Synthesis and antihypertensive activity of 5-O-substituted derivatives of 5-hydroxypicolinic acid.

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Abstract
5-O-Substituted derivatives of 5-hydroxypicolinic acids were synthesized from nojirimycin and studied for their antihypertensive activity in unanesthetized spontaneously hypertensive rats (SHR) restrained in wire mesh cage and acute toxicity in mice. 5-n-Butoxy-picolinic acid (ND-186) had antihypertensive activity comparable to fusaric acid and lesser acute toxicity. Introduction of halogeno group, in particular trifluoromethyl group to the .omega.-position of 5-n-butoxy group resulted in the enhancement of antihypertensive activity. The acute toxicity was also lowered 3-5 times compared to that of fusaric acid. Replacement of alkyl group with phenyl group resulted in a slight increment of activity. Some ester derivatives of ND-186 potentiated the antihypertensive activity and reduced the acute toxicity. There was good correlation between partition coefficient (log P) of ester groups and their antihypertensive activities; compound with higher lipophilicity showed higher antihypertensive activity under the condition of oral administration. Esterification of other compounds such as 5-halogenoalkoxy- and 5-(substituted) phenoxypicolinic acid was not accompanied with activity increment. Considering from the balance of the antihypertensive activity in SHR and the acute toxicity in mice, 5-(5'',5'',5''-trifluoropentoxy)-picolinic acid was selected as a candidate for further evaluation.

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