New polyaza-benzo-azulene compounds are transforming growth factor-beta receptor kinase inhibitors used for treating e.g. cancer, HIV infection and Alzheimer's disease

摘要

76 named polyaza-benzo[e]azulene compounds (A), are new. 76 Polyaza-benzo[e]azulene compounds (A), their derivatives, solvates, salts, tautomers and stereoisomers, including mixtures, are new: e.g. (R,S)-8-hydroxy-4-methyl-1-(6-methylpyridin-2-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-1-(3-chlorophenyl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-8-ol; (R,S)- or (+)-(S)-8-chloro-4-methyl-1-(6-methylpyridin-2-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-methoxy-4-methyl-1-(6-methylpyridin-2-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; 1-(6-methylpyridin-2-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-8-ol; (R,S)-1-(5-chloro-2-fluorophenyl)-8-(methoxy or hydroxy)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-4-methyl-1-(3-(CF 3or ethoxy)phenyl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S) -1-(3-bromophenyl)-8-chloro-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; 1-(2-chloropyridin-4-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-1-(2,5-dichlorophenyl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (-)-(R)-8-chloro-4-methyl-1-(6-methylpyridin-2-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-1-(5-chloro-2-fluorophenyl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-1-[8-chloro-4-methyl-1-(6-methylpyridin-2-yl)-4,5-dihydro-2,3,6,10b-benzo[e]azulen-6-yl]ethanone; (R,S)-4-methyl-1-pyridin-2-yl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-8-ol; (R,S)-1-(3-hydroxyphenyl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-8-ol; (R,S)-1-(3-chlorophenyl)-8-methoxy-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-methoxy-4-methyl-1-pyridin-2-yl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-1-(3-chlorophenyl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-4-methyl-1-pyridin-2-yl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; 8-chloro-1-(6-methylpyridin-2-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; 1-pyridin-2-yl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-8-ol; 8-methoxy-1-(6-methylpyridin-2-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; 3-(8-chloro-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-1yl)phenol; 1-(3-hydroxyphenyl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-8-ol; 8-chloro-1-(3-methoxyphenyl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; 8-chloro-1-(pyridin-2-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; 8-methoxy-1-(3-methoxyphenyl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; 8-methoxy-1-(pyridin-2-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; 9-bromo-1-(pyridin-3-yl or pyridin-4-yl)-5,6-dihydro-4H-2,3,6,7,10b-pentaaza-benzo[e]azulene; 9-bromo-1-(4-methoxyphenyl or phenyl)-5,6-dihydro-4H-2,3,6,7,10b-pentaaza-benzo[e]azulene; (R,S)-1-(4-methoxyphenyl or phenyl)-4-methyl-4,5-dihydro-6-thia-2,3,10b-triaza-benzo[e]azulene; 1-(2-methoxyphenyl or 4-methoxyphenyl)-4,5-dihydro-6-thia-2,3,10b-triaza-benzo[e]azulene; (R,S)-1-(4-hydroxyphenyl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-9-methoxy-1-(4-methoxyphenyl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-4-methyl-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-9-ol; (R,S)-8-chloro-4-methyl-1-(o-tolyl or m-tolyl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-1-(2-chlorophenyl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-4,9-dimethyl-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-4-methyl-1-phenyl-9-CF 3-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-4-methyl-1-phenyl-9-CF 3-4,5-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene-6-carbaldehyde; (R,S)-1-(5-bromopyridin-3-yl)-8-methoxy-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-1-(5-bromopyridin-3-yl)-8-chloro-9-methoxy-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-methoxy-4-methyl-1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-9-methoxy-4-methyl-1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-9-methoxy-4-methyl-1-[6-methylpyridin-2-yl]-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; 1-phenyl-4,5-dihydro-6-thia-2,3,10b-triaza-benzo[e]azulene; (R,S)-9-chloro-1-(5-chloro-2-fluorophenyl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene trifluoroacetate; (R,S)-8-chloro-1-(4-methoxypyridin-2-yl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-4-methyl-1-(2-methylthiazol-5-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-9-bromo-4-methyl-1-(6-methylpyridin-2-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-1-(3-fluorophenyl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-1-(3-CF 3O-phenyl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene; (R,S)-8-chloro-1-(5-chlorothiophen-2-yl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene and (R,S)-8-chloro-1-(5-methyl-2H-pyrazol-3-yl)-4-methyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene. ACTIVITY : Cytostatic; Vasotropic; Anti-HIV; Nootropic; Neuroprotective; Antiarteriosclerotic; Vulnerary. No details of tests are given. MECHANISM OF ACTION : Transforming growth factorbeta (TGFbeta ) receptor kinase inhibitor. (R,S)-8-hydroxy-4-methyl-1-(6-methylpyridin-2-yl)-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulene (A1) has IC50 for inhibition of TGFbeta of 1.8x10 -7M.