Various inflammatory diseases are currently treated with steroidal and non-steroidal anti inflammatory drugs

with steroidal and non-steroidal anti inflammatory drugs (NSAIDs). NSAIDs are drug with analgesic, antipyretic and in higher doses anti inflammatory effects. They inhibit synthesis of inflammation mediators. Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase (COX), by inhibiting the metabolism of arachidonic acid. COX catalyses the formation of prostaglandins (PGs) and thromboxane from arachidonic acid. PGs act as messenger molecules in the process of inflammation. Conventional NSAIDs that non-selectively inhibit major cyclooxygenase isoforms, (COX-1 and COX-2), are widely used to treat the signs and symptoms of inflammation, particularly arthritic pain. COX-1 is the constitutive isoform and is mainly responsible for the synthesis of cytoprotective PGs in gastrointestinal (GI) tract whereas COX-2 is inducible and plays a major role in PG biosynthesis in inflammatory cells. It is believed that the inhibition of COX-1 causes unfavorable GI side effects. NSAIDs vary in their potency, duration of action and the way in which they are eliminated from the body. Though selective COX-2 inhibitors (coxibs) with better safety profile have been marketed as a new generation of NSAIDs, but careful prospective examination of coxibs has revealed unexpected adverse effects. The two main adverse drug reactions (ADRs) associated with NSAIDs relate to GI effects and renal effects (kidney failure) of the agents. Also, they have shown unexpected cardiovascular adverse effects. Therefore, development of novel compounds having anti inflammatory activity with an improved safety profile is still a necessity. Literature survey revealed that many pyrazole derivatives have found their clinical application as NSAIDs. Among the highly marketed COX-2 inhibitors that comprise the pyrazole nucleus, celecoxib is the one which is treated as a safe anti inflammatory and analgesic agent. It is considered as a typical model of the diaryl heterocycle template that is known to selectively inhibit the COX-2 enzyme. Some other examples of pyrazole derivatives as NSAIDs are felcobutazone, mefobutazone, morazone, famprofazone and ramifenazone. But due to serious adverse effects (such as bone marrow depression, water and salt retention and carcinogenesis), the use of pyrazole derivative is limited. This limitation has led to the investigation of new pyrazole derivatives with that more potent activity and less toxicity. Motivated by the aforementioned findings, it was designed to synthesize novel series of pyrazole derivatives that would act as anti inflammatory agents. The substitution pattern of the pyrazole ring was rationalized so as to be correlated to the diaryl heterocycles template of compounds that are known to act selectively as COX-2 inhibitors, such as celecoxib. Compared with coxibs, new drugs were synthesized by keeping the original pyrazole moiety same in new drugs containing heterocycle (like phthalimide, N-pyridone and Opyridone) linked ethylene linker attached to oxygen adjacent to phenyl group containing nitrogen of pyrazole which provides flexibility to the molecule so that it will become easy to fit into the secondary pocket of COX-2 active site. The drugs were synthesized as acid derivatives (containing ester group), initiating the easy uptake of drug (in salt form). Presence of a small hydrophobic group, methyl group in pyrazole nucleus at position 3 can exert important influence on the activity and selectivity of related drug. Chemistry All compounds were synthesized via a general substitution reaction at room temperature. The starting material in the synthesis of substituted pyrazoles had been synthesized from reaction of ethyl acetoacetate 1 with phenyl hydrazine at refluxing temperature to synthesize 5-methyl2-phenyl-2,4-dihydro-pyrazol-3-one 2 (Chart 1). Reaction of 2 with carbon disulfide followed by methylation gave 4(bis-methyl sulfanyl-methylene)-5-methyl-2-phenyl-2,4-dihy634 Vol. 58, No. 5 Regular Article