Pharmacology, Efficacy, and Adverse Effects of Halazepam, A New Benzodiazepine

Abstract

Halazepam is a new benzodiazepine derivative that is molecularly similar to chlordiazepoxide and diazepam. Animal studies indicated that halazepam produces sedative and antianxiety effects with less toxicity than chlordiazepoxide or diazepam. Computer EEG and somatosensory evoked potential studies demonstrated that halazepam has a significant effect on the EEG, characteristic of changes that occur with benzodiazepines. In initial clinical studies, halazepam exhibited not only anxiolytic properties but also reduced symptoms of depression and had a therapeutic effect on epilepsy. In preliminary, uncontrolled clinical trials, halazepam was effective in ameliorating anxiety and tension in alcoholic and acute schizophrenic patients, with few adverse effects. Later double-blind studies generally demonstrated that halazepam is significantly superior to placebo in alleviating symptoms of anxiety and tension. Most comparative studies indicate that halazepam is equal to or more effective than diazepam with a lower frequency of side effects. Halazepam does not increase hostility and aggression, as chlordiazepoxide and diazepam have been shown to do, and it is effective in both situational and characterologic anxiety. Drowsiness and slight dry mouth are the only side effects reported in more than isolated instances, although geriatric patients may frequently become ataxic with higher doses.

Metabolism of halazepam by rat liver microsomes: Stereoselective formation and n‐dealkylation of 3‐hydroxyhalazepam

“…Six days after oral administration of 250 mg mcgkg of tritiated HZ to dogs, 47% of the dose was recovered in the feces, and 25% was found in the urine. 4 The main urinary metabolite after deconjugation is a 3-hydroxy deri~ative.4,'~ It was not clear if this "3-hydroxy deriv-atiVea4.14 was 3-OH-HZ or OX, since both may be converted to glucuronide and sulfate conjugates. Incorporation of trifluoroethyl group at the N1 position of NDZ was thought to resist N-dea1kylati0n.l~ Compared to the high extent of N-dealkylation in the metabolism of DZ and PZ, the results reported in this study (i.e., NDZ is formed at an amount considerably less than 3-OH-HZ) seem to be consistent with the idea that N1-trifluoroethyl group is resistant to N-dealkylation.14 It would be interesting to analyze the urinary metabolites following oral administration of HZ to determine the relative amounts of conjugates derived from 3-OH-HZ and OX.…”

[RhCp*Cl2]2-Catalyzed Indole Functionalization: Synthesis of Bioinspired Indole-Fused Polycycles

“…Indole/pyrrole-tethered heterocycles are of substantial importance in natural products due to their widespread bioactivity. Most notably are diazepines, in the process of drug discovery and natural product synthesis, namely, Lixivaptan­(II) (antidiuretic activity), benzo­[1,4]­diazepino­[1,7- a ]­indole (anti-HCV activity), and other exciting diazepines with widespread applications in pharmacology. − Inline, certain attempts were tried, most notably by Ohta, who investigated methods to cyclize indole-fused benzo-1,4-diazepines utilizing the Cu­(I) catalysis system . A similar attempt was made by Mangette to synthesize indolo/pyrrolodiazepines by intramolecular N-arylation …”

Recent Advances in [3+2]-Cycloaddition-Enabled Cascade Reactions: Application to Synthesize Complex Organic Frameworks

“…Tetrahydrobenzodiazepinones are heterocyclic molecules which can be found in plethora of biologically active compounds like halazepam, flurazepam, diazepam, etc. 36,[38][39][40][41] In 2019, Wei Zhang et al proposed a [3+2]-cycloadditionbased tandem radical reaction pathway for the synthesis of trifluoromethylated tetrahydrobenzodiazepin-3-ones. 9 They performed a multicomponent reaction using amino ester 71, maleimides 72, and 2-azidobenzaldehyde 73 (Scheme 15) to afford 74 which underwent [3+2] cycloaddition reaction followed by N-acylation with acryloyl chloride to generate the radical acceptor 75.…”