Benzothiadiazine Dioxides
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4997
imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (18, 0.5
g, 0.001 57 mol) and cyclopropylamine (5 mL) was heated in a
sealed vessel for 5 h at 150 °C. The excess amine was
eliminated by distillation under reduced pressure. The residue
was suspended in water, and the pH was adjusted to 12 with
2.5 M NaOH. The solution was treated with charcoal and
filtered, and the pH of the filtrate was adjusted to pH
3-4 with concentrated HCl. The precipitate that appeared
was collected by filtration, washed with water, dried, and
crystallized in hot MeOH (62%). Mp 295-297 °C (lit., 282-
285 °C53); IR (KBr); 1H NMR (DMSO-d6, 400 MHz). Anal.
(C10H9Cl2N3O2S) C, H, N, S.
tained as described for 22, starting from 6-chloro-7-fluoro-3-
(1H-imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (20,
0.5 g, 0.001 67 mol) and isopropylamine (5 mL) (59%). Mp
228-232 °C; IR (KBr); 1H NMR (DMSO-d6, 80 MHz). Anal.
(C10H11ClFN3O2S) C, H, N, S.
6-Chloro-3-(cyclobutylamino)-7-fluoro-4H-1,2,4-ben-
zothiadiazine 1,1-Dioxide (35). The title compound was
obtained as described for 27, starting from 6-chloro-7-fluoro-
3-(1H-imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (20,
0.5 g, 0.001 67 mol) and cyclobutylamine (1 mL) in dioxane (5
1
mL) (55%). Mp >290 °C; IR (KBr); H NMR (DMSO-d6, 400
MHz). Anal. (C11H11ClFN3O2S) C, H, N, S.
3-Cyclobutylamino-6,7-dichloro-4H-1,2,4-benzothiadi-
azine 1,1-Dioxide (27). 6,7-Dichloro-3-(1H-imidazol-1-yl)-4H-
1,2,4-benzothiadiazine 1,1-dioxide (18, 0.5 g, 0.001 57 mol) was
dissolved in dioxane (4 mL) and supplemented with cyclobu-
tylamine (1 mL). The mixture was heated in a sealed vessel
for 8 h at 140 °C. The excess amine was eliminated by
distillation under reduced pressure. The residue was sus-
pended in water (20 mL), and the pH was adjusted to 12 with
2.5 M NaOH. The solution was treated with charcoal and
filtered, and the pH was adjusted to pH 3-4 with concen-
trated HCl. The precipitate was collected by filtration, washed
with water, dried, and crystallized in hot MeOH (60%). Mp
7-Fluoro-3,6-di(isopropylamino)-4H-1,2,4-benzothiadi-
azine 1,1-Dioxide (36). The title compound was obtained as
described for 22, starting from 6,7-difluoro-3-(1H-imidazol-1-
yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (21, 0.5 g, 0.001 76
mol) and isopropylamine (5 mL) (65%). Mp 234-237 °C; IR
(KBr); 1H NMR (DMSO-d6, 80 MHz). Anal. (C13H19FN4O2S)
C, H, N, S.
7-Fluoro-3,6-di(propylamino)-4H-1,2,4-benzothiadi-
azine 1,1-Dioxide (37). The title compound was obtained as
described for 22, starting from 6,7-difluoro-3-(1H-imidazol-1-
yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (21, 0.5 g, 0.001 76
mol) and n-propylamine (5 mL) (62%). Mp 236 °C, then
256 °C; IR (KBr); 1H NMR (DMSO-d6, 400 MHz). Anal.
(C13H19FN4O2S) C, H, N, S.
1
320-326 °C; IR (KBr); H NMR (DMSO-d6, 400 MHz). Anal.
(C11H11Cl2N3O2S) C, H, N, S.
6,7-Dichloro-3-(hexylamino)-4H-1,2,4-benzothiadi-
azine 1,1-Dioxide (28). A mixture of 6,7-dichloro-3-(1H-
imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (18, 0.5
g, 0.001 57 mol) and n-hexylamine (5 mL) was refluxed for 4
h. The excess amine was eliminated by distillation under
reduced pressure. The residue was suspended in water and
stirred for 1 h. The precipitate was collected by filtration,
washed with water, dried, and crystallized in hot MeOH (64%).
Mp 282-286 °C; IR (KBr); 1H NMR (DMSO-d6, 400 MHz).
Anal. (C13H17Cl2N3O2S) C, H, N, S.
3,6-Di(cyclobutylamino)-7-fluoro-4H-1,2,4-benzothia-
diazine 1,1-Dioxide (38). The title compound was obtained
as described for 27, starting from 6,7-difluoro-3-(1H-imidazol-
1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (21, 0.5 g, 0.001 76
mol) and cyclobutylamine (1 mL) in dioxane (5 mL) (45%); IR
1
(KBr); H NMR (DMSO-d6, 400 MHz). Mp 258 °C, then 297
°C. Anal. (C15H19FN4O2S) C, H, N, S.
N-Ethyl-N′-(2-amino-4,5-difluorobenzenesulfonyl)thio-
urea (39). 2-Amino-4,5-difluorobenzenesulfonamide (17, 0.4
g, 0.0019 mol) was dissolved in dry acetone (3 mL) and
supplemented with K2CO3 (0.32 g) and ethyl isothiocyanate
(0.3 mL). The mixture was heated at 60 °C for 4 h. The solvent
was removed under reduced pressure, and the residue was
suspended in water (25 mL). The solution was adjusted to pH
3-4 with concentrated HCl and stirred at room temperature
for a few hours. The precipitate was collected by filtration,
washed with water, and dried. The crude product was used
without further purification (52%).
N-Isopropyl-N′-(2-amino-4,5-difluorobenzenesulfonyl)-
thiourea (40). The title compound was obtained as described
for 39, starting from 2-amino-4,5-difluorobenzenesulfonamide
(17) and isopropyl isothiocyanate. The crude product was used
without further purification (48%).
7-Bromo-6-chloro-3-(ethylamino)-4H-1,2,4-benzothia-
diazine 1,1-Dioxide (29). The title compound was obtained
as described for 22, starting from 7-bromo-6-chloro-3-(1H-
imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (19, 0.5
g, 0.001 38 mol) and an aqueous solution of ethylamine (70%,
5 mL). The final product was crystallized from hot MeOH
1
(60%). Mp >290 °C; IR (KBr); H NMR (DMSO-d6, 80 MHz).
Anal. (C9H9BrClN3O2S) C, H, N, S.
7-Bromo-6-chloro-3-(isopropylamino)-4H-1,2,4-benzo-
thiadiazine 1,1-Dioxide (30). The title compound was ob-
tained as described for 22, starting from 7-bromo-6-chloro-3-
(1H-imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (19,
0.5 g, 0.001 38 mol) and isopropylamine (5 mL) (62%). IR
(KBr); 1H NMR (DMSO-d6, 400 MHz). Mp >290 °C. Anal.
(C10H11BrClN3O2S) C, H, N, S.
N-Isobutyl-N′-(2-amino-4,5-difluorobenzenesulfonyl)-
thiourea (41). The title compound was obtained as described
for 39, starting from 2-amino-4,5-difluorobenzenesulfonamide
(17) and isobutyl isothiocyanate. The crude product was used
without further purification (37%).
7-Bromo-6-chloro-3-(cyclobutylamino)-4H-1,2,4-ben-
zothiadiazine 1,1-Dioxide (31). The title compound was
obtained as described for 27, starting from 7-bromo-6-chloro-
3-(1H-imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (19,
0.5 g, 0.001 38 mol) and cyclobutylamine (1 mL) in dioxane (5
6,7-Difluoro-3-(ethylamino)-4H-1,2,4-benzothiadi-
azine 1,1-Dioxide (42). N-Ethyl-N′-(2-amino-4,5-difluoroben-
zenesulfonyl)thiourea (39, 0.2 g, 0.68 mmol) and triethylamine
(0.2 mL) were dissolved in dry THF (5 mL). The mixture was
cooled in an ice/water bath and slowly supplemented with a
20% phosgene solution in toluene (0.5 mL). After 2 h at 0 °C,
the solvent was removed under reduced pressure and the
residue was triturated with water, adjusted to pH 12 with 2.5
M NaOH, treated with charcoal, and filtered. The filtrate was
adjusted to pH 3-4 with concentrated HCl, and the precipi-
tate that appeared was collected by filtration, washed with
1
mL) (58%). Mp >290 °C; IR (KBr); H NMR (DMSO-d6, 400
MHz). Anal. (C11H11BrClN3O2S) C, H, N, S.
6-Chloro-3-(ethylamino)-7-fluoro-4H-1,2,4-benzothia-
diazine 1,1-Dioxide (32). The title compound was obtained
as described for 22, starting from 6-chloro-7-fluoro-3-(1H-
imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (20, 0.5
g, 0.001 67 mol) and a 70% w/v aqueous solution of ethylamine
(5 mL) (65%). Mp >290 °C; IR (KBr); 1H NMR (DMSO-d6, 400
MHz). Anal. (C9H9ClFN3O2S) C, H, N, S.
6-Chloro-7-fluoro-3-(propylamino)-4H-1,2,4-benzothia-
diazine 1,1-Dioxide (33). The title compound was ob-
tained as described for 22, starting from 6-chloro-7-fluoro-
3-(1H-imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide
(20, 0.5 g, 0.001 67 mol) and propylamine (5 mL) (59%). Mp
1
water, and dried (75%). Mp 246-252 °C; IR (KBr); H NMR
(DMSO-d6, 400 MHz). Anal. (C9H9F2N3O2S) C, H, N, S.
6,7-Difluoro-3-isopropylamino-4H-1,2,4-benzothiadi-
azine 1,1-Dioxide (43). The title compound was obtained as
described for 42, starting from 2N-isopropyl-N′-(2-amino-4,5-
difluorobenzenesulfonyl)thiourea (40) (68%). Mp 242-244 °C;
IR (KBr); 1H NMR (DMSO-d6, 400 MHz). Anal. (C10H11F2N3O2S)
C, H, N, S.
1
287-289 °C; IR (KBr); H NMR (DMSO-d6, 400 MHz). Anal.
(C10H11ClFN3O2S) C, H, N, S.
6-Chloro-7-fluoro-3-(isopropylamino)-4H-1,2,4-benzo-
thiadiazine 1,1-Dioxide (34). The title compound was ob-