High-Affinity Partial Agonist Imidazo[1,5-a]quinoxaline Amides, Carbamates, and Ureas at the γ-Aminobutyric Acid A/Benzodiazepine Receptor Complex

Abstract

A series of imidazo[1,5-a]quinoxaline amides, carbamates, and ureas which have high affinity for the gamma-aminobutyric acid A/benzodiazepine receptor complex was developed. Compounds within this class have varying efficacies ranging from antagonists to full agonists. However, most analogs were found to be partial agonists as indicated by [35S]TBPS and Cl- current ratios. Many of these compounds were also effective in antagonizing metrazole-induced seizures in accordance with anticonvulsant and possible anxiolytic activity. Selected quinoxalines displayed limited benzodiazepine-type side effects such as ethanol potentiation and physical dependence in animal models. Dimethylamino urea 41 emerged as the most interesting analog, having a partial agonist profile in vitro while possessing useful activity in animal models of anxiety such as the Vogel and Geller assays. In accordance with its partial agonist profile, 41 was devoid of typical benzodiazepine side effects.

A short and efficient protocol for the synthesis of imidazo[1,5- a ]quinoxalin-4-ones from 3-aroylquinoxalinones and compounds with the aminomethylene moiety

“…[1,5-a]quinoxalin-4(5H)-one (3a). 1,28 Yield: 234 mg (90%), 174 (67%), 169 mg (65%), 52 mg (20%), 203 mg (78%), 26 mg (10%), 57 mg (22%), 39 mg (15%), 65 mg (25%) in the reactions of compound 1a with glycine 2a in the presence of NaOAc, glycine 2a without adding NaOAc, L -b-phenyl-a-alanine 2b, methylamine hydrochloride 2f, methylamine hydrochloride 2f in the presence of NaHCO 3 , isobutylamine 2h, isobutylamine 2h in the presence of NaHCO 3 , aminoethanol 2k, aminoethanol 2k in the presence of NaHCO 3 , respectively (Tables 1e4). White powder, mp >360 S (DMSO:CH 3 CN¼1:1) (lit.…”

“…The second approach involves the annulation of an imidazole ring to N-protected quinoxalin-2-one mediated by a dipolar cycloaddition of tosylmethyl or benzyl isocyanide as the key step. 1,14,15 While useful for the preparation of certain imidazo [1,5-a]quinoxalin-4-ones, this approach suffers a number of drawbacks such as the poor regioselectivity encountered in the formation of quinoxalin-2-ones with nonsymmetrical phenylene-1,2-diamines, the lack of control of the chemoselectivity of N-protection versus O-protection during the protection step, 14 and the difficulties involved in separating the regioisomers. The method requires not easily accessible, air-sensitive, unstable phenylene-1,2-diamines as initial precursors as well (Scheme 1).…”

Piperazine Imidazo[1,5-a]quinoxaline Ureas as High-Affinity GABAALigands of Dual Functionality

“…Imidazo-annulation of quinoxalin-2-one (5), 13,16 via the intermediate enol phosphonate using tert-butyl isocyanoacetate, provided imidazo [1,5-a]quinoxaline 6 in 60-80% yield. The carbamoyl chloride 7 was formed by reaction of 6 with phosgene or triphosgene in the presence of Hunig's base.…”

“…13 Unfortunately this analogue contained a 5′-cyclopropyl-1′,2′,4′-oxadiazole group at the 3-position, which in the case of 2 (pandiplon, PNU-78875) 9a is metabolized to release cyclopropanecarboxylic acid, leading to an increase in serum triglycerides. 14 Although 1 had a different metabolic profile than 2, concerns over possible degradation of the oxadiazole group to release cyclopropane carboxylic acid precluded further development of this compound.…”

1-Substituted 4-[Chloropyrazolyl][1,2,4]triazolo[4,3-a]quinoxalines: Synthesis and Structure-Activity Relationships of a New Class of Benzodiazepine and Adenosine Receptor Ligands

“…It has been found that many compounds, whose structures were apparently unrelated to benzodiazepines, are able to bind competitively to the benzodiazepine binding site of the GABA A receptor [5b-c] , e.g. [1,2,4]triazolo [1,5-c]quinazolin-5(6H)-ones [3a] , [1,2,4]triazolo [4,3-b]pyridazines [3d] , and imidazo [1,5-a]quinoxaline derivatives [6] .…”