Cardioactivity and Solid-State Structure of Two 4-Isoxazolyldihydropyridines Related to the 4-Aryldihydropyridine Calcium-Channel Blockers

Diethyl 2,6-dimethyl-4-(5-ethyl-3-phenylisoxazol-4-yl)-1,4-dihydroypridine-3,5-dicarboxylate (5) and diethyl 2,6-dimethyl-4-(5-isopropyl-3-phenylisoxazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate (6) were synthesized, and their molecular structures were determined by X-ray crystallography. In compound 5, which has an ethyl group at the C5 position of the isoxazole ring, the deviation from planarity in the dihydropyridine (DHP) ring is the smallest of all known DHP derivatives. The dihedral angle between the aromatic ring (the isoxazole) and the DHP ring, which is approximately 90° in similar biologically active dihydropyridines, is somewhat smaller (82.7° and 85.2°, respectively) in these two compounds. In both compounds, one of the ester groups is coplanar with the DHP ring while the other one is out of plane by 14.7° (ethyl) and 18.8° (isopropyl). Both 5 and 6 were found to be vasodilators in the Langendorff assay. The potency of 6 on cardiac flow was similar to that of nifedipine; however, that of 5 was considerably attenuated. Since isoxazolyl analogue 6 lacks the significant negative inotropic activity associated with nifedipine, 6 offers promise as an antihypertensive or antianginal agent.