4-(6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-yl)-2-piperazine-carboxamide derivatives useful for inhibition of farnesyl protein transferase

摘要

A 4-(6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-yl)-2-pipera zine-carboxamide derivative or a pharmaceutically acceptable salt or solvate thereof has the formula (1.0) wherein: a is N or NO-; Ra, Rb, Re and Rd are independently halo, alkyl or alkoxy provided that at least one, but not more than two of Ra, Rb, Re and Rd are H; the dotted line (---) is an optional double bond; R is H, -C(O)-CH2-O-(CH2)2-O-CH3, -S(O)2R1, -S(O)2NR1R2, -C(O)R1 or -C(O)NR1R2; R1 and R2 are independently H, optionally substituted alkyl, aryl, arylalkyl, triazolyl, 2-, 3- or 4-pyridyl or pyridyl N-oxide, heteroarylalkyl, cycloalkyl, cycloalkylalkyl or heterocycloalkyl; Re and Rf are independently H or optionally substituted alkyl, alkyloxyalkyl, aryl, arylalkyl, triazolyl, alkyloxyalkyloxyalkyl, 2-, 3- or 4-pyridyl or pyridyl N-oxide, imidazole, cycloalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkyl or Re is H, alkyl or aryl and Rf is -(CH2)n-R15 or Re and Rf together with the nitrogen to which they are bound form an optionally substituted piperidine or pyrrolidine; n is 0 to 8; R15 is C(O)NH2, -SO2NH2, benzodioxoxlyl or optionally substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl or R15 is -C(A)-B NR16R17; B is OH or NH2; A is NH, O, NOH or NCN; R16 is H or alkyl; R17 is H, alkyl, SO2CH3 or C(O)NH2 and Rh is H or =O; provided that when Rh is H and Rb and Rd are both H then Re is H and Rf is a group of formula (2) and heteroaryl alone or as part of heteroarylalkyl is a 5 or 6 membered heterocyclic having at least one heteroatom N, S or O. A pharmaceutical composition thereof is useful for inhibiting the abnormal growth of cells such as tumor cells expressing an activated ras oncogene specifically pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, or colon tumor cells.