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| Trade names | Ketogan |
| Other names | Ketobemidone, Cliradon, Cymidon, Ketogan, Ketorax |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration | By mouth,rectal,intravenous |
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| Pharmacokinetic data | |
| Bioavailability | 34~40% (oral), 44% (rectal) |
| Eliminationhalf-life | 2–4 hours |
| Duration of action | 3–5 hours |
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| ECHA InfoCard | 100.006.748 |
| Chemical and physical data | |
| Formula | C15H21NO2 |
| Molar mass | 247.338 g·mol−1 |
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Ketobemidone, sold under the brand nameKetogan (a mixture of ketobemidone andSpasmolytic A29) among others, is a powerfulsynthetic opioidpainkiller. Its effectiveness against pain is in the same range asmorphine, and it also has someNMDA-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 inDenmark,Iceland,Norway. Until 2024 it was available in, but is now withdrawn inSweden. It is used for severe pain.[3]
Ketobemidone was first synthesized in 1942 by Eisleb and colleagues,[4] at the laboratory ofI.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]
Pfizer manufactures ketobemidone under the tradenames Ketogan and Ketorax. It is available astablets,suppositories, and injection fluid. A sustained release formulation, sold as Ketodur, exists in some countries and contains 10 or 25 mg ketobemidone.
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,[7] 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 foreuphoria 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 theScandinavian countries, withDenmark topping the statistics.[9]
Analgesia after 5-10mg orally or 5–7.5 mgintravenously lasts 3–5 hours. Ketobemidone is also available in preparations with aspasmolytic, which can improve the analgesia.
Ketobemidone is mainly metabolized byconjugation of the phenolic hydroxyl group, and byN-demethylation. Only about 13-24% is excreted unchanged after intravenous administration.[10]
Ketobemidone is 1-methyl-4-(3-hydroxyphenyl)-4-propionylpiperidine. It is usually available as thehydrochloride, which is a white powder. It is synthesized by alkylating (3-methoxyphenyl)acetonitrile withbis(2-chloroethyl)methylamine, followed by reaction withethylmagnesium bromide, and finally O-demethylation withhydrobromic 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] (forN,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.
