| Autor: |
DeGraw, J. I., Colwell, W. T., Crase, J., Smith, R. L., Piper, J. R., Waud, W. R., Sirotnak, F. M. |
| Zdroj: |
Journal of Medicinal Chemistry; January 31, 1997, Vol. 40 Issue: 3 p370-376, 7p |
| Abstrakt: |
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 diacids were directly esterified in MeOH−HCl to afford the diesters. Alkylation of the sodio anions with ethyl iodide yielded the appropriate α-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-diamino-4-deoxy-10-carboxy-10-deazapteroic acids. The 10-carboxyl group was readily decarboxylated by heating in DMSO at temperatures of 110−135 °C to give the diamino 10-deaza heteropteroic acid intermediates. Coupling with diethyl l-glutamate followed by ester hydrolysis afforded the target aminopterins. The analogues were evaluated for antiinflammatory effect in the mouse type II collagen model. The thiophene analogue of 10-ethyl-10-deazaaminopterin was found to be an effective inhibitor in terms of reduced visual evidence of inflammation and swelling as determined by caliper measurement. |
| Databáze: |
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