Ketobemidone

Ketobemidone
Clinical data
AHFS/Drugs.com International Drug Names
Routes of
administration		 Oral, rectal, intravenous
ATC code N02AB01 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 34% (oral), 44% (rectal)
Biological half-life 2-4 hours
Identifiers
Synonyms Ketobemidone, Cliradon, Cymidon, Ketogan, Ketorax
CAS Number 469-79-4 N
PubChem (CID) 10101
ChemSpider 9697 YesY
UNII PQS1L514CF YesY
KEGG D08100 YesY
ChEMBL CHEMBL47072 YesY
ECHA InfoCard 100.006.748
Chemical and physical data
Formula C15H21NO2
Molar mass 247.333 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Ketobemidone (Cliradon, Ketogan, Ketodur, Cymidon, Ketorax, &c.) is a powerful opioid analgesic. Its effectiveness against pain is in the same range as morphine, and it also has some NMDA-antagonist properties imparted by its metabolite norketobemidone. This makes it useful for some types of pain that don't respond well to other opioids. The most commonly cited equalisation ratio for analgesic doses is 25 mg of oral ketobemidone hydrobromide to 60 mg of morphine hydrochloride or sulphate and about 8 mg of ketobemidone by injection and 10 mg of morphine.

The UN reported shortly after the beginning of marketing of ketobemidone that it was "nine times more active" than methadone, presumably as a euphoriant,[1] and was thus labelled as extra-dangerous along with dextromoramide ("three times more active than heroin") and several other synthetics about the same time, as expanded upon below.

It is used for all types of severe pain, such as postoperative, cancer, kidney stones and fractures.

History

Ketobemidone was first synthesized in 1942 by Eisleb and colleagues,[2] 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,[3] 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.[4]

Chemistry

Ketobemidone is 1-methyl-4-(3-hydroxyphenyl)-4-propionylpiperidine. It is usually available as the hydrochloride, which is a white powder. It is synthesized by alkylating (3-methoxyphenyl)acetonitrile with bis(2-chloroethyl)methylamine, followed by reaction with ethylmagnesiumbromide, and finally O-demethylation with hydrobromic acid.

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. 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[5] (for N,N-dimethylammonium) or catalytic hydrogenation[6] (for both compounds) to a common 4-(3-methoxyphenyl)-4-cyano-1-methyl-pyperidine. The later yields ketobemidone after grignard reaction with ethylmagnesium bromide and ether cleavage.

The synthesis of ketobemidone according to:[7]

Pharmacology

Experiments on former addicts indicated it was more addictive than other opioids, so in 1954 the Economic and Social Council took a resolution urging governments to stop manufacture and use of ketobemidone.[8] This result was not in agreement with clinical observations, and another study in 1958 did not find it more addictive than morphine. That study noticed that while for morphine the dose for euphoria is the same as that for analgesia, for ketobemidone the analgesic dose was well below the euphoric dose.[9] Ketobemidone is mostly used in the Scandinavian countries, with Denmark topping the statistics.[10]

Analgesia after 5-10 mg orally or 5-7.5 mg intravenously lasts 3–5 hours. Ketobemidone is also available in preparations with a spasmolytic, which can improve the analgesia.

Ketobemidone is mainly metabolised by conjugation of the phenolic hydroxyl group, and by N-desmethylation. Only about 13-24% is excreted unchanged after iv. administration.[11]

Pfizer manufactures ketobemidone under the tradenames Ketogan and Ketorax. It is available as tablets, suppositories and injection fluid. A sustained release formulation exists sold as Ketodur in some countries containing 10 or 25 mg ketobemidone.

See also

References

  1. ↑ Escohotado, pp 93
  2. ↑ GB patent 609763, "Manufacture of piperidyl ketones", published 1948-10-06, assigned to Ciba Ltd.
  3. ↑ US patent 2486796, Meischer, K.; Kaegi, H., "Esters of 1-alkyl-4-hydroxyphenyl-piperidil-4-ketones", issued 1949-11-01
  4. ↑ http://www.deadiversion.usdoj.gov/fed_regs/quotas/2013/fr0620.htm
  5. ↑ "The selective demethylation of quaternary ammonium salts". Tetrahedron Letters. Elsevier. 7 (13): 1375–1379. 1966. doi:10.1016/s0040-4039(01)99725-4. Retrieved 2015-04-29.
  6. ↑ "Über eine neue Synthese morphinähnlich wirkender 4-Phenylpiperidin-4-alkylketone und verwandter Verbindungen". Helvetica Chimica Acta. John Wiley & Sons. 32 (7): 2489–2507. 1949. doi:10.1002/hlca.19490320736. Retrieved 2015-04-29.
  7. ↑ Avison, A. W. D.; Morrison, A. L. (1950). "303. Synthetic Analgesics. Part VI. The Synthesis of Ketobemidone". Journal of the Chemical Society (Resumed). 1950: 1469–1471. doi:10.1039/JR9500001469.
  8. ↑ "Development of Synthetic Narcotic Drugs". Bulletin on Narcotic Drugs. UNODC. 1956 (1): 11–14. 1956. Retrieved 2012-07-05.
  9. ↑ Bondesson, U. (1982). "Biological Fate of Ketobemidone in Man". Abstracts of Uppsala Dissertations from the Faculty of Pharmacy. 68. ISBN 91-554-1243-2.
  10. ↑ "Statistical Information on Narcotic Drugs" (pdf). INCB. 2004. Retrieved 2006-09-07.
  11. ↑ Bondesson, U.; Hartvig, P.; Danielsson, B. (1981). "Quantitative Determination of the Urinary Excretion of Ketobemidone and four of its Metabolites after Intravenous and Oral Administration in Man". Drug Metabolism and Disposition. 9 (4): 376–380. PMID 6114838.
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