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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

from EtOH-H20 gave 92.2 g of pure 35, mp 120-121.5°, [a]JSD -89°(c 1.04, CHC1,).4-(p-Hydroxyphenyl)-l-naphthaleneacetic Add (21). A solution of 4.4 g (0.015 mol) of 4-(p-methoxyphenyl)-l-naphthaleneacetic add (20) in 50 ml of AcOH was treated with 25 ml of 47% HI and heated at reflux for 4 hr. After standing overnight, the product was filtered off. Recrystallization from EtOAc-cyclohexane gave pure 21.

Notesol-induced seizures are shown in Table II. All nitrobenzamides exhibited protection which ranged from 20 to 60%. Nitrobenzamides having 3-methylphenyl and 2-methoxyphenyl substituents (3, 6,10,13) at position 1 of the thiocarbamide moiety in both 3-nitroas well as 4-nitrobenzamides were found to exhibit 60% protection against pentylenetetrazol-induced seizures. It is evident from Table II that all 3-nitrobenzamides elicited low mortalities after 24 hr in

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