Discovery of 2-phenyl-3-sulfonylphenyl-indole derivatives as a new class of selective COX-2 inhibitors

Article abstract of DOI:10.1016/j.bmc.2003.09.008

2-Sulfonylphenyl-3-phenyl-indole derivatives have been reported to be highly potent and selective COX-2 inhibitors previously. In this paper, the regio-isomeric analogues-2-phenyl-3-sulfonylphenyl-indoles were identified as potent and selective COX-2 inhi

Full text of DOI:10.1016/j.bmc.2003.09.008

Bioorganic & Medicinal Chemistry 11 (2003) 5539–5544
Discovery of 2-Phenyl-3-sulfonylphenyl-indole Derivatives as a
New Class of Selective COX-2 Inhibitors
Wenhui Hu,a Zongru Guo,a,* Xiang Yi,a Changbin Guo,a Fengming Chua
and Guifang Chengb
aDepartment of Synthetic Medicinal Chemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing 100050, PR China
bDepartment of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing 100050, PR China
Received 9 May 2003; revised 29 August 2003; accepted 4 September 2003
Abstract—2-Sulfonylphenyl-3-phenyl-indole derivatives have been reported to be highly potent and selective COX-2 inhibitors
previously. In this paper, the regio-isomeric analogues-2-phenyl-3-sulfonylphenyl-indoles were identified as potent and selective
COX-2 inhibitors. This work led to the discovery of compounds 4a and 8a possessing higher activity than Celecoxib on cellular
assay.
# 2003Elsevier Ltd. All rights reserved.
Introduction
selective COX-2 inhibitors33,34 are sulfonanilide
inhibitors,35ꢀ37 and modifications of classical
NSAIDs.38ꢀ41 The pharmacophore of diarylheterocycles
inhibitors is characterized by a central carbocyclic or
heterocyclic ring system bearing two vicinal aryl moieties
and one benzene ring being substituted with a methyl-
sulfonyl or aminosulfonyl group at the para position.
The regio-isomeric analogues deriving from the altera-
tion of the position of sulfonylphenyl group on the
central ring exhibited different activity for COX-2, for
instance, the lactone I (IC50=0.01 mM) have significant
inhibitory activity for COX-2 whereas its isomeric ana-
logue II was found to be essentially inactive against the
same enzyme on cellular assay.7 Previously,42 we have
reported 2-sulfonylphenyl-3-phenyl-indole derivatives
(III) to be highly potent and selective COX-2 inhibitors.
We herein synthesized and evaluated the regio-isomeric
analogues (IV)—2-phenyl-3-sulfonylphenyl-indole deri-
vatives as a new class of selective COX-2 inhibitors.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
remain among the most widely prescribed drugs world-
wide for the treatment of inflammation including pain-
releasing, anti-pyretic and rheumatoild arthritis. The
mechanism of action was through their inhibition of
prostaglandin biosynthesis via the enzyme cyclooxygen-
ase-2 (COX-2).1 COX-2 and COX-1 are two similar but
distinct isoforms of cyclooxygenase (COX).2ꢀ5 COX-2 is
induced upon inflammatory stimuli and is responsible
for progression of inflammation, whereas COX-1 is a
constitutively expressed isoform and is responsible for
the maintenance of physiological homestasis, such as
gastrointestinal integrity and renal function. Thus
selective inhibition of COX-2 over COX-1 is useful for
the treatment of inflammation and inflammation-asso-
ciated disorders with reduced gastrointestinal toxicities
when compared with the traditional NSAIDs.
Current research has focused on developing safer
NSAIDs- selective COX-2 inhibitors. Several selective
COX-2 inhibitors such as Celecoxib,6 Rofecoxib7,8 and
Valdecoxib9 have been marketed as a new generation of
NSAIDs, structurally featuring with vicinal diarylhe-
terocycles inhibitors.10ꢀ32 The other two categories of
*Corresponding author. Tel.: +86-10-631-65249; fax: +86-10-831-
55752; e-mail: zrguo@imm.ac.cn
0968-0896/$ - see front matter # 2003Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.09.008

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W. Hu et al. / Bioorg. Med. Chem. 11 (2003) 5539–5544
Chemistry
All the target compounds were identified by spectro-
scopic data and confirmed by elemental analyses.
All the compounds 4 and 8 described herein were syn-
thesized by using the general routes outlined in Scheme
1 and 2. In method A (outlined in Scheme 1), McMurry
coupling reaction43ꢀ45 was employed in the key step of
the route to construct an indole skeleton. The commer-
cially available starting material 1 was taken Friedel–
Crafts reaction with 4-methylsulfonyl or 4-aminosulfo-
nyl benzoyl chloride, and then hydrolyzed by con-
centrated H2SO4 to give the substituted 2-amino-
benzophenone 2, which was then acylated with sub-
stituted benzoyl chloride to provide compound 3. The
intermediate 3 was cyclized to form the final compound
4 by the McMurry condensation.
Results and Discussion
For the ease of synthesis compounds 4 were prepared as
5-chloro-indole derivatives, except for 4i with 5-methyl
substitution. Compound 8 were prepared as both the
methyl sulfone 8a and the sulfonamide 8b. All the com-
pounds synthesized in this work were evaluated for their
ability to inhibit COX-2 and COX-1 by cellular assay
using freshly harvested mouse peritoneal macrophages
as described in the literature.46 The details of these
assays were described in the Experimental. The IC50
values for COX-1 inhibition by the compounds were not
able to determine due to the low inhibitory activity at
the concentration of 10 mM of the tested compounds.
The results reported in Table 1 showed that all the
compounds exhibited high inhibition against COX-2
compared to the inhibition for COX-1 (IC50>10 mM).
Compounds 4a (IC50=0.27 nM) and 8b (IC50=0.22
nM) were found to be more potent and selective than
Celecoxib (IC50=0.52 nM) against COX-2.
Method A:
The sulfonylphenyl group is necessary for the diaryl-
heterocycles inhibitors to exert selective inhibition
against COX-2. When the indole ring possesses two
methylsulfonylphenyl groups such as compounds 4h
and 4i, there were two possible binding modes:
2-methylsulfonylphenyl or 3-methylsulfonylphenyl
binding to the hydrogen bond pocket. Though it was
uncertain of the binding mode methylsulfonyl group was
identified as a poor group to enter into the nonselective
pocket by the activity of 4h (IC50=1.48 nM) and 4i
(IC50=3.57 nM) which were less than that of Celecoxib.
The sulfonamide 8a (IC50=0.22 nM) is more active than
the corresponding methylsulfone 8b (IC50=2.55 nM).
Scheme 1. Reagent: (a) (i) R2C6H4COCl, ZnCl2, 205 ꢁC; (ii) H2SO4,
120 ꢁC; (b) 4-R1SO2C6H4COCl, THF, Et3N, rt; (c) Zn, TiCl4, THF,
reflux.
Fischer indole synthesis method was carried out in
method B (outlined in Scheme 2). 4-Methyl(amino)-
sulfonyl- phenylacetyl chloride 5 was taken Friedel–
Crafts reaction with substituted benzene to give rise to
the corresponding substituted phenylacetophenone 6,
which was condensed with substituted phenylhydrazine
to give arylhydrazone 7. Finally the arylhydrazone 7
was cyclized to the target compound 8 in the presence of
acetic acid and BF3.
The comparison between the regio-isomeric analogues
showed that compound 8a (IC50=0.22 nM) is 2 times
more active than its regio-isomer 2-methylsulfonylphe-
nyl-3-phenyl-indole42 (IC50=0.60 nM), whereas 8b
(IC50=2.55 nM) is about 25 times less potent than its
Table 1. In vitroa inhibitory results
IC50 (nM)b COX-2 IC50 (mM)b COX-1
Method B:
No.
Structure
R2
R1
R3
4a
4b
4c
4d
4e
H
2-F
4-Cl
4-CH3
CH3 5-Cl
CH3 5-Cl
CH3 5-Cl
CH3 5-Cl
0.27
1.76
3.54
1.68
2.81
7.16
6.0
1.48
3.57
0.22
2.55
0.52
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
4-OCH3 CH3 5-Cl
4f 2-OCOCH3 CH3 5-Cl
4g 4-OCOCH3 CH3 5-Cl
4h 4-SO2CH3 CH3 5-Cl
4i
8a
4-SO2CH3 CH3 5-CH3
H
H
CH3
NH2
H
H
8b
Celecoxib
aCell level. For details, see Experimental.
bAll IC50 determinations including Celecoxib were carried out in trip-
licate and have less than 10% error.
Scheme
R3C6H4NHNH2 HCl, 130 C; (c) BF3 Et2O, AcOH, reflux.
2. Reagent: ꢁ(a)
AlCl3,
.
C6H5R1,
80 ꢁC;
(b)
.

W. Hu et al. / Bioorg. Med. Chem. 11 (2003) 5539–5544
5541
isomeric one 2-aminosulfonylphenyl-3-phenyl-indole42
(IC50=0.09 nM). The influence of the regio-isomeric
analogues for methylsulfone compounds on the inhibi-
tive activity is different from those for sulfonamide ser-
ies. However, compound 4a (IC50=0.27 nM) was found
to be comparable to its isomeric compound 2-methyl-
sulfonylphenyl-3-phenyl-5-chloro-indole (IC50=0.36
nM). It seems that no correlation between the regio-
isomers and the inhibitory activity exists because of the
limit of the sample number.
Cs, Ct, Cc refer to 6-keto-PGF1a concentration in
supernatants of calcimycin, test compound, and control
groups, respectively.
COX-2 assay
Macrophages were incubated with test compound at
different concentrations or solvent (Me2SO) for 1 h and
were stimulated with LPS 1 mg/L for 9 h. The amount
of PGE2 in supernatants was measured by RIA. The
inhibitory ratio was calculated using the same formula
as in COX-1 assay section. Cs, Ct, Cc refer to PGE2
concentration in supernatants of LPS, test compound,
and control groups, respectively.
Conclusions
The series of 2-phenyl-3-sulfonylphenyl-indole deriva-
tives described in this paper were proved to be potent
and selective inhibitors of COX-2. The indole ring was
proved to be an effective scaffold that derived two clas-
ses of COX-2 inhibitors. This work led to the discovery
of compounds 4a and 8a possessing higher activity than
Celecoxib on cellular assay.
Statistical analysis data were expressed as the
meanꢄSD of more than three independent experiments.
Dose–inhibitory effect curves were fit through ‘uphill
dose response curves, variable slope’ using Prism,
GraphPad version 3.00:
1
Y ¼
½ðlogIC50ÀXÞÂHillslopeꢀ
1 þ 10
Experimental
Biological methods
Chemistry
In vitro test of inhibitory activity for cyclooxygenase-1
and cyclooxygenase-2.
All solvents were used dried and freshly distilled. Melt-
ing points were determined using Yanaco melting point
apparatus and are uncorrected. 1H NMR were recorded
on a Bruker AM-300 (300 MHz) spectrometer. Ele-
mental analyses were performed at analytical division of
Institute of Material Medica and were within 0.4% of
the calculated values.
Cell culture
Adherent macrophages were harvested from the perito-
neal cells of male mice (C57BL-6J, Level 2, from
Experiment Animal Center, Academy of Military Med-
ical Science) after the injection (ip) of brewer thiogly-
collate medium (5 mL/100 g body weight) for 3days.
Shortly, peritoneal cells obtained from 3ꢂ4 mice were
mixed and seeded in 48 well cell culture cluster (Costar)
at a cell density of 1ꢃ109 cell/L in RPMI-1640 supple-
mented with 5% (v/v) newborn calf serum, 100 ku/L
penicillin and 100 g/L streptomycin. After settlement for
2ꢂ3h, non-adherent cells were washed by D-Hanks’
balanced salt solution. Then macrophages were cultured
in RPMI-1640 without serum. Almost all of adherent
cells were macrophages as assessed by Giemsa staining.
Cell viability was examined by trypan blue dye exclu-
sion. All incubation procedures were performed with
5% CO2 in humidified air at 37 ꢁC.
Method A
The general procedure for the preparation of sub-
stituted 2-phenyl-3-sulfonylphenyl-indoles (4a–4i) is
illustrated below in the synthesis of 2-phenyl-3-(4-
methylsulfonylphenyl)-5-chloro-indole (4a).
2 - Phenyl - 3 - (4 - methylsulfonylphenyl) - 5 - chloro - indole
(4a). Step 1: 2-amino-5-chloro-40-methylsulfonylbenzo-
phenone (2). A mixture of 20.0 g (0.1 mol) of p-methyl-
sulfonylbenzoic acid and 20 mL of thionyl chloride was
heated under reflux to give a clear solution. Removal of
the excess of thionyl chloride under reduced pressure
obtained white solid and immediately used for the next
reaction. To the p-methylsulfonylbenzoyl chloride at
140 ꢁC was added in portions with stirring 5.1 g (0.04
mol) of 4-chloroaniline. The mixture was heated to
180 ꢁC and 6.8 g (0.05 mol) of ZnCl2 was added. The
temperature was gradually increased to about 205 ꢁC
and kept for 2 h. After cooling to 120 ꢁC, 60 mL of 3N
HCl was added and the mixture stirred and heated
under reflux. The hot acid layer was decanted and this
procedure repeated three times. The water-insoluble
residue was dissolved in 80 mL of 70% sulfuric acid and
refluxed for 8 h, after cooling poured into a large
amount of ice water. The reaction mixture was neu-
tralized with aqueous ammonia and extracted with ethyl
acetate, dried over Na2SO4. The solvent was removed
COX-1 assay
Macrophages were incubated with test compound at
different concentrations or solvent (Me2SO) for 1 h and
were stimulated with calcimycin 1 mmol Lꢀ1 for 1 h. The
amount of 6-keto-PGF1a (a stable metabolite of PGI2) in
supernatants was measured by RIA according to manu-
facturer’s guide. The inhibitory ratio was calculated as
À
Á
Cs À Ct
IR ¼
ðCs À CcÞ

5542
W. Hu et al. / Bioorg. Med. Chem. 11 (2003) 5539–5544
and the residue was crystallized from 95% ethanol to
give the title compound 5.1 g as yellow needle crystals,
yield 40.9%, mp 176–177 ꢁC.
CH3), 6.97–7.92 (m, 11H, Ar–H), 11.87 (s, 1H, N–H).
Anal. calcd for: C22H18NO3SCl: C 64.15, H 4.40, N
3.40; Found: C 63.93, H 4.40, N 3.13.
Step 2: 2-N-(benzoyl)-amido-5-chloro-40-methylsulfo-
nyl-benzophenone (3a). To a solution of 3.1g, 0.010 mol
of 2-amino-40-methylsulfonylbenzophenone 2, 1.6 mL
0.011 mol of triethylamine in 20 mL of dry THF under
nitrogen was added a solution of 1.4 g (0.010 mol) of
benzoyl chloride in 10 mL of dry THF. The reaction
mixture was stirred at room temperature for 2 h, and
filtered. The filtrate was concentrated and the residue
was purified by column chromatograph on silica gel
(eluant: petroleum ether/ethyl acetate, 3/1) to give the
title compound 3.0 g as light yellow needle crystals,
yield 74.8%, mp 203–205 ꢁC.
2 - (2 - Acetyloxyphenyl) - 3 - (4 - methylsulfonylphenyl) - 5 -
chloro-indole (4f). The title compound was obtained as
white crystals, yield 67.0%, mp 238–240 ꢁC; H NMR
1
(300 MHz, DMSO) d 1.85 (s, 3H, CH3), 3.20 (s, 3H,
SO2CH3), 7.19–7.86 (m, 11H, Ar–H), 11.93(s, 1H, N–
H). Anal. calcd for: C23H18NO4SCl: C 62.80, H 4.12, N
3.18; Found: C 62.56, H 4.31, N 2.82.
2 - (4 - Acetyloxyphenyl) - 3 - (4 - methylsulfonylphenyl) - 5 -
chloro-indole (4g). The title compound was obtained as
white crystals, yield 70.0%, mp 248–250 ꢁC; H NMR
1
(300 MHz, DMSO) d 2.28 (s, 3H, CH3), 3.26 (s, 3H,
SO2CH3), 7.19–7.95(m, 11H, Ar–H), 12.02 (s, 1H, N–
H). Anal. calcd for: C23H18NO4SCl: C 62.80, H 4.12, N
3.18; Found: C 62.83, H 4.08, N 2.96.
Step 3: 2-phenyl-3-(4-methylsulfonylphenyl)-5-chloro-
indole (4a). To a suspension of 1.14 g (3mmol) of 2- N-
(benzoyl)-amido-5-chloro-40-methylsulfonyl-benzophe-
none (3a) and 0.87 g (12 mmol) of 90% Zn in 20 mL dry
THF was added dropwise 0.7 mL (6.2 mmol) of TiCl4
and heated under reflux for 1.5 h. The solvent was
removed and the residue was purified by silica gel col-
umn chromatography using petroleum ether/ethyl ace-
tate (3/1) as eluant. The title compound (0.45 g) was
obtained as white crystals, yield 54.2%, mp 273–275 ꢁC;
1H NMR (300 MHz, DMSO) d 3.25 (s, 3H, SO2CH3),
7.20–7.94 (m, 12H, Ar–H), 12.05 (s, 1H, N–H). Anal.
calcd for: C21H16NO2SCl: C 66.05, H 4.22, N 3.67;
Found: C 65.98, H 4.47, N 3.75.
2-(4-Methylsulfonylphenyl)-3-(4-methylsulfonylphenyl)-5-
chloro-indole (4h). The title compound was obtained as
ꢁ
1
white crystals, yield 46.8%, mp 173–175 C; H NMR
(300 MHz, DMSO) d 3.25 (s, 3H, SO2CH3), 3.27 (s, 3H,
SO2CH3), 7.23–7.96 (m, 11H, Ar–H), 12.16 (s, 1H, N–
H). Anal. calcd for: C22H18NO4S2Cl: C 57.45, H 3.94, N
3.05; Found: C 57.74, H 4.30, N 3.10.
2-(4-Methylsulfonylphenyl)-3-(4-methylsulfonylphenyl)-5-
methyl-indole (4i). The title compound was obtained as
light yellow crystals, yield 43.5%, mp 299–301 ꢁC; H
1
NMR (300 MHz, DMSO) d 2.37 (s, 3H, CH3), 3.25 (s,
3H, SO2CH3), 3.26 (s, 3H, SO2CH3), 7.05–7.96 (m, 11H,
Ar–H), 11.83(s, 1H, N–H). Anal. calcd for:
C23H21NO4S2: C 62.85, H 4.82, N 3.19; Found: C 62.88,
H 4.98, N 2.83.
The following compounds (4b–4i) were prepared
according to the general procedure described above.
2-(2-Fluorophenyl)-3-(4-methylsulfonylphenyl)-5-chloro-
indole (4b). The title compound was obtained as white
crystals, yield 60.0%, mp 246–248 ꢁC; 1H NMR
(300 MHz, DMSO) d 3.21 (s, 3H, SO2CH3), 7.21–7.88
(m, 11H, Ar–H), 12.04( s, 1H, N–H). Anal. calcd for:
C21H15FNO2SCl: C 63.07, H 3.78, N 3.50; Found: C
63.30, H 3.93, N 3.27.
Method B
2-phenyl-3-(4-methylsulfonylphenyl)-indole (8a). Step 1:
4-methylsulfonylphenylacetonphenone (6a). A mixture of
5.0 g (0.023mol) of 4-methylsulfonylphenyl-acetic acid
and 10 mL of thionyl chloride was heated under reflux
to give a clear solution. Removal of the excess of thionyl
chloride under reduced pressure to give a light yellow
solid and without purification put into the next reaction.
To the solution of the solid obtained above in 30 mL of
dry benzene was added in portions 4.7 g (0.035 mol) of
anhydrous aluminum chloride at 20–25 ꢁC. When addi-
tion was complete, the mixture was heated to reflux for
2 h, then cooled and poured into a mixture of ice and 10
mL of 1 N hydrochloric acid. The benzene was removed
in vacuo and the crude product was collected by fil-
tration and washed with sodium carbonate and water. The
filter cake was sucked to dryness and recrystallized from
95% ethanol to give 3.9 g of the title compound as light
yellow crystals, yield 60.9%, mp 190–192 ꢁC. Anal. calcd
for: C15H14O3S: C 65.67, H 5.14; Found: C 65.56, H 5.03.
2-(4-Chlorophenyl)-3-(4-methylsulfonylphenyl)-5-chloro-
indole (4c). The title compound was obtained as white
crystals, yield 79.9%, mp 269–271 ꢁC; 1H NMR
(300 MHz, DMSO) d 3.25 (s, 3H, SO2CH3), 7.20–7.94
(m, 11H, Ar–H), 12.05 (s, 1H, N–H). Anal. calcd for:
C21H15NO2SCl2: C 60.58, H 3.63, N 3.36; Found: C
60.58, H 3.68, N 3.07.
2-(4-Methylphenyl)-3-(4-methylsulfonylphenyl)-5-chloro-
indole (4d). The title compound was obtained as white
crystals, yield 69.2%, mp 238–240 ꢁC; 1H NMR
(300 MHz, DMSO) d 2.32 (s, 3H, CH3), 3.24 (s, 3H,
SO2CH3), 7.16–7.92 (m, 11H, Ar–H), 11.92 (s, 1H, N–
H). Anal. calcd for: C22H18NO2SCl: C 66.74, H 4.58, N
3.54; Found: C 66.81, H 4.58, N 3.54.
2 - (4 - Methoxyphenyl) - 3 - (4 - methylsulfonylphenyl) - 5 -
chloro-indole (4e). The title compound was obtained as
white crystals, yield 66.6%, mp 246–248 C; H NMR
Step 2: 2-phenyl-3-(4-methylsulfonylphenyl)-indole (8a).
A mixture of 0.9 g (3.3 mmol) of 4-methylsulfonylphe-
nyl-acetophenone 6a and 0.5 g (3.3 mmol) of phenylhy-
drazine hydrochloride was heated at 130 ꢁC for 0.5 h to
ꢁ
1
(300 MHz, DMSO) d 3.23 (s, 3H, SO2CH3), 3.74 (s, 3H,

W. Hu et al. / Bioorg. Med. Chem. 11 (2003) 5539–5544
5543
give the arylhydrazone 7a and without purification put
into the next reaction. To the solution of 7a in 20 mL of
C. M.; Perkins, W. E.; Seibert, K.; Isakson, P. C. J. Med.
Chem. 1994, 37, 3878.
.
acetic acid was added 0.2 g of BF3 Et2O and heated to
12. Li, J. J.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.;
Collins, J. T.; Garland, D. J.; Gregory, S. A.; Huang, H. C.;
Isakson, P. C.; Koboldt, C. M.; Logusch, E. W.; Norton,
M. B.; Perkins, W. E.; Reinhard, E. J.; Seibert, K.; Veenhui-
zen, A. W.; Zhang, Y.; Reitz, D. B. J. Med. Chem. 1995, 38,
4570.
13. Black, W. C.; Brideau, C.; Chan, C. C.; Charleson, S.;
Chauret, N.; Claveau, D.; Ethier, D.; Gordon, R.; Greig, G.;
Guay, J.; Hughes, G.; Jolicoeur, P.; Leblanc, Y.; Nicoll-Grif-
fith, D.; Ouimet, N.; Riendeau, D.; Visco, D.; Wang, Z.; Xu,
L.; Prasit, P. J. Med. Chem. 1999, 42, 1274.
reflux for 1 h. Acetic acid was removed in vacuo and the
resulting residue was suspended in water, filtered and
purified by column chromatography using petroleum
ether/ethyl acetate 3:1 as eluant, 0.45 g of the title com-
pound was obtained as white crystals, yield, 39.5%, mp
239–241 ꢁC; 1H NMR (300 MHz, DMSO) d 3.24 (s, 3H,
SO2CH3), 7.05–7.90 (m, 13H, Ar–H), 11.77 (s, 1H, N–
H). Anal. calcd for: C21H17NO2S: C 72.60, H 4.93, N
4.03; Found: C 72.35, H 5.03, N 4.25.
14. Huang, H. C.; Li, J. J.; Garland, D. J.; Chamberlain, T. S.;
Reinhard, E. J.; Manning, R. E.; Seibert, K.; Koboldt, C. M.;
Gregory, S. A.; Anderson, G. D.; Veenhuizen, A. W.; Zhang,
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15. Palomer, A.; Cabre, F.; Pascual, J.; Campos, J.; Trujillo,
M. A.; Entrena, A.; Gallo, M. A.; Garcia, L.; Mauleon, D.;
Espinosa, A. J. Med. Chem. 2002, 45, 1402.
2-Phenyl-3-(4-aminosulfonylphenyl)-indole (8b). The
procedure is according to the general procedure descri-
bed in method B. The title compound was obtained as
light yellow needle crystals, yield 29.5%, mp 223–
225 ꢁC. 1H NMR (300 MHz, DMSO) d 3.32 (s, 2H,
SO2NH2), 7.04–7.82 (m, 13H, Ar–H), 11.71 (s, 1H, N–
H). Anal. calcd for: C20H16N2O2S: C 68.94, H 4.63, N
8.04; Found: C 68.95, H 4.71, N 7.78.
16. Leblanc, Y.; Gauthier, J. Y.; Ethier, D.; Guay, J.; Man-
cini, J.; Riendeau, D.; Tagari, P.; Vickers, P.; Wong, E.; Prasit,
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Cromlish, W. A.; Gordon, R.; Kennedey, B. P.; Lau, P. K.;
Leger, S.; Wang, Z.; Ethier, D.; Guay, J.; Mancini, J.; Rien-
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Acknowledgements
This project was supported by the National Natural
Science Foundation of China (No. 20072057). We thank
the analytical division of Institute of Material Medica
for the spectroscopic data and elementary analyses.
References and Notes
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