Design and Synthesis of Some (S)-2-(6-Methoxynaphthalen-2-yl)-N-substituted Ethyl Propanamide Derivatives as Potent Non-ulcerogenic Anti-inflammatory and Analgesic Agents

Barkin Berk; Dilek Demir Erol; Esra Kupeli; Erdem Yesilada

doi:10.1055/s-0031-1296385

Arzneimittelforschung, Table of Contents

Arzneimittelforschung 2009; 59(4): 195-201
DOI: 10.1055/s-0031-1296385

Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs

Editio Cantor Verlag Aulendorf (Germany)

Design and Synthesis of Some (S)-2-(6-Methoxynaphthalen-2-yl)-N-substituted Ethyl Propanamide Derivatives as Potent Non-ulcerogenic Anti-inflammatory and Analgesic Agents

Barkin Berk

¹Yeditepe University, Faculty of Pharmacy, Istanbul, (Turkey)

,

Dilek Demir Erol

¹Yeditepe University, Faculty of Pharmacy, Istanbul, (Turkey)

,

Esra Kupeli

¹Gazi University, Faculty of Pharmacy, Ankara, (Turkey)

,

Erdem Yesilada

¹Yeditepe University, Faculty of Pharmacy, Istanbul, (Turkey)

› Author Affiliations

Abstract

The carboxylic acid group of the antiinflammatory drug, (S)-2-(6-methoxy-naphthalen-2-yl) propanoic acid, naproxen (CAS 22204-53-1) was reacted with the substituted ethylamine derivatives to form (S)-2-(6-methoxynaphthalen-2-yl)-N-substituted ethyl propanamides by using N,N’-dicyclohexyl carbodiimide (DCC) and 4-(dimethylamino) pyridine (DMAP). Anti-inflammatory and analgesic activities of the compounds were assessed in vivo by carrageenan-induced hind paw edema and p-benzoquinone induced abdominal contraction tests in mice, respectively. In addition, the ulcerogenic properties of the new compounds were evaluated, and compared to that of naproxen. Among the newly synthesized compounds, compound 2f showed the highest analgesic and antiinflammatory activity at 100 mg/kg oral dose, without inducing any gastric lesion. Although this compound induced less gastric lesions than naproxen, it was found to have less anti-inflammatory and analgesic activity when compared to indometacin (CAS 53-86-1). These new compounds therefore deserve further attention to develop new lead drugs.

Key words

Analgesics - Antiinflammatories - CAS 53-86-1 - CAS 22204-53-1 - Ethyl propanamide derivatives - Naproxen - Ulcerogenesis

Full Text

References

References
1 Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971; Jun 23 231 (25) 232-235
2 Busson M. Update on ibuprofen: review article. J Int Med Res. 1986; 14: 53-62
3 Cryer B. NSAID-associated deaths: The rise and fall of NSAID-associated GI mortality. Am J Gastroenterol. 2005; 100: 1694-1695
4 Go MF. Drug injury in the upper gastrointestinal tract: Nonsteroidal anti-inflammatory drugs. Gastrointest Endosc Clin N Am. 2006; 16: 83-97
5 James MW, Hawkey CJ. Assessment of non-steroidal antiinflammatory drug (NSAID) damage in the human gastrointestinal tract. Br J Clin Pharmacol. 2003; 56: 146-155
6 Lazzaroni M, Bianchi PG. Gastrointestinal side-effects of traditional non-steroidal anti-inflammatory drugs and new formulations. Aliment Pharmacol Ther. 2004; 20 (2) 48-58
7 Naesdal J, Brown K. NSAID-associated adverse effects and acid control aids to prevent them: A review of current treatment options. DrugSaf. 2006; 29: 119-132
8 Mounier G, Guy C, Berthoux F, Beyens MN, Ratrema M, Ollagnier M. Severe renal adverse events with arylcar-boxylic non-steroidal anti-inflammatory drugs: Results of an eight-year French national survey. Therapie. 2006; 61: 255-266
9 Schneider V, Lévesque LE, Zhang B, Hutchinson T, Brophy JM. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: A population-based, nested case-control analysis. Am J Epidemiol. 2006; 164: 881-889
10 Zadrazil J. Nonsteroidal antiinflammatory drugs and the kidney. Vnitr Lek. 2006; 52: 686-690
11 Adebayo D, Bjarnason I. Is non-steroidal anti-inflammaory drug (NSAID) enteropathy clinically more important than NSAID gastropathy. Postgrad Med J. 2006; 82: 186-191
12 Dogne JM, Supuran CT, Pratico D. Adverse cardiovascular effects of the coxibs. J Med Chem. 2005; 48: 2251-2257
13 Scheen AJ. Withdrawal of rofecoxib (Vioxx): What about cardiovascular safety of COX-2 selective non-steroidal anti-inflammatory drugs. Rev Med Liege. 2004; 59: 565-569
14 Chiroli V, Benedini F, Ongini E, Del Soldato P. Nitric oxide-donating non-steroidal anti-inflammatory drugs: the case of nitro derivatives of aspirin. Eur J Med Chem. 2003; 38: 441-446
15 Nitronaproxen: AZD 3582 HCT 3012 naproxen nitroxybu-tylester NO-naproxen. Drugs R D. 2006; 7: 262-266
16 Holm L, Phillipson M, Perry MA. NO-flurbiprofen maintains duodenal blood flow, enhances mucus secretion contributing to lower mucosal injury. Am J Physiol Gastrointest Liver Physiol. 2002; 283: G1090-G1097
17 Wallace JL, Muscará MN, De Nucci G, Zamuner S, Cirino G, Del Soldato P et al Gastric tolerability and prolonged prostaglandin inhibition in the brain with a nitric oxide-releasing flurbiprofen derivative, NCX-2216 [3-[4-(2-fluoro-a-methyl-[l.l’-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester]. J Pharmacol Exp Ther. 2004; 309: 626-633
18 Wallace JL, Reuter B, Cicala C, McKnight W, Grisham M, Cirino G. A diclofenac derivative without ulcerogenic properties. Eur J Pharmacol. 1994; 257: 249-255
19 Rigas B, Kashfi K. Nitric oxide-donating NSAIDs as agents for cancer prevention. Trends Mol Med. 2004; 10: 324-330
20 Wallace JL, McKnight W, Reuter B, Cicala C, Grisham M, Cirino G. Nitric-oxide releasing NSAID derivatives - antiinflammatory without gastropathy. Gastroenterology. 1994; 106: A208
21 Wallace JL, Reuter BK, Cirino G. Nitric oxide-releasing nonsteroidal anti-inflammatory drugs: A novel approach for reducing gastrointestinal toxicity. J Gastroenterol Hepatol. 1994; 9 (1) S40-S44
22 Csont T, Ferdinandy P. Cardioprotective effects of glyceryl trinitrate: Beyond vascular nitrate tolerance. Pharmacol Ther. 2005; 105: 57-68
23 Fung HL, Bauer JA. Mechanisms of nitrate tolerance. Cardiovasc Drugs Ther. 1994; 8: 489-499
24 Hu R, Siu CW, Lau EO, Wang WQ, Lau CP, Tse HF. Impaired nitrate-mediated dilatation could reflect nitrate tolerance in patients with coronary artery disease. Int J Cardiol. 2007; 120: 351-356
25 Rainsford KD. Mechanisms of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs. Scand J Gastroenterol Suppl. 1989; 163: 9-16
26 Lanza FL, Nelson RS, Chen TT et al The effects of ibuprofen, indomethacin, aspirin, naproxen, and placebo on the gastric mucosa of normal volunteers: a gastroscopic and photographic study. Dig Dis Sci. 1979; 24: 823-828
27 Cioli V, Putzolu S, Rossi V, Scorza BP, Corradino C. The role of direct tissue contact in the production of gastrointestinal ulcers by anti-inflammatory drugs in rats. Toxicol Appl Pharmacol. 1979; Sep 15 50 (2) 283-289
28 Akgün H, Tozkoparan B, Ertan M, Aksu F, Inan SY. Synthesis of some 2-arylpropionic acid amides as prodrugs. Arzneimittelforschung. 1996; 46 (9) 891-894
29 Shanbhag VR, Crider AM, Gokhale R, Harpalani A, Dick RM. Ester and amide prodrugs of ibuprofen and naproxen: synthesis, anti-inflammatory activity, and gastrointestinal toxicity. J Pharm Sci. 1992; 81 (2) 149-154
30 Khanand MSY, Akhter M. Synthesis, pharmacological activity and hydrolytic behavior of glyceride prodrugs of ibuprofen. Eur J Med Chem. 2005; 40: 371-376
31 Cocco MT, Congiu C, Onnis V, Morelli M, Cauli O. Synthesis of ibuprofen heterocyclic amides and investigation of their analgesic and toxicological properties. Eur J Med Chem. 2003; 38 (5) 513-518
32 Mahfouz NM, Omar FA, Aboul-Fadl T. Cyclic amide derivatives as potential prodrugs II: N-hydroxymethylsuccini-mide-/isatin esters of some NSAIDs as prodrugs with an improved therapeutic index. Eur J Med Chem. 1999; 34: 551-562
33 Möller NL, Dietzel KE, Schneider HT, Brune K. Novel 5-aminosalicylic acid NSAID conjugates: synthesis; pharmacological and toxicological properties. Eur J Med Chem. 1989; 2: 463-469
34 Ranatunge RR, Augustyniak ME, Dhawan V, Ellis JL, Garvey DS, Janero DR, et al. Synthesis and anti-inflammatory activity of a series of N-substituted naproxen glycolamides: nitric oxide-donor naproxen prodrugs. Bioorg Med Chem. 2006; 14: 2589-2599
35 Berk B, Aktay G, Yesilada E, Ertan M. Synthesis and pharmacological activities of some new 2-[1-(6-methoxy-2-naphthyl)ethyl]-6-(substituted)benzylidene thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one derivatives. Pharmazie. 2001; 56 (8) 613-616
36 Bergeron RJ, Huang G, McManis JS, Yao H, Nguyen JN. Synthesis and biological evaluation of aminopolyamines. J Med Chem. 2005; May 5 48 (9) 3099-3102
37 Kasahara Y, Hikino H, Tsurufuji S, Watanabe M, Ohuchi K. Anti-inflammatory actions of ephedrines in acute inflammations. Planta Med. 1985; 51: 325-331
38 Okun R, Liddon SC, Lasagna L. The effect of aggregation, electric shock and adrenergic blocking drugs on inhibition of the “writhing syndrome”. J Pharmacol Exp Ther. 1963; 139: 107-109
39 Kalgutkar AS, Marnett AB, Crews BC, Remmel RP, Marnett LJ. Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indometacin, as selective cyclooxygenase-2 Inhibitors. J Med Chem. 2000; 43: 2860-2870