Synthesis and structure/NMDA receptor affinity relationships of 1-substituted tetrahydro-3-benzazepines

A novel synthesis of 1-substituted tetrahydro-1H-3-benzazepines 4 is described. Starting with (2-bromophenyl)acetaldehyde acetal 5, the nitrostyrene 9 was prepared in three steps allowing the addition of various nucleophiles to yield the nitroacetals 10. The one-pot Zn/HCl reductive cyclization of the nitroacetals 10 provided the 3-benzazepines 4, which were investigated for their affinity to the phencyclidine binding site of the NMDA receptor. A one-atomic spacer between the 3-benzazepine system and the phenyl residue in position 1 seems to be favorable for high NMDA receptor binding. In this series the benzazepine 41 substituted with the conformationally restricted and H-bond accepting acetanilide substituent in position 1 displays the highest NMDA receptor affinity (K-i = 89 nM). (C) 2004 Elsevier Ltd. All rights reserved.