Tetrahydropyrrolo[1,2-a]quinoxalines and tetrahydropyrrolo[1,2-a]pyrido[3,2-a]pyrazines: vascular smooth muscle relaxants and antihypertensive agents

Abstract

A series of tetrahydropyrrolo[1,2-a]quinoxalines and tetrahydropyrrolo[1,2-a]pyrido[3,2-a]pyrazines were synthesized and tested for their ability to relax K+-depolarized aortic smooth muscle and antihypertensive activity. It was shown that compounds producing the most relaxation of aortic smooth muscle (5-[2,6-dimethoxyphenyl)methyl]-1,2,3,3a-tetrahydropyrrolo[1,2-a] quinoxalin-4(5H)-one and 5-[(2,6-dimethoxyphenyl)methyl]-5,6,6a,7,8,9-hexahydropyrrolo[1,2- a] pyrazine, 10 and 19, respectively) demonstrated the least hypotensive activity. Those compounds that were the most effective hypotensive agents (6a,7,8,9-tetrahydro-5-(phenylmethyl)pyrido[3,2-a]pyrrolo[1,2-a]++ +pyrazin- 6(5H)-one and 6a,7,8,9-tetrahydro-5-(4-pyridinylmethyl)pyrido[3,2-e]pyrrolo [1,2-a]pyrazin-6(5H)-one, 12 and 13, respectively) displayed little vascular smooth muscle relaxant activity.

Sequential Synthesis, Olfactory Properties, and Biological Activity of Quinoxaline Derivatives

“…The conversions of quinoxalinones 1 to 1,2,3,4-tetrahydroquinoxalines 2 were smoothly conducted using excess lithium aluminum hydride as the reducing agent ( Table 2 ). 8 …”

“…( S )-3-Methyl-3,4-dihydro-1 H -quinoxalin-2-one 1c (403 mg, 2.50 mmol), lithium aluminum hydride (840 mg, 22.0 mmol), and dry THF (80 mL) were used: brown solid; 360 mg, 98% yield; R f = 0.28 (hexanes/AcOEt = 4/1); mp 62.0–65.2 °C (lit. 88.1–89.5 °C); 8 [α] D 19 = −23.8 ( c 0.22, EtOH) (lit. [α] D 25 = −33.8 ( c 1.06, EtOH)); 17 1 H NMR (400 MHz, CDCl 3 ) δ 6.61–6.55 (m, 2H, Ar), 6.53–6.45 (m, 2H, Ar), 3.57 (brs, 1H, NH), 3.50 (t, J = 6.1 Hz, 1H), 3.30 (dd, J = 10.8, 2.2 Hz, 1H), 3.03 (t, J = 9.4 Hz, 1H), 1.18 (d, J = 6.1 Hz, 3H, Me); 13 C NMR (100 MHz, CDCl 3 ) δ 133.5, 133.1, 118.6 (2C), 114.4, 114.4, 48.2, 45.6, 19.8.…”

“…3-Ethyl-3,4-dihydro-1 H -quinoxalin-2-one 1d (484 mg, 2.70 mmol), lithium aluminum hydride (910 mg, 24.2 mmol), and dry THF (45 mL) were used: orange solid; 434 mg, 97% yield; R f = 0.33 (hexanes/AcOEt = 4/1); mp 67.0–68.0 °C (lit. 67.9–69.2 °C); 8 1 H NMR (400 MHz, CDCl 3 ) δ 6.60–6.54 (m, 2H, Ar), 6.51–6.46 (m, 2H, Ar), 3.64 (brs, 1H, NH), 3.37 (dd, J = 10.5, 2.9 Hz, 1H), 3.28 (dq, J = 7.2, 2.9 Hz, 1H), 3.06 (dd, J = 10.5, 7.2 Hz, 1H), 1.52 (quint, J = 7.2 Hz, 2H, CH 2 ), 1.00 (t, J = 7.6 Hz, 3H, Me); 13 C NMR (100 MHz, CDCl 3 ) δ 133.5, 133.4, 118.7, 118.5, 114.4, 114.4, 51.7, 46.3, 27.1, 10.0.…”

Pyrrolo[1,2-a]quinoxalines based on pyrroles (Review)

“…Compounds 34 were obtained by the condensation of 1-fluoro-2-nitrobenzenes 32 with pyrrolidine-2-carboxylic acid (33a) or its ester 33b [16][17][18] in boiling ethanol in the presence of NaHCO 3 . The reductive cyclization of compounds 34 and 35 was realized both with cyclohexene in boiling ethanol in the presence of 10% Pd/C [16] and with iron powder in acetic acid [17,18] and also for compound 34a with sodium dithionite in water [17].…”

Synthesis of Tri‐ and Tetracyclic Condensed Quinoxalin‐2‐ones Fused Across the C‐3−N‐4 Bond

“…Considering the previously studied2,6 compounds 1 and 2 as models, we decided to prepare some simple and fused quinoxalinones for further testing mainly as cytotoxic agents. Furthermore, many biological properties and technical applications have been reported7 for compounds containing this heterocyclic system and, in recent years, simple or fused quinoxalinones have become interesting compounds for study in the fields of antihypertensives,8 vascular smooth muscle relaxants,8 anti‐HIV agents,9 aldose reductase inhibitors,10 angiotensin II receptor antagonists,11 5‐HT 3 receptor agonists,12 and, especially, as GABA/benzodiazepine receptor ligands 9,13. Owing to the potential biological interest in these compounds, two different solid‐phase synthetic methods have been reported recently for the preparation of quinoxalin‐2‐one libraries 14.…”