654 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4
Bruncko et al.
4-[4-(2-Methylbenzyl)-4-methoxy-piperidin-1-yl]-benzoic Acid
7.09-7.19 (m, 4H), 6.92 (d, J ) 9.1 Hz, 2H), 4.19 (m, 1H), 3.62
(m, 2H), 3.39 (d, J ) 6.2 Hz, 2H), 3.15 (m, 2H), 3.10 (s, 3H), 3.02
(m, 2H), 2.75 (s, 6H), 2.14 (m, 2H), 1.88 (m, 2H), 1.51 (m, 2H),
1.41 (s, 2H), 0.98 (s, 9H). MS (ESI) m/z 710 (M - H)-. Anal.
(C36H49N5O6S2 ‚1.5 CF3CO2H ‚H2O) C, H, N.
N-[4-(4-Butyl-4-methoxy-piperidin-1-yl)-benzoyl]-4-((R)-3-
dimethylamino-1-phenylsulfanylmethyl-propylamino)-3-nitro-
benzenesulfonamide, Trifluoroacetate Salt, (8c). 8c was prepared
from 7c using the procedure described for the preparation of 8a.
1H NMR (500 MHz, DMSO-d6) δ 11.98 (br s, 1H), 9.40 (br s,
1H), 8.54 (d, J ) 2.4 Hz, 1H), 8.29 (d, J ) 9.0 Hz, 1H), 7.86 (dd,
J ) 9.1, 2.4 Hz, 1H), 7.73 (d, J ) 9.2 Hz, 2H), 7.10-7.25 (m,
6H), 6.93 (d, J ) 9.2 Hz, 2H), 4.17 (m, 1H), 3.60 (m, 2H), 3.39
(m, 2H), 3.10 (m, 2H), 3.07 (s, 3H), 3.02 (m, 2H), 2.75 (m, 6H),
2.15 (m, 2H), 1.75 (m, 2H), 1.43 (m, 4H), 1.24 (m, 4H), 0.87 (t, J
) 7.0 Hz, 3H). MS (ESI) m/z 696 (M - H)-. Anal. (C35H47N5O6S2
‚1.5 CF3CO2H) C, H, N.
Ethyl Ester (7j). 7j was prepared from 6j using the procedure
1
described for the preparation of 7a. H NMR (300 MHz, DMSO-
d6) δ 7.73 (d, J ) 9.2 Hz, 2H), 7.16-7.21 (m, 1H), 7.05-7.15 (m,
3H), 6.93 (d, J ) 9.2 Hz, 2H), 4.42 (s, 1H), 4.22 (q, J ) 7.1 Hz,
2H), 3.65 (d, J ) 13.2 Hz, 2H), 3.05-3.20 (m, 2H), 2.74 (s, 2H),
2.31 (s, 3H), 1.56-1.66 (m, 2H), 1.48-1.57 (m, 2H), 1.28 (t, J )
7.1 Hz, 3H). MS (DCI), m/z 368 [M + H]+.
4-[4-(2-Methoxybenzyl)-4-methoxy-piperidin-1-yl]-benzoic Acid
Ethyl Ester (7k). 7k was prepared from 6k using the procedure
1
described for the preparation of 7a. H NMR (500 MHz, DMSO-
d6) δ 7.73 (d, J ) 9.1 Hz, 2H), 7.18 (m, 1H), 7.12 (m, 1H), 6.93
(m, 3H), 6.86 (m, 1H), 4.22 (q, J ) 7.1 Hz, 2H), 3.75 (s, 3H), 3.61
(m, 2H), 3.28 (s, 3H), 2.98 (m, 2H), 2.80 (s, 2H), 1.73 (m, 2H),
1.49 (m, 2H), 1.27 (t, J ) 7.1 Hz, 3H). MS (ESI) m/z 384 [M +
H]+.
4-[4-(2-Bromobenzyl)-4-methoxy-piperidin-1-yl]-benzoic Acid
Ethyl Ester (7l). 7l was prepared from 6l using the procedure
N-[4-(4-Cyclohexylmethyl-4-methoxy-piperidin-1-yl)-benzoyl]-
4-((R)-3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-
3-nitro-benzenesulfonamide, Trifluoroacetate Salt, (8d). 8d was
prepared from 7d using the procedure described for the preparation
of 8a. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (br s, 1H), 9.41 (br
s, 1H), 8.54 (d, J ) 2.4 Hz, 1H), 8.28 (d, J ) 9.3 Hz, 1H), 7.87
(dd, J ) 9.0, 2.1 Hz, 1H), 7.73 (d, J ) 9.0 Hz, 2H), 7.23 (m, 2H),
7.08-7.18 (m, 4H), 6.92 (d, J ) 9.5 Hz, 2H), 4.19 (m, 1H), 3.59
(m, 2H), 3.39 (m, 2H), 3.13 (m, 2H), 3.07 (s, 3H), 3.03 (m, 2H),
2.75 (s, 6H), 2.15 (m, 2H), 1.78 (m, 2H), 1.72 (m, 2H), 1.53-1.65
(m, 3H), 1.44 (m, 3H), 1.32 (d, J ) 5.6 Hz, 2H), 1.20 (m, 2H),
1.10 (m, 1H), 0.95 (m, 2H). MS (ESI) m/z 736 (M - H)-.
N-[4-(4-Benzyl-4-methoxy-piperidin-1-yl)-benzoyl]-4-((R)-3-
dimethylamino-1-phenylsulfanylmethyl-propylamino)-3-nitro-
benzenesulfonamide, Trifluoroacetate Salt, (8e). 8e was prepared
from 7e using the procedure described for the preparation of 8a.
1H NMR (500 MHz, DMSO-d6) δ 11.97 (br s, 1H), 9.43 (br s,
1H), 8.55 (d, J ) 2.2 Hz, 1H), 8.29 (d, J ) 9.4 Hz, 1H), 7.87 (dd,
J ) 9.0, 2.2 Hz, 1H), 7.72 (d, J ) 9.0 Hz, 2H), 7.21-7.29 (m,
4H), 7.09-7.21 (m, 7H), 6.91 (d, J ) 9.0 Hz, 2H), 4.19 (m, 1H),
3.63 (m, 2H), 3.39 (d, J ) 6.2 Hz, 2H), 3.28 (s, 3H), 3.06-3.20
(m, 2H), 2.97-3.06 (m, 2H), 2.78 (s, 2H), 2.74 (s, 6H), 2.08-
2.19 (m, 2H), 1.68 (m, 2H), 1.41-1.53 (m, 2H). MS (ESI) m/z
730 (M - H)-. Anal. (C38H45N5O6S2 ‚1.4 CF3CO2H) C, H, N.
N-{4-[4-(2-Chloro-benzyl)-4-methoxy-piperidin-1-yl]-benzoyl}-
4-((R)-3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-
3-nitro-benzenesulfonamide, Trifluoroacetate Salt, (8f). 8f was
prepared from 7f using the procedure described for the preparation
of 8a. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (br s, 1H), 9.40 (br
s, 1H), 8.54 (d, J ) 2.4 Hz, 1H), 8.29 (d, J ) 9.0 Hz, 1H), 7.86
(dd, J ) 9.5, 2.1 Hz, 1H), 7.72 (d, J ) 9.1 Hz, 2H), 7.40 (m, 1H),
7.08-7.34 (m, 9H), 6.91 (d, J ) 9.1 Hz, 2H), 4.18 (m, 1H), 3.67
(m, 2H), 3.39 (m, 2H), 3.09-3.19 (m, 5H), 2.91-3.03 (m, 4H),
2.74 (m, 6H), 2.14 (m, 2H), 1.75 (m, 2H), 1.50 (m, 2H). MS (ESI)
m/z 764 (M - H)-. Anal. (C38H44ClN5O6S2 ‚2.0 CF3CO2H) C, H,
N.
N-{4-[4-(3-Chloro-benzyl)-4-methoxy-piperidin-1-yl]-benzoyl}-
4-((R)-3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-
3-nitro-benzenesulfonamide, Trifluoroacetate Salt, (8g). 8g was
prepared from 7g using the procedure described for the preparation
of 8a. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (br s, 1H), 9.33 (br
s, 1H), 8.53 (d, J ) 2.2 Hz, 1H), 8.29 (d, J ) 9.5 Hz, 1H), 7.86
(dd, J ) 9.2, 2.3 Hz, 1H), 7.72 (d, J ) 9.2 Hz, 2H), 7.09-7.32
(m, 10H), 6.91 (d, J ) 9.2 Hz, 2H), 4.18 (m, 1H), 3.64 (m, 2H),
3.39 (m, 2H), 3.07-3.20 (m, 5H), 3.01 (m, 4H), 2.79 (s, 2H), 2.74
(s, 6H), 2.13 (m, 2H), 1.65 (m, 2H), 1.47 (m, 2H). MS (ESI) m/z
764 (M - H)-. Anal. (C38H44ClN5O6S2 ‚1.5 CF3CO2H) C, H, N.
N-{4-[4-(4-Chloro-benzyl)-4-methoxy-piperidin-1-yl]-benzoyl}-
4-((R)-3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-
3-nitro-benzenesulfonami de, Trifluoroacetate Salt, (8h). 8h was
prepared from 7h using the procedure described for the preparation
of 8a. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (br s, 1H), 9.35 (br
s, 1H), 8.54 (d, J ) 2.0 Hz, 1H), 8.29 (d, J ) 9.5 Hz, 1H), 7.87
(dd, J ) 9.2, 2.4 Hz, 1H), 7.73 (d, J ) 9.1 Hz, 2H), 7.32 (m, 2H),
1
described for the preparation of 7a. H NMR (300 MHz, DMSO-
d6) δ 7.76 (d, J ) 9.1 Hz, 2H), 7.60 (m, 1H), 7.35 (m, 2H), 7.17
(m, 1H), 6.95 (d, J ) 9.1 Hz, 2H), 4.23 (q, J ) 7.1 Hz, 2H), 3.67
(m, 2H), 3.34 (s, 3H), 3.02 (s, 2H), 2.99 (m, 2H), 1.79 (m, 2H),
1.57 (m, 2H), 1.29 (t, J ) 7.1 Hz, 3H). MS (ESI) m/z 432 [M +
H]+.
4-(4-Biphenyl-2ylmethyl-4-methoxy-piperidin-1-yl]-benzoic Acid
Ethyl Ester (7m). 7m was prepared from 6m using the procedure
1
described for the preparation of 7a. H NMR (300 MHz, DMSO-
d6) δ 7.69 (d, J ) 9.2 Hz, 2H), 7.25-7.45 (m, 8H), 7.15 (m, 1H),
6.83 (d, J ) 9.1 Hz, 2H), 4.21 (q, J ) 7.1 Hz, 2H), 3.38 (m, 2H),
3.04 (s, 3H), 2.90 (s, 2H), 2.85 (m, 2H), 1.48 (m, 2H), 1.27 (t, J )
7.0 Hz, 3H), 1.20 (m, 2H). MS (ESI) m/z 430 [M + H]+.
4-(4-Biphenyl-4ylmethyl-4-methoxy-piperidin-1-yl]-benzoic Acid
Ethyl Ester (7n). 7n was prepared from 6n using the procedure
1
described for the preparation of 7a. H NMR (500 MHz, DMSO-
d6) δ 7.73 (d, J ) 9.1 Hz, 2H), 7.63 (m, 2H), 7.55 (d, J ) 8.2 Hz,
2H), 7.43 (m, 2H), 7.33 (m, 1H), 7.26 (d, J ) 8.5 Hz, 2H), 6.93
(d, J ) 8.8 Hz, 2H), 4.22 (q, J ) 7.0 Hz, 2H), 3.63 (m, 2H), 3.03
(m, 2H), 2.83 (s, 2H), 1.73 (m, 2H), 1.55 (m, 2H), 1.28 (t, J ) 7.1
Hz, 3H). MS (ESI) m/z 430 [M + H]+.
4-((R)-3-Dimethylamino-1-phenylsulfanylmethyl-propylamino)-
N-[4-(4-isobutyl-4-methoxy-piperidin-1-yl)-benzoyl]-3-nitroben-
zenesulfonamide, Trifluoroacetate Salt, (8a). A solution of 7a
(190 mg, 0.59 mmol) and LiOH (43 mg, 1.8 mmol) in 1:1:1 H2O/
MeOH/THF (15 mL) was heated at 50 °C overnight. After removal
of the volatiles in vacuo, the residue was acidified with 1 M
NaHSO4 solution (5 mL) and extracted with EtOAc. The organic
layer was dried over MgSO4 and concentrated to yield 170 mg
(98%) of the intermediate acid that was used without further
purification.
A solution of the above intermediate acid (47 mg, 0.16 mmol),
EDCI (70 mg, 0.36 mmol), DMAP (44 mg, 0.36 mmol), and 4 (74
mg, 0.17 mmol) in CH2Cl2 (2 mL) was stirred for 12 h and the
mixture partitioned between water and CH2Cl2. The organic phase
was washed twice with saturated aqueous NH4Cl and dried over
MgSO4. After concentration, the residue was purified by reversed
1
phase HPLC to yield 64 mg (56%) of 8a. H NMR (500 MHz,
DMSO-d6) δ 11.98 (br s, 1H), 9.40 (br s, 1H), 8.54 (d, J ) 2.3 Hz,
1H), 8.27 (d, J ) 9.3 Hz, 1H), 7.87 (dd, J ) 9.4, 2.0 Hz, 1H), 7.73
(d, J ) 9.0 Hz, 2H), 7.23 (m, 2H), 7.09-7.19 (m, 4H), 6.92 (d, J
) 9.1 Hz, 2H), 4.19 (m, 1H), 3.60 (m, 2H), 3.38 (m, 2H), 3.02-
3.18 (m, 7H), 2.75 (s, 6H), 2.14 (m, 2H), 1.78 (m, 2H), 1.73 (m,
1H), 1.45 (m, 2H), 1.34 (d, J ) 6.0 Hz, 2H), 0.91 (d, J ) 6.6 Hz,
6H). MS (ESI) m/z 696 [M - H]-. Anal. (C35H47N5O6S2‚
1.5CF3CO2H‚H2O) C, H, N.
4-((R)-3-Dimethylamino-1-phenylsulfanylmethyl-propylamino)-
N-{4-[4-(2,2-dimethyl-propyl)-4-methoxy-piperidin-1-yl]-benzoyl}-
3-nitro-benzenesulfonamide, Trifluoroacetate Salt, (8b). 8b was
prepared from 7b using the procedure described for the preparation
of 8a. 1H NMR (500 MHz, DMSO-d6) δ 11.95 (br s, 1H), 9.48 (br
s, 1H), 8.54 (d, J ) 2.2 Hz, 1H), 8.28 (d, J ) 9.4 Hz, 1H), 7.86
(dd, J ) 9.2, 2.0 Hz, 1H), 7.73 (d, J ) 9.0 Hz, 2H), 7.23 (m, 2H),