Celecoxib, synthesis

Meloxicam is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as celecoxib and may be considered "preferentially" selective rather than "highly" selective. The drug is popular in Europe and many other countries for the treatment of most rheumatic diseases and approved for treatment of osteoarthritis in the USA. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function (see common adverse effects above). 

With regard to the synthesis of celecoxib (1), several routes were described in the 1995 patent by G. D. Searle As shown in Scheme 1, dione 7 was prepared by the Claisen condensation of 4-methylacetophenone with ethyl trifluoroacetate in the presence of NaOMe in methanol under reflux. Subsequent diarylpyrazole formation from the condensation of dione 7 and 4-sulfonamidophenylhydrazine hydrochloride then delivered... 

Ongoing research led to the development of COX-2 selective inhibitors (e.g., rofecoxib and celecoxib). Celecoxib (Celebrex ) was approved by the FDA in 1998 to treat osteoarthritis and rheumatoid arthritis. Rofecoxib (Vioxx ) was approved in May 1999 to treat osteoarthritis, acute pain, and dysmenorrhea. Sales for the two drugs in 1999 were 1.5 billion and 373 million, respectively. Clinical studies have indicated a significant reduction in GI perforation, ulceration, or bleeding with the COX-2 inhibitors. The recognition of multiple COX isoforms has had one of the greatest impacts on the development of NSAIDs since the original synthesis of aspirin more than a century ago. 

Another example of fully automated PASP synthesis is the preparation of a 192-member 2D array of 1,5-biaryl pyrazoles. " The 1,5-biaryl pyrazole moiety is found in a number of important pharmaceuticals, such as the selective COX-2 inhibitor Celecoxib and the nonsteroidal antiinflammatory agent Tepoxaline. The synthetic route to the 1,5-biaryl pyrazoles, exemplified by the library member 42... 

A causal relation between celecoxib and these thrombotic events cannot be established with certainty on the basis of the available evidence. However, the temporal relation between the start of treatment and the thrombotic event was impressive, at least in three patients, and the findings were consistent with the hypothesis that thrombosis is an adverse consequence of reduced production of systemic prostaglandin I2 brought about by COX-2 inhibition. Reduced synthesis of prostaglandin I2 may act in concert with other thrombotic risk factors (such as those occurring in this series of patients) to precipitate acute vascular occlusion. 

Habeeb, A. G., Praveen Rao, P. N., Knaus, E. E. Design and synthesis of celecoxib and rofecoxib analogues as selective cycloox-ygenase-2 (COX-2) inhibitors replacement of sulfonamide and methylsulfonyl pharmacophores by an azido bioisostere. 7. Med. Chem. 2001,44(18), 3039-3042. 

Celecoxib is a selective COX-2 inhibitor/GI agent that reduces inflammation (e.g., pain, redness, swelling, heat), fever, and pain by inhibiting chemicals in the body that cause inflammation, fever, and pain. This is probably caused by the inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2) isoenzyme. Celecoxib is indicated in relief of symptoms of osteoarthritis relief of symptoms of rheumatoid arthritis in adults management of acute pain in adults treatment of primary dysmenorrhea and reduction of the number of adenomatous colorectal polyps in familial adenomatous polyposis (FAP), as an adjunct to usual care (e.g., endoscopic surveillance, surgery). 

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