Asymmetric synthesis and σ receptor affinity of enantiomerically pure 1,4-disubstituted tetrahydro-1H-3-benzazepines |
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Authors: | Syed Masood Husain Marie Theres Heim Dirk Schepmann Bernhard Wünsch |
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Institution: | Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany |
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Abstract: | A very short (three steps) asymmetric synthesis of enantiomerically pure 1,4-disubstituted tetrahydro-1H-3-benzazepines 14 has been elaborated upon, starting from the trans- and cis-configured 11a-substituted 3-phenyl-2,3,11,11a-tetrahydro1,3]oxazolo2,3-b]-3]-benzazepin-5(6H)-ones 6 and 7. The stereoisomerically pure lactams 6 and 7 were benzylated to give 6-benzyl-substituted products 8 and 9. NOE experiments showed a trans-configuration of the benzyl residue and the residue in the 11a-position indicated that the stereochemistry of the benzylation reaction was controlled by the stereocenter at the 11a-position. Reduction of the benzylated tricyclic benzolactams 8 and 9 with AlCl3/LiAlH4 (1/3) yielded the 1,3,4-trisubstituted 3-benzazepines 12 and 13, which were formed stereoselectively with the retention of configuration. Finally, removal of the N-(2-hydroxy-1-phenylethyl) residue by hydrogenolytic cleavage resulted in the formation of enantiomerically pure 1,4-disubstituted 3-benzazepines 14. The σ1, σ2, and NMDA receptor affinities of the enantiomerically pure 3-benzazepines 14 and ent-14 were investigated in competitive receptor binding studies. The butyl derivative ent-14c showed a high affinity towards σ1 and σ2 receptors, with Ki-values of 26 nM and 41 nM, respectively. |
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