2954 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16
Pirotte et al.
N-Cycloh exyl-4-ch lor op yr id in e-3-su lfon a m id e (18d ).
The title compound was obtained as described for 18b starting
from 4-hydroxypyridine-3-sulfonic acid (7.5 g, 42.8 mmol) and
cyclohexylamine (3.4 mL) (6.2 g, 53%): mp 123-125 °C; IR
(KBr) 3049 (N-H), 2928, 2852 (C-H aliph), 1568 (CdN), 1329,
and the residue was recrystallized in 2-propanol:petroleum
ether (40-60 °C), 1:3 (0.49 g, 80%): mp 215-217 °C; IR (KBr)
3361 (N-H), 2976 (C-H aliph), 1608, 1568, 1519 (N-H, Cd
N, CdC), 1314, 1168 (SdO) cm-1; 1H NMR (DMSO-d6, 80 MHz)
δ 0.95 (t, 3H, CH3), 1.70 (quint., 2H, CH2), 4.65 (m, 1H, CH),
6.70 (d, 1H, 5-H), 7.55 (bd, 1H, NH), 8.00 (b, 2H, SO2NH +
6-H), 8.40 (bs, 1H, 8-H). Anal. (C8H11N3O2S) C, H, N, S.
1
1165 (SdO) cm-1; H NMR (DMSO-d6, 80 MHz) δ 0.70-1.70
(bm, 10H, (CH2)5), 3.00 (bm, 1H, CH), 7.70 (d, 1H, 5-H), 8.10
(bd, 1H, SO2NH), 8.65 (d, 1H, 6-H), 8.95 (s, 1H, 2-H). Anal.
(C11H15ClN2O2S) C, H, N, S.
(R/S)-3-P r op yl-2,3-d ih yd r o-4H-p yr id o[4,3-e]-1,2,4-th ia -
d ia zin e 1,1-Dioxid e (21d ). The title compound was obtained
as described for 21c starting from 4-aminopyridine-3-sulfon-
amide (16) (0.5 g, 2.89 mmol) and butyraldehyde (0.42 g, 5.8
mmol). The compound was recrystallized in methanol:diethyl
ether, 1:2 (0.49 g, 75%): mp 229-234 °C; IR (KBr) 3361 (N-
H), 2965, 2948, 2878 (C-H aliph), 1613, 1571, 1525 (N-H,
N-Isopr opyl-4-am in opyr idin e-3-su lfon am ide (19b). The
mixture of N-isopropyl-4-chloropyridine-3-sulfonamide (18b)
(2 g, 8.5 mmol) in a saturated aqueous solution of ammonia
(20 mL) was heated in a sealed vessel at 150 °C for 18 h. After
cooling, the solution was concentrated to a small volume (5
mL) by distillation under reduced pressure. The resulting
crystalline precipitate was collected by filtration, washed with
water, and dried (1.37 g, 75%): mp 190-193 °C; IR (KBr) 3458,
3356 (N-H), 2974 (C-H aliph), 1636, 1600, 1546 (N-H, Cd
N, CdC), 1307, 1140 (SdO) cm-1; 1H NMR (DMSO-d6, 80 MHz)
δ 0.90 (d, 6H, 2 × CH3), 3.10 (m, 1H, CH), 6.60 (bm, 3H, NH2
+ 5-H), 7.50 (d, 1H, SO2NH), 8.05 (d, 1H, 6-H), 8.35 (s, 1H,
2-H). Anal. (C8H13N3O2S) C, H, N, S.
N-P en tyl-4-a m in op yr id in e-3-su lfon a m id e (19c). The
title compound was obtained as described for 19b starting from
N-pentyl-4-chloropyridine-3-sulfonamide (18c) (2 g, 7.6 mmol).
The crude compound was purified by dissolution in 0.1 N HCl
(200 mL), treatment with charcoal, filtration, and neutraliza-
tion of the filtrate with 0.1 N NaOH. The resulting precipitate
was collected by filtration, washed with water, and dried (0.65
g, 35%): mp 139-142 °C; IR (KBr) 3459, 3357 (N-H), 2961,
2931, 2857 (C-H aliph), 1640, 1599 (N-H, CdN, CdC), 1312,
1154 (SdO) cm-1; 1H NMR (DMSO-d6, 80 MHz) δ 0.75 (bt, 3H,
CH2(CH2)3CH3), 0.95-1.50 (bm, 6H, CH2(CH2)3CH3), 2.65 (m,
2H, CH2(CH2)3CH3), 6.65 (bm, 3H, NH2 + 5-H), 7.50 (bt, 1H,
SO2NH),8.00 (d,1H,6-H),8.30 (s,1H,2-H). Anal. (C10H17N3O2S)
C, H, N, S.
1
CdN, CdC), 1311, 1167 (SdO) cm-1; H NMR (DMSO-d6, 80
MHz) δ 0.85 (t, 3H, CH3), 1.15-1.95 (m, 4H, CH2CH2), 4.70
(bm, 1H, CH), 6.70 (d, 1H, 5-H), 7.70 (bd, 1H, NH), 8.05 (d,
1H, 6-H), 8.20 (bs, 1H, SO2NH), 8.45 (s, 1H, 8-H). Anal.
(C9H13N3O2S) C, H, N, S.
(R/S)-3-Isop r op yl-2,3-d ih yd r o-4H -p yr id o[4,3-e]-1,2,4-
th ia d ia zin e 1,1-Dioxid e (21e). The title compound was
obtained as described for 21d starting from 4-aminopyridine-
3-sulfonamide (16) (0.5 g, 2.89 mmol) and isobutyraldehyde
(0.42 g, 5.8 mmol) (0.54 g, 82%): mp 250-254 °C; IR (KBr)
3382 (N-H), 2984, 2969 (C-H aliph), 1608, 1566, 1517 (N-
1
H, CdN, CdC), 1314, 1165 (SdO) cm-1; H NMR (DMSO-d6,
80 MHz) δ 0.95 (2 d, 6H, 2 CH3), 1.95 (m, 1H, CH(CH3)2), 4.50
(bm, 1H, CH), 6.80 (d, 1H, 5-H), 7.45 (bd, 1H, NH), 7.85 (bs,
1H, SO2NH), 8.10 (d, 1H, 6-H), 8.45 (s, 1H, 8-H). Anal.
(C9H13N3O2S) C, H, N, S.
(R/S)-3-(1-E t h ylp r op yl)-2,3-d ih yd r o-4H -p yr id o[4,3-e]-
1,2,4-th ia d ia zin e 1,1-Dioxid e (21f). The title compound was
obtained as described for 21d starting from 4-aminopyridine-
3-sulfonamide (16) (0.5 g, 2.89 mmol) and 2-ethylbutyralde-
hyde (0.58 g, 5.8 mmol) (0.59 g, 80%): mp 224-226 °C; IR
(KBr) 3377 (N-H), 2973, 2879 (C-H aliph), 1605, 1511 (N-
1
N-Cycloh exyl-4-a m in op yr id in e-3-su lfon a m id e (19d ).
The title compound was obtained as described for 19b starting
from N-cyclohexyl-4-chloropyridine-3-sulfonamide (18d ) (2 g,
7.3 mmol) (1.5 g, 82%): mp 197-200 °C; IR (KBr) 3464, 3351
(N-H), 2929, 2856 (C-H aliph), 1636, 1600 (N-H, CdN, Cd
H, CdN, CdC), 1308, 1165 (SdO) cm-1; H NMR (DMSO-d6,
80 MHz) δ 0.85 (bt, 6H, 2 CH3), 1.10-1.65 (bm, 5H, CH(CH2-
CH3)2), 4.65 (dd, 1H, CH), 6.75 (d, 1H, 5-H), 7.35 (bd, 1H, NH),
7.70 (bs, 1H, SO2NH), 8.05 (d, 1H, 6-H), 8.35 (s, 1H, 8-H). Anal.
(C11H17N3O2S) C, H, N, S.
C), 1311, 1155 (SdO) cm-1 1H NMR (DMSO-d6, 80 MHz) δ
;
(R/S)-3-Cycloh exyl-2,3-d ih yd r o-4H-p yr id o[4,3-e]-1,2,4-
th ia d ia zin e 1,1-Dioxid e (21g). The title compound was
obtained as described for 21d starting from 4-aminopyridine-
3-sulfonamide (16) (0.5 g, 2.89 mmol) and cyclohexanecarbal-
dehyde (0.65 g, 5.8 mmol). The compound was recrystallized
in methanol:water, 1:2 (0.63 g, 80%): mp 272-276 °C; IR (KBr)
3369 (N-H), 2934, 2856 (C-H aliph), 1606, 1562, 1510 (N-
0.75-1.80 (bm, 10H, (CH2)5), 2.85 (bm, 1H, CH), 6.60 (bm, 3H,
NH2 + 5-H), 7.55 (d, 1H, SO2NH), 8.00 (d, 1H, 6-H), 8.30 (s,
1H, 2-H). Anal. (C11H17N3O2S) C, H, N, S.
2,3-Dih yd r o-4H-p yr id o[4,3-e]-1,2,4-th ia d ia zin e 1,1-Di-
oxid e Mon oh yd r a te (21a ). The mixture of 4-aminopyridine-
3-sulfonamide (16)37 (1 g, 5.77 mmol) and paraformaldehyde
(0.23 g, 7.66 mmol of CH2O) in 2-propanol (10 mL) supple-
mented with 10 drops of ethyl acetate saturated with dry HCl
was refluxed for 3-4 h. After cooling, the resulting precipitate
was collected by filtration, washed with 2-propanol and
recrystallized in hot water (0.88 g, 75%): mp 245-248 °C; IR
(KBr) 3557 (H-O-H), 3257 (N-H), 1608, 1525 (N-H, CdN,
1
H, CdN, CdC), 1308, 1164 (SdO) cm-1; H NMR (DMSO-d6,
80 MHz) δ 0.90-2.10 (bm, 11H, C6H11), 4.50 (bm, 1H, CH),
6.80 (d, 1H, 5-H), 7.45 (bd, 1H, NH), 7.85 (bs, 1H, SO2NH),
8.05 (d, 1H, 6-H), 8.40 (s, 1H, 8-H). Anal. (C12H15N3O2S) C,
H, N, S.
(R/S)-3-P h en yl-2,3-d ih yd r o-4H-p yr id o[4,3-e]-1,2,4-th ia -
d ia zin e 1,1-Dioxid e (21h ). The title compound was obtained
as described for 21d starting from 4-aminopyridine-3-sulfon-
amide (16) (0.5 g, 2.89 mmol) and benzaldehyde (0.61 g, 5.8
mmol). The compound was recrystallized in 2-propanol:
petroleum ether (40-60 °C), 1:3 (0.57 g, 75%): mp 214-216
°C; IR (KBr) 3373, 3175 (N-H), 1605, 1563, 1510, 1500 (N-
1
CdC), 1332, 1169 (SdO) cm-1; H NMR (DMSO-d6, 80 MHz)
δ 4.55 (bs, 2H, CH2), 6.60 (d, 1H, 5-H), 7.40-8.20 (b, 3H, NH
+ SO2NH + 6-H), 8.30 (bs, 1H, 8-H). Anal. (C6H7N3O2S‚H2O)
C, H, N, S.
(R/S)-3-Meth yl-2,3-d ih yd r o-4H-p yr id o[4,3-e]-1,2,4-th ia -
d ia zin e 1,1-Dioxid e Mon oh yd r a te (21b). The title com-
pound was obtained as described for 13c starting from
4-aminopyridine-3-sulfonamide (16) (1 g, 5.77 mmol) (0.95 g,
76%): mp 229-231 °C; IR (KBr) 3541 (H-O-H), 3367, 3285
(N-H), 1605, 1570, 1516 (N-H, CdN, CdC), 1308, 1144 (Sd
1
H, CdN, CdC), 1333, 1165 (SdO) cm-1; H NMR (DMSO-d6,
80 MHz) δ 5.80 (bd, 1H, CH), 6.70 (d, 1H, 5-H), 7.30-7.70 (m,
6H, NH + C6H5), 8.00 (bd, 1H, 6-H), 8.20 (bs, 1H, SO2NH),
8.45 (s, 1H, 8-H). Anal. (C12H11N3O2S) C, H, N, S.
O) cm-1 1H NMR (DMSO-d6, 80 MHz) δ 1.30 (d, 3H, CH3),
;
4-Met h yl-2,3-d ih yd r o-4H -p yr id o[4,3-e]-1,2,4-t h ia d ia z-
in e 1,1-Dioxid e Hyd r och lor id e (22a ). The mixture of
4-methylaminopyridine-3-sulfonamide (17a ) (1 g, 5.34 mmol)
and paraformaldehyde (1 g, 33.3 mmol of CH2O) in 2-propanol
(10 mL) and ethyl acetate saturated with dry HCl (4 mL) was
refluxed for 10 h. The solvent was removed by distillation
under reduced pressure, and the residue was dissolved in
methanol (50 mL). The insoluble material was eliminated by
filtration and the filtrate was mixed with two volumes of
diethylether. The resulting precipitate was collected by filtra-
3.10 (s, 2H, H2O), 4.75 (bq, 1H, CH), 6.50 (d, 1H, 5-H), 7.50
(bs, 1H, NH), 7.80 (bs, 1H, SO2NH), 8.00 (d, 1H, 6-H), 8.30
(bs, 1H, 8-H). Anal. (C7H9N3O2S‚H2O) C, H, N, S.
(R/S)-3-Eth yl-2,3-d ih yd r o-4H-p yr id o[4,3-e]-1,2,4-th ia d i-
a zin e 1,1-Dioxid e (21c). The mixture of 4-aminopyridine-
3-sulfonamide (16) (0.5 g, 2.89 mmol) and propionaldehyde
(0.34 g, 5.86 mmol) in 2-propanol (5 mL) supplemented with
10 drops of ethyl acetate saturated with dry HCl was refluxed
for 2 h. The reaction mixture was concentrated to dryness