Synthesis of 3-(2-Guanidinoethyl) and 3-[2-(S-Methylisothioureidoethyl)] Analogs of 5-Isopropyl 2,6-Dimethyl-1,4-dihydro-4-(2,3-dichlorophenyl) pyridine-3,5-dicarboxylate as a Respective Releaser of Nitric Oxide and Inhibitor of Nitric Oxide Synthase

Article abstract of DOI:10.1002/jhet.5570330127

The Hantzsch condensation of 2-azidoethyl acetoacetate with 2,3-dichlorobenzaldehyde and isopropyl 3-aminocrotonate afforded 3-(2-azidoethyl) 5-isopropyl 2,6-dimethyl-1,4-dihydro-4-(2,3- dichlorophenyl)pyridine-3,5-dicarboxylate (7). Reduction of the 3-(2-azidoethyl) moiety of 7 using 5% palladium-on-calcium carbonate and hydrogen gas gave the 3-(2-aminoethyl) derivative 8, which was subjected to guanylation using 1H-pyrazole-1-carboxamidine hydrochloride to yield the target 3-(2-guanidinoethyl) analog 9. The 3-(2-aminoethyl) product 8 was elaborated to the tide compound 3-[2-(S-methylisothioureidoethyl)] 5-isopropyl 2,6-dimethyl-1,4-dihydro-4-(2,3-dichlorophenyl)pyridine-3,5-dicarboxylate hydrochloride (12) via the intermediate 3-(2-thioureidoethyl) compound 10. The 3-(2-guanidinoethyl 9 and 3-[2-(S-methylisothioureidoethyl)] 12 compounds were about 116- and 23-fold less potent calcium channel antagonists, respectively relative to the reference drug nifedipine.