Orally Bioavailable Competitive CCR5 Antagonists
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 8 1951
(DMSO-d6) δ 7.18-7.12 m, 3 H), 7.05 (m, 2 H), 6.51 (d, J )
9.0 Hz, 2 H), 5.65 (d, J ) 8.0 Hz, 1 H), 4.01 (m, 1 H), 3.34 (m,
1 H), 3.17 (m, 2 H), 2.90 (m, 2 H), 2.79 (m, 1 H), 2.17 (s, 3 H),
2.15 (m, 2 H), 2.12 (s, 3 H), 1.91 (m, 3 H), 1.74 (m, 1 H), 1.40-
1.20 (m, 4 H), 0.89 (s, 3 H); MS ESI 485/487 [M + H]+
[4-(4-Ch lor o-p h en yla m in o)-4′-m eth yl-[1,4′]bip ip er id i-
n yl-1′-yl](2,6-d im eth ylp h en yl)m eth a n on e (21c): 1H NMR
(DMSO-d6) δ 7.15 (t, J ) 7.5 Hz, 1 H), 7.05 (m, 4 H), 6.55 (d,
J ) 8.5 Hz, 2 H), 5.61 (d, J ) 8.0 Hz, 1 H), 4.00 (m, 1 H), 3.34
(m, 1 H), 3.16 (m, 2 H), 2.90 (m, 2 H), 2.78 (m, 1 H), 2.17 (s, 3
H), 2.15 (m, 2 H), 2.12 (s, 3 H), 1.89 (m, 3 H), 1.75 (m, 1 H),
1.40-1.20 (m, 4 H), 0.89 (s, 3 H); HR-MS [M + H]+ observed
) 440.2467, estimated ) 440.2469.
(2,6-Dim e t h ylp h e n yl)[4′-m e t h yl-4-(4-t r iflu or om e t h -
ylph en ylam in o)-[1,4′]bipiper idin yl-1′-yl]m eth an on e (21d):
1H NMR (DMSO-d6) δ 7.33 (d, J ) 8.0 Hz, 2 H), 7.15 (t, J )
7.5 Hz, 1 H), 7.05 (m, 2 H), 6.65 (d, J ) 8.5 Hz, 2 H), 6.21 (d,
J ) 8.0 Hz, 1 H), 4.01 (m, 1 H), 3.38-3.13 (m, 3 H), 2.90 (m,
2 H), 2.80 (m, 1 H), 2.17 (s, 3 H), 2.17 (m, 2 H), 2.12 (s, 3 H),
1.91 (m, 3 H), 1.74 (m, 1 H), 1.42-1.20 (m, 4 H), 0.90 (s, 3 H);
HR-MS [M + H]+ observed ) 474.2737, estimated ) 474.2732.
[4-(Bip h en yl-4-yla m in o)-4′-m eth yl-[1,4′]bip ip er id in yl-
1′-yl](2,6-dim eth ylph en yl)m eth an on e (21e): 1H NMR (DM-
SO-d6) δ 7.53 (d, J ) 7.5 Hz, 2 H), 7.42-7.33 (m, 4 H), 7.20 (t,
J ) 7.5 Hz, 1 H), 7.15 (t, J ) 7.5 Hz, 1 H), 7.06 (m, 2 H), 6.64
(d, J ) 9.0 Hz, 2 H), 5.62 (d, J ) 8.0 Hz, 1 H), 4.01 (m, 1 H),
3.34 (m, 1 H), 3.19 (m, 2 H), 2.92 (m, 2 H), 2.81 (m, 1 H), 2.19
(m, 2 H), 2.17 (s, 3 H), 2.12 (s, 3 H), 1.94 (m, 3 H), 1.75 (m, 1
H), 1.42-1.20 (m, 4 H), 0.90 (s, 3 H); MS ESI 482 [M + H]+.
(2,6-Dim eth ylp h en yl)[4′-m eth yl-4-(1-m eth yl-1H-in d ol-
7-yla m in o)-[1,4′]bip ip er id in yl-1′-yl]m eth a n on e (21f): 1H
NMR (DMSO-d6) δ 7.15 (t, J ) 7.5 Hz, 1 H), 7.05 (m, 3 H),
6.87 (d, J ) 8.0 Hz, 1 H), 6.77 (t, J ) 7.5 Hz, 1 H), 6.37 (d, J
) 8.0 Hz, 1 H), 6.32 (d, J ) 3.0 Hz, 1 H), 4.63 (m, 1 H), 4.08
(s, 3 H), 3.99 (m, 1 H), 3.42-3.15 (m, 3 H), 2.92 (m, 2 H), 2.81
(m, 1 H), 2.21 (m, 2 H), 2.17 (s, 3 H), 2.12 (s, 3 H), 2.05-1.88
(m, 3 H), 1.74 (m, 1 H), 1.51 (m, 2 H), 1.38 (m, 1 H), 1.25 (m,
1 H), 0.91 (s, 3 H); HR-MS [M + H]+ observed ) 459.3121,
estimated ) 459.3124.
(2,6-Dim eth ylp h en yl)-[4′-m eth yl-4-(1-m eth yl-1H-in d ol-
6-yla m in o)-[1,4′]bip ip er id in yl-1′-yl]m eth a n on e (21g): 1H
NMR (DMSO-d6) δ 7.17 (m, 2 H), 7.05 (m, 2 H), 6.92 (d, J )
3.0 Hz, 1 H), 6.44 (m, 2 H), 6.16 (d, J ) 3.0 Hz, 1 H), 5.06 (m,
1 H), 4.01 (m, 1 H), 3.61 (s, 3 H), 3.41-3.14 (m, 3 H), 2.92 (m,
2 H), 2.81 (m, 1 H), 2.21 (m, 2 H), 2.17 (s, 3 H), 2.12 (s, 3 H),
2.04-1.88 (m, 3 H), 1.76 (m, 1 H), 1.42-1.20 (m, 4 H), 0.91 (s,
3 H); HR-MS [M + H]+ observed ) 459.3123, estimated )
459.3124.
H), 1.36 (m, 1 H), 1.23 (m, 1 H), 0.90 (s, 3 H); HR-MS [M +
H]+ observed ) 574.2436, estimated ) 574.2433.
(4-Ben zyla m in o-4′-m eth yl-[1,4′]bip ip er id in yl-1′-yl)(2,6-
d im eth ylp h en yl)m eth a n on e (24). A mixture of 20 (50 mg,
0.15 mmol), acetic acid (18 mg, 0.30 mmol), (CH3COO)3NaBH
(35 mg, 0.17 mmol), benzylamine (18 mg, 0.17 mmol), and
(CH2Cl)2 (3 mL) was stirred at 25 °C for 16 h. The mixture
was diluted with ethyl acetate and washed with NaOH,
NaHCO3, and brine. The organic phase was dried with Na2-
SO4, the solvent was removed, and the residue was subjected
to flash chromatography (SiO2, TBME/cyclohexane 4:1f TBME)
to yield compound 24 (19 mg, 30%) as a colorless oil: 1H NMR
(DMSO-d6) δ 7.32 (d, J ) 7.0 Hz, 2 H), 7.29 (t, J ) 7.5 Hz, 2
H), 7.19 (t, J ) 7.5 Hz, 1 H), 7.15 (t, J ) 7.5 Hz, 1 H), 7.05 (m,
2 H), 3.98 (m, 1 H), 3.70 (s, 2 H), 3.37 (m, 1 H), 3.16 (m, 1 H),
2.93-2.67 (m, 3 H), 2.32 (m, 1 H), 2.17 (m, 1 H), 2.17 (s, 3 H),
2.12 (s, 3 H), 2.06-1.63 (m, 7 H), 1.34 (m, 1 H), 1.20 (m, 1 H),
0.90 (s, 3 H); MS ESI 420 [M + H]+.
(4-Diben zyla m in o-4′-m eth yl-[1,4′]bip ip er id in yl-1′-yl)-
(2,6-d im eth ylp h en yl)m eth a n on e (25). A mixture of 20 (82
mg, 0.25 mmol), acetic acid (30 mg, 0.50 mmol), (CH3-
COO)3NaBH (117 mg, 0.55 mmol), dibenzylamine (54 mg, 0.28
mmol), and (CH2Cl)2 (5 mL) was stirred at 50 °C for 4 h. The
mixture was diluted with ethyl acetate and washed with
NaOH, NaHCO3, and brine. The organic phase was dried with
Na2SO4, the solvent was removed, and the residue subjected
to flash chromatography (SiO2, TBME/cyclohexane 4:1f TBME)
to yield compound 25 (51 mg, 40%) as a colorless solid: 1H
NMR (DMSO-d6) δ 7.35 (d, J ) 7.0 Hz, 4 H), 7.29 (t, J ) 7.5
Hz, 4 H), 7.19 (t, J ) 7.5 Hz, 2 H), 7.14 (t, J ) 7.5 Hz, 1 H),
7.04 (m, 2 H), 3.92 (m, 1 H), 3.59 (s, 4 H), 3.37 (m, 1 H), 3.16
(m, 1 H), 3.00-2.81 (m, 3 H), 2.35 (m, 1 H), 2.17 (s, 3 H), 2.12
(s, 3 H), 1.90-1.63 (m, 6 H), 1.58-1.43 (m, 2 H), 1.33 (m, 1
H), 1.20 (m, 1 H), 0.90 (s, 3 H); HR-MS [M + H]+ observed )
510.3488, estimated ) 510.3484.
(2,6-Dim eth ylp h en yl)(4-d ip h en yla m in o-4′-m eth yl-[1,4′]-
bip ip er id in yl-1′-yl)m eth a n on e (26a ). A mixture of com-
pound 27 (250 mg, 0.71 mmol), carboxylic acid 9 (320 mg, 2.13
mmol), HBTU (568 mg, 1.50 mmol), DMF (5 mL), and
diisopropyl ethylamine (DIPEA) (0.60 mL) was stirred for 16
h at 25 °C. The mixture was diluted with TBME and washed
with NaOH and brine. The organic phase was dried with Na2-
SO4, the solvent was removed, and the residue subjected to
flash chromatography (SiO2, TBME/cycylohexane 1:4 f TBME)
to yield compound 26a (240 mg, 70%) as a colorless foam: 1H
NMR (DMSO-d6) δ 7.27 (t, J ) 7.5 Hz, 4 H), 7.13 (t, J ) 7.5
Hz, 1 H), 7.03 (t, J ) 7.5 Hz, 2 H), 6.97 (t, J ) 7.5 Hz, 2 H),
6.78 (d, J ) 8.0 Hz, 4 H), 3.78 (m, 2 H), 3.35 (m, 1 H), 3.00 (m,
2 H), 2.85 (m, 2 H), 2.21 (m, 2 H), 2.13 (s, 3 H), 2.04 (s, 3 H),
1.90 (m, 2 H), 1.77 (m, 1 H), 1.61 (m, 1 H), 1.37 (m, 1 H), 1.22
(m, 3 H), 0.90 (s, 3 H); HR-MS [M + H]+ observed ) 482.3171,
estimated ) 482.3171.
[4-(Ben zylp h en yla m in o)-4′-m eth yl-[1,4′]bip ip er id in yl-
1′-yl](2,6-d im eth ylp h en yl)m eth a n on e (22). A suspension
of 21a (142 mg, 0.35 mmol), K2CO3 (242 mg, 1.75 mmol), and
benzyl bromide (600 mg, 3.5 mmol) in DMF (3 mL) was stirred
at 100 °C for 16 h. Ethyl acetate was added and the mixture
washed with NaHCO3 and brine. The organic phase was dried
with Na2SO4, the solvent was removed, and the residue was
subjected to flash chromatography (SiO2, TBME/cycohexane
2:1 f TBME/cyclohexane 4:1) to yield compound 22 (115 mg,
66%) as a colorless foam: 1H NMR (DMSO-d6) δ 7.32-7.23
(m, 4 H), 7.22-7.01 (m, 6 H), 6.66 (d, J ) 8.5 Hz, 2 H), 6.57 (t,
J ) 7.0 Hz, 1 H), 4.45 (s, 2 H), 4.03 (m, 1 H), 3.77 (m, 1 H),
3.39 (m, 1 H), 3.17 (m, 1 H), 3.00 (m, 1 H), 2.89 (m, 2 H), 2.25-
2.15 (m, 2 H), 2.17 (s, 3 H), 2.12 (s, 3 H), 1.90-1.52 (m, 6 H),
1.37 (m, 1 H), 1.23 (m, 1 H), 0.90 (s, 3 H); HR-MS [M + H]+
observed ) 496.3329, estimated ) 496.3328.
{4-[Ben zyl-(4-br om op h en yl)a m in o]-4′-m eth yl-[1,4′]bi-
p ip er id in yl-1′-yl}(2,6-d im eth ylp h en yl)m eth a n on e (23).
Compound 23 was prepared from 21b by following the
procedure described for the synthesis of 22: 1H NMR (DMSO-
d6) δ 7.29 (t, J ) 7.5 Hz, 2 H), 7.25-7.18 (m, 5 H), 7.14 (t, J )
7.5 Hz, 1 H), 7.04 (t, J ) 7.0 Hz, 2 H), 6.60 (d, J ) 9.0 Hz, 2
H), 4.45 (s, 2 H), 3.92 (m, 1 H), 3.75 (m, 1 H), 3.39 (m, 1 H),
3.16 (m, 1 H), 2.99 (m, 1 H), 2.88 (m, 2 H), 2.25-2.15 (m, 2
H), 2.16 (s, 3 H), 2.11 (s, 3 H), 1.86 (m, 1 H), 1.80-1.49 (m, 5
Compounds 26b-p were prepared from 27 by following
similar procedures as described for the synthesis of 26a .
(4-Dip h en yla m in o-4′-m eth yl-[1,4′]bip ip er id in yl-1′-yl)-
o-tolylm eth a n on e (26b): 1H NMR (DMSO-d6) (120°) δ 7.28-
7.14 (m, 7 H), 7.08 (d, J ) 8.0 Hz, 1 H), 6.95 (t, J ) 7.5 Hz, 2
H), 6.84 (d, J ) 7.5 Hz, 4 H), 3.84 (m, 1 H), 3.45-3.26 (m, 4
H), 2.96 (m, 2 H), 2.27 (m, 2 H), 2.20 (s, 3 H), 1.94 (m, 2 H),
1.75 (m, 2 H), 1.38 (m, 4 H), 0.97 (s, 3 H); HR-MS [M + H]+
observed ) 468.3018, estimated ) 468.3015.
(4-Dip h en yla m in o-4′-m eth yl-[1,4′]bip ip er id in yl-1′-yl)-
p h en ylm eth a n on e (26c): 1H NMR (DMSO-d6) δ 7.39 (m, 3
H), 7.33 (m, 2 H), 7.27 (t, J ) 8.0 Hz, 4 H), 6.97 (t, J ) 7.5 Hz,
2 H), 6.79 (d, J ) 8.0 Hz, 4 H), 3.86-3.70 (m, 2 H), 3.37-3.10
(m, 3 H), 2.92 (m, 2 H), 2.22 (m, 2 H), 1.92 (m, 2 H), 1.84-
1.61 (m, 2 H), 1.42-1.15 (m, 4 H), 0.97 (s, 3 H); HR-MS [M +
H]+ observed ) 454.2863, estimated ) 454.2858.
2-(4-Dip h en yla m in o-4′-m et h yl-[1,4′]b ip ip er id in yl-1′-
car bon yl)-N,N-dim eth ylben zam ide (26d): 1H NMR (DMSO-
d6) (120°) δ 7.41 (m, 2 H), 7.27 (m, 6 H), 6.97 (t, J ) 7.5 Hz, 2
H), 6.85 (d, J ) 8.0 Hz, 4 H), 3.85 (m, 1 H), 3.41-3.22 (m, 3
H), 2.96 (m, 2 H), 2.86 (s, 6 H), 2.26 (m, 2 H), 1.94 (m, 2 H),