Analogues of Methotrexate in Rheumatoid Arthritis. 1. Effects of 10-Deazaaminopterin Analogues on Type II Collagen-Induced Arthritis in Mice

Abstract

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 alpha-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 degrees 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.

A Direct Transformation of Aryl Aldehydes to Benzyl Iodides Via Reductive Iodination

“…62−64 4,136.7,131.6,130.0,128.6,128.0,127.4,115.1,70.0,6.5; 3, 141.3, 134.6, 129.81, 123.4, 122.6, 2.06 135.6,133.4,129.9,117.7,115.0,68.7,5.5;GCMS: 274. [ ( 5, 132.5, 131.5, 128.9, 128.7, 128.5, 128.4, 128.1, 127.9, 125.6, 123.1, 122.7, 95.8, 86.6, 4.4; GCMS: 318.…”

The diversity‐oriented synthesis of pteridines—achievements and potential for development

“…Alcohols, alkoxides, primary and secondary amines, and thiols have all been used. As examples of the variety of substituents introduced for medicinal chemical purposes, folate analogues with pyridine or thiophene rings in place of the benzene ring of 4‐aminobenzamide have been prepared (39) and, further down the side chain, derivatives fluorinated in the glutamic acid have been studied (40). For anti‐infective drugs, it is common to seek selectivity through various hydrophobic substituents at C6 because such compounds do not bind strongly to the human enzyme.…”

Nickel-Catalyzed Carbonylative Synthesis of Functionalized Alkyl Iodides

“…Functionalized alkyl iodides are potent chemicals in organic chemistry and biology, and many drugs were effectively prepared from alkyl iodides ( Trewick et al., 2002 , DeGraw et al., 1997 , Liu et al., 2014 ). Furthermore, ethers are widely used as solvents in organic transformations owing to their high chemical stability and relatively low boiling points.…”