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Ring Conformation in 3,4-Dihydropyrimidine-2-ones: An Ab Initio and Density Functional Theory Study

C. Oliver Kappe* and Walter M. F. Fabian

Institute of Organic Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria

Abstract

Introduction

Dihydropyrimidines of type 1 (DHPMs, Biginelli compounds) [1] represent a long-known class of heterocycles that show a diverse range of biological activities [2]. Most notable is the recently discovered cardiovascular (i.e. antihypertensive) activity exhibited by certain functionalized derivatives, e.g. 2, that compares very favorable with the activity displayed by the structurally related antihypertensive dihydropyridine drugs (DHPs) amlodipine and nicardipine (e.g. 3) [3,4]. Although several questions about the exact stereochemical and conformational requirements for activity remain, a reasonable pharmacophore model for DHP/DHPM calcium channel modulators has been proposed recently [5]. The main features of this model include: (i) a boat-like conformation of the DHP/DHPM ring; (ii) an axially positioned substituted aryl ring and (iii) an ester group at C5 oriented cis with respect to the C5=C6 double bond [5].