Ketobemidone

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Ketobemidone
Clinical data
Trade namesKetogan
Other namesKetobemidone, Cliradon, Cymidon, Ketogan, Ketorax
AHFS/Drugs.comInternational Drug Names
Routes of
administration		By mouth, rectal, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability34~40% (oral), 44% (rectal)
Elimination half-life2–4 hours
Duration of action3–5 hours
Identifiers
  • 1-[4-(3-Hydroxyphenyl)-1-methyl-4-piperidyl]propan-1-one
JSmol)
  • O=C(CC)C1(CCN(C)CC1)c2cc(O)ccc2
  • InChI=1S/C15H21NO2/c1-3-14(18)15(7-9-16(2)10-8-15)12-5-4-6-13(17)11-12/h4-6,11,17H,3,7-10H2,1-2H3 checkY
  • Key:ALFGKMXHOUSVAD-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Ketobemidone, sold under the brand name Ketogan among others, is a powerful

NMDA-antagonist properties imparted, in part, by its metabolite norketobemidone.[2] This may make it useful for some types of pain that do not respond well to other opioids.[2] It is marketed in Denmark, Iceland, Norway and Sweden and is used for severe pain.[3]

History

Ketobemidone was first synthesized in 1942 by Eisleb and colleagues,[4] at the laboratory of I.G. Farbenindustrie at Hoechst during the Second World War. The first study of it in humans was published in 1946,[5] and it was introduced in clinical medicine shortly after. It was not in clinical use in the United States when the Controlled Substances Act 1970 was promulgated and was assigned to Schedule I with an ACSCN of 9628. As of 2013, no annual manufacturing quota was assigned by the DEA.[6]

suppositories
, and injection fluid. A sustained release formulation, sold as Ketodur, exists in some countries and contains 10 or 25 mg ketobemidone.

Pharmacology

Experiments on former addicts indicated it was quite addictive and in high doses, compared to other opioids, may have increased abuse potential in former and current opioid addicts. While some effort was first suggested for drafting of a resolution urging governments to stop manufacture and use of ketobemidone,

euphoria is the same as that for analgesia, for ketobemidone the analgesic dose was well below the euphoric dose. Thus, even compared to morphine, ketobemidone may be much more effective without causing significant euphoria and thus having a lower risk of addiction under the supervision of a qualified clinician.[8]
Ketobemidone is mostly used in the Scandinavian countries, with Denmark topping the statistics.[9]

Analgesia after 5-10

intravenously lasts 3–5 hours. Ketobemidone is also available in preparations with a spasmolytic
, which can improve the analgesia.

Metabolism

Ketobemidone is mainly metabolized by

conjugation of the phenolic hydroxyl group, and by N-demethylation. Only about 13-24% is excreted unchanged after intravenous administration.[10]

Chemistry

Ketobemidone is 1-methyl-4-(3-hydroxyphenyl)-4-propionylpiperidine. It is usually available as the

bis(2-chloroethyl)methylamine, followed by reaction with ethylmagnesium bromide, and finally O-demethylation with hydrobromic acid.[11]

Because of a strong vesicant nature of bis(2-chloroethyl)methylamine there are many other routes developed for obtaining ketobemidone. A route depicted below lays through first alkylating the same (3-methoxyphenyl)acetonitrile with 2-chloro-N,N-dimethylethylamine or 2-chloro-N-benzyl-N-methylethylamine.[12] Next, those amines are alkylated once again using a mixed 1-bromo-2-chloroethane, thus completing the piperidine ring and obtaining a quaternary ammonium salt, which can be dequaternized using thiophenol salt[13] (for N,N-dimethylammonium) or catalytic hydrogenation[14] (for both compounds) to a common 4-(3-methoxyphenyl)-4-cyano-1-methyl-pyperidine. The latter yields ketobemidone after Grignard reaction with ethylmagnesium bromide and ether cleavage.

See also

References

  1. ^ https://www.ema.europa.eu/documents/psusa/ketobemidone-list-nationally-authorised-medicinal-products-psusa/0001807/202005_en.pdf [bare URL PDF]
  2. ^
    PMID 9783723
    .
  3. ^ Brayfield A, ed. (9 January 2017). "Ketobemidone Hydrochloride: Martindale: The Complete Drug Reference". MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 6 September 2017.
  4. ^ GB patent 609763, "Manufacture of piperidyl ketones", published 1948-10-06, assigned to Ciba Ltd. 
  5. ^ US patent 2486796, Meischer, K.; Kaegi, H., "Esters of 1-alkyl-4-hydroxyphenyl-piperidil-4-ketones", issued 1949-11-01 
  6. ^ "DEA Diversion Control Division". Archived from the original on 2017-05-14. Retrieved 2014-05-03.
  7. ^ "Development of Synthetic Narcotic Drugs". Bulletin on Narcotic Drugs. 1956 (1): 11–14. 1956. Retrieved 2012-07-05.
  8. ISBN 978-91-554-1243-2. {{cite book}}: |journal= ignored (help
    )
  9. INCB. 2004. Archived from the original
    (PDF) on 2006-10-07. Retrieved 2006-09-07.
  10. PMID 6114838
    .
  11. ISBN 9780815518563
    .
  12. doi:10.1039/JR9500001469
    .
  13. doi:10.1016/s0040-4039(01)99725-4
    .
  14. doi:10.1002/hlca.19490320736
    .

External links

  • "Ketobemidone". Drug Information Portal. U.S. National Library of Medicine.
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