piperidines and acetamide

We synthesized and evaluated the inhibitory activity of a series of 2-(1-alkylpiperidin-4-yl)-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]acetamide derivatives against T-type Ca(2+) channels. Structure-activity relationship studies revealed that the position of the amide structure was important for the potent inhibitory activity toward T-type Ca(2+) channels. In addition, the introduction of an appropriate substituent on the pendant benzene ring played a crucial role for the selectivity towards T-type Ca(2+) channels over L-type Ca(2+) channels and the potent bradycardic activity of these derivatives. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-2-(1-{2-[2-(2-methoxyethoxy)phenyl]ethyl}piperidin-4-yl)acetamide (4f), which had superior selectivity for T-type Ca(2+) channels over L-type Ca(2+) channels, lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.

Topics: Acetamides; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Fluorine; Male; Mibefradil; Piperidines; Rats; Structure-Activity Relationship

Expedient and highly stereoselective routes to orthogonally protected chiral 2-substituted 4-aminopiperidines have been developed. Diastereoselective nucleophilic substitution of the hydroxy group of (2R,4S)-2-[(S)-1,2-dibenzyloxyethyl]-4-hydroxy-1-[(S)-1-phenylethyl]piperidine using sodium azide afforded the corresponding azido derivative, which could be reduced and selectively protected to give (2R,4R)-1-tert-butoxycarbonyl-2-[(S)-1,2-dibenzyloxyethyl]-4-acetylaminopiperidine. This compound was easily converted into optically active 2-substituted 4-aminopiperidines using different synthetic methodologies such as epoxide nucleophilic ring opening reactions and Wittig olefination reactions among others.

Topics: Acetamides; Piperidines; Pyridones; Stereoisomerism; Substrate Specificity