CCR5 Antagonists as Anti-HIV-1 Agents
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 10 2061
3.40-3.60 (2H, m), 4.50 (2H, s), 7.30-7.70 (11H, m), 7.89 (2H,
d, J ) 8.4 Hz), 10.19 (1H, s).
1u : 1H NMR (DMSO-d6) δ 1.80-2.20 (10H, m), 2.63 (2H, t,
J ) 5.6 Hz), 2.81-2.84 (2H, m), 2.88 (6H, s), 3.24-3.44 (6H,
m), 3.54-3.65 (1H, m), 4.02-4.11 (2H, m), 4.46 (2H, s), 6.62
(2H, d, J ) 9.0 Hz), 7.25 (1H, d, J ) 7.8 Hz), 7.36-7.60 (7H,
m), 7.88 (2H, d, J ) 8.4 Hz), 10.22 (1H, s).
1d : 1H NMR (CDCl3) δ 2.60-2.75 (2H, m), 2.75-2.90
(2H, m), 3.22 (3H, s), 3.35-3.50 (2H, m), 3.55-3.75 (2H, m),
3.80-4.05 (4H, m), 5.13 (2H, s), 7.12 (1H, d, J ) 7.6 Hz), 7.25-
7.55 (9H, m), 7.71 (1H, s), 7.80-7.87 (2H, m), 8.95 (1H, s).
1g: 1H NMR (DMSO-d6) δ 1.45-1.90 (6H, m), 2.55-2.70
(2H, m), 2.80-3.17 (7H, m), 3.25-3.60 (6H, m), 7.25-7.80
(13H, m), 9.95 (1H, s).
1v: 1H NMR (DMSO-d6) δ 1.50-1.70 (6H, m), 1.80-1.95 (2H,
m), 2.00-2.10 (2H, m), 2.10-2.20 (2H, m), 2.60-2.70 (2H, m),
2.75-2.87 (2H, m), 2.88 (6H, s), 3.14-3.24 (6H, m), 3.53-3.65
(1H, m), 4.00-4.15 (2H, m), 4.46 (2H, s), 7.00 (2H, d, J ) 8.8
Hz), 7.26 (1H, d, J ) 8.0 Hz), 7.36 (1H, s), 7.46-7.62 (6H, m),
7.87 (2H, d, J ) 8.8 Hz), 10.22 (1H, s).
1
1h : H NMR (DMSO-d6) δ 1.40-2.00 (6H, m), 2.35 (3H, s),
2.55-2.67 (2H, m), 2.82-2.95 (5H, m), 3.22-3.35 (4H, m), 4.53
(2H, s), 7.24-7.35 (3H, m), 7.46-7.60 (7H, m), 7.89 (2H, d,
J ) 8.8 Hz), 10.15 (1H, s).
1
2: H NMR (DMSO-d6) δ 1.62 (2H, m), 1.88 (4H, m), 2.37
(3H, s), 2.93 (3H, s), 3.36 (4H, m), 4.55 (2H, s), 6.97 (1H, d,
J ) 15.8 Hz), 7.31 (2H, d, J ) 7.6 Hz), 7.50-7.90 (11H, m),
10.44 (1H, s).
1i: 1H NMR (CDCl3) δ 1.62-2.01 (4H, m), 2.36 (3H, s), 3.06
(3H, br s), 3.34-3.49 (2H, m), 3.60-3.76 (2H, m), 4.97 (2H, br
s), 5.04 (2H, br s), 6.85 (1H, d, J ) 8.4 Hz), 7.17 (2H, d, J )
8.2 Hz), 7.37-7.42 (3H, m), 7.47-7.52 (3H, m), 7.83-7.91 (3H,
m), 9.00 (1H, br s).
N,N-Dim eth yl-N-[4-[[[2-(4-m eth ylp h en yl)-6,7-d ih yd r o-
5H -b en zocycloh ep t en -8-yl]ca r b on yl]a m in o]b en zyl]t et -
r a h yd r o-2H-p yr a n -4-a m in iu m Ch lor id e (1r ). A solution
of 1w (75.0 g, 0.120 mol) in MeOH and water was subjected
to an ion exchange column chromatography (Dowex SBR,
20-50 mesh, Cl- form) to give crude prisms. Recrystallized
from EtOH to give 50.6 g (80%) of 1r as colorless prisms: 1H
NMR (DMSO-d6) δ 1.80-2.25 (6H, m), 2.35 (3H, s), 2.65 (2H,
t, J ) 6.4 Hz), 2.80-2.89 (2H, m), 2.89 (6H, s), 3.24-3.43 (2H,
m), 3.61 (1H, t, J ) 11.0 Hz), 4.04-4.10 (2H, m), 4.49 (2H, s),
7.26-7.32 (3H, m), 7.42 (1H, s), 7.50-7.61 (5H, m), 7.69 (1H,
d, J ) 1.8 Hz), 7.91 (2H, d, J ) 8.6 Hz), 10.32 (1H, s).
1r : Meth od B. To a solution of 26 (4.50 g, 34.8 mmol) in
DMF (50 mL) was added a solution of 9b (9.40 g, 23.4 mmol)
in DMF (50 mL), and the mixture was stirred for 23 h at room
temperature under nitrogen atmosphere. The solvent was
evaporated in vacuo, and the crude prisms were filtered,
washed with acetone. Recrystallized from EtOH to give 10.6
g (86%) of 1r as colorless prisms.
The following compounds (1e,f) were prepared by a manner
similar to that used for 1r (Method B).
1e: 1H NMR (CDCl3) δ 1.37 (9H, t, J ) 6.9 Hz), 2.72-2.96
(4H, m), 3.22 (6H, q, J ) 6.9 Hz), 4.62 (2H, s), 7.15-7.45 (7H,
m), 7.50-7.60 (3H, m), 7.99 (1H, s), 8.12 (2H, d, J ) 8.6 Hz),
10.19 (1H, s).
1f: 1H NMR (CDCl3) δ 2.60-2.90 (7H, m), 6.07 (2H, s),
7.04-7.15 (3H, m), 7.25-7.50 (7H, m), 7.65 (1H, d, J ) 7.8
Hz), 7.72-7.92 (4H, m), 8.12-8.22 (1H, m), 9.63 (1H, d, J )
6.2 Hz), 9.86 (1H, s).
(E )-Tr i-n -b u t yl[4-[[3-(4-m e t h ylp h e n yl)cin n a m oyl]-
a m in o]ben zyl]p h osp h on iu m Ch lor id e (B). To a solution
of (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnam-
amide (0.30 g, 0.83 mmol) in toluene (10 mL) was added tri-
n-butylphosphine (0.25 mL, 1.0 mmol), and the mixture was
heated for 3 days at 80 °C. After cooled to room temperature,
the resulting precipitate was filtered. Recrystallized from
MeOH and EtOAc to give 0.39 g (83%) of B as colorless
prisms: mp 216-217 °C; 1H NMR (DMSO-d6) δ 0.85-1.00 (9H,
m), 1.30-1.60 (12H, m), 2.05-2.25 (6H, m), 2.37 (3H, s), 3.79
(2H, d, J ) 15.2 Hz), 7.05 (1H, d, J ) 15.8 Hz), 7.25-7.35
(4H, m), 7.48-7.90 (9H, m), 10.61 (1H, s). Anal. (C35H47ClNOP)
C, H, N.
N,N-Dim eth yl-N-(tetr a h yd r op yr a n -4-yl)a m in e (26). To
a solution of tetrahydropyran-4H-one (60.0 g, 0.599 mol), water
(5.00 mL) and DMF (70.0 mL, 0.904 mol) was added formic
acid (46.0 mL, 1.22 mol), and the mixture was heated at 140
°C for 23 h. The solvent was evaporated in vacuo, and the
residue was distilled under reduced pressure to give a crude
liquid. The crude liquid was dissolved in aq HCl and washed
with CH2Cl2; the aqueous layer was basified using 1 N NaOH
and extracted with CH2Cl2 after being saturated with NaCl.
The organic layer was dried over K2CO3, and evaporated in
vacuo. The residue was purified by distillation to give 10.4 g
(29%) of 26 as a colorless liquid: bp29 75-82 °C; 1H NMR
(CDCl3) δ 1.40-1.82 (4H, m), 2.28 (6H, s), 2.25-2.40 (1H, m),
3.37 (2H, ddd, J ) 2.2, 11.8, 11.8 Hz), 3.97-4.05 (2H, m).
Bin d in g Assa ys. CHO-K1 and CHO/CCR5 cells (5 × 104
cells/100 µL) were cultured in a microtiter tray. After a 24-h
incubation at 37 °C, culture medium was replaced with the
1j: 1H NMR (DMSO-d6) δ 1.45-1.65 (2H, m), 1.80-1.94 (4H,
m), 1.99-2.09 (2H, m), 2.35 (3H, s), 2.64 (2H, t, J ) 6.1 Hz),
2.83-2.88 (2H, m), 2.91 (3H, s), 3.23-3.29 (4H, m), 4.53 (2H,
s), 7.26-7.38 (4H, m), 7.48-7.68 (6H, m), 7.87 (2H, d, J ) 8.6
Hz), 10.23 (1H, s).
1k : 1H NMR (DMSO-d6) δ 1.45-1.70 (2H, m), 1.70-1.95
(4H, m), 2.34 (3H, s), 2.91 (3H, s), 3.00 (2H, br), 3.24-3.34
(4H, m), 4.31 (2H, br), 4.53 (2H, s), 7.06 (1H, d, J ) 8.4 Hz),
7.27 (2H, d, J ) 8.0 Hz), 7.36 (1H, s), 7.48-7.59 (5H, m), 7.75
(1H, s), 7.86 (2H, d, J ) 8.8 Hz), 10.19 (1H, s).
1l: 1H NMR (DMSO-d6) δ 1.80-2.00 (2H, m), 2.10-2.25 (2H,
m), 2.35 (3H, s), 2.88 (6H, s), 2.95-3.05 (2H, m), 3.15-3.45
(2H, m), 3.45-3.70 (1H, m), 4.00-4.15 (2H, m), 4.25-4.35 (2H,
m), 4.46 (2H, s), 7.06 (1H, d, J ) 8.4 Hz), 7.27 (2H, d, J ) 7.6
Hz), 7.36 (1H, s), 7.50-7.60 (5H, m), 7.70-7.80 (1H, m), 7.86
(2H, d, J ) 8.8 Hz), 10.20 (1H, s).
1m : 1H NMR (DMSO-d6) δ 1.75-2.00 (2H, m), 2.34 (3H, s),
2.55-2.75 (4H, m), 2.75-2.85 (2H, m), 2.90 (6H, s), 3.00 (2H,
br), 3.14-3.25 (1H, m), 4.31 (2H, br), 4.47 (2H, s), 7.07 (1H, d,
J ) 8.4 Hz), 7.27 (2H, d, J ) 7.8 Hz), 7.36 (1H, s), 7.50-7.59
(5H, m), 7.74 (1H, d, J ) 2.2 Hz), 7.86 (2H, d, J ) 8.8 Hz),
10.19 (1H, s).
1
1n : H NMR (DMSO-d6) δ 2.09-2.24 (2H, m), 2.34 (3H, s),
2.41-2.61 (6H, m), 2.97 (6H, s), 2.97-3.00 (2H, m), 3.79-3.90
(1H, m), 4.31 (2H, t, J ) 4.4 Hz), 4.56 (2H, s), 7.07 (1H, d,
J ) 8.4 Hz), 7.27 (2H, d, J ) 8.2 Hz), 7.37 (1H, s), 7.55-7.60
(5H, m), 7.75 (1H, d, J ) 2.2 Hz), 7.88 (2H, d, J ) 8.8 Hz),
10.20 (1H, s).
1
1o: H NMR (CDCl3) δ 1.09 (6H, t, J ) 7.0 Hz), 1.60-1.80
(2H, m), 2.00-2.30 (2H, m), 2.36 (3H, s), 3.00 (6H, s), 3.00-
3.10 (2H, m), 3.30-3.40 (1H, m), 4.20-4.35 (2H, m), 4.81 (2H,
s), 6.98 (1H, d, J ) 8.8 Hz), 7.20 (2H, d, J ) 7.4 Hz), 7.35-
7.60 (6H, m), 7.70-7.80 (1H, m), 7.83 (2H, d, J ) 8.8 Hz), 8.83
(1H, s).
1p : 1H NMR (CDCl3 + CD3OD) δ 2.00-2.20 (2H, m), 2.40
(3H, s), 3.06-3.10 (2H, m), 3.10 (6H, s), 3.51-3.61 (2H, m),
3.73 (2H, t, J ) 5.4 Hz), 4.37 (2H, t, J ) 4.6 Hz), 4.61 (2H, s),
7.07 (1H, d, J ) 8.4 Hz), 7.25 (2H, d, J ) 8.2 Hz), 7.46-7.59
(7H, m), 7.81 (2H, d, J ) 8.2 Hz), 9.54 (1H, s).
1q: 1H NMR (CDCl3) δ 1.65-1.95 (6H, m), 2.35 (3H, s),
2.95-3.05 (4H, m), 3.25 (3H, s), 3.61-3.85 (6H, m), 4.29 (2H,
t, J ) 4.2 Hz), 7.01 (1H, d, J ) 8.4 Hz), 7.17-7.26 (4H, m),
7.40-7.50 (4H, m), 7.58 (2H, d, J ) 8.4 Hz), 7.70 (1H, d, J )
2.2 Hz), 8.49 (1H, br).
1
1s: H NMR (DMSO-d6) δ 1.41 (3H, t, J ) 7.0 Hz), 1.68-
1.98 (2H, m), 2.10-2.26 (2H, m), 2.94 (6H, s), 2.98-3.08 (2H,
m), 3.35-3.59 (3H, m), 3.96-4.16 (2H, m), 4.03 (2H, q, J )
7.0 Hz), 4.19-4.31 (2H, m), 4.84 (2H, s), 6.91 (2H, d, J ) 8.8
Hz), 6.97 (1H, d, J ) 8.4 Hz), 7.38 (1H, dd, J ) 8.4, 2.2 Hz),
7.44-7.57 (5H, m), 7.69 (1H, d, J ) 2.2 Hz), 7.80 (2H, d, J )
8.4 Hz), 8.01 (1H, s).
1t: 1H NMR (DMSO-d6) δ 1.42-1.66 (2H, m), 1.75-1.88 (2H,
m), 2.55 (6H, s), 2.62-2.72 (2H, m), 2.94-3.35 (3H, m), 3.68-
3.81 (2H, m), 3.96-4.08 (2H, m), 4.13 (2H, s), 6.80 (1H, d, J )
8.8 Hz), 7.05 (1H, s), 7.21 (2H, d, J ) 8.4 Hz), 7.34-7.40 (1H,
m), 7.44-7.63 (7H, m), 9.89 (1H, s).