Synthesis and Analgesic and Anti-inflammatory Activity of 6-Phenyl/(4-methylphenyl)-3(2H)-pyridazinon-2-propionamide Derivatives

Mehtap Gökçe; Meral Şirin Colak; Esra Kiipeli; Mustafa Fethi Şahin

doi:10.1055/s-0031-1296408

Arzneimittelforschung, Table of Contents

Arzneimittelforschung 2009; 59(7): 357-363
DOI: 10.1055/s-0031-1296408

Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs

Editio Cantor Verlag Aulendorf (Germany)

Synthesis and Analgesic and Anti-inflammatory Activity of 6-Phenyl/(4-methylphenyl)-3(2H)-pyridazinon-2-propionamide Derivatives

Authors

Mehtap Gökçe

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey
Meral Şirin Colak

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey
Esra Kiipeli

²Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, Turkey
Mustafa Fethi Şahin

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey

Abstract

For reducing gastrointestinal toxicity associated with non-steroidal anti-inflammatory drugs (NSAIDs) a variety of 6-phenyl/(4-methylphenyl)-3(2H)-pyridazi-non-2-propionamide were synthesized. The structures of these new pyridazinone derivatives were confirmed by their IR, ¹H-NMR spectra and elementary analysis. All the new compounds were tested in vivo for their analgesic and anti-inflammatory activities. The analgesic activity of the test compounds was determined by phenylbenzoquinone-induced writhing assay and the anti-inflammatory activity was evaluated by the carrageenan-induced rat paw edema model. 6-Phenyl-3(2H)-pyridazinon-2-yl-[4-(4-fluorophe-nyljpiperazinyl] propanamide IV a-3 was the most active one among the synthesized compounds. Also this compound exhibited most potent anti-inflammatory activity. Acetylsalicylic acid and Indometacin were used as reference drugs. Adverse effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with the reference NSAIDs.

Key words

Arylpiperazines - 3(2H)-Pyridazinone amides, analgesic activity, anti-inflammatory activity

Full Text

References

References
1 Hashash JG, Atweh LA, Saliba T, Chakhachiro Z. Acute NSAID-related transmural duodenitis and extensive duodenal ulceration. Clin Ther. 2007; 29: 2448-52
2 Ray WA, Chung CP, Stein CM, Smalley WE, Hall K, Arbogast PG et al. Risk of Peptic Ulcer Hospitalizations in Users of NSAIDs With Gastroprotective Cotherapy Versus Coxibs. Gastroenterology. 2007; 133: 790-8
3 Marco JL, Amariles P, Bosca B, Castello A. Risk factors associated with NSAID-induced upper gastrointestinal bleeding resulting in hospital admissions: A cross-sectional, retrospective, case series analysis in Valencia. Curr Ther Res. 2007; 68: 107-19
4 Funatsu T, Chono K, Hirata T, Keto Y, Kimoto A, Sasamata M. Mucosal acid causes gastric mucosal microcirculatory disturbance in nonsteroidal anti-inflammatory drug-treated rats. Eur J Pharmacol. 2007; 554: 53-9
5 Odabasoglu F, Cakir A, Suleyman H, Aslan A, Bayir Y, Halici M et al. Gastroprotective and antioxidant effects of usnic acid on indomethacin-induced gastric ulcer in rats. J Ethnopharmacol. 2006; 103: 59-65
6 Garcia S, Canionero M, Lopes G. Dipyrone-induced granulocytopenia: a case for awareness. Pharmacotherapy. 2006; 26 (3) 440-2
7 Prcic A, Aganovic D, Junuzovic D, Kulovac B. Comparative efficiency study, safety and usage of tested drugs in patients with renal colic. Med Arch. 2006; 60: 37-40
8 Yilmaz HL, Alparslan N, Yildizdas D, Bayram I, Alhan E. Intramuscular Dipyrone versus Oral Ibuprofen or Nimesulide for Reduction of Fever in the Outpatient. Setting. Clin Drug Invest. 2003; 23 (8) 519-26
9 Pompeia C, Boaventura MF, Curi R. Antiapoptotic effect of dipyrone on HL-60, Jurkat and Raji cell lines submitted to UV irradiation, arachidonic acid and cycloheximide treatments. Int Immunopharmacol. 2001; 1 (12) 2173-82
10 Ökçelik B, Ünlü S, Banoglu E, Küpeli E, Yesilada E, Şahin MF. Investigations of New Pyridazinone Derivatives for the Synthesis of Potent Analgesic and Anti-inflammatory Compounds with Cyclooxygenase Inhibitory Activity. Arch Pharm Pharm Med Chem. 2003; 336: 406-12
11 Matsuo T, Tsukamoto Y, Takagi T, Sato M. Synthesis and Biological Activity of Pyridazinooxazines. Chem Pharm Bull. 1982; 30 (3) 832-42
12 Takaya M, Sato M. Studies on Pyridazinone Derivatives XVI. Analgesic- Anti-inflammatory Activities of 3(2H)-Pyridazinone Derivatives. Yakugaku Zasshi. 1994; 114 (2) 94-110
13 Rohet F, Rubat C, Coudert P, Couquelet J. Synthesis and Analgesic Effects of 3-substituted-4,6-diarylpyridazine Derivatives. Bioorg Med Chem. 1997; 5 (4) 655-9
14 Gökçe M, Doğruer D, Şahin MF. Synthesis and Antinociceptive Activity of 6-Substituted-3(2H)-Pyridazinone Derivatives. Il Farmaco. 2001; 56: 221-4
15 Gökçe M, Şahin MF, Küpeli E, Yeşjlada E. Synthesis and Analgesic and Anti-inflammatory Activity of New 3(2H)-pyridazinone derivatives. Arzneimittelforschung. 2004; 54: 396-401
16 Şahin MF, Badiçoğlu B, Gökçe M, Küpeli E, Yeşilada E. Synthesis and Analgesic and Anti-inflammatory Activity of Methyl [6-substitue-3(2H)-piridazinone-2-yl] acetate Derivatives. Arch Pharm Pharm Med. 2004; 337: 445-52
17 Gökçe M, Bakir G, Şahin M F, Küpeli E, Yeşilada E. Synthesis of New Mannich Bases of Arylpyridazinones as Analgesic and Anti-inflammatory Agents. Arzneimittelforschung. 2005; 55: 318-25
18 Dündar Y, Gökçe M, Küpeli E, Şahin MF. Synthesis and Analgesic and Antiinflammatory Activity of Ethyl 6-Substituted-3(2H)-pyridazinone-2-ylacetate Derivatives. Arzneimittelforschung. 2007; 57: 777-81
19 Dal Piaz V, Vergelli C, Giovannoni MP, Scheider MA, Pet-rone G, Zaratin P. 4-Amino-3(2H)-pyridazinones Bearing Arylpiperazinylalkyl Groups and Related Compounds: Synthesis and Antinociceptive Activity. Il Farmaco. 1997; 58: 1063-71
20 Rubat C, Coudert P, Tronche P, Bastide J, Bastide P, Privat AM. Synthesis and Pharmacological Evaluation of N-Substituted 4,6-Diaryl-3-pyridazinones as Analgesic, Anti-inflammatory and Antipiretic Agent. Chem Pharm Bull. 1989; 37 (10) 2832-5
21 Rubat C, Coudert P, Albussion E, Bastide J, Couquelet J, Tronche P. Synthesis of Mannich Bases of Arylidenepyridazinones as Analgesic Agents. J Pharm Sci. 1992; 81: 1084-7
22 Dal Piaz V, Giovannoni MP, Ciciani G, Barlocco D, Giardina G, Petrone G et al. 4,5-Functionalized 6-phenyl-3(2H)-pyridazinones: Synthesis and Evaluation of Antinociceptive Activity. Eur Med Chem. 1996; 31: 65-70
23 Dal Piaz V, Vergelli C, Castellana C, Giovannoni MP, Scheideler MA, Petrone G et al. 4-Amino-5-vinyl-3(2H)-pyrida-zinones Bearing Arylpiperazinylalkyl Groups and Related Compounds: Synthesis and Antinociceptive Activity. Il Farmaco. 2002; 58: 1063-71
24 Giovannoni MP, Vergelli C, Chelardini C, Nicoletta G, Bartolini A, Dal Piaz V. [(3-Chlorophenyl)piperazinylpropyl]-pyridazinones and Analogues as Potent Antinociceptive Agents. J Med Chem. 2003; 46: 1055-9
25 Dogruer DS, Sahin MF, Unlu S, Ito S. Studies on Some 3(2H)-Pyridazinone Derivatives with Antinociceptive Activity. Arch Pharm Pharm Med Chem. 2000; 333: 79-86
26 Santagati NA, Duro F, Caruso A, Trombadore S, Amico-Roxas M. Synthesis and Pharmacological Study of a Series of 3(2H)-pyridazinones as Analgesic and Anti-inflammatory Agents. Il Farmaco Ed. Sci. 1985; 40: 921-9
27 Banoğlu E, Akoğlu Ç, Ünlü S, Küpeli E, Yeşilada E et al. Amide Derivatives of [6(5-Methy-3-phenylpyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic Acids as Potential Analgesic and Anti-inflammatory Compounds. Arch Pharm Pharm Med Chem. 2004; 337: 7-14
28 Okun R, Liddon SC, Lasagnal L. The Effect of Aggregation, Electric Shock and Adrenergic Blocking on Inhibition of the ‘Writhing Sydrome’. J Pharmacol Exp Ther. 1963; 139: 107-14
29 Kasahara Y, Hikino H, Tsurufuji S, Watanabe M, Ohucci K. Antiinflammatory Actions of Ephedrines in Acute Inflammations. Planta Med. 1985; 51: 325