Synthesis of dialkyl 1,4‐dihydro‐2,6‐dimethylpyridine‐3,5‐dicarboxylates and alkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates possessing a c‐4 2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl (uracil) substituent to determine calcium channel modulation structure‐activity relationships

The Hantzsch condensation of 5‐formyluracil ( 1 ) with methyl, isopropyl or isobutyl acetoacetate (2a‐c) in the presence of ammonium hydroxide afforded the respective dialkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,4‐dloxo‐1,2,3,4,‐tetrahydropyrimidin‐5‐yl)pyridine‐3,5‐dicarboxylate (3a‐c). A group of alkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl)pyridine‐5‐carboxylates (6a‐c) were also prepared using a modified Hantzsch reaction that involved the condensation of 5‐formyluracil with nitroacetone and either methyl, isopropyl or isobutyl 3‐aminocrotonate (5a‐c). A C‐4 2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl substituent is not a suitable bioisostere for the traditional C‐4 aryl or heteroaryl substituents present in 1,4‐dihydropyridine calcium channel modulators since diisopropyl 1,4‐dihydro‐2,6‐dimemyl‐4‐(2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl)pyridine‐3,5‐dicarboxylate (3b) and isobutyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2,4‐dloxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl)pyridine‐5‐carboxylate (6c) did not exhibit any in vitro calcium channel antagonist activity using a guinea pig smooth muscle calcium channel antagonist assay, or a guinea pig left atrium calcium channel agonist (positive inotropic) assay.