Synthesis and antihypertensive activity of 5-amino-2-pyridinecarboxylic acid derivatives
The synthesis of various substituted 5-amino-2-pyridinecarboxylic acids and their derivatives is described by three general methods: (1) reductive alkylation of methyl 5-amino-2-pyridinecarboxylates (2) and subsequent hydrolysis; (2) alkylation of the urethane (9), followed by hydrolysis; and (3) se...
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Published in | Journal of medicinal chemistry Vol. 23; no. 12; pp. 1405 - 1410 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Chemical Society
01.12.1980
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Subjects | |
Online Access | Get full text |
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Summary: | The synthesis of various substituted 5-amino-2-pyridinecarboxylic acids and their derivatives is described by three general methods: (1) reductive alkylation of methyl 5-amino-2-pyridinecarboxylates (2) and subsequent hydrolysis; (2) alkylation of the urethane (9), followed by hydrolysis; and (3) selective NaBH4 reduction of the appropriate amide of (2), followed by hydrolysis. A more specific process was used for the 5-(phenylamino) compound, i.e., nucleophilic displacement of nitrite from methyl 5-nitro-2-pyridinecarboxylate by sodioformanilide and subsequent hydrolysis. Many of these 2-pyridinecarboxylic acid derivatives were potent antihypertensive agents in the spontaneously hypertensive rat (SHR). Optimization of structural parameters for this activity yielded compounds 54, 55, 34, 65, and 22, which were selected for further study in the renal hypertensive dog (RHD). Based on these studies, one compound, 5-[(4-fluorobenzyl)amino]-2-pyridinecarboxylic acid (65), was selected for preclinical toxicity evaluation. Based on the toxicological findings, it was decided not to pursue compound 65 clinically. |
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Bibliography: | istex:2EC14047149B6DFCA5E84061E9497263E9F896D5 ark:/67375/TPS-8F0XRL4R-L |
ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/jm00186a022 |