H.S. Ibrahim et al. / European Journal of Medicinal Chemistry 85 (2014) 480e486
485
yield; 1H NMR (DMSO-d6)
d
(ppm) 3.53 (3H, s, OCH3), 4.20 (2H, s,
10.47 (s, 1H, D2O exchangeable, NHCO) and 10.72 (s, 1H, D2O
exchangeable, SO2NH).
CH2), 6.82 (d, 2H, J ¼ 8.7 Hz, AreH), 7.20 (d, 2H, J ¼ 8.7 Hz, AreH),
7.75e7.89 (m, 2H, H-6 and H-7 of phthalazine), 7.92 (d, 1H,
J ¼ 7.8 Hz, H-5 of phthalazine), 8.23 (d, 1H, J ¼ 7.5 Hz, H-8 phtha-
lazine), 12.56 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6)
4.1.5.5. 2-(4-Benzyl-1-oxophthalazin-2(1H)-yl)-N-(4-
sulfamoylphenyl)acetamide (15a). Method A, white crystals, 58%
yield; mp 212e214 ꢁC; IR (KBr) nmax/cmꢀ1 3470e3252 (NH2 þ NH),
1685 (2C]O) 1623 (C]N), 1330, 1151 (SO2); 1H NMR (DMSO-d6)
d
36.79 (benzylic CH2), 54.91 (OeCH3), 113.91, 118.93, 125.60,
125.94, 126.90, 127.90, 129.11, 129.45, 129.95, 131.28, 133.27, 145.42,
157.81, 159.37 (C]O).
d 4.20 (s, 2H, CH2 benzyl), 5.03 (s, 2H, COCH2), 7.20 (s, 2H, SO2NH2,
D2O exchangeable), 7.25e7.36 (m, 4H, AreH), 7.73e7.95 (m, 8H,
AreH), 8.28 (d, 1H, J ¼ 6.9 Hz, H-8 of phthalazine), 10.60 and 10.72
(s, 1H, D2O exchangeable, CONH, cis and trans conformers).
4.1.5. Synthesis of target compounds 10aed and 15aee
Method A. To a solution of the appropriate amides 7aee (2 mmol)
in acetone (20 mL), K2CO3 (0.69 g, 5 mmol) was added and reflux for
1 h. For this solution, the appropriate phthalazin-1(2H)-ones 9a, b or
14a, b (2 mmol) was added and the reflux was continued for 12 h,
then left to cool at roomtemperature and poured into cursed ice. The
resulted precipitate was filtered, dried and then recrystallized from
DMF/H2O to afford the targeted compounds.
4.1.5.6. 2-(4-(4-Methoxybenzyl)-1-oxophthalazin-2(1H)-yl)-N-(4-
sulfamoylphenyl)acetamide (15b). Method A, pale yellow crystals,
59% yield; mp 219e221 ꢁC; IR (KBr) nmax/cmꢀ1 3482e3244
(NH2 þ NH), 1686 (2C]O), 1629 (C]N), 1336, 1153 (SO2); 1H NMR
(DMSO-d6) d 3.69 (s, 3H, OCH3), 4.25 (s, 2H, CH2 benzyl), 5.03 (s, 2H,
Method B. To a stirred solution of the appropriate phthalazin-
1(2H)-one 14a, b (10 mmol) in dry DMF (20 mL), NaH (60%) (0.4 g,
10 mmol) was added and stirred for 30 min at room temperature.
After that the appropriate intermediates 7aee (10 mmol) were
added at room temperature then reflux for 8 h, then left to cool,
poured into crushed ice the obtained precipitate, then filtered and
washed with dioxan and recrystallization from DMF/H2O gave the
targeted compounds.
COCH2), 6.82 (d, 2H, J ¼ 8.6 Hz, AreH), 7.20 (s, 2H, SO2NH2, D2O
exchangeable), 7.24 (d, 2H, J ¼ 8.6 Hz, AreH), 7.73e7.96 (m, 7H,
AreH), 8.27 (d, 1H, J ¼ 7.2 Hz, H-8 phthalazine), 10.60 and 10.72 (s,
1H, D2O exchangeable, NHCO, cis and trans conformers). MS m/z (%)
479 (Mþþ1, 30.8), 478 (Mþ, 95), 308 (89.2), 266 (74.3), 252 (39.8),
172 (100), 121 (51.8).
4.1.5.7. 2-(4-(4-Methoxybenzyl)-1-oxophthalazin-2(1H)-yl)-N-(4-
(N-(pyrimidin-2-yl)sulfamoyl)phenyl)acetamide (15c). Method B,
yellow crystals, 37% yield; mp 240e242 ꢁC; IR (KBr) nmax/cmꢀ1
3322, 3275 (2NH), 1695 (2C]O) (C]N), 1335, 1135 (SO2); 1H NMR
4.1.5.1. 2-(1-Oxo-4-phenylphthalazin-2(1H)-yl)-N-(4-
sulfamoylphenyl)acetamide (10a). Method A, white crystals, 62%
yield; mp 229e231 ꢁC; IR (KBr) nmax/cmꢀ1 3476e3273 (NH2 þ NH),
1673 (2C]O) 1643 (C]N), 1334, 1153 (SO2); 1H NMR (DMSO-d6)
(DMSO-d6) d 3.69 (s, 3H, OCH3), 4. 26 (s, 2H, CH2 benzyl), 4.48 (s, 2H,
COCH2), 6.85 (d, 2H, J ¼ 9 Hz, AreH), 7.03 (t, 1H, J ¼ 4.8 Hz, H-5 of
pyrimidine), 7.18 (d, 2H, J ¼ 9 Hz, AreH), 7.63e7.73 (m, 3H, H-5, H-6
and H-7 of phthalazine), 7.82e7.95 (m, 2H, H-6 and H-7 of phtha-
lazine), 7.96 (d, 1H, J ¼ 7.2 Hz, H-5 of phthalazine), 8.41 (d, 1H,
J ¼ 6.9 Hz, H-8 phthalazine), 8.82 (d, J ¼ 4.8 Hz, 2H, H-4 and H-6 of
pyrimidine), 10.46 (s, 1H, D2O exchangeable, CONH), 11.66 (s, 1H,
D2O exchangeable, SO2NH).
d
5.07 (s, 2H, COCH2), 7.26 (s, 2H, SO2NH2, D2O exchangeable),
7.55e7.63 (m, 9H, AreH), 7.69e7.76 (m, 1H, H-5 phthalazine),
7.91e7.96 (m, 2H, H-6 and H-7 phthalazine), 8.37e8.40 (m, 1H, H-8
phthalazine), 10.68 and 10.81 (s, 1H, D2O exchangeable, NHCO, cis
and trans conformers).
4.1.5.2. 2-(1-Oxo-4-phenylphthalazin-2(1H)-yl)-N-(4-(N-(thiazol-2-
yl)sulfamoyl)phenyl)acetamide (10b). Method B, beige crystals, 42%
yield; mp >300 ꢁC; IR (KBr) nmax/cmꢀ1 3275, 3194 (2NH),1705 (2C]
4.1.5.8. 3-(4-(4-Methoxybenzyl)-1-oxophthalazin-2(1H)-yl)-N-(4-
sulfamoylphenyl)propanamide (15d). Method A, beige crystals, 48%
yield; mp 224e227 ꢁC; IR (KBr) nmax/cmꢀ1 3483, 3310 (NH2 þ NH),
1670 (2C]O) 1636 (C]N), 1335, 1101 (SO2); 1H NMR (DMSO-d6)
O), 1654 (C]N), 1356, 1133 (SO2); 1H NMR (DMSO-d6)
d 4.86 (s, 2H,
COCH2), 6.89 (d,1H, J ¼ 4.8 Hz, H-6 of thiazole), 7.28 (d, 2H, J ¼ 8.7 Hz,
AreH), 7.39 (d,1H, J ¼ 4.8 Hz, H-5 of thiazole), 7.47 (d, 2H, J ¼ 8.7 Hz,
AreH), 7.58e7.95 (m, 9H, AreH), 10.47 (s, 1H, D2O exchangeable,
CONH), 10.72 (s, 1H, D2O exchangeable, SO2NH); 13C NMR (DMSO-
d
2.93 (t, 1H, J ¼ 6.9 Hz, NeCH2), 3.69 (s, 3H, OCH3), 4.25 (s, 2H, CH2
benzyl), 4.48 (t, 2H, J ¼ 6.9 Hz, COCH2), 6.65 (d, 2H, J ¼ 8.1 Hz,
AreH), 6.83 (d, 2H, J ¼ 8.1 Hz, AreH), 7.18 (d, 2H, J ¼ 8.7 Hz, AreH),
7.23 (s, 2H, SO2NH2, D2O exchangeable), 7.71e7.93 (m, 5H, AreH),
8.27 (d, 1H, J ¼ 8.7 Hz, H-8 of phthalazine), 10.60 and 10.72 (s, 1H,
D2O exchangeable, NHCO, cis and trans conformers); MS m/z (%)
493 (Mþþ1, 20.4), 492 (Mþ, 67.8), 321 (100), 279 (70.3), 265 (100),
226 (59.8), 172 (100), 121 (100).
d6)
d 51.21 (eCH2CO), 105.90, 118.90, 126.03, 127.00, 128.57, 128.92,
129.18, 129.35, 137.43, 140.90, 164.82, 165.04 (C]O), 166.79 (C]O).
4.1.5.3. 2-(1-Oxo-4-phenylphthalazin-2(1H)-yl)-N-(4-(N-(pyr-
imidin-2-yl)sulfamoyl)phenyl)acetamide (10c). Method B, white
crystals, 45% yield; mp 276e278 ꢁC; IR (KBr) nmax/cmꢀ1 3282, 3111
(2NH), 1695 (2C]O), 1625 (C]N), 1353, 1138 (SO2); 1H NMR
4.1.5.9. 3-(4-(4-Methoxybenzyl)-1-oxophthalazin-2(1H)-yl)-N-(4-
(DMSO-d6)
d
2.90 (s, 2H, NeCH2), 4.98 (s, 2H, COCH2), 6.87 (d, 2H,
(N-(pyrimidin-2-yl)sulfamoyl)phenyl)propanamide
(15e).
J ¼ 9 Hz, AreH), 7.02 (t, 1H, J ¼ 4.9 Hz, H-5 of pyrimidine), 7.47e7.51
(m, 9H, AreH), 7.71e7.76 (m, 1H, H-5 phthalazine), 7.95e7.98 (m,
2H, H-6 and H-7 phthalazine), 8.35e8.40 (m, 1H, H-8 phthalazine),
8.66 (d, 2H, J ¼ 4.9 Hz, H-4 and H-6 of pyrimidine), 10.68 (s, 1H, D2O
exchangeable, NHCO),11.66 (s, 1H, D2O exchangeable, SO2NH).
Method A, pale yellow crystals, 42% yield; mp 240e242 ꢁC; IR (KBr)
nmax/cmꢀ1 3320, 3280 (2NH), 1695 (2C]O), 1637 (C]N), 1322, 1114
(SO2); 1H NMR (DMSO-d6)
d
2.92 (t, 2H, J ¼ 6.6 Hz, NeCH2), 3.56 (s,
3H, OCH3), 4.14 (s, 2H, CH2 benzyl), 4.46 (t, 2H, J ¼ 6.3 Hz, COCH2),
6.61 (d, 2H, J ¼ 9 Hz, AreH), 7.01 (t, 1H, J ¼ 4.8 Hz, H-5 of pyrimi-
dine), 7.15 (d, 2H, J ¼ 9 Hz, AreH), 7.20 (s, 2H, SO2NH2, D2O-
exchangeable), 7.73e7.80 (m, 3H, H-5, H-6 and H-7 of phthalazine),
7.80e7.89 (m, 2H, H-6 and H-7 of phthalazine), 7.85 (d, 1H,
J ¼ 7.2 Hz, H-5 of phthalazine), 8.24 (d, 1H, J ¼ 6.9 Hz, H-8 of
phthalazine) 8.46 (d, 2H, J ¼ 4.8 Hz, H-4 and H-6 of pyrimidine),
10.46 (s, 1H, D2O exchangeable, CONH) 11.66 (s, 1H, D2O
4.1.5.4. 2-(4-(4-Chlorophenyl)-1-oxophthalazin-2(1H)-yl)-N-(4-(N-
(thiazol-2-yl)sulfamoyl)phenyl)acetamide (10d). Method B, white
crystals, 53% yield; mp 274e276 ꢁC; IR (KBr) nmax/cmꢀ1 3276, 3195
(2NH), 1703 (2C]O), 1594 (C]N), 1359, 1137 (SO2); 1H NMR
(DMSO-d6)
d
4.85 (s, 2H, CH2CO), 6.90 (d, 1H, J ¼ 4.8 Hz, H-6 of
thiazole), 7.28 (d, 2H, J ¼ 9 Hz, AreH), 7.39 (d, 1H, J ¼ 4.8 Hz, H-5 of
exchangeable, SO2NH); 13C NMR (DMSO-d6)
36.87 (benzylic CH2), 46.44 (NeCH2e), 54.87 (OeCH3), 113.78,
d 35.28 (eCH2CO),
thiazole), 7.48 (d, 2H, J ¼ 9 Hz, AreH), 7.62e7.95 (m, 8H, AreH),