Patent ES-370861-A1 (ES)
Title: Benzothiazine dioxides
IPC: C07D/
Filed: 1969-08-26
Abstract: Novel compounds of Formul[mu] I and II and the base salts thereof with pharmacologically acceptable cations, wherein each of X and Y is hydrogen, fluorine, chlorine, bromine, nitro, alkyl or alkoxy having from one to five carbon atoms or trifluoromethyl R is piperidino, -N(CH 3 )R 4 , -OR 1 , or -NHR 2 , wherein R 1 is alkyl having from one to twelve carbon atoms or phenylalkyl having up to three carbon atoms in the alkyl moiety, and R 2 is hydrogen, alkyl having from one to eight carbon atoms, alkenyl having up to six carbon atoms, cyclo-alkyl having up to eight carbon atoms, phenylalkyl having up to three carbon atoms in the alkyl moiety, phenyl, nitrophenyl, naphthyl, piperidino, pyridyl, 3-methyl-2-pyridyl, 4-methyl-2- pyridyl, 5-methyl-2-pyridyl, 6-methyl-2- pyridyl, 4,6-dimethyl-2-pyridyl, 5-chloro-2- pyridyl, 5 - bromo - 2 - pyridyl, 5 - nitro - 2- pyridyl, 3 - hydroxy - 2 - pyridyl, 5 - carbamoyl- 2 - pyridyl, 2 - pyrazinyl, 2 - pyrimidyl, 4,5- dimethyl - 2 - pyrimidyl, 4 - pyrimidyl, 5- methyl - 3 - pyridazinyl, 6 - methoxy - 3- pyridazinyl, 1 - phenyl - 3 - pyrazolonyl, 2 - thiazolyl, 4 - methyl - 2 - thiazolyl, 4 - phenyl-2- thiazolyl, 5 - bromo - 2 - thiazolyl, 4,5 - dimethyl - 2 - thiazolyl, 3 - isothiazolyl, 2 - benzothiazolyl, 6 - methyl - 2. - benzothiazolyl, 4- chloro - 2 - benzothiazolyl, 6 - bromo - 2 - benzothiazolyl, 5 - chloro - 2 - benzoxazolyl, 1,3,4- thiadiazolyl, 5 - methyl - 1,3,4 - thiadiazolyl, 1,2,4 - triazolyl, 6 - phenyl - 1,2,4 - triazolyl, 7-indazolyl or mono- or di-substituted phenyl wherein each substituent is halogen, hydroxy, alkoxy or alkylthio having up to three carbon atoms, alkyl having up to four carbon atoms, trifluoromethyl, acetyl, methylsulfinyl or methylsulfonyl R 3 is hydrogen, alkyl having from one to six carbon atoms, alkenyl having up to four carbon atoms or phenylalkyl having up to three carbon atoms in the alkyl moiety R 4 is phenyl or chlorophenyl and Z is oxygen or sulfur, except when R is -OR 1 or -N(CH 3 )R 4 when it is oxygen are prepared (a) when R is -NHR 2 , by reacting a compound of Formula III or IV with a compound of formula R 2 NCZ, or (b) when Z is 0 and R is -NHR 2 or -N(CH 3 )R 4 , by reacting a corresponding benzothiazine-3- or 4-carboxylic ester with an amine of formula R 2 NH 2 or R 4 NH(CH 3 ), or (c) for compounds II in which -CZR is -COOR 1 , by reacting a corresponding benzothiazine - 4 - carboxanilide with an alcohol of formula R 1 OH, or (d) for compounds I in which -CZR is -COOR 1 , by reacting a 3 - oxo - 1,2 - benzothiazoline - 2- acetic acid alkyl ester with an alkali metal alkoxide or phenalkoxide in a polar organic solvent and acidifying the product to produce a corresponding alkyl or phenylalkyl 3,4-dihydro-4-oxo-2H- 1,2-benzothiazine 1,1-dioxide and, if desired, alkylating, alkenylating or phenylalkylating this compound in the 2-position. Compounds I in which R 3 is H may also be prepared by hydrogenolysis of corresponding compounds in which R 3 is benzyl. Compounds I in which R 2 is methylsulphinylphenyl may also be prepared by oxidation of corresponding compounds in which R 2 is methylthiophenyl. 3,4 - Dihydro - 2 - methyl - 3 - oxo - 2H - 1,2- benzothiazine-1,1 -dioxide is prepared by reacting N-methyl o-toluene-sulphonamide with dry ice to form 2-(N-methylsulphamoyl) phenylacetic acid and cyclizing this by treatment with p-toluene sulphonic acid. 3,4 - Dihydro - 2,7 - dimethyl-3- oxo - 2H - 1,2 - benzothiazine - 1,1 - dioxide is similarly prepared. Pharmaceutical compositions having antiinflammatory activity, for oral or parenteral activity, comprise one of the above novel compounds together with a pharmaceutical carrier.