SYNTHESIS OF DIALKYL DIMETHYL-4-(HETEROARYL)PYRIDINE-3,5-DICARBOXYLATES AS CALCIUM-CHANNEL ANTAGONISTS

The Hantzsch condensation of the heteroarylcarboxaldehydes 3a-c with a lkyl acetoacetates 4a-c and alkyl 3-aminocrotonates 5a-b afforded the respective dialkyl imethyl-4-(heteroaryl)-pyridine-3,5-dicarboxylates 6a-f possessing a C-4 4-quinolinyl, 8-quinolinyl or 1-oxido-4-pyridiny l substituent. Calcium channel antagonist structure-activity relations hips acquired indicate that i) the position of the quinolyl nitrogen a tom was not a determinant of activity, ii) increasing the size of the C-3 and C-5 alkyl ester substituents decreases potency and iii) a C-4 1-oxido-4-pyridinyl substituent abolishes activity. The most active, a nd equipotent C-4 4-quinolinyl 6a and 8-quinolinyl 6b analogs, were ap proximately 8-fold less potent calcium channel antagonists than the re ference drug nifedipine.