Synthesis and antiemetic activity of 3-(4-substituted-piperazin-1-ylmethyl)-1,2,3,9-tetrahydro-carbazol-4-one derivatives

One of the two carbonyl groups of starting material 1,3-cyclohexandione (1) was condensed with phenylhydrazine hydrochloride to form monophenylhydrazone (2). 1,2,3,9-tetrahydro-carbazol-4-one (3) was prepared from 2 through cyclization and rearrangement in the presence of ZnCl2. Through methylation reaction, compound 3 is converted to 9-methyl-1,2,3,9-tetrahydro-carbazol-4-one (4). 3-Dimethylaminomethyl-substituted compound (5) was synthesized from 4 by Mannich reaction in glacial acetic acid. Nine novel 3-(4-substituted-piperazin-1-ylmethyl)-1,2,3,9-tetrahydro-carbazol-4-one derivatives 6a similar to 6i were synthesized via nucleophilic substitution reaction of 5 with piperazines. The structures of all the target compounds were determined by elemental analysis, IR, MS, H-1 NMR and C-13 NMR spectra. The results of preliminary pharmacological test show that part of the novel compounds have antiemetic activity comparable to that of the control ondansetron.