1396 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Lee et al.
washed with water (2 × 5 mL) and brine (2 × 5 mL), dried, and
evaporated to afford a yellow oil which was purified via column
chromatography (5% EtOAc-hexanes) to afford sulfonamide 56
(0.020 g, 17% yield), a colorless oil. 1H NMR (300 MHz, CDCl3)
δ 1.18-1.33 (m, 2 H), 2.37-2.61 (m, 4 H), 2.87 (t, J ) 6.9 Hz, 2
H), 3.70 (s, 3 H), 3.77 (s, 2 H), 3.94 (t, J ) 7.1 Hz, 2 H), 6.31 (d,
J ) 8.8 Hz, 1 H), 6.52 (s, 1 H), 6.57-6.71 (m, 3 H), 6.77-6.89
(m, 4 H), 6.94-7.00 (m, 1 H), 7.01-7.14 (m, 10 H), 7.31 (d, J )
1.9 Hz, 1 H), 7.76 (d, J ) 8.8 Hz, 2 H).
4-{2-[5-Chloro-2-(2-{[(4-chlorobenzyl)sulfonyl]amino}ethyl)-
1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoic Acid (119).
The sulfonamide ester was prepared from methyl 4-{2-[2-(2-
aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-
benzoate amine 32b (100 mg, 0.19 mmol) and [(4-chloromethyl)-
phenyl]methanesulfonyl chloride (52 mg, 0.23 mmol) according
to the Schotten-Baumann general procedure and purified using
flash chromatography (20 f 40% EtOAc-hexanes) to afford the
sulfonamide methyl ester (98 mg, 73% yield) as a white foam. 1H
NMR (300 MHz, CDCl3) δ 2.86 (q, J ) 6.9 Hz, 2 H), 3.07 (t, J )
7.4 Hz, 2 H), 3.18 (t, J ) 6.5 Hz, 2 H), 3.87 (s, 3 H), 3.98 (s, 2 H),
4.17-4.36 (m, 3 H), 6.52 (d, J ) 8.8 Hz, 2 H), 6.83 (appar d, J )
8.5 Hz, 3 H), 6.89 (s, 1 H), 7.00-7.13 (m, 6 H), 7.17-7.25 (m, 2
H), 7.28-7.39 (m, 5 H), 7.54 (d, J ) 1.6 Hz, 1 H), 7.95 (d, J )
8.8 Hz, 2 H).
4-{2-[2-{3-[(Benzylsulfonyl)amino]propyl}-5-chloro-1-(diphe-
nylmethyl)-1H -indol-3-yl]ethoxy}benzoic Acid (57). Hydrolysis
of methyl ester 56 (0.020 g, 0.02 mmol) using the general procedure
1
afforded carboxylic acid 57 (0.013 g, 80%). H NMR (300 MHz,
CDCl3) δ 1.27-1.48 (m, 2 H), 2.58-2.80 (m, 4 H), 3.00 (t, J )
6.7 Hz, 2 H), 3.98-4.14 (m, 5 H), 6.35 (d, J ) 8.8 Hz, 1 H),
6.56-6.74 (m, 4 H), 6.83-6.96 (m, 4 H), 7.05-7.20 (m, 11 H),
7.35 (d, J ) 1.9 Hz, 1 H), 7.81 (d, J ) 8.8 Hz, 2 H).
The ester from above (98 mg, 0.13 mmol) was hydrolyzed
according to the general procedure to afford the title acid (95 mg,
1
99% yield) as a white foam. H NMR (300 MHz, DMSO-d6) δ
Methyl 4-{2-[2-[3-(Benzylthio)propyl]-5-chloro-1-(diphenyl-
methyl)-1H-indol-3-yl]etho xy}benzoate (58). A solution of benzyl
mercaptan (0.211 g, 1.7 mmol) in DMF (1 mL) was added to a
suspension of NaH (0.074 g, 60% in mineral oil, 1.9 mmol) in
DMF (1 mL). After 30 min a solution of bromide 55 (0.260 g,
0.40 mmol) in DMF (0.5 mL) was added. After 1 h the mixture
was quenched with H2O and extracted with EtOAc (10 mL).
The organic layer was washed with water (2 × 5 mL) and brine (2
× 5 mL), dried, and concentrated. Column chromatography (5%
EtOAc-hexanes) afforded thioether 58 (0.160 g, 57%), a colorless
3.02 (br s, 4 H), 3.12-3.25 (m, 2 H), 4.22 (t, J ) 7.1 Hz, 2 H),
4.28 (s, 2 H), 6.46 (d, J ) 9.1 Hz, 1 H), 6.80 (dd, J ) 8.9, 2.1 Hz,
1 H), 6.99 (d, J ) 8.8 Hz, 2 H), 7.03-7.15 (m, 5 H), 7.17-7.50
(m, 11 H), 7.67 (d, J ) 1.9 Hz, 1 H), 7.86 (d, J ) 8.5 Hz, 2 H).
HRMS calcd for [C39H34Cl2N2O5S + H] 713.1638 found 713.1643.
4-{2-[5-Chloro-2-(2-{[(2,3-dichlorobenzyl)sulfonyl]amino}-
ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoic Acid
(120). To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-
1H-indol-3-yl]ethoxy}benzoate amine 32b (215 mg, 0.4 mmol) was
added (2,3-dichlorophenyl)methanesulfonyl chloride (0.51 g, 2.0
mmol) according to the Schotten-Baumann procedure to generate
the sulfonamide methyl ester (154 mg, 50% yield) as a white foam.
1H NMR (300 MHz, CDCl3) δ 2.93 (d, J ) 8.0 Hz, 2 H), 3.03-
3.13 (m, 2 H), 3.18 (t, J ) 6.6 Hz, 2 H), 3.86 (s, 3 H), 4.20 (t,
J ) 6.6 Hz, 2 H), 4.33 (s, 2 H), 4.39 (s, 1 H), 6.52 (d, J ) 9.1 Hz,
1 H), 6.77-6.86 (m, 3 H), 6.91 (s, 1 H), 7.03-7.11 (m, 4 H), 7.27-
7.35 (m, 8 H), 7.40 (dd, J ) 8.0, 1.4 Hz, 1 H), 7.53 (d, J ) 1.9 Hz,
1 H), 7.94 (d, J ) 8.8 Hz, 2 H).
1
oil. H NMR (300 MHz, CDCl3) δ 1.49-1.66 (m, 2 H), 2.23 (t,
J ) 6.9 Hz, 2 H), 2.69 (dd, J ) 9.2, 6.7 Hz, 2 H), 3.02 (t, J ) 7.1
Hz, 2 H), 3.40 (s, 2 H), 3.71 (s, 3 H), 4.00 (t, J ) 7.1 Hz, 2 H),
6.30 (d, J ) 8.8 Hz, 1 H), 6.61 (dd, J ) 8.9, 2.1 Hz, 1 H), 6.70 (d,
J ) 8.8 Hz, 3 H), 6.91 (dd, J ) 5.6, 3.7 Hz, 4 H), 6.96-7.07 (m,
5 H), 7.10-7.18 (m, 6 H), 7.34 (d, J ) 2.2 Hz, 1 H), 7.74-7.84
(m, 2 H).
4-{2-[2-[3-(Benzylsulfonyl)propyl]-5-chloro-1-(diphenylmethyl)-
1H-indol-3-yl]ethoxy}benzoic Acid (59). To a solution of thioether
58 (0.075 g, 0.10 mmol) in CH2Cl2 (1 mL) was added 55% MCPBA
(0.075 g, 0.20 mmol). After 2 h the reaction mixture was diluted
with EtOAc (25 mL) and washed with sat. NaHCO3 and brine,
dried, and evaporated. Flash chromatography (15% EtOAc-
hexanes) afforded the sulfone (0.052 g, 66%), a yellow oil.
Hydrolysis of the sulfone methyl ester (0.060 g, 0.10 mmol) using
the general procedure afforded the carboxylic acid 59 (0.049 g,
85%). 1H NMR (300 MHz, DMSO-d6) δ 1.58-1.78 (m, 2 H), 2.81
(dd, J ) 8.9, 6.5 Hz, 2 H), 2.88-3.05 (m, 4 H), 4.03 (t, J ) 6.5
Hz, 2 H), 4.15 (s, 2 H), 6.35-6.41 (m, 1 H), 6.63 (dd, J ) 6.7, 2.1
Hz, 1 H), 6.79 (d, J ) 8.8 Hz, 1 H), 6.89 (d, J ) 6.0 Hz, 4 H),
7.00 (d, J ) 6.6 Hz, 4 H), 7.09-7.29 (m, 9 H), 7.47 (d, J ) 1.9
Hz, 1 H), 7.65 (d, J ) 8.8 Hz, 2 H).
4-{2-[5-Chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-
1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoic Acid (118). To
the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-
3-yl]ethoxy}benzoate amine 32b (215 mg, 0.4 mmol) was added
(2-chlorophenyl)methanesulfonyl chloride (0.45 g, 2.0 mmol) using
the Schotten-Baumann general procedure to generate the sulfona-
mide methyl ester (250 mg, 86% yield) as a white foam. 1H NMR
(300 MHz, CDCl3) δ 2.88-2.97 (m, 2 H), 3.01-3.11 (m, 2 H),
3.18 (t, J ) 6.5 Hz, 2 H), 3.88 (s, 3 H), 4.19 (t, J ) 6.5 Hz, 1 H),
4.26 (t, J ) 6.0 Hz, 1 H), 4.34 (s, 2 H), 6.50 (t, J ) 8.8 Hz, 1 H),
6.78-6.93 (m, 4 H), 7.02-7.12 (m, 4 H), 7.14-7.28 (m, 2 H,)
7.28-7.36 (m, 7 H), 7.41 (d, J ) 7.1 Hz, 1 H), 7.53 (d, J ) 1.6
Hz, 1 H), 7.95 (d, J ) 8.0 Hz, 2 H).
The ester from above (154 mg, 0.2 mmol) was hydrolyzed by
stirring with KOH (67 mg, 1.0 mmol) in THF (5 mL), MeOH (5
mL), and H2O (2 mL). The reaction mixture was monitored by
TLC (10% MeOH-CH2Cl2) for the disappearance of starting
material. The mixture was stirred overnight at room temperature
and then concentrated, diluted with H2O, and acidified to pH 2-4
using 1 M HCl. The aqueous phase was extracted with EtOAc,
and the organic phase was washed with brine, dried over Na2SO4,
and concentrated to afford the desired product 120 (134 mg, 98%
yield). 1H NMR (300 MHz, CDCl3) δ 2.88-3.00 (m, 2 H,) 3.04-
3.15 (m, 2 H), 3.19 (t, J ) 6.3 Hz, 2 H), 4.22 (t, J ) 6.6 Hz, 2 H),
4.34 (s, 2 H), 4.52 (t, J ) 6.2 Hz, 1 H), 6.52 (d, J ) 8.8 Hz, 1 H),
6.78-6.94 (m, 4 H), 7.03-7.21 (m, 5 H), 7.31 (d, 7 H), 7.39 (dd,
J ) 8.1, 1.5 Hz, 1 H), 7.53 (d, J ) 1.9 Hz, 1 H), 7.98 (d, J ) 8.8
Hz, 2 H). HRMS calcd for [C39H33Cl3N2O5S + H] 747.1249 found
747.1254.
4-{2-[5-Chloro-2-(2-{[(2,4-dichlorobenzyl)sulfonyl]amino}-
ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoic Acid
(121). To methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-
1H-indol-3-yl]ethoxy}benzoate amine 32b (215 mg, 0.4 mmol) was
added (2,4-dichlorophenyl)methanesulfonyl chloride (0.51 g, 2.0
mmol) according to the general Schotten-Baumann procedure to
generate sulfonamide methyl ester (323 mg, 98% yield). 1H NMR
(300 MHz, CDCl3) δ 2.93 (d, J ) 7.7 Hz, 2 H), 3.04-3.14 (m, 2
H), 3.19 (t, J ) 6.5 Hz, 2 H), 3.88 (s, 3 H), 4.21 (t, J ) 6.5 Hz, 3
H), 4.27 (s, 2 H), 6.79-6.88 (m, 3 H), 6.91 (s, 1 H), 7.03-7.11
(m, 4 H), 7.17 (dd, J ) 8.2, 2.2 Hz, 1 H), 7.28-7.38 (m, 8 H),
7.53 (d, J ) 1.9 Hz, 1 H), 7.95 (d, J ) 8.8 Hz, 2 H).
The ester from above (250 mg, 0.3 mmol) was hydrolyzed
according to the general procedure to afford 118 (237 mg, 90%
1
yield) as a yellow foam. H NMR (300 MHz, CDCl3) δ 2.95 (d,
The ester from above (323 mg, 0.42 mmol) was hydrolyzed
according to the general procedure to afford 121 (302 mg, 90%
yield) as a white foam. 1H NMR (300 MHz, CDCl3) δ 2.88-3.01
(m, 2 H), 3.05-3.16 (m, 2 H), 3.20 (t, J ) 6.6 Hz, 2 H), 4.23 (t,
J ) 6.5 Hz, 3 H), 4.27 (s, 2 H), 4.54 (s, 1 H), 6.52 (d, J ) 8.8 Hz,
1 H), 6.78-6.94 (m, 4 H), 7.02-7.11 (m, 4 H), 7.16 (dd, J ) 8.4,
2.1 Hz, 1 H), 7.28-7.37 (m, 8 H), 7.53 (d, J ) 2.2 Hz, 1 H), 7.99
J ) 14.0 Hz, 2 H), 3.02-3.13 (m, 2 H), 3.19 (t, J ) 6.5 Hz, 2 H),
4.21 (t, J ) 6.5 Hz, 2 H), 4.34 (s, 2 H), 4.48 (t, J ) 5.9 Hz, 1 H),
6.50 (d, J ) 8.8 Hz, 1 H), 6.78-6.94 (m, 4 H), 7.03-7.12 (m, 4
H), 7.14-7.25 (m, 2 H), 7.28-7.35 (m, 7 H), 7.41 (dd, J ) 7.4,
1.9 Hz, 1 H), 7.53 (d, J ) 2.2 Hz, 1 H), 8.00 (d, J ) 8.8 Hz, 2 H);
HRMS calcd for [C39H34Cl2N2O5S + H] 713.1638 found 713.1644.