Thietane derivatives containing phenyl and dime thylaminomethyl substituents were synthesized as potential narcotic analgetics of the methadone type. These compounds which are structurally derived from the sulfone analogue of methadone by joining 0-2 to C-5, are conformationally more restricted than methadone and thus may he useful in elucidating the conformation of methadone when bound to its receptor (pharmacophoric conformation).
The photocycloaddition reaction of thiobenzo-phenone and an appropiate olefinic nitrile provided 2,2-diphenyl-3-cyanothietane, cis-2,2-diphenyl-3-cyano-4-methylthietane and trans-2,2-diphenyl-3-cyano-4-methyl-thietane, cis-2,2-diphenyl-3-methyl-4-cyanothietane and trans-2.2-diphenyl-3-methyl-4-cyanothietane. Treatment of the first three thietane derivatives with m-chloroper-oxybenzoic acid gave 2,2-diphenyl-3-cyanothietane 1,1-dioxide, cis-2,2-diphenyl-3-cyano-4-niethylthietane 1-oxide, cis-2,2-diphenyl-3-cyano-4-methylthietane 1,1-dioxide and trans-2,2-diphenyl-3-cyano-4-methylthietane 1,1-dioxide. Submitting the cyanothietane 1,1-dioxides to hydroboration reduction gave the corresponding primary amines which were catalytically dimethylated with formaldehyde at room temperature to give 2,2-diphenyl-3-dimethylaminomethylthietane 1,1-dioxide, cis-2,2-diphenyl-3-dimethylaminome thyl-4-me thylthietane 1,1-dioxide and trans-2,2-diphenyl-3-dimethylaminome thyl-4-me thylthietane 1,1-dioxide.
Two attempts to synthesize the precursors of thietane derivatives containing a dimethylaminomethyl side chain attached to the carbon ⍺ to the sulfonyl group gave unexpected results. The reaction of β-chloroethanesulfonyl chloride and β-dimethylaminostyrene generated an acyclic sulfone, ⍺-(vinylsulfonyl)-β-dimethylaminostyrene, instead of the expected cyclic adduct, 2-phenyl-3-dimethyl-amino-4-chloromethylthietane 1,1-dioxide. The reported reaction of methoxyallene and thiobenzophenone to give 2,2-diphenyl-3-methoxy-4-methylenethietane was found to proceed in a different course. The reaction was proved to occur thermally as opposed to a photochemical reaction.
During the course of the studies, several reactions were performed on 2,4-diphenylthiete 1,1-dioxide with a hope of generating 2,4-diphenylthietan-3-one 1,1-dioxide for antiinflammatory studies:
Treating 2,4-diphenylthiete 1,1-dioxide with sodium hydroxide resulted in the cleavage of the thietane ring and formation of dibenzyl sulfone. The expected product, 2,2-diphenyl-3-hydroxythietane 1,1-dioxide was likely formed but rapidly underwent ring cleavage to give dibenzyl sulfone.
The reaction of 2,2-diphenylthiete 1,1-dioxide with concentrated sulfuric acid resulted in formation of two rare compounds, 3,c-5-diphenyl-1,r-2-oxathiacyclo-penta-3-ene 2-oxide and 3,t-5-diphenyl-1,r-2-oxathiacyclopenta-3-ene 2-oxide. This reaction did not occur with 2-phenylthiete 1,1-dioxide and 2-phenyl-4-methylthiete 1,1-dioxide.
Hone of three compounds tested showed significant analgesic activity in an in vitro experiment based on the inhibition of the contractions of electrically stimulated guinea-pig ileum by narcotic analgetics. In an in vivo experiment, the compounds were also unable to modify the pain threshold of a rabbit towards electrical stimulation on tooth-pulp. The results indicate the exacting requirement for binding of methadone to the narcotic receptor. / Pharmaceutical Sciences, Faculty of / Unknown
| Identifer | oai:union.ndltd.org:UBC/oai:circle.library.ubc.ca:2429/21625 |
| Date | January 1978 |
| Creators | Leung, Chun-Cheung |
| Source Sets | University of British Columbia |
| Language | English |
| Detected Language | English |
| Type | Text, Thesis/Dissertation |
| Rights | For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. |
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