Abstract
In this study, the synthesis of a novel series Mannich bases of 5-nitro-3-substituted piperazino-methyl-2-benzoxazolinones are described. The structures attributed to compounds 3a-3k were elucidated using IR,1H-NMR spectroscopic techniques besides elemental analysis. The compounds were examined for their in vivo antiinflammatory and analgesic activities in two different bioassays, namely, carrageenan-induced hind paw edema and p-benzoquinone-induced abdominal constriction tests in mice, respectively. In addition, the ulcerogenic effects of the compounds were determined. Among the tested derivatives most promising results were obtained for the compounds bearing electron-withdrawing substituents (F, Cl, COCH3) in the ortho/para position of the phenyl nucleus on the piperazine ring at 3 position of benzoxazoli-none moiety (3a, 3b, 3c, 3d, 3h). The analgesic activities of all compounds are higher than their antiinflammatory activities. Antiinflammatory inhibitory ratios for all compounds were above 30% for the last two measurements. Because of this compounds 3a, 3b, 3c, 3d deserve attention and may be considered for further evaluation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abdelaal, S. M., Kong, S., and Bauer, L., Synthesis of 1-[3- methyl-2(3H)-benzoxazolon-5-or 6-yl]-4-4-[cis-2-(2,4-di- chlorophenyl)-2-(1H-imidazo-1-ylmethyl)-1,3-dioxolan-4-yl] methyleoxy phenylpiperazines.J. Heterocyclic Chem., 29, 1069 (1992).
Bonte, J. P., Piancastelli, J. P., Lesieur, M. C. I., Lamar, J. C., Beaughard, M., and Dureng, G., Amino ketone and amino alcohol derivatives of benzoxazolinone: Synthesis, adrenergic and antihypertensive properties.Eur. J. Med. Chem., 25, 361–368 (1990).
Brunet, C., Cazin, J. C., and Cazin, M., Antiooedematous properties of benzoxazolinone β-aminoketones.Arzneim.- Forsch./Drug Res., 30, 8, 1287–1291 (1980).
Calhoun, W., Carlson, R. P., Crossley, R., Datko, L. J., Dietrich, S., Heatherington, K., Marshall, L. A., Meade, P. J., Opalko, A., and Shepherd, R. G., Synthesis and antiinflammatory activity of certain 5, 6, 7, 8-tetrahydroquinolines and related compounds.J. Med. Chem., 38, 1473–1481 (1995).
Dannhardt, G. and Kiefer, W., Cylooxygenase inhibitors-current status and future prospects,Eur. J. Med. Chem., 36, 109–126 (2001).
Erdogan, H., Ünlü, S., and Sunal, R., Analgesic activity of some 3-(arylpiperidinomethyl)-2-benzoxazolinone derivatives.Arch. Pharm., 322, 75–78 (1989).
Erdogan, H., Debaert, M., and Cazin, J. C., Synthesis of some 2-benzoxazolinone derivatives and their analgesic properties.Arzneim. Forsch./Drug Res., 41, 73–76 (1991).
Flouzat, C., Bresson Y., Mattio, A., Bonnet, J., and Guillaumet, G., Novel nonopioid non-antiinflammatory analgesics: 3- (aminoalkyl)- and 3-[(4-aryl-1-piperazinyl)alkyl]oxazolo[4,5- b]pyridin-2(3H)-ones.J. Med. Chem., 36, 497–503 (1993).
Gavalas, A., Kourounakis, L., Litina, D., and Kourounakis, P., Anti-inflammatory and immuno-modulating effects of the novel agent γ-(2-aminoethylamino)-2-butyrothienone. inhibitory effects on mouse paw oedema.Arzneim. Forsch./Drug Res., 41, 423–426 (1991).
Gökhan, N., Erdogan, H., Durlu, T., and Demirdamar, R., Novel antiinflammatory analgesics: 3-(2-/4-pyridylethyl)-benzoxa- zolinone and oxazolo[4,5-b]pyridin-2-one derivatives.Archiv. Pharm., 332, 43–49 (1999).
Gökhan, N., Erdogan, H., Durlu, N. T., Demirdamar, R., and Özalp, M., Synthesis and evaluation of analgesic, antiinflammatory and antimicrobial activities of 6-acyl-3-piperazinomethyl- 2-benzoxazolinones.Arzneim. Forsch./Drug Res., 53, 114- 120 (2003).
Katsura, Y. Nishio, S., and Takasugi H., Studies on Antiulcer Drugs. I. Synthesis and Antiulcer Activities of lmidazo[1,2-a] Pyridinyl-2-Oxobenzoxazolidines-3-Oxo-2H-1,4-Benzoxazines and Related Compounds,Chem. Pharm. Bull., 39(11), 2937–2943(1991).
Kawanaka, Y., Kobayashi, K., Kusuda, S., Tatsumi, T., Murota, M., Nishiyama, T., Hisaichi, K., Fujii, A., Hirai, K., Naka, M., Komeno, M., Nakai, H., and Toda, M., Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. Part 1: synthesis and biological evaluation of dihydropyridin-2-imines.Bio & Med. Chem. Letters, 12(17), 2291–2294 (2002).
Mavel, S., Rubat, C., Coudert, P., Privat, A. M., Couquelet, J., Tronche, P., and Bastide, P., Synthesis of new 5-substituted- pyrazolo-[1,5-d][1,2,4]triazine derivatives and their analgesic, antiinflammatory and antipyretic properties.Arzneim. Forsch./ Drug Res., 43, 464–468 (1993).
Mokrosz, J., Pietrasiervicz, L., Duszynska, M. M., and Marek, C., Structure-activity relationship studies of central nervous system (CNS) agents. 5. Effect of the hydrocarbon chain on the affinity of 4-substituted 1-(3-chlorophenyl)piperazines for 5-HT1A receptor sites.J. Med. Chem., 35, 2369–2374 (1992).
Moreau, S., Coudert, P., Rubat, C., Albuisson, E., and Couquelet, J., Synthesis of peripherally acting analgesic 3-arylpiper- azinyl-5-benzyl-pyridazines.Arzneim. Forsch./Drug Res., 46, 800–805 (1996).
Okun, R., Liddon, S. C., and Lasagnal, L., The effect of aggregation, electric shock and adrenergic blocking drugs on inhibition of the “Writhing Syndrome”,J. Pharmacol. Exp. Ther., 139, 107–114 (1963).
Perregaard, J., Arnt, J., Bogeso, P. K., Hyttel, J., and Sanchez, C., Noncataleptogenic, centrally acting dopamine D-2 and serotonin 5-HT2 antagonists within a series of 3-substituted 1-(4-fluorophenyl)-1H-indoles.J. Med. Chem., 35, 1092–1101 (1992).
Rohet, F., Rubat, C., Coudert, P., and Couquelet, J., Synthesis and analgesic effects of 3-substituted 4,6-diarylpyridazine derivatives of the arylpiperazine class.Bioorg. Med. Chem., 5, 655–659 (1997).
Shankaran, K., Donnelly, K. L., Shah, S. K., Humes, J. L., Pacholok, S. G., Grant, S. K., Green, B. G., and MacCoss, M., Inhibition of nitric oxide synthase by benzoxazolones.Bio & Med. Chem. Letters, 7, 2887–2892 (1997).
Tsurumi, K., Kyuki, K., Niwa, M., Kokuba, S., and Fujimura, H., Pharmacological investigations of the new antiinflammatory agent 2-(10, 11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid.Arzneim. Forsch./Drug Res., 36, 1796–1803(1986).
Unlü, S., Baytas, S. N., Kupeli, E., and Yesilada, E., Studies on novel 7-acyl-5-chloro-2-oxo-3h-benzoxazole derivatives as potential analgesic and antiinflammatory Agents.Arch Pharm. Pharm. Med. Chem., 336, 310–321 (2003).
Viaud, M. C., Jamoneau, P., Flouzat, C., Bizot-Espiard, J. G., Pfeiffer, B., Renard, P., Caignard, D. H., Adam, G., and Guillaumet, G., N-Substituted oxazolo[5,4-b]pyridin-2(1H)- ones: A new class of non-opiate antinociceptive agents.J. Med. Chem., 38, 1278–1286 (1995).
Von der Saal W., Hölck, J. P., Kampe, W. Mertens, A., and Müller-Beckmann, B., Nonsteroidal cardiotonics. 2. The inotropic activity of linear, tricyclic 5-6-5 fused heterocycles.J. Med. Chem., 32, 1481–1496 (1989).
Weinstok, J., Gaitanopoulos, D. E., Stringer, O. D., Franz, R. G., Hieble, J. P., Kinter, L. B., Mann, W. B., Flaim, K. E., and Gessner, G., Synthesis and evaluation of non-catechol D-1 and D-2 dopamine receptor agonists: Benzimidazol-2-one, benzoxazol-2-one and the highly potent: benzothiazol-2-one- 7-ethylamines.J. Med. Chem., 30, 1166 (1987).
Yesilada, E. and Küpeli, E.,Berberis crataegina DC. root exhibits potent antiinflammatory, analgesic and febrifuge effects in mice and rats.Journal of Ethnopharmacology, 79, 237–248 (2002).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Köksal, M., Gökhan, N., Küpeli, E. et al. Analgesic and antiinflammatory activities of some new mannich bases of 5-nitro-2-benzoxazolinones. Arch Pharm Res 30, 419–424 (2007). https://doi.org/10.1007/BF02980214
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02980214