Antagonist, Partial Agonist, and Full Agonist Imidazo[1,5-a]quinoxaline Amides and Carbamates Acting through the GABAA/Benzodiazepine Receptor

Abstract

(4RS)-1-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-12,12a-dihyd roimidazo[1,5- a]pyrrolo[2,1-c]quinoxalin-10(11H)-one (1a), 5-benzoyl-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5- dihydroimidazo[1,5-a]quinoxaline (13b), and tert-butyl (4S)-12,12a-dihydroimidazo[1,5-a]pyrrolo[2,1- c]quinoxaline-1-carboxylate (1e), as well as other imidazo[1,5-a]quinoxaline amides and carbamates, represent a new series of compounds which bind with high affinity to the GABAA/benzodiazepine receptor. These compounds exhibit a wide range of intrinsic efficacies as measured by [35S]TBPS binding ratios. The synthesis of 1a begins with the addition of DL-glutamic acid to 1-fluoro-2-nitrobenzene, followed by reduction of the nitro group and subsequent ring closure to form 3-(carbethoxymethyl)-1,2,3,4-tetrahydroquinoxalin-2-one, followed by a second ring closure to afford (4RS)-1,5-dioxo-1,2,3,4,5,6-hexahydropyrrolo[1,2-a]quinoxali ne as the key intermediate. Appendage of a substituted imidazo ring via the anion of 5-cyclopropyl-1,2,4-oxadiazol-3-yl gives 1a. The (-)- and (+)-isomers of 1a were prepared from 1-fluoro-2-nitrobenzene and L- and D-glutamic acid, respectively. 1a and its enantiomers demonstrated affinity for the [3H]flunitrazepam binding site with Ki's of 0.87, 0.62, and 0.65 nM, respectively.

Chemistry, Biological Properties and SAR Analysis of Quinoxalinones

“…In Fig. (30) are reported some examples: 1,2-diaminobenzene derivative (1) reacts with diethyl dibromomalonate (2) (in methanol at r.t.) to give 2-ethoxycarbonylquinoxalin-3-one (3) [154]; with ethyl 2-bromo-2-methylpropanoate (4) (in DMF and Hunig's base, at 80-100 °C) to give 1H,4H-3,3-dimethylquinoxalin-2-one (5) [155]; with methyl 2-bromo-2-phenylacetate (6) (in refluxing methyl acetate, KI, K 2 CO 3 for 12 h, and then CH 3 ONa and benzene under reflux for 7 h) to give 3-phenylquinoxalin-2-one (7) [156]; with ethyl ethoxycarbonylformamidate (8) (in absolute ethanol at 25 °C) to give 3-aminoquinoxalin-2-one (9) [157][158].…”

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

“…Anal. (C24H32N5O3Cl) C,H,N,Cl. N,N-Dibenzyl-2-nitro-4-trifluoromethylaniline (16). A solution of 4-chloro-3-nitrobenzotrifluoride (15,10.0 mL, 67.0 mmol), dibenzylamine (25.0 mL, 130 mmol), and diisopropylethylamine (15.0 mL, 86.1 mmol) was heated at 140°C for 5 h. The solution was allowed to cool and stir overnight at room temperature.…”

“…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.…”

Timesavings Associated with Microwave‐Assisted Synthesis: A Quantitative Approach

“…The initial step was to approach the literature and identify previous syntheses of the scaffold shown in Scheme 8.2. The literature survey provided two routes to the desired intermediates 16 ; however, no single publication had generated the desired final compounds, so some level of reaction evaluation and optimization would be required for the synthesis. …”