[Benzomorphan analogs with doxpicomine partial structure: synthesis andpsychopharmacologic investigations of 5-aminomethyl- and 5-(alpha-aminobenzyl)- substituted 2,6-epoxy-3-benzoxocines].
Addition of the beta-alanine derivative 6 to the homophthalaldehyde monoacetal 5 and subsequent LiAlH4-reduction led to the dihydroxy acetal 8, which was cyclized with acid to give the 5-aminomethyl-2,6-epoxy-3-benzoxocines 2a and 2b. The reaction of 5 with the anion of the beta-lactam 9 yielded two separable diastereomers: 10a with u,l-configuration and 10b with 1,1-configuration. Via the 2-benzopyran 11a (11b), the aminoalcohol 12a (12b), and the secondary amine 13a (13b), the beta-lactam adduct 10a (10b) was transformed to give the 5-(alpha-dimethylaminobenzyl)-2,6-epoxy-3-benzoxocine 3d (3b). The relative configurations of all these "beta-lactam route" products (10-13, 3d, and 3b) were established by their 1H-NMR-spectra. Attempts failed to get the missing diastereomers 3a and 3c by epimerization of the beta-lactams 11a and 11b or by reductive amination of the benzoyl derivatives 17a and 17b. Finally, 3a and 3c were obtained by phenylmagnesium bromide addition to the nitriles 21a and 21b, followed by LiAlH4-reduction, formaldehyde/NaBH3CN methylation and chromatographic separation. In the Irwin-screen (mouse) only 2a.HCl, 3b, and 3d (100 mg/kg body weight) caused weak central effects.
Wünsch
B
B
Institut für Pharmazie und Lebensmittelchemie, Universität München.
Bauschke
G
G
D000818:Animals; D001575:Benzomorphans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D011725:Pyridines / Q000737:chemistry
D001575:Benzomorphans; D002491:Central Nervous System Agents; D011725:Pyridines; C020698:doxpicodin
Benzomorphan-Analoga mit Doxpicomin Partialstruktur: Synthese und psychopharmakologische Untersuchung von 5-Aminomethyl und 5-(alpha-Aminobenzyl) substituierten 2,6-Epoxy-3-benzoxocinen.