ANALOGS OF METHOTREXATE IN RHEUMATOID-ARTHRITIS .1. EFFECTS OF 10-DEAZAAMINOPTERIN ANALOGS ON TYPE-II COLLAGEN-INDUCED ARTHRITIS IN MICE

Carbonation of the dianions (LDA) of 5-methylthiophene-2-carboxylic, 2 -methylpyridine-5-carboxylic, and 3-methylpyridine-6-carboxylic acids provided the respective carboxy heteroarylacetic acids. The crude diac ids were directly esterified in MeOH-HCl to afford the diesters. Alkyl ation of the sodio anions with ethyl iodide yielded the appropriate a- ethyl diesters. The anions of the various diester substrates were then alkylated by 2,4-diamino-6-(bromomethyl)-pteridine followed by ester saponification at room temperature to afford the respective 2,4-diamin o-4-deoxy-10-carboxy-10-deazapteroic acids. The 10-carboxyl group was readily decarboxylated by heating in DMSO at temperatures of 110-135 d egrees C to give the diamino 10-deaza heteropteroic acid intermediates . Coupling with diethyl L-glutamate followed by ester hydrolysis affor ded the target aminopterins. The analogues were evaluated for antiinfl ammatory effect in the mouse type II collagen model. The thiophene ana logue of 10-ethyl-10-deazaaminopterin was found to be an effective inh ibitor in terms of reduced visual evidence of inflammation and swellin g as determined by caliper measurement.