Excretion and metabolism of a nonsteroidal antiinflammatory agent, 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxanilide 1,1-dioxide, in rat, dog, monkey, and man

Abstract

Metabolism of a Nonsteroidal Antiinflammatory Agent to the starting ester in DMSO, a slurry of NaOCHs in DMSO was added with stirring over a 1-hr period while maintaining the temp below 30°. After complete addn and 15 min of addl stirring, acidification (qxcess 3 N HC1), filtration, and recrystn (IPO) gave a 59% yield of the desired estgr Ic.2-Methyl-4-hydroxy-277-l,2-benzothiazine-3-carboxylic AcidMethyl Ester 1,1-Dioxide (VI).-A yellow soln resulted from a combination of 2.95 g (0.012 mole) of 4-hy droxy-277-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide, 2.4 ml of Mel, 11 ml of H20, 40 ml of EtOH, and 12 ml of 1 N NaOH.After standing at room temp for 18 hr the resulting heavy yellow ppt was filtered, washed with H20, and dried to give 2.4 g (78%) of VI, mp 162-165°. A sample in MeOH soln gave a wine-red color with 5% FeCI3.; Titration in 2:1 dioxane-H20 indicated neut equiv 266 (caled 269) and pffa = 8.4; nmr (DCC13) -2.04 (s, 1, exchanges with D20, enol OH), 1.8-2.4 (m, 4, arom protons), 6.05 (s, 3, OCHO, 7.06 (s, 3, NCH3). Anal. (CnH"N05S) C, H, N.By an analogous alkylating procedure using either Etl, PrI, allyl bromide, or benzyl bromide the corresponding 2-aIkyl-4hydroxy-277-l,2-benzothiazine-3-carboxylic acid methyl ester 1.1-dioxides were made (see Table IV).2-Benzyl-and 2-AUyl-2H-l,2-benz<jthiazin-4(3J?)-one 1,1-Dioxides.-The 2-step procedure employed for prepg these compds is essentially the same as that reported by Zinnes,8 et al, for the 2-Me analog. Alkylation of 277-1,2-benzothiazin-4 (377 )-one 1.1-dioxide ethylene ketal8 (II) with benzyl bromide gave a 75% yield of 2-benzyI-277-l,2-benzothiazin-4(377)-one 1,1-dioxide ethylene ketal, mp 83-86°. Anal. (C17H17NO4S) C, , N. Hy-drolysis8 of this ketal gave 88% yield of 2-benzyl-277-i ,2-benzothiazine-4(377)-one 1,1-dioxide, mp 123-126°. Anal. (CisHis-N03S) c, h, N.Alkylation of 277-1,2-benzothiazin-4 (377 )-one 1,1-dioxide ethylene ketal8 (II) with allyl bromide gave a 88% yield of 2-alIyl-277-1,2-benzothiazin-4(377)-one 1,1-dioxide ethyl eneketal, mp 75-77°. Anal. (CisHieNOiS) C, II, N. Hydrolysis8 of this ketal gave a 78% yield of 2-ally1-277-1,2-benzothiazin-4(377)one 1,1-dioxide as a viscous liquid which was purified by column chroma tog (silica gel G, E. Merck, A. G., eluted with CHCls). A sample was vacuum distd for analysis. Anal. (CnHuNOsS) C, , N. 2,N -Dimethyl-4-hydroxy-277-l ,2-benzothiazin-3-carboxanilide

1,2-Benzothiazines. 6. 3-Carbamoyl-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxides as antiinflammatory agents

“…3,4-Dihydro-5-methyl-3-phenyl-2//, SH- [1,3] oxazino [5,6-c ] -1,2benzothiazine-2,4-dione 6,6-Dioxide (13). A solution of 0.03 mol of phosgene in 28 g of benzene was diluted with 30 ml of tetrahydrofuran.…”

“…Of those reported, compound 2 appeared to be of particular interest, since a paper describing its metabolism was published. 3 We have independently found compound 2 to be a potent antiinflammatory agent and have prepared a variety of derivatives in an effort to find more active compounds and perhaps define structure-activity relationships (Scheme I).…”

Oxicams, a class of nonsteroidal anti‐inflammatory drugs and beyond

“…Further exploration of the anti‐inflammatory activities of structurally related 2‐arylbenzo[ b ]thiophene‐3(2 H )‐one 1,1‐dioxides and 1,3(2 H ,4 H )‐dioxoisoquinoline‐4‐carboxanilides revealed compounds with similar potency to that of phenylbutazone, with extended plasma half‐life in animal models. The related scaffold, 3,4‐dihydro‐2‐alkyl‐3‐oxo‐2 H −1,2‐benzothiazine‐4‐carboxamide 1,1‐dioxide, which contained an isosteric heterocyclic replacement of the dioxoisoquinoline nucleus, provided an even longer plasma half‐life and potent antiedema activity . As this series of 4‐carboxamides was being developed, compounds based on a 2‐alkyl‐4‐hydroxy‐2 H −1,2‐benzothiazine‐3‐carboxamide 1,1‐dioxide scaffold were also synthesized to fully develop the SAR for the 1,2‐benzothiazine 1,1‐dioxide nucleus .…”

“…The SAR of oxicams has been extensively explored for optimization of anti‐inflammatory activity, mainly during the first decades when the class of NSAIDs was introduced . As most of these experiments were conducted before the discovery of the importance of PGs and COX in inflammation, pharmacological models without in vitro experiments were used to carry out SAR investigations.…”