1,2-Dihydro-2-oxo-6-(2,2-dimethylpropyl)-3-pyridinecarboxylic acid, analogues, and derivatives. A new class of oral hypoglycemic agents.
1,2-Dihydro-2-oxo-6-(2-methylpropyl)-3-pyridinecarboxylic acid was found to be a hypoglycemic agent but not to have the undesirable mechanism of action possessed by nicotinic acid. A series of 1,2-dihydro-2-oxo-3-pyridinecarboxylic acids with a substituent primarily at the 6-position was prepared by hydrolysis of the corresponding nitriles. The nitriles were prepared by reaction of the sodium enolate of the appropriate 3-substituted 3-oxopropionaldehyde with cyanoacetamide. The sodium enolates were synthesized from ethyl formate and the appropriate ketone and sodium or sodium hydride. The active 1,2-dihydro-2-oxo-3-pyridinecarboxylic acids, listed in order of decreasing hypoglycemic potency, had the following substituents: 6-(2,2-dimethylpropyl), 6-(2,2-dimethylbutyl), 6-(1,1-dimethylethyl), 6-(2-methylpropyl), 6-(1,1-dimethylpropyl), 1-methyl-6-(2-methylpropyl), 6-hydrogen. The inactive compounds were those with 6-methyl, 6-(1-methylethyl), 6-pentyl, 4-(2,2-dimethylpropyl), 6-(3-methylbutyl), 6-(1,1-dimethylheptyl), 6-(2,2-dimethyloctyl), 6-(1-cyclobutylmethyl), and 1-methyl-6-(2,2- dimethylpropyl) substituents. The corresponding alcohol, aldehyde, tetrazole, sodium salt, and ethyl ester of the most potent acid were also active compounds. The corresponding amide, decarboxyl compound, and 2-deoxo compound were inactive.
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D005215:Fasting; D005502:Food; D007004:Hypoglycemic Agents; D009539:Nicotinic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D009539:Nicotinic Acids