Synthesis of 8-chloro-benzo[c]quinolizin-3-ones as potent and selective inhibitors of human steroid 5alpha-reductase 1

The synthesis of a series of differently substituted 8-chloro-benzo[c]quinolizin-3-ones, as potent and selective human steroid 5alpha-reductase type 1 inhibitors, has been accomplished by a four-step procedure based on the TiCl4-promoted tandem Mannich-Michael cyclization of 2-silyloxy-1,3-butadienes with N-t-Boc iminium ions from quinolin-2-ones. The presence on the benzo[c]quinolizinone nucleus of a methyl group and a double bond at positions 6 and 4-4a, respectively, as in compound 1d, gave rise to one of the most potent non-steroidal 5alphaR-1 inhibitors reported so far (IC50 = 14 nM).