Design, Synthesis and Pharmacological Evaluation of a Series of 5-Carbethoxy-4-chloro-6-(substituted amino)pyrimidines as Potential Analgesic and Anti-flammatory Agents with Very Low Ulcerogenic Potential

Abstract

A series of 5-carbethoxy-4-chloro-6-(substituted amino)pyrimidines was designed on the basis of its good 3-dimensional structural similarity with mefenamic acid (CAS 61-68-7), a well known anti-inflammatory drug. Synthesis of some 5-carbethoxy-4-chloro-6-(substitutedamino) pyrimidines has been achieved by cyclization of N-(cyanovinyl)formamidine intermediate in the presence of

dry HCl. Target compounds were evaluated for their analgesic and anti-inflammatory potential by known experimental models. Some of the compounds emerged as more potent analgesic and anti-inflammatory agents than the standard drug diclofenac sodium (CAS 15307-79-6). A very low ulcer index was observed with the most potent compound.

Key words

4-Chloropyrimidine, analgesic activity, anti-inflammatory activity, ulcerogenic potential - N-(Cyanovinyl)formamidine

• Literature

• 1 Palomer A, Cabre F, Pascual J, Campos J, Trujillo MA, Entrena A et al Identification of Novel Cyclooxygenase-2 Selective Inhibitors Using Pharmacophore Models. J Med Chem. 2002; 45: 1402-11
• 2 Charlier C, Michaux C. Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase(5-LOX) as a new strategy to provide safer non-steroidal anti-inflammatory drugs. Eur J Med Chem. 2008; 38: 645-59
• 3 http://www.fda.gov/cder/drug/infopage/Vioxx/default.htm (Access date: 1st October 2008)
• 4 Brown DJ. The Chemistry of Heterocyclic Compounds. The Pyrimidines: Supplement 1. New York Interscience Publishers; 1962.
• 5 Foldi Z, Salamon A. Beitrag zur Bildung von Pyrimidin-Ringen. Chem. Ber. 1941; 74: 1126-8
• 6 Nishigaki S, Senga K, Aida K, Takabatake T, Yoneda F. Condensation Reactions of Ethyl Ethoxymethylenecyanoacetate with Amidines. Chem Pharm Bull. 1970; 18: 1003-7
• 7 Juby PF, Hudyma TW, Brown M, Essery JM, Partyka RA. Antiallergy agents. 2. 2-Phenyl-5-(1H-tetrazol-5-yl)pyrimidin-4(3H)-ones. J Med Chem. 1982; 25: 1145-50
• 8 Chauhan SMS, Junjappa H. Ketene-S,S-acetals-V: The reactions of a-keto and a-cyanoketene-S,S-acetals with guanidine and thiourea: a new general synthesis of alkoxy-pyrimidines. Tetrahedron. 1976; 14: 1779-87
• 9 Shishoo CJ, Devani MB, Bhadti VS, Ananthan S, Ullas GV. Heterocyclization of functionalized ketene acetals: Synthesis of pyrimidines via vinylamidine intermediates. Tetrahedron Lett. 1984; 25: 1291-2
• 10 Shishoo CJ, Chhabria MT, Gandhi TP, Bangaru R. Synthesis and antihyperlipaemic activity of some novel N-cyanovinylformamidines. Arzneimittelforschung 1997; 47: 35-8
• 11 Shishoo CJ, Devani MB, Bhadti VS, Ananthan S, Ullas GV. Reaction of nitriles under acidic conditions: a novel, direct formation of condensed 4-chloropyrimidines. Tetrahedron Lett. 1983; 24: 4611-2
• 12 Chhabria MT, Bhatt HG, Raval HG, Oza P. Synthesis and biological evaluation of some 5-ethoxycarbonyl-6-isopropylamino-4-substitutedphenyl) aminopyrimidines as potent analgesic and anti-inflammatory agents. Bioorg Med Chem Lett. 2007; 17: 1022-4
• 13 Robert IT, Dorothy DG, Rendell JK, Irvin S. Agoinst and antagonist interactions of opiods on acetic acid-induced abdominal stretching in mice. J Pharmacol Exp Ther. 1969; 169: 29-38
• 14 Winter CA, Risely EA, Nuss GW. Carrageenan-induced edema in the hind paw of rat as an assay for anti-inflammatory activity. Proc Soc Exp Biol Med. 1962; 11: 544-7
• 15 Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W et al Pharmacological and biological demonstration of the role of cyclooxygenase 2 in-inflammation and pain. Proc Natl Acad Sci. 1994; 91: 12013-17