Heterocyclic Ring-Fused 1,2-Thiazines

The outstanding anti-inflammatory activity exhibited by sudoxicam (20), and piroxicam (29) (see Section II,D) has prompted exploration of structure-activity relationships (SAR) of oxicam anti-inflammatory agents. This 

Analogously, methyl 4-chlorosulfonylthiophene-3-carboxylate (156) was converted to 4-hydroxy-3-methoxy carbonyl-2-methyl-2H-thieno [3,4-e]-1,2-thiazine 1,1-dioxide (159), which with 2-aminothiazole gave 160. 

A number of halogenated derivatives of 155, 160, and 165 have been prepared.129 For example, the thieno-1,2-thiazine analog 166 has been converted to eneamine derivative 167 which has been acylated (phosgene/ triethylamine) to afford acid chloride 168. Treatment of 168 with 2-aminopyridine gave 169 (Eq. 36). This process is completely analogous to the 1,2-benzothiazine synthesis depicted in Eq. (6). 

Pfister and co-workers130 have also prepared the three isomeric thieno-l,2-thiazin-3-one ring systems. The acid chloride 171 of 3-(2-N-methylsulfamoyl)thiopheneacetic acid (170) with sodium bicarbonate gave 3,4-dihydro-2-methyl-3-oxo-2//-thieno[3,2-e]-l,2-thiazine 1,1-dioxide (172) (Eq. 37). 

Treatment of 172 with aromatic or heteroaromatic isocyanates yielded the expected 4-carbamoyl derivatives 173 claimed to have anti-inflammatory activity.130 4-Carbamoyl-3,4-dihydro-3-hydroxy-2-methyl-2/f-thieno [3,4-e]-and [2,3-e]-l,2-thiazine l,l-dioxides(174and 175) were prepared analogously 

Pfister and co-workers recently prepared derivatives of the third possible thieno-l,2-thiazin-4-one. Methyl 2-chlorosulfonylthiophene-3-car-boxylate (161) with glycine methyl ester gave intermediate 162, which afforded 

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Heterocyclic Ring-fused Thiazines and Ring-fused 2,1-Benzothiazine Derivatives... 

Multicyclic ring systems are also found to be present in synthetic heterocyclic pharmaceuticals. These drugs may be benzo derivatives of monocyclic heterocycles or they may contain other fused-on (said to be annelated or annulated) heterocyclic rings. An important example of a dibenzo derivative, namely, a derivative of the tricyclic phe-nothiazine ring system, is the valuable antihistamine methopromazine (9.142). Its synthesis employs conventional reactions of aromatic chemistry to constmct the interior thiazine ring, as is outlined in Scheme 9.84. 

The continuing interest in the chemistry of the 1,3-oxazines and the related thiazines and pyrimidines may arise in part from their versatile synthetic applicability and their pharmacological usefulness. Although six-membered saturated or partially saturated 1,3-heterocycles and their derivatives fused with a benzene ring have been thoroughly studied since the beginning of the twentieth century, much less attention has been paid to their saturated counterparts, the related cycloalkane-fused bicyclic 1,3-heterocycles. 

Progress in the chemistry of l,3-thiazin-4-ones is mainly attributable to their applications in the pharmaceutical area. In the search for new drugs, the most intensive investigation has focused on the modification of substituents in the thiazinone ring and in the syntheses of thiazinones fused with heterocycles. 

Volume 70 of Advances in Heterocyclic Chemistry consists of three chapters together with the Subject Index for Volumes 61 through 70. The first contribution by Dr. Istvan Hermecz (Chinoin, Hungary) continues with Part II of his set of three chapters on condensed pyridines. Part I, in Volume 69, covered pyrido[l,2-ft][l,2]oxazines, -thiazines, and -pyridazines, and the present chapter deals with [l,2-c]-fused 1,3-oxanes, 1,2-thiazines, and -pyrimidines. The third part will appear in a subsequent volume of our series and will deal with 1,4-oxazines and 1,4-thiazines, fused pyridine rings. 

Reactions with aromatic binucleophiles form fused ring heterocycles (00T7267). Thus, when the reaction is performed with 2-aminothiophenol, compound 99 is converted into 2-trifluoroacety 1-4/7-1,4-benzothiazine (identified by X-ray crystallography) (Scheme 106). In the case of thioethanolamine hydrochloride, the product is 2-trifluoroacetyl-47/-1,4-thiazine. 

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