153802-44-9Relevant articles and documents
Analogues of methotrexate in rheumatoid arthritis. 2. Effects of 5- deazaaminopterin, 5,10-dideazaaminopterin, and analogues on type II collagen- induced arthritis in mice
Piper, James R.,DeGraw, Joseph I.,Colwell, William T.,Johnson, Cheryl A.,Smith, R. Lane,Waud, William R.,Sirotnak, Francis M.
, p. 377 - 384 (2007/10/03)
Twenty-six compounds derived from the 5-deaza- and 5,10- dideazaaminopterin series of aminopterin analogues were evaluated for antiarthritic activity in the mouse type II collagen model. New compounds in the 5-deaza series were prepared by alkylation of an appropriate N- substituted (4-aminobenzoyl)-L-glutamic acid dialkyl ester or N-(5-amino-2- thenoyl)-L-glutamate diester with a 2,4-diamino-5-alkyl-6-(bromomethyl)-5- deazapteridine. 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- pyridyl)acetic acid dimethyl esters. The diesters of the 2,4-diamino-4- deoxy-10-carboxy-5,10-dideazapteroic acid types so obtained were saponified and then readily decarboxylated by heating in Me2SO solution to provide the 2,4-diamino-5,10-dideazapteroic acid-type intermediates. Peptide coupling with diethyl L-glutamate followed by ester hydrolysis at room temperature afforded the new 5,10-dideazaaminopterin analogues. 5-Deazaaminopterins bearing an alkyl substituent at the 5-position were generally quite effective as antiinflammatory agents. Thus 5-propyl-5-deazaaminopterin, 5-methyl-10- propargyl-5-deazaaminopterin, 5-methyl-10-allyl-5-deazaaminopterin, 5-ethyl- 5-deazamethotrexate, and 2,5-disubstituted thiophene analogue of 5-methyl-5- deazaaminopterin showed potencies greater than methotrexate by intraperitoneal or oral administration and were active over a considerably broader dose range. Useful activity in the 5,10-dideaza series was only observed for 5,10-dideazaaminopterin and its 10-methyl analogue. Alkyl substitution at C-5 or C-10 was generally detrimental to antiinflammatory activity in this series.
