Analogues of Methotrexate in Rheumatoid Arthritis. 2. Effects of 5-Deazaaminopterin, 5,10-Dideazaaminopterin, and Analogues on Type II Collagen-Induced Arthritis in Mice
- 1 January 1997
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 40 (3) , 377-384
- https://doi.org/10.1021/jm950553y
Abstract
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.Keywords
This publication has 13 references indexed in Scilit:
- Further evaluation of 5‐alkyl‐5‐deaza antifolates. 5‐propyl‐ and 5‐butyl‐5‐deaza analogues of aminopterin and methotrexateJournal of Heterocyclic Chemistry, 1995
- Synthesis and antitumor activity of 10-propargyl-10-deazaaminopterinJournal of Medicinal Chemistry, 1993
- Structure-activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine analogs: effect of substitutions at the C-6 phenyl ring and at the C-5 position on anti-HIV-1 activityJournal of Medicinal Chemistry, 1992
- Synthesis and antifolate activity of 5-methyl-5,10-dideaza analogs of aminopterin and folic acid and an alternative synthesis of 5,10-dideazatetrahydrofolic acid, a potent inhibitor of glycinamide ribonucleotide formyltransferaseJournal of Medicinal Chemistry, 1988
- Synthesis of 5,10‐dideazaminopterinJournal of Heterocyclic Chemistry, 1986
- Synthesis and antifolate properties of 10-alkyl-8,10-dideazaminopterinsJournal of Medicinal Chemistry, 1984
- Competitive reactions of alkylidenetriphenylphosphoranes and methylsulfinyl carbanion with 3-methylenespiro[5.5]undeca-1,4-dieneThe Journal of Organic Chemistry, 1983
- Synthesis and antitumor activity of 10-alkyl-10-deazaminopterins. A convenient synthesis of 10-deazaminopterinJournal of Medicinal Chemistry, 1982
- Pyrido[2,3-d]pyrimidines. The synthesis of the 5-deaza analogs of aminopterin, methotrexate, folic acid, and N10-methylfolic acidThe Journal of Organic Chemistry, 1982
- A potent antitumour quinazoline inhibitor of thymidylate synthetase: Synthesis, biological properties and therapeutic results in micePublished by Elsevier ,1981