Oxicam derivatives

Piroxicam (Feldene) is the prototypical oxicam derivative, with analgesic, antipyretic, and antiinflammatory properties. Its long half-life (45 hours) favors compliance, since only one dose per day is given. Side effects are similar to those encountered with other NSAIDs gastric disturbances, tinnitus, and headache. Piroxicam is indicated for inflammatory and rheumatoid conditions. 

Endothelin receptor antagonists 134 and 135 were prepared from the triflated oxicam derivative 136 (Scheme 18) <1998BMC1447>. Addition of aryl thiol 137 to the position gave product 134. Palladium-catalyzed Suzuki coupling of aryl boronic acid 138 and aryl triflate 136 affords the sulfonamide product 135. 

Significant research has centered on the preparation and investigation of oxicam derivatives as pharmaceutical agents. This interest was fueled by the successes of the nonsteroidal anti-inflammatory drugs (NSAIDs) piroxicam (Feldene ) 21, meloxicam (Mobic ) 22, and tenoxicam 23 (Figure 24). 

Lornoxicam, an oxicam derivative, is a nonsteroidal anti-inflammatory derivative. It is used in muscularskeletal and joint disorders such as osteoarthritis and rheumatoid arthritis. It is also used in the treatment of other painful conditions including postoperative pain. In the treatment of osteoarthritis and rheumatoid arthritis lornoxicam is given by mouth in a daily dose of 12 mg in two or three divided doses. Lornoxicam is given in doses of 8-16 mg daily by mouth for the treatment of pain. Doses above 8 mg should be given in divided doses. Similar doses may be given by intravenous or intramuscular injection, although in rare cases the maximum initial daily dose may be increased to 24 mg treatment by injection should be limited to two days [2]. 

Data are insufficient to indicate whether the oxicam NSAID lornoxicam is safer for the gastrointestinal tract than other oxicam derivatives (SEDA-16, 113). 

As will be discussed later, a new oxicam derivative, meloxicam, has been approved as a selective COX-2 inhibitor for the treatment of osteoarthritis. 

The most widely used variant of the Gabriel-Colman is the conversion of saccharine derivatives to benzothiazine derivatives. The reaction has been extensively studied as benzothiazines are important pharmacophores, particularly in the oxicam class of antiinflammatories. The first reported instance of this transformation was in 1956 where 43 was treated with sodium methoxide to provide 44. The rearrangement also works with esters " and some amides " in addition to ketones. 

The standard means for preparing oxicams 285, initially developed by Lombardino, is through the base-promoted rearrangement reaction of isothiazole dioxides 286, which in turn are prepared from saccharin derivatives such as 287 (Scheme 40) <1981AHC(28)73>. The oxicam core can be further derivatized by N-alkylation of oxicam 285 and amidation of the C-3 ester functionality of 288 to form the common drug scaffold 289. 

Parke-Davis workers have performed SAR studies on endothelin receptor antagonists derived from a dimethoxy-substituted oxicam in the search of treatments for hypertension, congestive heart failure, renal failure, pulmonary hypertension, ischemia, and cerebral vasospasm <1998BMC1447>. Compound 295 displayed a 40-fold selectivity for endothelin receptor antagonist A (ETa) over endothelin receptor antagonist B (ETb) (Figure 26). 

Piroxicam (84, Feldene in the US), a non-selective COX inhibitor with both analgesic and antipyretic properties, is one of the most used NSAIDs and serves as prototype of the oxicam family. This drug is utilized to relieve the symptoms of arthritis, menstrual pains or cramps and fever. It is also used in veterinary medicine to treat certain neoplasias expressing COX receptors, such as bladder, colon and prostate cancers. Variation on the structure of piroxicam has produced several other analogues with the benzene ring replaced by a thiophene ring and/or derivatives of the amide moiety, including meloxicam (85, a thiazole amide), isoxicam (86, an isoxazole amide), tenoxicam (87a, a thiophene derivative) and lornoxicam (87b, a chlorothiophene derivative). 

Widespread use of naproxen, sulindac, diclofenac, and diflunisal probably explains why they were the most frequently rmphcated, rather than because they have a greater tendency to cause these adverse effects. NSAIDs differ in their ability to cause adverse skin reactions in terms of both frequency and severity pyrazolones, butazones, and oxicams are most often blamed, and among the arylalkanoic acid derivatives fenbufen and carprofen are most often incriminated. 

Oxicams are a class of recently introduced enolic acid derivatives, including ineloxicain, piroxlcam and tenoxicam. So far only piroxicam has any extensive usage and is mainly used to treat rheumatoid and osteoarthritis, and for musculoskeletal pain. 

The eight groups of nonsteroidal anti-inflammatory drugs are salicylates, parachlorobenzoic acid derivatives, pyrazolone derivatives, propionic acid derivatives, fenamates, oxicams, phenylacetic acid, and selective COX-2 inhibitors. 

About 10% of asthmatics are hypersensitive to aspirin, and in some individuals life-threatening bronchoconstriction can occur. This is not a drug-drug interaction but an adverse response of asthmatic patients to aspirin, whether taking an anti-asthmatic drug or not. The reasons are not fully understood. Those known to be sensitive to aspirin may also possibly react to other NSAIDs, in particular the acetylated salicylates, the indole and indene acetic acids, and the propionic acid derivatives (see Table 6.1 , (p.l34)). The fenamates, oxicams, pyrazolones and pyrazolidinediones are better tolerated. The nonacetylated salicylates (sodium salicylate, salicylamide, choline magnesium trisalicylate) are normally well tolerated. Aspirin-sensitive individuals are also less likely to react to nimesulide. ... 

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