Crystal structure of (1S*,2R*)-7-benz-yloxy-2-methyl-3-tosyl-2,3,4,5-tetra-hydro-1H-3-benz-azepin-1-ol: elucidation of the relative configuration of potent allosteric GluN2B selective NMDA receptor antagonists.

Bastian Tewes,Bernhard Wünsch,Roland Fröhlich,Bastian Frehland

doi:10.1107/s2056989016005855

Bastian Tewes, Bernhard Wünsch + Show 2 more

Open Access

https://doi.org/10.1107/s2056989016005855

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Abstract

In the title compound, C25H27NO4S, which crystallized as a racemate, the relative configuration of the adjacent OH and CH3 groups on the azepine ring is trans. The seven-membered azepin ring has a chair-like conformation. The planar aromatic rings of the benzyl and tosyl-ate moiety are inclined to the planar 3-benzazepine ring by 78.39 (15) and 77.03 (14)°, respectively, and to each another by 13.82 (15)°. In the crystal, mol-ecules are linked via O-H⋯O and C-H⋯O hydrogen bonds, forming double-stranded chains along the a-axis direction. The chains are linked via C-H⋯π inter-actions, forming a three-dimensional architecture.

Highlights

Crystal structure of (1S*,2R*)-7-benzyloxy-2methyl-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
C25H27NO4S, which crystallized as a racemate, the relative configuration of the adjacent OH and CH3 groups on the azepine ring is trans
The NMDA receptor consists of four proteins, which form a cation channel allowing the penetration of Ca2+ and Na+ ions into the neuron (Furukawa et al, 2005)

Summary

Chemical context

Receptors represents a promising strategy for the treatment of acute (e.g. stroke, epilepsy, traumatic brain injury) and chronic neuronal disorders (e.g. neuropathic pain, depression, Alzheimer’s and Parkinson’s disease) (Bräuner-Osborne et al., 2000; Kew & Kemp, 2005; Paoletti et al, 2013; Wu & Zhou, 2009). GluN2B subunit are an attractive target for the development of innovative drugs, since the expression of the GluN2B subunit is limited to only a few regions of the central nervous system, including cortex, striatum and hippocampus The GluN2B subunit can be addressed selectively by ligands interacting with the so-called ifenprodil binding site, which is formed at the interface between GluN2B and GluN1 subunits (Karakas et al, 2011; Paoletti et al, 2013). The 2-piperidino-1-phenylpropan-1-ol derivative ifenprodil (Paoletti et al, 2013; Williams, 2001) (Fig. 1) represents the first ligand interacting with this binding site at the NMDA receptor. As a result of its poor selectivity and low bioavailability, ifenprodil has not been developed as a drug for clinical use. (Tewes et al, 2010a,b; Schepmann et al, 2010; Falck et al., 2014)

Elucidation of the relative configuration

Structural commentary

Synthesis and crystallization

Refinement details