Benzopiperazinones and Tetrahydroquinoxalines

Although benzopiperazinones (l,2,3,4-tetrahydroquinoxalin-2-ones) are structurally related to benzodiazepines, their use in drug discovery is less well established. Examples of biological activity of benzopiperazinones include their action as inhibitors of aldose reductase [208], as partial agonists of the y-aminobutyric acid (GABA)/benzodiazepine receptor complex [209, 210], and as angiotensin II receptor antagonists [211]. In addition, derivatives with antiviral acti vity associated vfith HIV have been reported [212, 213]. 

Several synthetic strategies for obtaining tetrahydroquinoxaline derivatives have 

A 50-mL single-necked, round-bottomed flask was charged with the 4-fluoro-3-nitrobenzoic acid loaded resin 172, the appropriate amino add ester hydrochloride salt (2 equiv.), and 5% DIEA/DMF. The mixture was agitated at rt for 24 h, filtered, and then the resin was washed with DMF (three times), CH2CI2 (three times), iPrOH (three times) and then again in the same order, and dried to afford enantiomerically pure aniline intermediate 173. 

To resin 178 (0.067 mmol) in CH2CI2 (0.5 mL) was added pyridine (0.20 mL of a 1 M solution in CH2CI2) followed by the acid chloride or sulfonyl chloride (0.20 mL of a 1 m solution in CH2CI2, 3 equiv). In the case of isocyanates, the pyridine was omitted. The mixture was shaken for 2 h, the volatiles were removed, and the resin was washed sequentially with CH2CI2, DMF, and further CH2CI2. It was then treated with a mixture of CH2CI2 and saturated NH3 in MeOH (2 mL 1 1, v/v) for 2 h. Thereafter, the resin was filtered off, and the filtrate was collected and concentrated to dryness to afford the tetrahydro-P-carboHne 180 as a solid. 

Synthesis on 4-hydroocyphenyl thioether resin To a slurry of 4-hydroxythiophe-nol-linked Merrifield resin [235] (15 g, 11.3 mmol) in DMF (60 mL) was added Boc-L-tryptophan (6.85 g, 22.5 mmol, 2 equiv.), followed by HOBt (3.04 g, 22.5 mmol, 2 equiv.), DMAP (0.14 g, 1.13 mmol, 0.1 equiv.), and DlC (3.52 mL, 22.5 mmol, 2 equiv). The slurry was shaken for 24 h at 27 °C, then filtered, and the resin 184 was washed thoroughly with DMF and CH2CI2. 

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