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

Abstract

5-HT₃ 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-4H-carbazol-4-one (3) was prepared from 2via cyclization and rearranged in the presence of ZnCl₂. Through a methylation reaction, compound 3 was converted to 1,2,3,9-tetrahydro-9-methyl-4H-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)- 4H-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, ¹H NMR and ¹³C 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.

Keywords

5-HT₃ receptor antagonist / 1 / 2 / 3 / 9-tetrahydro-4H-carbazol-4-one / Mannich reaction / antiemetic

References

[1] Milne R J, Heel R C. Ondansetron: therapeutic use as an antiemetic. Drugs, 1991, 41(4): 574-595

[2] Markham A, Sorkin E M. Ondansetron: an update of its therapeutic use in chemotherapy-induced and postoperative nausea and vomiting. Drugs, 1993, 45(6): 931-952

[3] Wilde M I, Markham A. Ondansetron: a review of its pharmacology and preliminary clinical findings in novel applications. Drugs, 1996, 52(5): 773-794

[4] Kohler D R, Goldspiel B R. Ondansetron: a serotonin receptor (5-HT3) antagonist for antineoplastic chemotherapy-induced nausea and vomiting. DICP, 1991, 25(4): 367-380

[5] Roberson C R, McLeskey C H. Ondansetron: in a class (5-HT3) of its own. Semin Anesth, 1996, 15 (1): 41-46

[6] Culy C R, Bhana N, Plosker G L. Ondansetron: A review of its use as an antiemetic in children. Paediatr Drugs, 2001, 3(6): 441-479

[7] Hilbert M F, Hoffmann R, Miller R C, Carr A A. Conformation-Activity Relationship study of 5-HT3 receptor antagonists and a definition of a model for this receptor site. J Med Chem, 1990, 33(6): 1594-1600

[8] Clemo G R, Felton D G I. The Chemistry of the Carbazoles:1,2,3,4-Tetrahydro-4-ketocarbazoles. J Chem Soc, 1951, 700-702

[9] Oikawa Y, Yonemitsu O. Selective oxidation of the side chain at C-3 of indoles. J Org Chem, 1977, 42: 1213-1246

[10] Chen G H. Synthesis of antiemetic ondansetron. Chin J Pharm, 1993, 24(6): 241-242 (in Chinese)

[11] Mongolsuk S, Robertson A, Towers R. 2,4,3',5'-Tetrahydroxystilbene from Artocarpus lakoocha. J Chem Soc, 1957, 2231-2233

[12] Littell R, Greenblatt E N, Allen G R. Mannich bases of 2,3-dihydro-4(1H)-carbazolones as potential psychotropic agents. J Med Chem, 1972, 15(8), 875-876

[13] Bermudez J, Boyle E A, Miner W D, Sanger G J. The anti-emetic potential of the 5-hydroxytryptamine 3 receptor antagonist BRL 43694. Br J Cancer, 1988, 58(5): 644-650

[14] Stables R, Andrews P L R, Bailey H E, Costall B, Gunning S J, Hawthorn J, Naylor R J, Tyers M B. Antiemetic properties of the 5-HT3 receptor antagonist, GR 38032F. Cancer Treat Rev, 1987, 14: 333-336

[15] Littell R, Allen G R. 3-(Morpholinomethyl)-2,3-dihydrocarbazol-4(1H)-ones. <patent>US 3634420</patent>, 1972 [Chem Abstr, 1972, 76, 72400]

[16] Kuang Y Q, Zhang S Y, Sun X L. Synthesis of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one. Chin J Pharm, 1994, 25(1): 36-37 (in Chinese)

[17] Maikeru B T. Medicine. <patent>J P 63165314</patent>, 1988 [Chem Abstr, 1989, 110, 205704]

[18] Coates I H, Bell J A, Humber D C, Ewan G B. 3-Imidazolylmethyl-1,2,3,9-tetrahydro-4H-carbazol-4-one derivatives. <patent>DE 3502508</patent>, 1985 [Chem Abstr, 1986, 104, 19589]

[19] Zinnes H. Process for the preparation of 4-keto-1,2,3,4-tetrahydrocarbazole. <patent>US 3892766</patent>, 1975 [Chem Abstr, 1975, 83, 178814]

[20] Lu J R, Shi X Z. Synthesis of Ondansetron Hydrochloride. J China Pharm Univ, 1999, 30(4): 246-248 (in Chinese)

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg