Author Topic: 14-methoxy-oxymorphone and 14-methoxy-Metopon  (Read 1908 times)

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merbst

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14-methoxy-oxymorphone and 14-methoxy-Metopon
« on: December 26, 2003, 01:18:00 PM »
Hello Bees, I have read with much intrigue ning's "OTC piperidone --> fentanyl" thread, and feel that is an interesting avenue of opioid research.  Highly overlooked by the hive has been modifications to the oxymorphone molecule.  When the 14-HO of oxymorphone is replaced with an alkyl group, this class of drugs is called the 14-alkoxymorphinans.  The 14-alkoxymorphinans include some of the strongest opiates known to man such as

14-phenylpropoxymetopon

(https://www.thevespiary.org/rhodium/Rhodium/pdf/14-phenylpropoxymetopon.pdf).  The avenue I will investigate in this thread is the optimization of the production of oxymorphone, 14-methoxy-oxymorphone, and 5-methyl-14-methoxy-oxymorphone (

14-methoxy-metopon

(https://www.thevespiary.org/rhodium/Rhodium/pdf/14-methoxymetopon.pdf)).

Pharmacological Data:

14-Methoxymetopon, A Potent Opioid, Induces No Respiratory Depression, Less Sedation, and Less Bradycardia than Sufentanil in the Dog
   Anesth. Analg. 1999, 88, 332.

http://www.anesthesia-analgesia.org/cgi/content/abstract/90/6/1359


   14-methoxymetopon (HS-198), which is 20,000 times more potent than morphine in the acethylcholine-writhing test, was given in graded IV doses (3, 6, and 12 µg/kg) to awake, trained canines (n = 7).

14-Methoxymetopon, a very potent mu-opioid receptor-selective analgesic with an unusual pharmacological profile
   Eur J Pharmacol. 2003 Jan 17;459(2-3):203-9

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12524147&dopt=Abstract


   14-Methoxymetopon is a potent opioid analgesic. When given systemically, it is approximately 500-fold more active than morphine. However, this enhanced potency is markedly increased with either spinal or supraspinal administration, where its analgesic activity is more than a million-fold greater than morphine.

Binding characteristics of [3H]14-methoxymetopon, a high affinity µ-opioid receptor agonist
   European Journal of Neuroscience Volume 18 Issue 2 Page 290  - July 2003

http://www.blackwell-synergy.com/links/doi/10.1046/j.1460-9568.2003.02744.x/


   To a solution of 7,8-didehydro-4,5-epoxy-3-hydroxy-14-methoxy-5,17-dimethylmorphinan-6-one (14-methoxy-5-methylmorphinon) (Schmidhammer et al., 1990) (1.68 mg, 5.1 µmol) in N,N-dimethylformamide (1 mL) PdO/BaSO4 (9.9 mg) was added. The mixture was stirred for 80 min in the presence of 555 GBq (15 Ci) of 3H2 and diisopropylethylamine (3.5 µL) at room temperature in a closed vacuum manifold (Tóth et al., 1996). The excess of 3H2 was removed by absorption on pyrophoric uranium. The catalyst was filtered off by use of a Whatman GF/C glass fibre filter. The labile 3H2 was removed by repeated evaporation with ethanol : water (1 : 1) affording 115 mCi of crude product. Purification of 60 mCi of the crude product by thin layer chromatography (Merck Kieselgel 60 F254 plate; eluent - dichloromethane : methanol : concentrated ammonia, 90 : 9 : 1) yielded 30.2 mCi of [15,16-3H2]-14-methoxymetopon with a specific radioactivity of 15.9 Ci/mmol and a purity of >95%.

Intrinsic efficacy and addiction to opioids
   European Neuropsychopharmacology Volume 5, Issue 3 , September 1995, Page 403

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T26-4293HTX-RV&_coverDate=09%2F30%2F1995&_alid=133771035&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4910&_sort=d&view=c&_acct=C000000152&_version=1&_urlVersion=0&_userid=112642&md5=c7710df33addf01f827fc6355af75135


   Tolerance to opiods is measured after 8 weeks for Fentanyl, 14-Methoxymetopon, morphine and 6-azido-dihydroisomorphine.  Morphine developed 3 times more tolerance than the other 3 drugs.

Biochemical and Pharmacological Characterization of Highly Potent Novel Opioid Agonists in the 14-Alkoxymetopon Series
   Eur. J. Pharmacol. 236: 209-215, 1993.

Opioid Binding Characteristics of 14-Alkoxy Derivatives of Methylmorphinan-6-ones
   Analgesia 1995, 1, 590.

Characterisation of 14-O-Ethyl-5-methylnaltrexone: A Novel Opioid Receptor Antagonist
   Br. J. Pharmacol. 109, 99 (1993)

Highly potent novel opioid receptor agonist in the 14-alkoxymetopon series
   European Journal of Pharmacology Volume 236, Issue 2, 19 May 1993, Pages 209-215

http://dx.doi.org/10.1016/0014-2999%2893%2990591-5


   The newly synthesized 14-alkoxymetopon derivatives, 14-methoxymetopon, 14-methoxy-5-methylmorphinone, exhibit high affinity for the naloxone binding sites in rat brain. A substantial decrease in affinity was observed, in the presence of NaCl indicating a high degree of agonist activity. All three 14-alkoxymetopon derivatives displayed high affinity for [3H][D-Ala2,(Me)Phe4,Gly-ol5]enkephalin ([3H]DAMGO) binding sites, much less potency toward  sites and were the least effective at  sites. Isolated tissue studies using the guinea pig ileum preparation confirmed their high agonist potency. Following administration the new compounds produced naloxone reversible antinociceptive effects and were 130–300 times more potent than morphine in the acetic acid induced abdominal constriction model in the mouse, and the hot plate and tail flick tests in the rat. The compounds also produced dose-dependent muscle rigidity, and potentiated barbiturate-induced narcosis. The in vivo apparent pA2 values for naloxone against 14-ethoxymetopon and morphine were similar in analgesia, suggesting an interaction with the same () receptor site. The dependence liability of 14-alkoxymetopon derivatives in the withdrawal jumping test was less pronounced than that of morphine in either rats or mice, similar to tolerance to the their analgesic action. It is concluded that the 14-alkoxymetopon derivatives studied are selective and potent agonists at  opioid receptors, with reduced dependence liability.

Self-administration of 14-Methoxymetopon in rats
   European Opioid Conference Uppsala, Uppsala, 2002

Effects of 14-methoxymetopon, a potent opioid agonista, on the responses to the tail electric stimulation test and plus-maze activity in male rats.
   Brain Res. Bull. 57, 661-6

Signal transduction efficacy of the highly potent mu opioid agonist 14-methoxymetopon

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10809184&dopt=Abstract


   Life Sci. 2000 Mar 31;66(19):1871-7.

Synthesis data:

Patent US4362733


   14-alkoxymorphinans including a step by step procedure of methylation using methyl iodide and sodium hydride (Same as: EP0068382, CA1170654, JP58008068, DE3262036D)
Why this is important:
   This means that one could treat 14-hydroxycodeinone with methyl iodide and sodium hydride, then hydrogenate to get the codeinone version of 14-methoxy-oxymorphone.
   One could then demethylate this at the 3 position to get 14-methoxy-oxymorphone.
   Could one treat oxymorphone (made from morphine obtained from pods) with https://www.thevespiary.org/rhodium/Rhodium/chemistry/methyliodide.html&quot%3B&gt%3Bmethyl

iodide and sodium hydride yielding 14-methoxy-oxymorphone?
   This would increase the potency of morphine 400X in 3 steps...

Patent US4272540


   (Page 3): 14-hydroxycodeinone is treated with methyl iodide and sodium hydride to give 14-methoxycodeinone

http://www.pharmcast.com/Patents/Yr2003/Mar2003/030403/6528520_Coronary030403.htm

References the above patent
Why this is important:
   Most straightforward description of addition of 14-O-methyl group

Patent US4045440


   J. Med. Chem. 18:1074-1076 (November 1975).
   Producing the O-6 methyl ethers from codeine and morphine using potassium hydride and methyl iodide as the O-alkylation agents
   This was then oxidized with Gamma MnO2 to Thebaine
   Codeine -> O-6 methyl ether using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
   Morphine -> Heterocodeine using only Methyl iodide
Why this is important:
   It suggests that Sodium hydride may be replaced or omitted (when considered with the following patent

Patent WO0056735

)

Patent WO0056735


   The first step of the process involves protection of the parent morphinan compound by synthesis of the phenolic 3-methyl ether analog, except in the case of oxycodone or codeine, which start with a methyl ether at the 3 position (R1 is CH3).  Thus schema A shows the starting material where R1 of Formula 1 is H.  This is accomplished by reactin gthe free base of the parent compound with a methylating agent in the presence of a base in a suitable organic solvent as shown in Schema A.  The methylating agent may be a typical methylating agent, such as dimethyl sulfate, methyl iodide, methyl trifluoromethane sulfonate, methyl para-toluene sulfonate or methyl bromide.  The base may be an amine, a trialkylamine, sodium hydride, lithium diisopropyl amide (LDA), a strong inorganic base such as NaOH, or a weaker base such as a carbonate (Na, Li, Cs, K, Ca, Mg, Ba). The solvent may be any suitable non-reactive, preferably polar, organic solvent, DMF is a preferred organic solvent.
Why this is important:
   If a morphinan is methylated using these methods it will form the 3-methyl ether, except for oxycodone and codeine which are methylated elsewhere (14-methyl ether?) (see pg 6)

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 1. Highly Potent Opioid Agonists in the Series of (-)-14-Methoxy-N-methylmorphinan-6-ones
   J. Med. Chem. 1984, 27, 1575

http://pubs.acs.org/cgi-bin/archive.cgi/jmcmar/1984/27/i12/pdf/jm00378a009.pdf


   This article has been sent to rhodium for inclusion in his site.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6094809&dopt=Abstract

J Med Chem. 1984 Dec;27(12):1575-9
   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.
Why this is important:
   O-methylation in position 14, was accomplished with dimethyl sulfate; 14-Methoxy-Oxymorphone (#15) is 400X morphine, with reduced respiratory depression.

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 8. 14-Methoxymetopon, an Extremely Potent Opioid Agonist
   Helv. Chim. Acta 1990, 73, 1784-1787

https://www.thevespiary.org/rhodium/Rhodium/pdf/14-methoxymetopon.pdf


   14-Methoxymetopon (=5,14-O-dimethyloxymorphone; 4) and 14-ethoxymetopon (5) were synthesized from 14-hydroxy-5-methylcodeinone (6).In the AcOH-writhing test in mice, compound 4 was found to be ca. 20000 times more potent than morphine.
Why this is important:
   This is the first synthesis of 14-methoxymetopon and 14-ethoxymetopon and includes experimental details of many steps.

Synthesis of opioid receptor ligands in the 14-Alkoxymorphinan Series

http://www.arcs.ac.at/dissdb/rn038996

(if its down use google cache, or web.archive.org)

14-Alkoxymorphinans - a Series of Highly Potent and Selective Opioid Agonists and Antagonists
   Current Topics in Med. Chem. 1993, 1, 261.

So to summarize, 14-methoxy-metopon is oxymorphone, with a 14-O-methyl group added and a 5-methyl group added.
The 14-methoxy group may be added one of the following ways:
   Methyl Iodide and sodium hydride
   Methyl Iodide and potassium hydride
   Methyl iodide in alkaline solution
   Dimethyl Sulfate (Dont forget

Post 478120

(Vitus_Verdegast: "To avoid having to make DMS", Methods Discourse)
for substitutes)
These may be replaced with their ethyl versions to create 14-ethoxy-metopon.

My next posts will include a list of references regarding the 5-methylation of the morphinan skeleton, many novel 3-demethylation reactions for opiates (codone->morphone & codeine->morphine) including some OTC ones, an extraction of thebaine from poppy pods so simple mother nature could do it, an extraction of morphine from pods, and a comprehensive list of all possible routes within this branch of opiate chemistry.

Disclaimer: I am not a chemist, I have spent many hours researching this out of curiosity.

BieneMaya

  • Guest
Thanks a lot, merbst for this great research.
« Reply #1 on: December 28, 2003, 01:24:00 AM »
Thanks a lot, merbst for this great research.
Never heard of these opioids before.

I also read your thread about alternative
hydrogeneration of 14- hydroxycodeinone
which was also great.
Next time I`ll give it a try. Did dope_amins version of oxycodon synthesis first with little success.

Nice to have another very interested member in opioid chemistry in this forum.
Cause it seems that not much of us are present here.

merbst

  • Guest
More information
« Reply #2 on: December 28, 2003, 02:56:00 AM »
I forgot to mention in the first post that it also seems that any opiate can be 14-methoxylated or 14-ethoxylated yielding a more potent compound.  Although the most studied compounds seem to be the derivatives of oxymorphone.  This may turn out to be extremely useful in conjunction with

Post 471554

(merbst: "14-hydroxycodeinone -> oxymorphone !!!", Methods Discourse)
my post in the methods forum regarding converting 14-hydroxycodeinone directly to oxymorphone. This would allow:
Step 1 - codeine phosphate to codeine freebase
Step 2 - codeine freebase to 14-hydroxycodeineone
Step 3 - 14-hydroxycodeinone to oxymorphone
Step 4 - oxymorphone to 14-methoxy-oxymorphone

For a realistic facile 4000X potency increase of codeine.
I will post in the near future references which indicate to me that it may be possible to use a more OTC acid such as HI or HCl in place of HBr in this reduction.

merbst

  • Guest
Some references are now up on Rhodium's site
« Reply #3 on: December 29, 2003, 08:51:00 AM »
Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 1. Highly Potent Opioid Agonists in the Series of (-)-14-Methoxy-N-methylmorphinan-6-ones
J. Med. Chem. 1984, 27, 1575

https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/1%20-%20Highly%20Potent%20Opioid%20Agonists%20in%20the%20Series%20of%2014-Methoxy-N-methylmorphinan-6-ones.pdf



Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 14. 14-Ethoxy-5-methyl Substituted Indolomorphinans with mu Opioid Receptor Selectivity
Bioorg. Med. Chem. Lett. 1997, 7, 151.

https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/14%20-%20ethoxymetopon.pdf



Behavioural effects of some non-quaternary ionisable derivatives of 14-methoxymetopon in rats
Addiction S392 P.5.017

https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/14-methoxymetopon-less-abusable-ha.pdf



Effects of 14-methoxymetopon, a potent opioid agonista, on the responses to the tail electric stimulation test and plus-maze activity in male rats.
Brain Res. Bull. 57, 661-6

https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/merbst/14-methoxymetopon%20on%20tail%20electric%20and%20plus%20maze.pdf



Could some kind mod please allow me to tidy up the post at the top by fixing some links, and adding some more references?

Yoff

  • Guest
a bit doubt about potency
« Reply #4 on: March 09, 2004, 06:53:00 PM »
The quote from the PDF entitled “Biological evaluation of compounds for their physical dependence potential and abuse liability...”: “NIH 10968 in table 2, 14-methoxymetopon, was found to be a potent and fairly selective µ-agonist. It was about fifty times more potent than morphine in the monkey single-dose-suppression assay, and had about that potency in antinociceptive assays as well. This potency is somewhat less than noted in the literature as determined from an acetic acid writhing antinociceptive assay (Schmidhammer et al., 1990 )…” So, 14-methoxy group seems to be not as dramatic increased potency as this is described in Schmidhammer’s PDFs above.
And there is another simple group (6-methylene-) increases potency 70-fold, but I have no any data about possibly changes in selectivity and affinity which appeared after such ones in molecule. So, I would be very grateful for any info. As far as I know there is only one 6-methylene compound on the market – nalmefene (Revex), is a 6-methylene analogue of naltrexone. Nalmefene has the advantage over naltrexone of being less hepatotoxic. If its dosage for the treatment of alcohol craving would be enough high to be worthy to deal with, Revex would be great candidate for N-demethylation, then phenethylation…

scarmani

  • Guest
Other Opoids with Interesting Activity Profile
« Reply #5 on: March 17, 2004, 12:13:00 PM »
Identification of Opioid Ligands Possessing Mixed µ Agonist/delta Antagonist Activity among Pyridomorphinans Derived from Naloxone, Oxymorphone, and Hydromorphone
Subramaniam Ananthan, Naveen K. Khare, Surendra K. Saini, Lainne E. Seitz, Jeffrey L. Bartlett, Peg Davis, Christina M. Dersch, Frank Porreca, Richard B. Rothman, and Edward J. Bilsky

J. Med. Chem. 2004, 47(6), 1400-1412 (2004)

(http://www.streamload.com/scarmani/Opioids/Identification_of_Opioid_Ligands_Possessing_Mixed_Agonist_Antagonist_Activity_among_Pyridomorphinans_Derived_from_Naloxone_Oxymorphone_and_Hydropmorphone.pdf)

DOI:

10.1021/jm030311v



.

Abstract:

A series of pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone (7a-k) were synthesized and evaluated for binding affinity at the opioid mu, delta, and kappa receptors in brain membranes using radioligand binding assays and for functional activity in vitro using [35S]GTP-gamma-S binding assays in brain tissues and bioassays using guinea pig ileum (GPI) and mouse vas deferens (MVD) smooth muscle preparations.  The pyridine ring unsubstituted pyridomorphinans possessing the oxymorphone and hydromorphone framework displayed nearly equal binding affinity at the mu and delta receptors.  Their affinities at the kappa site were nearly 10-fold less than their binding affinities at the mu and delta sites.  Introduction of aryl substituents at the 5'-position on the pyridine ring improved the binding affinity at the delta site while decreasing the binding affinity at the mu site.  Nearly all of the ligands possessing an N-methyl group at the 17-position with or without a hydroxyl group at the 14-position of the morphinan moiety displayed agonist activity at the mu receptor with varying potencies and efficacies.  In the [35S]GTP-gamma-S binding assays, most of these pyridomorphinans were devoid of any significant agonist activity at the delta and kappa receptors but displayed moderate to potent antagonist activity at the delta receptors.  In antinociceptive evaluations using the warm-water tail-withdrawal assay in mice, the pyridomorphinans produced analgesic effects with varying potencies and efficacies when administered by the intracerebroventricular route.  Among the ligands studied, the hydromorphone-derived 4-chlorophenylpyridomorphinan 7h was identified as a ligand possessing a promising profile of mixed mu agonist / delta antagonist activity in vitro and in vivo.  In a repeated administration paradigm in which the standard mu agonist morphine produces significant tolerance, repeated administration of the mu agonist / delta antagonist ligand 7h produced no tolerance.  These results indicate that appropriate molecular manipulations of the morphinan templates could provide ligands with mixed mu agonist / delta antagonist profiles and such ligands may have the potential of emerging as novel analgesic drugs devoid of tolerance, dependence, and related side effects.