantiomeric potency ratio of unity. This is in marked contrast to the stereochemical behavior of α-24where potency and enantiomeric stereoselectivity are one order of magnitude lower [(3R,4S)/(3S,4R) = 25] than α-3. Moreover, β-24also shows a striking difference (when compared to β-3) in that it possesses moderate enantiomeric stereoselectivity [(3S,4S)/(3R,4R) = 13].

AB - We recently have reported2on the relative stereochemistries of racemic diastereomers of 1 and have noted that, unlike the prodines 2, the α isomer is considerably more potent than the β isomer. The corresponding allyl racemates also were found to possess a qualitatively similar stereostructure-activity relationship; however, on a quantitative basis (±)-α-3 is 15 times more potent than morphine and 24 times that of (±)-α-1. A subsequent report3on the optical isomers of 3 revealed that α-3 possesses high enantiomeric stereoselectivity [potency ratio, (3R,4S)/(3S,4R) = 260], while the much less active β-3 exhibits an enantiomeric potency ratio of unity. This is in marked contrast to the stereochemical behavior of α-24where potency and enantiomeric stereoselectivity are one order of magnitude lower [(3R,4S)/(3S,4R) = 25] than α-3. Moreover, β-24also shows a striking difference (when compared to β-3) in that it possesses moderate enantiomeric stereoselectivity [(3S,4S)/(3R,4R) = 13].

UR - http://www.scopus.com/inward/record.url?scp=0015966083&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0015966083&partnerID=8YFLogxK

U2 - 10.1021/jm00247a024

DO - 10.1021/jm00247a024

M3 - Article

VL - 17

SP - 129

EP - 131

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 1

ER -