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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
Author(s) -
Iqbal Nadeem,
Knaus Edward E.
Publication year - 1996
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570330127
Subject(s) - chemistry , isopropyl , hydrochloride , moiety , pyridine , yield (engineering) , medicinal chemistry , amidine , derivative (finance) , stereochemistry , organic chemistry , materials science , economics , financial economics , metallurgy
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 1 H ‐pyrazole‐1‐carboxamidine hydrochloride to yield the target 3‐(2‐guanidinoethyl) analog 9 . The 3‐(2‐aminoethyl) product 8 was elaborated to the title 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.