164
S.D. Tala et al. / European Journal of Medicinal Chemistry 76 (2014) 155e169
prepared from 16 hydrochloride (3.3 g, 11 mmol)]; Yield: 1.4 g; 1H
NMR (DMSO-d6):
136.64, 152.98, 162.04; HRMS [ESþ]: calcd for C29H40Cl2N6O2,
d
¼ 1.23e1.27 (t, J ¼ 7.2 Hz, 6H, CH3), 3.21e3.25 (q,
575.5729 [M þ H]þ, found 575.2663.
J ¼ 7.5 Hz, 4H, CH2), 3.68e3.71 (m, 8H, CH2), 4.11 (s, 2H, CH2), 6.69e
6.72 (d, J ¼ 8.6 Hz, 2H, AreH), 7.26e7.29 (d, J ¼ 8.8 Hz, 2H, AreH),
7.41e7.43 (d, J ¼ 8.9 Hz, 2H, AreH), 7.49e7.52 (d, J ¼ 8.9 Hz, 2H, Are
H), 8.72 (brs, 1H, NH), 8.96 (brs, 1H, NH), 9.69 (brs, 1H, NH), 10.72 (s,
4.2.1.7. N-(4-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)-
phenyl)-3-(dimethylamino)-propanamide (19a). Compound 19a
was prepared from 15l (1.15 g, 5.5 mmol) and N-mustard isocyanate
17 [freshly prepared from 16 (3.4 g, 11 mmol)]; Yield: 1.6 g; 1H NMR
1H, HCl); 13C NMR (DMSO-d6):
d
¼ 9.37, 41.57, 48.90, 53.22, 53.31,
113.65, 118.53, 120.62, 132.24, 137.10, 153.43, 163.16; HRMS [ESþ]:
(DMSO-d6):
d
¼ 2.77 (s, 6H, CH3), 2.84e2.87 (t, J ¼ 7.1 Hz, 2H, CH2),
calcd for C23H31Cl2N5O2, 480.4305 [M þ H]þ, found 480.1928.
3.32e3.35 (t, J ¼ 6.7 Hz, 2H, CH2), 3.68e3.70 (m, 8H, CH2), 6.71e
6.73 (d, J ¼ 8.6 Hz, 2H, AreH), 7.27e7.29 (d, J ¼ 8.8 Hz, 2H, AreH),
7.36e7.38 (d, J ¼ 8.8 Hz, 2H, AreH), 7.48e7.50 (d, J ¼ 8.8 Hz, 2H, Are
H), 7.95 (1H, brs, NH), 8.82 (1H, brs, NH), 9.02 (1H, brs, NH), 10.24 (s,
4.2.1.3. N-(4-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-
2-(pyrrolidin-1-yl)-acetamide (18c). Compound 18c was prepared
from 15h (1.9 g, 8.6 mmol) and N-mustard isocyanate 17 [freshly
prepared from 16 (5.3 g, 17 mmol)]; Yield: 1.6 g; 1H NMR (DMSO-
1H, HCl); 13C NMR (DMSO-d6):
d
¼ 30.50, 41.00, 42.10, 52.52, 52.58,
112.95, 117.95, 119.74, 120.02, 130.64, 132.64, 135.77, 140.96, 152.85,
167.25; HRMS [ESþ]: calcd for C22H29Cl2N5O2, 466.4040 [M þ H]þ,
found 466.1771.
d6):
d
¼ 1.90e1.95 (m, 4H, CH2), 3.11e3.17 (m, 2H, CH2), 3.60e3.62
(m, 2H, CH2), 3.65e3.76 (m, 8H, CH2), 4.21e4.22 (m, 2H, CH2), 6.71e
6.73 (d, J ¼ 8.9 Hz, 2H, AreH), 7.27e7.29 (d, J ¼ 8.9 Hz, 2H, AreH),
7.40e7.42 (d, J ¼ 8.9 Hz, 2H, AreH), 7.49e7.52 (d, J ¼ 8.9 Hz, 2H, Are
H), 8.89 (brs,1H, NH), 9.14 (brs,1H, NH),10.31 (brs,1H, NH),10.67 (s,
4.2.1.8. N-(4-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-
3-(diethylamino)-propanamide (19b). Compound 19b was prepared
from 15m (1.2 g, 5.0 mmol) and N-mustard isocyanate 17 [freshly
prepared from 16 (3.0 g, 10 mmol)]; Yield: 1.6 g; 1H NMR (DMSO-
1H, HCl); 13C NMR (DMSO-d6):
d
¼ 23.24, 41.67, 53.12, 54.49, 56.09,
113.42, 118.55, 120.53, 120.64, 131.05, 132.31, 136.96, 141.76, 153.44,
163.33; HRMS [ESþ]: calcd for C23H29Cl2N5O2, 478.4147 [M þ H]þ,
found 478.1771.
d6):
d
¼ 1.22e1.25 (t, J ¼ 7.1 Hz, 6H, CH3), 2.85e2.88 (t, J ¼ 7.1 Hz, 2H,
CH2), 3.11e3.14 (m, 4H, CH2), 3.33e3.34 (m, 2H, CH2), 3.68e3.70 (m,
8H, CH2), 6.73e6.75 (d, J ¼ 8.2 Hz, 2H, AreH), 7.28e7.30 (d,
J ¼ 8.6 Hz, 2H, AreH), 7.36e7.38 (d, J ¼ 8.7 Hz, 2H, AreH), 7.49e7.51
(d, J ¼ 8.8 Hz, 2H, AreH), 8.90 (brs, 1H, NH), 9.09 (brs, 1H, NH),10.26
4.2.1.4. N-(4-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-
2-(piperidin-1-yl)acetamide (18d). Compound 18d was prepared
from 15i (2.0 g, 8.6 mmol) and N-mustard isocyanate 17 [freshly
prepared from 16 (5.3 g, 17 mmol)] in dry DMF. Yield: 1.9 g; 1H NMR
(brs,1H, NH),10.30 (s,1H, HCl); 13C NMR (DMSO-d6):
d
¼ 8.35, 30.11,
41.07, 46.32, 46.72, 52.49, 112.76, 118.0, 119.71, 120.09, 130.39,
(DMSO-d6) d: 1.40e1.41 (m, 1H, CH), 1.68e1.79 (m, 6H, CH2), 3.07e
132.69, 135.74, 141.19, 152.83, 167.22; HRMS [ESþ]: calcd for
3.08 (m, 2H, CH2), 3.46e3.49 (m, 2H, CH2), 3.68e3.72 (m, 8H, CH2),
4.08 (s, 2H, CH2), 6.70e6.72 (d, 2H, J ¼ 9.0 Hz, AreH), 7.27e7.29 (d,
2H, J ¼ 8.9 Hz, AreH), 7.41e7.43 (d, 2H, J ¼ 8.9 Hz, AreH), 7.50e7.52
(d, 2H, J ¼ 8.9 Hz, AreH), 8.79 (brs, 1H, NH), 9.05 (brs, 1H, NH), 9.85
C
24H33Cl2N5O2, 494.4571 [M þ H]þ, found 494.2078.
4.2.1.9. N-(4-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-
3-(pyrrolidin-1-yl)-propanamide (19c). Compound 19c was pre-
pared from 15n (1.2 g, 5.0 mmol) and N-mustard isocyanate 17
[freshly prepared from 16 (3.0 g, 10 mmol)]; Yield: 1.2 g; 1H NMR
(1H, brs, NH), 10.70 (s, 1H, HCl); 13C NMR (DMSO-d6):
d
¼ 21.55,
22.66, 41.69, 53.05, 53.41, 57.48, 113.30, 118.57, 120.64, 120.70,
130.87, 132.19, 137.07, 141.91, 153.42, 162.70. HRMS [ESþ]: calcd for
(DMSO-d6)
d
: 1.88e1.99 (m, 4H, CH2), 2.83e2.87 (t, J ¼ 7.1 Hz, 2H,
C
24H31Cl2N5O2, 492.4412 [M þ H]þ, found 492.1928.
CH2), 3.02e3.10 (m, 2H, CH2), 3.39e3.41 (m, 2H, CH2), 3.49e3.51
(m, 2H, CH2), 3.68e3.70 (m, 8H, CH2), 6.69e6.71 (d, J ¼ 8.8 Hz, 2H,
AreH), 7.26e7.28 (d, J ¼ 8.8 Hz, 2H, AreH), 7.36e7.38 (d, J ¼ 8.8 Hz,
2H, AreH), 7.48e7.50 (d, J ¼ 8.8 Hz, 2H, AreH), 8.70 (brs, 1H, NH),
8.91 (brs, 1H, NH), 10.20 (brs, 1H, NH), 10.47 (s, 1H, HCl); 13C NMR
4.2.1.5. N-(4-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)phenyl)-
2-morpholinoacetamide (18e). Compound 18e was prepared from
15j (1.9 g, 8.1 mmol) and N-mustard isocyanate 17 [freshly prepared
from 16 (5.0 g, 16 mmol)]; Yield: 3.13 g; 1H NMR (DMSO-d6):
(DMSO-d6):
d
¼ 22.59, 31.80, 41.03, 49.70, 52.54, 52.91, 112.87,
d
¼ 3.16e3.28 (m, 2H, CH2), 3.43e3.49 (m, 2H, CH2), 3.68e3.72 (m,
117.99, 119.73, 120.08, 130.53, 132.69, 135.73, 141.08, 152.84, 167.12;
HRMS [ESþ]: calcd for C24H31Cl2N5O2, 492.4412 [M þ H]þ, found
492.1928.
8H, CH2), 3.79e3.85 (m, 2H, CH2), 3.96e4.03 (m, 2H, CH2), 4.19 (s,
2H, CH2), 6.71e6.73 (d, J ¼ 8.8 Hz, 2H, AreH), 7.27e7.29 (d,
J ¼ 8.9 Hz, 2H, AreH), 7.41e7.43 (d, J ¼ 8.9 Hz, 2H, AreH), 7.50e7.52
(d, J ¼ 90 Hz, 2H, AreH), 8.87 (1H, brs, NH), 9.13 (1H, brs, NH), 10.63
4.2.1.10. N-(4-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)
phenyl)-3-(piperidin-1-yl)-propanamide (19d). Compound 19d was
prepared from 15o (1.2 g, 5.0 mmol) and N-mustard isocyanate 17
[freshly prepared from 16 (3.0 g, 10 mmol)]; Yield: 1.8 g; 1H NMR
(1H, brs, NH), 10.75 (s, 1H, HCl); 13C NMR (DMSO-d6):
d
¼ 41.61,
51.70, 52.26, 53.16, 57.34, 63.51, 113.52, 118.56, 120.64, 120.67,
131.13, 132.15, 137.10, 141.66, 153.43, 162.47; HRMS [ESþ]: calcd for
C
23H29Cl2N5O3, 494.4141 [M þ H]þ, found 494.1720.
(DMSO-d6):
d
¼ 1.33e1.42 (m,1H, CH), 1.68e1.79 (m, 5H, CH), 2.86e
2.89 (m, 4H, CH2), 3.30e3.35 (m, 2H, CH2), 3.39e3.42 (m, 2H, CH2),
3.68e3.72 (m, 8H, CH2), 6.70e6.72 (d, J ¼ 8.8 Hz, 2H, AreH), 7.26e
7.28 (d, J ¼ 8.8 Hz, 2H, AreH), 7.35e7.38 (d, J ¼ 8.8 Hz, 2H, AreH),
7.47e7.49 (d, J ¼ 8.8 Hz, 2H, AreH), 8.66 (brs, 1H, NH), 8.86 (brs, 1H,
NH), 10.04 (brs, 1H, NH) 10.18 (s, 1H, HCl); 13C NMR (DMSO-d6):
4.2.1.6. 2-([1,40-Bipiperidin]-10-yl)-N-(4-(3-(4-(bis(2-chloroethyl)
amino)phenyl)ureido)phenyl)-acetamide (18f). Compound 18f was
prepared from 15k (1.9 g, 6.0 mmol) and N-mustard isocyanate 17
[freshly prepared from 16 (3.7 g, 12 mmol)]; Yield: 2.2 g; 1H NMR
(DMSO-d6):
d
¼ 1.40e1.43 (m, 1H, CH), 1.69e1.72 (m, 1H, CH), 1.79e
d
¼ 21.17, 22.25, 30.20, 41.10, 51.70, 52.01, 52.44, 112.66, 118.02,
1.92 (m, 4H, CH2), 2.16e2.22 (m, 2H, CH2), 2.33e2.36 (m, 2H, CH2),
2.88e2.96 (m, 2H, CH2), 3.22e3.25 (m, 2H, CH2), 3.36e3.39 (m, 3H,
CH), 3.66e3.73 (m, 10H, CH2), 4.11e4.15 (m, 2H, CH2), 6.69e6.72 (d,
J ¼ 9.0 Hz, 2H, AreH), 7.27e7.29 (d, J ¼ 9.0 Hz, 2H, AreH), 7.41e7.43
(m, J ¼ 8.9 Hz, 2H, AreH), 7.50e7.52 (m, J ¼ 8.9 Hz, 2H, AreH), 8.82
(1H, brs, NH), 9.09 (1H, brs, NH), 10.35 (1H, brs, NH), 10.75 (s, 1H,
119.74, 120.15, 130.26, 132.71, 135.72, 141.31, 152.82, 167.21; HRMS
[ESþ]: calcd for C25H33Cl2N5O2, 506.4678 [M
506.2084.
þ
H]þ, found
4.2.1.11. N-(4-(3-(4-(bis(2-chloroethyl)amino)phenyl)ureido)
phenyl)-3-morpholinopropanamide (19e). Compound 19e was pre-
pared from 15p (1.3 g, 5.0 mmol) and N-mustard isocyanate 17
[freshly prepared from 16 (3.0 g, 10 mmol)]; Yield: 1.7 g; 1H NMR
HCl); 13C NMR (DMSO-d6):
50.93, 52.57, 56.70, 59.07, 112.83, 118.02, 118.27, 120.16, 131.68,
d
¼ 21.43, 22.33, 23.05, 41.24, 49.01,