8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines with substituents at C-4.

A series of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines with substituents at C-4 was prepared and evaluated for antianxiety potential. It was found that substitution at this position generally decreased the activity in this series.

2,4-Dihydro-6-phenyl-1H-s-triazolo[4,3-a][1,4]benzoidiazepin-1-ones with antianxiety and antidepressant activity.

A series of 2,4-dihydro-6-phenyl-1H-s-triazolo[4,3-a][1,4]benzodiazepin-1-ones was prepared and evaluated for central nervous system activity. It was found that the 2-methyl-substituted analogues had interesting activity in tests useful for detecting anxiolytic agents, while N-2 substitution with omega-(dialkylamino)alkyl substituents give compounds with antidepressant potential as well as antianxiety activity.

1-(Aminoalkyl)-6-aryl-4-H-s-triazolo[4,3-a][1,4]benzodiazepines with antianxiety and antidepressant activity.

A series of 1-(aminoalkyl)-6-aryl-4H-s-triazolo[4,3-a][1,4]benzodiazepines has been prepared and evaluated for central nervous system activity. We have found that members of this series have activity in pharmacological test systems designed to detect both anxiolytic and antidepressant activity. Each type of activity could be varied independently by appropriate substituent selections.

Novel anxiolytic agents derived from alpha-amino-alpha-phenyl-o-tolyl-4H-triazoles and -imidazoles.

Several new alpha-amino-alpha-phenyl-o-tolytriazoles and -imidazoles have been prepared in one step by means of a novel reductive rearrangement of the corresponding benzodiazepines with hydrazine hydrate. These new triazoles were found to have moderate sedative and muscle relaxing activity in mice (i.e., these compounds depressed the traction and dish reflexes at higher doses than did diazepam) but were very potent antagonists of the clonic convulsions induced in mice by the administration of pentylenetetrazole. Furthermore, they antagonized the lethality induced by thiosemicarbazide. While these new compounds were very active in mice, most were inactive in rats. These results are discussed with reference to the metabolism of compound 13.

Synthesis and pharmacology of novel anxiolytic agents derived from 2-[(dialkylamino)methyl-4H-triazol-4-yl] benzophenones and related heterocyclic benzophenones.

A series of novel [(dialkylamino)methyl-4H-1,2,4-triazol-4-yl]benzophenones and related compounds has been prepared via total synthesis from substituted aminodiphenylmethanes or by hydrolysis and subsequent methylation of triazolobenzodiazepines. These new triazole compounds were found to have potent sedative and muscle relaxing activity in mice (i.e., these compounds depressed the traction and dish reflexes). In addition, the title compounds antagonized the clonic convulsions induced in mice by the administration of pentylenetratrazole (Metrazol, 85 mg/kg), with ED50's varying from 2.0 to 23.0 mg/kg, and the lethality induced by thiosemicarbazide, with ED50's varying from 0.02 to 9.0 mg/kg. In several biological tests, the potency of seven new benzophenone derivatives approached or exceed that of diazepam (35a) or its glycylaminobenzophenone analogue 36.

Butyrophenones as hypotensive agents. Derivatives of 4-aryl-4-(hydroxymethyl)cyclohexylamine.

The preparation of butyrophenone derivatives of 4-aryl-4-(hydroxymethyl)cyclohex-1-ylamines starting from the corresponding 4-cyano-4-phenylcyclohexan-1-ones is described. Substitution was varied with both rings; both isomers of 4-phenyl-4-(hydroxymethyl)cyclohex-1-ylamine were characterized. Those derivatives which carried p-fluoro substitution on the butyrophenone exhibited hypotensive activity in the rat with diminished CNS activity compared to compounds lacking the hydroxymethyl group. The effect of substitution on the 4-aryl ring is discussed.

Comparison of triazolam and methyprylon as a hypnotic in insomniacs.

The hypnotic effect of a new triazolobenzodiazepine, triazolam (0.5 mg) and methyprylon was compared in 30 outpatient volunteers with insomnia using the preference technique. On the first night of the 2 night trial, triazolam or methyprylon was given on a double-blind basis and on the 2nd night the outpatients received the alternate medication. Following each trial night the patients were interviewed in regard to their sleep. Of the 28 patients who completed the study, 21 patients preferred triazolam, 5 preferred methyprylon and 2 had no preference (p = 0.001). Analysis of the various sleep parameters showed that triazolam helped the patients sleep more than methyprylon (p = 0.026), there were fewer awakenings on triazolam (p = 0.064), a longer duration of sleep (p = 0.064) and a better feeling in the a.m. (p = 0.020). The sleep onset was the same after both medications. The number and severity of the side effects was considerably higher after methyprylon.