Inhibition of Tumor-Associated Isozyme IX
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2193
(s, 2H: NH2); 13C NMR (DMSO-d6), δ, ppm: 145.83 (C4Ph),
132.66 (C1Ph), 129.48 (2C: C2,C6Ph), 106.11 (2C: C3,C5Ph);
IR (KBr), cm-1: 1150, 1315, 1610, 3340, 3430; Anal. C6H6-
Br2N2O2S (C, H, N).
(d, J ) 8.6 Hz, 1H: H5), 6.27 (v.br.s, 2H: NH2); 13C NMR
(DMSO-d6), δ, ppm: 166.61 (C5 thiadiazole), 157.72 (C2
thiadiazole), 148.92 (C4Ph), 127.33 (C1Ph), 127.28 (C2Ph),
126.33 (C6Ph), 115.85 (C3Ph), 114.41 (C5Ph); IR (KBr), cm-1
:
1160, 1310, 1500, 1580, 1620, 3360, 3430; Anal. C8H8ClN5O4S3
(C, H, N).
4-Amino-3-bromo-5-iodobenzenesulfonamide 13: mp 233-
235 °C (EtOH); 1H NMR (DMSO-d6), δ, ppm: 8.08 (s, 1H: H6),
7.91 (s, 1H: H2), 7.33 (s, 2H: SO2NH2), 5.98 (s, 2H: NH2);
13C NMR (DMSO-d6), δ, ppm: 151.92 (C4Ph), 139.94 (C6Ph),
137.62 (C1Ph), 134.20 (C2Ph), 108.53 (C3Ph), 85.44 (C5Ph);
IR (KBr), cm-1: 1150, 1310, 1610, 3330, 3420; Anal. C6H6-
BrIN2O2S (C, H, N).
5-(4-Amino-3-bromobenzenesulfonamido)-1,3,4-thiadiazole-
2-sulfonamide 17d : mp 253.5-255 °C (EtOH); 1H NMR
(DMSO-d6), δ, ppm: 8.46 (s, 3H: SO2NH2+ SO2NH), 7.70 (d,
J ) 2.1 Hz, 1H: H2), 7.49 (dd, J ) 8.6, 2.2 Hz, 1H: H6), 6.84
(d, J ) 8.6 Hz, 1H: H5), 6.23 (v.br.s, 2H: NH2); 13C NMR
(DMSO-d6), δ, ppm: 166.66 (C5 thiadiazole), 157.71 (C2
thiadiazole), 149.99 (C4Ph), 130.42 (C2Ph), 127.80 (C1Ph),
4-Amino-3,5-diiodobenzenesulfonamide 14: mp 274-276 °C
1
(lit.27 mp 265 °C); H NMR (DMSO-d6), δ, ppm: 7.99 (s, 2H:
H2,H6), 7.20 (s, 2H: SO2NH2), 5.71 (s, 2H: NH2); 13C NMR
(DMSO-d6), δ, ppm: 149.92 (C4Ph), 136.57 (2C: C2,C6Ph),
134.33 (C1Ph), 79.80 (2C: C3,C5Ph); IR (KBr), cm-1: 1160,
1310, 1610, 3320, 3340, 3400; Anal. C6H6I2N2O2S (C, H, N).
5-(4-Acetamido-3-fluorobenzenesulfonamido)-1,3,4-thiadia-
zole-2-sulfonamide 16b: mp 223-224 °C; 1H NMR (DMSO-
126.85 (C6Ph), 114.30 (C5Ph), 105.59 (C3Ph); IR (KBr), cm-1
:
1150, 1315, 1510, 1580, 1620, 3350, 3400; Anal. C8H8BrN5O4S3
(C, H, N).
5-(4-Amino-3-iodobenzenesulfonamido)-1,3,4-thiadiazole-2-
1
sulfonamide 17e: mp 260-261 °C (EtOH); H NMR (DMSO-
d6), δ, ppm: 8.45 (s, 3H: SO2NH2+ SO2NH), 7.94 (d, J ) 2.2
Hz, 1H: H2), 7.49 (dd, J ) 8.6, 2.2 Hz, 1H: H6), 6.79 (d, J )
8.6 Hz, 1H: H5), 6.10 (v.br.s, 2H: NH2); 13C NMR (DMSO-
d6), δ, ppm: 166.63 (C5 thiadiazole), 157.69 (C2 thiadiazole),
157.70 (C4Ph), 135.87 (C2Ph), 128.20 (C1Ph), 127.43 (C6Ph),
112.87 (C5Ph), 80.92 (C3Ph); IR (KBr), cm-1: 1160, 1315, 1520,
1575, 1620, 3360, 3430; Anal. C8H8IN5O4S3 (C, H, N).
d6), δ, ppm: 10.09 (s, 1H: CONH), 8.50 (s, 3H: SO2NH2
+
SO2NH), 8.28 (m, 1H: H5), 7.68 (dd, J ) 10.6, 2.1 Hz, 1H:
H2), 7.65 (dd, J ) 8.1, 2.1 Hz, 1H: H6), 2.14 (s, 3H: CH3); 13
C
NMR (DMSO-d6), δ, ppm: 169.33 (CO), 167.72 (C5 thiadiaz-
ole), 158.16 (C2 thiadiazole), 151.77 (d, J Cipso-F ) 249.6 Hz,
C3Ph), 136.09 (d, J Cm-F ) 6.0 Hz, C1Ph), 130.83 (d, J Co-F
)
11.1 Hz, C4Ph), 122.92 (C6Ph), 122.62 (d, J Cm-F ) 3.3 Hz,
C5Ph), 113.36 (d, J Co-F ) 22.6 Hz, C2Ph), 23.76 (CH3); IR
(KBr), cm-1: 1160, 1310, 1330, 1510, 1560, 1605, 1680, 3350;
Anal. C10H10FN5O5S3 (C, H, N).
5-(4-Amino-5-chloro-3-fluorobenzenesulfonamido)-1,3,4-thia-
1
diazole-2-sulfonamide 18: mp 230-232 °C (EtOH); H NMR
(DMSO-d6), δ, ppm: 8.43 (s, 3H: SO2NH2 + SO2NH), 7.84
(br.s, 1H: H6), 7.31 (dd, J ) 10.5, 1.7 Hz, 1H: H2), 4.96 (v.br.s,
2H: NH2); 13C NMR (DMSO-d6), δ, ppm: 169.19 (C5 thiadia-
zole), 157.58 (C2 thiadiazole), 148.81 (d, J Cipso-F ) 239.0 Hz,
5-(4-Acetamido-3-chlorobenzenesulfonamido)-1,3,4-thiadia-
zole-2-sulfonamide 16c: mp 236-238 °C (EtOH); 1H NMR
(DMSO-d6), δ, ppm: 9.74 (s, 1H: CONH), 8.49 (s, 3H: SO2-
NH2+ SO2NH), 8.08 (d, J ) 8.6 Hz, 1H: H5), 7.86 (d, J ) 2.1
Hz, 1H: H2), 7.77 (dd, J ) 8.6, 2.1 Hz, 1H: H6), 2.15 (s, 3H:
CH3); 13C NMR (DMSO-d6), δ, ppm: 169.22 (CO), 167.90 (C5
thiadiazole), 158.25 (C2 thiadiazole), 139.08 (C4Ph), 137.44
(C1Ph), 126.94 (C2Ph), 125.32 (C6Ph), 125.14 (C3Ph), 125.03
(C5Ph), 23.69 (CH3); IR (KBr), cm-1: 1155, 1300, 1310, 1510,
1580, 1685, 3330; Anal. C10H10ClN5O5S3 (C, H, N).
5-(4-Acetamido-3-bromobenzenesulfonamido)-1,3,4-thiadia-
zole-2-sulfonamide 16d : mp 242-244 °C (EtOH/H2O); 1H
NMR (DMSO-d6), δ, ppm: 9.65 (s, 1H: CONH), 8.49 (s, 3H:
SO2NH2+ SO2NH), 8.00 (d, J ) 2.0 Hz, 1H: H2), 7.94 (d, J )
8.6 Hz, 1H: H5), 7.81 (dd, J ) 8.6, 2.1 Hz, 1H: H6), 2.13 (s,
3H: CH3); 13C NMR (DMSO-d6), δ, ppm: 169.03 (CO), 167.92
(C5 thiadiazole), 158.26 (C2 thiadiazole), 140.43 (C4Ph), 138.13
(C1Ph), 130.03 (C2Ph), 126.08 (C5Ph), 125.80 (C6Ph), 116.25
(C3Ph), 23.58 (CH3); IR (KBr), cm-1: 1150, 1300, 1325, 1515,
1580, 1680, 3340, 3370; Anal. C10H10BrN5O5S3 (C, H, N).
5-(4-Acetamido-3-iodobenzenesulfonamido)-1,3,4-thiadiazole-
2-sulfonamide 16e: mp 249-250.5 °C (EtOH); 1H NMR
(DMSO-d6), δ, ppm: 9.57 (s, 1H: CONH), 8.48 (s, 3H: SO2-
NH2+ SO2NH), 8.22 (d, J ) 2.1 Hz, 1H: H2), 7.81 (dd, J )
8.6, 2.1 Hz, 1H: H6), 7.72 (d, J ) 8.6 Hz, 1H: H5), 2.11 (s,
3H: CH3); 13C NMR (DMSO-d6), δ, ppm: 168.81 (CO), 167.86
(C5 thiadiazole), 158.21 (C2 thiadiazole), 142.81 (C4Ph), 140.50
(C1Ph), 136.19 (C2Ph), 126.58 (C6Ph), 126.33 (C5Ph), 96.06
(C3Ph), 23.46 (CH3); IR (KBr), cm-1: 1160, 1300, 1320, 1510,
1575, 1680, 3370; Anal. C10H10IN5O5S3 (C, H, N).
C3Ph), 140.39 (d, J Co-F ) 12.8 Hz, C4Ph), 136.82 (d, J Cm-F
)
13.8 Hz, C5Ph), 128.50 (d, J Cm-F ) 4.8 Hz, C1Ph), 12123.48
(C6Ph), 113.14 (d, J Co-F ) 20.5 Hz, C2Ph); IR (KBr), cm-1
1150, 1315, 1520, 1580, 1620, 3350, 3460; Anal. C8H7-
ClFN5O4S3 (C, H, N).
:
5-(4-Amino-5-bromo-3-fluorobenzenesulfonamido)-1,3,4-thia-
1
diazole-2-sulfonamide 19: mp 252-254 °C (EtOH); H NMR
(DMSO-d6), δ, ppm: 8.46 (s, 3H: SO2NH2+ SO2NH), 7.61 (dd,
J ) 2.0, 1.2 Hz 1H: H6), 7.46 (d, J ) 10.5, 2.0 Hz, 1H: H2),
6.27 (v.br.s, 2H: NH2); 13C NMR (DMSO-d6), δ, ppm: 167.24
(C5 thiadiazole), 157.94 (C2 thiadiazole), 148.58 (d, J Cipso-F
244.7 Hz, C3Ph), 139.45 (d, J Co-F ) 14.6 Hz, C4Ph), 127.15
(d, J Cm-F ) 5.8 Hz, C1Ph), 126.24 (C6Ph), 112.32 (d, J Co-F
)
)
21.5 Hz, C2Ph), 106.37 (d, J Cm-F ) 4.8 Hz, C5Ph); IR (KBr),
cm-1: 1160, 1320, 1520, 1575, 1620, 3340, 3430; Anal. C8H7-
BrFN5O4S3 (C, H, N).
5-(4-Amino-3-fluoro-5-iodobenzenesulfonamido)-1,3,4-thia-
1
diazole-2-sulfonamide 20: mp 242-244 °C (EtOH); H NMR
(DMSO-d6), δ, ppm: 8.45 (s, 3H: SO2NH2+ SO2NH), 7.76 (dd,
J ) 2.0, 1.2 Hz, 1H: H6), 7.44 (dd, J ) 10.6, 2.0 Hz, 1H: H2),
6.08 (v.br.s, 2H: NH2); 13C NMR (DMSO-d6), δ, ppm: 167.23
(C5 thiadiazole), 157.88 (C2 thiadiazole), 147.20 (d, J Cipso-F
)
245.2 Hz, C3Ph), 141.81 (d, J Co-F ) 13.1 Hz, C4Ph), 132.25
(d, J Cpara-F ) 2.4 Hz, C6Ph), 128.45 (d, J Cm-F ) 6.0 Hz, C1Ph),
112.86 (d, J Co-F ) 21.5 Hz, C2Ph), 81.67 (d, J Cm-F ) 2.8 Hz,
C5Ph); IR (KBr), cm-1: 1150, 1315, 1520, 1570, 1620, 3340,
3460;Anal. C8H7FIN5O4S3 (C, H, N).
5-(4-Amino-3,5-dichlorobenzenesulfonamido)-1,3,4-thiadia-
zole-2-sulfonamide 21: mp 286-288 °C (EtOH); 1H NMR
(DMSO-d6), δ, ppm: 8.50 (s, 3H: SO2NH2 + SO2NH), 7.62 (s,
2H: H2,H6), 6.50 (v.br.s, 2H: NH2); 13C NMR (DMSO-d6), δ,
ppm: 167.25 (C5 thiadiazole), 157.97 (C2 thiadiazole), 145.20
(C4Ph), 127.78 (C1Ph), 125.94 (2C: C2,C6Ph), 117.20 (2C: C3,-
C5Ph); IR (KBr), cm-1: 1160, 1325, 1515, 1580, 1620, 3400,
3500; Anal. C8H7Cl2N5O4S3 (C, H, N).
5-(4-Amino-3-fluorobenzenesulfonamido)-1,3,4-thiadiazole-
2-sulfonamide 17b: mp 231-233 °C (EtOH); 1H NMR (DMSO-
d6), δ, ppm: 8.48 (s, 3H: SO2NH2+ SO2NH), 7.37 (dt, J ) 11.0,
2.1, 1.7 Hz, 1H: H2), 7.25 (dd, J ) 8.4, 2.1 Hz, 1H: H6), 6.83
(dt, J ) 8.5, 8.4, 1.7 Hz, 1H: H5), 6.10 (v.br.s, 2H: NH2); 13
C
NMR (DMSO-d6), δ, ppm: 166.59 (C5 thiadiazole), 157.68 (C2
thiadiazole), 150.43 (d, J Cipso-F ) 240.4 Hz, C3Ph), 141.30 (d,
J Co-F ) 12.9 Hz, C4Ph), 126.13 (d, J Cm-F ) 5.3 Hz, C1Ph),
123.73 (C6Ph), 114.90 (d, J Cm-F ) 4.7 Hz, C5Ph), 113.08 (d,
J Co-F ) 20.8 Hz, C2Ph); IR (KBr), cm-1: 1150, 1315, 1510,
1580, 1620, 3390, 3480; Anal. C8H8FN5O4S3 (C, H, N).
5-(4-Amino-3-chlorobenzenesulfonamido)-1,3,4-thiadiazole-
2-sulfonamide 17c: mp 245-245.5 °C (EtOH); 1H NMR
(DMSO-d6), δ, ppm: 8.47 (s, 3H: SO2NH2+ SO2NH), 7.57 (d,
J ) 2.1 Hz, 1H: H2), 7.47 (dd, J ) 8.6, 2.2 Hz, 1H: H6), 6.86
5-(4-Amino-5-bromo-3-chlorobenzenesulfonamido)-1,3,4-thi-
adiazole-2-sulfonamide 22: mp 263-265 °C (EtOH); 1H NMR
(DMSO-d6), δ, ppm: 8.49 (s, 3H: SO2NH2+ SO2NH), 7.73 (d,
J ) 2.0 Hz, 1H: H6), 7.64 (d, J ) 2.0 Hz, 1H: H2), 6.39 (v.br.s,
2H: NH2); 13C NMR (DMSO-d6), δ, ppm: 167.28 (C5 thiadia-
zole), 157.97 (C2 thiadiazole), 146.05 (C4Ph), 129.10 (C6Ph),
128.54 (C1Ph), 126.48 (C2Ph), 116.90 (C3Ph), 106.60 (C5Ph);