IE43307B1 - 5,6-diaryl-1,2,4-triazines - Google Patents

Description

The present invention relates to 5,6-diaryl1,2,4-triazines, which are topically-active anti-inflammatory agents.

Inflammation is an essentially protective and normal response to injury, although the etiology and pathogenesis of many inflammatory conditions remain obscure. In general, anti-inflammatory agents are employed primarily to relieve the symptoms of inflammation. In such symptomatic therapy, topically-applied anti-inflammatory agents present special problems. Inflammatory conditions calling for the topical application of ari anti-inflammatory agent are almost exclusively treated with steroids. Topically-applied steroids, however, may carry considerable systemic toxicity. Thus, the need continues for safer, better tolerated topically-active anti-inflammatory agents. 3-Alkoxy, 3-alkyl, and 3-alkylthio triazines having in the 5 and 6 positions unsubstituted phenyl groups are known. 3-Methylthio-5,6-bis(4-methoxyphenyl)-1,2,4triazine also was disclosed previously. However, the only utility disclosed for these prior art compounds was as anti-bacterial agents. No utility as anti-inflammatory agents was disclosed in the prior art.

The object of the present invention is to provide novel 5,6-diaryl-l,2,4-triazine compounds which are topically active anti-inflammatory agents.

The present invention, provides novel 5,5diaryl-l,2,4-triazines having the formula, -24 3 3 0 7 Rs.

VA ·. · ,9 izYv'· wherein R is (°)nRp in which n is an integer which is either 0 or 1, and is C^-Cg alkyl, Ο-,-Οθ aralkyl, Cg-Οθ cycloalkyl, or C4-Cg (cycloalkyl) alkyl; and Rj and R3 independently are halo, C^-Cj alkyl, Cj-C3 alkoxy and di(C^-C3 alkyl)amino; and the pharmaceutically-acceptable acid addition salts of basic members thereof.

The present invention also provides a process for preparing the novel 5,6-diaryl-l,2,4-triazines of formula I φ wherein R, Rj and R3 are as defined above, which comprises reacting a triazine compound of the formula wherein Rj and R3 are as defined above and X^is chloro or mercapto, with a compound of the formula R1 “ Y 111 wherein R^ is as defined above and Y is halo, triphenylphos-3·» 43307 phoniumhalide or -O-alkalimetal.

There also are provided anti-inflamratory compositions which comprise an inert carrier and as active ingredient a compound of the formula I wherein R is hydrogen 5 or -(X^R^, where X is oxygen or sulphur,.n is an integer. which is either 0 or 1, and Rx is Cg-Cg alkyl, C7~Cg aralkyl Cg-Cg cycloaikyl, or C^-Cg (cycloaikyl)alkyl; and Rg and Rg independently are halo, C^-Cg alkyl, C^-Cg alkoxy and di(C^-Cg alkyl)amino; and the pharmaceutically-acceptable acid addition salts of basic members thereof.

The compounds of formula I are useful as topically active anti-inflammatory agents in warm-blooded mammals, such as guinea pigs, mice, rats, dogs, monkeys, or humans.

As used above, the term C^-Cg alkyl includes 15 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tert-butyl, pentyl, isopentyl, 1-methylbutyl, 1-ethyIpropyl, neopentyl, tert-pentyl, 1,2-dimethyIpropyl, hexyl, isohexyl, 2-ethylbutyl, 1-ethyl-1-methyIpropyl, heptyl, 2-ethy1-1-methylbutyl, 2,4-dimethylpentyl, octyl, 2o 2-ethylhexyl, or 1,1-diethylbutyl.

The term Cy-Cg aralkyl includes benzyl, 2phenylethyl, p-methyIbenzyl, m-methylbenzyl, or o-mehhylbenzyl.

The term Cg-Cg cycloaikyl includes cyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-ethy1-3-methylcyclobutyl, cyclopentyl, 3-isopropylcyclopentyl, cyclohexyl, 1-methylcyclohexyl, 2,5-dimethylcyclohexyl, cycloheptyl, 5-methylcycloheptyl, or cyclooctyl. -443307 The term C^-Cg (cycloalkyl)alkyl includes cyclopropylmethyl, 3-cyclopropyl-2-methylbutyl, 3-(2methylcyclobutyl)propyl, 2-cyclopentylethyl, 4-methylcyclohexylmethyl, or cycloheptylmethyl.

The term C^-Cg alkoxy means methoxy, ethoxy, propoxy, and isopropoxy. The term C^-Cg alkyl includes methyl, ethyl, propyl, and isopropyl.

The term halo rfeans fluoro, bromo, chloro, and iodo.

Illustrative of the triazine compounds of formula I are the following: .6- bis(4-methoxyphenyl)-1,2,4-triazine, .6- bis(4-dimethylaminophenyl)-1,2,4-triazine, .6- bis(4-dipropylaminophenyl)-1,2,4-triazine, -(4-diethylaminophenyl)-6-(4-methoxyphenyl)1,2,4-triazine, .6- bis(4-methoxyphenyl)-3-methy1-1,2,4-triazine, 3-ethyl-5,6-bis(4-methoxyphenyl-l,2,4-triazine, .6- bis(4-methoxyphenyl)-3-propyl-l,2,4-triazine, 3-isopropyl-5,6-bis(4-methoxyphenyl)-1,2,4triazine, 3-tert-butyl-5,6-bis(4-methoxyphenyl)-1,2,4triazine, 3-(1,2-dimethylpropyl)-5,6-bis(4-methoxyphenyl)1,2,4-triazine, 3-heptyl-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, .6- bis (4-ethoxyphenyl)-3-methy1-1,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-ethyl-l,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-propyl-l,2,4-triazine, -55.6- bis(4-ethoxyphenyl)-3-isopropyl-l,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-hexyl-l,2,4-triazine, 3-ethyl-5,6-bis(4-propoxyphenyl)-1,2,4-triazine, 3-(1-methylbutyl)-5,6-bis(4-propoxyphenyl)-1,2,4 triazine, 3-neoheptyl-5,6-bis(4-propoxyphenyl)-1,2,4triazine, .6- bis(4-isopropoxyphenyl)-3-methyl-l,2,4-triazine, 3-sec-butyl-5,6-bis(4-isopropoxyphenyl)-1,2,4triazine, .6- bis(4-isopropoxyphenyl)-3-oxtyl-l,2,4-triazine, - (4-methoxyphenyl)3-methyl-6-(4-propoxyphenyl)1,2,4-triazine, 6- (4-ethoxyphenyl)-5-(4-isopropoxyphenyl)-3(2,3,4-trimethylpentyl)-1,2,4-triazine, .6- bis(4-dimethylaminophenyl)-3-methyl-l,2,4triazine, .6- bis(4-dimethylaminophenyl)-3-ethyl-l,2,4triazine, .6- bis(4-dimethylaminophenyl)-3-propyl-l,2,4triazine, .6- bis(4-diemthylaminophenyl)-3-isopropyl1,2,4-triazine, .6- bis(4-dimethylaminophenyl)-3-isopentyl1,2,4-triazine, -65.6- bis(4-dimethylaminophenyl)-3-(2-ethylhexyl)1,2,4-triazine, .6- bis(4-diethylaminophenyl)-3-methyl-l,2,4triazine, .6- bis(4-diethylaminophenyl)-3-ethyl-l,2,4-triazine, .6- bis(4-diethylaminophenyl)-3-propyl-l,2,4-triazine, .6- bis(4-diethylaminophenyl)-3-isopropyl-1,2,4triazine, .6- bis(4-diethylaminophenyl)-3-(2,2,3-trimethylbutyl)-1,2,4-triazine, .6- bis(4-dipropylaminophenyl)-3-methyl-l,2,4trlazine, 3-sec-butyl-5,6-bis(4-dipropylaminophenyl)-1,2,4triazine, .6- bis(4-dipropylaminophenyl)-3-(2-ethylbutyl)1,2,4-triazine, .6- bis(4-diisopropylaminophenyl)-3-ethyl-l,2,4triazine, .6- bis(4-diisopropylaminophenyl)-3-tert-pentyl1,2,4-triazine, .6- bis(4-diisopropylaminophenyl)-3-(2,2,4-trimethylpentyl)-1,2,4-triazine, 6-(4-diisopropylaminophenyl)-5-(4-dimethylaminophenyl) -3-neoheptyl-l,2,4-triazine, -(4-diisopropylaminophenyl)-6-(4-ethoxyphenyl)3-methyl-l,2,4-triazine, -7433 0 7 3-benzyl-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, .6- bis(4-methoxyphenyl)-3-(m-methylbenzyl)-1,2,4triazine, .6- bis(4-ethoxyphenyl)-3-(2-phenylethyl)-1,2,4triazine, 3-(1-phenylethyl)-5,6-bis(4-propoxyphenyl)-1,2,4triazine, .6- bis(4-isopropoxyphenyl)-3-(o-methyIbenzyl)1,2,4-triazine, 3-benzyl-5-(4-methoxyphenyl)-6-(4-propoxyphenyl)1,2,4-triazine, .6- bis(4-diethylaminophenyl)-3-(p-methyIbenzyl)1,2,4-triazine, -(4-diethylaminophenyl)-6-(4-diisopropylaminophenyl)-3-(2-phenylethyl)-1,2,4-triazine, 3-benzyl-6-(4-diethylaminophenyl)-5-(4-ethoxyphenyl)-1,2,4-triazine, 3-cyclopropyl-5,6-bis(4-methoxyphenyl)-1,2,4triazine, 3-oyclopentyl-5,6-bis(4-propoxyphenyl)-1,2,4triazine, 3-cyclobutyl-5-(4-ethoxyphenyl)-6-(4-methoxyphenyl) -1,2,4-triazine, 3-cyclooctyl-5,6-bis(4-dimethylaminophenyl)-1,2,4triazine, .6- bis(4-dipropylaminophenyl)-3-(2-ethylcyclopropyl)-1,2,4-triazine, -(4-diethylaminophenyl)-6-(4-dipropylaminophenyl) 3-(2-ethylcyclobutyl)-1,2,4-triazine, -843307 3-cycloheptyl-6-(4-dipropylaminophenyl)-5-(4methoxyphenyl)-1,2,4-triazine. 3-(2-cyolohexylethyl)-5,6-bis(4-ethoxyphenyl)1,2,4-triazine, 3-cyclobutyImethy1-5,6-bis(4-isopropoxyphenyl)1,2,4-triazine, -(4-ethoxyphenyl)-6-(4-isopropoxyphenyl)-3-(2methylcyolohexylmethyl)-1,2,4-triazine, 3-oyclopropylmethyl-5,6-bis(4-diethylaminophenyl)10 1,2,4-triazine, .6- bis(4-dipropylaminophenyl)-3-[2-(2-methylcyclobutyl)ethyl]-1,2,4-triazine, 3-cycloheptylmethyl-5,6-bis(4-diisopropylaminophenyl)-1,2,4-triazine, 15 3-(1-cyclohexylethyl)-5-(4-diethylaminophenyl)-6(4-dimethylaminophenyl)-1,2,4-triazine, 3-cyolopentylmethyl-5-(4-diethylaminophenyl)-6(4-ethoxyphenyl)-1,2,4-triazine, 3-methoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, 20 3-ethoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, .6- bis(4-methoxyphenyl) -3-propoxy-l,2,4-triazine, 3-isopropoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, 3-hexyloxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, 25 3-(1,2-diethylbutoxy)-5,6-bis(4-methoxyphenyl)1,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-methoxy-1,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-ethoxy-l,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-propoxy-l,2,4-triazine, -943307 .6- bis(4-ethoxyphenyl)-3-isopropoxy-l,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-neopentyloxy-l,2,4triazine, .6- bis(4-ethoxyphenyl)-3-(l-ethyl-2-methylbutoxy)1,2,4-triazine, 3-methoxy-5,6-bis(4-propoxyphenyl)-1,2,4-triazine, 3-ethoxy-5,6-bis(4-propoxyphenyl)-1,2,4-triazine, 3-propoXy-5,6-bis(4-propoxyphenyl)-1,2,4-triazine, 3-hexyloxy-5,6-bis(4-propoxyphenyl)-1,2,4-triazine, 3-ethoxy-5,6-bis(4-isopropoxyphenyl)-1,2,4-triazine, 3-(1-ethylbutoxy)-5,6-bis(4-isopropoxyphenyl)1,2,4-triazine, 3-(2-ethylhexyloxy)-5,6-bis(4-isopropoxyphenyl)1,2,4-triazine, 6-(4-ethoxyphenyl)-5-(4-isopropoxyphenyl)-3(2,2,3-trimethylbutoxy)-1,2,4-triazine, .6- bis(4-dimethylaminophenyl)-3-methoxy-l,2,4triazine, .6- bis(4-dimethylaminophenyl)-3-ethoxy-l,2,4triazine, .6- bis(4-dimethylaminophenyl)-3-propoxy-l,2,4triazine, .6- bis(4-dimethylaminophenyl)-3-isopropoxy-l,2,4triazine, 3-butoxy-5,6-bis(4-dimethylaminophenyl)-1,2,4triazine, .6- bis(4-dimethylaminophenyl)-3-isoheptyloxy1,2,4-triazine, -1043307 .6- bis(4-diethylaminophenyl)-3-methoxy-l,2,4triazine, .6- bis(4-diethylaminophenyl)-3-ethoxy-l,2,4triazine, 5 5,6-bis(4-diethylaminophenyl)-3-propoxy-l,2,4triazine, .6- bis(4-diethylaminophenyl)-3-isopropoxy-l,2,4triazine, .6- bis(4-diethylaminophenyl)-3-pentyloxy-l,2,410 triazine, .6- bis(4-dipropylaminophenyl)-3-methoxy-l,2,4triazine, 3-tert-butoxy-5,6-bis(4-dipropylaminophenyl)1,2,4-triazine, 15 5,6-bis(4-dipropylaminophenyl)-3-neoheptyloxy1,2,4-triazine, .6- bis(4-diisopropylaminophenyl)-3-methoxy1,2,4-triazine, 3-butoxy-5,6-bis(4-diisopropylaminophenyl)-1,2,420 triazine, .6- bis(4-diisopropylaminophenyl)-3-(1-ethyl1-methylpropoxy)-1,2,4-triazine, -(4-diisopropylaminophenyl)-6-(4-dimethylaminophenyl) -3-methoxy-l,2,4-triazine, 25 6-(4-diethylaminophenyl)-3-ethoxy-5-(4-methoxyphenyl ) - 1 , 2 , 4- triaz ine , 3-benzyloxy-5,6-bis(4-ethoxyphenyl)-1,2,4-triazine, .6- bis(4-isopropoxyphenyl)-3-(2-phenylethoxy)1,2,4-triazine, -1143307 -(4-ethoxyphenyl)-3-(o-methylbenzyloxy)—6-(4propoxyphenyl)-1,2,4-triazine, 3-benzyloxy-5,6-bis(4-dimethylaminophenyl)-1,2,4triazine, - (4-diethylaminophenyl)-6-(4-diisopropylaminophenyl) -3-(1-phenylethoxy)-1,2,4-triazine, 6- (4-dipropylaminophenyl)-5-(4-methoxyphenyl)-3(m-methylbenzyloxy)-1,2,4-triazine, 3-cycloheptyloxy-5,6-bis(4-ethoxyphenyl)-1,2,4triazine, 3-cyclobutyloxy-5,6-bis(4-isopropoxyphenyl)-1,2,4triazine, 3-cyclohexyloxy-5-(4-ethoxyphenyl)-6-(4-propoxyphenyl )-1,2,4-triazine, .6- bis(4-diethylaminophenyl)-3-(2-methylcyclopentyloxy)-1,2,4-triazine, 3-cyclobutyloxy-5,6-bis(4-diisopropylaminophenyl)1,2,4-triazine, 3-cyclohexyloxy-6-(4-diethylaminophenyl)-5-(4dimethylaminophenyl)-1,2,4-triazine, -(4-dipropylaminophenyl)-6-(4-ethoxyphenyl)-3(2-ethyl-3-methylcyclopentyloxy)-1,2,4-triazine, .6- bis(4-methoxyphenyl)-3-(2-methylcyclobutylmethoxy)-1,2,4-triazine, 3-(3-methylcyclopentylmethoxy)-5,6-bis(4-propoxyohenyl)-1,2,4-triazine, 3-cyclohexylmethoxy-5,6-bis(4-dimethylaminophenyl) .,2,4-triazine, 3-cyclopropylmethoxy-5,6-bis(4-dipropylaminohenyl)-l,2,4-triazine, -125-(4-diethylaminophenyl)-6-(4-dimethylaminophenyl)3-[2-(2-ethylcyclobutyl)ethoxy]-1,2,4-triazine, 3-(4-cyclopropylbutoxy)-6-(4-dipropylaminophenyl)5-(4-isopropoxyphenyl)-1,2,4-triazine, 3-ethylthio-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, .6- bis(4-methoxyphenyl)-3-propylthio-l,2,4triazine, 3-isopropylthio-5,6-bis(4-methoxyphenyl)-1,2,4triazine, 3-butylthio-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, .6- bis(4-methoxyphenyl)-3-neoheptylthio-l,2,4triazine, .6- bis(4-ethoxyphenyl)-3-methylthio-l,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-ethylthio-l,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-propylthio-l,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-isopropylthio-l,2,4triazine, bis (4-ethoxyphenyl)-1,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-(3-methylpentylthio)1,2,4-triazine, .6- bis(4-ethoxyphenyl)-3-octylthio-l,2,4-triazine, 3-methylthio-5,6-bis(4-propoxyphenyl)-1,2,4-triazine, 3-ethylthio-5,6-bis(4-propoxyphenyl)-1,2,4-triazine, .6- bis(4-propoxyphenyl)-3-propylthio-l,2,4triazine, 3-isopropylthio-5,6-bis(4-propoxyphenyl)-1,2,4triazine, 3-(1,2-dimethylpropylthio)-5,6-bis(4-propoxyphenyl,* 1,2,4-triazine, -133-heptyloxy-5,6-bis(4-propoxyphenyl)-1,2,4-triazine, .6- bis(4-isopropoxyphenyl)-3-methylthio-l,2,4triazine, .6- bis(4-isopropoxyphenyl)-3-pentylthio-l,2,4triazine, 6-(4-isopropoxyphenyl)-3-methylthio-5-{4-propoxyphenyl) -1,2, 4-triazine, .6- bis(4-dimethylaminophenyl)-3-methylthio-l,2,4triazine, .6- bis(4-dimethylaminophenyl)-3-ethylthio-l,2,4triazine, .6- bis(4-dimethylaminophenyl)-3-propylthio-ί,2,4triazine, .6- bis(4-dimethylaminophenyl)-3-isopropylthio1,2,4-triazine, .6- bis(4-dimethylaminophenyl)-3-isoheptylthio1,2,4-triazine, .6- bis(4-diethylaminophenyl)-3-methylthio-l,2,4triazine, .6- bis(4-diethylaminophenyl)-3-ethylthio-l,2,4triazine, .6- bis(4-diethylaminophenyl)-3-propylthio-l,2,4triazine, .6- bis(4-diethylaminophenyl)-3-isopropylthio-l,2,4triazine, .6- bis(4-diethylaminophenyl)-3-pentylthio-l,2,4triazine, .6- bis(4-diethylaminophenyl)-3-(1,1-dimethylhexylthio-1,2,4-triazine, -1443307 .6- bis(4-dipropylaminophenyl)-3-ethylthio-l,2,4triazine, 3-(1,2-dimethylpropylthio)-5,6-bis(4-dipropylaminophenyl)-1,2,4-triazine, ,6-bis(4-dipropylaminophenyl)-3-(l-ethyl-2methylbutyIthio)-1,2,4-triazine, , 6-bis(4-diisopropylaminophenyl)-3-ethylthio1,2,4-triazine, .6- bis(4-diisopropylaminophenyl)-3-isobutylthio10 1,2,4-triazine, .6- bis(4-diisopropylaminophenyl)-3-(2-methylpentyIthio)-1,2,4-triazine, 6- (4-diethylaminophenyl)-5-(4-diisopropylaminophenyl) -3-isohexylthio-l,2,4-triazine, -(4-dimethylaminophenyl)-6-(4-isopropoxyphenyl)-3(2-isopropyl-3-methylbutylthio)-1,2,4-triazine, 3-benzylthio-5,6-bis(4-methoxyphenyl)-1,2,4triazine, 6-(4-isopropoxyphenyl)-5-(4-methoxyphenyl)-3-(220 phenylethylthio)-1,2,4-triazine, .6- bis(4-dipropylaminophenyl)-3-(g-methylbenzylthio)-1,2,4-triazine, 6-(4-diethylaminophenyl)-5-(4-dipropylaminophenyl)-3-(o-methylbenzylthio)-1,2,4-triazine, 3-benzylthio-5-(4-dimethylaminophenyl)-6-(4methoxyphenyl)-1,2,4-triazine, 3-(2-isopropylcyclopentylthio)-5,6-bis(4-methoxyphenyl) -1,2,4-triazine, -1543307 3-(2-ethylcyclobutylthio)-5,6-bis(4-isopropoxyphenyl) -1,2, 4- triazine, 3-eyclobutylthio-6-(4-ethoxyphenyl)-5-(4-methoxyphenyl)-1,2,4-triazine, 3-cyclopropylthio-5,6-bis(4-dimethylaminophenyl)1,2,4-triazine, .6- bis(4-diethylaminophenyl)-3-(4-ethylcycloh6xylthio)-1,2,4-triazine, 3-cyclopentylthio-5-(4-dimethylaminophenyl)-6-(4dipropylaminophenyl)-1,2,4-triazine, 6-(4-dipropylaminophenyl)-5-(4-ethoxyphenyl)-3(2-methylcyclopropylthio)-1,2,4-triazine, 3-(3-methylcyclohexyImethylthio)-5,6-bis(4-methoxy phenyl)-1,2,4-triazine, 3-(2-cyclobutylethylthio)-5,6-bis(4-ethoxyphenyl)1,2,4-triazine, 3-cyclooctylthio-6-(4-isopropoxyphenyl)-5-(4propoxyphenyl)-1,2,4-triazine, 3-cyclopropylmethylthio-5,6-bis(4-dimethylaminophenyl ) - 1 , 2 , 4 - tri a z ine , .6- bis(4-dipropylaminophenyl)-3-[2-(4-methylcyclopentyl)ethylthio]-1,2,4-triazine, -(4-diethylaminophenyl)-6-(4-dipropylaminophenyl) 3-(2,3-dimethylcyclopentylmethylthio)-1,2,4-triazine, 3-(2-cyclobutylbutylthio)-6-(4-dimethylamino>henyl)-5-(4-methoxyphenyl)-1,2,4-triazine, .6- bis(4-fluorophenyl)-3-methyl-l,2,4-triazine, .6- bis(4-fluorophenyl)-3-methoxy-l,2,4-triazine, .6- bis(4-fluorophenyl)-3-methylthio-l,2,4riazine, -16•13 3 0 7 3-methy1-5,6-bis(4-methylphenyl)-1,2,4-triazine, 3-methoxy-5,6-bis(4-methylphenyl)-1,2,4-triazine, .6- bis(4-methylphenyl)-3-methylthio-l,2,4triazine, - (4-fluorophenyl)-3-methyl-6-(4-methylphenyl)1,2,4-triazine, 6- (4-fluorophenyl)-3-methoxy-5-(4-methylphenyl)1,2,4-triazine, - (4-methoxyphenyl)-6-(4-methylphenyl)-3-methylthio-l , 2,4-triazine, 6- (4-dimethylaminophenyl)-3-methy1-5-(4-methylphenyl) -1,2,4-triazine, -(4-dimethylaminophenyl)-6-(4-fluorophenyl)-3methoxy-1,2,4-triazine, - (4-chlorophenyl)-6-(4-fluorophenyl)-3-methy11,2,4-triazine, 6- (4-chlorophenyl)-3-neopentyloxy-5-(4-propylphenyl)-1,2,4-triazine, 3-(2,3-dimethylpentyIthio)-5-(4-ethylphenyl)-6(4-isopropoxyphenyl)-1,2,4-triazine, 3-Benzyl-5-(4-methylphenyl)-6-(4-propylphenyl)1,2,4-triazine, 6-(4-dimethylaminophenyl)-5-(4-isopropylphenyl)3-£-methylbenzyloxy-l,2,4-triazine, 3-cyclobutyl-5-(4-ethoxyphenyl)-6-(4-ethylphenyl)1,2,4-triazine, 3-cyclopropyloxy-6-(4-dipropylaminophenyl)-5(4-fluoropheny1)-1,2,4-triazine, .6- bis(4-fluorophenyl)-3-(3-methyleyelohexylthio)-1,2,4-triazine, -174 3 3 0^ ,6-bis(4-ethylphenyl)-3-[2-(3-methylcyClopentyl)ethyl]-1,2,4-triazine, 3-cyclobutylmethoxy-5-(4-diethylaminophenyl)-6(4-methylphenyl)-1,2,4-triazine, and the pharmaceutically-acceptable acid addition salts of the basic triazines.

The preferred triazines are those wherein R2 and R3 in the above-defined formula are cj_“C3 alkoxy. More preferably, R2 and Rg will be the same, and most preferably are methoxy. With respect to the substituent in the 3position, the preferred groups are C-^-Cg alkyl, C^-Cg alkoxy, and C2-Cg alkylthio. More preferably, the 3-substituent is C^-Cg alkyl or C^-Cg alkoxy. Most preferably, the 3-substituent is C^-Cg alkyl or C^-C3 alkoxy.

The compounds of formula I are prepared by a variety of methods known to those having ordinary skill in the art. Starting materials and intermediates also are prepared by known methods. The preparation of 5,6-diaryl1,2,4-triazines is described generally by J. G. Erickson in The 1,2,3- and 1,2,4- Triazines, Tetrazines and Pentrazines, The Chemistry of Heterocyclic Compounds, Vol. 10, Interscience Publishers, Inc., New York, Ν.Ϋ., 1956, Chapter II, pp. 44-84. The 5,6-diaryl-l,2,4-triazines which are unsubstituted in the 3-position can be prepared by the catalytic reduction of the corresponding 3-chlorotriazines.

The specific procedure employed to prepare a given 3-substituted-5,6-diary1-1,2,4-triazine in part is dependent -18upon the substituent in the 3-position. For example, 3-alkyl-, 3-aralkyl-, 3-cycloalkyl-, and 3-(cycloalkyl)alkyl5, 6-diaryl-l, 2, 4-triazines can be prepared from 3-chloro5,6-diaryl-l,2,4-triazines by the procedure of E. C. Taylor and S. F. Martin [J. Amer. Chem. Soc., 94, 2874 (1972)] which involves the nucleophilic displacement of chlorine by a Wittig reagent which may be generated in situ from an alkyl-, aralkyl-, cycloalkyl-, or (cycloalkyl)alkyltriarylphosphonium halide. 3-Chloro-5,6-diaryl-l,2,4-triazines also can be employed to prepare the 3-alkoxy, 3-aralkoxy-, 3-cycloalkoxy-, 3-(cycloalkyl)alkoxy-, 3-alkylthio-, 3-aralkylthio-, 3-cycloalkylthio-, and 3-(cycloalkyl)alkylthio-5,6-diaryl1.2.4- triazines via the nucleophilic displacement of chlorine by the appropriate alcohol or thiol. The 3-alkylthio-, 3aralkylthio-, 3-cycloalkylthio-, and 3-(cycloalkyl)alkylthio- compounds can be converted to the 3-alkoxy-, 3-aralkoxy-, 3-cycloalkoxy-, and 3-(cycloalkyl)alkoxy-5,6-diaryl-l,2,4triazines, again via nucleophilic displacement by the appropriate alcohol. The 3-alkylthio-, 3-aralkylthio-, 3-cycloalkylthio and 3-(cycloalkyl)alkylthiotriazines also can be prepared by treating a 3-mercapto-5,6-diaryl1.2.4- triazine with the appropriate hydrocarbyl halide in the presence of base. 3-Chloro-5,6-diaryl-l,2,4-triazines are readily obtained by treating the appropriate 3-hydroxytriazine with phosphorus oxychloride, (see Patent Specification No. 42782). 3-Hydroxyand 3-mercapto-5,6-diaryl-l,2,4-triazines in turn can be prepared by condensing -1943307 an appropriate benzil with semicarbazide or thiosemicarbazide, respectively.

The required benzils are prepared by the oxidation of the corresponding benzoins with copper sulfate in pyridine? see Η. T. Clarke and Ε. E. Driger, Org. Synthesis, Coll. Vol. £, 87 (1941). The benzoins are prepared by the condensation of aromatic aldehydes with cyanide ion; see W.

S. Ide and J. S. Buck, Org. Reactions, £, 269 (1948).

Certain of the 5,6-diaryl-l,2,4-triazines described herein are sufficiently basic to form acid addition salts, especially when the triazine contains one or more dialkylamino groups on the phenyl rings. Pharmaceuticallyacceptable acid addition salts are well known to those skilled in the art and in general are formed by reacting in a mutual solvent a stoichiometric amount of a suitable acid with a basic triazine. Such salts should not be substantially more toxic to warm-blooded animals than the triazines.

While the choice of a salt-forming acid is not critical, in some instances a particular acid may result in a salt having special advantages, such as ready solubility, or ease of crystallization. Representative and suitable acids include, among others, the following: hydrochloric, hydrobromic, hydriodic, sulfuric, nitric, phosphoric, methanesulfonic, or g-toluenesulfonic As stated hereinbefore, the compounds of formula I are useful in treating inflammation in a warm-blooded mammal when administered topically to such animal.

A modification of the method of Winder was used to neasure the anti-inflammatory activates of the compounds of :ormula I; see C. V, Winder, et al., Arch. Int. Pharmacodyn., -2043307 116, 261 (1958). Albino guinea pigs of either sex, weighing 225-300 grains, were shaved on the back and chemically depilated (Nail® Lotion Hair Remover, Carter Products, N.Y., N.Y.) 18-20 hours before exposure to ultraviolet light. The animals, in groups of four and bearing identifying ear tags, , 2 were treated by applying to an area of skin of about 12 cm a solution of test compound dissolved in 0.1 cc of ethanol.

The control treatment consisted of administering only the drug vehicle, ethanol, to a group of four animals. Groups of four animals each were given different treatment levels of test compound to obtain dose-reponses. Random order and blind administration of the test compounds were employed; drug identification was not made until after all animals were graded. Immediately prior to drug application, the animals were exposed in groups of four to a high-intensity ultraviolet light for a measured period of time (usually four to seven seconds). The ultraviolet light source, a Hanovia (Trade Mark) Lamp (Kromayer-Model 10; the word KROMAYER is a Trade Mark), was placed in contact with the skin of the animal's back. A gummed notebook paper reinforcement was affixed to the lamp lens to provide an unexposed area of contrast for grading the erythema.

Beginning one hour after exposure and thereafter at halfhour intervals for another 1-1/2 hours, the degree of resulting erythema was graded by an arbitrary scoring system based upon the degree of contrast and redness formed. Anti-inflammatory agents delay the development of the erythema and usually have their greatest effect at the initial grading periods. The scores were, therefore, weighted by factors of 4, 3, 2, and 1 at the 1.0, 1.5, 2.0, -2143307 and 2.5 hour scoring times, respectively. The erythema was graded as follows: Erythema Scoring System Score Appearance of Exposed Area No redness and no contrast Slight redness with a faint reinforcement outline Slight to moderate redness with a distinct outline Marked redness with a distinct circular outline Total scores from each treatment group of four guinea pigs were compared to the control treatment, and the percent inhibition was calculated as follows: Control Treatment 100 x Score - Score = Percent Inhibition Control Score A dose-response graph was obtained by plotting dose versus percent inhibition, the points representing the average of each treatment group of four guinea pigs. The 2 2 dose (ED^q) in micrograms per 12 cm (meg./12 cm ) which produced a 50¾ inhibition of the erythemic response for the particular compound tested was obtained in several instances by extrapolation. Table I below summarizes the results obtained from testing representative compounds of the invention by the foregoing method. The plotted or calculated ΕΟ^θ for the particular compound tested, where available, is given in the last column of Table I. -2243307 Erythemic response inhibition of 5,6-Diaryl-l,2,4-triazines fi o fe fe tf 7$ c fe z—X fe X fe fi fi o m □ w fe I * I fel I tf tf fe in xr fe • · cm xr i** fe o O I I I f fe cn ro m cn cn tf as as tf « G υ υ G G O o o O O cn cn co cn tf tf as tf G G u G O O o O | o o fe fe I I I o o cn tf υ Ό in tf CM υ ι •d fe tf □ ι in tf CM G I -2343307 (Ο ο ιη Q W σ» ro Η CM •tf in > ι cn © co H CM A 1 tn σ\ a & 1 ι I ro I •tf I I 0 •H +1 •H Λ ta s H φ β J3 ω o o Φ a 0 1 1 © 1 o I | fi H Q rH rH β •Η β β 0 m ro ro ro co H υ te ffl ffl to ffl CO 0 u o υ o O ffl fc JO o o o o O ΐ □ A H ffl 1 I 1 I 1 ri φ 0 0 rH A A ta m ro co co (O A Eh » ffl ffl . ffl ffl co •ri o U ϋ □ a ffl CM o o o o o fe a ffl 1 1 1 β Φ 8 β H rH rH rH rH H rH CM 0 g o w ω W W W cn o 8 ΰ 0 CM •ri rH A X « •H CM β A in tn •rH rH β CO β ffl ϋ A ffl xt te CO ID 6 ri m u H a β β H fc ω ffl *—' ffl CM co ro ri 0 te CM ffl 1X5 ffl ffl ffl H dt> ffl ffl u 1 a 1 o υ 1 a O O 1 cti A 0 •24· The toxicities of representative compounds of formula I, determined as the dose (LD5Q) in milligrams per kilogram (mg./kg.) of animal body weight which is lethal to 50 percent of mice treated orally, typically are greater than 1000 mg./kg., and in some cases are greater than 1500 mg./kg.

In the use of the compounds of formula I as antiinflammatory agents, one (or more) of the anti-inflammatory triazines is topically administered to a warm-blooded animal in an amount sufficient to provide at least about 1 meg./ cm. ; such administration can be repeated periodically as needed. Because of the relatively low order of toxicity of such triazines, the maximum level of application is limited only by the esthetics of the mode of administration. As a practical matter, however, such triazines normally need not 3 2 be administered at a level much above about 10 meg./12 cm. , 5 2 although levels of about 10 meg./12 cm. or higher can be employed if desired.

The topical administration of the anti-inflammatory compounds can be made according to any of the well known prior art procedures. Thus, such administration can utilize aerosols, creams, emulsions, lotions, or ointments.

In each case, the compounds are utilized in combination with one or more adjuvants suited to the particular mode of application. For example, ointments and solutions for topical administration can be formulated with any of a number of pharmaceuticaliy-acceptable carriers, including ethanol, animal and vegetable oils, mixtures of waxes, solid and liquid hydrocarbons, or glycols. Thus, a typical 25ointment composition comprises the following ingredients per gram of ointment: Triazine mg. 0.1-100 Polyethylene glycol 300 450-700 (N.F.) Polyethylene glycol 4000 300-450 (U.S.P.) The concentration of the anti-inflammatory triazine in the final topical preparation is not critical. Xn general, such concentration can range from about O.OO1 percent to about 50 percent (w/w or w/v), or higher. Φ The following examples further illustrate the preparations of the compounds of formula I or compounds of formula I which may be used in the pharmaceutical formulations of the invention.

Example 1 Preparation of 5,6-Bis(4-methoxyphenyl)-3methy1-1,2,4-triazine (A) 3-hydroxy-5,6-bis(4-methoxyphenyl)-1,2,4-t riazine, Two moles, 540 g., of anisil (4,4'-dimethoxybenzil), 222g. (2 moles) of semicarbazide hydrochloride, 180 g. (2.2 moles) of sodium acetate and 2,5 liters of acetic acid were heated at reflux overnight.

The cooled reaction mixture was poured into 5 liters of water. The crude solid product was collected by filtration, washed with water and recrystallized from acetic acid. The yield was 434 g. of 3-hydroxy-5,6bis(4-methoxyphenyl)“l,2,4-triazine, mp about 272-274°C.

Analysis: CL7H15N3°3 Calc: C, 66.01; H, 4.89; N, 13.58 Found: C, 65.92; H, 5.04; N, 13.66 - 26 43307 (B) 3-Chloro-5,6-bis(4-methoxyphenyl)-1,2,4-trlazine.

Ten grams of 3-hydroxy-5,6-bis(4-methoxyphenyl)1,2,4-triazine and 50 ml. of phosphorous oxychloride were heated at reflux for 1.5 hours. The cooled mixture was poured onto crushed ice and the resultant mixture was extracted with ether. The extract was washed successively with 2 percent sodium hydroxide and water until the washings were neutral. The ether extract was dried over anhydrous sodium sulfate and evaporated. The residue was taken up in ether, filtered and the filtrate was evaporated to yield 9.0 g. of 3-chloro-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, mp about 130-132°C.

Analysis: C17H14ClN3°2 Calc: C, 62.30; H, 4.31; Cl, 10.82; N, 12,82 Found: C, 62.50; H, 4.48; Cl, 10,53; N, 12.99 (C) 5,6-Bis(4-methoxyphenyl)-3-methyl-l,2,4-triazine.

A one-liter, three-necked reaction flask, equipped with a mechanical stirrer, thermometer, nitrogen inlet, and condenser, was charged with 150 ml. of dry tetrahydrofuran and 11.7 g. (0.033 mole) of methyltriphenylphosphonium bromide. To the resulting slurry at -35°C. was added, over a 15-minute period, 20 ml. (0.033 mole) of n-butyl lithium.

The reaction mixture was stirred for one hour. To the reaction mixture at -35 to -40eC. was added over a 10-minute period a solution of 5.7 g. (0.0165 mole) of 3-chloro5,6-bis(4-methoxyphenyl)-1,2,4-triazine in 50 ml. of tetrahydrofuran. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. A solution of 1.05 g. (0.0165 mole) of sodium carbonate in 50 ml. of water was added dropwise to the reaction mixture which then -2743307 was heated at reflux for three hours. The reaction mixture was cooled, poured over ice, and extracted with diethyl ether. The diethyl ether extract was washed with water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was chromatographed over silica gel, with three fractions being collected. After evaporation of solvent, the third fraction solidified, mp about 109-113eC. The solid was identified as 5,6-bis(4-methoxyphenyl)-3-methyl1,2,4-triazine by nuclear magnetic resonance analysis, mass spectrographic analysis, and elemental microanalysis.

Analysis: C18H17h°2 Calc: C, 70.34; H, 5.58; N, 13.67 Found: C, 70.42; H, 5.66; N, 13.33 Example 2 The following compound was prepared by the method of Example 1(C) using the appropriate phosphonium bromide, except that the diethyl ether concentrate solidified and was recrystallized from petroleum ether/ethyl acetate: 3-ethyl-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, mp about 73-75.5°C. Analysis:C19H19N3°2 Calc: C, 71.01; H, 5.96; N, 13.08 Found: C, 71.30; H, 6.01; N, 13.10 Example 3 ..Preparation of 5,6-Bis(4-ffiethoxy phenyl)-3-methylthio-l,2,4-triazine (A) 3-mercapto-5,6-bis(4-methoxyphenyl)-1,2,4-triazine.

One hundred grams of anisil (4,4'-dimethoxybenzil) were added to 600 ml. of acetic acid and the mixture was -28heated to about 100°C. with stirring. Thiosemicarbazide, 68.4 g., was added and the mixture was heated at reflux for about an hour. The mixture was cooled and the solid product was collected by filtration. The solid was washed with acetic acid and water. The product was filtered and air dried to yield 96.3 g. of 3-mercapto-5,6-bis(4-methoxyphenyl)1,2,4-triazine, mp about 233-236°C.

Analysis: C^? H15N3°2S Calc: C, 62.75; H, 4.65; N, 12.91; S, 9.85 Found: C, 62.61; H, 4.57; N, 12.66; S, 9.73 (B) 3-Methylthio-5,6-bis(4-methoxyphenyl)-1,2,4-triazine.

Eitht grams (0.20 mole) of sodium hydroxide were dissolved in 600 ml. of ethanol by warming. The basic solution was cooled to room temperature and 67.0 grams (0.20 mole) of 3-mereapto-5,6-bis(4-methoxyphenyl)-1,2,4-triazine were added. Methyl iodide, 67 g. (0.47 mole), was added to the reaction mixture and the mixture immediately became a slurry. Three hundred milliliters of ethanol were added to the slurry and stirring was continued for about 3 hours.

One hundred milliliters of water were added to the reaction mixture and the solid product was collected by filtration.

The yield of 3-methylthio-5,6-bis(4-methoxyphenyl)-l,2,4triazine, mp about 152-155°C., was 67.3 g.

Analysis: C^gH^NgOgS Calc: C, 63.70; H, 5.05; N, 12.38 Found: C, 63.82; H, 5.31; N, 12.10 Examples 4-7 The following compounds were prepared by the method of Example 3 (B), using the appropriate alkyl halide (given in parenthesis after the compound name): 3-ethylthio-5,6-bis(4-methoxyphenyl)-1,2,4triazine (from ethyl bromide), mp about 118-120°C., 6.7 g.

Analysis: ci9HxgN3O2S Calc: C, 64.57; H, 5.42; S, 9.07 Found: C, 64.78; H, 5.24; S, 9.00 I 3-isopropylthio-5,6-bis(4-methoxyphenyl)-1,2,4triazine (from isopropyl iodide), mp about 109-lll°C.

Analysis: C20H21N3°2S Calc: C, 65.37; H, 5.76; S, 8.73 Found: C, 65.65; H, 5.53; S, 8.63 3-hexylthio-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (from hexyl bromide), mp about 92-94°C., 7 g.

Analysis: C23^27N3°2S Calc: C, 67.45; H, 6.65; S, 7.83; N, 10.26 Found: C, 67.66; H, 6.71; S, 8.00; N, 10.26 3-benzylthio-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (from benzyl chloride), mp about 128-130°C., 10.3 g.

Analysis: C24H21N3°2S Calc: ' C, 69.40; H, 5.09; S, 7.71 Found: C, 69.37; H, 5.19; S, 7.37 Example 8 Preparation of 3-Methoxy-5,6-bis(4methoxyphenyl)-1,2,4-triazine (A) Procedure A.

A 500-ml., three necked reaction flask, equipped with a mechanical stirrer, thermometer, condenser and -3043307 nitrogen inlet, was charged with 100 ml. of dry methanol. Sodium, 3.0 g. (0.13 mole), then was added piecewise to the flask, followed by the addition of a slurry of 31.6 g. (0.1 mole) of 5,6-bis(4-methoxyphenyl)-3-methyIthio-1,2,4-triazine B in methanol. The reaction mixture was heated at reflux □ overnight. The reaction mixture was cooled and filtered.

The filter cake and filtrate were extracted with diethyl ether. The diethyl ether was concentrated, giving a solid, mp >220°C. The solid was taken up in diethyl ether and the insoluble material was removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated to give a solid residue which was recrystallized from petroleum ether to give 3-methoxy-5,6-bis(4-methoxyphenyl)-1,2,4triazine, mp about 105-108eC.

Analysis: Cale: C, 66.86; H, 5.30; N, 13.00 Found: C, 67.26; H, 5.97; N, 11.69 (B) Procedure B.

A one-liter, three-necked reaction flask, equipped with a mechanical stirrer, thermometer, condenser, and nitrogen inlet, was charged with 100 ml. of dry methanol. Sodium, 0.91 g. (0.04 mole), was added piecewise to the flask, followed by the portionwise addition of 11.6 g. (0.036 mole) of 3-chloro-5,6-bis(4-methoxyphenyl)-l,2,4triazine. The reaction mixture was heated at reflux for three hours, cooled, and stirred overnight. The reaction mixture was cooled and filtered. The filtrate was concentrated and the solid residue was crystallized from petroleum ether/ethyl acetate, to give 8.5 g. of 3-methoxy-314330^ ,6-bis(4-methoxyphenyl)-1,2,4-triazine, mp about 135137eC.

Analysis: ci8Hi7N3°3 Calcs C, 66.86; H, 5.30; O, 14.86; N, 13.00 Found: C, 66.84; H, 5.52; 0, 14.86; N, 12.79 Examples 9-10 The following compounds were prepared by the method of Example 8 (Β), using appropriate starting materials 3-ethoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine, mp about 120-122eC., 7.1 g.

Analysis: ci9Hi9N3°3 Calcs C, 67.64; H, 5.68; 0, 14.23; N, 12.46 Found: C, 67.92; H, 5.56; 0, 14.43; N, 12.38 3-methoxy-5,6-bis (4-methylphenyl) 1,2, .4-triazine, mp about 125-128°C.

Analysis: cigHi7N3° Calc: C, 74.20; H, 5.88; N, 14.42 Found: C, 74.11; H, 5.83; N, 14.17 Example 11 Preparation of 5,6-Bis(4-methoxy phenyl)-1,2,4-triazine A Parr Low Pressure Hydrogenation Apparatus was charged with 1.5 g. of five percent palladium on charcoal, about 200 ml. of ethyl acetate, 10 g. of 3-chloro-5,6bis(4-methoxyphenyl)-1,2,4-triazine, and 6 ml. of triethylamine. The apparatus was charged at room temperature with hydrogen and agitated until theoretical hydrogen uptake was obtained. The reaction mixture was filtered and the filtrate was concentrated. The residue solidified and was recrystallized from ethanol to give 6.3 g. of 5,6-bis(4-32- methoxyphenyl)-1,2, 4-triazine, mp about 118 :-120°C. Analysis:C17H15N3°2 Calc: C, 69.61; H, 5.15; N, 14.33; 0, 10.91 Found: C, 69.37; H, 4.93; N, 14.07; 0, 10.99 Example 12 Preparation of 5,6-Bis(4-fluoro phenyl) -3-methylthio-1,2,4-triazine (A) 5,6-Bis(4-fluorophenyl)-3-mercapto-l,2,4-triazine.

A solution of 80 g. of 4,4'-difluorobenzil in 400 ml. of ethanol was heated to reflux. Water then was added to the point of turbidity, followed by the addition of 80 g. of thiosemicarbazide and 96 g. of sodium acetate. The reaction mixture was heated at reflux for one hour. Water again was added to the reaction mixture to the point of incipient turbidity. Sodium hydroxide, 80 g., then was added gradually to the reaction mixture, which then was heated at reflux for one hour. The reaction mixture was poured into a 3-fold volume of ice water and aqueous hydrochloric acid was added until the mixture was strongly acidic. The solid which precipitated was isolated by filtration and recrystallized from acetic acid to give 57.5 g. of 5,6-bis(4-fluorophenyl)-3-mercapto-l,2,4-triazine, mp about 180-182°C.

Analysis: C^gHgFjNgS Calc: C, 59.79; H, 3.01; N, 13.95 Found: C, 59.96; H, 3.12; N, 14.05 (B) 5,6-Bis(4-fluorophenyl)-3-methylthio-l,2,4-triazine.

To a solution of 26.5 g. of 5,6-bis(4-fluorophenyl) -3-mercapto-l,2,4-triazine and 4 g. of sodium hydroxide in 300 ml. of ethanol was added 24.2 g. of methyl -3343307 iodide. The mixture was agitated at ambient temperature.

The precipitate which formed was isolated by filtration and recrystallized from ethanol, giving 14 g. of 5,6-bis(4fluorophenyl)-3-methylthio-l,2,4-triazine, mp about 134-136’C.

Analysis: cigHixF2N3S Calc: C, 60.94; H, 3.52; F, 12.05; N, 13.33 Found: C, 60.72; H, 3.48; F, 11.92; N, 13.04 Example 13 Preparation of 5-(4-Dimethylaminophenyl)-6(4-fluorophenyl)-3-methylthio-l,2,4-triazine (A) 5-(4-Dimethylamihophenyl)-6-(4-fluorophenyl)-3-mercapto1,2,4-triazine.

To a solution of 8.1 g. of 4-dimethylamino-4'~ fluorobenzil in 65 ml. of acetic acid was added 3.3 g. of thiosemicarbazide. The reaction mixture then was heated at reflux for three hours. The solid which precipitated was isolated by filtration, washed successively with ethanol and water, and dried, giving 4.3 g. of 5-(4-dimethylaminophenyl)-6-(4-fluorophenyl)-3-mercapto-l,2,4-triazine, mp about 262-264°C.

Analysis: ci7Hi5FN4S Calc: C, 62.57; H, 4.63; F, 5.82; N, 17.17 Found: C, 62.83; H, 4.73; F, 5.70; N, 17.29 (B) 5-(4-Dimethylamlnophenyl)-6-(4-fluorophenyl)-3-methyl thio-1,2,4-triazine.

To a solution of 0.48 g. of sodium hydroxide in 100 ml. of ethanol was added 4 g. of 5-(4-dimethylaminophenyl)-6-(4-fluorophenyl)-3-mercapto-l,2,4- triazine. To the resulting solution was added, with agitation, 2.1 g. of methyl iodide. The precipitate which formed was isolated by filtration and crystallized from ethanol to give 2.9 g. of •3443307 -(4-dimethylaminophenyl)-6-(4-fluorophenyl)-3-methylthio-1,2,4-triazine, mp about 144-146eC.

Analysis: CjL8Hi7PN4S Calc: C, 63.51; H, 5.03; N, 16.46; S, 9.42 Found: C, 63.22; H, 5.30; N, 16.24; S, 9.23 Example 14 Preparation of 5,6-Bis(4-methylphenyl)-3methylthio-1,2,4-triazine (A) 3-Mercapto-5,6-bis(4-methylpheny1)-1,2,4-triazine.

To a solution of 85 g. of 4,4'-dimethylbenzil in 360 ml. of acetic acid heated to about 80-100’C. was added .5 g. of thiosemicarbazide, portionwise, over a 10-minute period. The reaction mixture was heated at reflux for two hours. The reaction mixture was cooled and diluted with 500 ml. of water. The solid which precipitated was isolated by filtration, washed with water, and recrystallized from ethanol to give 22 g. of 3-mercapto-5,6-bis(4-methylphenyl)1,2,4-triazine, mp about 220-223’C.

Analysis: ci7Hi5N3S Calc: C, 69.60; H, 5.15; N, 14.32 Found: C, 69.32; H, 5.36; N, 14.60 (B) 5,6-Bis(4-methylphenyl)-3-methylthio-l,2,4-triazine.

To a solution of 24 g. sodium hydroxide in about one liter of ethanol was added 146.5 g. of 3-mercapto5,6-bis(4-methylphenyl)-1,2,4-triazine. To the resulting solution was added 88.2 g. of methyl iodide. The reaction mixture was agitated overnight at ambient temperature. The solid which precipitated was isolated by filtration and washed with ethanol; the solid was recrystallized from ethanol to give 101.1 g. of 5,6-bis(4-methylphenyl)-325 -35methylthio-1,2,4-triazine, mp about 170-172°C. Analysis: C^gH^NgS Calc: C, 70.33; H, 5.57; N, 13.67 Found: C, 70.25; H, 5.78; H, 13.72

Claims (17)

1. CLAIMS:1. Anti-inflammatory compositions which comprise an inert carrier and as active ingredient a 5,6-diaryl-l,2,4triazine compound of the formula, R Y\ As A,/ 5 wherein R is hydrogen or -(XJ^R^, in which X is either 0 or S, n is an integer which is either 0 or 1, and Rg is Cg-Cg alkyl, Cy-Cg aralkyl, Cg-Cg cycloalkyl, or C 4 “C g (cycloalkyl) alkyl; and Rj and Rg independently are halo, Cg-Cg alkyl, Cg-Cg alkoxy and di(Cg-Cg alkyDamino; and the 10 pharmaceutically-acceptable acid addition salts of basic members thereof.

2. The anti-inflammatory composition of claim 1, wherein the active ingredient is any of the following compounds of formula Is 3. -methyl-5,6-bis(4-methoxyphenyl)-1,2,4-triazine 15 3-ethyl-5,6-bis(4-methoxyphenyl)-1,2,4-triazine 3-methylthio-5,6-bis(4-methoxyphenyl)-1,2,4-triazine 3-ethylthio-5,6-bis(4-methoxyphenyl)-1,2,4-tri20 azine 3-isopropylthio-5,6-bis(4-methoxyphenyl)-1,2,4triazine 3-hexylthio-5,6-bis(4-methoxyphenyl)-1,2,4-triazine 3-benzylthio-5,6-bis(4-methoxyphenyl)-1,2,4-triazine 5 3-methoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine 3-ethoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine 3-methoxy-5,6-bis(4-methyIpheny1)-1,2,4-triazine 5,6-bis(4-methoxyphenyl)-1,2,4-triazine 3-methyIthio-5,6-bis(4-fluorophenyl)-1,2,4-triazine 10 3-methylthio-5-(4-dimethylaminophenyl)-6-(4fluo ropheny1)-1,2,4-triazine 3-methylthio-5,6-bis(4-methylphenyl)-1,2,4-triazine.

3. 5,6-Diaryl-l,2,4-triazine compounds of the 15 formula I .as defined in claim 1 wherein R is Ln which X is Ο , n is an integer which is either 0 or 1, and is C^-Cg alkyl, C^-Cg aralkyl, Cg-Cg cycloaikyl, or C 4 -C 8 alkyl; and R 2 and R 3 independently are halo, C^-C 3 alkyl, C^-C 3 alkoxy and di(C^-Cg alkyl)amino; >0 and the pharmaceutically-acceptable acid addition salts of basic members thereof.

4. The compound of claim 3, in which is C^-Οθ alkyl.

5. The compound of claim 3 or 4, wherein π is 0.

6. The compound of claim 3 or 4, wherein X is 0 and n is 1. -384 3 3 0 7

7. The compound of any of claims 3 to 6, wherein Rg and Rg are C^-Cg alkoxy and are the same.

8. The compound of claim 7, wherein R_ and R are methoxy.

9. 3-Methy1-5,6-bis(4-methoxyphenyl)-1,2,4-triazine.

10. 3-Ethyl-5,6-bis(4-methoxyphenyl)-1,2,4-triazine.

11. 3-methoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine.

12. 3-Ethoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine.

13. 3-Methoxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine,

14. A process for preparing the 5,6-diaryl-l,2,4-triazine compounds as claimed in any of claims 3 to 13, which comprises reacting a triazine compound of the formula: wherein Rg and R g are as defined in claim 3 and X is chloro or mercapto, with a compound of the formula 15. R T -Y HI wherein R^ is as defined in claim 3 and Y is halo, triphenylphosphoniumhalide or -0-alkali metal,

15. A process for preparing 5,6-diaryl-l,2,4-triazine compounds of formula I, wherein R, Rg, and Rg are as defined in claim 3, substantially 20 as hereinbefore described with particular reference to any one of the Examples 2,8,9 or 10. - 39 433 0 7

16. 5,6-Diaryl-l,2,4-triazine compounds of formula I wherein R, R^ and R^ are as defined in claim 3, substantially as hereinbefore described with particular reference to any one of Examples 2,8,9 or 10.

17. Anti-inflammatory composition comprising an inert carrier and a compound of formula X as defined in claim I, substantially as hereinbefore described.