Tricyclic epines. Novel (E)- and (Z)-11H-dibenz[b,e]azepines as potential central nervous system agents. Variation of the basic side chain

Abstract

The synthesis and pharmacological activity of new (E),(Z)-[6-(alkylamino)-11H-dibenz[b,e]azepin-11- ylidene]acetonitriles 12-45 and (E),(Z)-[6-(aminoalkoxy)-11H-dibenz[b,e]azepin-11-ylidene] acetonitriles 46-51 are described. The introduction of the cyanomethylene group into the 11-position of the 11H-dibenz[b,e]azepine framework has been carried out by a Wittig-Horner reaction under mild conditions. The (E),(Z) isomers were separated by fractional crystallization, assignment being achieved by X-ray analysis. A number of (E),(Z)-[6-(alkylamino)-11H-dibenz-[b,e]azepin-11-ylidene] acetonitriles (12, 14, 16, 20) show potent neuroleptic activity (2-7 times that of clozapine) in animal tests. The screening included tests for sedative and anticholinergic activity in mice, apomorphine and tryptamine antagonism in rats, and muscle-relaxing activity in rabbits. The divergence in the activity profile in the case of the separated (E),(Z) isomers has been observed as an interesting new aspect: the (Z) isomers show a significantly higher sedative and muscle-relaxant activity, whereas the (E) isomers possess a higher anticholinergic efficacy and somewhat greater apomorphine antagonism. Broad changes in the basic side chain were made in order to investigate structure-activity relationships. The important geometrical parameters for the molecules, obtained by X-ray analysis, were compared with the corresponding features in dopamine agonists and antagonists.

Valence isomerization of cyclohepta-1,3,5-triene and its heteroelement analogues

“…For instance, 3 H -3-benzazepin-2-amines 27 possess antihypertensive activity [97], and all tricyclic dibenzo[ b , f ]azepines (e.g., 28 ; Fig. 3) bearing a basic side chain affect the central nervous system [98]. …”

Synthesis of Novel 7‐methylene‐6,7‐dihyrobenzo[f]Benzo[4,5]Imidazo[1,2‐d][1,4]Oxazepines via Base‐mediated Regioselective Intramolecular Hydroamination

“…Compounds containing “a fused seven‐membered benzoxazepine ring” have been of pivotal interest over the past few years because of their wide range of biological activities and pharmacological properties . For instance, 5,6‐dihydrobenzo[f]imidazo[1,2d] [1,4] oxazepine scaffolds (Fig.…”

A new and convenient synthetic method for 1,2,3,5,6,11b-hexahydroimidazo [1,2-d][1,4]benzoxazepine and its derivatives

“…[1][2][3][4][5] Most syntheses of 2,3,4,5-tetrahydro-1,4-benzoxazepines involve the reduction of the carbonyl group(s) as for 5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine, 3-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine, and 3,5-dioxo-2,3,4,5-tetrahydro-1,4-benzoxazepine, or the reduction of a double bond as for 2,3-dihydro-1,4-benzoxazepine. 1,[6][7][8] Alternatively, 2,3,4,5-tetrahydro-1,4-benzoxazepines are accessible by one of the following known benzoxazepine syntheses: (i) condensation of 2-aryloxyethylamines with 2-formylbenzoic acid to form aminonaphthalides followed by cyclization: (ii) rearrangement of methyl 2-(8-methoxy-2,3-dihydro-1,4-benzoxazepin-5-yl)benzoate using Bischler-Napieralski conditions; (iii) scandium or copper triflate-catalyzed acylaminoalkylation of α-methoxy-isoindolones with the formation of 1,4-benzoxazepines.…”