Synthesis of alkyl 6‐methyl‐4‐(2‐trifluoromethylphenyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates possessing a N‐3 nitro substituent to determine calcium channel modulation structure‐activity relationships

The Bigenelli acid catalyzed condensation of 2‐trifluoromethylbenzaldehyde ( 1 ), urea ( 2 ) and an alkyl acetoacetate ( 3 ) afforded the respective alkyl (Me, Et, i‐Pr, i‐Bu) 6‐methyl‐4‐(2‐trifluoromethylphenyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylate ( 4‐7 ). Subsequent N³‐nitration of the alkyl esters ( 4‐7 ) using Cu(NO₃)₂ 3H₂O and Ac₂O furnished the target alkyl 6‐methyl‐3‐nitro‐4‐(2‐trifluoromethylphenyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates ( 8‐11 ). The N³‐nitro compounds ( 8‐11 ) were less potent calcium channel antagonists (IC₅₀ values in the 1.9 × 10^?7 to 3.9 × 10^?6 M range) on guinea pig ileal longitudinal smooth muscle than the reference drug nifedipine (Adalat®, IC₅₀ = 1.4 × 10^?8 M). In vitro calcium channel modulation studies on guinea pig left atrium (GPLA) showed that the methyl and ethyl esters ( 8‐9 ) induced a weak‐to‐modest positive inotropic (agonist) effect, and that the inactive isopropyl ( 10 ) and isobutyl ( 11 ) esters did not alter the cardiac contractile force of GPLA.