Crystal structure of (1S*,2R*)-7-benzyloxy-2-methyl-3-tosyl-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ol: elucidation of the relative configuration of potent allosteric GluN2B selective NMDA receptor antagonists

Abstract

Tetra­hydro-3-benzazepines with a hy­droxy group in the 1-position and a methyl group in the 2-position were designed as conformationally restricted ifenprodil analogues. The enanti­omerically pure 3-benzazepine (S,R)-4 representing a constitutional isomer of ifenprodil shows high affinity towards the ifenprodil binding site (Ki = 26 nM) and high antagonistic activity at the NMDA receptor (IC50 = 9.0 nM). The crystal structure analysis of the inter­mediate sulfonamide (S,R)-2 was performed in order to assign unequivocally the relative configuration of the methyl and hy­droxy groups.

Enantiomerically Pure 2-Methyltetrahydro-3-benzazepin-1-ols Selectively Blocking GluN2B Subunit Containing N-Methyl-d-aspartate Receptors

“…The configuration of the stereoisomers 31 was derived from the configuration of the analogous stereoisomeric methyl ethers 21 . However, an X-ray crystal structure analysis of the mixture of ( S , R )- 28 /( R , S )- 28 confirmed unequivocally the trans -configuration and thus the relative and absolute configuration of all four stereoisomers of 28 and 31 (Figure SI-6).…”

“…Therefore, X-ray crystal structures of (S,R)-21 (42% ee) and (R,R)-21 (52% ee) were recorded. 23 The X-ray crystal structure (Figure SI-4) clearly shows trans-configuration of the OH moiety and the methyl group, proving unlike-configuration of (S,R)-21 (42% ee). On the other hand cis-orientation of these substituents is displayed in Figure SI-5, proving likeconfiguration of (R,R)-21 (52% ee).…”