Nuclear magnetic resonance studies and conformational analysis of bicyclic inhibitors of angiotensin-converting enzyme. Part 2. The octahydro-6H-pyridazo[1,2-a][1,2]diazepines
Abstract
The conformations are determined of a number of bicyclic heterocycles synthesised as part of a programme related to the design of inhibitors of angiotensin-converting enzyme (ACE). In these compounds, a six-membered ring is fused to a seven-membered ring via a diaza bridge. By detailed 1H n.m.r. spectroscopy, the 6-oxo series is shown to be rigid with the axial 1-carboxy anchoring the system. In the 6-deoxy series some flexibility in the seven-membered ring is apparent, though nitrogen inversion is prevented. X-Ray diffraction, molecular graphics, and MNDO calculations are employed to assist in the conformational analyses. The three-dimensional arrangement of the three enzyme-binding groups in these compounds provides very potent inhibitors (l50 1.6–3nM).