INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE - 4-AMIDO, 4-CARBAMOYL, AND 4-CARBOXAMIDO DERIVATIVES OF ENZO[5,6]CYCLOHEPTA[1,2-B]PYRIDIN-11-YL)PIPERAZINE AND ENZO[5,6]CYCLOHEPTA[1,2-B]PYRIDIN-11-YL)PIPERAZINE

The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxa mido derivatives of 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin -11-yl)piperazine to explore the SAR of of this series of FPT inhibit ors is described. This resulted in the synthesis of the 4- and 3-pyrid ylacetyl analogues 45a and 50a, respectively, both of which were orall y active but were found to be rapidly metabolized in vivo. Identificat ion of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interes ting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. No vel replacements for the pyridylacetyl moiety were also sought, and th is resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopipe ridinylacetyl derivatives 135a and 160a, respectively. All of these de rivatives exhibited greatly improved pharmacokinetics. The synthesis o f the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxa midopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioav ailability in vivo in nude mice and cynomolgus monkeys and exhibited e xcellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.