37115-34-7

Upstream product

• 39479-72-6 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo<4,3-a><1,4>benzodiazepine 
• 37115-33-6 N-Demethyladinazolam 
• 18091-89-9 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 

Downstream Products

• 37115-32-5 adinazolam 
• 37115-31-4 (8-chloro-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-1-ylmethyl)-diethyl-amine 

Relevant academic research and scientific papers

Kinetic characterization and identification of the enzymes responsible for the hepatic biotransformation of adinazolam and N-desmethyladinazolam in man

The kinetics of the N-demethylation of adinazolam to N-desmethyladinazolam (NDMAD), and of NDMAD to didesmethyladinazolam (DDMAD), were studied with human liver microsomes using substrate concentrations in the range 10-1000 μM. The specific cytochrome P450 (CYP) isoforms mediating the biotransformations were identified using microsomes containing specific recombinant CYP isozymes expressed in human lymphoblastoid cells, and by the use of CYP isoform-selective chemical inhibitors. Adinazolam was demethylated by human liver microsomes to NDMAD, and NDMAD was demethylated to DDMAD; the substrate concentrations, K(m), at which the reaction velocities were 50% of the maximum were 92 and 259 μM, respectively. Another metabolite of yet undetermined identity (U) was also formed from NDMAD (K(m) 498 μM). Adinazolam was demethylated by cDNA-expressed CYP 2C19 (K(m) 39 μM) and CYP 3A4 (K(m) 83 μM); no detectable activity was observed for CYPs 1A2, 2C9, 2D6 and 2E1. Ketoconazole, a relatively specific CYP 3A4 inhibitor, inhibited the reaction; the concentration resulting in 50% of maximum inhibition, IC50, was 0.15 μM and the inhibition constant, K(i), was 0.04 μM in five of six livers tested. Troleandomycin, a specific inhibitor of CYP 3A4, inhibited adinazolam N-demethylation with an IC50 of 1.96 μM. The CYP 2C19-inhibitor omeprazole resulted in only partial inhibition (IC50 21 μM) and sulphaphenazole, α-naphthoflavone, quinidine and diethyldithiocarbamate did not inhibit the reaction. NDMAD was demethylated by cDNA-expressed CYP 3A4 (K(m) 220 μM, Hill number A 1.21), CYP 2C19 (K(m) 187 μM, Hill number A 1.29) and CYP 2C9 (K(m) 1068 μM). Formation of U was catalysed by CYP 3A4 alone. Ketoconazole strongly inhibited NDMAD demethylation (IC50 0.14 μM) and formation of U (IC50 0.1 μM) whereas omeprazole and sulphaphenazole had no effect on reaction rates. These results show that CYP 3A4 is the primary hepatic CYP isoform mediating the N-demethylation of adinazolam and NDMAD. Co-administration of adinazolam with CYP 3A4 inhibitors such as ketoconazole or erythromycin might lead to reduced efficacy, since adinazolam by itself has relatively weak benzodiazepine agonist activity, with much of the pharmacological activity of adinazolam being attributable to its active metabolite NDMAD.

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

A series of 1-(Aminoalkyl)-6-aryl;-4H-s-triazole[4,3-a][1,4]benzodiazepines has been prepared and evaluated for central nervous system activity. The authors 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.

Intermediates and process for the production of certain triazolobenzodiazepines

A multi-step process for the preparation of 1-[(amino - or substituted amino)methyl]-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepines of the formula VI: SPC1 wherein R' is hydrogen or alkyl of 1 to 3 carbon atoms, inclusive, and wherein the rings A and B are unsubstituted or substituted by one or two substituents selected from the group consisting of chloro, fluoro, bromo, nitro, and trifluoromethyl, which comprises: treating a compound of the formula I: SPC2 wherein rings A and B are defined as above, with acetic anhydride and formic acid to obtain compound II: SPC3 wherein A and B rings have the significance as above, treating compound II with sufficient formaldehyde to produce compound III, the 3,5-bis(hydroxymethyl)derivative of II; treating III with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give compound IV, the 3,5-bis(phthalimidomethyl) derivative of II; and treating IV with hydrazine hydrate to obtain a compound of formula V SPC4 wherein rings A and B are defined, as herein above. Compound V can then be alkylated in known manner to give those compounds of formula VIa which corresponds to formula VI when R' is desired to be alkyl. The compounds of formula VI have antidepressant and antianxiety effects in mammals and birds.