Synthesis of asymmetric 4-aryl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylates with vasodilating and antihypertensive activities.

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Abstract
Asymmetric 4-aryl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylates with a 2-ethylene-dioxypropyl, 2-oxopropyl, or cyclopropylmethyl group as the ester moiety and related derivatives were synthesized and tested for vasodilating activity in anesthetized open-chest dogs and for antihypertensive activity in conscious spontaneously hypertensive rats. Cyclopropylmethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (5f, MPC-2101) and methyl 2-oxopropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate (8i, MPC-1304) exhibited potent cerebral vasodilating and antihypertensive activities, respectively. The maximum increase of vertebral blood flow after intravenous administration at 3.0 .mu.g/kg was 221.4% for 5f, compared with 187.0 and 166.3% for nifedipine and nicardipine hydrochloride, respectively. The maximum falls of systolic blood pressure after oral administration of 8i at 0.3 and 1.0 mg/kg were 42.2 and 54.0 mmHg, while those of nifedipine, nicardipine, and hydralazine hydrochloride at 3.0 mg/kg were 23.3, 16.8, and 24.5 mmHg, respectively. The durations of significant vasodilating and antihypertensive effects for 5f and 8i were longer than those of nifedipine and nicardipine.