Analogues of 1-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta[1,2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase

The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo- 6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]-pyridin-11-yl)piperazine/piper idine 3 is described. This study was aimed at identifying fomesyl protein t ransferase (FPT) inhibitors in these two series of tricycles containing dif ferent phenyl ring substituents. The in vitro activity profile of the initi al group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers o f these compounds were found to exhibit potent in vitro FPT inhibition acti vity. (C) 1999 Elsevier Science Ltd. All rights reserved.