Antimitotic Antitumor Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5 699
exchanges with D2O), 6.51-6.90 (m, 3H, Ar-H), 7.81 (br s,
1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3320 (NH), 1640
(CdO) cm-1. Anal. (C11H15ClN2O) C, H, N.
1.43-1.55 (m, 3H, CH, CH2), 2.55-2.58 (m, 2H, ArCH2), 3.57-
3.65 (m, 4H, CH2CH2Cl), 5.21 (br s, 1H, NHCH2, exchanges
with D2O), 7.07-7.19 (dd, 4H, Ar-H), 7.25 (br s, 1H, ArNH,
exchanges with D2O); ΙR (KBr) ν 3330 (NH), 1640 (CdO) cm-1
.
N-(2,4,6-Tr im eth ylph en yl)-N′-2-ch lor oeth ylu r ea (9): yield
1
Anal. (C14H21ClN2O) C, H, N.
72%; mp 192-194 °C; H NMR (CDCl3) δ 2.04, 2.08 (2s, 9H,
CH3), 3.36-3.39 (m, 4H, CH2CH2Cl), 6.60 (br s, 1H, NHCH2,
exchanges with D2O), 6.68-6.72 (s, 2H, Ar-H), 6.74 (br s, 1H,
ArNH, exchanges with D2O); ΙR (KBr) ν 3300 (NH), 1640 (Cd
O) cm-1. Anal. (C12H17ClN2O) C, H, N.
N-(4-Hexylph en yl)-N′-2-ch lor oeth ylu r ea (20): yield 66%;
1
mp 130-132 °C; H NMR (CDCl3) δ 0.79 (t, J ) 7.1 Hz, 3H,
CH3), 1.18-1.21, 1.47-1.49 (2m, 8H, CH2), 2.44-2.47 (m, 2H,
ArCH2), 3.49-3.54 (m, 4H, CH2CH2Cl), 6.08 (br s, 1H, NHCH2,
exchanges with D2O), 6.97-7.18 (dd, 4H, Ar-H), 7.86 (br s,
1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3320 (NH), 1640
(CdO) cm-1. Anal. (C15H23ClN2O) C, H, N.
N-(4-Eth ylph en yl)-N′-2-ch lor oeth ylu r ea (10): yield 53%;
1
mp 161-163 °C; H NMR (CDCl3) δ 1.08 (t, J ) 7.2 Hz, 3H,
CH3), 2.46 (q, J ) 7.1 Hz, 2H, CH2CH3), 3.45-3.49 (m, 4H,
CH2CH2Cl), 6.10 (br s, 1H, NHCH2, exchanges with D2O),
6.96-7.16 (dd, 4H, Ar-H), 7.90 (br s, 1H, ArNH, exchanges
with D2O); ΙR (KBr) ν 3320 (NH), 1640 (CdO) cm-1. Anal.
(C11H15ClN2O) C, H, N.
N-(4-Cycloh exylph en yl)-N′-2-ch lor oeth ylu r ea (21): yield
63%; mp 164-166 °C; 1H NMR (CDCl3) δ 1.23-1.25, 1.68-
1.73, 2.28-2.32 (3m, 11H, cyclohexyl), 3.46-3.49 (m, 4H, CH2-
CH2Cl), 6.07 (br s, 1H, NHCH2, exchanges with D2O), 6.97-
7.16 (dd, 4H, Ar-H), 7.87 (br s, 1H, ArNH, exchanges with
N-(4-P r op ylp h en yl)-N′-2-ch lor oeth ylu r ea (11): yield
D2O); ΙR (KBr) ν 3340 (NH), 1640 (CdO) cm-1. Anal. (C15H21
ClN2O) C, H, N.
-
1
69%; mp 154-156 °C; H NMR (CDCl3) δ 0.75 (t, J ) 7.2 Hz,
3H, CH3), 1.39-1.41 (m, 2H, CH2CH3), 2.46 (t, J ) 7.3 Hz,
2H, CH2 CH2CH3), 3.39-3.43 (m, 4H, CH2CH2Cl), 6.08 (br s,
1H, NHCH2, exchanges with D2O), 6.87-7.10 (dd, 4H, Ar-
H), 7.92 (br s, 1H, ArNH, exchanges with D2O); ΙR (KBr) ν
3320 (NH), 1640 (CdO) cm-1. Anal. (C12H17ClN2O) C, H, N.
N-(4-Isop r op ylp h en yl)-N′-2-ch lor oeth ylu r ea (12): yield
65%; mp 140-142 °C; 1H NMR (CDCl3) δ 1.10 (d, J ) 6.8 Hz,
6H, CH3), 2.70-2.72 (m, 1H, CH CH3), 3.43-3.46 (m, 4H, CH2-
CH2Cl), 6.06 (br s, 1H, NHCH2, exchanges with D2O), 6.98-
7.16 (dd, 4H, Ar-H), 7.87 (br s, 1H, ArNH, exchanges with
N-(4-Hep tylp h en yl)-N′-2-ch lor oeth ylu r ea (22): yield
1
76%; mp 129-131 °C; H NMR (CDCl3) δ 0.77 (t, J ) 7.2 Hz,
3H, CH3), 1.16-1.19, 1.45-1.47 (2m, 10H, CH2), 2.40-2.44 (m,
2H, ArCH2), 3.45-3.49 (m, 4H, CH2CH2Cl), 6.09 (br s, 1H,
NHCH2, exchanges with D2O), 6.94-7.18 (dd, 4H, Ar-H), 7.86
(br s, 1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3320 (NH),
1640 (CdO) cm-1. Anal. (C16H25ClN2O) C, H, N.
N-(4-Octylp h en yl)-N′-2-ch lor oeth ylu r ea (23): yield 81%;
1
mp 127-129 °C; H NMR (CDCl3) δ 0.78 (t, J ) 7.2 Hz, 3H,
D2O); ΙR (KBr) ν 3320 (NH), 1640 (CdO) cm-1. Anal. (C12H17
ClN2O) C, H, N.
-
CH3), 1.15-1.18, 1.46-1.49 (2m, 12H, CH2), 2.41-2.44 (m, 2H,
ArCH2), 3.48-3.52 (m, 4H, CH2CH2Cl), 6.07 (br s, 1H, NHCH2,
exchanges with D2O), 6.96-7.18 (dd, 4H, Ar-H), 7.85 (br s,
1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3330 (NH), 1640
(CdO) cm-1. Anal. (C17H27ClN2O) C, H, N.
N-(4-Bu tylph en yl)-N′-2-ch lor oeth ylu r ea (13): yield 56%;
1
mp 139-141 °C; H NMR (CDCl3) δ 0.84 (t, J ) 7.2 Hz, 3H,
CH3), 1.24-1.27 (m, 2H, CH2CH3), 1.49-1.52 (m, 2H, CH2-
CH2CH3), 2.47-2.49 (t, J ) 7.3 Hz, 2H, CH2 CH2CH2CH3),
3.49-3.52 (m, 4H, CH2CH2Cl), 6.08 (br s, 1H, NHCH2,
exchanges with D2O), 6.98-7.20 (dd, 4H, Ar-H), 7.81 (br s,
1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3330 (NH), 1640
(CdO) cm-1. Anal. (C13H19ClN2O) C, H, N.
N-(4-Decylph en yl)-N′-2-ch lor oeth ylu r ea (24): yield 53%;
1
mp 124-126 °C; H NMR (CDCl3) δ 0.78 (t, J ) 7.1 Hz, 3H,
CH3), 1.14-1.17, 1.45-1.48 (2m, 16H, CH2), 2.40-2.43 (m, 2H,
ArCH2), 3.47-3.51 (m, 4H, CH2CH2Cl), 6.05 (br s, 1H, NHCH2,
exchanges with D2O), 6.95-7.17 (dd, 4H, Ar-H), 7.83 (br s,
1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3320 (NH), 1640
(CdO) cm-1. Anal. (C19H31ClN2O) C, H, N.
N-(4-Isobu tylp h en yl)-N′-2-ch lor oeth ylu r ea (14): yield
60%; mp 105-107 °C; 1H NMR (CDCl3) δ 1.07 (d, J ) 7.1 Hz,
6H, CH3), 1.50-1.53 (m, 1H, CHCH3), 2.40-2.43 (m, 2H, CH2-
CH), 3.51-3.54 (m, 4H, CH2CH2Cl), 6.08 (br s, 1H, NHCH2,
exchanges with D2O), 7.00-7.20 (dd, 4H, Ar-H), 7.81 (br s,
1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3320 (NH), 1640
(CdO) cm-1. Anal. (C13H19ClN2O) C, H, N.
N-(4-sec-Bu tylp h en yl)-N′-2-ch lor oeth ylu r ea (15): yield
95%; mp 89-91 °C; 1H NMR (CDCl3) δ 0.74 (t, J ) 7.4 Hz,
3H, CH2CH3), 1.14 (d, J ) 7.0 Hz, 3H, CHCH3), 1.48-1.52 (m,
2H, CH2CH3), 2.44-2.47 (m, 1H, CHCH3), 3.51-3.54 (m, 4H,
CH2CH2Cl), 6.06 (br s, 1H, NHCH2, exchanges with D2O),
7.00-7.21 (dd, 4H, Ar-H), 7.80 (br s, 1H, ArNH, exchanges
with D2O); ΙR (KBr) ν 3320 (NH), 1640 (CdO) cm-1. Anal.
(C13H19ClN2O) C, H, N.
N-(4-Dod ecylp h en yl)-N′-2-ch lor oeth ylu r ea (25): yield
1
74%; mp 123-125 °C; H NMR (CDCl3) δ 0.79 (t, J ) 7.1 Hz,
3H, CH3), 1.15-1.18, 1.44-1.47 (2m, 20H, CH2), 2.41-2.44 (m,
2H, ArCH2), 3.48-3.52 (m, 4H, CH2CH2Cl), 6.05 (br s, 1H,
NHCH2, exchanges with D2O), 6.95-7.18 (dd, 4H, Ar-H), 7.82
(br s, 1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3330 (NH),
1640 (CdO) cm-1. Anal. (C21H35ClN2O) C, H, N.
N-(3-Iod op h en yl)-N′-2-ch lor oeth ylu r ea (26): yield 95%;
mp 143-145 °C; 1H NMR (DMSO-d6) δ 3.40-3.42, 3.64-3.66
(2m, 4H, CH2CH2Cl), 6.98 (br s, 1H, NHCH2, exchanges with
D2O), 7.03-7.95 (m, 4H, Ar-H), 8.88 (br s, 1H, ArNH,
exchanges with D2O); ΙR (KBr) ν 3320 (NH), 1640 (CdO) cm-1
Anal. (C9H10ClIN2O) C, H, N.
.
N-(4-ter t-Bu tylp h en yl)-N′-2-ch lor oeth ylu r ea (16): yield
60%; mp 134-136 °C; H NMR (CDCl3) δ 1.20 (s, 9H, CH3),
3.49-3.53 (m, 4H, CH2CH2Cl), 6.09 (br s, 1H, NHCH2,
exchanges with D2O), 7.15-7.21 (dd, 4H, Ar-H), 7.85 (br s,
1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3300 (NH), 1640
(CdO) cm-1. Anal. (C13H19ClN2O) C, H, N.
N-(4-Iod op h en yl)-N′-2-ch lor oeth ylu r ea (27): yield 81%;
mp 194-196 °C; 1H NMR (DMSO-d6) δ 3.40-3.42, 3.62-3.64
(2m, 4H, CH2CH2Cl), 6.43 (br s, 1H, NHCH2, exchanges with
D2O), 7.22-7.54 (dd, 4H, Ar-H), 8.77 (br s, 1H, ArNH,
1
exchanges with D2O); ΙR (KBr) ν 3320 (NH), 1635 (CdO) cm-1
.
Anal. (C9H10ClIN2O) C, H, N.
N-(4-P en tylph en yl)-N′-2-ch lor oeth ylu r ea (17): yield 69%;
mp 135-137 °C; H NMR (CDCl3) δ 0.88 (t, J ) 7.2 Hz, 3H,
CH3), 1.21-1.26, 1.58-1.62 (m, 6H, CH2), 2.53-2.58 (m, 2H,
ArCH2), 3.58-3.70 (m, 4H, CH2CH2Cl), 6.33 (br s, 1H, NHCH2,
exchanges with D2O), 7.10-7.17 (dd, 4H, Ar-H), 7.25 (br s,
1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3320 (NH), 1640
(CdO) cm-1. Anal. (C14H21ClN2O) C, H, N.
N-(4-Br om op h en yl)-N′-2-ch lor oet h ylu r ea (28): yield
77%; mp 184-186 °C; 1H NMR (DMSO-d6) δ 3.39-3.41, 3.61-
3.66 (2m, 4H, CH2CH2Cl), 5.15 (br s, 1H, NHCH2, exchanges
with D2O), 6.27 (br s, 1H, ArNH, exchanges with D2O), 7.19-
1
7.43 (dd, 4H, Ar-H); ΙR (KBr) ν 3320 (NH), 1635 (CdO) cm-1
.
Anal. (C9H10BrClN2O) C, H, N.
N-(4-Ch lor op h en yl)-N′-2-ch lor oeth ylu r ea (29): yield
72%; mp 153-155 °C; 1H NMR (DMSO-d6) δ 3.39-3.41-3.62-
3.66 (m, 4H, CH2CH2Cl), 6.44 (br s, 1H, NHCH2, exchanges
with D2O), 7.24-7.43 (dd, 4H, Ar-H), 8.80 (br s, 1H, ArNH,
N-(4-Neopen tylph en yl)-N′-2-ch lor oeth ylu r ea (18): yield
1
70%; mp 122-124 °C; H NMR (CDCl3) δ 0.88 (s, 9H, CH3),
2.45 (s, 2H, CH2), 3.59-3.73 (m, 4H, CH2CH2Cl), 5.21 (br s,
1H, NHCH2, exchanges with D2O), 7.07-7.19 (dd, 4H, Ar-
H), 7.25 (br s, 1H, ArNH, exchanges with D2O); ΙR (KBr) ν
3330 (NH), 1640 (CdO) cm-1. Anal. (C14H21ClN2O) C, H, N.
N-(4-Isop en tylp h en yl)-N′-2-ch lor oeth ylu r ea (19): yield
exchanges with D2O); ΙR (KBr) ν 3330 (NH), 1635 (CdO) cm-1
Anal. (C9H10Cl2N2O) C, H, N.
.
N-(2-Na p h t h yl)-N′-2-ch lor oet h ylu r ea (30): yield 40%;
mp 185-187 °C; 1H NMR (DMSO-d6) δ 3.45-3.53 (2m, 4H,
CH2CH2Cl), 6.25 (br s, 1H, NHCH2, exchanges with D2O),
1
75%; mp 147-149 °C; H NMR (CDCl3) δ 0.92 (s, 6H, CH3),