ANALOGS OF METHOTREXATE IN RHEUMATOID-ARTHRITIS .2. EFFECTS OF 5-DEAZAAMINOPTERIN, 5,10-DIDEAZAAMINOPTERIN, AND ANALOGS ON TYPE-II COLLAGEN-INDUCED ARTHRITIS IN MICE

Twenty-six compounds derived from the 5-deaza- and 5,10-dideazaaminopt erin series of aminopterin analogues were evaluated for antiarthritic activity in the mouse type II collagen model. New compounds in the 5-d eaza series were prepared by alkylation of an appropriate N-substitute d (4-aminobenzoyl)-L-glutamic acid dialkyl ester or N-(5-amino-2-theno yl)-L-glutamate diester with a -diamino-5-alkyl-6-(bromomethyl)-5-deaz apteridine. The resultant 5-deazaaminopterin diesters were saponified to provide the target 5-deaza analogues. 5,10-Dideazaaminopterins were synthesized by similar alkylation of the carbanions of appropriate 4- carboxyphenylacetic, (5-carboxy-2-thienyl)acetic, or (5-carboxy-2-pyri dyl)acetic acid dimethyl esters. The diesters of the 2,4-diamino-4-deo xy-10-carboxy-5,10-dideazapteroic acid types so obtained were saponifi ed and then readily decarboxylated by heating in Me(2)SO solution to p rovide the 2,4-diamino-5,10-dideazapteroic acid-type intermediates. Pe ptide coupling with diethyl L-glutamate followed by ester hydrolysis a t room temperature afforded the new 5,10-dideazaaminopterin analogues. 5-Deazaaminopterins bearing an alkyl substituent at the 5-position we re generally quite effective as antiinflammatory agents. Thus 5-propyl -5-deazaaminopterin, 5-methyl-10-propargyl-5-deazaaminopterin, 5-methy l-10-allyl-5-deazaaminopterin, 5-ethyl-5-deazamethotrexate, and 2,5-di substituted thiophene analogue of 5-methyl-5-deazaaminopterin showed p otencies greater than methotrexate by intraperitoneal or oral administ ration and were active over a considerably broader dose range. Useful activity in the 5,10-dideaza series was only observed for 5,10-dideaza aminopterin and its 10-methyl analogue. Alkyl substitution at C-5 or C -10 was generally detrimental to antiinflammatory activity in this ser ies.