A Novel Route to Isoquinoline[2,1-g][1,6]naphthyridine, Pyrazolo[5,1-a] isoquinoline and Pyridazino[4′,5′:3,4]pyrazolo[5,1-a]isoquinoline Derivatives With Evaluation of Antitumor Activities

(E)-2-Chloro-3-(2-cyanovinyl)-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a] isoquinoline-1-carbonitrile (5) was obtained by treatment of the 2-chloro-3-formylpyrido[2,1-a]isoquinoline derivative 3 with 2-(triphenylphosphoranylidene)acetonitrile (4). Treatment of 5 with sodium azide afforded the corresponding azido compound 6 which could be reduced by sodium dithionite to compound 7. A novel isoquinolino[2,1-g][1,6]naphthyridine derivative 11 was obtained by the reaction of phenyl isothiocyanate with the phosphorane compound 8, which was prepared by the reaction of compound 6 with triphenylphosphine. Treatment of 5 with amines 12a–c and thiophenols 14a–c in refluxing ethanol afforded the corresponding substitution products 13a–c and 15a–c, respectively. Also, the reaction of 1 with α-oxo hydroxamoyl chlorides 16 was reinvestigated, and the synthesized pyrazoloisoquinolines 19a–f and pyridazinopyrazoloisoquinolines 20a, e were screened for their in vitro antitumor activities.