Synthesis and biological evaluation of substituted 2-sulfonyl-phenyl-3-phenyl-indoles: A new series of selective COX-2 inhibitors

Article abstract of DOI:10.1016/S0968-0896(03)00046-4

A new series of substituted 2-sulfonyphenyl-3-phenyl-indole derivatives were synthesized and evaluated for their ability to inhibit COX-2 and COX-1enzymes. Most of the compounds synthesized were found to be highly potent and selective inhibitors of COX-2. This work led to the discovery of 2-aminosulfonylphenyl-3-phenyl-indole 5a which possesses higher activity and selectivity for COX-2 than Celecoxib both in vitro and in vivo.

Full text of DOI:10.1016/S0968-0896(03)00046-4

Bioorganic & Medicinal Chemistry 11 (2003) 1153–1160
Synthesis and Biological Evaluation of Substituted
2-Sulfonyl-phenyl-3-phenyl-indoles: A New Series of
Selective COX-2 Inhibitors
Wenhui Hu,a Zongru Guo,a,* Fengming Chu,a Aiping Bai,a Xiang Yi,a
Guifang Chengb and Jing Lib
aDepartment of Synthetic Medicinal Chemistry, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing 100050, China
bDepartment of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing 100050, China
Received 9October 2002; accepted 8 January 2003
Abstract—A new series of substituted 2-sulfonyphenyl-3-phenyl-indole derivatives were synthesized and evaluated for their ability
to inhibit COX-2 and COX-1enzymes. Most of the compounds synthesized were found to be highly potent and selective inhibitors
of COX-2. This work led to the discovery of 2-aminosulfonylphenyl-3-phenyl-indole 5a which possesses higher activity and selec-
tivity for COX-2 than Celecoxib both in vitro and in vivo.
# 2003 Elsevier Science Ltd. All rights reserved.
Introduction
COX-2 inhibitors such as Celecoxib,6 Rofecoxib7,8 and
Valdecoxib9 have been marketed as a new generation of
NSAIDs. These compounds all have the diarylhetero-
cyclic structural features.10ꢀ32 The other two categories
of 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 moi-
eties and one benzene ring being substituted with
methylsulfonyl or aminosulfonyl group at the para
position. The major difference in the compounds of this
class is the structure of the central ring. Thus, alteration
in the central ring will lead to new COX-2 inhibitors.
Indole ring constitutes an important template for drug
design such as the classical NSAIDs indomethacin and
indoxole.42 We herein developed a new series of COX-2
inhibitors of diarylheterocycles using indole as the cen-
tral ring (I).
Nonsteroidal anti-inflammatory drugs (NSAIDs)
remain among the most widely prescribed drugs world-
wide for the treatment of inflammation that can cause
pain and fever among other symptoms. The mechanism
of action is through their inhibition of prostaglandin
biosynthesis via the enzyme cyclooxygenase-2 (COX-2).1
COX-2 and COX-1 are two similar but distinct isoforms
of cyclooxygenase (COX).2ꢀ5 COX-2 is induced in
response to inflammatory stimuli and is responsible for
the 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
Chemistry
All the compounds (I) described here (except com-
pounds 5o and 5p) were synthesized by using the general
routes outlined in Schemes 1 and 2. The key step of the
*Corresponding author. Tel.: 086-010-63165249; fax: 086-010-
83155752; e-mail: zrguo@imm.ac.cn
0968-0896/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00046-4

1154
W. Hu et al. / Bioorg. Med. Chem. 11 (2003) 1153–1160
routes is to construct an indole skeleton by McMurry
coupling reaction. Aromatic acylamido-substituted
benzophenones can be cyclized to indole derivatives
upon the treatment with the low-valent titanium
reagents.43ꢀ45 In this paper the coupling reagent ‘low-
valent’ Ti was prepared in situ from TiCl4 and Zn in
reflux THF. In Scheme 1, o-aminobenzoic acid 1 was
subjected Friedel–Crafts reaction after being protected
by tosylation (2), and then hydrolyzed by concentrated
H2SO4 to give the substituted 2-amino-benzophenone
(3), which was acylated with 4-methylsulfonyl or 4-amino-
sulfonyl benzoyl chloride to give rise to 4. The inter-
mediate 4 was cyclized to provide the final compounds 5
by the McMurry condensation.
functional group transformation was carried out in the
46
synthesis of 5o by demethylation of 5i with BBr3 in
CH2Cl2 (Scheme 3).
To investigate the effect of the modification of the
aminosulfonyl group on the activity, we prepared the
acetylsulfonamide compound 5p by acetylation of 5a
with Ac2O and DMAP (Scheme 4).
All the target compounds were identified by spectro-
scopic data and confirmed by elemental analyses.
Results and Discussion
An alterative method is outlined in Scheme 2 with a
slight difference in the initial steps from Scheme 1.
We have synthesized three series of the indole analogues
(Table 1) with: different substitutents (R2) at the para-
position of the 3-phenyl ring such as hydrogen, halogen,
methoxy, methyl and others (5a–5o); chloro group at
different position of the 3-phenyl ring (9a–9f) and var-
ious substitutent (R3) at 5-position of the indole ring
(9g–9n). All the compounds except for 5o and 5p were
prepared as both the methyl sulfones and the corres-
ponding sulfonamides.
The target compound 5o containing a hydroxy group
cannot be prepared directly from the general synthetic
route due to the Friedel–Crafts reaction limitation. The
The compounds synthesized in this work are evaluated
for their ability to inhibit COX-2 and COX-1 by cellular
assay, using freshly harvested mouse peritoneal macro-
phages as described in the literature.47 The details of
these assays were described in the Experimental. We
were unable to determine the IC50 values for COX-1
inhibition by these compounds due to their low inhibi-
tory activities at the concentrations as high as 10 mM.
The results showed that all the compounds showed
potent inhibition against COX-2 compared to the inhi-
bition for COX-1 (IC50>10 mM) as listed in Table 1.
Scheme 1. Reagent: (a) Na2CO3, TsCl, 60–85 ꢁC; (b) (i) PCl5, 50 ꢁC,
(ii) AlCl3, C6H5R2, 80–90 ꢁC; (c) H2SO4, 120 ꢁC; (d) 4-R1SO2C6H4-
COCl, THF, Et3N, rt; (e) Zn, TiCl4, THF, reflux.
Scheme 3.
Scheme 2. Reagent: (a) (i) R2C6H4COCl, ZnCl2, 205 ꢁC (ii) H2SO4,
120 ꢁC; (b) 4-R1SO2C6H4COCl, THF, Et3N, rt; (c) Zn, TiCl4, THF,
reflux.
Scheme 4.

W. Hu et al. / Bioorg. Med. Chem. 11 (2003) 1153–1160
Table 1. In vitroa and in vivob inhibitory results
1155
No.
Structure
IC50 (nM)c
COX-2
IC50 (mM)
COX-1
Carrageenan edema
(10 mg/kg, % inhibition)
5a
5b
5c
5d
5e
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R1=NH2
R1=NHAc
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R1=NH2
R1=CH3
R2=H
R2=H
R2=4-F
0.09
0.60
5.15
0.02
33.5
146.0
8.36
0.37
0.006
0.02
0.07
0.09
1.46
0.17
6.44
0.18
0.54
85.1
3.13
0.8
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
53.9
56.1
41.2
18.4
25.6
50.4
N.D.d
16.1
38.5
27.1
N.D.
47.2
N.D.
43.1
N.D.
N.D.
N.D.
N.D.
23.4
N.D.
N.D.
N.D.
49.4
R2=4-F
R2=4-Cl
R2=4-Cl
R2=4-Br
R2=4-Br
R2=4-OCH3
R2=4-OCH3
R2=4-CH3
R2=4-CH3
R2=3,4-(CH3)2
R2=3,4-(CH3)2
R2=4-OH
R2=H
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
Celecoxib
R2=4-Cl
R2=4-Cl
R2=3-Cl
R2=3-Cl
R2=2-Cl
R2=2-Cl
R3=5-F
100.0
10.0
2.0
R3=5-F
5.0
60.8
57.8
53.2
N.D.
N.D.
22.6
46.1
49.7
R3=5-Cl
R3=5-Cl
R3=5-Br
R3=5-Br
R3=5-CH3
R3=5-CH3
0.14
0.36
5.0
1.41
0.02
0.28
0.52
aCell level. For details, see Experimental.
b% Inhibition produced by tested compounds on rat carrageenan-induced foot pad edema assay. For details, see Experimental.
cAll IC50 determinations including Celecoxib were carried out in triplicate and have less than 10% error.
dN.D.=not done.
Nearly half of the compounds (14 out of 30) were
found to be more potent and selective than Celecoxib
against COX-2, and three compounds (5b, 9d, 9e)
appeared to be equipotent to Celecoxib. Compound 5i
was the most potent inhibitor in this series with the
activity (IC50=0.006 nM) 87-fold higher than Cel-
ecoxib (IC50=0.52 nM). Four compounds (5d, 5j, 5 h,
5k) (IC50<0.02 nM) were 26 times more active than
Celecoxib.
Acetylation of 5a gave rise to acetylsulfonamide (5p),
which did not cause significant variation in the activity
(IC50=0.09nM vs 0.18 nM)
Compounds with alteration in the positions of chloro
substitution at the ortho-, meta- and para- positions of the
3-phenyl ring exhibited change in the inhibition against
COX-2. Subsitution with chloro at the ortho-position (9e
and 9f) resulted in low inhibition compared to the para-
position for sulfonamides (9a, IC50=0.54 nM) and
meta-position for methylsulfones (9d, IC50=0.8 nM).
The SAR studies demonstrated that the presence of a
methoxy (5i, 5j) and methyl group (5k, 5l) at the para-
position of the phenyl ring contributes excellent prop-
erties. However substitution with 3-, 4-dimethyl (5m,
5n) resulted in the reduction of COX-2 inhibitory activ-
ity. Sulfonamides substituted with halogen (5c, 5e, 5g)
are less potent than the unsubstituted compound 5a,
whereas no correlation existed between halogen sub-
stitution (5d, 5f, 5 h) and inhibition in the series of
methylsulfones.
Several 5-substituted indole analogues including F, Cl,
Br and CH3 were prepared. The comparison of the
activity among the analogues showed that methyl com-
pounds 9m and 9n were more active than the hydrogen
compounds 5a and 5b, respectively.
Compounds with sufficient potency and selectivity for
COX-2 were advanced for assessment of the activity in

1156
W. Hu et al. / Bioorg. Med. Chem. 11 (2003) 1153–1160
Table 2. In vivo pharmacological properties of compounds 5a and 5b
at 4 h after carrageenan injection
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 L-1 for 1 h. The amount of 6-keto-PGF1a (a
stable metabolite of PGI2) in supernatants was mea-
sured by RIA according to manufacturer’s guide. The
inhibitory ratio was calculated as
No.
5a
5b
Celecoxiba
29.6
ED50, mmol/kg (4 h)
15.0
27.1
aActivity data were from the author’s experiments.
ðCs À CtÞ
IR ¼
the rat carrageenan-induced foot-pad edema model.
The results listed in Table 1 showed that six com-
pounds (5a, 5b, 5f, 9 h, 9i, 9j) were more potent than
Celecoxib and four compounds (5c, 5l, 9g, 9n) were
comparable to Celecoxib. Some compounds, such as
compound 5i, with higher activity in vitro assay failed
to exhibit potency in vivo. This may be due to their
low bio-availability.
ðCs À CcÞ
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 9h. The amount of PGE 2 in supernatants was mea-
sured 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.
Compounds 5a and 5b with high in vitro and in vivo
activities were tested more extensively using the rat paw
edema model (Table 2). Compounds 5a and 5b pos-
sessed an ED50 of 15.0 and 27.1 mmol/kg respectively
compared to Celecoxib (29.6 mmol/kg) at 4 h.
Statistical analysis data were expressed as the
meanꢃSD of more than three independent experiments.
Dose-inhibitory effect curves were fit through ‘uphill
dose–response curves, variable slope’ using Prism,
GraphPad version3.00:
Conclusions
The series of substituted 2-sulfonylphenyl-3-phenyl-
indole described in this paper were proved to be potent
and highly selective inhibitors of COX-2. The indole
ring was proved to be an effective central ring that
derives a new diarylheterocycle class of COX-2 inhibi-
tors. The structure–activity relationship of the series of
inhibitors was analyzed and the acetylation of sulfon-
amide compound still retained the activity against
COX-2. This work led to the discovery of compound 5a
possessing higher activity both in vitro and in vivo
than Celecoxib as a prominent candidate for further
development.
1
Y ¼
½ðlogIC50ÀXÞÂHillslopeꢀ
1 þ 10
2. In vivo test (rat carrageenan-induced foot pad edema
assay). Male Sprgue–Dawley rats (190–220 g) were fas-
ted with free access to water at least 16 h prior to
experiments. The rats were dosed orally with a 1 mL
suspension of test compound in vehicle (0.5% methyl
cellulose and 0.025% Tween-20) or with vehicle alone.
One h later a subplantar injection of 0.1 mL of 1%
solution of carageenan in 0.9% strile saline was admi-
nistered to the right hind foot pad. Paw volume was
measured with a displacement plethysmometer 4 h after
carrageenan injection.
Experimental
Biological methods
1. In vitro test of inhibitory activity for cyclooxygenase-1
and cyclooxygenase-2. Cell culture. Adherent macro-
phages were harvested from the peritoneal cells of male
mice (C57BL-6J, Level 2, from the Experiment Animal
Center, Academy of Military Medical Science) after the
injection (ip) of brewer thioglycollate medium (5 mL/
100 g body weight) for 3 days. Shortly, peritoneal cells
obtained from 3–4 mice were mixed and seeded in 48
well cell culture cluster (Costar) at a cell density of
1ꢂ109 cell/L in RPMI-1640 supplemented with 5% (v/v)
newborn calf serum, 100 ku/L penicillin and 100 g/L
streptomycin. After settlement for 2–3 h, non-adherent
cells were washed by D-Hanks’ balanced salt solution.
Then macrophages were cultured in RPMI-1640 without
serum. Almost all of the adherent cells were macro-
phages as assessed by Giemsa staining. Cell viability
was examined by trypan blue dye exclusion. All incu-
bation procedures were performed with 5% CO2 in
humidified air at 37 ꢁC.
Chemistry
All solvents were dried and freshly distilled. Melting
points were determined using Yanaco melting point
1
apparatus and are uncorrected. HNMR 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.
The general procedure for the preparation of substituted
2-sulfonylphenyl-3-phenyl-indoles (5a–5n) is illustrated
below in the synthesis of 2-(4-aminosulfonylphenyl)-3-
phenyl-indole (5a). 2-(4-Aminosulfonylphenyl)-3-phenyl-
indole (5a)
Step 1: p-Toluenesulfonylanthranilic acid (2).47 Anthra-
nilic acid (1) (13.7 g, 0.1 mol) was added in three

W. Hu et al. / Bioorg. Med. Chem. 11 (2003) 1153–1160
1157
portions to the warmed solution of 26.0g of sodium car-
bonate in 150 mL of water, 23.0 g (0.12mol) of p-toluene-
sulfonyl chloride was added to the solution in 5 portions
over a period of 20min. The reaction mixture was warmed
at 60–70 ꢁC for additional 0.5 h, and raised to 85ꢁC, 1.0 g
of Norit was added cautiously and the solution was
fitered. The filtrate was cooled and acidified with dilute
HCl, the product was collected and washed with dilute
hydrochloric acid and then water. Recrystallization from
95% ethanol there was obtained the title compound
(20.0 g) as white crystal, yield 68.7%, mp 229–232 ꢁC.
2-(4-Methylsulfonylphenyl)-3-phenyl-indole (5b). The
title compound was obtained as white crystal, yield
ꢁ
1
56.2%, mp 221–222 C; H NMR (300 MHz, DMSO) d
3.23 (s, 3H, SO2CH3), 7.03–7.49(m, 9H, Ar–H), 7.55–
8.15 (dd, 4H, Ar–H), 11.67 (s, 1H, N–H ). Anal. calcd
for: C21H17NO2S: C 72.60, H 4.93, N 4.03; Found: C
72.39, H 5.14, N 3.83.
2-(4-Aminosulfonylphenyl)-3-(4-fluorophenyl)-indole (5c).
The title compound was obtained as white crystal, yield
54.3%, mp 228–230 ꢁC; H NMR (300 MHz, DMSO) d
1
3.33 (s, 2H, SO2NH2), 7.04–7.80 (m, 12H, Ar–H), 11.71
(s, 1H, N–H); anal. calcd for: C20H15N2FO2S: C 65.56,
H 4.13, N 7.65; found: C 65.46, H 4.23, N 7.35.
Step 2: 2-amino-benzophenone (3a).47 A mixture of
14.6 g (0.050 mol) of p-toluenesulfonylanthranilic acid
(2) and 11.9g (0.057 mol) of phosphorus pentachloride
in 150 mL of dry benzene was heated to about 50 ꢁC for
0.5 h. Cooled to 20–25 ꢁC, 29.0 g (0.218 mol) of an-
hydrous aluminum chloride was added in portions.
When addition was complete, the mixture was heated at
80–90ꢁC for 4 h and then cooled, poured onto a mixture
of ice and 60mL of 1 N hydrochloride acid. The benzene
was removed by vacuo distillation, the crude product
was collected by filtration and washed with sodium car-
bonate and water. The filter cake is dissolved in 160 mL of
concd sulfuric acid and heated to 120 ꢁC for 15min. The
reaction mixture was cooled and poured onto a mixture
of ice and 1 g of norit, and the solution is filtered. The fil-
trate was neutralized with 12 N ammonium hydroxide.
The solid was filtered off, washed with water, dried and
recrystallized from 95% ethanol to give the title compound
(6.63 g) as yellow crystal, yield 65.0%, mp 105–106 ꢁC.
2 - (4 - Methylsulfonylphenyl) - 3 - (4 - fluorophenyl) - indole
(5d). The title compound was obtained as white crystal,
yield 75.3%, mp 224–226 ꢁC; 1H NMR (300 MHz,
DMSO) d 3.24 (s, 3H, SO2CH3), 7.04–7.91 (m, 12H,
Ar–H), 11.77 (s, 1H, N-H); anal. calcd for:
C21H16NFO2S: C 69.02, H 4.41, N 3.83; found: C 69.19,
H 4.56, N 4.00.
2-(4-Aminosulfonylphenyl)-3-(4-chlorophenyl)-indole (5e).
The title compound ꢁwas obtained as white crystal, yield
3.29(s, 2H, SO NH2), 7.05–7.50 (m, 8H, Ar–H), 7.53–
1
73.9%, mp 298–300 C; H NMR (300 MHz, DMSO) d
2
7.81 (dd, 4H, Ar–H), 11.75 (s, 1H, N–H); anal. calcd
for: C20H15ClN2O2S: C 62.74, H 3.95, N 7.35; found: C
62.68, H 3.77, N 7.44.
2-(4-Methylsulfonylphenyl)-3-(4-chlorophenyl)-indole (5f).
The title compound was obtained as white crystal, yield
65.5%, mp 198.5–200.5 ꢁC; 1H NMR (300 MHz,
CDCl3) d 3.09(s, 3H, SO 2CH3), 7.16–7.85 (m, 12H, Ar–
H), 8.65 (s, 1H, N–H); anal. calcd for: C21H16ClNO2S:
C 66.05, H 4.22, N 3.67; found: C 66.03, H 4.48, N 3.64.
Step 3: 2-N-(4-aminosulfonylbenzoyl)-amide-benzophenone
(4a). To a solution of 2.0 g (0.010 mol) of 2-amino-
benzophenone (3a), 1.6 mL (0.011 mol) of triethylamine
in 20 mL of dry THF under nitrogen was added a solu-
tion of 2.0 g (0.010 mol) of 4-aminosulfonylbenzoyl
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 pur-
ified by column chromatograph on silica gel (eluent:
petroleum ether–ethyl acetate, 1:1) to give the title
compound as white needle crystal, yield 59.5%, mp
216–218 ꢁC; anal. calcd for: C20H16N2O4S: C 63.15, H
4.24, N 7.36; found: C 63.37, H 4.36, N 7.44.
2-(4-Aminosulfonylphenyl)-3-(4-bromophenyl)-indole (5g).
The title compound was obtained as white crystal, yield
51.7%, mp 277–279 ꢁC; H NMR (300 MHz, CDCl3) d
1
3.23 (s, 2H, SO2NH2), 7.04–7.80 (m, 12H, Ar–H), 11.70
(s, 1H, N–H); anal. calcd for: C20H15BrNO2S: C 56.21,
H 3.54, N 6.56; found: C 56.46, H 3.70, N 6.72.
2-(4-Methylsulfonylphenyl)-3-(4-bromophenyl)-indole (5h).
The title compound was obtained as white crystal, yield
Step 4: 2-(4-aminosulfonylphenyl)-3-phenyl-indole (5a).
2-N-(4 - aminosulfonylbenzoyl) - amide - benzophenone
(4a) (1.04 g, 3 mmol), 0.87 g (12 mmol) of 90% Zn was
suspended in 20 mL dry THF. To the mixture 0.7 mL
(6.2 mmol) of TiCl4 was added dropwise and heated to
reflux for 1.5 h. The solvent was removed in vacuo and
the residue was purified by column chromatography
using petroleum ether–ethyl acetate (3:1) as elutant. The
title compound (0.45 g) was obtained as white crystal,
yield 43.9%, mp 231–232 ꢁC; 1H NMR (300 MHz,
DMSO) d 3.03 (s, 2H, SO2NH2), 7.03–7.49(m, 9H, Ar–
H), 7.65–7.89(dd, 4H, Ar–H), 10.8 ( s, 1H, N-H ); anal.
calcd for: C20H16N2O2S: C 68.94, H 4.63, N 8.04;
found: C 68.99, H 4.61, N 8.18.
75.2%, mp 225–226 ꢁC; H NMR (300 MHz, DMSO) d
1
3.09(s, 3H, SO CH3), 7.16–7.84 (m, 12H, Ar–H), 8.69
(s, 1H, N-H); anal. calcd for: C21H16BrNO2S: C 59.16,
H 3.78, N 3.29; found: C 59.04, H 3.85, N 3.20.
2
2-(4-Aminosulfonylphenyl)-3-(4-methoxyphenyl)-indole (5i).
The title compound was obtained as white crystal, yield
73.9%, mp 280–282 ꢁC; H NMR (300 MHz, DMSO) d
1
3.28 (s, 2H, SO2NH2), 3.79(s, 3H, OCH ), 6.97–7.78
3
(m, 12H, Ar–H), 11.59(s, 1H, N–H); anal. calcd for:
C21H18N2O3S: C 66.65, H 4.79, N 7.40; found: C 66.35,
H 5.02, N 6.86.
2-(4-Methylsulfonylphenyl)-3-(4-methoxyphenyl)-indole
(5j). The title compound was obtained as white crystal,
The following compounds (5b–5n) were prepared
according to the general procedure described above.
yield 74.7%, mp 218.5–220.5 ꢁC; H NMR (300MHz,
1

1158
W. Hu et al. / Bioorg. Med. Chem. 11 (2003) 1153–1160
CDCl3) d 3.08 (s, 3H, SO2CH3), 3.87 (s, 3H, OCH3),
6.95–7.86 (m, 12H, Ar–H), 8.41 (s, 1H, N–H); anal.
calcd for: C22H19NO3S: C 69.98, H 5.07, N 3.71; found:
C 69.90, H 5.12, N 3.99.
yield 59.30%, mp 221–222 ꢁC; 1H NMR (300 MHz,
DMSO) d 1.92(s, 3H, CH3), 7.05–7.86 (m, 13H, Ar–H),
11.69( s, 1H, N–H ), 12.04 ( s, 1H, N–H ); anal. calcd
for: C22H18N2O3S: C 67.67, H 4.65, N 7.17; Found: C
67.79, H 4.68, N 7.08.
2 - (4 - Aminosulfonylphenyl) - 3 - (4 - methylphenyl) - indole
(5k). The title compound was obtained as white crystal,
yield 55.3%, mp 293–295 ꢁC; 1H NMR (300 MHz,
DMSO) d 2.34 (s, 3H, CH3), 3.43 (s, 2H, SO2NH2),
7.01–7.77 (m, 12H, Ar–H), 11.59(s, 1H, N–H); anal.
calcd for: C21H18N2O2S: C 69.60, H 5.01, N 7.73;
found: C 69.45, H 5.25, N 7.53.
The general procedure for the preparation of substituted
2-sulfonylphenyl-3-phenyl-indole (9a–9n) is illustrated
below in the synthesis of 2-(4-aminosulfonylphenyl)-3-(4-
chlorophenyl)-5-chloro-indole (9a). 2-(4-aminosulfonyl-
phenyl)-3-(4-chlorophenyl)-5-chloro-indole (9a)
Step 1: 2-amino-5-chloro-40-chloro-benzophenone (7a). A
mixture of 21.0 g (0.135 mol) of p-chlorobenzoic acid (6)
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
benzoyl chloride heated to 120 ꢁC was added in portions
with stirring 6.3 g (0.05 mol) of 4-chloroaniline. The
mixture was heated to 180 ꢁC and 8.5 g (0.063 mol) of
ZnCl2 was added. The temperature was gradually
increased to about 205 ꢁC and kept there for 2 h. After
cooling to 120 ꢁC, 60 mL of 3 N HCl was added and the
mixture stirred and heated to reflux. The hot acid layer
was decanted and this procedure repeated two or three
times. The water-insoluble residue was dissolved in
80 mL of 70% sulfuric acid and reflux for 8 h and then,
after cooling poured into a large amount of ice water.
The reaction mixture was neutralized with aqueous
ammonia hydroxy and extracted with ethyl acetate,
dried over Na2SO4. The solvent was removed and the
residue was crystallized from 95% ethanol to give the
title compound as golden yellow crystal 5.1 g, yield
38.5%, mp 106–107 ꢁC; HRMS m/e calcd, 265.006119;
found, 265.008696.
2-(4-Methylsulfonylphenyl)-3-(4-methylphenyl)-indole (5l).
The title compound ꢁwas obtained as white crystal, yield
1
77.4%, mp 197–198 C; H NMR (300 MHz, DMSO) d
2.35(s, 3H, CH3), 3.21 (s, 3H, SO2CH3), 7.01–7.88 (m,
12H, Ar–H), 11.64 (s, 1H, N–H); anal. calcd for:
C22H19NO2S: C 73.10, H 5.02, N 3.88; found: C 72.82,
H 5.42, N 3.97.
2-(4-Aminosulfonylphenyl)-3-(3,4-dimethylphenyl)-indole
(5m). The title compound was obtained as white crys-
tal, yield 49.6%, mp 251–253 ꢁC; H NMR (300 MHz,
1
DMSO) d 2.24 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.43 (s,
2H, SO2NH2), 7.00–7.78 (m, 11H, Ar–H), 11.64 (s, 1H,
N-H); anal. calcd for: C22H20N2O2S: C 70.19, H 5.35, N
7.44; found: C 70.13, H 5.42, N 7.33.
2-(4-Methylsulfonylphenyl)-3-(3,4-dimethylphenyl)-indole
(5n). The title compound was obtained as white crystal,
yield 67.0%, mp 206–207 ꢁC; 1H NMR (300 MHz,
DMSO) d 2.23 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.21 (s,
3H, SO2CH3), 6.99–7.88 (m, 11H, Ar–H), 11.62 (s, 1H,
N–H); anal. calcd for: C23H21NO2S: C 73.57, H 5.64, N
3.73; found: C 73.32, H 5.65, N 3.58.
2-(4-Aminosulfonylphenyl)-3-(4-hydroxyphenyl)-indole (5o).
2-(4-Aminosulfonylphenyl)-3-(4-methoxyphenyl)-indole
(5i) (300 mg, 0.79mmol) was suspended in 20 mL of
CH2Cl2 cooled in an ice-salt bath and the cold solution
of 0.41 mL (4.4 mmol) of BBr3 in 5 mL of CH2Cl2 was
added in dropwise. When addition was complete, the
ice-salt bath was removed and the reaction mixture was
stirred at room temperature for 3 h. The solvent was
removed and the residue was purified by column
chromtography eluting with 3:1 petroleum: ethyl acetate
to give 180 mg of title compound as light yellow crystal,
yield 62.31%, mp 241–243 ꢁC; 1H NMR (300 MHz,
DMSO) d 3.26 (s, 2H, SO2NH2), 6.80–7.77 (m, 11H,
Ar–H), 9.43 (s, 1H, OH), 11.56 (s, 1H, N–H); anal.
calcd for: C20H16N2O3S: C 56.92, H 4.43, N 7.69;
Found: C 56.81, H 4.34, N 7.47.
Step 2: 2-N-(4-aminosulfonylbenzoyl)-amide-5-chloro-40-
chloro-benzophenone (8a). The procedure is in the same
manner as described in the preparation of 4a. The title
compound was obtained as needle yellow crystal, yield
76.2%, mp 234–236 ꢁC; HRMS m/e calcd, 448.005134;
found, 448.005693.
Step 3: 2-(4-aminosulfonylphenyl)-3-(4-chlorophenyl)-5-
chloro-indole (9a). The procedure is in the same manner
as described in the preparation of 5a. The title com-
pound was obtained as white crystal, yield 71.8%, mp
245–247 ꢁC; 1H NMR (300 MHz, DMSO) d 3.32 (s, 2H,
SO2NH2), 7.20–7.83 (m, 11H, Ar–H), 12.00 (s, 1H, N–
H); anal. calcd for: C20H14N2O2SCl2: C 57.56, H 3.38,
N 6.71; found: C 57.65, H 3.34, N 6.56.
The following compounds (9b–9o) were prepared accord-
ing to the general procedure described above.
2-(N-Acetamide-sulfonylphenyl)-3-phenyl-indole (5p). To
a solution of 1.5 g (4.3 mmol) of 2-(4-aminosulfonyl-
phenyl)-3-phenyl-indole (5a), 5 mg of DMAP and 0.5 g
(5.2 mmol) of triethylamine in 20 mL dry THF was
added dropwise 0.5 g (5.2 mmol) of acetic anhydride.
The reaction mixture was stirred at room temperature
for 5 h and then the solvent was removed in vacuo. The
residue was crystallized from dichloromethane to afford
1.0 g of the title compound as needle yellow crystal,
2-(4-Methylsulfonylphenyl)-3-(4-chlorophenyl)-5-chloro-
indole (9b). The title compound was obtained as white
crystal, yield 76.9%, mp 281–283 ꢁC; 1H NMR
(300 MHz, DMSO) d 3.26 (s, 3H, SO2CH3), 7.22–7.95
(m, 11H, Ar–H), 12.06 (s, 1H, N-H); anal. calcd for:
C21H15NO2SCl2: C 60.58, H 3.63, N 3.36; found: C
60.72, H 3.79, N 3.30.

W. Hu et al. / Bioorg. Med. Chem. 11 (2003) 1153–1160
1159
2-(4-Aminosulfonylphenyl)-3-(3-chlorophenyl)-5-chloro-
indole (9c). The title compound was obtained as white
crystal, yield 68.2%, mp 249–251 ꢁC; 1H NMR
(300 MHz, DMSO) d 3.27 (s, 2H, SO2NH2), 7.21–7.84
(m, 11H, Ar–H), 12.00 (s, 1H, N–H); anal. calcd for:
C20H14NO2SCl: C 57.56, H 3.38, N 6.71; found: C
57.53, H 3.44, N 6.43
3.31 (s, 2H, SO2NH2), 7.29–7.78 (m, 12H, Ar–H), 11.94
(s, 1H, N–H); anal. calcd for: C20H15N2O2SBr: C 56.23,
H 3.54, N 6.56; found: C 56.45, H 3.76, N 6.60.
2-(4-Methylsulfonylphenyl)-3-phenyl-5-bromo-indole (9l).
The title compound was obtained as white crystal, yield
69.1%, mp 262–264 ꢁC; H NMR (300 MHz, DMSO) d
1
3.23 (s, 3H, SO2CH3), 7.30–7.90 (m, 12H, Ar–H), 12.01
(s, 1H, N–H); anal. calcd for: C21H16NO2SBr: C 59.17,
H 3.78, N 3.29; found: C 59.11, H 3.71, N 3.44.
2-(4-Methylsulfonylphenyl)-3-(3-chlorophenyl)-5-chloro-
indole (9d). The title compound was obtained as white
crystal, yield 56.0%, mp 254–257 ꢁC; 1H NMR
(300 MHz, DMSO) d 3.26 (s, 3H, SO2CH3), 7.22–7.96
(m, 11H, Ar–H), 12.10 (s, 1H, N–H); anal. calcd for:
C21H15NO2SCl2: C 60.58, H 3.63, N 3.36; found: C
60.56, H 3.75, N 3.34.
2-(4-Aminosulfonylphenyl)-3-phenyl-5-methyl-indole (9m).
The title compound was obtained as white crystal, yield
76.2%, mp 242–244 ꢁC; H NMR (300 MHz, DMSO) d
1
2.36 (s, 3H, CH3), 3.32 (s, 2H, SO2NH2), 7.01–7.77 (m,
12H, Ar–H), 11.57 (s, 1H, N–H); anal. calcd for:
C21H18N2O2S: C 69.59, H 5.01, N 7.73; found: C 69.78,
H 4.95, N 7.71.
2-(4-Aminosulfonylphenyl)-3-(2-chlorophenyl)-5-chloro-
indole (9e). The title compound was obtained as white
crystal, yield 47.6%, mp 268–240 ꢁC; 1H NMR
(300 MHz, DMSO) d 3.28 (s, 2H, SO2NH2), 7.10–7.77
(m, 11H, Ar–H), 12.01 (s, 1H, N–H); anal. calcd for:
C20H14N2O2SCl: C 57.56, H 3.38, N 6.71; found: C
57.30, H 3.48, N 6.15.
2-(4-Methylsulfonylphenyl)-3-phenyl-5-methyl-indole (9n).
The title compound was obtained as white crystal, yield
71.8%, mp 245–247 ꢁC; H NMR (300 MHz, DMSO) d
1
3.21 (s, 3H, SO2CH3), 7.20–7.83 (m, 11H, Ar–H), 12.00
(s, 1H, N–H); anal. calcd for: C20H14N2O2SCl2: C
57.56, H 3.38, N 6.71; found: C 57.65, H 3.34, N 6.56.
2-(4-Methylsulfonylphenyl)-3-(2-chlorophenyl)-5-chloro-
indole (9f). The title compound was obtained as white
crystal, yield 70.2%, mp 300–301.5 ꢁC; 1H NMR
(300 MHz, DMSO) d 3.23 (s, 3H, SO2CH3), 7.10–7.91
(m, 11H, Ar–H), 12.13 (s, 1H, N–H); anal. calcd for:
C21H15NO2SCl2: C 60.58, H 3.63, N 3.36; Found: C
60.59, H 3.62, N 3.40.
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.
2-(4-Aminosulfonylphenyl)-3-phenyl-5-fluoro-indole (9g).
The title compound was obtained as white crystal, yield
59.3%, mp 302–304 ꢁC; H NMR (300 MHz, DMSO) d
1
3.35 (s, 2H, SO2NH2), 7.01–7.79(m, 12H, Ar–H), 11.82
(s, 1H, N–H); anal. calcd for: C20H15N2FO2S: C 65.56,
H 4.13, N 7.65; found: C 65.46, H 4.16, N 7.43.
References and Notes
1. Vane, J. R. Nature 1971, 231, 232.
2. Allison, M. C.; Howatson, A. G.; Torrance, C. J.; Lee,
F. D.; Russell, R. I. N. Engl. J. Med. 1992, 327, 749.
3. O’Banion, M. K.; Sadowski, H. B.; Winn, V.; Young, D. A.
J. Biol. Chem. 1991, 266, 23261.
2-(4-Methylsulfonylphenyl)-3-phenyl-5-fluoro-indole (9h).
The title compound ꢁwas obtained as white crystal, yield
1
79.8%, mp 243–245 C; H NMR (300 MHz, DMSO) d
3.24 (s, 3H, SO2CH3), 7.02–7.91 (m, 12H, Ar–H), 11.89
(s, 1H, N–H); anal. calcd for: C21H16NFO2S: C 69.02,
H 3.83, N 4.41; found: C 69.18, H 4.34, N 3.65.
4. Kujubu, D. A.; Herschmann, H. R. J. Biol. Chem. 1992,
267, 7991.
5. De Brum-Fernandez, A. J. J. Rheumatol. 1997, 24, 246–
248.
6. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Mal-
echa, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu,
S. S.; Anderson, G. D.; Burton, E. l. G.; Cogburn, J. N.;
Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med.
Chem. 1997, 40, 1347.
2-(4-Aminosulfonylphenyl)-3-phenyl-5-chloro-indole (9i).
The title compound ꢁwas obtained as white crystal, yield
1
27.5%, mp 297–299 C; H NMR (300 MHz, DMSO) d
3.32 (s, 2H, SO2NH2), 7.18–7.79(m, 12H, Ar–H), 11.94
(s, 1H, N–H); anal. calcd for: C20H15ClN2O2S: C 62.74,
H 3.95, N 7.32; found: C 62.59, H 4.08, N 7.30.
7. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C. C.; Charleson,
S.; Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchinson,
A. W.; Gauthier, J. Y. Bioorg. Med. Chem. Lett. 1999, 9, 1773.
8. Nicoll-Griffith, D. A.; Yergey, J. A.; Trimble, L. A.; Silva,
J. M.; Li, C.; Chauret, N.; Gauthier, J. Y.; Grimm, E.; Leger,
S.; Roy, P.; Therien, M.; Wang, Z.; Prasit, P.; Zamboni, R.;
Young, R. N.; Brideau, C.; Chan, C. C.; Mancini, J.; Rien-
deau, D. Bioorg. Med. Chem. Lett. 2000, 10, 2683.
9. Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.;
Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers,
R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K.
J. Med. Chem. 2000, 43, 775–777.
2-(4-Methylsulfonylphenyl)-3-phenyl-5-chloro-indole (9j).
The title compound was obtained as white crystal, yield
84.3%, mp 281–283 ꢁC; H NMR (300 MHz, DMSO) d
1
3.24 (s, 3H, SO2CH3), 7.20–7.91 (m, 12H, Ar–H), 12.00
(s, 1H, N–H); anal. calcd for: C21H16ClNO2S: C 66.05,
H 4.22, N 3.67; found: C 66.11, H 4.04, N 3.91.
2-(4-Aminosulfonylphenyl)-3-phenyl-5-bromo-indole (9k).
The title compound was obtained as white crystal, yield
55.3%, mp 310–312 ꢁC; H NMR (300 MHz, DMSO) d
1

1160
W. Hu et al. / Bioorg. Med. Chem. 11 (2003) 1153–1160
10. Frenette, R.; Blouin, M.; Brideau, C.; Chauret, N.;
Ducharme, Y.; Friesen, R. W.; Hamel, P.; Jones, T. R.; Lali-
berte, F.; Li, C.; Masson, P.; McAuliffe, M.; Girard, Y.
Bioorg. Med. Chem. Lett. 1996, 6, 2677.
26. Li, J. J.; Norton, M. B.; Reinhart, E. J.; Anderson, G. D.;
Gregory, S. A.; Isakson, P. C.; Koboldt, C. M.; Masferrer,
J. L.; Perkins, W. E.; Seibert, K.; Zhang, Y.; Zweifel, B. S.;
Reitz, D. B. J. Med. Chem. 1996, 39, 1846.
11. Reitz, D. B.; Li, J. J.; Norton, M. B.; Reinhard, E. J.;
Collins, J. T.; Anderson, G. D.; Gregory, S. A.; Koboldt,
C. M.; Perkins, W. E.; Seibert, K. J. Med. Chem. 1994, 38,
3878.
27. Friesen, R. W.; Brideau, C.; Chan, C. C.; Charleson, S.;
Deschenes, D.; Dube, D.; Ethier, D.; Fortin, R.; Gauthier,
J. Y.; Girard, Y.; Gordon, R.; Greig, G. M.; Riendeau, D.;
Savoie, C.; Wang, Z. Y.; Wong, E.; Visco, D.; Xu, L. J.;
Young, R. N. Bioorg. Med. Chem. Lett. 1998, 8, 2777.
28. Dube, D.; Brideau, C.; Deschenes, D.; Fortin, R.; Friesen,
R. W.; Gordon, R.; Girard, Y.; Riendeau, D.; Savoie, C.;
Chan, C. C. Bioorg. Med. Chem. Lett. 1999, 9, 1715.
29. Almansa, C.; de Arriba, A. F.; Cavalcanti, F. L.; Gomez,
L. A.; Miralles, A.; Merlos, M.; Garcia-Rafanell, J.; Forn, J.
J. Med. Chem. 2001, 43, 350.
30. Therien, M.; Brideau, C.; Chan, C. C.; Cromlish, W. A.;
Gauthier, J. Y.; Gordon, R.; Greig, G.; Kargman, S.; Lau,
C. K.; Leblanc, Y.; Li, C. S.; Oneill, G. P.; Riendeau, D.; Roy,
P.; Wang, Z. Y.; Xu, L. J.; Prasit, P. Bioorg. Med. Chem. Lett.
1997, 7, 47.
31. Roy, P.; Leblanc, Y.; Ball, R. G.; Brideau, C.; Chan, C. C.;
Chauret, N.; Cromlish, W.; Ethier, D.; Gauthier, J. Y.; Gor-
don, R.; Greig, G.; Guay, J.; Kargman, S.; Lau, C. K.;
O’Neill, G.; Silva, J.; Therien, M.; vanStaden, C.; Wong, E.;
Xu, L.; Prasit, P. Bioorg. Med. Chem. Lett. 1997, 7, 57.
32. de Leval, X.; Delarge, J.; Somers, F.; de Tullio, P.; Hen-
rotin, Y.; Pirotte, B.; Dogne, J. M. Current Med. Chem. 2000,
7, 1041.
33. Dannhardt, Gerd; Werne, Kiefe Eur. J. Med. Chem. 2001,
36, 109.
34. Futaki, N.; Takahashi, S.; Yokoyama, I.; Arai, I.; Higu-
chi, S.; Otomo, S. Prostaglandins 1994, 47, 55.
35. Li, C. S.; Black, W. C.; Chan, C. C.; Fordhutchinson,
A. W.; Gauthier, J. Y.; Gordon, R.; Guay, D.; Kargman, S.;
Lau, C. K.; Mancini, J.; Ouimet, N.; Roy, P.; Vickers, P.;
Wong, E.; Young, R. N.; Zamboni, R.; Prasit, P. J. Med.
Chem. 1995, 38, 4897.
36. Ouimet, N.; Chan, C. C.; Charleson, S.; Claveau, D.;
Gordon, R.; Guay, D.; Li, C. S.; Ouellet, M.; Percival, D. M.;
Riendeau, D.; Wong, E.; Zamboni, R.; Prasit, P. Bioorg. Med.
Chem. Lett. 1999, 9, 151.
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. J. Med. Chem. 1995, 38, 4570.
13. Black, W.Cameron; Brideau, Christine; Chan, Chi-Chung;
Charleson, Stella; Chauret, Nathalie; Claveau, David; Ethier,
Diane; Gordon, Robert; Greig, Gillian; Guay, Jocelyne;
Hughes, Gregory; Jolicoeur, Paule; Leblanc, Yves; Nicoll-
Griffith, Deborah; Ouimet, Nathalie; Riendeau, Denis; Visco,
Denise; Wang, Zhaoyin; Xu, Lijing; Prasit, P. J. Med. Chem.
1999, 42, 1274.
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,
Y.; Perkins, W. E.; Burton, E. G.; Cogburn, J. N.; Isakson,
P. C.; Reitz, D. B. J. Med. Chem. 1996, 39, 253–266.
15. de Leval, X.; Delarge, J.; Somers, F.; de Tullio, P.; Hen-
rotin, Y.; Pirotte, B.; Dogne, J. M. Curr. Med. Chem. 2000, 7,
1041.
16. Leblanc, Y.; Gauthier, J. Y.; Ethier, D.; Guay, J.; Man-
cini, J.; Riendeau, D.; Tagari, P.; Vickers, P.; Wong, E.; Prasit,
P. Bioorg. Med. Chem. Lett. 1995, 5, 2123.
17. Gauthier, J. Y.; Leblanc, Y.; Black, W. C.; Chan, C. C.;
Cromlish, W. A.; Gordon, R.; Kennedey, B. P.; Lau, C. K.;
Leger, S.; Wang, Z. Y.; Ethier, D.; Guay, J.; Mancini, J.;
Riendeau, D.; Tagari, P.; Vickers, P.; Wong, E. Bioorg. Med.
Chem. Lett. 1996, 6, 87.
18. Khanna, I. K.; Weier, R. M.; Yu, Y.; Collins, P. W.;
Miyashiro, J. M.; Koboldt, C. M.; Veenhuizen, A. W.; Currie,
J. L.; Seibert, K.; Isakson, P. C. J. Med. Chem. 1997, 40, 1619.
19. Leblanc, Y.; Roy, P.; Boyce, S.; Brideau, C.; Chan, C. C.;
Charleson, S.; Gordon, R.; Grimm, E.; Guay, J.; Leger, S.; Li,
C. S.; Riendeau, D.; Visco, D.; Wang, Z.; Webb, J.; Xu, L. J.;
Prasit, P. Bioorg. Med. Chem. Lett. 1999, 9, 2207.
20. Lau, C. K.; Brideau, C.; Chan, C. C.; Charleson, S.;
Cromlish, W. A.; Ethier, D.; Gauthier, J. Y.; Gordon, R.;
Guay, J.; Kargman, S.; Li, C. S.; Prasit, P.; Riendeau, D.;
Therien, M.; Visco, D. M.; Xu, L. J. Bioorg. Med. Chem. Lett.
1999, 9, 3187.
21. Shin, S. S.; Noh, M. S.; Byun, Y. J.; Choi, J. K.; Kim,
J. Y.; Lim, K. M.; Ha, J. Y.; Kim, J. K.; Lee, C. H.; Chung, S.
Bioorg. Med. Chem. Lett. 2001, 11, 165–168.
37. Kalgutkar, A. S.; Crews, B. C.; Rowlinson, S. W.; Garner,
C.; Seibert, K.; Marnett, L. J. Science 1998, 280, 1268.
38. Kalgutkar, A. S.; Marnett, A. B.; Crews, B. C.; Remmel,
R. P.; Marnett, L. J. J. Med. Chem. 2000, 43, 2860.
39. Black, W. C.; Bayly, C.; Belley, M.; Chan, C. C.; Charle-
son, S.; Denis, D.; Gauthier, J. Y.; Gordon, R.; Guay, D.;
Kargman, S.; Lau, C. K.; Leblanc, Y.; Mancini, J.; Ouellet,
M.; Percival, D.; Roy, P.; Skorey, K.; Tagari, P.; Vickers, P.;
Wong, E.; Xu, L.; Prasit, P. Bioorg. Med. Chem. Lett. 1996, 6,
725.
22. Bai, A. P.; Guo, Z. R.; Hu, W. H.; Shen, F.; Cheng, G. F.
Chin. Chem. Lett. 2001, 12 (9), 775.
23. Khanna, I. K.; Weier, R. M.; Yu, Y.; Xu, X. D.; Koszyk,
F. J.; Collins, P. W.; Koboldt, C. M.; Veenhuizen, A. W.;
Perkins, W. E.; Casler, J. J.; Masferrer, J. L.; Zhang, Y. Y.;
Gregory, S. A.; Seibert, K.; Isakson, P. C. J. Med. Chem.
1997, 40, 1634.
40. Bayly, C. I.; Black, W. C.; Leger, S.; Ouimet, N.; Ouellet,
M.; Percival, M. D. Bioorg. Med. Chem. Lett. 1999, 9, 307.
41. Lednicer, D. Current Med. Chem. 2002, 9, 1457.
42. Furstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org.
¨
Chem. 1994, 59, 5215.
24. Khanna, I. K.; Yu, Y.; Huff, R. M.; Weier, R. M.; Xu, X.;
Koszyk, F. J.; Collins, P. W.; Cogburn, J. N.; Isakson, P. C.;
Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Yuan, J.; Yang, D.; Zhang, Y. Y. J. Med.
Chem. 2000, 43, 3168.
43. Furstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117,
¨
4468.
44. Furstner, A.; Jumbam, D. N. Tetrahedron 1992, 48, 5991.
¨
45. von Angerer, Erwin; Prekajac, Jelica; Strohmeier, Josef J.
Med. Chem. 1984, 27, 1439.
25. Puig, C.; Crespo, M. I.; Godessart, N.; Feixas, J.; Ibarzo,
46. Hu, Yufang; Cheng, Guifang Acta Pharm. Sin. 2000, 35,
343.
47. 2-Aminobenzophenone. Org. Syn. Collect. John-Wiley:
New York, Vol. 4, 1963, pp 34–38.
J.; Jime
M.; Puig, J.; Beleta, J.; Huerta, J. M.; Lo
Ryder, H.; Palacios, J. M. J. Med. Chem. 2000, 43, 214 –223.
´
nez, J.; Soca, L.; Cardelu
´
s, I.; Heredia, A.; Miralpeix,
´
pez, M.; Segarra, V.;