Structure-activity relationship of cinnamic acylsulfonamide analogues on the human EP3 prostanoid receptor

Article abstract of DOI:10.1016/S0968-0896(01)00110-9

Potent and selective antagonists of the human EP₃ receptor have been identified. The structure-activity relationship of the chemical series was conducted and we found several analogues displaying sub-nanomolar K_i values at the EP₃ receptor and micromolar activities at the EP₁, EP₂ and EP₄ receptors. The effect of added human serum albumin (HSA) on the binding affinity at the EP₃ receptor was also investigated.

Full text of DOI:10.1016/S0968-0896(01)00110-9

Bioorganic & Medicinal Chemistry 9 (2001) 1977–1984
Structure–Activity Relationship of Cinnamic Acylsulfonamide
Analogues on the Human EP3 Prostanoid Receptor
Helene Juteau, Yves Gareau,* Marc Labelle, Claudio F. Sturino, Nicole Sawyer,
Nathalie Tremblay, Sonia Lamontagne, Marie-Claude Carriere, Danielle Denis
and Kathleen M. Metters
´
Merck Frosst Canada & Co., PO Box 1005, Pointe-Claire-Dorval, Quebec, Canada H9R 4P8
Received 5 February 2001; accepted 28 February 2001
Abstract—Potent and selective antagonists of the human EP3 receptor have been identified. The structure–activity relationship of
the chemical series was conducted and we found several analogues displaying sub-nanomolar Ki values at the EP3 receptor and
micromolar activities at the EP1, EP2 and EP4 receptors. The effect of added human serum albumin (HSA) on the binding affinity at
the EP3 receptor was also investigated. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
The lack of selective and specific EP3 antagonists has
become a crucial issue for the characterization of the
EP3 receptor pharmacology.
In response to various extracellular stimuli, pros-
taglandins are rapidly generated through the con-
secutive action of the cyclo-oxygenases and distinct
synthases on membrane arachidonic acid and exert their
action in close proximity to the site of their synthesis.
The eight known human prostanoid receptors have been
cloned and their sequences determined.1 PGE2 will bind
preferentially to the EP1, EP2, EP3 and EP4 receptors,
PGD2 to the DP receptor, PGF2a to the FP receptor,
PGI2 to the IP receptor and TXA2 to the TP receptor.2,3
The pharmacological action of the prostanoids at their
respective receptors results ultimately in a variety of
biological responses in different tissues. PGE2 binding
to the EP3 receptor has been found to play a key role in
the regulation of ion transport, smooth muscle contrac-
tion of the GI tract, acid secretion, uterine contraction
during fertilization and implantation, fever generation
and PGE2-mediated hyperalgesia. The EP3 receptor has
been detected in many organs such as the kidney, the
gastrointestinal tract, the uterus and the brain.4 So far,
studies for understanding the roles of EP3 have been
Results and Discussion
Recently, we have reported a new class of EP3 antago-
nist based on the arylmethyl cinnamic acid skeleton 4.
6
This series was found to be active at the EP3 receptor
with Ki values between 20 and 100 nM for the most
potent analogues.7 The three step synthesis of this class
of compounds is illustrated in Scheme 1. A Suzuki cou-
pling reaction was first performed between the benzyl
bromide 2 and an aryl boronic acid. Hydrolysis under
basic conditions gave the desired arylmethyl cinnamic
acid 4 witha Ki of 20 nM on the EP3 receptor when
Ar=2-naphthyl. In an effort to improve the potency in
this series, an extensive SAR study was carried out
focusing on four different positions. These positions are
the top and bottom ring, the methylene linker and the
carboxylic acid moiety, the latter being the first position
investigated.
conducted mainly withPGE and other prostanoid-like
2
compounds.5 However, these compounds behave as
agonists and cross react withother prostanoid receptors.
The acidic character of the molecule is essential for
activity. Neutral compounds were found to be inactive
on EP3. We thus focused our effort on identifying acid
surrogates withimproved binding affinity. Tetrazole is
probably the most widely used replacement for carboxylic
acid. The tetrazole analogue of 4 (Ar=2-naphthyl) was
*Corresponding author. Tel.: +1-514-428-3001; fax: +514-428-4900;
e-mail: yves_gareau@merck.com
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00110-9

1978
H. Juteau et al. / Bioorg. Med. Chem. 9 (2001) 1977–1984
Scheme 1.
prepared from the nitrile and was found to be 10-fold
less active witha Ki of 190 nM on EP3. This series was
no longer pursued.
EP3 witha Ki of 153 nM when compared to the sulfur
6b (Ki=6.7 nM) or the methylene tether 5. This loss of
potency may be attributed to the difference in con-
formation between the oxygen and the methylene linker
(the conjugation of the oxygen lone pair with the aro-
matic rings slow down the rotation around this bond).
Among the analogues that we prepared, the sulfone 6d
turned out to be the least shifted (20-fold) but the
potency on EP3 was not improved. We could have used
the sulfone linker to investigate the top aromatic ring
but decided, for practical reasons, to continue SAR with
the methylene moiety. Next, the naphthyl group was
replaced by a phenyl and the substitution of the ring
was looked at. We first noticed that polarity played an
important role in this region of the molecule. Strong
electron-withdrawing groups such as sulfoxide 7b and
sulfone 7c at the 4-position were not tolerated at all,
which resulted in dramatic losses of potency with activ-
ities of 3.7 and 1.3 mM, respectively. On the other hand,
lipophilic groups such as chlorine and thioether were
better tolerated. The Ki values of these analogues ran-
ged from 1.9 to 6.3 nM and they were also quite selec-
tive over the other EP receptors (7a, 8a, 8b, and 8c). The
3,4-dichlorophenyl 8c gave the best substitution on the
Among various changes looked at, we found that
incorporation of 2-thiophenesulfonamide to form an
acylsulfonamide suchas 5 would greatly improve the
potency of compound 4. The adduct 5 was 1.1 nM on
the EP3 receptor and very selective over the other EP
receptors (Table 1). The high shift in the presence of
HSA was the major drawback of this compound. The Ki
value at the EP3 receptor in the presence of 0.05%
human serum albumin (HSA) was 263 nM (>200-fold
shift). We decided at this time to carry out further SAR
studies with the 2-thiophene acyl sulfonamide and to re-
investigate the issue of protein shift later on. Acylsulfo-
namide 5 was easily prepared from carboxylic acid 4
and 2-thiophenesulfonamide in the presence of a
coupling reagent (EDC) according to Scheme 1.
The second position we looked at for the SAR was the
methylene linker. Replacement by heteroatoms such as
oxygen and sulfur did not improve the binding affinity.
The oxygen linker 6a was surprisingly less potent on
Table 1. Binding affinity of cinnamic analogues bearing various tether
Ki (nM)a
Compound
X
EP1
EP2
EP3
EP3
(+0.05% HSA)
EP4
5
CH2
O
S
SO
SO2
OCH2
>5000
>5000
>5000
>5000
>5000
>5000
>5000
2000
3333
>5000
>5000
>5000
1.1
153
6.7
17
2.1
9.9
263
1500
356
200
41
1236
1300
1300
>5000
1567
1380
6a
6b
6c
6d
6e
1794
aKi determinations are averages based on at least two experiments.

H. Juteau et al. / Bioorg. Med. Chem. 9 (2001) 1977–1984
1979
ring witha Ki of 1.9 nM but was highly shifted in the
presence of HSA to 1.7 mM (1000-fold shift).
presence of HSA (Table 2). This part of the molecule
was kept constant and a new SAR was initiated on the
naphthyl and phenyl group. The para position to the
methylene group on the aromatic ring of the cinnamoyl
moiety was investigated next. Substituting witheht-
eroatoms suchas fluorine, chlorine or methoxy ( 10a,
10b, 10c) resulted in no gain of potency. Although the
fluoro analogue showed a smaller shift in the presence
of HSA, the selectivity against EP4 (Ki=715 nM) was
reduced. Also, increasing the size of the group from
hydrogen, chlorine, methoxy to allyl 10d yielded less
potent antagonists on EP3. We decided to carry on the
SAR on the naphthyl group with the chlorine sub-
stituent since this analogue 10b was more selective over
the other EP receptors. Quinoline analogues such as 11c
were looked at but were rapidly abandoned due to the
lack of improvement on the binding affinity. We then
looked at substituted naphthyl derivatives; two repre-
sentatives (11a and 11b) are shown in Table 3. Sub-
stitution on the naphthyl moiety with fluorine or
chlorine resulted in very potent compounds on the EP3
receptor and highly selective over the PGE receptors
with only 10-fold shift in the presence of HSA. The
synthesis of these compounds is outlined in Scheme 3.9
First, the zinc derivative of 3-(2-bromomethyl-5-chloro-
phenyl)-acrylic acid ethyl ester was prepared from the
corresponding halide. The zinc intermediate 12 was then
coupled to the corresponding substituted naphthyl
We then directed our efforts to find a thiophene repla-
cement. This was accomplished with a solid supported
reagent to simplify the work up procedure and speed up
the process. The carboxylic acid 4 was coupled to var-
ious aryl and alkyl sulfonamides using a polymer-sup-
ported coupling reagent (EDC, Scheme 2).8 Typically,
the reaction was performed using an excess of the cou-
pling reagent and DMAP (the latter being used due to
the low reactivity of the sulfonamide nucleophile). To
avoid any unreacted sulfonamide contamination at the
end of the reaction, we used 0.8 equivalents of sulfona-
mide (with 1 equivalent of the carboxylic acid). The
excess of carboxylic acid remains bound to the resin and
does not diminishproduct purity. Amberlyst-15 was
also used at the end of the reaction as a proton source to
protonate the acylsulfonamide and to remove the
DMAP from the solution. The work up of this reaction
involved a simple filtration to remove the resin bound
reagent and the DMAP. Overall, 62 compounds were
prepared with this procedure with high yields and puri-
ties. We were able to find a thiophene replacement that
showed superior activity and better behavior in the pre-
sence of HSA. The 5-bromo-2-methoxybenzene sulfo-
namide 9 was the best analogue in terms of potency with
a Ki of 0.3 nM on EP3. It was shifted only 14-fold in the
Scheme 2.
Table 2. Binding affinity of substituted phenyl analogues
Ki (nM)a
Compound
X
EP1
EP2
EP3
EP3
(+0.05% HSA)
EP4
7a
7b
7c
8a
8b
8c
8d
4-SME
4-SOMe
4-SO2Me
4-Cl
2,4-Cl
3,4-Cl
3,5-Cl
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
5.1
3750
1300
1045
NDb
NDb
1890
579
>5000
>5000
>5000
4750
3700
2522
6.3
2.5
1.9
1690
3856
26
3700
aKi determinations are averages based on at least two experiments.
bNot determined.

1980
H. Juteau et al. / Bioorg. Med. Chem. 9 (2001) 1977–1984
Table 3. Binding affinity of substituted phenyl analogues
Ki (nM)a
EP3
Compound
Z
X
Y
EP1
EP2
EP3
(+0.05% HSA)
EP4
9
CH
CH
CH
CH
CH
CH
CH
N
H
H
H
H
H
F
H
F
Cl
OMe
Allyl
Cl
Cl
Cl
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
0.3
0.3
0.8
1.5
4.2
1.2
9.2
28.1
400
4.7
4.1
22.1
916
10a
10b
10c
10d
11a
11b
11c
715
>5000
2050
4600
5350
48
0.5
0.6
1.5
l
H
>5000
1557
aKi determinations are averages based on at least two experiments.
Scheme 3.
triflate 13 withPd(dba) and dppf to yield the desired
2
Chemistry
adduct 14. Basic hydrolysis of the ester followed by the
sulfonamide coupling afforded compounds 11a and 11b.
General procedure for the preparation of cinnamate
ester. Methyl-3-(2-methylphenyl)-2-propenoate (1a). To
a solution of 2-methylcinnamic acid (100.0 g, 617 mmol)
in 1.2 L of DMF was added DBU (112.6 g, 740 mmol).
After 15 min, methyl iodide (131.3 g, 925 mmol) was
added dropwise and the mixture was stirred overnight.
The solution was then diluted in ether and washed with
HCl (10%), water and brine. The solvent was removed
to give 106.8 g (98%) of the title compound 1a. 1H
NMR (400 MHz, CDCl3) d 7.95 (d, J=15.1 Hz, 1H),
7.52 (d, J=8.0 Hz, 1H), 7.22 (m, 3H), 6.35 (d, J=15.1
Hz, 1H), 3.80 (s, 3H), 2.41 (s, 3H). The ethyl ester 1b
was prepared in a different fashion. To 2-methyl ben-
zaldehyde (5.0 g, 41.6 mmol) and triethyl phosphono-
acetate (9.9 mL, 50.0 mmol) in 150 mL of toluene at
0 ꢀC, was added sodium hydride (2.52 g, 63.0 mmol,
60% w/w in oil) portionwise. After 2 hof stirring, the
mixture was quenched with an ammonium acetate
solution (25%) and extracted with ethyl acetate. The
organic phase was dried over MgSO4 and the solvent
removed to give 7.1 g (90%) of the desired ethyl cinna-
Conclusion
We have described the SAR studies in the arylmethyl
cinnamic acylsulfonamide series that allowed identifica-
tion of compounds withnanomolar potency on teh
human EP3 receptor and high selectivity over the other
EP receptors.10 One of them, compound 11b, was 0.6
nM at the EP3 receptor and 4.1 nM in the presence of
HSA (7-fold shift). This compound was also highly
selective over the other EP receptors. Pharmacological
studies of this compound will be disclosed elsewhere.
Experimental
Biological assays
See ref 2 for stable expression of prostanoid receptors in
the human embryonic kidney (HEK) 293 (EBNA) cell
line and also for prostanoid receptor binding assays.
1
mate. H NMR (400 MHz, CDCl3) d 7.95 (d, J=15.1
Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.20 (m, 3H), 6.35 (d,

H. Juteau et al. / Bioorg. Med. Chem. 9 (2001) 1977–1984
1981
J=15.1 Hz, 1H), 4.23 (q, J=7.3 Hz, 2H), 2.39 (s, 3H),
1.33 (t, J=7.3 Hz, 3H).
sis calcd for the sodium salt C24H18NNaO3S2.H2O: C,
60.87; H, 4.22; N, 2.96; S, 13.54; found: C, 60.36; H,
4.25; N, 3.29; S, 12.53.
General procedure for the preparation of benzylic bro-
mide. 3-(2-bromomethyl-phenyl)-acrylic acid methyl ester
(2a). To 1a (18.5 g, 105 mmol) and NBS (19.6 g, 110.3
mmol) in refluxing CCl4 was added benzoyl peroxide
(1.27 g, 5.24 mmol). The solution was stirred 12 h under
reflux then cooled to rt and filtered. The solvent was
removed and the crude oil purified by silica gel chro-
matography using 5% ethyl acetate in hexane to yield
14.2 g (53%) of the title compound 2a. 1H NMR
(400 MHz, CDCl3) d 8.05 (d, J=15.2 Hz, 1H), 7.57 (m,
1H), 7.30 (m, 3H), 6.45 (d, J=15.2 Hz, 1H), 4.60 (s,
2H), 3.85 (s, 3H).
Thiophene-2-sulfonic acid {3-[2-(naphthalen-2-yloxy)-
phenyl]-acryloyl}-amide (6a). A mixture of 2-naphthol
(3.50 g, 24.2 mmol), 2-fluorobenzaldehyde (3.05 g, 24.2
mmol) and potassium carbonate (3.71 g, 26.6 mmol) in
30 mL of dimethylacetamide was stirred under reflux for
2 h 1.1 After cooling down to rt, the mixture was diluted
with ethyl acetate and washed with water and brine. The
organic phase was dried over MgSO4 and evaporated to
dryness. Purification on silica gel using 10% ethyl ace-
tate in hexane afforded 3.42 g (57%) of 2-(naphthalen-2-
yloxy)-benzaldehyde. 1H NMR (400 MHz, CDCl3) d
10.51 (s, 1H), 8.05 (m, 1H), 7.92 (m, 2H), 7.75 (d, J=7.1
Hz, 1H), 7.52 (m, 3H), 7.35 (s, 1H), 7.31 (m, 1H), 7.25
(m, 1H), 6.95 (d, J=7.1 Hz, 1H). Olefination to the a,b-
unsaturated ester using triethylphosphonoacetate fol-
lowed by hydrolysis and coupling with 2-thiophene-
sulfonamide as previously described for compound 5
General procedure for the Suzuki coupling reaction. 3-(2-
naphthalen-2-ylmethyl-phenyl)-acrylic acid methyl ester
(3a). A mixture of benzyl bromide 2a (0.50 g, 1.86
mmol), 2-naphthylboronic acid (0.63 g, 3.71 mmol),
CsF (1.13 g, 7.43 mmol) and (Ph3P)4Pd (0.11 g, 0.09
mmol) in 10 mL of DME was heated to reflux for 10 h.
The mixture was cooled to rt, quenched with an
ammonium acetate solution (25%) and extracted with
ethyl acetate. The organic phases were combined, dried
and the solvent removed. Purification by silica gel
chromatography using 10% ethyl acetate in hexane
afforded 0.35 g (63%) of the title compound 3a. 1H
NMR (400 MHz, CDCl3) d 8.05 (d, J=15.4 Hz, 1H),
7.75 (m, 3H), 7.60 (d, J=7.0 Hz, 1H), 7.52 (s, 1H), 7.41
(m, 2H), 7.25 (m, 4H), 6.32 (d, J=15.5 Hz, 1H), 4.25 (s,
2H), 3.75 (s, 3H).
1
afforded the title compound 6a. H NMR (400 MHz,
CDCl3) d 7.99 (m, 2H), 7.92 (m, 2H), 7.74 (m, 2H),
7.55–7.40 (m, 3H), 7.37 (m, 1H), 7.29 (dd, J=8.8 and 2.0
Hz, 1H), 7.24 (m, 1H), 7.15 (dd, J=4.5 and 4.0 Hz, 1H),
6.97 (d, J=8.0 Hz, 1H), 6.91 (d, J=16.0 Hz, 1H); HR-
MS calcd for the sodium salt C23H16NNaO4S2+H+:
458.0497; found: 458.0497.
Thiophene-2-sulfonic acid {3-[2-(naphthalen-2-sulfanyl)-
phenyl]-acryloyl}-amide (6b). A mixture of 2-naphthale-
nethiol (5.33 g, 33.0 mmol), 2-fluorobenzaldehyde (3.71
g, 30.0 mmol) and potassium carbonate (4.62 g, 33.0
mmol) in 28 mL of isopropanol was stirred overnight
under reflux.12 After cooling down to rt, the mixture
was diluted with ethyl acetate and washed with water
and brine. The organic phase was dried over MgSO4
and evaporated to dryness. Purification on silica gel
using 10% ethyl acetate in hexane afforded 7.82 g (99%)
General procedure for ester hydrolysis. 3-(2-naphthalen-
2-ylmethyl-phenyl)-acrylic acid (4). Hydrolysis of the
previous ester 3a (0.33 g, 1.10 mmol) was performed in
THF/MeOH (6:3 mL) witha 2 N sodium hydroxyde
solution (1.1 mL, 2.20 mmol). After 4 h, the solution
was diluted with ethyl acetate and quenched with HCl
(10%). The organic phase was dried over Na2SO4 and
the solvent removed. Purification was done by a tri-
turation with hexane to yield 0.21 g (66%) of the title
1
of 2-(naphthalen-2-ylsulfanyl)-benzaldehyde. H NMR
(400 MHz, CDCl3) d 10.41 (s, 1H), 8.05 (s, 1H), 7.85 (m,
4H), 7.52 (m, 2H), 7.45 (m, 1H), 7.35 (m, 2H), 7.11 (d,
J=7.1 Hz, 1H). Olefination to the a,b-unsaturated ester
using triethylphosphonoacetate afforded 3-[2-(naphtha-
len-2-ylsulfanyl)-phenyl]-acrylic acid ethyl ester. Hydro-
lysis followed by coupling with2-thiophenesulfonamide
1
compound 4. H NMR (400 MHz, CDCl3) d 8.19 (d,
J=15.1 Hz, 1H), 7.73 (m, 3H), 7.62 (d, J=7.5 Hz, 1H),
7.52 (s, 1H), 7.40–7.21 (m, 6H), 6.32 (d, J=15.1 Hz, 1H),
4.29 (s, 2H); elemental analysis calcd for C20H16O2.1/
4H2O: C, 82.16; H, 5.63; found: C, 81.70; H, 5.66.
1
afforded the title compound 6b. H NMR (400 MHz,
acetone-d6) d 8.31 (d, J=15.5 Hz, 1H), 7.82 (m, 7H),
7.47 (m, 2H), 7.41 (m, 3H), 7.33 (m, 1H), 7.12 (m, 1H),
6.66 (d, J=15.5 Hz, 1H); HR-MS calcd for the sodium
salt C23H16NO3S3Na+H+: 474.0268; found: 474.0270.
General procedure for the acylsulfonamide preparation.
Thiophene-2-sulfonic acid [3-(2-naphthalen-2-ylmethyl-
phenyl)-acryloyl]-amide (5). To the acid 4 (100 mg; 0.35
mmol), 2-thiophenesulfonamide (60 mg; 0.37 mmol)
and DMAP (86 mg; 0.70 mmol) in 2 mL of CH2Cl2, was
added EDCI (134 mg; 0.70 mmol). The mixture was
stirred overnight. The solution was then diluted with
ethyl acetate, quenched with HCl (10%) and washed
with brine. The organic phase was dried over Na2SO4
and the solvent removed. Purification by silica gel
chromatography using 5% methanol in dichloro-
methane afforded 87 mg (57%) of the title compound 5.
1H NMR (400 MHz, CDCl3): d 8.08 (d, J=15.2 Hz,
1H), 7.84 (m, 1H), 7.81–7.15 (m, 12H), 7.02 (m, 1H),
6.31 (d, J=15.2 Hz, 1H), 4.24 (s, 2H); elemental analy-
Thiophene-2-sulfonic acid {3-[2-(naphthalene-2-sulfinyl)-
phenyl]-acryloyl}-amide (6c). To a solution of 3-[2-
(naphthalen-2-ylsulfanyl)-phenyl]-acrylic acid ethyl
ꢀ
ester (2.98 g, 9.05 mmol) in 45 mL of CH2Cl2 at 0 C
was added m-CPBA (1.72 g, 9.91 mmol). After 1 h, the
reaction was quenched with a sodium thiosulfate solu-
tion and extracted with ethyl acetate. The organic phase
was washed with water, brine and dried over MgSO4.
After evaporation to dryness and purification on silica
gel using 30% ethyl acetate in hexane, 2.35 g (74%) of
3-[2-(naphthalene-2-sulfinyl)-phenyl]-acrylic acid ethyl

1982
H. Juteau et al. / Bioorg. Med. Chem. 9 (2001) 1977–1984
1
ester was obtained. H NMR (400 MHz, CDCl3) d 8.31
(s, 1H), 8.25 (d, J=15.5 Hz, 1H), 8.12 (d, J=7.9 Hz,
1H), 7.85 (m, 1H), 7.81 (m, 2H), 7.55 (m, 4H), 7.45 (m,
2H), 6.33 (d, J=15.3 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H),
1.35 (t, J=7.1 Hz, 3H). Hydrolysis followed by coupling
with2-thiophenesulfonamide afforded the title compound
reaction with (4-methylthio)phenylboronic acid affor-
ded 3-[2-(4-methylsulfanyl-benzyl)-phenyl]-acrylic acid
ethyl ester in 60% yield. H NMR (400 MHz, CDCl3) d
1
8.05 (d, J=15.3 Hz, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.25
(m, 2H), 7.15 (d, J=7.1 Hz, 3H), 7.05 (d, J=7.7 Hz,
2H), 6.31 (d, J=15.4 Hz, 1H), 4.22 (q, J=7.3 Hz, 2H),
4.06 (s, 2H), 2.43 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).
Hydrolysis followed by coupling with 2-thiophenesulfo-
namide afforded the title compound 7a. 1H NMR
(400 MHz, CDCl3) d 8.03 (d, J=15.3 Hz, 1H), 7.89 (s,
1H), 7.61 (s, 1H), 7.49 (m, 1H), 7.32–6.91 (m, 8H), 6.33
(d, J=15.3 Hz, 1H), 4.01 (s, 2H), 2.40 (s, 3H); elemental
1
6c. H NMR (400 MHz, CD3OD-d4) d 8.17 (s, 1H), 8.12
(d, J=7.3 Hz, 1H), 7.99 (d, J=15.4 Hz, 1H), 7.85–7.72 (m,
4H), 7.67 (d, J=7.9 Hz, 1H), 7.55 (m, 2H), 7.45 (m, 3H),
7.22 (dd, J=8.7 and 1.8 Hz, 1H), 7.12 (m, 1H), 6.19 (d,
J=15.4 Hz, 1H); elemental analysis calcd for the sodium
salt C23H16NNaO4S3.1/2H2O: C, 55.36; H, 3.40; N, 2.81;
S, 19.27; found: C, 55.00; H, 3.62; N, 2.81; S, 18.18.
.
analysis calcd for the sodium salt C21H18NNaO3S3 1/
2H2O: C, 54.77; H, 4.13; N, 3.04; S, 20.88; found: C,
54.55; H, 4.01; N, 3.06; S, 20.58.
Thiophene-2-sulfonic acid {3-[2-(naphthalene-2-sulfonyl)-
phenyl]-acryloyl}-amide (6d). To a solution of 3-[2-
(naphthalen-2-ylsulfanyl)-phenyl]-acrylic acid ethyl
Thiophene-2-sulfonic acid {3-[2-(4-methylsulfinylbenzyl)-
phenyl]-acryloyl}-amide (7b). To a solution of 3-[2-(4-
methylsulfanyl-benzyl)-phenyl]-acrylic acid ethyl ester
(384 mg, 1.23 mmol) in 6 mL of CH2Cl2 at 0 ꢀC was
added m-CPBA (233 mg, 1.35 mmol) and the mixture
was stirred overnight. The solution was then diluted
with ethyl acetate, washed with a sodium thiosulfate
solution, water and brine. The organic phase was dried
over MgSO4 and evaporated to dryness. After purifica-
tion on silica gel using 100% ethyl acetate, 340 mg
(88%) of 3-[2-(4-methanesulfinyl-benzyl)-phenyl]-acrylic
acid ethyl ester was obtained. 1H NMR (400 MHz,
CDCl3) d 7.95 (d, J=15.6 Hz, 1H), 7.62 (d, J=7.2 Hz,
1H), 7.55 (d, J=7.5 Hz, 2H), 7.31 (m, 4H), 7.15 (d,
J=7.2 Hz, 1H), 6.32 (d, J=15.3 Hz, 1H), 4.25 (q,
J=7.2 Hz, 2H), 4.23 (s, 2H), 2.70 (s, 3H), 1.33 (t, J=7.4
Hz, 3H). Hydrolysis followed by coupling with2-thio-
ꢀ
ester (1.02 g, 3.05 mmol) in 15 mL of CH2Cl2 at 0 C
was added m-CPBA (1.58 g, 9.15 mmol). The solution
was stirred 1 h. Work-up and purification were done as
previously described for compound 6c to give 853 mg
(76%) of 3-[2-(naphthalene-2-sulfonyl)-phenyl]-acrylic
1
acid ethyl ester. H NMR (400 MHz, CDCl3) d 8.61 (s,
1H), 8.52 (d, J=15.4 Hz, 1H), 8.35 (m, 1H), 7.95 (d,
J=7.6 Hz, 1H), 7.85 (m, 2H), 7.70 (d, J=7.9 Hz, 1H),
7.55 (m, 5H), 6.05 (d, J=15.3 Hz, 1H), 4.25 (q, J=7.2
Hz, 2H), 1.35 (t, J=7.1 Hz, 3H). Hydrolysis followed
by coupling with 2-thiophenesulfonamide gave the
1
desired compound 6d. H NMR (400 MHz, acetone-d6)
d 8.71 (d, J=15.6 Hz, 1H), 8.66 (s, 1H), 8.32 (m, 1H),
8.12 (d, J=8.0 Hz, 1H), 7.91 (m, 5H), 7.60 (m, 5H), 7.15
(t, J=4.5 Hz, 1H), 6.32 (d, J=15.6 Hz, 1H); elemental
analysis calcd for the sodium salt C23H16NNaO5S3.3/
2H2O: C, 51.87; H, 3.57; N, 2.63; S, 18.05; found: C,
51.70; H, 3.33; N, 2.75; S, 17.70.
1
phenesulfonamide afforded the title compound 7b. H
NMR (400 MHz, acetone-d6) d 8.05 (d, J=15.3 Hz,
1H), 7.95 (d, J=4.5 Hz, 1H), 7.86 (d, J=4.3 Hz, 1H),
7.64 (d, J=7.7 Hz, 1H), 7.56 (d, J=7.9 Hz, 2H), 7.42
(d, J=6.6 Hz, 1H), 7.33 (m, 4H), 7.22 (m, 1H), 6.61 (d,
J=15.5 Hz, 1H), 4.31 (s, 2H), 2.60 (s, 3H); HR-MS
calcd for the sodium salt C21H18NO4S3Na+H+:
468.0374; found: 468.0373.
Thiophene-2-sulfonic acid {3-[2-(naphthalen-2-yloxyme-
thyl)-phenyl]-acryloyl}-amide (6e). A solution of 2-
naphthol (147 mg, 1.00 mmol), benzyl bromide 1b (250
mg, 0.90 mmol) and cesium carbonate (394 mg, 1.20
mmol) in 5 mL of DMF was heated at 40 ꢀC overnight.
After cooling to rt and diluted with ethyl acetate, the
organic phase was washed with water, brine and dried
over MgSO4. After evaporation, the product was pur-
ified over silica gel using 10% ethyl acetate in hexane to
yield 245 mg (85%) of 3-[2-(naphthalen-2-yloxymethyl)-
phenyl]-acrylic acid ethyl ester. 1H NMR (400 MHz,
CDCl3) d 8.05 (d, J=15.2 Hz, 1H), 7.82 (m, 3H), 7.65
(m, 1H), 7.55 (m, 1H), 7.41–7.30 (m, 4H), 7.23–7.11 (m,
2H), 6.41 (d, J=15.5 Hz, 1H), 5.30 (s, 2H), 4.25 (q,
J=7.3 Hz, 2H), 1.35 (t, J=7.3 Hz, 3H). Hydrolysis
followed by coupling with 2-thiophenesulfonamide
afforded the desired compound 6e. 1H NMR (400 MHz,
CDCl3) d 8.07 (d, J=15.6 Hz, 1H), 7.83 (s, 1H), 7.71
(m, 3H), 7.53 (m, 3H), 7.41 (m, 4H), 7.15 (m, 2H), 7.02
(brs, 1H), 6.39 (d, J=15.4 Hz, 1H), 5.22 (s, 2H); ele-
mental analysis calcd for the sodium salt
C24H28NNaO4S2.3/2H2O: C, 57.82; H, 4.21; N, 2.81;
found: C, 58.31; H, 3.96; N, 2.91.
Thiophene-2-sulfonic acid {3-[2-(4-methylsulfonylbenzyl)-
phenyl]-acryloyl}-amide (7c). To a solution of 3-[2-(4-
methylsulfanyl-benzyl)-phenyl]-acrylic acid ethyl ester
ꢀ
(384 mg, 1.23 mmol) in 6 mL of CH2Cl2 at 0 C was
added m-CPBA (637 mg, 3.69 mmol) and the mixture
was stirred 1 h. The solution was then diluted with ethyl
acetate, washed with a sodium thiosulfate solution,
water and brine. The organic phase was dried over
MgSO4 and evaporated to dryness. After purification
on silica gel using 50% ethyl acetate in hexane, 390 mg
(96%)
of
3-[2-(4-methanesulfonyl-benzyl)-phenyl]-
acrylic acid ethyl ester was obtained. 1H NMR
(400 MHz, CDCl3) d 7.91 (d, J=15.4 Hz, 1H), 7.82 (d,
J=7.6 Hz, 2H), 7.60 (d, J=7.5 Hz, 1H), 7.31 (m, 4H),
7.23 (d, J=7.1 Hz, 1H), 6.31 (d, J=15.6 Hz, 1H), 4.22
(q, J=7.4 Hz, 2H), 4.22 (s, 2H), 3.05 (s, 3H), 1.33 (t,
J=7.3 Hz, 3H). Hydrolysis followed by coupling with
2-thiophenesulfonamide afforded the title compound 7c.
1H NMR (400 MHz, acetone-d6) d 8.05 (m, 2H), 7.87 (d,
J=4.4 Hz, 1H), 7.82 (d, J=7.6 Hz, 2H), 7.65 (d, J=7.8
Hz, 1H), 7.35 (m, 5H), 7.22 (m, 1H), 6.62 (d, J=15.3
Thiophene-2-sulfonic acid {3-[2-(4-methylsulfanylbenzyl)-
phenyl]-acryloyl}-amide (7a). The compound was pre-
pared according to Scheme 1. The Suzuki coupling

H. Juteau et al. / Bioorg. Med. Chem. 9 (2001) 1977–1984
1983
Hz, 1H), 4.32 (s, 2H), 3.11 (s, 3H); HR-MS calcd for the
sodium salt C21H18NO5S3Na+H+: 484.0323; found:
484.0323.
7.05 (m, 1H), 6.75 (d, J=8.6 Hz, 1H), 6.41 (d, J=15.2 Hz,
1H), 4.17 (s, 2H), 3.70 (s, 3H); elemental analysis calcd for
the sodium salt C27H20BrFNNaO4S.H2O: C, 54.56; H,
3.70; N, 2.36; Found C, 54.73, H, 3.61; N, 2.45.
Thiophene-2-sulfonic acid {3-[2-(4-chlorobenzyl)-phenyl]-
acryloyl}-amide (8a). The compound was prepared
according to Scheme 1. H NMR (400 MHz, CDCl3) d
8.05 (d, J=15.5 Hz, 1H), 7.85 (d, J=2.9 Hz, 1H), 7.55
(m, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.31 (m, 1H), 7.14 (m,
4H), 7.05 (m, 1H), 6.95 (d, J=8.4 Hz, 2H), 6.34 (d, J=15.4
Hz, 1H), 4.05 (s, 2H); HR-MS calcd for the sodium salt
C20H16NO3S2ClNa+H+: 440.0158; found: 440.0160.
5-bromo-N-[3-(5-chloro-2-naphthalen-2-ylmethyl-phenyl)-
acryloyl]-2-methoxy-benzenesulfonamide (10b). The
compound was prepared according to Scheme 1 using 3-
(2-bromomethyl-5-chloro-phenyl)-acrylic acid ethyl
ester for the Suzuki coupling reaction and 5-bromo-2-
1
1
methoxyphenylsulfonamide for the final step. H NMR
(400 MHz, DMSO-d6) d 8.05 (d, J=2.5 Hz, 1H), 7.91
(d, J=15.8 Hz, 1H), 7.82 (m, 4H), 7.62 (m, 2H), 7.41
(m, 5H), 7.23 (d, J=8.9 Hz, 1H), 6.66 (d, J=15.7 Hz,
1H), 4.31 (s, 2H), 3.85 (s, 3H); elemental analysis calcd
for the sodium salt C27H20BrClNNaO4S.H2O: C, 53.08;
H, 3.64; N, 2.29; S, 5.25; found: C, 53.25; H, 3.89; N,
2.91; S, 4.97.
Thiophene-2-sulfonic acid {3-[2-(2,4-dichlorobenzyl)-
phenyl]-acryloyl}-amide (8b). The compound was pre-
pared according to Scheme 1. 1H NMR (400 MHz,
CDCl3) d 7.92 (d, J=15.5 Hz, 1H), 7.87 (d, J=3.8 Hz,
1H), 7.56 (d, J=5 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H),
7.33 (s, 1H), 7.25 (m, 2H), 7.05 (m, 2H), 6.95 (d, J=7.6
Hz, 1H), 6.72 (d, J=8.3 Hz, 1H), 6.42 (d, J=15.4 Hz,
1H), 4.11 (s, 2H); elemental analysis calcd for the sodium
salt C20H14Cl2NNaO3S2: C, 50.64; H, 2.97; N, 2.95; S,
13.52; found: C, 50.30; H, 3.01; N, 2.89; S, 13.75.
5-Bromo-2-methoxy-N-[3-(5-methoxy-2-naphthalen-2-yl-
methyl-phenyl)-acryloyl]-benzenesulfonamide (10c). The
compound was prepared according to Scheme 1 using 3-
(2-bromomethyl-5-methoxy-phenyl)-acrylic acid ethyl
ester for the Suzuki coupling reaction and 5-bromo-2-
1
Thiophene-2-sulfonic acid {3-[2-(3,4-dichlorobenzyl)-
phenyl]-acryloyl}-amide (8c). The compound was pre-
pared according to Scheme 1. 1H NMR (400 MHz,
CDCl3) d 7.97 (d, J=15.4 Hz, 1H), 7.88 (d, J=2.0 Hz,
1H), 7.63 (d, J=4.9 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H),
7.32 (m, 1H), 7.24 (m, 2H), 7.07 (m, 3H), 6.85 (d, J=8.2
Hz, 1H), 6.33 (d, J=15.4 Hz, 1H), 4.07 (s, 2H); ele-
mental analysis calcd for the sodium salt
C20H14Cl2NNaO3S2.1/2H2O: C, 49.7; H, 3.1; N, 2.9; S,
13.27; found: C, 49.46; H, 2.9; N, 2.86; S, 13.73.
methoxyphenylsulfonamide for the final step. H NMR
(400 MHz, CDCl3) d 9.12 (brs, 1H), 8.15 (d, J=2.5 Hz,
1H), 7.95 (d, J=15.5 Hz, 1H), 7.80–7.60 (m, 3H), 7.57
(dd, J=8.8 and 2.5 Hz, 1H), 7.37 (m, 3H), 7.20–7.10 (m,
2H), 7.02 (d, J=2.6 Hz, 1H), 6.85 (m, 1H), 6.70 (d,
J=8.9 Hz, 1H), 6.40 (d, J=15.5 Hz, 1H), 4.13 (s, 2H),
3.77 (s, 3H), 3.72 (s, 3H).
N-[3-(5-allyl-2-naphthalen-2-ylmethyl-phenyl)-acryloyl]-
5-bromo-2-methoxy-benzenesulfonamide (10d). The com-
pound was prepared according to Scheme 1 using 3-(5-
allyl-2-bromomethyl-phenyl)-acrylic acid ethyl ester for
the Suzuki coupling reaction and 5-bromo-2-methoxy-
phenylsulfonamide for the final step. 1H NMR
(400 MHz, CDCl3) d 9.05 (brs, 1H), 8.20 (d, J=2.5 Hz,
1H), 8.05 (d, J=15.6 Hz, 1H), 7.65 (m, 4H), 7.25 (m,
7H), 6.75 (d, J=8.9 Hz, 1H), 6.41 (d, J=15.6 Hz, 1H),
5.92 (m, 1H), 5.10 (m, 2H), 4.22 (s, 2H), 3.75 (s, 3H),
3.35 (m, 2H); HR-MS calcd for the sodium salt
C30H25NO4SBrNa+Na+: 620.0483; found: 620.0481.
Thiophene-2-sulfonic acid {3-[2-(3,5-dichlorobenzyl)-
phenyl]-acryloyl}-amide (8d). The compound was pre-
pared according to Scheme 1. 1H NMR (400 MHz,
CDCl3) d 7.98 (d, J=15.4 Hz, 1H), 7.91 (d, J=3.8 Hz,
1H), 7.72 (d, J=3.8 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H),
7.44 (s, 1H), 7.31 (m, 2H), 7.15 (m, 3H), 6.95 (s, 2H),
6.55 (d, J=15.4 Hz, 1H), 4.11 (s, 2H); HR-MS calcd for
C20H15NO3S2Cl2+H+: 451.9949; found: 451.9949.
5-Bromo-2-methoxy-N-[3-(2-naphthalen-2-ylmethyl-phenyl)-
acryloyl]-benzenesulfonamide (9). Carboxylic acid 4 was
coupled with5-bromo-2-metohxybenzenesulfonamide
5-Bromo-N-{3-[5-chloro-2-(6-fluoro-naphthalen-2-ylmethyl)-
phenyl]-acryloyl}-2-methoxybenzenesulfonamide (11a).
Preparation of the zinc bromide 12:9 to a solution of
activated zinc (389 mg, 5.95 mmol) in 3 mL of DMF
was added 3-(2-bromomethyl-5-chloro-phenyl)-acrylic
acid ethyl ester (1.81 g, 5.95 mmol). The reaction was
1
to afford the title compound 9 in 73% yield. H NMR
(acetone-d6-DMSO-d6) d 8.01 (d, J=15.2 Hz, 1H), 7.91
(m, 5H), 7.65–7.55 (m, 2H), 7.50–7.35 (m, 4H), 7.31 (m,
1H), 7.15 (d, 1H), 6.65 (d, J=15.2 Hz, 1H), 4.31 (s, 2H),
3.85 (s, 3H); elemental analysis calcd for the sodium salt
C27H21BrNNaO4S.1/2H2O: C, 57.15; H, 3.88; N, 2.47;
found: C, 56.88; H, 3.73; N, 2.52.
ꢀ
heated at 100 C for 30 min then cooled down to rt. To
a solution of Pd(dba)2 (137 mg, 0.24 mmol) and dppf
(133 mg, 0.24 mmol) in 20 mL of THF was added tri-
fluoromethanesulfonic acid 6-fluoro-naphthalen-2-yl
ester 1313 (1.75 g, 5.95 mmol) followed by the solution
of zinc bromide 12 previouꢀsly prepared. The reaction
was stirred overnight at 65 C, diluted in ethyl acetate
and quenched with HCl 10%. The organic phase was
washed with brine, dried over MgSO4 and evaporated
to dryness. Purification by flash chromatography affor-
ded 1.03 g (47%) of 3-[5-chloro-2-(6-fluoro-naphthalen-
2-ylmethyl)-phenyl]-acrylic acid ethyl ester 14. 1H NMR
5-Bromo-N-[3-(5-fluoro-2-naphthalen-2-ylmethyl-phenyl)-
acryloyl]-2-methoxy-benzenesulfonamide (10a). The
compound was prepared according to Scheme 1 using 3-
(2-bromomethyl-5-fluoro-phenyl)-acrylic acid ethyl
ester for the Suzuki coupling reaction and 5-bromo-2-
1
methoxyphenylsulfonamide for the final step. H NMR
(400MHz, CDCl3) d 8.52 (brs, 1H), 8.16 (s, 1H), 7.97 (d,
J=15.4 Hz, 1H), 7.65 (m, 4H), 7.42 (m, 3H), 7.23 (m, 3H),

1984
H. Juteau et al. / Bioorg. Med. Chem. 9 (2001) 1977–1984
(400 MHz, CDCl3) d 7.91 (d, J=15.2 Hz, 1H), 7.72 (s,
1H), 7.65 (d, J=7.6 Hz, 2H), 7.55 (s, 1H), 7.43 (s, 1H),
7.32 (d, J=7.6 Hz, 1H), 7.25 (m, 2H), 7.11 (d, J=7.4
Hz, 1H), 6.31 (d, J=15.2 Hz, 1H), 4.20 (q, J=7.3 Hz,
2H), 4.15 (s, 2H), 1.33 (t, J=7.2 Hz, 3H). Hydrolysis
followed by coupling with5-bromo-2-meotxhy-
phenylsulfonamide afforded the title compound 11a.
1H NMR (400 MHz, DMSO-d6) d 7.90–7.75 (m, 5H),
7.64 (m, 1H), 7.58 (d, J=15.8 Hz, 1H), 7.51 (s, 1H),
7.47 (m, 1H), 7.35 (m, 2H), 7.27 (d, J=8.4 Hz, 1H), 7.17
(d, J=8.9 Hz, 1H), 6.53 (d, J=15.7 Hz, 1H), 4.22 (s,
2H), 3.78 (s, 3H); elemental analysis calcd for the
sodium salt C27H19BrFClNNaO4S.2H2O: C, 50.13; H,
3.58; N, 2.17; S, 4.96; found: C, 49.75; H, 3.20; N, 2.29;
S, 4.62.
Adam, M.; Metters, K. M. J. Biol. Chem. 1993, 268, 26767.
EP2: Regan, J. W.; Bailey, T. J.; Pepperl, D. J.; Pierce, K. L.;
Bogardus, A. M.; Donello, J. E.; Fairbairn, C. E.; Kedzie,
K. M.; Woodward, D. F.; Gil, D. W. Mol. Pharmacol. 1994,
46, 213. EP3: Adam, M.; Boie, Y.; Rushmore, T. H.; Muller,
G.; Bastien, L.; McKee, K. T.; Metters, K. M.; Abramovitz,
M. FEBS Lett. 1994, 338, 170. EP4: Bastien, L.; Sawyer, N.;
Grygorczyk, R.; Metters, K. M.; Adam, M. J. Biol. Chem.
1994, 269, 11873. DP: Boie, Y.; Sawyer, N.; Slipetz, D. M.;
Metters, K. M.; Abramovitz, M. J. Biol. Chem. 1995, 270,
18910. FP: Abramovitz, M.; Boie, Y.; Nguyen, T.; Rushmore,
T. H.; Bayne, M. A.; Metters, K. M.; Slipetz, D. M.; Gry-
gorczyk, R. J. Biol. Chem. 1994, 269, 2632. IP: Boie, Y.;
Rushmore, T. H.; Darmon-Goodwin, A.; Grygorczyk, R.;
Slipetz, D. M.; Metters, K. M.; Abramovitz, M. J. Biol. Chem.
1994, 269, 12173. TP: Hirata, M.; Hayashi, Y.; Ushikubi, F.;
Yokota, Y.; Kageyama, R.; Nakanishi, S.; Narumiya, S. Nat-
ure 1991, 349, 617.
5-Bromo-N-{3-[5-chloro-2-(6-chloro-naphthalen-2-ylmethyl)-
phenyl]-acryloyl}-2-methoxybenzenesulfonamide (11b).
The compound was prepared according to Scheme 3.
1H NMR (400 MHz, acetone-d6) d 7.98 (s, 1H), 7.92–
7.75 (m, 5H), 7.59 (d, J=15.1 Hz, 1H), 7.55 (s, 1H),
7.45 (m, 2H), 7.40–7.30 (m, 2H), 7.20 (d, J=8.0 Hz,
1H), 6.53 (d, J=15.1 Hz, 1H), 4.22 (s, 2H), 3.78 (s, 3H);
elemental analysis calcd for the sodium salt
C27H19BrCl2NNaO4S.2H2O: C, 49.01; H, 3.33; N, 2.14;
found: C, 48.89, H, 3.47; N, 2.11.
2. Abramovitz, M.; Adam, A.; Boie, Y.; Godbout, C.;
Lamontagne, S.; Rochette, C.; Sawyer, N.; Tremblay, N. M.;
Belley, M.; Gallant, M.; Dufresne, C.; Gareau, Y.; Ruel, R.;
Juteau, H.; Labelle, M.; Ouimet, N.; Metters, K. M. Biochim.
Biophys. Acta 2000, 1483, 285.
3. Kiryiama, A.; Ushikubi, F.; Kobayashi, T.; Hirata, M.;
Sugimoto, Y.; Narumiya, S. Br. J. Pharmacol. 1997, 122, 217.
4. Sugimoto, Y.; Narumiya, S.; Ichikawa, A. Prog. Lipid. Res.
2000, 39, 289. Narumiya, S.; Sugimoto, Y.; Ushikubi, F. Phy-
siol. Rev. 1999, 79, 1193. Coleman, R. A.; Smith, W. L.; Nar-
umiya, S. Pharmacol. Rev. 1994, 46, 205.
5. Shimazaki, Y.; Kameo, K.; Tanami, T.; Tanaka, H.; Ono,
N.; Kiuchi, Y.; Okamoto, S.; Sato, F.; Ichikawa, A. Bioorg.
Med. Chem. 2000, 8, 353.
6. Juteau, H.; Gareau, Y.; Labelle, M.; Lamontagne, S.;
Tremblay, N.; Carriere, M. C.; Sawyer, N.; Denis, D.; Met-
ters, K. M. Bioorg. Med. Chem. Lett. 2001, 11, 747.
7. The subtype used for this assay was EP3-III.
8. For the methodology, see: Sturino, C. F.; Labelle, M. Tet-
rahedron Lett. 1998, 39, 5891.
9. Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org.
Chem. 1988, 53, 2392. Knochel, P.; Palmer, N.; Rottlander,
M. Synlett 1996, 573.
5-Bromo-N-{3-[5-chloro-2-(6-chloroquinolin-2-ylmethyl)-
phenyl]-acryloyl}-2-methoxy-benzenesulfonamide (11c).
The compound was prepared according to Scheme 3.
1H NMR (400 MHz, DMSO-d6) d 8.22 (d, J=8.9 Hz,
1H), 8.05 (s, 1H), 7.95 (d, J=15.4 Hz, 1H), 7.92 (s, 1H),
7.82 (m, 2H), 7.67 (m, 1H), 7.55 (s, 1H), 7.41 (m, 3H),
7.23 (d, J=8.8 Hz, 1H), 6.55 (d, J=15.3 Hz, 1H), 4.42 (s,
2H), 3.82 (s, 3H); HR-MS calcd for the sodium salt
C26H18N2O4SCl2BrNa+Na+: 648.9343; found: 648.9344.
10. All the compounds described in this paper behave as full
antagonists.
Acknowledgements
11. Yeager, G. W.; Schissel, D. N. Synthesis 1995, 28.
12. Suschitzky, H.; Bentley, R. L. J. Chem. Soc. Perkin I 1976,
1725.
The authors would like to thank Dr. John Colucci for
proofreading this manuscript.
13. Ellingboe, J. W.; Lombardo, L. J.; Alessi, T. R.; Nguyen,
T. T.; Guzzo, F.; Guinosso, C. J.; Bullington, J.; Browne,
E. N. C.; Bagli, J. F.; Wrenn, J.; Steiner, K.; McCaleb, M. L.
J. Med. Chem. 1993, 36, 2485. Adcock, W.; Dewar, M. J. S. J.
Am. Chem. Soc. 1967, 89, 386. Yu, K. L.; Ostrowski, J.; Chen,
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References and Notes
1. EP1: Funk, C. D.; Furci, L.; FitzGerald, G. A.; Gry-
gorczyk, R.; Rochette, C.; Bayne, M. A.; Abramovitz, M.;