Synthesis and antiinflammatory activity of some 3-carboxamides of 2-alkyl-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide

Abstract

A number of 3-carboxamides of 2-alkyl-4-hydroxy-2i7-l,2-benzothiazine 1,1-dioxide were synthesized and their antiinflammatory activity was investigated. A procedure for isomerizing saccharin-2-acetic ester to 4-hydroxy-2if-l,2-benzothiazine-3-carboxylic ester 1,1-dioxide in DMSO is described. Reasons for the enhanced acidity observed for the 3-carboxamides as compared to the 3-carboxylic ester derivatives of this heterocyclic system are discussed. Most compounds were inhibitors of carrageenin-induced rat foot edema and some exceeded phenylbutazone in potency. Similar activity was also demonstrated in adrenalectomized rats. Of the 49 compounds tested, 4-hydroxy-2-methyl-2Zf-l,2-benzothiazine-3-carboxanilide 1,1-dioxide proved most active with approximately twice the potency of phenylbutazone and an IDM% of 37 mg/kg in the rat foot edema test.The search for more effective antiinflammatory agents has led medicinal chemists to explore a wide variety of chemical structures.1•2 A majority of these compounds, especially those with proven clinical efficacy, are acidic, i.e., carboxylic acids such as aspirin, indomethacin, and flufenamic acid, or /3-diketones such as phenylbutazone. Some antiinflammatory agents have previously been found in these laboratories among acidic /3-diketones, such as 2-ary 1-1,3-indandiones3 and certain ß-keto amides such as 1,3-dioxoisoquinoline-4-carboxanilides4a and 3-oxo-l,2-benzothiazine-4-carboxamides.4b The pKa's of these active classes of compounds were generally in the range of 4-6, when measured in 2:1 dioxane-H20. The 1,2-benzothiazin-4-(3.60-one 1,1-dioxide heterocyclic system has received little attention and, in view of the activity found for the aforementioned /3-diketonic acids,3•4 5appeared attractive as a potential source of acidic, and possibly biologically active, compounds. This present paper reports the discovery of potent antiinflammatory activity for certain acidic /3-keto carboxamides derived from this class of compounds.Chemistry.-Comparatively little has been published on the 26f-l,2-benzothiazin-4(36f)-one 1,1-dioxide system.5-10 Abe and coworkers6 were the first to apply the principle of the Gabriel-Colman rearrangement of phthalimideslla>b to the rearrangement of N-phenacy¡saccharin which gave 3-benzoy 1-261-1,2-benzothiazin-4(366)-one 1,1-dioxide (la). Zinnes, et al.,1

Oxicams Bind in a Novel Mode to the Cyclooxygenase Active Site via a Two-water-mediated H-bonding Network

“…H, benzyl, allyl, ethyl, propyl) either removes the interaction between the protein residues or introduces steric bulk that prevents binding in this region. Thus, such substituents were less active than the 2-methyl compounds (39,41). Among ana- logs of 3-carboxamides with anilide substituents, meta-substituted anilides exhibit more potent activity than para-substituted anilides.…”

“…The methyl substituent at the 2 position of the benzothiazine is optimal for anti-inflammatory activity (39). This methyl group interacts with residues Leu-359, Tyr-355, and Val-349.…”

Tilcotil® Studies [3+2] additions with isothiazol‐3(2H)‐one 1,1‐dioxide

“…-The ring-enlargement procedure [3], when applied directly to the precursors 18a, 20a, and 21 (Schemes 3 and 4 ) , does not give satisfactory results. It can be assumed that the reaction involves opening of the 'saccharin ring' to a diester [26], which then undergoes a Dieckmann cyclization to the p-keto-ester 6 (Scheme 1).…”

“…[ 2 ] , i.e. that the saccharin derivative 3 (Scheme I) undergoes a methoxide-induced ring enlargement to the thiazinone 4; the procedure has subsequently been extended [3] to the rearrangement of 5, which similarly yields 6. Piroxicam 1 is then obtained from 6 by a chemoselective methylation, affording 7, followed by aminolysis with 2-aminopyridine [4].…”

Synthesis of Potential Biologically Active 1,2-Benzothiazin-3-yl-quinazolin-4(3H)-ones

“…1) Among these, 1,2-benzothiazine-3-carboxamide-1,1-dioxides such as piroxicam, 2) ampiroxicam 3) and meloxicam 4) are well known for their analgesic and anti-inflammatory activities. Some of the 3,4-dihydro-1,2-benzothiazine-3-carboxylate 1,1-dioxide a-ketomide 5) and P(2)-P(3) peptide mimetic aldehyde 6) compounds act as potent calpain I inhibitors, while 1,4-benzothiazines generally possess significant antifungal activities.…”