3-Phenyl-Substituted Imidazo[1,5-a]quinoxalin-4-ones and Imidazo[1,5-a]quinoxaline Ureas That Have High Affinity at the GABA_A/Benzodiazepine Receptor Complex

Abstract

A series of imidazo[1,5-alpha]quinoxalin-4-ones and imidazo[1,5-alpha]quinoxaline ureas containing substituted phenyl groups at the 3-position was developed. Compounds within the imidazo[1,5-alpha]quinoxaline urea series had high affinity for the GABAA/benzodiazepine receptor complex with varying in vitro efficacy, although most analogs were partial agonists as indicated by [35S]TBPS and Cl- current ratios. Interestingly, a subseries of piperazine ureas was identified which had biphasic efficacy, becoming more antagonistic with increasing concentration. Analogs within the imidazo[1,5-alpha]quinoxalin-4-one series had substantially decreased binding affinity as compared to the quinoxaline urea series. These compounds ranged from antagonists to full agonists by in vitro analysis, with several derivatives having roughly 4-fold greater intrinsic activity than diazepam as indicated by Cl- current measurement. Numerous compounds from both series were effective in antagonizing metrazole-induced seizures, consistent with anti-convulsant properties and possible anxiolytic activity. Most of the quinoxaline ureas and quinoxalin-4-ones were active in an acute electroshock physical dependence side effect assay in mice precluding further development.

Design and synthesis of novel benzimidazole derivatives as inhibitors of hepatitis B virus

“…The base fragments 8a-c were prepared according to the reported methods. [25][26][27] Thereafter, compound 8a-c was condensed with different aromatic acids (compounds 5, 7, 9 and 10) using EDAc, and subsequently refluxed in acetic acid to produce the target molecule (Scheme 1). 28,29 Derivatives with substituents in position 5 was synthesized from intermediates 16a,b, which were prepared from 4-fluoro-3-nitro-benzoic acid methyl ester (15) according to reported methods.…”

Synthesis of Saturated Imidazolidin[1,5-a]- and Thiazolidin[3,4-a]perhydroquinoxalin-4-one and Imidazolidin[1,5-a]piperazin-4-one Derivatives. Ring Contraction of Perhydroquinoxalin-4-one to Perhydrobenzimidazolin-2-one

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] In particular the imidazo[1,5-a]quinoxaline system has attracted considerable attention in recent years. Derivatives of these fused system exhibit activity on the central nervous system 1,2 and are useful as anticonvulsants and/or anxiolytics, [3][4][5][6][7][8][9] or sedative/hypnotic agents. 3,7 Moreover, some derivatives of this type are tested as cardiotonic, 10 cardiovascular, 11 inotropic, 12 and antiallergic agents.…”

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

“…(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. The reaction mixture was partitioned between ether (500 mL) and water (250 mL).…”

“…While the use of an ester substituent at the 3-position also maintained affinity, intrinsic activity was notably decreased. In our exploration of the 3-phenyl series, 15 the use of a cis-2,6-dimethylpiperazine as the urea substituent was found to dramatically improve CNS penetration and duration of action (by ex vivo assay) as compared to other ureas lacking a basic nitrogen. More importantly, compounds such as 3 (PNU-97035, Figure 1) were found to display biphasic efficacy by in vitro measurement, becoming increasingly antagonistic with increasing drug concentration.…”