Asymmetric synthesis of enantiomerically pure 2-substituted tetrahydro-3-benzazepines and their affinity to sigma1 receptors.
A very short asymmetric synthesis of enantiomerically pure 2-substituted tetrahydro-3-benzazepines is described. First, 3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-ones 3a-d and 4a-d were synthesized by condensation of 2-(2-oxoalkyl)phenylacetic acids 1a-d with (R)-phenylglycinol (2). With the exception of the 11a-phenyl derivatives 3d/4d (ratio 91:9), the ratio of the diastereomeric 11a-alkyl derivatives 3a-c/4a-c was almost 50:50. The configuration of the newly formed chiral center in position 11a was proved by NOE experiments as well as X-ray crystal structure analysis. The reduction of the oxazolo[2,3-b][3]benzazepin-5(6H)-ones trans-3 and cis-4 with AlCl(3)/LiAlH(4) (1:3) took place with retention of configuration and yielded 2,3-disubsituted tetrahydro-3-benzazepines 10 and11. In the final step, removal of the N-(2-hydroxy-1-phenylethyl) residue from 10 and 11 by hydrogenolysis provided four pairs of enantiomerically pure 2-substituted tetrahydro-3-benzazepines 12a-d and ent-12a-d, which were tested for their sigma(1), sigma(2), and NMDA receptor affinities. The 2-butyl and the 2-phenyl derivatives 12c and 12d show very high sigma(1) affinity with K(i) values of 16 and 50 nM, respectively. The eudismic ratios are greater than 50, reflecting highly stereoselective interaction with the sigma(1) receptor. Both sigma(1) ligands are very selective against the sigma(2) subtype and the PCP binding site of the NMDA receptor.
Husain
Syed Masood
SM
Institut für Pharmazeutische and Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Fröhlich
Roland
R
Schepmann
Dirk
D
Wünsch
Bernhard
B
D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry; D003500:Cyclization; D006859:Hydrogen / Q000737:chemistry*; D007189:Indans / Q000737:chemistry; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry; D013237:Stereoisomerism
D001552:Benzazepines; D007189:Indans; D010080:Oxazoles; C064210:oxazolidine; D006859:Hydrogen; C013352:indacrinone