RÉSUMÉ
10-(Alkylamino)thieno[3,4-b][1,5]benzoxazepines (3) and 10-(alkylamino)thieno[3,4-b][1,5]benzothiazepines (4) were prepared by derivatization of the respective lactams (7 and 8) via phosphorus pentachloride and subsequent condensation with the appropriate alkylamines. 9-(Alkylamino)-4H-thieno[3,4-b][1,4]benzodiazepines (5) were prepared by titanium tetrachloride catalyzed condensation of the lactam 11 with alkylamines. 9-(Alkylamino)-4-methylthieno[3,4-b][1,4]benzodiazepines (6) were prepared by reductive alkylation of 5. The compounds were tested for potential neuroleptic activity by means of the blockade of d-amphetamine lethality in aggregated mice and/or effects on locomotor activity in rats. Antidepressant activity was examined using inhibition of tetrabenazine-induced depression in mice. Most of the title compounds 3-6 were found to have neuroleptic activity. In addition, introduction of a 3-chloro substituent in the oxygen and sulfur systems (3p and 4c), as well as introduction of an N-alkyl in the dinitrogen system (6), was found to produce antidepressant effects. Structure-activity relationships are discussed.
Sujet(s)
Azépines/synthèse chimique , Benzodiazépines/synthèse chimique , Oxazépines/synthèse chimique , Psychoanaleptiques/synthèse chimique , Thiazépines/synthèse chimique , Thiophènes/synthèse chimique , Animaux , Anxiolytiques/synthèse chimique , Neuroleptiques/synthèse chimique , Phénomènes chimiques , Chimie , Relation dose-effet des médicaments , Lactames , Souris , Activité motrice/effets des médicaments et des substances chimiques , Rats , Relation structure-activitéRÉSUMÉ
An investigation of the structural requirements for CNS activity of the title compounds was undertaken. A synthesis of the precursor dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-ones was achieved and three routes for their conversion to the title compounds were developed. The compounds were tested for neuroleptic activity by means of the blockade or d-amphetamine lethality in aggregated mice and/or effects on locomotor activity in rats. Antidepressant activity was examined using inhibition of tetrabenazine-induced depression in mice. Most of the compounds were found to be potent neuroleptic agents with several exhibiting additional antidepressant activity.
