Analogs of 4-(3-bromo-8-methyl-10-methoxy-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidine N-oxide as inhibitors of farnesyl protein transferase

A series of 3-substituted analogs 3 of 4-(3-bromo-8-methyl-10-methoxy-6,11- dihydro-5H-benzo[5,6]-cyclohepta[1,2b]pyridin-11-yl)-1-(4-pyridinylacetyl)p iperidine N-oxide 2 was prepared and evaluated as FPT inhibitors. The objec tive of this study was to identify other substituents at C-3 in this series of FPT inhibitors that would have the FPT potency enhancement similar to t hat found for a C-3 bromo substituent. The 3-methyl analog 17b was found to be tenfold less active than 2, and other C-3 substituents having more ster ic bulk were found to cause a further reduction in activity, (C) 1999 Elsev ier Science Ltd. All rights reserved.