Synthesis and biological evaluation of 3,4-diaryloxazolones: A new class of orally active cyclooxygenase-2 inhibitors

Article abstract of DOI:10.1021/jm991106b

A series of 3,4-diaryloxazolones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors we

Full text of DOI:10.1021/jm991106b

214
J . Med. Chem. 2000, 43, 214-223
Syn th esis a n d Biologica l Eva lu a tion of 3,4-Dia r yloxa zolon es: A New Cla ss of
Or a lly Active Cyclooxygen a se-2 In h ibitor s
Carles Puig, Mar´ıa I. Crespo,* Nu´ria Godessart, J oan Feixas, J avier Ibarzo, J uan-Miguel J ime´nez, L´ıdia Soca,
Ignasi Cardelu´s, Ascensio´n Heredia, Montserrat Miralpeix, J aume Puig, J ordi Beleta, J osep M. Huerta,
Manel Lo´pez, Victor Segarra, Hamish Ryder, and J ose´ M. Palacios
Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024 Barcelona, Spain
Received J une 23, 1999
A series of 3,4-diaryloxazolones were prepared and evaluated for their ability to inhibit
cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out
within this series, and a number of potent and selective COX-2 inhibitors were identified. The
replacement of the methyl sulfone group on the 4-phenyl ring by a sulfonamide moiety resulted
in compounds with superior in vivo antiinflammatory properties. In the sulfonamide series,
the introduction of a methyl group at the 5-position of the oxazolone ring gave rise to very
COX-2-selective compounds but with decreased in vivo activity. Selected 3,4-diaryloxazolones
exhibited excellent activities in experimental models of arthritis and hyperalgesia. The in vivo
activity of these compounds was confirmed with the evaluation of their antipyretic effectiveness
and their ability to inhibit migration of proinflammatory cells. As expected from their COX-2
selectivity, most of the active compounds lacked gastrointestinal toxicity in vivo in rats after
a 4-day treatment of 100 mg/kg/day. Within this novel series, sulfonamides 9-11 have been
selected for further preclinical evaluation.
Ch a r t 1. Structures of Some Selective COX-2 Inhibitors
In tr od u ction
The use of nonsteroidal antiinflammatory drugs
(NSAIDs) for the treatment of inflammation and pain
is often accompanied by gastrointestinal ulcerations and
bleeding. The inhibition of cyclooxygenase (COX), the
enzyme that catalyzes the conversion of arachidonic acid
into prostaglandins and thromboxane, was considered
for a long time to be responsible for both the therapeutic
and the adverse effects of NSAIDs. In 1990, the exist-
ence of a second COX enzyme, named COX-2, was
described.1,2 COX-2 is an immediate-early gene induced
by mitogenic and proinflammatory stimuli,3 and it has
been postulated to be the isoform involved in inflam-
matory processes.4 In contrast, COX-1 is expressed
constitutively and is believed to play a role in physi-
ological processes such as gastroprotection and vascular
homeostasis.5 Currently available NSAIDs inhibit both
COX-1 and COX-2, most of them exhibiting a selectivity
for COX-1.6
The discovery and characterization of COX-2 sug-
gested that selective inhibition of this enzyme might
avoid the side effects of currently available NSAIDs
while retaining their therapeutic efficacy. The hypoth-
esis was partially proven when the first selective
compounds, NS-398 and DuP-697 (Chart 1), were tested
in animal models. Both compounds showed antiinflam-
matory, analgesic, and antipyretic activities, but they
did not cause gastrointestinal lesions at high doses.7-10
Extensive libraries of selective COX-2 inhibitors have
been developed by different laboratories in the last 5
years. Most of the compounds fit into three main
categories: (1) acidic sulfonamides such as NS-398,7
L-745,337,11 and flosulide,12 (2) diaryl heterocycles such
as DuP-697,9 rofecoxib,13 and celecoxib14 (Chart 1), and
(3) modifications of classical NSAIDs such as zomepirac
and indomethacin derivatives.
Recently two selective COX-2 inhibitors, celecoxib and
rofecoxib, have demonstrated efficacy in clinical trials
of acute pain, osteoarthritis, and rheumatoid arthri-
tis.15-17 Furthermore, both compounds showed a supe-
rior gastrointestinal safety profile when compared to
naproxen, diclofenac, or ibuprofen, confirming that this
approach constitutes a promising alternative for the
treatment of rheumatic diseases.
In this work we report the characterization of a new
diaryl heterocyclic series, the 3,4-diaryloxazolones, a
family of orally active, potent, and selective COX-2
inhibitors.
* To whom correspondence should be addressed. Tel: 34-3-291-35-
86. Fax: 34-3-291-34-20. E-mail: macrespo@almirallprodesfarma.com.
10.1021/jm991106b CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/30/1999

Synthesis/ Evaluation of 3,4-Diaryloxazolones
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 2 215
Sch em e 1a
Potent and selective COX-2 inhibitors were evaluated
in vivo in the rat carrageenan-induced foot paw edema
model. Compounds showing good oral antiinflammatory
activity in this model were then tested in an assay of
inflammatory pain (hyperalgesia), in a chronic model
of inflammation (adjuvant-induced arthritis), in an
experimental model of fever (pyresis), and in a model
of cellular infiltration (air pouch). Finally, gastrointes-
tinal toxicity of selected compounds was evaluated in a
4-day administration protocol.
Resu lts a n d Discu ssion
Str u ctu r e-Activity Rela tion sh ip . In the diaryl
heterocyclic class of COX-2 inhibitors, it has been well-
established that a p-methyl sulfone or sulfonamide on
one of the phenyl groups is a requirement for good
COX-2 potency and selectivity.14,20 In the 3,4-diarylox-
azolone series, we found that only the compounds with
these substituents on the 4-phenyl ring were active. So,
taking into account this structural restriction, we
planned the structure-activity relationship work using
4-(4-methanesulfonylphenyl)oxazolone and 4-(4-sulfam-
oylphenyl)oxazolone as templates. Since the N3 sub-
stituents offered the most flexibility with regards to
maintenance of COX-2 inhibitory activity, we explored
modifications at this site while holding constant the
5-substituent as either hydrogen or methyl. Results are
shown in Table 1.
In the 5HO sulfone family (compounds 1-8), the
presence of halogen atoms on the N3-phenyl ring
generally enhanced the COX-2 activity with respect to
the unsubstituted analogue 1. The 2- and 4-fluoro
derivatives (compounds 2 and 3, respectively) were
3-fold more potent than compound 1, while compound
8 (2,4-difluoro), with similar COX-2 activity, was less
selective. The most active halogen derivative was 4 (4-
chloro), with a potency similar to that of indomethacin
and almost 50-fold selectivity. Increased COX-2 activity
was maintained in the 4-alkyl analogues 6 and 7 with
the latter compound being among the most selective.
For the 4-trifluoromethyl derivative 5, COX-2 potency
was maintained while COX-1 was completely elimi-
nated.
Preliminary results had shown that 5HO sulfones
were less active in vivo after oral administration than
the corresponding 5HO sulfonamides. This finding is in
close agreement with literature results for related
series.14,21 Consequently, synthetic efforts were focused
on the sulfonamide series.
Within the 5HO sulfonamide analogues (compounds
9-28), modifications at the N3 position also yielded
interesting compounds. In general, introduction of sub-
stituents at the 3- and 4-positions of the N3-phenyl
group resulted in more potent COX-2 inhibitors than
the unsubstituted analogue 9. By way of contrast,
modifications at the 2-position gave more variable
results. When the substituent was fluorine, the result-
ing compounds, 10 and 23, were as potent as compound
9, while the slightly more bulky substituents chlorine
(compound 12) and methyl (compound 16) led to a
reduction of activity. These results suggest that the
steric effect of these substituents at the ortho position
promotes a conformation with lower affinity for the
a
Reagents: (a) Br2, CHCl3; (b) betaine, EtOH then saturated
NaHCO3; (c) 100 °C then AcOH, reflux.
Ch em istr y
The synthetic route for the sulfones 1-8 is outlined
in Scheme 1. The commercially available 1-(4-methane-
sulfonylphenyl)ethanone was converted to the phenacyl
alcohol 35 through the bromo derivative 34. Thus,
treatment of 34 with betaine yielded the intermediate
ester which was hydrolyzed in situ to 35 in mild aqueous
basic conditions. The addition of 35 to the appropriately
substituted phenyl isocyanate and subsequent cycliza-
tion in acidic medium afforded the oxazolones 1-8 in
moderate yields (21-56%).
In a similar way, the synthesis of the 5H-oxazolone
(5HO) sulfonamide derivatives 9-28 (see Scheme 2) was
achieved by the same addition/cyclization process start-
ing from the phenacyl alcohol 38. This intermediate
alcohol was obtained from the commercially available
sodium 4-acetylbenzenesulfonate in three steps com-
prising the formation of the sulfonamide 36, its bromi-
nation to 37, and final hydrolysis analogous to that
described for the sulfone 35. As mentioned above, the
addition of 38 to the corresponding isocyanate and
subsequent cyclization in acetic acid yielded the oxazo-
lones 39-58. Final debenzylation was achieved with
concentrated sulfuric acid to give the target sulfon-
amides 9-28 (yields: 20-80%).
The 5-methyloxazolone (5MO) sulfonamide deriva-
tives 29-33 were obtained from the corresponding 5HO
sulfonamides via bromination and subsequent Stille
coupling reaction with tetramethyltin (see Scheme 3),
followed by debenzylation as described above for the
5HO analogues.
Biology
All compounds described herein were tested for their
ability to inhibit human COX-1 and COX-2 using the
whole blood assay described by Patrignani et al.18 This
assay, in our hands, was much more predictive of
functional selectivity and hence gastrointestinal safety
than cell culture models such as monocytes or endo-
thelial cells. Furthermore, the same whole blood assay
has been used to evaluate the inhibition of COX-2 ex
vivo after oral administration to healthy subjects.19

216 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 2
Puig et al.
Sch em e 2a
a
Reagents: (a) POCl3 then Bn2NH, Et3N, THF; (b) Br2, CHCl3; (c) betaine, EtOH then saturated NaHCO3; (d) toluene, reflux then
AcOH, reflux; (e) H2SO4.
Sch em e 3a
33 showed a COX-2 activity comparable to its corre-
sponding demethylated analogue 24 but was 5-fold more
selective.
In summary, within the 3,4-diaryloxazolone series, we
found COX-2 inhibitors as potent as indomethacin and
with selectivities comparable to or greater than that of
celecoxib.
In Vivo Activity. Compounds displaying reasonable
COX-2 inhibitory activity and some degree of selectivity
over COX-1 were evaluated by oral route in the carra-
geenan paw edema assay (Table 1). In the sulfone series,
only the fluoro analogues 2, 3, and 8 showed a good
inhibition of edema. Other derivatives (compounds 1
and 4-7), despite good COX-2 potency, were moderately
active in vivo. A lack of dose-response effect was
observed for some of these compounds, with a plateau
of an average of 30% inhibition at 3-30 mg/kg. No
conclusive explanation for this behavior has been found.
For the 5HO sulfonamide family, the activity in the
carrageenan edema test was consistently good. Two of
the most active compounds in this in vivo assay, the
methylated analogues 17 and 18, showed also the best
COX-2 potency. The introduction of a 5-methyl sub-
stituent in the oxazolone ring caused a loss in oral
activity. In general, ED35 values for 5MO sulfonamides
were lower than those for their corresponding 5HO
analogues.
a
Reagents: (a) Br2, CHCl3; (b) Me4Sn, Pd(OAc)2, P(o-tolyl)3,
Et3N, DMF; (c) H2SO4.
COX-2 enzyme. In the 3- and 4-methyl derivatives 17
and 18, the COX-2 inhibitory activity and selectivity
were enhanced with respect to their corresponding
halogen-susbstituted analogues (compounds 11, 13, and
14). As with the sulfone series, the introduction of
4-trifluoromethyl resulted in a complete loss of COX-1
activity, while the COX-2 potency was maintained.
4-Methoxy substitution (compound 20) increased the
affinity for both enzymes while reducing selectivity. The
undesired COX-1 activity was modulated slightly by
introduction of a halogen atom R to the 4-methoxy group
(compounds 25 and 26), in agreement with published
literature.14,21 By way of contrast, the same modification
using the 4-chloro analogue 14 as a template gave a
3-fold improvement in COX-2 potency and a decrease
in selectivity (compound 24). The compounds substi-
tuted by a carboxylic group were completely inactive
(compounds 21 and 22). The non-phenyl derivatives
cyclohexyl and 2-naphthyl (compounds 27 and 28,
respectively) were less potent.
A selected group of 3,4-diaryloxazolones with good
activity in the carrageenan assay and/or superior COX-2
selectivity was evaluated by oral route in adjuvant-
induced arthritis and carrageenan-induced hyperalgesia
(Table 2). Superior in vivo activity was observed for the
5HO sulfonamide series. These compounds, when com-
pared to their corresponding 5HO sulfone derivatives,
displayed a 4-10-fold decrease in ED50 values in
arthritis (see compounds 10 and 11 versus compounds
2 and 3). Among the 5MO sulfonamides tested (com-
pounds 29, 30, and 33), compound 33 exhibited the best
analgesic and antiarthritic profile. Furthermore, a
decrease in ED50 values in both assays was observed
for compounds 29 and 30 with respect to their corre-
sponding 5HO sulfonamides.
The COX-2 selectivity was significantly enhanced by
the introduction of a methyl group at the 5-position of
the oxazolone ring (5MO sulfonamides 29-33), while
the potency was maintained. For example, compound

Synthesis/ Evaluation of 3,4-Diaryloxazolones
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 2 217
Ta ble 1. 4-Phenyloxazolones as COX Inhibitors
rat carrageenan
oxazolone series
5HO sulfone
compd
R1
R2
R3
COX-1a
COX-2a
COX-1/COX-2
paw edemab
1
2
3
4
5
6
7
8
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
H
33.6 ( 0.8
13.4 ( 3.2
5.1 ( 1.3
13.6 ( 2.2
>100
11.6 ( 1.7
42.4 ( 10.5
6.94 ( 0.04
24.4 ( 1.8
27.9 ( 0.7
13.2 ( 1.8
35.4 ( 8.2
10.8 ( 4.6
7.0 ( 1.2
>100
1.6 ( 0.3
0.66 ( 0.04
0.51 ( 0.14
0.32 ( 0.05
2.0 ( 0.1
21
20
10
42
>50
24
61
5
10
13
9
5
7
24 ( 7
2.4
0.6
2-FC6H4
4-FC6H4
4-ClC6H4
4-CF3C6H4
4-CH3C6H4
4-CH3CH2C6H4
2,4-diFC6H3
C6H5
2-FC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
10
21 ( 5
27 ( 6
23 ( 8
1.4
0.4
1.7
2.0
nt
1.3
1.6
2.4
nt
0.9
0.7
3.9
nt
nt
nt
2.3
nt
3.0
2.4
nt
13 ( 11
1.7
1.1
23 ( 7
2.6
4.4
1.0
0.45
1.1
0.48 ( 0.01
0.69 ( 0.24
1.35 ( 0.06
2.4 ( 0.7
5HO sulfonamide
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
2.2 ( 0.9
1.5 ( 0.4
6.5 ( 2.3
1.5 ( 0.2
4-ClC6H4
1.2 ( 0.2
6
4-CF3C6H4
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-CH3CH2C6H4
4-CH3OC6H4
3-HOOCC6H4
4-HOOCC6H4
2,4-diFC6H3
3,4-diClC6H3
4-CH3O,3-FC6H3
2.0 ( 0.1
>50
29.0 ( 1.4
6.6 ( 1.0
10.9 ( 2.2
10.4 ( 4.7
0.9 ( 0.2
>100
9.7 ( 4.3
3
0.51 ( 0.26
0.79 ( 0.04
1.56 ( 0.06
0.21 ( 0.04
>100
13
14
7
4
-
>100
59% ( 17
2.3 ( 0.9
0.4 ( 0.1
-
15.3 ( 1.0
1.5 ( 0.4
5.1 ( 2.2
5.8 ( 0.7
>100
7
4
5
7
>5
8
27
90
18
26
38
1
1.13 ( 0.05
0.78 ( 0.14
18.9 ( 5.0
4.7 ( 2.1
4-CH3O,3-ClC6H3 NH2
cyclohexyl
1-naphthyl
C6H5
NH2
NH2
37.1 ( 9.4
49.3 ( 17.2
45.8 ( 14.0
16.9 ( 3.5
43.5 ( 8.1
8.7 ( 0.5
0.25 ( 0.03
11.0 ( 1.4
14.2 ( 4.4
5MO sulfonamide 29
NH2 CH3
NH2 CH3
NH2 CH3
NH2 CH3
NH2 CH3
1.8 ( 0.5
30
31
32
33
4-FC6H4
0.51 ( 0.23
0.93 ( 0.11
1.7 ( 0.2
3-CH3C6H4
4-CH3C6H4
3,4-diClC6H3
0.23 ( 0.05
0.22 ( 0.07
18.9 ( 2.9
1.1 ( 0.2
indomethacin
naproxen
celecoxib
0.6
13
a
b
Data are indicated as IC50 (µM) or percentage of inhibition at 100 µM ( SEM (n ) 3). Data are indicated as ED35 (mg/kg) using four
doses (6-8 animals/group) or percentage of inhibition at 3 mg/kg ( SEM (6-7 animals); nt: not tested.
The most active sulfonamides in arthritis (ED50 < 2
mg/kg) were further evaluated in pyresis and in the air
pouch model (Table 2). Whereas all the compounds
displayed good activity in the air pouch assay, com-
pounds 15 and 33 showed a low potency as antipyretics.
Both compounds were also the least active in arthritis.
The higher oral activity of the 5HO sulfonamide
family, particularly in arthritis (a 7-day assay with once
a day administration), suggests that these compounds
might have a superior pharmacokinetic profile.
The evaluation of a selected group of sulfonamides
on gastrointestinal toxicity (Table 3) showed that these
compounds did not cause any ulceration or hemoglobin
loss after a 4-day treatment at 100 mg/kg/day. Only
compound 14 exhibited ulcerogenic properties, but these
were very mild when compared to the classical NSAIDs
indomethacin or naproxen. Another important indica-
tion of general toxicity, body weight loss, was not
observed for any of the sulfonamides tested.
domethacin, naproxen, and celecoxib. Excellent oral
activity combined with a lack of gastrointestinal side
effects suggests that these compounds could be a safer
alternative to classical NSAIDs in the treatment of
acute and chronic inflammatory processes.
Con clu sion s
We have identified a novel series of 3,4-diaryloxazo-
lones as potent and selective COX-2 inhibitors. We have
demonstrated that the replacement of the methyl sul-
fone group on the 4-phenyl ring by a sulfonamide moiety
enhances in vivo potency. The in vitro COX-2 selectivity
could be increased by the introduction of a methyl at
the 5-position of the oxazolone ring, although there is a
concomitant decrease in in vivo activity. A selected
group of 3,4-diaryloxazolones exhibited excellent oral
activity when tested in acute and chronic assays of
inflammation, fever, and pain. Furthermore, these
compounds were devoid of gastrointestinal toxicity at
high doses. The overall pharmacological activity of the
3,4-diaryloxazolones suggests that these novel com-
pounds constitute a promising series of oral antiinflam-
In conclusion, the overall pharmacological profiles of
the 5HO sulfonamides tested were similar to or better
than those exhibited by the reference compounds in-

218 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 2
Puig et al.
Ta ble 2. In Vivo Pharmacological Profile of Selected
Oxazolones
triplicate. Plasma was separated by centrifugation (4 min at
13000 rpm) and kept at -30 °C until PGE2 levels were
measured using an ELISA kit (Amersham). IC50 values were
obtained by nonlinear regression using InPlot, GraphPad
software.
In Vivo Assa ys: Gen er a l P r oced u r es. Male Wistar rats
(Interfauna, U.K., Ltd.) were used. Test compounds were
suspended in a vehicle containing 0.5% methyl cellulose and
0.1% Tween and administered in a volume of 10 mL/kg. Unless
indicated, rats were fasted with free access to water for 18 h
prior to the assay. Statistical analysis between the different
treatment groups was calculated according to the analysis of
variance ANOVA test. A value of p < 0.05 was considered to
be significant.
hyper- adjuvant
air
oxazolone series
5HO sulfone
compd
algesiaa arthritisa pyresisa pouchb
2
3
8
9
10
11
14
15
17
18
32
2.5
21
1.1
2.7
3.9
0.5
8.1
7.2
3.8
7.7
>3
2.8
nt
nt
nt
0.5
1.2
2.4
2.3
11
nt
nt
nt
2.5
0.15
0.27
0.6
0.2
1
5HO sulfonamide
1.2
1.6
0.4
1.2
2.6
0.47
1.7
nt
nt
0.85
2
1.4
3
0.6
0.34
>3
1.8
3.3
nt
5MO sulfonamide 29
All the experimental protocols used in this paper have been
approved by the appropriate animal ethics committees.
30
33
14
3
1.2
5.2
6.2
3
nt
1.6
0.22
6.1
0.5
8.7
1.5
0.8
0.6
Ca r r a geen a n -In d u ced P la n ta r Ed em a in th e Ra t. The
experimental protocol described by Winter et al. was used.22
Rats (150-175 g) were randomly distributed in groups of 6
animals each, and at time 0, drug or vehicle was administered
by oral route. One hour later, 0.1 mL of a carrageenan
suspension (1% w/v in saline solution) was injected subcutane-
ously in the left hind paw of the animals. Volume of paw edema
(mL) was measured using a water plethysmometer immedi-
ately after carrageenan injection and 3 h later. The increase
in paw volume between time 0 and time +3 h was determined.
The percentage of inhibition versus the mean value of the
control group was calculated.
Ca r r a geen a n -In d u ced Hyp er a lgesia . Rats (200-230 g)
were treated as previously described for the carrageenan
edema test. Five hours after the injection of carrageenan, each
animal was introduced in a transparent plastic cage (80 × 80
× 30 cm) with a wood shavings bed. The difficulty of walking
was assessed by an observer unaware of the treatment. An
score of 0, 1, or 2 was used indicating different degrees of
disability in the movement of the inflammed paw. The score
obtained by each animal was compared with that of the
vehicle-treated group and the percentage of inhibition was
calculated. Linear regression was used to calculate the ED50
values.
Ad ju va n t-In d u ced Ar th r itis. Rats (175-200 g) had free
access to food and water along the assay. On day 0, the animals
received an intraplantar injection of a suspension of Myco-
bacterium tuberculosis in paraffine oil (0.5 mg/rat) on the left
hind paw. A group of 8 nonarthritic control rats were injected
with paraffine oil alone. On days 11 and 14 after the induction
of arthritis, the volume of the hind paws of each rat was
measured using a water plethysmometer and rats whose paw
volumes increased during that time were selected. Animals
were distributed in groups of 8 animals having equivalent
mean paw volumes and standard deviations.
Tests compounds were administered by oral route once daily
for 7 days (days 14-20). Nonarthritic and arthritic control rats
received vehicle alone for 7 days. Hind paw volumes were
measured 20 h after the last dose (on day 21). Body weight
was determined every day.
indomethacin
naproxen
celecoxib
a
Data are indicated as ED50 (mg/kg) using four doses, 6-8
b
animals/group. Data are indicated as ED35 (mg/kg) using four
doses, 6-8 animals/group; nt: not tested.
Ta ble 3. Effect of Selected Oxazolones on Gastrointestinal
Toxicity
dose
Hgb
oxazolone series
5HO sulfonamide
compd
(mg/kg) PUa NPUa (g/dl)b
9
100
100
100
100
100
100
100
100
10
0
0
0
3
0
0
0
0
0
0
0
14.8
11.6
12.6
10
11
14
15
17
18
2.1 12.5
0
0
0
0
11.5
12.8
12.9
14.6
5.7*
7.5*
13.2
5MO sulfonamide 33
indomethacinc
naproxenc
celecoxib
280 300
50
100
192
0
96
0
a
PU: perforated ulcers; NPU: nonperforated ulcers. Results
are expressed as ulcer score per incidence (percentage of animals
b
with ulcers). Hemoglobin levels for the vehicle-treated groups in
the different assays ranged from 11.5 to 14.7 g/dl. c A significant
body weight loss was only observed following indomethacin and
naproxen treatments; *p < 0.01.
matory agents with the potential for an improved side
effect profile. Compounds 9-11, on the basis of their in
vivo activity profiles and lack of gastrointestinal toxicity,
have been selected for further preclinical and clinical
profiling. Results of these studies will be reported in due
course.
Exp er im en ta l Section
COX-1 Activity in Hu m a n Wh ole Blood . Fresh blood
from healthy volunteers who had not taken any NSAIDs for
at least 7 days prior to blood extraction was collected in
heparinized tubes (20 U/mL). Aliquots of 500 µL of blood were
incubated either with 5 µL of vehicle (DMSO) or 5 µL of test
compound solution for 1 h at 37 °C. Five to six different
concentrations of each compound were used and determina-
tions made in triplicate. Calcium ionophore A23187 (25 µM)
was added 20 min before stopping the reaction. Plasma was
separated by centrifugation (4 min at 13000 rpm) and kept at
-30 °C until TXB2 levels were measured using an ELISA kit
(Amersham). IC50 values were obtained by nonlinear regres-
sion using InPlot, GraphPad software.
COX-2 Activity in Hu m a n Wh ole Blood . Aliquots of 500
µL of blood (obtained as indicated above) were incubated with
either 5 µL of vehicle (DMSO) or 5 µL of test compound
solution in the presence of LPS (10 µg/mL) for 24 h at 37 °C to
induce COX-2 expression.18 Five to six different concentrations
of each compound were used and determinations made in
Percentages of inhibition of inflammation (measured as paw
volume inhibition) and ED50 values were calculated for each
treatment.
P yr esis. Rats (180-200 g) were randomly distributed in
groups of 6 animals each. The day before drug administration,
a measure of the body temperature was determined at 10:00
a.m. with a rectal probe (YSI, model LN-423) connected to a
digital thermometer (Cibertec, model P-6). Six hours later, a
suspension of 15% yeast extract (Saccharomyces cerevisiae) in
saline (10 mg/kg) was injected subcutaneously at the back of
the animals. A group of 6 animals received sterile saline alone
(normothermic group). All animals were then fasted overnight
with water ad libitum. The day after, a measure of rectal
temperature was taken in the morning and 1 h later, the
compounds were administered by oral route. A group of 6
animals injected with yeast extract (hyperthermic group) and
the normothermic group received vehicle alone. Measurements

Synthesis/ Evaluation of 3,4-Diaryloxazolones
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 2 219
of rectal temperature were taken at intervals of 60 min for
the next 5 h.
3H-oxa zol-2-on e (1). A solution of 3.00 g (14.0 mmol) of 35
and 5 mL (5.48 g, 46.0 mmol) of phenyl isocyanate was heated
at 100 °C for 2 h. After being cooled, the mixture was treated
with ethyl ether. The resulting solid was filtered and sus-
pended in 43 mL of acetic acid. The mixture was refluxed for
8 h, cooled, and diluted with 15 mL of EtOH. The crystallized
solid was filtered and dried to yield 1.90 g (43%) of the title
compound: mp 207-209 °C dec; 1H NMR (CDCl3) δ 7.83 (d, J
) 8 Hz, 2H), 7.46-7.34 (m, 3H), 7.27 (d, J ) 8 Hz, 2H), 7.23-
7.14 (m, 3H), 3.00 (s, 3H). Anal. (C16H13NO4S) C, H, N, S.
3-(2-F lu or op h en yl)-4-(4-m et h a n esu lfon ylp h en yl)-3H -
oxa zol-2-on e (2) was prepared according to method A starting
from 35 (2.00 g) and 2-fluorophenyl isocyanate. Recrystalli-
zation from CH3CN and ethyl ether gave 1.00 g (32%) of 2:
mp 186-187 °C; 1H NMR (DMSO) δ 7.95 (s, 1H), 7.87 (d, J )
8 Hz, 2H), 7.61-7.50 (m, 2H), 7.42-7.31 (m, 2H), 7.38 (d, J )
8 Hz, 2H), 3.20 (s, 3H). Anal. (C16H12FNO4S) C, H, N, S.
3-(4-F lu or op h en yl)-4-(4-m et h a n esu lfon ylp h en yl)-3H -
oxa zol-2-on e (3) was prepared according to method A starting
from 35 (1.00 g) and 4-fluorophenyl isocyanate. Purification
by flash chromatography, eluting with CHCl3, gave 0.70 g
(45%) of 3: mp 167-168 °C; H NMR (DMSO) δ 7.87 (d, J )
8 Hz, 2H), 7.84 (s, 1H), 7.41-7.28 (m, 4H), 7.34 (d, J ) 8 Hz,
2H), 3.20 (s, 3H). Anal. (C16H12FNO4S) C, H, N, S.
3-(4-Ch lor op h en yl)-4-(4-m et h a n esu lfon ylp h en yl)-3H-
oxa zol-2-on e (4) was prepared according to method A starting
from 35 (2.00 g) and 4-chlorophenyl isocyanate. Crystallization
from EtOH/ethyl ether gave 1.80 g (55%) of 4: mp 220 °C; 1H
NMR (DMSO) δ 8.00 (d, J ) 8.5 Hz, 2H), 7.87 (s, 1H), 7.53 (d,
J ) 8.5 Hz, 2H), 7.37 (d, J ) 8.5 Hz, 2H), 7.32 (d, J ) 8.5 Hz,
2H), 3.23 (s, 3H). Anal. (C16H12ClNO4S) C, H, N, S.
The area under the curve (AUC0-5h) using the mean value
of each treatment was calculated taking into account the
maximum and minimum values stablished by both the hyper-
thermic and normothermic groups. The percentage of inhibi-
tion and the ED50 values were calculated for each treatment.
Ulcer ogen ic Activity. Rats (150-175 g) had free access
to food and water along the assay. Animals were distributed
at random in groups of 10 rats each. Vehicle or test compounds
were administered by the oral route once a day for 4 consecu-
tive days. In each experiment a group administered with 10
mg/kg indomethacin was included for interassay comparisons.
Body weight was assessed every day. The animals were
anesthetized 24 h after the last dosing, 1 mL of blood was
extracted by cardiac puncture using heparin (10 U/mL) as
anticoagulant, and the hemoglobin levels were measured. Rats
were killed by cervical dislocation and the abdomen was
incised along the midline. The whole intestine was removed,
opened longitudinally, and gently washed. The macroscopic
severity of the intestinal erosions was assessed using a
parametric scale, evaluating the number of the perforated and
nonperforated ulcers by means of a lesion index ranging from
0 to 3 (0: no ulcers, 1: <10 ulcers, 2: 10-25 ulcers, 3: >25
ulcers). The percentage of animals with both types of ulcers
was also determined for each group. No gastric ulcers were
observed using this protocol.
Ca r r a geen a n -In d u ced Air P ou ch . Rats (150-175 g) were
distributed at random in groups of 6 rats each. On day 0,
animals received an injection of 20 mL of air into the
subcutaneous tissue of the back. On day 3, vehicle or test
compounds were administered by oral gavage. One hour later,
5 mL of a 0.4% carrageenan suspension was injected into the
cavity. Five hours after carrageenan injection, rats were
sacrificed, the air pouch was washed with 5 mL of saline and
opened, and exudate volumes and number of white blood cells
were recorded (Sismex K-800). Percentage of inhibition of the
total cell number in the pouch and the ED50 values were
determined for each treatment.
1
4-(4-Me t h a n e su lfon ylp h e n yl)-3-(4-t r iflu or om e t h yl-
p h en yl)-3H-oxa zol-2-on e (5) was prepared according to
method A starting from 35 (2.00 g) and 4-trifluoromethyl-
phenyl isocyanate. Recrystallization from EtOH gave 2.00 g
1
(56%) of 5: mp 189-190 °C; H NMR (DMSO) δ 7.92 (d, J )
8 Hz, 2H), 7.90 (s, 1H), 7.84 (d, J ) 8.5 Hz, 2H), 7.51 (d, J )
8 Hz, 2H), 7.38 (d, J ) 8.5 Hz, 2H), 3.22 (s, 3H). Anal.
(C17H12F3NO4S) C, H, N, S.
Ch em istr y: Gen er a l. Reagents, starting materials, and
solvents were purchased from commercial suppliers and used
as received. All organic solutions were dried over sodium
sulfate. Concentration refers to evaporation under vacuum
using a Bu¨chi rotatory evaporator. Reaction products were
purified, when necessary, by flash chromatography on silica
gel (40-63 µm) with the solvent system indicated. Spectro-
scopic data were recorded on a Varian Gemini 300 spectrom-
eter. Melting points were recorded on a Bu¨chi 535 apparatus.
Where analyses are indicated only by symbols of the elements,
results obtained were within 0.4% of the theoretical values.
2-Br om o-1-(4-m eth a n esu lfon ylp h en yl)eth a n on e (34).
To a cooled solution of 5.40 g (27.3 mmol) of 1-(4-methane-
sulfonylphenyl)ethanone in 75 mL of CHCl3 was added drop-
wise a solution of 1.23 mL (3.82 g, 24.0 mmol) of bromine in
10 mL of CHCl3. After being stirred at -5 °C for 1 h, the
mixture was warmed to room temperature and washed with
water. The organic layer was dried and evaporated. The
resulting solid was recrystallized from EtOAc /hexane (1:1) to
give 5.80 g (77%) of the title compound: 1H NMR (CDCl3) δ
8.15 (d, J ) 8 Hz, 2H), 8.08 (d, J ) 8 Hz, 2H), 4.46 (s, 2H),
3.10 (s, 3H).
2-Hyd r oxy-1-(4-m eth a n esu lfon ylp h en yl)eth a n on e (35).
A mixture of 5.80 g (20.9 mmol) of 34 and 2.82 g (24.1 mmol)
of betaine in 58 mL of EtOH was heated at 50 °C for 2 h. The
reaction was cooled at 0 °C and the resulting solid was filtered
and washed with isopropyl alcohol. The intermediate ester was
dissolved in 100 mL of saturated NaHCO3. After being stirred
at room temperature for 15 min, the resulting solid was
extracted with CH2Cl2. The organic layer was washed, dried,
and concentrated to give 3.90 g (87%) of 35: 1H NMR (CDCl3)
δ 8.14 (d, J ) 8.4 Hz, 2H), 8.08 (d, J ) 8.4 Hz, 2H), 4.92 (s,
2H), 3.83 (br, 1H), 3.12 (s, 3H).
4-(4-Meth a n esu lfon ylp h en yl)-3-(4-m eth ylp h en yl)-3H-
oxa zol-2-on e (6) was prepared according to method A starting
from 35 (2.00 g) and 4-methylphenyl isocyanate. Recrystalli-
zation from CH3CN and isopropyl ether gave 0.80 g (26%) of
6: mp 213-214 °C; 1H NMR (DMSO) δ 7.87 (d, J ) 8 Hz, 2H),
7.85 (s, 1H), 7.35 (d, J ) 8 Hz, 2H), 7.27 (d, J ) 8 Hz, 2H),
7.17 (d, J ) 8 Hz, 2H), 3.21 (s, 3H), 2.31 (s, 3H). Anal. (C17H15
-
NO4S) C, H, N, S.
3-(4-Eth ylp h en yl)-4-(4-m eth a n esu lfon ylp h en yl)-3H-ox-
a zol-2-on e (7) was prepared according to method A starting
from 35 (4.60 g) and 4-ethylphenyl isocyanate. Purification by
flash chromatography, eluting with EtOAc/hexane (1:1), gave
1.70 g (23%) of 7: mp 199 °C; 1H NMR (DMSO) δ 7.88 (s, 1H),
7.87 (d, J ) 8 Hz, 2H), 7.36 (d, J ) 8 Hz, 2H), 7.31 (d, J ) 8
Hz, 2H), 7.21 (d, J ) 8 Hz, 2H), 3.22 (s, 3H), 2.64 (q, J ) 7.5
Hz, 2H), 1.19 (t, J ) 7.5 Hz, 3H). Anal. (C18H17NO4S) C, H, N,
S.
3-(2,4-Diflu or op h en yl)-4-(4-m et h a n esu lfon ylp h en yl)-
3H-oxa zol-2-on e (8) was prepared according to method A
starting from 35 (2.00 g) and 2,4-difluorophenyl isocyanate.
Purification by flash chromatography, eluting with EtOAc,
1
gave 0.70 g (21%) of 8: mp 155-156 °C; H NMR (DMSO) δ
7.97 (s, 1H), 7.90 (d, J ) 8.5 Hz, 2H), 7.70 (m, 1H), 7.52 (m,
1H), 7.38 (d, J ) 8.5 Hz, 2H), 7.26 (m, 1H), 3.20 (s, 3H). Anal.
(C
16H11F2NO4S) C, H, N, S.
4-Acetyl-N,N-d iben zylben zen esu lfon a m id e (36). A mix-
ture of 60.0 g (0.27 mol) of sodium 4-acetylbenzenesulfonate
in 100 mL of POCl3 was refluxed for 3 h. After being cooled,
the solvent was evaporated, and the residue was partitioned
between ethyl ether and water. The organic layer was washed,
dried, and concentrated. The solid residue was dissolved in
200 mL of anhydrous THF, and the resulting solution was
added dropwise to a mixture of 51.0 g (0.26 mol) of dibenzyl-
amine and 36 mL (26.1 g, 0.26 mol) of triethylamine in 300
mL of anhydrous THF. After being stirred at room tempera-
Gen er a l P r oced u r e for th e Syn th esis of Oxa zolon es
1-8. Meth od A. 4-(4-Meth a n esu lfon ylp h en yl)-3-p h en yl-

220 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 2
Puig et al.
ture overnight, the mixture was concentrated, and the residue
was partitioned between EtOAc and water. The organic
extracts were dried and concentrated. Crystallization from
ethyl ether gave 73.7 g (72%) of the title compound: 1H NMR
(DMSO) δ 8.15 (d, J ) 9 Hz, 2H), 8.00 (d, J ) 9 Hz, 2H), 7.25-
7.15 (m, 6H), 7.10 (m, 4H), 4.35 (s, 4H), 2.68 (s, 3H).
N,N-Diben zyl-4-(2-b r om oa cet yl)ben zen esu lfon a m id e
(37). To a solution of 73.7 g (0.19 mol) of 36 in 400 mL of CHCl3
was added dropwise a solution of 9.9 mL (30.9 g, 0.19 mol) of
bromine in 200 mL of CHCl3. The mixture was stirred at room
temperature for 1 h and concentrated. The resulting oil was
dissolved in ethyl ether. After cooling, the obtained solid was
filtered and recrystallized from EtOH to give 62.1 g (71%) of
37: 1H NMR (CDCl3) δ 8.05 (d, J ) 8 Hz, 2H), 7.90 (d, J ) 8
Hz, 2H), 7.26-7.20 (m, 6H), 7.05 (m, 4H), 4.45 (s, 2H), 4.37
(s, 4H).
N ,N -D ib e n zy l-4-(2-h y d r o x y a c e t y l)b e n ze n e s u lfo n -
a m id e (38). A suspension of 41.8 g (0.091 mol) of 37 and 12.7
g (0.108 mol) of betaine in 250 mL of EtOH was heated at 60
°C for 5 h. The mixture was cooled and concentrated, and the
residue was treated with EtOAc. The obtained solid was
dissolved in 1 L of water. To the resulting solution was added
dropwise 13 mL of saturated NaHCO3. After being stirred 10
min, the solid was filtered, washed with water, and dried to
give 27.4 g (76%) of 38: 1H NMR (DMSO) δ 8.10 (d, J ) 8 Hz,
2H), 8.00 (d, J ) 8 Hz, 2H), 7.30-7.15 (m, 6H), 7.06 (m, 4H),
5.30 (br, 1H), 4.86 (s, 2H), 4.30 (s, 4H).
Gen er a l P r oced u r e for th e Syn th esis of Oxa zolon es
39-58. Meth od B. N,N-Diben zyl-4-(2-oxo-3-p h en yl-2,3-
d ih yd r ooxa zol-4-yl)ben zen esu lfon a m id e (39). To a solu-
tion of 7.00 g (17.7 mmol) of 38 in 25 mL of toluene was added
2.10 mL (2.31 g, 19.4 mmol) of phenyl isocyanate. The mixture
was refluxed for 2 h. After being cooled, the resulting solid
was filtered and suspended in 70 mL of acetic acid. The
mixture was refluxed for 8 h, cooled, and concentrated. The
solid residue was crystallized with ethyl ether to yield 6.38 g
(73%) of the title compound: 1H NMR (CDCl3) δ 7.72 (d, J )
9 Hz, 2H), 7.45-7.35 (m, 3H), 7.29-7.17 (m, 9H), 7.14 (d, J )
6 Hz, 2H), 7.03 (m, 4H), 4.36 (s, 4H).
N,N-Diben zyl-4-[3-(2-flu or op h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (40) was prepared accord-
ing to method B starting from 38 (5.00 g) and 2-fluorophenyl
isocyanate. Crystallization from ethyl ether gave 2.50 g (38%)
of 40: 1H NMR (DMSO) δ 7.95 (s, 1H), 7.80 (d, J ) 9 Hz, 2H),
7.66-7.51 (m, 2H), 7.46-7.35 (m, 2H), 7.32 (d, J ) 9 Hz, 2H),
7.25-7.14 (m, 6H), 7.02 (m, 4H), 4.27 (s, 4H).
N,N-Diben zyl-4-[3-(4-flu or op h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (41) was prepared accord-
ing to method B starting from 38 (8.00 g) and 4-fluorophenyl
isocyanate. Crystallization from ethyl ether gave 6.15 g (59%)
of 41: 1H NMR (CDCl3) δ 7.74 (d, J ) 9 Hz, 2H), 7.33-7.13
(m, 11H), 7.10 (d, J ) 9 Hz, 2H), 7.03 (m, 4H), 4.32 (s, 4H).
N,N-Diben zyl-4-[3-(2-ch lor op h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (42) was prepared accord-
ing to method B starting from 38 (5.00 g) and 2-chlorophenyl
isocyanate. Crystallization from isopropyl ether gave 2.29 g
(34%) of 42: 1H NMR (CDCl3) δ 7.70 (d, J ) 9 Hz, 2H), 7.50
(m, 1H), 7.43-7.41 (m, 2H), 7.26-7.17 (m, 10H), 7.01 (m, 4H),
4.30 (s, 4H).
N,N-Diben zyl-4-[3-(3-ch lor op h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (43) was prepared accord-
ing to method B starting from 38 (5.00 g) and 3-chlorophenyl
isocyanate. Crystallization from EtOH gave 2.30 g (34%) of
43: 1H NMR (CDCl3) δ 7.74 (d, J ) 8 Hz, 2H), 7.39-7.14 (m,
13H), 7.04 (m, 4H), 4.33 (s, 4H).
pared according to method B starting from 38 (5.00 g) and
4-trifluoromethylphenyl isocyanate. Crystallization from ethyl
ether gave 4.40 g (62%) of 45: 1H NMR (CDCl3) δ 7.76 (d, J )
9 Hz, 2H), 7.64 (d, J ) 9 Hz, 2H), 7.31 (d, J ) 6 Hz, 2H), 7.27-
7.18 (m, 7H), 7.14 (d, J ) 6 Hz, 2H), 7.04 (m, 4H), 4.33 (s,
4H).
N,N-Diben zyl-4-[3-(2-m eth ylp h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (46) was prepared accord-
ing to method B starting from 38 (5.00 g) and 2-methylphenyl
isocyanate. Crystallization from ethyl ether gave 2.96 g (46%)
of 46: 1H NMR (CDCl3) δ 7.65 (d, J ) 9 Hz, 2H), 7.39-7.14
(m, 11H), 7.10 (d, J ) 9 Hz, 2H), 7.02 (m, 4H), 4.31 (s, 4H),
2.22 (s, 3H).
N,N-Diben zyl-4-[3-(3-m eth ylp h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (47) was prepared accord-
ing to method B starting from 38 (10.0 g) and 3-methylphenyl
isocyanate. Crystallization from ethyl ether gave 9.88 g (76%)
of 47: 1H NMR (CDCl3) δ 7.72 (d, J ) 9 Hz, 2H), 7.31-7.10
(m, 12H), 7.02 (m, 4H), 6.89 (d, J ) 7.5 Hz, 1H), 4.32 (s, 4H),
2.35 (s, 3H).
N,N-Diben zyl-4-[3-(4-m eth ylp h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (48) was prepared accord-
ing to method B starting from 38 (5.92 g) and 4-methylphenyl
isocyanate. Crystallization from ethyl ether gave 2.66 g (35%)
of 48: 1H NMR (CDCl3) δ 7.70 (d, J ) 9 Hz, 2H), 7.31-7.04
(m, 13H), 7.02 (m, 4H), 4.31 (s, 4H), 2.36 (s, 3H).
N,N-Dib en zyl-4-[3-(4-et h ylp h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (49) was prepared accord-
ing to method B starting from 38 (3.00 g) and 4-ethylphenyl
isocyanate. Purification by flash chromatography, eluting with
EtOAc/hexane (1:2), gave 0.50 g (13%) of 49: 1H NMR (CDCl3)
δ 7.72 (d, J ) 8.7 Hz, 2H), 7.27-7.10 (m, 13H), 7.03 (m, 4H),
4.32 (s, 4H), 2.68 (q, J ) 7.5 Hz, 2H), 1.24 (t, J ) 7.5 Hz, 3H).
N,N-Diben zyl-4-[3-(4-m eth oxyph en yl)-2-oxo-2,3-dih ydr o-
oxa zol-4-yl]ben zen esu lfon a m id e (50) was prepared accord-
ing to method B starting from 38 (12.0 g) and 4-methoxyphenyl
isocyanate. Crystallization from ethyl ether gave 11.4 g (67%)
of 50: 1H NMR (CDCl3) δ 7.74 (d, J ) 8 Hz, 2H), 7.34-7.11
(m, 11H), 7.04 (m, 4H), 6.93 (d, J ) 8 Hz, 2H), 4.34 (s, 4H),
3.80 (s, 3H).
3-[4-(4-Dib en zylsu lfa m oylp h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-3-yl]ben zoic Acid (51). To a solution of 4.00 g (10.1
mmol) of 38 in 20 mL of toluene was added 1.27 mL (1.93 g,
10.1 mmol) of 3-isocyanatobenzoic acid ethyl ester. The
mixture was refluxed overnight. After being cooled, the result-
ing solid was filtered and suspended in 75 mL of acetic acid
and 25 mL of 2 N HCl. The mixture was refluxed for 5 h,
cooled, and concentrated. The residue was dissolved in CH2Cl2.
The organic layer was washed with water, dried, and concen-
trated. The resulting oil was refluxed with 40 mL of acetic acid
overnight. After being concentrated, the solid was crystallized
with ethyl ether to yield 1.96 g (36%) of the title compound:
1H NMR (DMSO) δ 8.10 (d, J ) 8 Hz, 1H), 7.91 (s, 1H), 7.72
(d, J ) 8 Hz, 2H), 7.54-7.38 (m, 3H), 7.28 (s, 1H), 7.24-7.18
(m, 7H), 7.03 (m, 4H), 4.31 (s, 4H).
4-[4-(4-Dib en zylsu lfa m oylp h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-3-yl]ben zoic a cid (52) was obtained following the
same procedure described for compound 51, starting from 3.95
g (0.01 mmol) of 38 and 4-isocyanatobenzoic acid ethyl ester.
Crystallization with ethyl ether gave 1.63 g (30%) of 52: 1H
NMR (DMSO) δ 8.03 (d, J ) 8 Hz, 2H), 7.92 (s, 1H), 7.82 (d,
J ) 8 Hz, 2H), 7.42 (d, J ) 8 Hz, 2H), 7.30 (d, J ) 8 Hz, 2H),
7.29-7.20 (m, 6H), 7.05 (m, 4H), 4.31 (s, 4H).
N,N-Dibenzyl-4-[3-(2,4-difluorophenyl)-2-oxo-2,3-dihydro-
oxa zol-4-yl]ben zen esu lfon a m id e (53) was prepared accord-
ing to method B starting from 38 (4.30 g) and 2,4-difluoro-
phenyl isocyanate. Crystallization from EtOH gave 2.60 g
(45%) of 53: 1H NMR (CDCl3) δ 7.73 (d, J ) 9 Hz, 2H), 7.39
(m, 1H), 7.31-7.18 (m, 8H), 7.14 (d, J ) 9 Hz, 2H), 7.02 (m,
4H), 6.89 (m, 1H), 4.31 (s, 4H).
N,N-Diben zyl-4-[3-(4-ch lor op h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (44) was prepared accord-
ing to method B starting from 38 (4.00 g) and 4-chlorophenyl
isocyanate. Crystallization from EtOH gave 1.90 g (35%) of
44: 1H NMR (CDCl3) δ 7.75 (d, J ) 8.5 Hz, 2H), 7.46 (d, J )
8.5 Hz, 2H), 7.37 (d, J ) 8.5 Hz, 2H), 7.29-7.12 (m, 9H), 7.05
(m, 4H), 4.33 (s, 4H).
N,N-Diben zyl-4-[3-(3,4-d ich lor op h en yl)-2-oxo-2,3-d ih y-
d r ooxa zol-4-yl]ben zen esu lfon a m id e (54) was prepared
according to method B starting from 38 (5.00 g) and 3,4-
dichlorophenyl isocyanate. Crystallization from EtOH gave
N,N-Diben zyl-4-[2-oxo-3-(4-tr iflu or om eth ylp h en yl)-2,3-
d ih yd r ooxa zol-4-yl]ben zen esu lfon a m id e (45) was pre-

Synthesis/ Evaluation of 3,4-Diaryloxazolones
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 2 221
3.40 g (47%) of 54: 1H NMR (DMSO) δ 7.91 (s, 1H), 7.87 (d, J
) 9 Hz, 2H), 7.78 (s, 1H), 7.75 (d, J ) 9 Hz, 1H), 7.35 (d, J )
9 Hz, 2H), 7.29 (d, J ) 9 Hz, 1H), 7.25-7.15 (m, 6H), 7.02 (m,
4H), 4.31 (s, 4H).
N,N-Diben zyl-4-[5-br om o-3-(3,4-d ich lor op h en yl)-2-oxo-
2,3-d ih yd r ooxa zol-4-yl]ben zen esu lfon a m id e (63) was pre-
pared according to method C starting from 54 (5.54 g).
Crystallization from ethyl ether gave 4.40 g (70%) of 63: 1H
NMR (CDCl3) δ 7.80 (d, J ) 9 Hz, 2H), 7.37 (s, 1H), 7.30 (d, J
) 9 Hz, 2H), 7.27-7.14 (m, 7H), 7.09 (m, 4H), 6.88 (d, J ) 9
Hz, 1H), 4.37 (s, 4H).
Gen er a l P r oced u r e for th e Syn th esis of Oxa zolon es
64-68. Met h od D. N,N-Dib en zyl-4-(5-m et h yl-2-oxo-3-
p h en yl-2,3-d ih yd r ooxa zol-4-yl)ben zen esu lfon a m id e (64).
To a solution of crude 59 (17.8 mmol) in 45 mL of anhydrous
DMF were added 6.36 g (35.6 mmol) of tetramethyltin, 0.07 g
(0.33 mmol) of palladium(II) acetate, 0.43 g (1.42 mmol) of tri-
o-tolylphosphine, and 2.46 mL (1.79 g, 17.8 mmol) of Et3N.
The mixture was heated at 100 °C overnight. After being
cooled, the mixture was diluted with 45 mL of dioxane and
filtered through Celite. The filtrate was partitioned between
EtOAc and water. The organic layer was washed, dried, and
concentrated. The residue was purified by column chromatog-
raphy, eluting with EtOAc/hexane (1:2), to give 6.46 g (71%)
of the title compound: 1H NMR (CDCl3) δ 7.73 (d, J ) 9 Hz,
2H), 7.35-7.07 (m, 13H), 7.02 (m, 4H), 4.33 (s, 4H), 2.31 (s,
3H).
N,N-Diben zyl-4-[3-(3-flu or o-4-m et h oxyp h en yl)-2-oxo-
2,3-d ih yd r ooxa zol-4-yl]ben zen esu lfon a m id e (55). To a
solution of 5.31 g (37.6 mmol) of 3-fluoro-4-methoxyaniline in
100 mL of dry dioxane was added dropwise a solution of 2.3
mL (3.75 g, 18.8 mmol) of trichloromethyl chloroformate in 40
mL of dry dioxane. The mixture was heated at 60 °C overnight.
After cooling, the solvent was concentrated and the residue
was suspended in 200 mL of pentane. The insoluble material
was filtered and washed with 3 × 50 mL of pentane, and the
combined filtrates were concentrated. Crude 3-fluoro-4-meth-
oxyphenyl isocyanate (3.50 g) was used, without further
purification, in the preparation of 55, which was prepared
according to method B starting from 38 (7.44 g). Crystallization
from ethyl ether gave 5.49 g (49%) of the title compound: 1H
NMR (CDCl3) δ 7.74 (d, J ) 9 Hz, 2H), 7.30-7.16 (m, 9H),
7.41 (s, 1H), 7.06 (m, 4H), 6.97 (d, J ) 9 Hz, 1H), 6.93 (s, 1H),
4.33 (s, 4H), 3.91 (s, 3H).
N,N-Diben zyl-4-[3-(3-ch lor o-4-m eth oxyp h en yl)-2-oxo-
2,3-d ih yd r ooxa zol-4-yl]ben zen esu lfon a m id e (56) was pre-
pared according to method B starting from 38 (5.00 g) and
3-chloro-4-methoxyphenyl isocyanate.23 Purification by flash
chromatography, eluting with EtOAc/hexane (1:1), gave 1.50
g (21%) of 56: 1H NMR (DMSO) δ 7.87 (s, 1H), 7.82 (d, J )
8.7 Hz, 2H), 7.58 (s, 1H), 7.34 (d, J ) 8.7 Hz, 2H), 7.26 (s,
1H), 7.22-7.19 (m, 7H), 7.04 (m, 4H), 4.28 (s, 4H), 3.89 (s, 3H).
N,N-Diben zyl-4-(3-cycloh exyl-2-oxo-2,3-d ih yd r ooxa zol-
4-yl)ben zen esu lfon a m id e (57) was prepared according to
method B starting from 38 (4.50 g) and cyclohexyl isocyanate.
Crystallization from ethyl ether gave 1.50 g (26%) of 57: 1H
NMR (CDCl3) δ 7.89 (d, J ) 8.5 Hz, 2H), 7.42 (d, J ) 8.5 Hz,
2H), 7.27-7.22 (m, 6H), 7.10 (m, 4H), 6.83 (s, 1H), 4.36 (s, 4H),
3.49 (m, 1H), 2.31-2.19 (m, 2H), 1.86-1.62 (m, 5H), 1.26-
1.16 (m, 3H).
N,N-Diben zyl-4-[(3-n a p h th a len -1-yl)-2-oxo-2,3-dih ydr o-
oxa zol-4-yl]ben zen esu lfon a m id e (58) was prepared accord-
ing to method B starting from 38 (7.00 g) and 1-naphthyl
isocyanate. Crystallization from ethyl ether gave 7.36 g (76%)
of 58: 1H NMR (CDCl3) δ 8.03-7.91 (m, 2H), 7.77 (m, 1H),
7.62-7.27 (m, 9H), 7.24-7.06 (m, 6H), 7.00-6.89 (m, 4H), 4.20
(s, 4H).
Gen er a l P r oced u r e for th e Syn th esis of Oxa zolon es
59-63. Meth od C. N,N-Diben zyl-4-(5-br om o-2-oxo-3-ph en -
yl-2,3-d ih yd r ooxa zol-4-yl)ben zen esu lfon a m id e (59). To a
solution of 8.86 g (17.8 mmol) of 39 in 85 mL of CHCl3 was
added dropwise a solution of 0.95 mL (2.96 g, 18.5 mmol) of
bromine in 10 mL of CHCl3; meanwhile the evolved HBr was
displaced by nitrogen. After being stirred at room temperature
for 2 h, the mixture was washed with water and 40% NaHSO3,
dried, and concentrated. Crude 59 was used in the next step
without further purification: 1H NMR (CDCl3) δ 7.73 (d, J )
9 Hz, 2H), 7.40-7.14 (m, 13H), 7.02 (m, 4H), 4.34 (s, 4H).
N,N-Diben zyl-4-[5-br om o-3-(4-flu or op h en yl)-2-oxo-2,3-
d ih yd r ooxa zol-4-yl]ben zen esu lfon a m id e (60) was pre-
pared according to method C starting from 41 (7.41 g), to yield
7.60 g (89%) of 60: 1H NMR (CDCl3) δ 7.77 (d, J ) 9 Hz, 2H),
7.32-7.15 (m, 8H),7.13-6.95 (m, 8H), 4.35 (s, 4H).
N,N-Diben zyl-4-[3-(4-flu or op h en yl)-5-m eth yl-2-oxo-2,3-
d ih yd r ooxa zol-4-yl]ben zen esu lfon a m id e (65) was pre-
pared according to method D starting from 60 (4.65 g).
Purification by flash chromatography, eluting with EtOAc/
hexane (1:2), gave 1.86 g (45%) of 65: 1H NMR (CDCl3) δ 7.76
(d, J ) 9 Hz, 2H), 7.31-7.10 (m, 10H), 7.17 (d, J ) 9 Hz, 2H),
7.06 (m, 4H), 4.36 (s, 4H), 2.29 (s, 3H).
N,N-Dib en zyl-4-[5-m et h yl-3-(3-m et h ylp h en yl)-2-oxo-
2,3-d ih yd r ooxa zol-4-yl]ben zen esu lfon a m id e (66) was pre-
pared according to method D starting from crude 60 (3.00 g).
Purification by flash chromatography, eluting with EtOAc/
hexane (1:2), gave 2.10 g (79%) of 66: 1H NMR (CDCl3) δ 7.73
(d, J ) 8 Hz, 2H), 7.24-7.20 (m, 7H), 7.17 (d, J ) 8 Hz, 2H),
7.12-6.78 (m, 7H), 4.33 (s, 4H), 2.32 (s, 3H), 2.30 (s, 3H).
N,N-Dib en zyl-4-[5-m et h yl-3-(4-m et h ylp h en yl)-2-oxo-
2,3-d ih yd r ooxa zol-4-yl]ben zen esu lfon a m id e (67) was pre-
pared according to method D starting from 62 (1.56 g).
Purification by flash chromatography, eluting with EtOAc/
hexane (1:2), gave 0.74 g (54%) of 67: 1H NMR (CDCl3) δ 7.73
(d, J ) 9 Hz, 2H), 7.30-7.20 (m, 8H), 7.14 (d, J ) 9 Hz, 2H),
7.09-6.93 (m, 6H), 4.33 (s, 4H), 2.35 (s, 3H), 2.30 (s, 3H).
N,N-Diben zyl-4-[3-(3,4-dich lor oph en yl)-5-m eth yl-2-oxo-
2,3-d ih yd r ooxa zol-4-yl]ben zen esu lfon a m id e (68) was pre-
pared according to method D starting from 63 (5.55 g).
Purification by flash chromatography, eluting with EtOAc/
hexane (1:2), gave 3.37 g (75%) of 68: 1H NMR (CDCl3) δ 7.80
(d, J ) 9 Hz, 2H), 7.44-7.19 (m, 8H), 7.16 (d, J ) 9 Hz, 2H),
7.06 (m, 4H), 6.87 (d, J ) 6 Hz, 1H), 4.36 (s, 4H), 2.33 (s, 3H).
Gen er a l P r oced u r e for th e Syn th esis of Oxa zolon es
9-33. Meth od E. 4-(2-Oxo-3-p h en yl-2,3-d ih yd r ooxa zol-4-
yl)ben zen esu lfon a m id e (9). A suspension of 6.38 g (12.8
mmol) of 39 in 17 mL of concentrated H2SO4 was stirred at
room temperature for 20 min. The mixture was poured into
ice. The resulting solid was filtered, washed with water, and
dried. Purification by flash chromatography, eluting with
AcOH/CH2Cl2/EtOAc (1:78:10), gave 2.81 g (69%) of the title
1
compound: mp 208 °C; H NMR (DMSO) δ 7.82 (s, 1H), 7.73
(d, J ) 8.7 Hz, 2H), 7.50-7.42 (m, 3H), 7.40 (s, 2H), 7.31-
7.26 (m, 2H), 7.29 (d, J ) 8.7 Hz, 2H). Anal. (C15H12N2O4S) C,
H, N, S.
N,N-Dib en zyl-4-[5-b r om o-3-(3-m et h ylp h en yl)-2-oxo-
2,3-d ih yd r ooxa zol-4-yl]ben zen esu lfon a m id e (61) was pre-
pared according to method C starting from 47 (3.00 g). Crude
61 was used in the next step without further purification: 1H
NMR (CDCl3) δ 7.74 (d, J ) 8.5 Hz, 2H), 7.30 (d, J ) 8.5 Hz,
2H), 7.26-7.15 (m, 9H), 7.06-6.81 (m, 5H), 4.32 (s, 4H), 2.31
(s, 3H).
N,N-Dib en zyl-4-[5-b r om o-3-(4-m et h ylp h en yl)-2-oxo-
2,3-d ih yd r ooxa zol-4-yl]ben zen esu lfon a m id e (62) was pre-
pared according to method C starting from 48 (2.00 g).
Crystallization from ethyl ether gave 1.60 g (69%) of 62: 1H
NMR (CDCl3) δ 7.74 (d, J ) 9 Hz, 2H), 7.31 (d, J ) 9 Hz, 2H),
7.27-7.21 (m, 8H), 7.17 (d, J ) 9 Hz, 2H), 7.02 (m, 4H), 4.36
(s, 4H), 2.35 (s, 3H).
4-[3-(2-Flu or oph en yl)-2-oxo-2,3-dih ydr ooxazol-4-yl]ben -
zen esu lfon a m id e (10) was prepared according to method E
starting from 40 (2.50 g). Purification by flash chromatogra-
phy, eluting with AcOH/CH2Cl2/EtOAc (1:78:10), gave 0.60 g
(37%) of 10: mp 176-178 °C; 1H NMR (DMSO) δ 7.88 (s, 1H),
7.76 (d, J ) 8.5 Hz, 2H), 7.61-7.51 (m, 2H), 7.43 (m, 1H), 7.40
(s, 2H), 7.37 (m, 1H), 7.33 (d, J ) 8.5 Hz, 2H). Anal. (C15H11
FN2O4S) C, H, N, S.
-
4-[3-(4-Flu or oph en yl)-2-oxo-2,3-dih ydr ooxazol-4-yl]ben -
zen esu lfon a m id e (11) was prepared according to method E
starting from 41 (4.90 g). Recrystallization from EtOH/CH2Cl2

222 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 2
Puig et al.
gave 1.40 g (44%) of 11: mp 211-213 °C; 1H NMR (DMSO) δ
7.81 (s, 1H), 7.76 (d, J ) 8.5 Hz, 2H), 7.40 (s, 2H), 7.38-7.34
(m, 4H), 7.30 (d, J ) 8.5 Hz, 2H). Anal. (C15H11FN2O4S) C, H,
N, S.
3-[2-Oxo-4-(4-su lfa m oylp h en yl)-2,3-d ih yd r ooxa zol-3-yl]-
ben zoic a cid (21) was prepared according to method E
starting from 51 (1.95 g). Purification by flash chromatogra-
phy, eluting with AcOH/CH2Cl2/EtOAc/MeOH (1:78:10:5), gave
1
0.83 g (66%) of 21: mp 253 °C; H NMR (DMSO) δ 12.87 (br,
4-[3-(2-Ch lor oph en yl)-2-oxo-2,3-dih ydr ooxazol-4-yl]ben -
zen esu lfon a m id e (12) was prepared according to method E
starting from 42 (8.50 g). Recrystallization from EtOAc gave
1.97 g (30%) of 12: mp 169 °C; 1H NMR (DMSO) δ 7.90 (s,
1H), 7.74 (d, J ) 8.5 Hz, 2H), 7.71-7.63 (m, 2H), 7.55-7.50
1H), 7.97 (d, J ) 8.5 Hz, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.68
(d, J ) 8.5 Hz, 2H), 7.57 (t, J ) 8.5 Hz, 1H), 7.45 (d, J ) 8.5
Hz, 1H), 7.40 (s, 2H), 7.31 (d, J ) 8.5 Hz, 2H). Anal.
(C16H12N2O6S) H, N, S; C: calcd, 53.33; found, 53.92.
4-[2-Oxo-4-(4-su lfa m oylp h en yl)-2,3-d ih yd r ooxa zol-3-yl]-
ben zoic a cid (22) was prepared according to method E
starting from 52 (1.63 g). Purification by flash chromatogra-
phy, eluting with AcOH/CH2Cl2/EtOAc/MeOH (1:78:10:5), gave
(m, 2H), 7.39 (s, 2H), 7.29 (d, J ) 8.5 Hz, 2H). Anal. (C15H11
ClN2O4S) C, H, N, S.
-
4-[3-(3-Ch lor oph en yl)-2-oxo-2,3-dih ydr ooxazol-4-yl]ben -
zen esu lfon a m id e (13) was prepared according to method E
starting from 43 (2.30 g). Purification by flash chromatogra-
phy, eluting with CH2Cl2/MeOH (95:5), gave 0.80 g (53%) of
13: mp 176-177 °C; 1H NMR (DMSO) δ 7.83 (s, 1H), 7.78 (d,
J ) 8.5 Hz, 2H), 7.53 (m, 1H), 7.49 (m, 1H), 7.46 (s, 1H), 7.42
1
0.52 g (48%) of 22: mp 236 °C; H NMR (DMSO) δ 12.90 (br,
1H), 8.02 (d, J ) 8.3 Hz, 2H), 7.86 (s, 1H), 7.78 (d, J ) 8.3 Hz,
2H), 7.42, (s, 2H), 7.40 (d, J ) 8.3 Hz, 2H), 7.31 (d, J ) 8.3
Hz, 2H). Anal. (C16H12N2O6S‚0.2H2O) C, H, S; N: calcd, 7.70;
found, 7.21.
(s, 2H), 7.32 (d, J ) 8.5 Hz, 2H), 7.19 (m, 1H). Anal. (C15H11
ClN2O4S) C, H, N, S.
-
4-[3-(2,4-Diflu or op h en yl)-2-oxo-2,3-d ih yd r ooxa zol-4-yl]-
ben zen esu lfon a m id e (23) was prepared according to method
E starting from 53 (2.60 g). Recrystallization from MeOH gave
4-[3-(4-Ch lor oph en yl)-2-oxo-2,3-dih ydr ooxazol-4-yl]ben -
zen esu lfon a m id e (14) was prepared according to method E
starting from 44 (1.90 g). Recrystallization from CH3CN gave
1
0.50 g (30%) of 23: mp 190-191 °C; H NMR (CDCl3) δ 7.85
(d, J ) 8.5 Hz, 2H), 7.40 (m, 1H), 7.22 (s, 1H), 7.21 (d, J ) 8.5
Hz, 2H), 7.04-6.93 (m, 2H), 6.71 (s, 2H). Anal. (C15H10F2N2O4S)
C, H, N, S.
1
0.50 g (40%) of 14: mp 213-214 °C; H NMR (DMSO) δ 7.82
(s, 1H), 7.77 (d, J ) 8.7 Hz, 2H), 7.54 (d, J ) 8.7 Hz, 2H), 7.41
(s, 2H), 7.32 (d, J ) 8.7 Hz, 2H), 7.31 (d, J ) 8.7 Hz, 2H).
Anal. (C15H11ClN2O4S) C, H, N, S.
4-[3-(3,4-Dich lor op h en yl)-2-oxo-2,3-d ih yd r ooxa zol-4-
yl]ben zen esu lfon a m id e (24) was prepared according to
method E starting from 54 (3.40 g). Purification by flash
chromatography, eluting with CHCl3/MeOH (20:1), gave 1.49
4-[2-Oxo-3-(4-tr iflu or om eth ylph en yl)-2,3-dih ydr ooxazol-
4-yl]ben zen esu lfon a m id e (15) was prepared according to
method E starting from 45 (4.40 g). Purification by flash
chromatography, eluting with EtOAc/hexane (1:1), gave 1.65
1
g (64%) of 24: mp 157-159 °C dec; H NMR (DMSO) δ 7.83
(s, 1H), 7.80 (s, 1H), 7.74 (d, J ) 8.5 Hz, 2H), 7.71 (d, J ) 8.5
Hz, 2H), 7.41 (s, 2H), 7.31 (d, J ) 8.5 Hz, 2H), 7.22 (d, J ) 8.5
Hz, 2H). Anal. (C15H10Cl2N2O4S) C, H, N, S.
1
g (55%) of 15: mp 196 °C; H NMR (DMSO) δ 7.84 (s, 1H),
7.83 (d, J ) 8 Hz, 2H), 7.76 (d, J ) 8 Hz, 2H), 7.48 (d, J ) 8
Hz, 2H), 7.40 (s, 2H), 7.29 (d, J ) 8 Hz, 2H). Anal.
(C16H11F3N2O4S) C, H, N, S.
4-[3-(3-F lu or o-4-m et h oxyp h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (25) was prepared accord-
ing to method E starting from 55 (9.78 g). Purification by flash
chromatography, eluting with AcOH/CH2Cl2/EtOAc (1:78:10),
4-[3-(2-Meth ylph en yl)-2-oxo-2,3-dih ydr ooxazol-4-yl]ben -
zen esu lfon a m id e (16) was prepared according to method E
starting from 46 (2.96 g). Purification by flash chromatogra-
phy, eluting with AcOH/CH2Cl2/EtOAc (1:78:10), gave 0.80 g
1
gave 3.60 g (55%) of 25: mp 184 °C; H NMR (DMSO) δ 7.80
(s, 1H), 7.77 (d, J ) 8 Hz, 2H), 7.40-7.35 (m, 3H), 7.32 (d, J
) 8 Hz, 2H), 7.23 (t, J ) 9.5 Hz, 1H), 7.08 (d, J ) 8.5 Hz, 1H),
3.85 (s, 3H). Anal. (C16H13FN2O5S) C, H, N, S.
1
(42%) of 16: mp 99-101 °C; H NMR (DMSO) δ 7.91(s, 1H),
7.70 (d, J ) 8 Hz, 2H), 7.42-7.20 (m, 6H), 7.40 (s, 2H), 2.14
(s, 3H). Anal. (C16H14N2O4S) C, H, N, S.
4-[3-(3-Ch lor o-4-m et h oxyp h en yl)-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (26) was prepared accord-
ing to method E starting from 56 (1.50 g). Purification by flash
chromatography, eluting with EtOAc/hexane (1:1), gave 0.68
4-[3-(3-Meth ylph en yl)-2-oxo-2,3-dih ydr ooxazol-4-yl]ben -
zen esu lfon a m id e (17) was prepared according to method E
starting from 47 (16.0 g). Purification by flash chromatogra-
phy, eluting with AcOH/CH2Cl2/EtOAc (1:78:10), gave 7.26 g
(70%) of 17: mp 192 °C; 1H NMR (DMSO) δ 7.82 (s, 1H), 7.74
(d, J ) 8.7 Hz, 2H), 7.40 (s, 2H), 7.32 (m, 1H), 7.29 (d, J ) 8.7
Hz, 2H), 7.23 (d, J ) 8 Hz, 1H), 7.20 (s, 1H) 7.01 (d, J ) 8 Hz,
1H), 2.31 (s, 3H). Anal. (C16H14N2O4S) C, H, N, S.
4-[3-(4-Meth ylph en yl)-2-oxo-2,3-dih ydr ooxazol-4-yl]ben -
zen esu lfon a m id e (18) was prepared according to method E
starting from 48 (2.66 g). Purification by flash chromatogra-
phy, eluting with AcOH/CH2Cl2/EtOAc (1:78:10), gave 1.00 g
(58%) of 18: mp 223 °C; 1H NMR (DMSO) δ 7.80 (s, 1H), 7.74
(d, J ) 8 Hz, 2H), 7.40 (s, 2H), 7.29 (d, J ) 8.7 Hz, 2H), 7.26
(d, J ) 8.7 Hz, 2H), 7.17 (d, J ) 8 Hz, 2H), 2.33 (s, 3H). Anal.
(C16H14N2O4S) C, H, N, S.
4-[3-(4-Eth ylp h en yl)-2-oxo-2,3-d ih yd r ooxa zol-4-yl]ben -
zen esu lfon a m id e (19) was prepared according to method E
starting from 49 (0.50 g). Purification by flash chromatogra-
phy, eluting with AcOH/CH2Cl2/EtOAc (1:78:10), gave 0.25 g
(79%) of 19: mp 199 °C; 1H NMR (DMSO) δ 7.81 (s, 1H), 7.73
(d, J ) 8 Hz, 2H), 7.39 (s, 2H), 7.30 (d, J ) 8 Hz, 4H), 7.19 (d,
J ) 8 Hz, 2H), 2.64 (q, J ) 7.5 Hz, 2H), 1.86 (t, J ) 7.5 Hz,
3H). Anal. (C16H14N2O4S) C, H, N, S.
1
g (67%) of 26: mp 194 °C; H NMR (DMSO) δ 7.80 (s, 1H),
7.76 (d, J ) 8.7 Hz, 2H), 7.55 (m, 1H), 7.40 (s, 2H), 7.32 (d, J
) 8.7 Hz, 2H), 7.22-7.20 (m, 2H), 3.88 (s, 3H). Anal. (C16H13
ClN2O5S) C, H, N, S.
-
4-(3-Cycloh exyl-2-oxo-2,3-d ih yd r ooxa zol-4-yl)ben zen e-
su lfon a m id e (27) was prepared according to method E
starting from 57 (1.50 g). Purification by flash chromatogra-
phy, eluting with EtOAc/hexane (1:1), gave 0.40 g (42%) of
1
27: mp 167-169 °C; H NMR (DMSO) δ 7.94 (d, J ) 8.5 Hz,
2H), 7.61 (d, J ) 8.5 Hz, 2H), 7.50 (s, 2H), 7.42 (s, 1H), 3.46
(m, 1H), 2.13-2.00 (m, 2H), 1.77-1.74 (m, 4H), 1.55 (m, 1H),
1.18-1.06 (m, 3H). Anal. (C15H18N2O4S) C, H, N, S.
4-[(3-Na p h t h a len -1-yl)-2-oxo-2,3-d ih yd r ooxa zol-4-yl]-
ben zen esu lfon a m id e (28) was prepared according to method
E starting from 58 (7.36 g). Purification by flash chromatog-
raphy, eluting with AcOH/CH2Cl2/EtOAc (1:78:10), gave 1.81
1
g (37%) of 28: mp 186 °C; H NMR (DMSO) δ 8.10-8.04 (m,
2H), 8.00 (s, 1H), 7.75 (m, 1H), 7.67-7.59 (m, 4H), 7.60 (d, J
) 8 Hz, 2H), 7.28 (s, 2H), 7.24 (d, J ) 8 Hz, 2H). Anal.
(C19H14N2O4S‚0.35H2O) C, H, S; N: calcd, 7.52; found, 7.02.
4-(5-Meth yl-2-oxo-3-ph en yl-2,3-dih ydr ooxazol-4-yl)ben -
zen esu lfon a m id e (29) was prepared according to method E
starting from 64 (6.46 g). Purification by flash chromatogra-
phy, eluting with AcOH/CH2Cl2/EtOAc (1:78:10), gave 2.90 g
(70%) of 29: mp 101 °C; 1H NMR (DMSO) δ 7.73 (d, J ) 6 Hz,
2H), 7.41-7.35 (m, 5H), 7.20 (d, J ) 6 Hz, 2H), 7.18 (d, J ) 7
Hz, 2H), 2.21 (s, 3H). Anal. (C16H14N2O4S) C, H, N, S.
4-[3-(4-Meth oxyp h en yl)-2-oxo-2,3-d ih yd r ooxa zol-4-yl]-
ben zen esu lfon a m id e (20) was prepared according to method
E starting from 50 (11.40 g). Purification by flash chromatog-
raphy, eluting with EtOAc/hexane (1:1), gave 1.40 g (20%) of
1
20: mp 196 °C; H NMR (CDCl3) δ 7.84 (d, J ) 8.7 Hz, 2H),
7.23 (d, J ) 8.7 Hz, 2H), 7.13 (s, 1H), 7.12 (d, J ) 9 Hz, 2H),
6.92 (d, J ) 9 Hz, 2H), 4.78 (s, 2H), 3.82 (s, 3H). Anal.
(C16H14N2O5S) H, N, S; C: calcd, 55.48; found, 56.01.
4-[3-(4-Flu or oph en yl)-5-m eth yl-2-oxo-2,3-dih ydr ooxazol-
4-yl]ben zen esu lfon a m id e (30) was prepared according to

Synthesis/ Evaluation of 3,4-Diaryloxazolones
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 2 223
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Gordon, R.; Guay, D.; Hill, R. G.; Li, C.; Mancini, J .; Penneton,
M.; Prasit, P.; Rasori, R.; Riendeau, D.; Roy, P.; Tagari, P.;
Vickers, P.; Wong, E.; Rodger, I. W. Pharmacology of a Selective
Cyclooxygenase-2 Inhibitor, L-745,337: a Novel Nonsteroidal
Antiinflammatory Agent with an Ulcerogenic Sparing Effect in
Rat and Nonhuman Primate Stomach. J . Pharmacol. Exp. Ther.
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Mechanistic Studies on the Selective Inhibition of Cyclooxy-
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(14) Penning, T. D.; Talley, J . J .; Bertenshaw, S. R.; Carter, J . S.;
Collins, P. W.; Docter, S.; Graneto, M. J .; Lee, L. F.; Malecha, J .
W.; Miyashiro, J . M.; Rogers, R. S.; Rogier, D. J .; Yu S. S.;
Anderson, G. D.; Burton, E. G.; Cogburn, J . N.; Gregory, S. A.;
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method E starting from 65 (2.96 g). Purification by flash
chromatography, eluting with EtOAc/hexane (1:2), gave 1.20
g (61%) of 30: mp 100-105 °C; 1H NMR (DMSO) δ 7.77 (d, J
) 8.5 Hz, 2H), 7.40 (s, 2H), 7.33 (d, J ) 8.5 Hz, 2H), 7.29-
7.25 (m, 4H), 2.22 (s, 3H). Anal. (C16H13FN2O4S) C, H, N, S.
4-[5-Meth yl-3-(3-m eth ylph en yl)-2-oxo-2,3-dih ydr ooxazol-
4-yl]ben zen esu lfon a m id e (31) was prepared according to
method E starting from 66 (1.60 g). Purification by flash
chromatography, eluting with AcOH/CH2Cl2/EtOAc (1:78:10),
1
gave 0.83 g (80%) of 31: mp 165 °C; H NMR (DMSO) δ 7.75
(d, J ) 8.5 Hz, 2H), 7.41 (s, 2H), 7.33 (d, J ) 8.5 Hz, 2H), 7.25
(m, 1H), 7.17-7.12 (m, 2H), 6.90 (m, 1H), 2.27 (s, 3H), 2, 23
(s, 3H). Anal. (C17H16N2O4S) C, H, N, S.
4-[5-Meth yl-3-(4-m eth ylph en yl)-2-oxo-2,3-dih ydr ooxazol-
4-yl]ben zen esu lfon a m id e (32) was prepared according to
method E starting from 67 (0.74 g). Purification by flash
chromatography, eluting with AcOH/CH2Cl2/EtOAc (1:78:10),
gave 0.37 g (76%) of 32: mp 103-104 °C; 1H NMR (DMSO) δ
7.77 (d, J ) 8 Hz, 2H), 7.39 (s, 2H), 7.30 (d, J ) 8 Hz, 2H),
7.18 (d, J ) 8.5 Hz, 2H), 7.06 (d, J ) 8.5 Hz, 2H), 2.26 (s, 3H),
2.19 (s, 3H). Anal. (C17H16N2O4S) C, H, N, S.
4-[3-(3,4-Dich lor op h en yl)-5-m eth yl-2-oxo-2,3-d ih yd r o-
oxa zol-4-yl]ben zen esu lfon a m id e (33) was prepared accord-
ing to method E starting from 68 (3.37 g). Purification by flash
chromatography, eluting with AcOH/CH2Cl2/EtOAc (1:78:10),
gave 1.44 g (62%) of 33: mp 132-135 °C; 1H NMR (DMSO) δ
7.81 (d, J ) 8 Hz, 2H), 7.66 (d, J ) 7 Hz, 1H), 7.65 (s, 1H),
7.43 (s, 2H), 7.36 (d, J ) 8 Hz, 2H), 7.11 (d, J ) 7 Hz, 1H),
2.23 (s, 3H). Anal. (C16H12Cl2N2O4S) C, H, N, S.
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Inhibitor, has Clinical Efficacy Comparable to Ibuprofen in the
Treatment of Knee and Hip Osteoarthritis (OA) in a 6-Week
Controlled Clinical Trial. Arthritis Rheum. 1998, 41 (Suppl.),
Abstr. 984.
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