Arch. Pharm. Chem. Life Sci. 2014, 347, 777–785
1,2,4-Benzothiadiazine-1,1-dioxides as iGluR Ligands
783
6-Chloro-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-
7.34–7.37 (m, 5H, ar), 7.52 (d, 1H, ar, J ¼ 8.6 Hz), 10.40 (s, 1H,
SO2NH). IR: 1375, 1464, 3192, 3392, 3488. Anal. calcd. for
C13H13ClN2O3S: C, 49.92; H, 4.19; N, 8.96. Found: C, 47.55; H, 5.88;
N, 7.55.
1,1-dioxide (8)
Yield 50%; m.p. 326–328°C (water). 1H NMR: 7.26 (s, 1H, ar), 7.34
(d, 1H, ar, J ¼ 8.2 Hz), 7.81 (d, 1H, ar, J ¼ 8.2 Hz), 11.35 (br s, 1H,
NH). IR: 1370, 1736, 3292. Anal. calcd. for C7H5ClN2O3S: C, 36.14;
H, 2.17; N, 12.04. Found: C, 35.21; H, 3.66; N, 11.00.
2-Amino-N-benzyloxy-4-trifluoromethyl-benzene-
sulfonamide (27)
1
6-Trifluoromethyl-3-oxo-2H-1,2,4-benzothiadiazine-1,1-
Yield 95%; m.p. 104–106°C (water/ethanol). H NMR: 4.85 (s, 2H,
CH2), 6.49 (s, 2H, NH2), 6.91 (d, 1H, ar, J ¼ 8.4 Hz), 7.18 (s, 1H, ar),
7.32–7.37 (m, 5H, ar), 7.72 (d, 1H, ar, J ¼ 8.4 Hz), 10.57 (s, 1H,
SO2NH). IR: 1349, 1449, 3210, 3368, 3458. Anal. calcd. for
C14H13F3N2O3S: C, 48.55; H, 3.78; N, 8.09. Found: C, 49.23; H, 5.01;
N, 10.71.
dioxide (10)
Yield 52%; m.p. 227–228°C (water). 1H NMR: 7.54 (s, 1H, ar), 7.60
(d, 1H, ar, J ¼ 8.2 Hz), 8.00 (d, 1H, ar, J ¼ 8.2 Hz), 11.41 (br s, 1H,
NH). IR: 1340, 1736, 3514, 3554. Anal. calcd. for C8H5F3N2O3S: C,
36.10; H, 1.89; N, 10.52. Found: C, 38.22; H, 2.50; N, 9.02.
General procedure for the synthesis of 2-benzyloxy-3-oxo-
1,2,4-benzothiadiazine-1,1-dioxides (9 and 28)
General procedure for the synthesis of N-benzyloxy-2-
[(ethoxycarbonyl)amino]benzenesulfonamides (24 and 25)
A solution of triethylamine (8.0 mmol) and O-benzylhydroxyl-
amine hydrochloride (8.1 mmol) in a mixture tetrahydrofuran/
water (7:3, 10 mL), was portionwise added to a suspension
of sulfonyl chloride 20, 21 (4.0 mmol) in tetrahydrofuran
(5 mL). At the end of addition, the mixture was stirred at
room temperature for 24 h. Then, evaporation of the solvent
and dilution with water (15 mL) yielded a mixture, which
was adjusted to pH 1 with 6 N HCl. After 2 h stirring, the
precipitate was collected by filtration, washed with water, and
recrystallized.
Triphosgene (3.1 mmol) was added to a solution of 2-amino-
benzenesulfonamide 26, 27 (6.2 mmol) in anhydrous tetrahydro-
furan (50 mL). The mixture was stirred at room temperature for
24–48 h (TLC monitoring: eluting system AcOEt/CHX/MeOH/
NH4OH 2:3:0.4:0.1). Evaporation of the solvent at reduced
pressure yielded a solid, which was treated with water, collected
by filtration, washed with water, and recrystallized.
2-Benzyloxy-6-chloro-3-oxo-3,4-dihydro-2H-1,2,4-
benzothiadiazine-1,1-dioxide (9)
1
Yield 98%; m.p. 228–229°C (ethanol). H NMR: 5.11 (s, 2H, CH2),
N-Benzyloxy-4-chloro-2-[(ethoxycarbonyl)amino]-
7.31 (d, 1H, ar, J ¼ 1.9 Hz), 7.41–7.46 (m, 4H, ar), 7.48–7.51 (m, 2H,
ar), 8.03 (d, 1H, ar, J ¼ 8.5 Hz), 11.78 (s, 1H, NH). IR: 1376, 1462,
1715. Anal. calcd. for C14H11ClN2O4S: C, 49.64; H, 3.27; N, 8.27.
Found: C, 50.85; H, 4.56; N, 9.62.
benzenesulfonamide (24)
Yield 80%; m.p. 79–81°C (cyclohexane). 1H NMR: 1.26 (t, 3H, CH3,
J ¼ 7.1 Hz), 4.18 (q, 2H, CH2, J ¼ 7.1 Hz), 4.89 (s, 2H, CH2), 7.31–7.39
(m, 6H, ar), 7.83 (dd, 1H, ar, J ¼ 7.6, 2.1 Hz), 8.97 (s, 1H, NHCOO),
10.90 (s, 1H, SO2NH). IR: 1376, 1461, 1734, 3192, 3357. Anal. calcd.
for C16H17ClN2O5S: C, 49.94; H, 4.45; N, 7.28. Found: C, 51.16; H,
4.07; N, 9.77.
2-Benzyloxy-3-oxo-6-trifluoromethyl-3,4-dihydro-2H-
1,2,4-benzothiadiazine-1,1-dioxide (28)
1
Yield 94%; m.p. 215–216°C (ethanol). H NMR: 5.12 (s, 2H, CH2),
7.43–7.50 (m, 5H, ar), 7.59 (s, 1H, ar), 7.72 (d, 1H, ar, J ¼ 8.4 Hz),
8.25 (d, 1H, ar, J ¼ 8.2 Hz), 11.94 (s, 1H, NH). IR: 1339, 1462, 1728.
Anal. calcd. for C15H11F3N2O4S: C, 48.39; H, 2.98; N, 7.52. Found: C,
47.16; H, 3.16; N, 8.43.
N-Benzyloxy-2-[(ethoxycarbonyl)amino]-4-trifluoromethyl-
benzenesulfonamide (25)
1
Yield 83%; m.p. 113–115°C (water/ethanol). H NMR: 1.26 (t, 3H,
CH3, J ¼ 7.1 Hz), 4.18 (q, 2H, CH2, J ¼ 7.1 Hz), 4.91 (s, 2H, CH2), 7.32–
7.37 (m, 5H, ar), 7.66 (d, 1H, ar, J ¼ 8.6 Hz), 8.04 (d, 1H, ar,
J ¼ 8.3 Hz), 8.56 (s, 1H, ar), 9.05 (s, 1H, NHCOO), 11.07 (s, 1H,
SO2NH). IR: 1376, 1439, 1727, 3110, 3397. Anal. calcd. for
C17H17F3N2O5S: C, 48.80; H, 4.10; N, 6.70. Found: C, 47.21; H, 3.56;
N, 7.68.
General procedure for the synthesis of 2-hydroxy-3-oxo-
1,2,4-benzothiadiazine-1,1-dioxides (1 and 5)
A solution of BBr3 in CH2Cl2 (1 M, 11.3 mL) was, drop-by-drop,
added to a cooled (ꢂ70°C) suspension of compounds 9, 28
(5.7 mmol) in anhydrous dichloromethane (50 mL). At the end
of addition, the suspension was allowed to warm at ꢂ20°C
for 1 h and 30 min. The solution was diluted with water
(50 mL) under vigourous stirring and, after 12 h, the resulting
precipitate was collected by filtration, washed with water, and
recrystallized.
General procedure for the synthesis of N-benzyloxy-2-
amino-benzenesulfonamides (26 and 27)
A solution of 2-[(ethoxycarbonyl)amino]benzenesulfonamides 24,
25 (2.2 mmol) in an aqueous solution of NaOH (4%, 7 mL) was
stirred at 100°C for 2 h. After cooling, the reaction mixture was
diluted with water (20 mL) and acidified with 6 N HCl. The
precipitate was collected by filtration, washed with water, and
recrystallized.
6-Chloro-2-hydroxy-3-oxo-3,4-dihydro-2H-1,2,4-
benzothiadiazine-1,1-dioxide (1)
Yield 72%; m.p. 153–156°C (water). 1H NMR: 7.29 (d, 1H, ar,
J ¼ 1.8 Hz), 7.40 (dd, 1H, ar, J ¼ 8.6, 1.8 Hz), 7.96 (d, 1H, ar,
J ¼ 8.6 Hz), 11.17 (s, 1H, NH or OH), 11.57 (s, 1H, OH or NH). IR:
1714, 3482, 3578. Anal. calcd. for C7H5ClN2O4S: C, 33.81; H, 2.03;
N, 11.27. Found: C, 35.12; H, 3.76; N, 12.36.
2-Amino-N-benzyloxy-4-chloro-benzenesulfonamide (26)
Yield 93%; m.p. 83–85°C (water/ethanol). 1H NMR: 4.83 (s, 2H,
CH2), 6.31 (br s, 2H, NH2), 6.67 (d, 1H, ar, J ¼ 8.6 Hz), 6.89 (s, 1H, ar),
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim