S.J.A. van Kuijk et al. / European Journal of Medicinal Chemistry xxx (2016) 1e12
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4.1.13. 4-(4-(Bis(2-chloroethyl)amino)phenyl)butyl (4-
sulfamoylphenyl)carbamate(5a)
J ¼ 13.0, 6.8, 2H), 3.02e2.90 (m, 6H), 2.11e1.99 (m, 2H); 13C NMR
(101 MHz, DMSO-d6),
d
157.56, 153.64, 142.79, 141.97,
mp: 156e158 ꢀC; 1H NMR (400 MHz, DMSO-d6),
d
10.01 (s, 1H),
130.10e127.99, 125.35, 112.78, 41.77, 32.35, 31.60, 25.25; MS (ESIþ)
m/z 386.13 [MþH]þ. HRMS (ESIþ) [MþH]þ calculated for
[C18H20N5O3S]þ: 386.1287, found: 386.1291.
7.76e7.69 (m, 2H), 7.64e7.56 (m, 2H), 7.22 (s, 2H), 7.04 (d, J ¼ 8.7,
2H), 6.66 (d, J ¼ 8.7, 2H), 4.12 (t, J ¼ 6.0, 2H), 3.77e3.63 (m, 8H),
1.70e1.54 (m, 4H); 13C NMR (101 MHz, DMSO-d6),
d 153.50, 144.40,
142.34, 137.48, 130.06, 129.30, 126.77, 117.50, 111.89, 64.43, 52.22,
41.17, 33.68, 28.09, 27.62; MS (ESIþ) m/z 488.12 [MþH]þ, 490.12
[Mþ2]þ. HRMS (ESIþ) [MþH]þ calculated for [C21H28N3O4SCl2]þ:
488.1178, found: 488.1184.
4.1.19. 3-((4-Sulfamoylphenethyl) amino)-7,8-dihydro-6H-indeno
[5,6-e][1,2,4] triazine 1,4-dioxide (11)
Compound 11 was synthesized from 10 by using a general
oxidation method resulting in an orange red solid with a yield of
46%. mp: 218e220 ꢀC; 1H NMR (400 MHz, DMSO-d6),
d 8.19 (s, 1H),
4.1.14. 4-(4-(Bis(2-chloroethyl)amino)phenyl)butyl (4-
sulfamoylbenzyl)carbamate(5b)
7.98 (d, J ¼ 24.2, 2H), 7.75 (d, J ¼ 7.8, 2H), 7.46 (d, J ¼ 7.7, 2H), 7.29 (s,
2H), 3.65 (d, J ¼ 6.2, 2H), 3.12e2.92 (m, 6H), 2.17e1.99 (m, 2H); 13
C
mp: 98e100 ꢀC; 1H NMR (400 MHz, DMSO-d6),
d
7.76 (t, J ¼ 8.5,
NMR (101 MHz, DMSO-d6), d 154.56, 149.25, 145.07, 143.22, 142.15,
3H), 7.41 (d, J ¼ 8.5, 2H), 7.31 (s, 2H), 7.02 (d, J ¼ 8.6, 2H), 6.66 (d,
J ¼ 8.6, 2H), 4.23 (d, J ¼ 6.1, 2H), 3.98 (s, 2H), 3.75e3.63 (m, 8H), 2.47
129.23, 125.71, 41.76, 32.74, 31.80, 25.24; MS (ESIþ) m/z 402.12
[MþH]þ. HRMS (ESIþ) [MþH]þ calculated for [C18H20N5O4S]þ:
402.1236, found: 402.1234.
(s, 2H), 1.55 (m, 4H); 13C NMR (101 MHz, DMSO-d6),
d 156.63,
144.37, 143.97, 142.61, 130.13, 129.26, 127.27, 125.70, 111.88, 63.84,
52.23, 43.37, 41.18, 33.68, 28.31, 27.64; MS (ESIþ) m/z 502.13
[MþH]þ, 504.13 [Mþ2]þ. HRMS (ESIþ) [MþH]þ calculated for
[C22H30N3O4SCl2]þ: 502.1334, found: 502.1338.
4.1.20. 6-(4-(Methylsulfonyl)phenyl)-N-phenyl-3-
(sulfamoylamino)pyrazine-2-carboxamide (12)
Compound 12 was synthesized from commercially purchased
VE-821 by using the general procedure described above, which
resulted in a yellow solid with an overall yield of 58%. mp:
4.1.15. 4-(4-(Bis(2-chloroethyl)amino)phenyl)butyl (4-
sulfamoylphenethyl)carbamate(5c)
233e235 ꢀC; 1H NMR (400 MHz, DMSO-d6),
d 11.27 (s, 1H), 10.82 (s,
mp: 100e102 ꢀC; 1H NMR (400 MHz, DMSO-d6),
d
7.77e7.70 (m,
1H), 9.28 (s, 1H), 8.64 (d, J ¼ 8.6, 2H), 8.08 (d, J ¼ 8.6, 2H), 7.83e7.76
2H), 7.37 (d, J ¼ 8.2, 2H), 7.30 (s, 2H), 7.19 (t, J ¼ 5.5, 1H), 7.02 (d,
J ¼ 8.6, 2H), 6.66 (d, J ¼ 8.6, 2H), 3.94 (d, J ¼ 5.5, 2H), 3.69 (s, 8H),
3.21 (dd, J ¼ 13.3, 6.6, 2H), 2.76 (dd, J ¼ 16.9, 9.8, 2H), 2.46 (s, 2H),
(m, 2H), 7.68 (s, 2H), 7.48e7.39 (m, 2H), 7.23 (dd, J ¼ 14.0, 6.6, 1H),
3.30 (s, 3H); 13C NMR (101 MHz, DMSO-d6),
d 164.59e163.27,
149.32e147.73, 144.46e143.38, 141.16, 139.57, 137.17e136.45,
128.69, 127.46, 125.15, 122.08, 43.46; MS (ESIþ) m/z 448.07 [MþH]þ.
HRMS (ESIþ) [MþH]þ calculated for [C18H18N5O2S2]þ: 448.0749,
found: 448.0748.
1.52 (s, 4H); 13C NMR (101 MHz, DMSO-d6),
d 156.30, 144.37, 143.58,
142.03, 130.15, 129.19, 125.67, 111.88, 63.51, 52.23, 41.28, 35.09,
33.67, 28.32, 27.63; MS (ESIþ) m/z 516.15 [MþH]þ, 518.15 [Mþ2]þ.
HRMS (ESIþ) [MþH]þ calculated for [C23H32N3O4SCl2]þ: 516.1491,
found: 516.1490.
4.1.21. 5-(4-(Isopropylsulfonyl) phenyl)-3-(3-(4-((methylamino)
methyl) phenyl) isoxazol-5-yl) pyrazin-2-carboxamide (13)
4.1.16. 3-(4-Sulfamoylphenethylamino) benzo [e][1,2,4] triazine 1-
oxide (7)
Compound 13 was synthesized from commercially purchased
VE-822 by using the general procedure described above, which
resulted in a yellow solid with an overall yield of 65%. mp:
Compound 7 was synthesized from 6 by a general amination
method and resulted in a yellow solid with a yield of 94%. mp:
242e244 ꢀC; 1H NMR (400 MHz, DMSO-d6),
d 8.94 (s, 1H), 8.38 (d,
250e252 ꢀC; 1H NMR (400 MHz, DMSO-d6),
d
8.15 (s, 1H), 8.13 (s,
J ¼ 8.5, 2H), 8.02 (d, J ¼ 8.2, 2H), 7.93 (d, J ¼ 8.5, 2H), 7.79 (s,1H), 7.54
(d, J ¼ 8.2, 2H), 7.20 (s, 2H), 6.96 (s, 2H), 4.17 (s, 2H), 3.54e3.38 (m,
1H), 2.58 (s, 3H), 1.17 (t, J ¼ 14.1, 6H); 13C NMR (101 MHz, DMSO-d6),
1H), 8.03 (s, 1H), 7.82e7.71 (m, 3H), 7.60 (d, J ¼ 8.0, 1H), 7.47 (d,
J ¼ 8.0, 2H), 7.38e7.30 (m, 1H), 7.28 (s, 2H), 3.60 (d, J ¼ 6.2, 2H), 3.01
(dd, J ¼ 6.2, 2H); 13C NMR (101 MHz, DMSO-d6)
d
158.80, 143.70,
d 167.67, 162.00, 151.75, 142.47, 141.04, 139.53, 137.62, 135.78,
142.07, 135.76, 129.25, 125.92, 124.66, 119.93, 41.92, 34.09; MS
(ESIþ) m/z 346.10 [MþH]þ. HRMS (ESIþ) [MþH]þ calculated for
[C15H16N5O3S]þ: 346.0974, found: 346.0973.
129.00, 127.17, 125.69, 124.47, 102.16, 54.22, 53.49, 34.94, 15.19; MS
(ESIþ) m/z 543.15 [MþH]þ. HRMS (ESIþ) [MþH]þ calculated for
[C24H27N6O5S2]þ: 543.1484, found: 543.1484.
4.1.17. 3-((4-Sulfamoylphenethyl)amino)benzo[e][1,2,4]triazine 1,4-
dioxide (8)
Compound 8 was synthesized from 7 by a general oxidation
method, resulting in an orange red solid with a yield of 96%. mp:
4.1.22. 3-Methyl-4-oxo-N-(4-sulfamoylphenethyl)-3,4-
dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (15a)
Compound 15a was synthesized from 14 by reacting it with 4-
(2-aminoethyl) benzene sulfonamide using the general procedure
for synthesizing temozolomide derivatives described above. This
reaction resulted in a white solid with a yield of 50%. mp:
210e212 ꢀC; 1H NMR (400 MHz, DMSO-d6),
d
8.31 (t, J ¼ 6.1, 1H),
8.22 (d, J ¼ 8.1, 1H), 8.13 (d, J ¼ 8.1, 1H), 7.97e7.89 (m, 1H), 7.75 (d,
J ¼ 8.3, 2H), 7.61e7.53 (m, 1H), 7.47 (d, J ¼ 8.3, 2H), 7.29 (s, 2H), 3.67
(dd, J ¼ 7.2, 6.1, 2H), 3.03 (t, J ¼ 7.2, 2H); 13C NMR (101 MHz, DMSO-
195e197 ꢀC; 1H NMR (400 MHz, DMSO-d6),
d 8.83 (s, 1H), 8.58 (t,
J ¼ 5.9,1H), 7.74 (d, J ¼ 8.3, 2H), 7.44 (d, J ¼ 8.3, 2H), 7.30 (s, 2H), 3.86
d6),
d 149.67, 143.19, 142.16, 138.19, 135.48, 130.07, 129.26, 127.04,
(s, 3H), 3.58 (dd, J ¼ 13.4, 6.8, 2H), 2.96 (t, J ¼ 7.1, 2H); 13C NMR
125.71, 121.13, 116.89, 41.76, 34.18; MS (ESIþ) m/z 362.09 [MþH]þ.
HRMS (ESIþ) [MþH]þ calculated for [C15H16N5O4S]þ: 362.0923,
found: 362.0928.
(101 MHz, DMSO-d6), d 159.67, 143.64, 142.05, 139.20, 134.45,
130.30, 129.14, 128.46, 125.73, 36.16, 34.78; MS (ESIþ) m/z 378.10
[MþH]þ. HRMS (ESIþ) [MþH]þ calculated for [C14H16N7O4S]þ:
378.0984, found: 378.0986.
4.1.18. 3-(4-Sulfamoylphenethylamino)-7,8-dihydro-6H-indeno
[5,6-e][1,2,4] triazine 1-oxide (10)
4.1.23. 3-Methyl-4-oxo-N-(sulfamoyloxy)-3,4-dihydroimidazo[5,1-
d][1,2,3,5]tetrazine-8-carboxamide (15b)
Compound 15b was synthesized from 14 by reacting it with
aminoxysulfonamide using the general procedure for synthesizing
temozolomide derivatives described above. This reaction resulted
Compound 10 was synthesized from 9 by using a general ami-
nation method, which resulted in a yellow solid with a 85% yield.
mp: 238e240 ꢀC; 1H NMR (400 MHz, DMSO-d6),
d
7.95 (s, 1H), 7.82
(s, 1H), 7.74 (t, J ¼ 10.0, 2H), 7.49e7.39 (m, 3H), 7.28 (s, 2H), 3.57 (dd,
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