10-Oxo-Morphinans as Potential Kappa Selective Analgesics

Henderson, Calum Fraser (1993) 10-Oxo-Morphinans as Potential Kappa Selective Analgesics. PhD thesis, University of Glasgow.

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Ethylketocyclazocine (EKC), a benzomorphan drug with a 10-oxo group, binds preferentially to kappa opiate receptors. The aim of the present research was to introduce a 10-oxo group into known, potent, mu-selective, morphinan analgesics and possibly thereby obtain kappa-selectivity. It was hoped that this might cause separation of analgesia from the well documented side effects associated with mu receptors. The benzylic, 10-oxo group was introduced by making use of an unusual reaction of thebaine. Thebaine was known to react with tetranitromethane, in benzene in the presence of oxygen, to form a bridged peroxide, 8alpha,10alpha-epidioxy-8,14-dihydro-14beta-nitrothebaine. This readily isomerises in the presence of base to give the 10-oxo alcohol, 8,14-dihydro-8beta-hydroxy-14beta-nitro-10-oxothebaine. In the present study the yield of the epidioxide was increased from 29% to 72% by conducting the nitration in the presence of ammonia gas to ensure complete reaction of the thebaine. It was further found that the epidioxide rearranged on Grade I alumina to give an isomeric acetal in which a peroxide oxygen had inserted into the C(7)-C(8) bond. The epidioxide was first deoxygenated with triphenylphosphine to give the known 14beta-nitro-8alpha,10alpha-epoxide, which was then reduced with zinc and ammonium chloride to yield the corresponding 14beta-amino derivative. The aim was to use this new derivative as starting material for the preparation of 10-oxygenated analogues of a known series of potent analgesics, the 14beta-acylamino-codeinones and -morph-inones. Accordingly, the 14beta-amino-8alpha,10alpha-epoxide was converted into a series of 14beta-acylamino compounds. The most potent of these, the N-3-phenylpropanoyl derivative, underwent ring opening with aqueous or methanolic hydrogen chloride to give 10alpha-hydroxy-14beta-(3-phenylpropanoylamino)codeinone and the corresponding dimethyl acetal, respectively. Oxidation of the former gave the corresponding 10-oxo-codeinone. However, this 10-oxo analogue of 14beta-(3-phenylpropanoyl-amino)codeinone was much less potent than the parent 10-methylene compound, and less potent even than normorphine. No kappa-selectivity was observed. The only compounds to show any measurable kappa activity were the 4-chloro- and 4-methyl-cinnamoyl derivatives of the 14beta-amino-8alpha,10alpha-epoxide. Thevinols, produced by Grignard reactions of thevinone, the Diels-Alder cycloadduct of thebaine and but-3-en-2-one, are very potent analgesics. It was hoped that 10-oxo derivatives of thevinols might be potent, kappa-selective compounds. 10-oxothebaine, a new derivative of wider synthetic potential, was synthesised in the following way. The epidioxide was converted with sodium ethoxide into the 10-oxo alcohol, described earlier. The 14beta-nitro group was removed reductively with tributyltin hydride and the resulting alcohol was dehydrated with phosphorus oxychloride to give 10-oxothebaine. As expected, this diene reacted with but-3-en-2-one to give 10-oxothevinone.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: G W Kirby
Keywords: Pharmacology
Date of Award: 1993
Depositing User: Enlighten Team
Unique ID: glathesis:1993-74853
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Sep 2019 15:50
Last Modified: 27 Sep 2019 15:50
URI: http://theses.gla.ac.uk/id/eprint/74853

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