Oxicam

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. 

Oxicams, e.g. piroxicam, tenoxicam, meloxicam and lornoxicam are non-specific inhibitors of COX. Like diclofenac, meloxicam inhibits COX-2 ten times more potently than COX-1. This property can be exploited clinically with doses up to 7.5 mg per day, but at higher doses COX-1-inhibition becomes clinically relevant. Since the dose of meloxicam commonly used is 15 mg daily, this agent cannot be regarded as a COX-2-selective NS AID and considerable caution needs to be exercised when making comparisons between the actions of meloxicam and those of other conventional NSAIDs. The average daily dose in anti-rheumatic therapy is 20 mg for piroxicam and tenoxicam, 7.5-15 mg for meloxicam and 12-16 mg for lornoxicam. Oxicams have long elimination half-lives (lornoxicam 3-5 h, meloxicam - 20 h, piroxicam 40 h and tenoxicam 70 h). 

Another compound structurally related to the oxicams is RU 43526 (159) [387], which gave approximately equipotent inhibition of seminal vesicle CO (2.1 //M) and of rat ISN (3.0 //M). Removal of the 2-substituent had no effect on the CO inhibition, but drastically reduced 5-LO potency. RU 43526 was orally active, but only in NSAID-sensitive models (CPE 4 mg/kg, RAA 0.7 mg/kg). It was unknown whether the 5-LO inhibition made any contribution to the anti-inflammatory activity of this compound. 

Oxicames are representatives of another series of anti-inflammatory, analgesic, and fever-reducing compounds whose mechanisms of action are most likely the suppression of prostaglandin synthesis. These drugs are capable of relieving painful symptoms of medium intensity. 

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. 

The most biologically active members of the benzothiazines, known as the oxicams, include piroxicam (Feldene ) 21, meloxicam (Mobic ) 22, and tenoxicam 23 which have a 1,2-benzothiazine 1,1,4-trioxide structure. Recently, the... 

The H NMR spectrum of simple iV-methyl-substituted oxicam 48 has been determined (Figure 15) <1997JME980>. The A -methyl group occurs at 2.95 ppm, while the methyl ester protons are observed at 3.96 ppm. The aromatic protons (C-3 to C-6) occur as an unresolved multiplet in the range of 7.71-8.05 ppm. 

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. 

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). 

Several examples of non-oxicam-type 1,2-thiazine-containing small molecule enzyme inhibitors have been disclosed. The landmark work in this area involves the antiepileptic drug sulthiame 10, first discovered and approved for use over 30 years ago. Interest in this carbonic anhydrase inhibitor has been renewed by recent work on its efficacy in treatment of both childhood benign and focal epilepsies <2002MI469>. 

Among the many other non-oxicam-type substances discovered are a sultam pro-drug for potential P3-lactam thrombin inhibitors <1998BML3683>. Furthermore, an anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) pharmacophore based on the 1,2-thiazine structure has also been recently disclosed <1999BML673>. Workers at Bristol-Meyers Squibb have synthesized and evaluated sultam hydroxamates as MMP-2 inhibitors <2004JME2981>. Hydroxamate 38 displayed the best selectivity for MMP-2 over the other proteins in this superfamily of peptidases (Figure 27). As noted in Section 8.07.3.1, an X-ray crystal structure of 38 bound to the protein MMP-13 protein has been solved. 

Piroxicam, an oxicam (Figure 36-1), is a nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. Its long half-life (Table 36-1) permits once-daily dosing. 

Acidic enolic compounds (pyrazolidine-3,5-diones, oxicams)... 

Lornoxicam reaches peak plasma concentrations within 2 to 6 h and shows high degree of binding to plasma protein (99.7%). In contrast to other oxicams, lornoxicam has a short plasma elimination half-life of about 4 h (Olkkola et al., 1994) and is metabolised mainly to the inactive compound 5 -hydroxy-lornoxicam (Dittrich et al., 1990) and excreted in the urine ( 33%) and faeces ( 66%) (Hitzenberger et al., 1990). 

Tenoxicam is an oxicam similar to piroxicam and shares its nonselective COX inhibition, long half-life (72 hours), efficacy, and toxicity profile. It is available abroad but not in the USA. 

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