1.2.4- Triazolo benzodiazepines

Of the various possible 1,2,4-triazolo-benzodiazepines relevant to this chapter, only the three types, 535-537, have been synthesized. 

Pourbaix S, Desager JP, Hulhoven R, Smith RB, Harvengt C. Pharmacokinetic consequences of long term coadministration of cimetidine and triazolo-benzodiazepines, alprazolam and triazolam, in healthy subjects. Int J Clin Pharmacol Ther Toxicol 1985 23(8) 447-51. 

Estazolam Eurodin Esilgan Takeda Abbott Triazolo-benzodiazepine 1976 2-4 p.o. 

Triazolam Halcion Upjohn (Pharmacia) Triazolo-benzodiazepine 1978 0.125-0.50p.o. 

Annelating the 1,2-bond of ring B with an additionai eiectron-rich (i.e., proton acceptor) ring, such as s-triazoie or imidazole, also results in pharmacologically active benzodiazepine derivatives with high affinity for the BZR (Fig. 22.17). For example, the s-triazolo-benzodiazepines triazolam, alprazolam, and estazolam and the imidazo-benzodiazepine midazolam are popularly prescribed, clinically effective anxiolytic agents (Fig. 22.16). 

The manufacturers of imatinib predict that it may raise the levels of pimozide with potentially serious consequences [arrhythmias] because of CYP3A4 inhibition. They also suggest that imatinib may raise the levels of the triazolo-benzodiazepines (e.g. triazolam, midazolam). This could lead to increased and prolonged sedation. 

A particularly interesting example of this method of synthesis is the cy-clrzation of the 4-amino-3-(2-aminophyenyl)-l,2,4-triazoloes 73 with cyanogen bromide. Primarily, this reaction was applied to synthesize the 6-amino-l,2,4-triazolo[4,3-d]benzodiazepine hydrobromides 74 the obtained products, however, were found to be the l,5-diamino-l,2,4-triazolo-[l,5-c]quinazolin-ium bromides 77. Structure elucidation of 77 was accomplished by direct... 

Chemicel Name 8-Chloro-1 methyl-6-phenyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepine Common Name —... 

Chloro-1 -methyl-6-phenyl4H-s-triazolo-[4,3-a] [1,4] -benzodiazepine A stirred suspension of 5-chloro-2-[3-(bromomethyl)-5-methyl4H-1,2,4-triazol4-yl] -benzophenone (391 mg, 0.001 mol) in tetrahydrofuran (15 ml) was cooled in an ice-bat hand treated with a saturated solution of ammonia in methanol (12.5 ml). The resulting solution was allowed to warm to ambient temperature and stand for 24 hours. It was then concentrated in vacuo. The residue was suspended in water, treated with a little sodium bicarbonate and extracted with methylene chloride. The extract was washed with brine, dried with anhydrous potassium carbonate and concentrated. The residue was crystallized from methylene chloride-ethyl acetate to give... 

Chemical Name 8-chloro-6-phenyl-4H-[1,2,4l-triazolo[4,3-a] [ 1,4] benzodiazepine Common Name -Structural Formula ... 

In contrast to the relatively limited number of non-fused 1,2,4-triazole syntheses that were reported in 1996, the preparation of several ting-fused 1,2,4-triazole-containing structures were published. For example, the frrst practical synthesis of fused[a]triazolo[l,4]benzodiazepine-5,11-diones 16 via the hydrazone IS was reported (Y = H, Cl, Me R = H, Me, Ph X = O, S) <96JHC275>. Oxidative cyclization of N-heteroarylamidines allowed the preparation of... 

For testing sedative hypnotic drugs of the triazolam type the preparation was undertaken of 8-chloro-6-(o-chlorophenyl)-4ff-.y-triazolo[4,3-a][l,4]benzodiazepin-1 -valeric acid methyl ester as an intermediate, with subsequent cyclization and amida-... 

A series of 2-phenyl [ 1,2,3 triazolo[l,2-tf][l,2,4]bcnzotriazin-l,5(6//)-diones display submicromolar/nanomolar potency at the central benzodiazepine receptor. The most potent compound 687 (Kj= 2.8 nM) with enhanced affinity is a full agonist at al and aZ receptor subtypes, and has an antagonist efficacy at a5 receptors <2005JME2936>. 

With regard to the structural relationship of WEB 2086 to triazolo-diazepines, it is interesting to note that up to the highest dose tested (400 mg) no diazepine-characteristic central nervous adverse effects were observed, confirming in man the dissociation of PAF- and benzodiazepine-like effects reported in animals. 

Reactions of 4,5-disubstituted triazoles with appropriate substrates provide very useful methods for building triazolo fused bicyclic or tricyclic systems. 5-Azido-1,2,3-triazoles bearing an appropriate substituent (e.g., CHO, CN, CO2R) at the 4-position can be transformed with active methylene nitriles into tricyclic heterocycles (e.g., (368)) <86BSB679,87BSB587). A new tricyclic system, 5//-1,2,3-triazolo[5,l-c][l,4]benzodiazepine (e.g., (370) and (371)), is prepared by the intramolecular ring closure of triazoles (369) <89JHC1605). 

Garanti et al. (30a) reported a synthesis of the l,2,3-triazolo[l,5-a][4.1]benzox-azepine 149 via an intramolecular cycloaddition of an aryl azide with an acetylene (Scheme 9.30). By using a similar strategy, the l,2,3-triazolo[l,5-a][l,4-l ]benzo-diazepine 150, an analogue of Flumazenil, was also reported (30b,c). As an extension of this method, the l,2,3-triazolo[l,5-a][l,4]benzodiazepine-6-one 153 was synthesized using an intramolecular 1,3-dipolar cycloaddition of an azide with a cyano group (30d). 

That the benzodiazepine structure was a prerequisite for the characteristic tranquilizer profile and specific binding at the benzodiazepine receptor was a long-held belief. This has now been shown not to be the case by the discovery of a range of different compounds that bind to the benzodiazepine receptor [Figure 29-2). These include the 3-carbolines (e.g., abecarnil), the triazolo-pyridazines [e.g., GL 218,872), the imidazopyridines (e.g., zolpidem), the cyclopyrrol ones [e.g., suriclone), and the pyrazoloquinolines. 

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