Synthesis and aromatase inhibitory activity of novel 1-(4-aminophenyl)-3-azabicyclo[3.1.0[hexane- and -[3.1.1]heptane-2,4- diones

Article abstract of DOI:10.1021/jm00108a013

The synthesis of 3-(cyclohexylmethyl)-1-(4-aminophenyl)-3-azabicyclo [3.1.0]hexane-2,4-dione (1h), with its optical enantiomers, and a series of novel achiral 1-(4-aminophenyl)-3- azabicyclo[3.1.1]haptane-2,4-diones (2a-i,k) is described. These compounds were tested in vitro for inhibition of human placental aromatase, a cytochrome-P₄₅₀-dependent enzyme responsible for the conversion of androgens to estrogens. All of them displayed enzyme-inhibiting activity, and 3-cyclohexyl derivative 2g and 3-cyclohexylmethyl derivative 1h both proved more potent (>140-fold) than the clinically effective agent aminoglutethimide [3-(4-aminophenyl)- 3-ethylpiperidine-2,6-dione, AG]. As with AG and its derivatives, the 1R-(+)-enantiomer of 1h was responsible for the enzyme inhibitory activity. These novel compounds are of interest as potential drugs for endocrine therapy of hormone-dependent tumors, e.g. breast cancer.