Useful tricyclic amide in the treatment of proliferative diseases and inhibition of protein function G-

摘要

81 Specific tricyclic amides and their salts are claimed e.g. (1.0). In an example a solution of 3-bromo-8-chloro-11-piperidin-4-yl-11H-benzo[5,6]cyclohepta[1,2-b]pyridine (1.16 g) in DMF (20 ml) was treated with 4-methylmorpholine (0.3914 g), DEC (0.7418 g), HOBT (0.5229 g) and 1-N-tert-butoxycarbonyl-piperidinyl-4-acetic acid (0.8795 g) for 2 days. The residue was purified by chromatography to give 1.72 g (A). 1.67 g (A) in CH2Cl2 (20 ml) at 0 deg C was stirred with trifluoroacetic acid (20 ml) for 2 hours. 1 M NaOH was added (A) and extracted with CH2Cl2. The organic phase gave 1.16 g (B). 0.5 g (B) in CH2Cl2 (20 ml) was treated with Me3SiNCO (4.5 equivalents). The residue was purified to give 0.26 g 4-{2-[4-(3-bromo-8-chloro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-piperidin-1-yl]-2-oxo-ethyl}-piperidin-1-carboxylic acid amide. The product showed an IC50 for inhibition of farnesyl protein transferase of less than 0.034 ~mM. The compound also showed an IC50 for inhibition of tumour cell growth of less than 1.6 ~mM.