Ureas as Microtubule Disrupters
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 23 5061
s, 1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3320 (NH), 1640
(CdO) cm-1. Anal. (C15H23ClN2O) C, H, N.
CH2Cl), 4.03-4.10 (m, 1H, NCHCH2CH3), 4.84 (broad s, 1H,
NHCH, exchanges with D2O), 7.18-7.24 (m, 4H, Ar-H), 6.25
(broad s, 1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3320
(NH), 1640 (CdO) cm-1. Anal. (C14H21ClN2O) C, H, N.
(R)-N-(4-Iod op h en yl-N′-(1-m et h yl-2-ch lor o)et h ylu r ea
(18a ): yield, 40%; mp 118-120°C; [R]25D +22.5 (c 1.00, MeOH);
1H NMR (DMSO-d6) δ 1.15 (d, J ) 6.9 Hz, 3H, NCHCH3),
3.51-3.68 (m, 2H, CH2Cl), 3.96-4.03 (m, 1H, NCHCH3), 6.29
(broad s, 1H, NHCH, exchanges with D2O), 7.21-7.54 (m, 4H,
Ar-H), 8.62 (broad s, 1H, ArNH, exchanges with D2O); ΙR
(KBr) ν 3320 (NH), 1635 (CdO) cm-1. Anal. (C10H12ClIN2O)
C, H, N.
(R)-N-(4-sec-Bu tyl)p h en yl-N′-(1-m eth yl-2-ch lor o)eth yl-
u r ea (14a ): yield, 88%; mp 127-129 °C; [R]25 +13.3 (c 1.10,
D
CHCl3); 1H NMR (CDCl3) δ 0.80 (t, J ) 7.4 Hz, 3H, CH3CH2),
1.20 (d, J ) 6.8 Hz, 3H, NCHCH3), 1.24 (d, J ) 6.8 Hz, 3H,
CHCH3), 1.51-1.61 (m, 4H, CH2CH3), 2.53-2.60 (m, 1H, CH),
3.55-3.60, 3.72-3.78 (2 m, 2H, CH2Cl), 4.10-4.12 (m, 1H,
NCH), 4.84 (broad s, 1H, NHCH2, exchanges with D2O), 6.21
(broad s, 1H, ArNH, exchanges with D2O), 7.11-7.19 (m, 4H,
Ar-H); ΙR (KBr) ν 3320 (NH), 1640 (CdO) cm-1. Anal. (C14H21
ClN2O) C, H, N.
-
(S)-N-(4-sec-Bu tyl)p h en yl-N′-(1-m eth yl-2-ch lor o)eth yl-
(S)-N-(4-Iod op h en yl-N′-(1-m et h yl-2-ch lor o)et h ylu r ea
(18b): yield, 20%; mp 118-120 °C; [R]25D -25.8 (c 1.00, MeOH);
1H NMR (DMSO-d6) δ 1.15 (d, J ) 6.8 Hz, 3H, NCHCH3, 3.31-
3.67 (m, 2H, CH2Cl), 3.96-4.03 (m, 1H, NCHCH3), 6.25 (broad
s, 1H, NHCH, exchanges with D2O), 7.21-7.54 (m, 4H, Ar-
H), 8.60 (broad s, 1H, ArNH, exchanges with D2O); ΙR (KBr)
ν 3320 (NH), 1635 (CdO) cm-1. Anal. (C10H12ClIN2O) C, H, N.
u r ea (14b): yield, 81%; mp 124-126 °C; [R]25 -16.3 (c 2.10,
D
CHCl3); 1H NMR (CDCl3) δ 0.80 (t, J ) 7.4 Hz, 3H, CH3CH2),
1.17-1.25 (2d, J ) 6.7, 6.8 Hz, 6H, CHCH3, NCHCH3), 1.51-
1.61 (m, 2H, CH2CH3), 2.53-2.60 (m, 1H, CH), 3.46-3.60,
3.73-3.78 (2 m, 2H, CH2Cl), 4.27-4.29 (m, 1H, NCH), 5.96
(broad s, 1H, NHCH2, exchanges with D2O), 6.21 (broad s, 1H,
ArNH, exchanges with D2O), 7.12-7.19 (m, 4H, Ar-H); ΙR
(KBr) ν 3320 (NH), 1640 (CdO) cm-1. Anal. (C14H21ClN2O) C,
H, N.
(R)-N-(4-Iodoph en yl-N′-(1-eth yl-2-ch lor o)eth ylu r ea (19a):
1
yield, 15%; mp 144-146 °C; [R]25 +23.8 (c 1.00, MeOH); H
D
NMR (DMSO-d6) δ 0.88 (t, J ) 7.3 Hz, 3H, NCHCH2CH3),
1.49-1.60 (m, 2H, NCHCH2CH3), 3.63-3.78 (m, 3H, CHCH2-
Cl), 5.80 (d, J ) 8.1 Hz, 1H, NHCH, exchanges with D2O),
7.18-7.42 (m, 4H, Ar-H), 8.54 (broad s, 1H, ArNH, exchanges
with D2O); ΙR (KBr) ν 3300 (NH), 1635 (CdO) cm-1. Anal.
(C11H14ClIN2O) C, H, N.
(R)-N-(4-sec-Bu t yl)p h en yl-N′-(1-et h yl-2-ch lor o)et h yl-
u r ea (15a ): yield, 50%; mp 135-137 °C; [R]25 +30.8 (c 1.10,
D
CHCl3); 1H NMR (CDCl3) δ 0.78 (t, J ) 7.3 Hz, 3H,
NCHCH2CH3), 0.90 (t, J ) 7.4 Hz, 3H, CH2CH3), 1.18 (d, J )
6.8 Hz, 3H, CHCH3), 1.47-1.62 (m, 4H, CH2CH3, NCHCH2-
CH3), 2.48-2.56 (m, 1H, CHCH3), 3.56-3.71 (m, 2H, CH2Cl),
4.00-4.06 (m, 1H, NCH), 5.45 (d, J ) 8.5 Hz, 1H, NHCH,
exchanges with D2O), 7.08-7.25 (m, 4H, Ar-H), 7.65 (broad
s, 1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3320 (NH), 1640
(CdO) cm-1. Anal. (C15H23ClN2O) C, H, N.
(S)-N-(4-Iodoph en yl-N′-(1-eth yl-2-ch lor o)eth ylu r ea (19b):
1
yield, 20%; mp 144-146 °C; [R]25 +23.3 (c 1.00, MeOH); H
D
NMR (DMSO-d6) δ 0.89 (t, J ) 7.4 Hz, 3H, NCHCH2CH3),
1.41-1.64 (m, 2H, NCHCH2CH3), 3.68-3.81 (m, 3H, CHCH2-
Cl), 6.20 (d, J ) 8.1 Hz, 1H, NHCH, exchanges with D2O),
7.22-7.55 (m, 4H, Ar-H), 8.62 (broad s, 1H, ArNH, exchanges
with D2O); ΙR (KBr) ν 3320 (NH), 1635 (CdO) cm-1. Anal.
(C11H14ClIN2O) C, H, N.
(S)-N-(4-sec-Bu t yl)p h en yl-N′-(1-et h yl-2-ch lor o)et h yl-
u r ea (15b): yield, 67%; mp 134-136 °C; [R]25 -31.5 (c 1.00,
D
CHCl3); 1H NMR (CDCl3) δ 0.82 (t, J ) 7.3 Hz, 3H,
NCHCH2CH3), 0.95 (t, J ) 7.4 Hz, 3H, CH2CH3), 1.21 (d, J )
6.8 Hz, 3H, CHCH3), 1.52-1.68 (m, 4H, CH2CH3, NCHCH2-
CH3), 2.50-2.60 (m, 1H, CHCH3), 3.73-3.78 (m, 2H, CH2Cl),
4.05-4.09 (m, 1H, NCH), 4.90 (d, J ) 8.5 Hz, 1H, NHCH,
exchanges with D2O), 7.11-7.20 (m, 4H, Ar-H), 7.32 (broad
s, 1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3320 (NH), 1640
(CdO) cm-1. Anal. (C15H23ClN2O) C, H, N.
(R)-N-(2-Naph th yl-N′-(1-m eth yl-2-ch lor o)eth ylu r ea (20a):
1
yield, 52%; mp 136-138 °C; [R]25 +29.2 (c 1.00, MeOH); H
D
NMR (DMSO-d6) δ 1.23 (d, J ) 6.6 Hz, 3H, NCHCH3), 3.54-
3.80 (m, 2H, CH2Cl), 4.31-4.35 (m, 1H, NCHCH3), 7.25-7.83
(m, 7H, Ar-H); ΙR (KBr) ν 3320 (NH), 1630 (CdO) cm-1. Anal.
(C14H15ClN2O) C, H, N.
(S)-N-(2-Naph th yl-N′-(1-m eth yl-2-ch lor o)eth ylu r ea (20b):
(R)-N-(4-Isop r op yl)p h en yl-N′-(1-m eth yl-2-ch lor o)eth yl-
1
yield, 59%; mp 138-140 °C; [R]25 -32.5 (c 1.00, MeOH); H
D
u r ea (16a ): yield, 70%; mp 125-127 °C; [R]25 +15.7 (c 1.40,
D
NMR (DMSO-d6) δ 1.23 (d, J ) 7.0 Hz, 3H, NCHCH3), 3.54-
3.78 (m, 2H, CH2Cl), 4.31-4.34 (m, 1H, NCHCH3), 7.25-7.82
(m, 7H, Ar-H); ΙR (KBr) ν 3310 (NH), 1630 (CdO) cm-1. Anal.
(C14H15ClN2O) C, H, N.
CHCl3); 1H NMR (CDCl3) δ 1.23 (d, J ) 6.7 Hz, 3H, NCHCH3),
1.24 (d, J ) 6.6 Hz, 6H, CH3), 2.85-2.91 (m, 1H, CHCH3),
3.56-3.60, 3.73-3.78 (2 m, 2H, CH2Cl), 4.28-4.30 (m, 1H,
NCH), 4.84 (broad s, 1H, NHCH2, exchanges with D2O), 6.20
(broad s, 1H, ArNH, exchanges with D2O), 7.16-7.18 (m, 4H,
(R)-N-(2-Flu or en yl-N′-(1-m eth yl-2-chlor o)eth ylu r ea (21a):
1
yield, 57%; mp 194-196 °C; [R]25 +20.1 (c 0.70, MeOH); H
Ar-H); ΙR (KBr) ν 3320 (NH), 1640 (CdO) cm-1. Anal. (C13H19
ClN2O) C, H, N.
-
D
NMR (DMSO-d6) δ 1.25 (d, J ) 7.0 Hz, 3H, NCHCH3), 3.50-
3.85 (m, 3H, CH2Cl, CH2 fluorenyl), 4.20-4.40 (m, 1H,
NCHCH3), 4.90 (d, J ) 8.1 Hz, 1H, NHCH, exchanges with
D2O), 6.35 (broad s, 1H, ArNH, exchanges with D2O), 7.10-
(S)-N-(4-Isop r op yl)p h en yl-N′-(1-m eth yl-2-ch lor o)eth yl-
u r ea (16b): yield, 82%; mp 128-130 °C; [R]25 -12.6 (c 0.90,
D
CHCl3); 1H NMR (CDCl3) δ 1.23 (d, J ) 6.7 Hz, 3H, NCHCH3),
1.24 (d, J ) 6.6 Hz, 6H, CH3), 2.83-2.92 (m, 1H, CHCH3),
3.55-3.60, 3.72-3.77 (2 m, 2H, CH2Cl), 4.29-4.31 (m, 1H,
NCH), 4.90 (broad s, 1H, NHCH2, exchanges with D2O), 6.29
(broad s, 1H, ArNH, exchanges with D2O), 7.15-7.18 (m, 4H,
7.75 (m, 7H, Ar-H); ΙR (KBr) ν 3320 (NH), 1630 (CdO) cm-1
Anal. (C17H17ClN2O) C, H, N.
.
(S)-N-(2-Flu or en yl-N′-(1-m eth yl-2-ch lor o)eth ylu r ea (21b):
1
yield, 55%; mp 194-196 °C; [R]25 -23.3 (c 1.00, MeOH); H
D
Ar-H); ΙR (KBr) ν 3320 (NH), 1640 (CdO) cm-1. Anal. (C13H19
ClN2O) C, H, N.
-
NMR (DMSO-d6) δ 1.26 (d, J ) 6.7 Hz, 3H, NCHCH3), 3.55-
3.83 (m, 3H, CH2Cl, CH2 fluorenyl), 4.29-4.32 (m, 1H,
NCHCH3), 5.29 (d, J ) 8.1 Hz, 1H, NHCH, exchanges with
D2O), 7.18-7.70 (m, 7H, Ar-H); ΙR (KBr) ν 3320 (NH), 1630
(CdO) cm-1. Anal. (C17H17ClN2O) C, H, N.
(R)-N-(4-Isop r op yl)p h en yl-N′-(1-et h yl-2-ch lor o)et h yl-
u r ea (17a ): yield, 60%; mp 145-147 °C; [R]25 +33.5 (c 1.00,
D
CHCl3); 1H NMR (CDCl3) δ 0.86 (t, J ) 7.4 Hz, 3H,
NCHCH2CH3), 1.14 (d, J ) 6.7 Hz, 6H, CH3), 1.48-1.54 (m,
2H, NCHCH2CH3), 2.76-2.80 (m, 1H, CH), 3.56-3.63 (2 m,
2H, CH2Cl), 3.95-3.98 (m, 1H, NCHCH2CH3), 5.26 (broad s,
1H, NHCH, exchanges with D2O), 7.08-7.14 (m, 4H, Ar-H),
6.92 (broad s, 1H, ArNH, exchanges with D2O); ΙR (KBr) ν 3320
(NH), 1640 (CdO) cm-1. Anal. (C14H21ClN2O) C, H, N.
(R)-N-(5-In dan yl-N′-(1-m eth yl-2-ch lor o)eth ylu r ea (22a):
1
yield, 50%; mp 146-148 °C; [R]25 +14.8 (c 1.00, MeOH); H
D
NMR (DMSO-d6) δ 1.23 (d, J ) 7.0 Hz, 3H, NCHCH3), 2.02-
2.17, 2.83-2.90 (2m, 6H, CH2 indanyl), 3.46-3.76 (m, 2H, CH2-
Cl), 4.25-4.30 (m, 1H, NCHCH3), 6.95-7.17 (m, 7H, Ar-H);
ΙR (KBr) ν 3300 (NH), 1640 (CdO) cm-1. Anal. (C13H17ClN2O)
C, H, N.
(S)-N-(4-Isop r op yl)p h en yl-N′-(1-et h yl-2-ch lor o)et h yl-
u r ea (17b): yield, 60%; mp 146-148 °C; [R]25D (c 1.00, CHCl3)
-36.6;1H NMR (CDCl3)δ0.94 (t, J )7.4 Hz, 3H, NCHCH2CH3),
1.23 (d, J ) 6.7 Hz, 6H, CH3), 1.41-1.61 (m, 2H, NCHCH2-
CH3), 2.83-2.92 (m, 1H, CH isopropyl), 3.62-3.77 (2 m, 2H,
(S)-N-(5-In dan yl-N′-(1-m eth yl-2-ch lor o)eth ylu r ea (22b):
1
yield, 55%; mp 148-150 °C; [R]25 -14.8 (c 1.00, MeOH); H
D
NMR (DMSO-d6) δ 1.23 (d, J ) 7.0 Hz, 3H, NCHCH3), 2.03-
2.16, 2.83-2.90 (2m, 6H, CH2 indanyl), 3.53-3.78 (m, 2H, CH2-