Novel GluN2B selective NMDA receptor antagonists: relative configuration of 7-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ols

Introduction of the flexible aminoalcohol substructure of ifenprodil into a more rigid ring system resulted in 2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ols, (3) and (4), showing GluN2B affinity in the low nanomolar range. The chiral pool synthesis starting with (R)-alanine led to two diastereomers. The relative configuration of the benzazepines (3) and (4), that crystallized as racemates, was determined to be (S*,R*)-3 and (R*,R*)-4.


Chemical context
(S)-Glutamate is the most important excitatory neurotransmitter in the central nervous system. It interacts with different metabotropic and ionotropic glutamate receptors. The NMDA (N-methyl-d-aspartate) receptor is one of three ionotropic receptors, which control the influx of cations, in particular Na + and Ca 2+ ions, into neurons (Brä uner-Osborne et al., 2000;Kew & Kemp, 2005). Physiological activation of the NMDA receptor is associated with processes like learning and memory. However, over-activation of the NMDA receptor is connected with damage of neuronal cells leading finally to neuronal cell death. Therefore, inhibition of the NMDA associated ion channel could be useful for the treatment of traumatic brain injury, cerebral ischemia, neuropathic pain, depression and neurodegenerative disorders like Alzheimer's and Parkinson's disease (Brä uner-Osborne et al., 2000;Kew & Kemp, 2005;Paoletti et al., 2013;Wu & Zhou, 2009).
As a result of the flexibility of the tetrahydro-3-benzazepine system of (1)-(4), the relative configuration of the 3-benzazepines (3) and (4) could not be determined unequivocally by interpretation of NMR spectra. However, crystallization of 70:30 mixtures of (S,R)-3 and (R,S)-3, as well as (R,R)-4 and (S,S)-4, led to colourless crystals which were suitable for X-ray crystal structure analysis. In both cases, the crystals proved to be of a racemic mixture, with the compounds having relative configurations (S*,R*)-3 and (R*,R*)-4.

Figure 2
The molecular structure of compound (S*,R*)-3, with atom labelling. Displacement ellipsoids are drawn at the 30% probability level.

Figure 3
The molecular structure of compound (R*,R*)-4, with atom labelling. Displacement ellipsoids are drawn at the 30% probability level.
In compound (R*,R*)-4 the 4-phenylbutyl side chain exists in a twisted conformation torsion angle C16-C17-C18-C19 = 76.1 (9) ]. The CH 3 group is on the opposite side of the azepine ring adopting an almost axial orientation, as for (S*,R*)-3. However, here the OH group adopts a more equatorial orientation at the seven-membered azepine ring, in contrast to the OH group of (S*,R*)-3. The angles of the aliphatic part of the 3-benzazepine ring are close to the tetrahedral angle value.
In both cases, the compounds were used for recrystallization with ethyl acetate and the crystals obtained were used for the subsequent X-ray crystal structure analyses. The crystals thus obtained proved to be racemic mixtures, with the compounds having relative configurations (R*,S*)-3 and (R*,R*)-4.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 3 Table 2; for clarity, only the H atoms involved in these interactions are included. For both compounds, data collection: COLLECT (Nonius, 1998); cell refinement: COLLECT (Nonius, 1998); data reduction: DENZO-SMN (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009). Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.