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SYNTHESIS AND STABILITY STUDY ON AN ASPIRIN DERIVATIVE WITH POTENTIAL SELECTIVE COX-2 INHIBITOR

S. A. Al-Mikhlafi, O. A.M
Published 2008 · Chemistry

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The synthesis of N– [5– Methyl– 2– (1, 3, 4 COX-2 selective inhibitor and the preliminary kinetic study for hydrolysis of this compound is studied in this paper. The compound was prepared from the corresponding aspirin and 2–amino–5–methyl–1,3,4– thiadiazole in the presence of N,N-dicyclohexylcarbodiimide (DCC) as coupling agent . The preliminary kinetic study for hydrolysis of this compound and the effect of pH on the rate of hydrolysis in buffer solution citrate–phosphate–borate/HCl was studied. The structure was confirmed by infrared, nuclear magnetic resonance (H–NMR), and elemental microanalysis assay. The compound underwent slightly hydrolysis at low and high pH with a fairly stabile so, provide a chance for it to be absorbed intact with highly bioavailability, longer half life, and with lower G1 toxicity. INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin and selective cyclo-oxygenase-2 (COX-2) inhibitors are some of the most commonly prescribed medications worldwide, these drugs are used to treat painful inflammatory conditions such as arthritis, traumatic injuries, pain and fever (1,2) . These agents act via inhibition of the COX enzyme which catalyzes the first step (*) Corresponding author. Tel+967 711639234. EMail address: sadik1966@hotmail.com. SYNTHESIS AND STABILITY STUDY ON 2 of the biosynthesis of prostaglandins(3). Two isoforms of this enzyme have been discovered. The first isoform COX-l is constitutively expressed particularly in the gastrointestinal tract and the kidneys. It is responsible for the physiological production of prostaglandins. The other isoform COX-2 is induced during inflammation process(6,7). The development of selective COX-2 inhibitors leads to discovery of drugs with significantly reduced renal and gastrointestinal side effects(8). Traditional NSAIDs inhibit both isoforms of the enzyme COX (8,9). In studies of rofecoxib and lumiracoxib as selective COX-2 inhibitors, the absolute risk of serious upper gastrointestinal ulceration and bleeding is reduced by 50-60% or more compared to other NSAIDS (8,10). Recent studies have shown that small tumors of the sympathetic nervous system (neuroblastoma) "have abnormal levels of COX-2 expressed. These studies report that an overexpression of the COX-2 enzyme has an adverse effect on the tumor suppressor (11). On the other hand, recent reviews of aspirin induced asthma (AIA) (12,13), the use of the COX-2 preferential inhibitor nimesulide in asthmatic patients intolerant to NSAIDS (14,15). This study discuss the importance of inhibiting prostaglandin E2 (PGE2) synthesis in AlA, and the relative safety of NSAIDs that preferentially inhibit COX-2 (16). Only one small study has been reported on the use of meloxicam in five patients with AIA. NSAID intolerant patients dyspnoea occurred in two with aspirin and two with ketoprofen, but three of these four had no dyspnoea with 11 mg meloxicam (therapeutic dose 7.5-15 mg daily) (17). The importance of chemical modification of commercially available traditional NSAIDS such as piroxicam [1] to produces preferential COX-2 selective inhibitors, meloxicam [2]. We were encouraged to search for novel COX-2 as selective inhibitors. By conversion of carboxyl group of aspirin to carboxamid group by conjugating the selected moiety of heterocyclic compound, 2 – amino – 5–methyl –1, 3, 4–thiadiazole, may impart towards COX– 2 inhibitors with lower G1 toxicity, also these conjugates are Al-Mikhlafi S. A. et al. 3 similar that of isosteric functional groups of meloxicam derivatives (18,19).
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