M. Sun et al. / European Journal of Medicinal Chemistry 45 (2010) 2299–2306
2303
chromatography (silica gel 60, mesh size 200–300, ethyl acetate/
petroleum ether, v/v) to afford the compounds 1a–1k and 2a–2k
Fig. 1.
1299.73, 1246.44, 1168.78, 1145.09, 1127.20, 1066.19, 701.49, 630.03;
1H NMR(DMSO-d6, 300 MHz)
(ppm): 7.04–7.12 (m, 4H, Ar-H), 7.31
d
(d, J ¼ 7.52 Hz, 1H, Ar-H), 7.49–7.61 (m, 4H, Ar-H), 7.73 (d, J ¼ 3.25 Hz,
Compounds 1a–1k and 2a–2k were characterized as follows.
1H, Ar-H), 7.89 (d, J ¼ 3.25 Hz,1H, Ar-H), 7.93–7.97 (m, 2H, Ar-H), 8.03
(s, 1H, Ar-H), 8.85 (s, 1H, –NHCONH–), 9.04 (s, 1H, –NHCONH–); 13
C
6.8.1. 1-(4-Chlorophenyl)-3-{4-[4-(thiazol-2-
NMR(DMSO-d6, 75 MHz) d(ppm): 114.08, 114.13, 117.68, 119.71,
yl)phenoxy]phenyl}urea (1a)
120.19, 120.28, 121.75, 127.74, 127.93, 129.75, 135.80, 140.51, 143.55,
150.05, 152.48, 159.26, 166.50; HRMS (ESI) m/z: Calcd for
C23H16F3N3O2S [M þ H]þ 456.0951, Found 456.0981; Anal. Calcd for
C23H16F3N3O2S (%): C 60.65, H 3.54, N 9.23; Found: C 60.99, H 3.44, N
9.43.
Off-white solid, yield: 51%, mp 192–193 ꢁC; IR(KBr, cmꢂ1):
3299.56, 1639.92, 1602.54, 1567.16, 1505.39, 1492.54, 1482.64,
1255.82, 1236.06, 829.78; 1H NMR(DMSO-d6, 300 MHz)
d(ppm):
7.01–7.06 (m, 4H, Ar-H), 7.28–7.31 (m, 2H, Ar-H), 7.44–7.50
(m, 4H, Ar-H), 7.70 (d, J ¼ 3.26 Hz, 1H, Ar-H), 7.85 (d, J ¼ 3.26 Hz,
1H, Ar-H), 7.90–7.93 (m, 2H, Ar-H), 8.73 (s, 1H, –NHCONH–), 8.78
6.8.6. 1-[4-Fluoro-3-(trifluoromethyl)phenyl]-3-{4-[4-(thiazol-2-
yl)phenoxy]phenyl} urea (1f)
(s, 1H, –NHCONH–); 13C NMR (DMSO-d6, 75 MHz)
d(ppm): 117.77,
119.73, 119.79, 120.16, 120.22, 125.39, 127.85, 128.00, 128.52,
136.05, 138.70, 143.60, 150.04, 152.49, 159.35; ESI-MS m/z:
422.2[M þ H]þ.
White solid, yield: 53%, mp 187–188 ꢁC; IR(KBr, cmꢂ1): 3309.82,
1654.45, 1608.70, 1556.61, 1503.03, 1482.04, 1425.52, 1408.85,
1336.62, 1301.00, 1251.83, 1219.65, 1162.36, 1130.68, 1052.54,
840.33, 631.22; 1H NMR(DMSO-d6, 300 MHz)
d(ppm): 7.03–7.11
6.8.2. 1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-{4-[4-(thiazol-2-
yl)phenoxy]phenyl} urea (1b)
(m, 4H, Ar-H), 7.43 (t, J ¼ 19.51 Hz, 1H, Ar-H), 7.50–7.55 (m, 2H,
Ar-H), 7.63–7.68 (m, 2H, Ar-H), 7.73 (d, J ¼ 3.26 Hz, 1H, Ar-H), 7.88
(d, J ¼ 3.26 Hz, 1H, Ar-H), 7.92–7.97 (m, 2H, Ar-H), 8.11 (dd, J ¼ 2.66,
6.47 Hz, 1H, Ar-H), 8.83 (s, 1H, –NHCONH–), 9.01 (s, 1H, –NHCONH–
White solid, yield: 53%, mp 135–136 ꢁC; IR(KBr, cmꢂ1): 3304.98,
1645.91, 1601.07, 1556.23, 1501.78, 1415.30, 1251.96, 1175.09,
1139.86, 823.38; 1H NMR(DMSO-d6, 300 MHz)
d(ppm): 7.04–7.11
); 13C NMR(DMSO-d6, 75 MHz)
d(ppm): 115.90,115.96,117.17,117.45,
(m, 4H, Ar-H), 7.51–7.54 (m, 2H, Ar-H), 7.59–7.67 (m, 2H, Ar-H), 7.73
(d, J ¼ 3.26 Hz, 1H, Ar-H), 7.88 (d, J ¼ 3.25 Hz, 1H, Ar-H), 7.92–7.97
(m, 2H, Ar-H), 8.11 (d, J ¼ 2.27 Hz, 1H, Ar-H), 8.87 (s, 1H, –NHCONH–
117.66, 119.58, 120.02, 120.32, 127.73, 127.85, 135.67, 136.42, 136.45,
143.45, 150.10, 152.49, 159.15, 166.42; ESI-MS m/z: 474.1[M þ H]þ;
Anal. Calcd for C23H15F4N3O2S (%): C 58.35, H 3.19, N 8.88; Found: C
58.73, H 3.15, N 9.01.
), 9.14 (s, 1H, –NHCONH–); 13C NMR(DMSO-d6, 125 MHz)
d(ppm):
117.61, 118.17, 119.77, 120.32, 121.75, 127.67, 127.96, 128.69, 136.27,
139.63, 143.60, 149.68, 152.53, 159.40, 166.54; ESI-MS m/z:
490.0[M þ H]þ.
6.8.7. 1-{4-[4-(Thiazol-2-yl)phenoxy]phenyl}-3-p-tolylurea (1g)
White solid, yield: 57%, mp 223–224 ꢁC; IR(KBr, cmꢂ1): 3301.42,
1640.85, 1604.07, 1568.54, 1505.35, 1482.05, 1241.24, 829.88; 1H
6.8.3. 1-Phenyl-3-{4-[4-(thiazol-2-yl)phenoxy]phenyl}urea (1c)
White solid, yield: 48%, mp 198–199 ꢁC; IR(KBr, cmꢂ1): 3221.00,
1642.70, 1594.66, 1559.43, 1498.58, 1482.56, 1408.90, 1300.00,
NMR(DMSO-d6, 300 MHz) d(ppm): 2.22 (s, 3H, Ar-CH3), 7.00–7.07
(m, 6H, Ar-H), 7.32 (d, J ¼ 8.39 Hz, 2H, Ar-H), 7.46–7.50 (m, 2H,
Ar-H), 7.70 (d, J ¼ 3.24 Hz, 1H, Ar-H), 7.85 (d, J ¼ 3.25 Hz, 1H, Ar-H),
7.89–7.93 (m, 2H, Ar-H), 8.51 (s, 1H, –NHCONH–), 8.64 (s, 1H,
1229.54, 829.18; 1H NMR(DMSO-d6, 300 MHz)
d(ppm): 6.97
(t, J ¼ 14.67 Hz, 1H, Ar-H), 7.03–7.10 (m, 4H, Ar-H), 7.25–7.31 (m, 2H,
Ar-H), 7.44–7.48 (m, 2H, Ar-H), 7.50–7.54 (m, 2H, Ar-H), 7.73
(d, J ¼ 3.26 Hz, 1H, Ar-H), 7.88 (d, J ¼ 3.26 Hz, 1H, Ar-H), 7.92–7.96
–NHCONH–); 13C NMR(DMSO-d6, 75 MHz)
d(ppm): 20.16, 117.66,
118.36, 119.63, 119.88, 120.15, 127.74, 127.93, 129.01, 130.60, 136.32,
137.03, 143.53, 149.76, 152.57, 159.36, 166.53; ESI-MS m/z:
402.1[M þ H]þ; Anal. Calcd for C23H19N3O2S (%): C 68.81, H 4.77, N
10.47; Found: C 68.51, H 4.71, N 10.50.
(m, 2H, Ar-H), 8.65 (s,1H, –NHCONH–), 8.71 (s,1H, –NHCONH–); 13
C
NMR(DMSO-d6, 125 MHz) d(ppm): 116.72, 116.76, 117.73, 119.80,
120.25, 120.47, 122,22, 123.00, 127.77, 127.98, 131.91, 135.67, 139.33,
143.61, 150.17, 152.42, 159.27, 166.52; HRMS (ESI) m/z: Calcd for
C22H17N3O2S [M þ H]þ 388.1041, Found 388.1095; Anal. Calcd for
C22H17N3O2S$1/2H2O (%): C 66.65, H 4.58, N 10.60; Found: C 66.97,
H 4.68, N 10.25.
6.8.8. 1-[2-Chloro-5-(trifluoromethyl)phenyl]-3-{4-[4-(thiazol-2-
yl)phenoxy]phenyl} urea (1h)
Off-white solid, yield: 44%, mp 199–200 ꢁC; IR(KBr, cmꢂ1):
3301.42, 1640.85, 1604.07, 1568.54, 1505.35, 1482.05, 1241.24,
6.8.4. 1-(4-Chloro-3-nitrophenyl)-3-{4-[4-(thiazol-2-yl)phenoxy]-
phenyl}urea (1d)
829.88; 1H NMR(DMSO-d6, 300 MHz)
d
(ppm) 3301.69, 1649.79,
1600.71, 1559.83, 1500.86, 1482.60, 1409.07, 1301.75, 1221.39,
1166.59, 832.22; 1H NMR(CDCl3, 500 MHz)
(ppm): 6.99–7.03
Yellow solid, yield: 50%, mp 179–180 ꢁC; IR(KBr, cmꢂ1): 3340.21,
1658.47, 1595.71, 1556.38, 1531.36, 1504.66, 1480.92, 1343.74,
1305.38, 1245.74, 1228.95, 1198.38, 833.55; 1H NMR(DMSO-d6,
d
(m, 4H, Ar-H), 7.19 (dd, J ¼ 1.94, 8.40 Hz, 1H, Ar-H), 7.32 (d, J ¼ 3.3 Hz,
1H, Ar-H), 7.34–7.38 (m, 2H, Ar-H), 7.39 (d, J ¼ 8.36 Hz,1H, Ar-H), 7.48
(s, 1H, Ar-H), 7.61 (br, 1H, –NHCONH–), 7.85 (d, J ¼ 3.3 Hz, 1H, Ar-H),
7.89–7.92 (m, 2H, Ar-H), 8.59 (d, J ¼ 1.8 Hz, 1H, –NHCONH–); 13C
500 MHz) d(ppm): 7.04–7.09 (m, 4H, Ar-H), 7.52–7.54 (m, 2H, Ar-H),
7.64–7.65 (m, 2H, Ar-H), 7.72 (d, J ¼ 3.25 Hz, 1H, Ar-H), 7.88
(d, J ¼ 3.24 Hz, 1H, Ar-H), 7.93–7.95 (m, 2H, Ar-H), 8.31
(t, J ¼ 2.66 Hz, 1H, Ar-H), 8.65 (s, 1H, –NHCONH–), 8.71 (s, 1H,
NMR(CDCl3, 75 MHz) d(ppm): 118.13, 118.52, 118.80, 120.07, 120.61,
123.64, 128.38, 128.43, 129.50, 133.53, 136.05, 143.42, 152.85, 159.51,
–NHCONH–); 13C NMR(DMSO-d6, 75 MHz)
d
(ppm): 114.20, 116.57,
168.34; ESI-MS m/z: 490.0[M þ H]þ.
117.73, 119.72, 120.17, 120.47, 123,01, 127.77, 127.93, 131.65, 135.49,
139.81, 143.56, 147.41, 150.27, 152.25, 159.19, 166.48; ESI-MS m/z:
465.0[M ꢂ H]ꢂ; Anal. Calcd for C22H15ClN4O4S$1/4H2O (%): C 56.05,
H 3.31, N 11.89; Found: C 56.04, H 3.31, N 12.09.
6.8.9. 1-[3-Bromo-5-(trifluoromethyl)phenyl]-3-{4-[4-(thiazol-2-
yl)phenoxy]phenyl} urea (1i)
White solid, yield: 53%, mp 208–209 ꢁC; IR(KBr, cmꢂ1): 3308.19,
1648.13, 1591.86, 1560.61, 1505.80, 1483.14, 1457.47, 1333.43,
1304.51, 1244.41, 1224.77, 1171.24, 1129.79, 836.43, 694.40; 1H
6.8.5. 1-{4-[4-(Thiazol-2-yl)phenoxy]phenyl}-3-[3-
(trifluoromethyl)phenyl]urea (1e)
NMR(DMSO-d6, 300 MHz)
d(ppm): 7.05–7.10 (m, 4H, Ar-H),
White solid, yield: 59%, mp 193–194 ꢁC; IR(KBr, cmꢂ1): 3308.76,
1636.55, 1603.26, 1568.96, 1507.51, 1491.29, 1480.86, 1344.36,
7.51–7.55 (m, 3H, Ar-H), 7.73 (d, J ¼ 3.22 Hz, 1H, Ar-H), 7.89
(d, J ¼ 3.17 Hz, 1H, Ar-H), 7.94–7.97 (m, 3H, Ar-H), 8.98 (s, 1H,