Quinoxaline N-oxide containing potent angiotensin II receptor antagonists: synthesis, biological properties, and structure-activity relationships

Abstract

A series of novel quinoxaline heterocycle containing angiotensin II receptor antagonist analogs were prepared. This heterocycle was coupled to the biphenyl moiety via an oxygen atom linker instead of a carbon atom. Many of these analogs exhibit very potent activity and long duration of effect. Interestingly, the N-oxide quinoxaline analog was more potent than the nonoxidized quinoxaline as in the comparison of compounds 5 vs 30. In order to improve oral activity, the carboxylic acid function of these compounds was converted to the double ester. This change did result in an improvement in oral activity as represented by compound 44.

Preparation of 6-Substituted Quinoxaline JSP-1 Inhibitors by Microwave Accelerated Nucleophilic Substitution

“…Based on these reactions DMSO was selected as the solvent for subsequent work. The effect of the base, sodium hydroxide or 1,8-diazabicyclo [5,4,0]undec-7-ene (DBU), was also investigated, but no yield improvements were observed (Table 1, entries 6-7) and more side products were detected in both cases. When the amount of pyrrolidine used was reduceded to one equivalent, the yield also decreased ( Table 1, entry 8).…”

“…Quinoxalines are an important class of nitrogen-containing heterocycles with a variety of biological activities, specifically as AMPA/Gly N receptor antagonists [1][2][3], angiotensin II receptor antagonists [4][5], anticancer agents [6][7][8][9], antiinfection agents [10][11] and immunomodulating agents [12][13].…”

Rutile phase nanoTiO2 as an effective heterogeneous catalyst for condensation reaction of isatin derivatives with 1,2-diaminobenzene under solvent free conditions: A greener “NOSE” approach

“…While, quinoxaline is a versatile nitrogen containing heterocyclic compound and has been considered as a wonder nucleus that posses a variety of biological activities, specifically as AMPA/GlyN receptor antagonists (Auberson et al, 1998;Nikam et al, 1999) angiotensin-II receptor antagonists (Kim et al, 1993a(Kim et al, , 1993b anti-cancer (Corona et al, 2000;Melero et al, 2004;Piras et al, 2004), anti-infection (Carta et al, 2003;Hui et al, 2006) activities. Its core structure is a part of several naturally occurring compounds such as flavor-enzymes, riboflavin, molybdopterines and antibiotics of Streptomyces (Veroni et al, 2008).…”

Synthesis of Quinoxaline Azido and Amino Reverse Ribofuranoside and TheirO-Regioisomers

“…[3] The quinoxalines are a class of heterocyclic compounds with different applications in various fields, including pharmacology [4,5] and agricultural chemistry. [6,7] The pharmacological applications of quinoxalines are reported as angiotension II receptor antagonists, [8] N -methyl-D-aspartate (NMDA) antagonists, [9] anti-inflammatory, [10] antidepressanttranquilizing, [11,12] antitumor agents [13,14] as well as agents against hepatitis B virus (HBV). [15] Quinoxaline derivatives have been shown to block selectively EGFR kinase.…”