Nitrendipine: identification and synthesis of main metabolites

(+/-)-Ethylmethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (nitrendipine, Bay e 5009) 1, a calcium antagonistic 1,4-dihydropyridine derivative, is currently under development as an antihypertensive. A pharmacokinetic study with 14C-nitrendipine in the rat revealed as major metabolites the pyridine 2, 3, 4, 5, 6 and 9 using glc-, tlc- and gc/ms-techniques. A potential metabolic pathway is discussed involving oxidation to the pyridine form, saponification of the ester groups and hydroxylation of the methyl groups as general biotransformation steps. 1,4-Dihydropyridines bearing appropriate functionalities were precursors in the synthesis of the reference metabolites 2, 3, 4, 7, 8 and 10.