The design and synthesis of novel tacrine analogues
From the basic structure of 9-amino-1,2,3,4-tetrahydroacridine (36), was designed a range of analogues. These compounds were synthesised using a Lewis acidmediated cyclodehydration reaction involving anthranilonitrile (150) and various 1-tetralones. 1-benzosuberones and 2-benzosuberone. Heterocyclic ketones such as 7-chloro-1,2,3,4-tetrahydroquinolines, 1,2,3,4-tetrahydrobenzazepinones and 1,2,3,4,5,6-hexahydrobenzazocinone were also substituted into the reaction to produce novel heterocycles. Their protected nitrogen moieties were detosylated with sodium naphthalenide. Bridged tacrine analogues were investigated using norcamphor (210) and R(+)-camphor (212). All the resultant products were subjected to pharmacological assay and from inspection of the results further molecular design was possible. Synthetic routes were extended to include imine and enamine intermediates. In particular, N-(4-methyl-5-oxo-cyclopenten-1-y1)-2-aminobenzonitrile (263a) was an important enamine intermediate which cyclised to give 9-amino-2,3-dihydro-2,3-disubstituted-3-hydroxy-[1H]-cyclopenta-[b]quinolines with use of organolithium reagents. These were dehydrated to their respective alkenes. This cyclisation was further investigated with the use of vinyl anions produced by the Shapiro reaction. Compounds were produced which showed activity as anticholinesterase agents and 5-HT uptake inhibitors.