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

5-HT 3 receptor antagonists, such as Ondansetron, are used for anti-emesis after chemotherapy, radiotherapy and operations. Some Ondansetron analogs possessing piperazine ring as side chains were synthesized in our lab. Thus, 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-4 H -carbazol-4-one ( 3 ) was prepared from 2 via cyclization and rearranged in the presence of ZnCl 2 . Through a methylation reaction, compound 3 was converted to 1,2,3,9-tetrahydro-9-methyl-4 H -carbazol-4-one ( 4 ). 3-Dimethylaminomethyl substituted compound ( 5 ) was synthesized from 4 by a Mannich reaction in glacial acetic acid. Nine novel 1,2,3,9-tetrahydro-9-methyl-3-(4-substituted-piperazin-1-ylmethyl)-4 H -carbazol-4-one derivatives ( 6a–6i ) were synthesized through nucleophilic substitution reaction of 5 with piperazines. The structures of all the target compounds were determined by elemental analysis, IR, MS, 1 H NMR and 13 C 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.