Abstract
A group of 4-(3-(1-methoxycarbonyl-1,6-dihydropyridyl))- derivatives of alkyl 1,4-dihydro-2,6- dimethyl-3-nitro-5-pyridinecarboxylates 8a-e were synthesized by the regioselective reduction of the corresponding 4-(3-pyridyl)- analogs in the presence of methyl chloroformate using Li(t- BuO)3AlH. Alternatively, a related group of 4-(3-(1-methoxycarbonyl-4-substituted-1,4- dihydropyridyl))- compounds 14-18 were prepared using a modified Hantzsch reaction involving the condensation of 1-methoxycarbonyl-4-substituted-1,4-dihydropyridyl-3-carboxaldehydes 11a-c with an alkyl 3-aminocrotonate 12 and nitroacetone 13. In contrast to the 4-(3-pyridyl)- compound 2b, which exhibits an undesirable calcium channel agonist smooth muscle
Highlights
The design of cardioselective Hantzsch 1,4-dihydropyridine (DHP) L-type voltage sensitive calcium channel (CC) agonist positive inotropes has presented a significant challenge to medicinal chemistrs.[1,2,3]
The prototype 1,4-DHP CC agonist (S)-(+)-Bay K 8644 1 simultaneously promotes calcium entry into vascular smooth muscle, inducing vasconstriction, that prevents its clinical use for the treatment of congestive heart failure (CHF).[4,5]
Subsequent nuclear Overhauser enhancement (NOE) studies for compounds 4-5 indicated that there is a significant rotamer fraction in solution where the pyridyl nitrogen is oriented above the 1,4-DHP ring, irrespective of whether a substituent (Me, Ph) is located at the 6- (R1) or 3-position (R2) of the pyridyl ring
Summary
The design of cardioselective Hantzsch 1,4-dihydropyridine (DHP) L-type voltage sensitive calcium channel (CC) agonist positive inotropes has presented a significant challenge to medicinal chemistrs.[1,2,3] the prototype 1,4-DHP CC agonist (S)-(+)-Bay K 8644 1 simultaneously promotes calcium entry into vascular smooth muscle, inducing vasconstriction, that prevents its clinical use for the treatment of congestive heart failure (CHF).[4,5] Recently, we discovered a novel third generation class of isomeric isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro4-(pyridyl)-5-pyridinecarboxylates 2a-c with different CC modulation activities.[6].
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