Synthesis of Dialkyl 1,4-Dihydro-2,6-dimethyl-4-(heteroaryl)-pyridine-3,5-dicarboxylates as Calcium Channel Antagonists

The Hantzsch condensation of the heteroarylcarboxaldehydes 3a-c with alkyl acetoacetates 4a-c and alkyl 3-aminocrotonates 5a-b afforded the respective dialkyl 1,4-dihydro-2,6-dimethyl-4-(heteroaryl)-pyridine-3,5-dicarboxylates 6a-f possessing a C-4 4-quinolinyl, 8-quinolinyl or 1-oxido-4-pyridinyl substituent Calcium channel antagonist structure-activity relationships acquired indicate that i) the position of the quinolyl nitrogen atom was not a determinant of activity, ii) increasing the size of the C-3 and C-S alkyl ester substituents decreases potency and iii) a C-4 1-oxido-4-pyridinyl substituent abolishes activity. The most active, and equipotent C-4 4-quinolinyl 6a and 8-quinolinyl 6b analogs, were approximately 8-fold less potent calcium channel antagonists than the reference drug nifedipine.