Synthesis and antihypertensive activity of 5-thio-2-pyridinecarboxylic acid derivatives

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Abstract
Synthesis of various substituted 5-thio-2-pyridinecarboxylic acids and their derivatives is described by 3 methods, i.e., displacement of nitrite from methyl 5-nitro-2-pyridinecarboxylate by a thiol anion, alkylation of methyl 5-thio-2-pyridinecarboxylate derived from reaction of the diazotized methyl 5-amino-2-pyridinecarboxylate with thiocyanate followed by borohydride reduction of the product, and alkylation of 5-thio-2-pyridinecarbonitrile followed by hydrolysis. 5-Thio-2-pyridinecarbonitrile was obtained from butyl 6-methyl-3-pyridyl sulfoxide by nitrosation and dehydration of the oxime. Many of these 5-thio-2-pyridinecarboxylic acid derivatives were orally active antihypertensive agents in the spontaneously hypertensive rat. Optimization of the structural parameters for this activity yielded 5-[(m-trifluorobenzyl)thio]-2-pyridinecarboxylic acid and its sulfoxide. Further biological studies with these compounds are described.

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