Synthesis and benzodiazepine binding activity of a series of novel [1,2,4]triazolo[1,5-c]quinazolin-5(6H)-ones

Abstract

Investigation of tricyclic heterocycles related to the 2-arylpyrazolo[4,3-c]quinolin-3(5H)-ones, structures with high affinity for the benzodiazepine (BZ) receptor, led to the synthesis of 2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one, a compound with 4 nM binding affinity to the BZ receptor. Analogues were prepared to assess the importance of the 2-substituent and ring substitution in modifying activity. Several novel synthetic routes were designed to prepare the target compounds, including a two-step synthesis beginning with an anthranilonitrile and a hydrazide. Of the 34 compounds screened in this series, three compounds were found to be potent BZ antagonists in rat models. The leading compound, 9-chloro-2-(2-fluorophenyl) [1,2,4]triazolo[1,5- c]quinazolin-5(6H)-one (CGS 16228), showed activity comparable to that of CGS 8216 from the pyrazolo[4,3-c]quinoline series.

Synthesis and Anticancer Activity of 2-(Alkyl-, Alkaryl-, Aryl-, Hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines

“…The latter method was less effective than the previous because of a lower yield. It is important, that in all cases, intermediate [1,2,4]triazolo[4,3- c ]-quinazolines are ANRORC-rearranged forming 2-R-[1,2,4]triazolo[1,5- c ]quinazolines ( 5.1–5.40 ) [21]. The 1 H-NMR spectra of compounds 5.1–5.40 were significantly different from the spectra of hydrazides 3.1–3.40 and hydrazones 4.1–4.6 .…”

“…It is known, that [1,2,4]triazolo[1,5- c ]quinazoline derivatives possess adenosine and benzodiazepine receptor affinity [1, 2], antiasthmatic, tranquilizing, neurostimulating [3], phosphodiesterase 10A inhibitive [4], antimicrobial and antifungal [5–7], anti-inflammatory, and sedative activities [8, 9]. As a result, their derivatives surely will have biological activity because of the potent pharmacophore they have in their structures.…”

2‐Amino[1,2,4]triazolo[1,5‐c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure–Activity Relationships of Potent Adenosine Receptor Antagonists

“…Starting materials 22 b, [35] 22 i, [36] 22 o, [35] 22 p, [37] 22 q, [38] 26, [39] 28, [18] and 30 [40] were prepared according to published procedures. Syntheses of products 11 b, [41] 11 n, [41b,c] 12 b, [42] 13 a, [43] 13 b, [42, 43b, 44] 15 b, [45] and 16 b [45,46] were previously reported. (R,S)-2-Phenylpropionyl chloride and 3-(3,4,5-trimethoxyphenyl)propionyl chloride were prepared from the corresponding acids.…”

Synthesis and Pharmacological Evaluation of Novel Triazolo [4, 3‐a] tetrahydrobenzo (b) thieno [3, 2‐e] pyrimidine‐5(4H)‐ones

“…Number of references showed that condensed 1, 2, 4‐triazoles exhibited excellent CNS depressant and anticonvulsant activities. Significant CNS depressant activity was reported for triazoles, especially triazoloquinazoline , triazoloquinazolinediones , triazolopyrimidines , triazolothienopyrimidine , 1,3,4‐thiadiazolotetrahydrobenzothienopyrimidine , and 1,3,4‐thiadiazole‐quinazoline have given an impetus to synthesize some non‐benzodiazepine ligands (bioisosteric triazolotetrahydrobenzo( b )thienopyrimidines), which are devoid of typical benzodiazepine mediated side effect such as physical dependence, amnesia, and over sedation.…”