1,2-Diarylpyrroles as potent and selective inhibitors of cyclooxygenase- 2

Article abstract of DOI:10.1021/jm970036a

Series of 1,2-diarylpyrroles has been synthesized and found to contain very potent and selective inhibitors of the human cyclooxygenase-2 (COX-2) enzyme. The paper describes short and practical syntheses of the target molecules utilizing the Paal-Knorr reaction. Electrophilic substitution on 1 proceeds in a regioselective fashion, and the method was used to generate a number of tetrasubstituted pyrroles. Detailed SAR on the series has been studied by modifications of the aryl rings and the substituents in the pyrrole ring. Diarylpyrrole 1 is a very potent (COX-2, IC₅₀ = 60 nm) and selective (COX-1/COX-2 = > 1700) inhibitor whereas the isomeric 2 is completely inactive against COX-2. Modifications of the substituents on the fluorophenyl ring in 1 yields very potent inhibitors of COX-2 (IC₅₀ = 40- 80 nm) with excellent selectivity(1200 to >2500) vs COX-1, Analog 20 containing a sulfonamide group is an excellent inhibitor of COX-2 with an IC₅₀ of 14 nm. Tetrasubstituted pyrroles containing groups such as COCF₃, SO₂CF₃, or CH₂OAr at position 3 in the pyrrole ring give excellent inhibitors (COX-2, IC₅₀ = 30-120 nm). In vivo testing in the carrageenan- induced paw edema model in the rat establishes that the 1,2-diarylpyrroles are orally active antiinflammatory agents. Compound 3 is the most potent inhibitor of edema with an ED₅₀ of 4.7 mpk.

Full text of DOI:10.1021/jm970036a

J . Med. Chem. 1997, 40, 1619-1633
1619
1,2-Dia r ylp yr r oles a s P oten t a n d Selective In h ibitor s of Cyclooxygen a se-2
Ish K. Khanna,* Richard M. Weier, Yi Yu, Paul W. Collins, J ulie M. Miyashiro, Carol M. Koboldt,
Amy W. Veenhuizen, J erry L. Currie, Karen Seibert, and Peter C. Isakson
Discovery Medicinal Chemistry and Inflammatory Disease Research, Searle Research and Development,
4901 Searle Parkway, Skokie, Illinois 60077
Received J anuary 16, 1997X
Series of 1,2-diarylpyrroles has been synthesized and found to contain very potent and selective
inhibitors of the human cyclooxygenase-2 (COX-2) enzyme. The paper describes short and
practical syntheses of the target molecules utilizing the Paal-Knorr reaction. Electrophilic
substitution on 1 proceeds in a regioselective fashion, and the method was used to generate a
number of tetrasubstituted pyrroles. Detailed SAR on the series has been studied by
modifications of the aryl rings and the substituents in the pyrrole ring. Diarylpyrrole 1 is a
very potent (COX-2, IC50 ) 60 nm) and selective (COX-1/COX-2 ) >1700) inhibitor whereas
the isomeric 2 is completely inactive against COX-2. Modifications of the substituents on the
fluorophenyl ring in 1 yields very potent inhibitors of COX-2 (IC50 ) 40-80 nm) with excellent
selectivity (1200 to >2500) vs COX-1. Analog 20 containing a sulfonamide group is an excellent
inhibitor of COX-2 with an IC50 of 14 nm. Tetrasubstituted pyrroles containing groups such
as COCF3, SO2CF3, or CH2OAr at position 3 in the pyrrole ring give excellent inhibitors (COX-
2, IC50 ) 30-120 nm). In vivo testing in the carrageenan-induced paw edema model in the
rat establishes that the 1,2-diarylpyrroles are orally active antiinflammatory agents. Compound
3 is the most potent inhibitor of edema with an ED50 of 4.7 mpk.
In tr od u ction
relationship studies of substituted 1,2-diarylpyrroles.
Bimetopyrol is one of the earlier known 4,5-diaryl-
pyrroles13a showing a spectrum of antiinflammatory and
analgesic properties similar to typical NSAIDs. In rats,
chronic administration of bimetopyrol at >25 mpk
caused gastrointenstinal ulceration in some animals,
suggesting that the compound is probably a nonselective
COX inhibitor. More recently, Wilkerson et al. have
reported13b-d substituted 4,5-diarylpyrroles (e.g., I and
II) as antiinflammatory agents. These compounds are
believed to be competitive, time dependent inhibitors12e
of COX-2. Although only moderately potent and selec-
tive against the COX-2 enzyme,13c these compounds
seem to offer better gastrointestinal safety13d in labora-
tory animals.
Nonsteroidal antiinflammatory drugs (NSAIDs) are
widely used for treatment of the symptoms of acute and
chronic inflammatory disorders such as osteoarthritis
and rheumatoid arthritis. These agents reduce the pain
and swelling of joints by blocking the production of
prostaglandins (PG’s)1 from arachidonic acid. The
chronic usage of these agents has been associated with
adverse effects including gastrointenstinal ulceration
and suppression of renal function.2 The undesirable
effects associated with NSAIDs are also believed to be
due to the inhibition of prostaglandin production in the
affected organs. It has recently been shown that the
cyclooxygenase enzyme exists in two isoformssa con-
stitutive form cyclooxygenase-1 (COX-1) and an induc-
ible form cyclooxygenase-2 (COX-2).3-5 The COX-1
enzyme is responsible for maintaining homeostasis
(gastric and renal integrity) whereas COX-2 induces
inflammatory conditions6-8 in response to the inflam-
matory and mitogenic stimuli, suggesting that COX-1
and COX-2 serve different physiological and pathologi-
cal functions.
As part of our search for a potent and selective
inhibitor of COX-2, compound III was identified as a
lead through a broad screening program. The com-
pound was a weak inhibitor of human COX-2 (IC50
)
4.6 µM) and COX-1 (IC50 ) 25 µM) enzymes. In the
whole cell assays, the compound was active against
COX-2 (IC50 ) 2.4 µM in IL-1-stimulated dermal
fibroblasts) although not selective, COX-1 (IC50 ) 1.0
µM in retinoic acid stimulated HL-60 cells). Similarly,
in the human whole blood assays, compound III inhib-
ited both LPS-induced PGE2 production (IC50 ) 1.5 µM)
and the ionophore A23187-induced TXB2 production
(IC50 ) 0.3 µM). The substitution pattern and the
biological profile of III seemed different than the other
diaryl heterocycles reported in the literature, and this
prompted us to explore the series in depth. In the first
attempt, the effect of a non-carboxylic acid functionality
(e.g., Me) on the potency of the COX enzymes was
studied. The compounds (V) containing (R1 ) OMe or
F) were inactive against the human COX-2 and COX-1
enzymes. Attempted replacement of the COMe group
in structure V with other isosteres such as CO2Me, CO2-
The hypothesis that selective COX-2 inhibitors could
offer therapeutic advantages over the current NSAIDs
has generated a lot of interest in the field, and a number
of research laboratories are aggressively pursuing this
objective. In this regard diaryl heterocycles are emerg-
ing as attractive templates for the synthesis of potent
and selective inhibitors of cyclooxygenase-2 enzyme.
Several interesting compounds (e.g., DuP 697,9 SC-
58635,10 and SC-5766611) (Chart 1) and other variants
of the central ring system have been reported.12,13 This
paper describes the synthesis and structure-activity
X Abstract published in Advance ACS Abstracts, April 15, 1997.
S0022-2623(97)00036-8 CCC: $14.00 © 1997 American Chemical Society

1620 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Khanna et al.
Ch a r t 1
Ta ble 1. 1,2-Diarylpyrroles as Cyclooxygenase Inhibitors
IC50, µM
On the basis of the encouraging results reported in
Table 1, different portions of the molecules 1 and 3 were
modified to define and optimize the structural features
essential for achieving the potency and selectivity
against the human COX-2 and COX-1 enzymes.
compd
COX-2
COX-1
COX-1/COX-2
1
2
3
4
0.06
>100
0.51
>100
>100
>100
>100
>1700
>200
Ch em istr y
10.2
Depending upon the substitution pattern, the 1,2-
diarylpyrroles reported in this paper were synthesized
using the Schemes 1-8. Our general synthetic strategy
entailed the preparation of suitable 1,4-diketones fol-
lowed by heating with appropriate amines in the Paal-
Knorr condensation, cyclization to yield the targets. The
analogs (IV) having an alkyl group (R3 ) Me or Et) at
position 5 in the pyrrole ring were synthesized following
the Schemes 1 and 2. The Stetter reaction16 of substi-
tuted benzaldehydes with R,â-unsaturated ketones us-
ing the thiazolium salt catalyst proved very versatile
and high yielding (NEt3, EtOH, reflux, 60-90%). One
exception was the synthesis of methylsulfonyl bearing
compound VIIb, which gave variable yields and was
prepared preferentially by Oxone oxidation (MeOH/H2O,
room temperature, 2 h; >90%) of intermediate VIIa .
The condensation of VII with aryl amines (Scheme 1)
or aliphatic amines (Scheme 2) proceeded smoothly to
give good yields (50-80%) of the desired pyrroles.
The syntheses of 1,2-diarylpyrroles without any sub-
stitution at position 5 in the pyrrole ring (e.g., 3 and 4)
were achieved utilizing the Schemes 3 and 4. In Scheme
3, the 2-(hydroxypropyl)-1,3-dioxane (IX) prepared17
from dihydrofuran and 2,2-dimethyl-1,3-propanediol
was oxidized to the aldehyde (X) using Swern oxidation.
Addition of (4-fluorophenyl)magnesium bromide to X
(-70 to 20 °C, 18 h; 87%), followed by oxidation of the
resulting intermediate XI with PCC (20 °C, 3 h; 85%),
gave the useful 1,4-keto acetal (XII). The intermediate
XII was converted to the target pyrrole (21) by condens-
ing with VIIIc in the presence of p-toluenesulfonic acid.
The synthesis of reversed analog 4 was accomplished
by conversion of XII to XIII by direct displacement
(NaSO2Me, DMF, 120-130 °C, 72 h; 79%) followed by
the Paal-Knorr condensation with 4-fluoroaniline.
Alternately, these compounds could be prepared in a
shorter route (Scheme 4) by reacting the Grignard
reagent from commercially available 2-(2-bromoethyl)-
1,3-dioxolane with 4-fluorobenzaldehyde (-70 °C, 2 h;
NEt2, SOMe, or SO2Me (2) gave inactive compounds
against human COX-2.
Interestingly, on reversing the substitution of aryl
groups in 2, the resulting compound (1) showed excel-
lent potency (IC50, COX-2 ) 60 nm) and selectivity (IC50,
COX-1 ) >100 µM). Similarly, the desmethyl com-
pound 3 inhibited COX-2 with an IC50 ) 0.5 µm while
showing no inhibition of COX-1 at 100 µM. The isomer
4 obtained by reversing the aryl substitution pattern
in 3 was much less potent. The activity of these
isomeric pyrroles (1-4) against the human COX en-
zymes is summarized in Table 1. These results suggest
that the presence of a substituent at C-5 in the pyrrole
ring, next to the aryl ring bearing a SO2Me group, might
have deleterious effect on its activity against COX-2
enzyme.14 Although this observation would seem to
contradict the biological activity observed with III, it is
speculated that III containing the propionic acid chain
might be binding to the COX enzymes differently15 than
the diarylpyrroles exemplified in this paper.

1,2-Diarylpyrroles as Inhibitors of Cyclooxygenase-2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1621
Sch em e 1
Sch em e 2
A number of tetrasubstituted pyrroles were synthe-
sized (Scheme 7) by direct electrophilic substitution20
on the pyrrole 1. These reactions proceeded with very
high regioselectivity, possibly because of the steric
influence of the aryl ring bearing the methyl sulfone
group. The regiochemistry of substitution was estab-
lished by the NOE studies on the products. The yields
on the reactions varied with electrophile chosen and the
conditions employed (Table 2). No attempts were made
to optimize the yields. The reaction of 1 with TFA-
TFAA (50 °C, 3 h) gave 28 in 77% yield, whereas
Friedel-Crafts acylations with acetyl chloride (AlCl3,
room temperature, 18 h), benzoyl chloride (AlCl3, room
temperature, 18 h), and triflic anhydride (AlCl3, 44 °C,
48 h) gave 29, 30, and 31 in poorer yields (30%, 8%,
and 10%, respectively) because of the lower conversions
under the conditions used. The cyano derivative (33)
was prepared in 77% yield by reaction with chlorosul-
fonyl isocyanate. Vilsmeier Haack (POCl3, DMF) and
Mannich (HCHO, HNMe2) reactions gave 32 and 36 in
yields of 71 and 23%, respectively. Similarly, reaction
of 1 with AcOH and HCHO gave the acetoxymethylene
derivative 37 in 22% yield. Direct halogenation of 1
with NBS and NCS gave the bromo (34) and the chloro
(35) analogs in 88% and 10% yield, respectively.
The other substituents at position 3 in 1,2,3,5-tetra-
substituted pyrroles were obtained (Scheme 8) by
manipulation of the functional groups. For example
sodium borohydride reduction of 32 gave 38 in quanti-
tative conversion. Compound 38 was reacted with
substituted phenols under Mitsunobu reaction condi-
tions (PPh3, DEAD) to give the (aryloxy)methylene
derivatives 39 and 40 (Scheme 8). The trifluoroacetyl
group in 28 was subjected to similar transformations
to yield 41 and 43. The trifluoroethyl compound 42 was
prepared from 41 using hydrogenation conditions (5%
Pt on carbon, 60 psi, TFA, 48 h; 43%).
83%). Oxidation of the resulting alcohol (XIV) to the
keto acetal (XV) followed by condensation and aroma-
tization with substituted anilines under conditions
described in Scheme 3 gave the desired pyrroles.
1,2-Diarylpyrroles containing a propionic acid side
chain (24 and 26) were synthesized as shown in Scheme
5. The aldol condensation of furaldehyde with 4-fluo-
roacetophenone (NaOMe, MeOH, room temperature, 20
h) gave the unsaturated ketone XVI in 95% yield. The
treatment of XVI with ethanol-aqueous hydrochloric
acid (4/1) at 80-85 °C caused the furan ring opening,
giving XVII and XVIII in yields of 33% and 26%,
respectively. When subjected to reaction conditions
individually, both XVII and XVIII yielded the thermo-
dynamic ratio of the mixture (approximately 6/4) as
judged by TLC. Compound XVII was reacted with
VIIIa (TsOH, toluene, reflux; 76%) to give the pyrrole
(23). The base hydrolysis of the ethyl ester (EtOH, aq.
NaOH; 69%) yielded the targeted pyrrole (24) containing
a propionic acid chain. To accomplish the synthesis of
isomeric pyrrole 26, compound XVII was converted to
XIX by displacement reaction (NaSO2Me, DMF, 135-
140 °C, 30 h; 26%) and reacted with 4-fluoroaniline
(TsOH, toluene, reflux; 75%). The base-catalyzed hy-
drolysis of the resulting ester (25) yielded the intended
pyrrole (26) in 90% yield.
1,2-Diarylpyrrole (27) with a CF3 group at position 5
was synthesized, in a one-step conversion from 4,
following the methodology reported by Baciocchi et al.18
The reaction of 4 with trifluoromethyl iodide in the
presence of FeSO4 and H2O2 gave the desired 27 in an
isolated yield of 43% (Scheme 6). The regiochemistry
of the CF3 group in the pyrrole ring was established
using the NOE difference experiments.19
Resu lts a n d Discu ssion
All test compounds were evaluated for inhibitory
activity against the consitutive (COX-1) and the induc-
ible form (COX-2) of the human recombinant enzymes.
Each IC50 value is an average of at least two indepen-

1622 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Khanna et al.
Sch em e 3
dent determinations. Some compounds were also tested
in the cell and the human whole blood assay (see the
Experimental Section). Potent and COX-2 selective
compounds were studied further in the carrageenan-
induced paw edema model in the rat.
position 3 (9) resulted in 3-4-fold loss of potency
compared to 1. The biological data in Table 3 indicates
that this aryl ring might be somewhat forgiving and that
the desirable biological properties might be accom-
plished by attenuating the substituents in this region.
Ar yl Rin g Va r ia tion s. To evaluate the importance
of 1,2-diaryl ring arrangement in 1, the N-aryl ring was
replaced by H or benzyl substituents (15 and 11 in Table
3). Neither compound showed inhibition of the COX
enzymes up to >100 µM. The cylcohexyl analog (12)
was the most encouraging of these variations but was
about 8 times less potent than the aryl analog (1). The
branched alkyl or n-alkyl derivatives (e.g., 13 and 14)
were inactive, suggesting that the 1,2-diaryl arrange-
ment was important for the optimum potency and
selectivity in this series of compounds.
Ar yl Su lfon e Rin g Mod ifica tion s. In order to
understand the significance of SO2Me group in binding
to the COX enzymes, both the sulfone (SO2R) and the
ring substituents in 3 were modified. The results from
this study are summarized in Table 5. Increasing the
size of methyl in SO2Me to ethyl (17) or phenyl (18)
resulted in total loss of activity. Interestingly, adding
a Cl group ortho to the SO2Me (19) yielded a completely
inactive compound. The isosteric sulfonamide deriva-
tive (20) was a very potent compound with an IC50
)
14 nm against the COX-2 enzyme and with selectivity
(COX-1/COX-2) of 750. In consonance with the results
on sulfone, increasing the size of sulfonamide group (21,
22) destroyed the enzyme inhibitory activity completely.
In addition, the regioisomeric derivative 16 obtained on
moving the SO2Me in 3 from position 4 to position 3
showed no inhibition against either of the COX en-
zymes. The results clearly suggest that the SO2Me (or
SO2NH2) group is an important part of the pharma-
cophore and the potency against the COX-2 enzyme is
greatly affected by the small variations in the surround-
ings.
Ar yl Su bstitu en ts. Having established that aryl
groups were important for optimum potency against the
COX-2 enzyme, we concentrated our efforts on under-
standing the influence of aryl substituents on the
activity (Table 4). Replacement of the fluoro substituent
in 1 with H (5), Me (7), or CF3 (6) resulted in very potent
(IC50 ) 40-80 nm) and selective (COX-1/COX-2 )
>1200) inhibitors of COX-2. The compound 8, contain-
ing a substituent with increased size and polarity
(COMe), was considerably less active. Similarly, the
introduction of a smaller substituent such as F at

1,2-Diarylpyrroles as Inhibitors of Cyclooxygenase-2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1623
Sch em e 4
P yr r ole Su bstitu en ts. Having established earlier
(Table 1) that the compound with a Me group at position
5 of pyrrole (1) was better than the noranalog (4), we
explored the effect of other substituents at this position
(Table 6). Increasing the size of the methyl group to
CF3 (27) or ethyl (10) resulted in substantial loss of
activity against the COX-2 enzyme. The methyl group
appears to yield the optimum potency at this position,
and the small variations in the substituents seem to
affect the binding to the COX enzyme adversely. To
correlate with the initial lead (III), a propionic acid
chain was introduced at position 5, but the resulting
compound (26) was inactive against COX-2 up to 100
µM. The isomeric pyrrole (24, Scheme 5) was a weak
inhibitor of COX-2 enzyme with an IC50 of 7.5 µM.
Similar to III, compound 24 also inhibited the LPS-
induced PGE2 production in the human whole blood
assay with an IC50 of 4.4 µM. Unlike III, the analog
24 was more selective (IC50 for TXB2 production ) >50
µM). The isomeric pyrrole (26), on the other hand, failed
to inhibit either PGE2 or TXB2 production up to a
concentration of 50 µM. The results, on the compounds
(III, 24) bearing the propionic acid chain, suggest that
these might be binding to the active sites on the COX
enzymes differently than 26 or other diarylpyrroles
listed in Table 6.
Tetr a su bstitu ted P yr r oles. To explore the influ-
ence of substituents in the pyrrole ring and to stabilize
the ring against potential oxidative metabolism, the
pyrrole ring was modified by introducing substituents
at position 3. The COX-2 potent and easily accessible
1 was used as the template for the study. The pyrrole
ring in 1 was substituted at position 3 with groups such
as halogens, acyl, nitrile, alkyl, alkoxyalkyl, aryloxy-
alkyl, alkyl sulfones, and the like (Table 7). Trifluoro-
acetyl derivative (28) inhibited COX-2 enzyme with an
IC50 of 120 nm whereas the other acyl modifications
such as acetyl (29) and benzoyl (30) were about 8-12
times less potent. Trifluoromethyl sulfone analog (31)
was very potent (COX-2, IC50 ) 60 nm) and selective
(COX-1, IC50 ) >100 µM). The cyano (33) and the
formyl (32) derivatives were less potent than the acyl
or the sulfone analogs. Substitution with bromo or
chloro (34, 35) gave very potent compounds (COX-2, IC50
) 20 and 50 nm, respectively) although the selectivity
was much less than desirable. The trifluoroethyl com-
pound (42) was very potent (COX-2, IC50 ) 140 nm) and
selective while its hydroxylated derivative (41) was
about 10 times less potent. The acetoxymethyl com-
pound (37) was more potent than the hydroxymethyl
(38) or dimethylamino (36) analogs. (Aryloxy)methyl
compounds (39 and 40) were excellent inhibitors of the
COX-2 enzyme (IC50 ) 30 and 80 nm, respectively) while
showing no activity against the COX-1 up to 100 µm.
Branching the methylene in 40 by addition of a CF3
group (43) abolishes the activity completely. In general,
the position 3 of pyrrole seems much more permissive
and tolerant to a number of substituents and functional
groups. The study proved very fruitful in generating a
number of very potent and selective compounds.
R a t Ca r r a geen a n -In d u ced E d em a . To assess
their antiinflammatory activity, the selected 1,2-di-
arylpyrroles were evaluated in the carrageenan induced
paw edema model in the rat (Table 8). Each test
compound was dosed orally 2 h prior to the induction
of inflammation by carrageenan injection, and the
inhibition was measured 3 h after induction. All the
compounds were screened at 10 or 20 mpk, and the
maximum response observed was 66%. Compound 3
was the most potent of those listed in Table 8, control-
ling the edema with an ED50 of 4.7 mpk. The sulfona-
mide 20 was also active but seemed to show variable
response at different dosages (e.g., 33% and 34% at 3
and 30 mpk, respectively). The bromo (34) and the
trifluoromethylsulfone (31) derivatives were active with
ED50s of approximately 10 and 20 mpk, respectively.
(Aryloxy)methylene compound 14 showed very poor
inhibition, probably because of its relatively larger
molecular weight and poor cell penetration.

1624 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Khanna et al.
Sch em e 5
Sch em e 6
Sch em e 7
Ta ble 2. Electrophilic Substitution in the Pyrrole Ring
Con clu sion
compd
electrophile
R
yield, %
The series of 1,2-diarylpyrroles described in this paper
are very potent (IC50 ) 15-100 nm) and selective (COX-
1/COX-2 >1000) inhibitors of human COX-2 enzyme.
The enzymatic potency and selectivity observed with
these compounds is significantly superior to that re-
ported on 4,5-diarylpyrroles.13b-d Detailed SAR studies
on different portions of the molecule suggest that the
potency and selectivity against the COX-2 enzyme is
greatly influenced by the substitution pattern. Replace-
ment of fluoroaryl ring with benzyl, cyclohexyl, or alkyl
groups yields inactive or significantly less active com-
pounds. The fluoro group in 1 may be substituted by
H (5), CF3 (6), or Me (7) groups to give compounds with
excellent potency and selectivity. The aryl sulfone ring
seems very sensitive, and small variation on the ring
or the SO2R group destroys the activity completely. A
1,2-diarylpyrrole containing the sulfonamide (20) is the
28
29
30
31
32
33
34
35
36
37
TFA, TFAA
AcCl, AlCl3
PhCOCl, AlCl3
Tf2O, AlCl3
DMF, POCl3
ClSO2NCO
NBS
NCS
HCHO, HNMe2
HCHO, AcOH
COCF3
COCH3
COPh
SO2CF3
CHO
CN
Br
Cl
77
30
8
10
71
77
88
10
23
22
CH2NMe2
CH2OAc
most potent compound reported in this paper (IC50
)
14 nm). In the pyrrole substitutions, the methyl group
at position 5 gives the optimum activity and selectivity.
Removal of the methyl or replacement with larger alkyls
(CF3, Et, or CH2CH2CO2H) yields significantly less
active compounds. A number of tetrasubstituted pyr-
roles with groups such as COCF3, SO2CF3, or CH2OAr

1,2-Diarylpyrroles as Inhibitors of Cyclooxygenase-2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1625
Sch em e 8
Ta ble 3. Modification of the Aryl Ring
at position 3 show excellent potency (IC50 ) 30-120
nm). The oral activity observed with 3 (ED50 ) 4.7 mpk)
and other diarylpyrroles in the carrageenan-induced
paw edema model of inflammation in the rat indicates
the potential utility of this series as antinflammatory
agents. The SAR information reported in this paper
should facilitate the development of other diaryl het-
erocycles derived COX-2 selective inhibitors. The paper
also describes practical methods for the syntheses of 1,2-
diarylpyrroles.

1626 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Ta ble 4. Modification of the Aryl Substitutents
Khanna et al.
Ta ble 7. Tetrasubstituted Pyrroles
IC50, µM
compd
R
COX-2
COX-1
COX-1/COX-2
IC50, µM
1
5
6
7
8
9
4-F
H
4-CF3
4-CH3
4-COCH3
3,4-diF
0.06
0.06
0.08
0.04
2.87
0.25
>100
>100
>100
>100
>100
>100
>1700
>1700
>1250
>2500
>30
ompd
R
COX-2
COX-1
1
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
H
0.06
0.12
1.61
1.02
0.06
3.23
0.75
0.02
0.05
100
0.47
3.88
0.03
0.08
1.44
0.14
>100
>100
>10
>100
>30
>100
>100
>100
0.8
COCF3
COCH3
COPh
SO2CF3
CHO
CN
>400
Ta ble 5. Modification of the Aryl Sulfone Ring
Br
Cl
4.5
CH2NMe2
>100
>100
>100
>100
>100
>100
>100
>100
CH2OAc
CH2OH
CH2OPh(p-Cl)
CH2OPh(m-Cl)
CH(OH)CF3
CH2CF3
IC50, µM
CH(CF3)OPh(m-Cl)
compd
X
Y
COX-2
0.51
>100
>100
>100
>100
COX-1
3
16
17
18
19
20
21
22
SO2Me
H
SO2Et
SO2Ph
SO2Me
SO2NH2
SO2NHMe
SO2NMe2
H
>100
>100
>100
>100
>100
10.5
Ta ble 8. Inhibition of Carrageenan-Induced Edema in Rats
SO2Me
rat paw edema %
inhibn (10 mpk)
rat paw edema %
inhibn (10 mpk)
H
H
Cl
H
H
H
compd
compd
1
3
5
6
7
9
25
42
21
31
25
17
14
20
29
31
34
41
1
30
0.014
>100
>100
>100
>100
13
30a
34
15a
Ta ble 6. 5-Substituted 1,2-Diarylpyrroles
a
Dosed at 20 mpk.
relative to tetramethylsilane (TMS, δ ) 0.00 ppm) and
expressed in ppm. Infrared spectra were recorded on a Perkin-
Elmer Model 681 grating spectrophotometer in CHCl3 solution
or using KBr pellets; frequencies are expressed in cm-1. MIR
were recorded on a Bio-Rad FTS-45 spectrophotometer. Melt-
ing points were determined on a Thomas-Hoover capillary
melting point apparatus. DSC measurements were performed
on a Dupont Model 912 Dual DSC system and run under
nitrogen. Mass spectra were obtained on either a Finnigan-
MAT Model 4500 or a Finnigan-MAT 8430 system. Mi-
croanalyses (C, H, N, S) were performed by the Microanalytical
Group of the Physical Methodology Department, G. D. Searle
& Co.
IC50, µM
COX-2
0.06
10.2
>100
>100
>100
ompd
R
COX-1
1
4
10
26
27
Me
H
Et
>100
>100
>100
>100
>100
CH2CH2CO2H
CF3
4-(Methylsulfonyl)aniline, 3-(methylsulfonyl)aniline, sulf-
anilamide, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bro-
mide and other starting materials and reagents, unless
otherwise specified, were all commercial products. Solvents
used were reagent grade or were dried using conventional
procedures. The reactions were routinely carried out under
an inert atmosphere unless otherwise indicated. Analytical
chromatography was performed on EM Reagents 0.25 mm
silica gel 60-F plates. Preparative chromatographic separa-
tions were carried out on Merck silica gel 60 (230-400 mesh).
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,4-Dik e-
ton es VIIa -e. These compounds were prepared utilizing
Stetter reaction (Scheme 1). The intermediates VIIb and VIIe
were synthesized by oxidation of VIIa and VIId , respectively.
The preparations of VIIa and VIIb are described below as
examples.
Exp er im en ta l Section
Biologica l Meth od s. Expression and purification of hu-
man COX-1 and COX-2 enzymes and in vitro COX-1 and
COX-2 enzyme assays have been described previously.21 The
inhibition of LPS-induced PGE2 production and A23187-
induced TXB2 production in the human whole blood was
studied utilizing the literature protocols.22 The production of
prostaglandins by human dermal fibroblasts and HL-60 cells
after stimulation with IL-1 and retinoic acid was used as a
cell-based assay for COX-2 and COX-1 activity, respectively.24
The details of the carrageenan-induced paw edema model in
the rats have been described previously.11d,e,23
Ch em istr y: Gen er a l. NMR spectra were recorded in
CDCl3, DMSO-d6, or MeOH-d4 (Merck Isotopes) solution in 5
mm o.d. tubes (Wilmad-535) at 20 °C and were collected on
either a General-Electric QE-300, a Varian VXR-400, or a
1-[4-(Meth ylth io)p h en yl]p en ta n e-1,4-d ion e (VIIa ). To
a solution of 4-(methylthio)benzaldehyde (12 mL, 0.09 mol) in
ethanol (30 mL), triethylamine (19.5 mL, 0.14 mol), methyl
vinyl ketone (5.8 mL, 0.07 mol), and 3-ethyl-5-(2-hydroxyethyl)-
4-methylthiazolium bromide (3.53 g, 0.014 mol) were added.
The mixture was heated at 75-80 °C for 20 h and cooled. The
1
Varian VXR-500 spectrometer at 300, 400, or 500 MHz for H
(75, 100, or 125 MHz for 13C). Nuclear Overhauser effect
(NOE) difference spectra and two-dimensional NMR spectra
were determined on the VXR-400. The chemical shifts (δ) are

1,2-Diarylpyrroles as Inhibitors of Cyclooxygenase-2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1627
solvent was removed under reduced pressure and the residue
treated with 2 N HCl (300 mL). After extraction with
methylene chloride, the organic layer was washed with aque-
ous sodium bicarbonate and water. The organic fractions were
dried over MgSO4, filtered, and concentrated to give a crude
orange liquid (16.2 g). After chromatography on silica gel
(hexane/ethyl acetate, 7/3), the desired compound VIIa was
isolated as a pale yellow solid (12.3 g, 71%): mp (DSC) 75 °C;
(DSC) 173 °C, IR (KBr) 3466, 3370, 3250, 3229, 3040, 2974,
2874, 1917, 1788, 1637, 1597, 1570, 1504, 1471, 1456, 1334;
1H NMR (CDCl3) 7.56 (d, J ) 8 Hz, 2H), 6.72 (d, J ) 8 Hz,
2H), 2.64 (s, 3H); MS (EI) 200 (M+). Anal. (C8H12N2SO2) C,
H, N, S.
4-(Eth ylsu lfon yl)an ilin e (VIIIe). To a solution of 1-fluoro-
4-nitrobenzene (2 mL, 19.05 mmol) in DMF (50 mL) was added
sodium thioethoxide (2.4 g, 28.58 mmol), and the mixture was
heated at 90 °C. After 18 h, the solvent was partially removed
under reduced pressure, and the residue was redissolved in
methylene chloride and washed with water and brine. The
organic fractions were dried (MgSO4), filtered, and concen-
trated. The crude (3.04 g) obtained as an orange liquid was
chromatographed (silica gel, hexane/ethyl acetate, 8/2) to give
1-(ethylthio)-4-nitrobenzene (1.91 g, 55%) as a yellowish
solid: mp (DSC) 45 °C; IR (KBr) 3426, 3094, 3065, 2978, 2926,
1913, 1722, 1658, 1591, 1577, 1510, 1477, 1454, 1402, 1381;
1H NMR (CDCl3) 8.13 (d, J ) 8 Hz, 2H), 7.32 (d, J ) 8 Hz,
2H), 3.05 (q, J ) 7.5 Hz, 2H), 1.39 (t, J ) 8 Hz, 3H). Anal.
(C8H9NSO2) C, H, N, S.
To a solution of 1-(ethylthio)-4-nitrobenzene (0.9 g, 4.92
mmol) in methylene chloride (100 mL) was added 3-chloro-
peroxybenzoic acid (3.9 g, 50-60%, 11.3 mmol) over 15 min.
After 3 h, the reaction mixture was concentrated, and the
residue was redissolved in ethyl acetate and washed with 4%
NaOH, water, and brine. The organic fractions were dried
(MgSO4), filtered, and concentrated to give 1-(ethylsulfonyl)-
4-nitrobenzene (1.01 g, 95%) as a light orange solid: mp (DSC)
139 °C; IR (KBr) 3433, 3113, 3067, 2883, 1940, 1689, 1608,
1533, 1475, 1452, 1414, 1400, 1381; 1H NMR (CDCl3) 8.43 (d,
J ) 8 Hz, 2H), 8.14 (d, J ) 8 Hz, 2H), 3.18 (q, J ) 7.5 Hz, 2H),
1.32 (t, J ) 8 Hz, 3H); MS (DCI, NH3-PCI) 216 (MH+). Anal.
(C8H9NSO4) C, H, N, S.
1
IR (KBr) 3410, 3030, 1711, 1680, 1591, 1556, 1491, 1427; H
NMR (CDCl3) 7.87 (d, J ) 8.0 Hz, 2H), 7.26 (d, J ) 8.0 Hz,
2H), 3.23 (t, J ) 7 Hz, 2H), 2.87 (t, J ) 7 Hz, 2H), 2.52 (s, 3H),
2.25 (s, 3H); MS (EI) 222 (M+). Anal. (C12H14SO2) C, H.
1-[4-(Meth ylsu lfon yl)p h en yl]p en ta n e-1,4-d ion e (VIIb).
To a solution of VIIa (7.8 g, 35 mmol) in methanol (150 mL)
was added over 5 min Oxone (37.7 g, 61.4 mmol) dissolved in
water (150 mL). After stirring at 25 °C for 2 h, the reaction
mixture was diluted with water (400 mL) and extracted with
methylene chloride (3 × 400 mL). The organic layer was
washed with brine (200 mL), water (200 mL), and dried
(MgSO4). After filtration and concentration, the crude mate-
rial was chromatographed (silica gel; hexane/ethyl acetate, 3/1)
to give VIIb (8.0 g, 91%) as a white crystalline compound: mp
(DSC) 138 °C; IR (KBr) 3435, 3098, 3003, 1944, 1713, 1686,
1
1593, 1572, 1406; H NMR (CDCl3) 8.16 (d, J ) 8.0 Hz, 2H),
8.06 (d, J ) 8.0 Hz, 2H), 3.28 (t, J ) 7 Hz, 2H), 3.08 (s, 3H),
2.96 (t, J ) 7 Hz, 2H), 2.26 (s, 3H); MS (DCI, NH3-PCI) 255
(MH+). Anal. (C12H14SO4) C, H.
1-(4-F lu or op h en yl)p en ta n e-1,4-d ion e (VIIc): mp (DSC)
53 °C; IR (KBr) 3910, 3416, 3107, 2912, 2602, 1979, 1917, 1676,
1641, 1595, 1508, 1408; 1H NMR (CDCl3) 8.00 (complex dd, J
) 9, 5, 2H), 7.12 (complex t, J ) 9 Hz, 2H), 3.23 (t, J ) 6 Hz,
2H), 2.88 (t, J ) 6 Hz, 2H), 2.24 (s, 3H); MS (DCI, NH3-PCI)
195 (MH+). Anal. (C11H11O2F‚0.1H2O) C, H.
1-[4-(Meth ylth io)p h en yl]h exa n e-1,4-d ion e (VIId ): mp
60-61 °C; MIR 2971, 2931, 1709, 1668, 1653, 1586, 1401, 1346;
1H NMR (CDCl3) 7.93 (d, J ) 8 Hz, 2H), 7.23 (d, J ) 8 Hz,
2H), 3.25 (t, J ) 7 Hz, 2H), 2.82 (t, J ) 7 Hz, 2H), 2.52 (q, J
) 7 Hz, 2H), 2.46 (s, 3H), 1.10 (t, J ) 7 Hz, 2H); HRMS calcd
for M+ 236.0871, found 236.0868. Anal. (C13H16SO2) C, H.
1-[4-(Meth ylsu lfon yl)p h en yl]h exa n e-1,4-d ion e (VIIe):
mp 125-127 °C; MIR 3005, 2968, 2924, 2904, 1709, 1683,
A solution of 1-(ethylsulfonyl)-4-nitrobenzene (1.0 g, 4.65
mmol) in methanol (20 mL) was taken in a Parr bottle, and
Raney nickel in methanol (∼1 g) was added. The reaction
mixture was flushed with nitrogen and hydrogen several times
and then maintained under hydrogen at a delivery pressure
of 5 psi. After being stirred at 25 °C for approximately 6 h,
the reaction mixture was vented and purged with nitrogen.
The contents of the reaction were filtered and concentrated to
give VIIIe as a white solid (0.81 g, 93%): mp (DSC) 91 °C; IR
(KBr) 3449, 3362, 3250, 3071, 2986, 1919, 1786, 1637, 1597,
1572, 1506, 1454, 1441, 1406;
1
1408, 1394, 1370, 1278; H NMR (CDCl3) 8.15 (d, J ) 8 Hz,
2H), 8.06 (d, J ) 8 Hz, 2H), 3.26 (t, J ) 7 Hz, 2H), 3.10 (s,
3H), 2.90 (t, J ) 7 Hz, 2H), 2.48 (q, J ) 7 Hz, 2H), 1.12 (t, J
) 7 Hz, 2H); HRMS calcd for M+ 269.0837, found 269.0838.
Anal. (C13H16SO4) C, H.
1H NMR (CDCl3) 7.62 (d, J ) 8
Hz, 2H), 6.68 (d, J ) 8 Hz, 2H), 3.03 (q, J ) 7.5 Hz, 2H), 1.23
(t, J ) 8 Hz, 3H); MS (EI) 185 (M+). Anal. (C8H11NSO2) C,
H, N.
4-Am in o-N-m eth ylben zen esu lfon a m id e (VIIIc). To a
suspension of of 4- nitrobenzenesulfonyl chloride (5 g, 22.56
mmol) in ether (250 mL) was added methylamine (5 mL, 40%
aqueous solution, 56.4 mmol), and the mixture stirred at room
temperature. After 16 h, the reaction mixture was concen-
trated to remove the solvent and the residue resuspended in
methylene chloride. After the mixture was washed with 2 N
HCl and brine, the organic fractions were dried (MgSO4),
filtered, and concentrated to give 4-nitro-N-methylbenzene-
sulfonamide (4.8 g, 98%): mp (DSC) 109 °C; IR (KBr) 3302,
3113, 2868, 1936, 1606, 1531, 1477, 1415, 1352, 1331, 1307;
1H NMR (CDCl3) 8.40 (d, J ) 8 Hz, 2H), 8.07 (d, J ) 8 Hz,
2H), 4.84 (broad q, J ) 5 Hz, 1H), 2.73 (d, J ) 5 Hz, 3H). Anal.
(C7H8N2SO4) C, H, N.
4-(P h en ylsu lfon yl)an ilin e (VIIIf). To a solution of 1-fluoro-
4-nitrobenzene (4 g, 28.34 mmol) in dimethylformamide (100
mL) was added sodium benzenesulfinate (11.63 g, 70.87 mmol).
The reaction mixture was heated at 85-90 °C for 32 h. After
cooling, the solvent was removed under reduced pressure and
the reaction mixture diluted with water. The product was
extracted with methylene chloride and washed with brine.
After drying (MgSO4), filtration, and concentration, the crude
brownish solid (9.2 g) was chromatographed (silica gel, hexane/
ethyl acetate, 7/3) to give 1-nitro-4-(phenylsulonyl)benzene (2.9
g, 39%) as a white solid: mp (DSC) 144 °C; IR (KBr) 3426,
3103, 3069, 2876, 2365, 1936, 1801, 1686, 1606, 1583, 1531,
1
1479, 1452, 1400, 1356; H NMR (CDCl3) 8.35 (d, J ) 8 Hz,
2H), 8.14 (d, J ) 8 Hz, 2H), 7.98 (d, J ) 8 Hz, 2H), 7.52-7.68
(complex band, 3H); MS (EI) 263 (M+). Anal. (C12H9NSO4)
C, H, N.
A solution of 4-nitro-N-methylbenzenesulfonamide (4.8 g,
22.2 mmol) in methanol (100 mL) was taken in a Parr bottle,
and Raney nickel in methanol (∼2 g) was added. The reaction
mixture was flushed with nitrogen and hydrogen several times
and then maintained under hydrogen at delivery pressure of
5 psi. After being stirred at 25 °C for approximately 20 h, the
reaction was vented and purged with nitrogen. The contents
of the reaction were filtered and concentrated to give VIIIc
as a white solid (4.1 g, 100%): mp (DSC) 105 °C; IR (KBr)
3464, 3373, 3244, 2980, 2932, 1900, 1628, 1597, 1502, 1468,
A solution of 1-nitro-4-(phenylsulfonyl)benzene (2.9 g, 11
mmol) in methanol (58 mL) was taken in a Parr bottle, and
Raney nickel in methanol (∼1.5 g) was added. The reaction
mixture was flushed with nitrogen and hydrogen several times
and then maintained under hydrogen at a delivery pressure
of 5 psi. After being stirred at 25 °C for approximately 2 h,
the reaction mixture was vented and purged with nitrogen.
The contents of the reaction were filtered and concentrated to
give VIIIf as a white solid (2.46 g, 96%): mp (DSC) 177 °C;
IR (KBr) 3424, 3350, 3244, 3059, 2681, 1911, 1772, 1635, 1591,
1
1439, 1408; H NMR (CDCl3) 7.62 (d, J ) 8 Hz, 2H), 6.68 (d,
J ) 8 Hz, 2H), 4.22 (broad q, J ) 5 Hz, 1H), 2.62 (d, J ) 5 Hz,
3H); MS (EI) 186 (M+). Anal. (C7H10N2SO2‚0.25H2O) C, H,
N.
1
1504, 1477, 1444, 1392; H NMR (CDCl3) 7.91 (d, J ) 8 Hz,
4-Am in o-N,N-dim eth ylben zen esu lfon am ide (VIIId) was
synthesized from 4-nitrobenzenesulfonyl chloride and di-
methylamine using the preparation described for VIIIc: mp
2H), 7.70 (d, J ) 8 Hz, 2H), 7.42-7.53 (complex band, 3H),
6.63 (d, J ) 8 Hz, 2H), 4.16 (broad s, 2H); MS (EI) 233 (M+).
Anal. (C12H11NSO2) C, H, N.

1628 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Khanna et al.
3-Ch lor o-4-(m eth ylsu lfon yl)a n ilin e (VIIIg) was synthe-
sized from 3-chloro-4-fluoronitrobenzene and sodium thio-
methoxide using the three-step preparation described for
VIIIe: mp (DSC) 174 °C; IR (KBr) 3476, 3372, 3248, 3100,
2926, 2646, 2386, 1936, 1792, 1633, 1593, 1550, 1485, 1429,
1421, 1402; H NMR (CDCl3) 7.86 (d, J ) 8 Hz, 1H), 6.73 (d,
J ) 2 Hz, 1H), 6.58 (dd, J ) 8, 2 Hz, 1H), 4.38 (broad s, 2H),
3.20 (s, 3H). Anal. (C7H8NClSO2) C, H, N.
0.72 (s, 3H); MS (DCI, NH3-PCI) 327 (MH+). Anal. (C16H22
SO5) C, H, S.
-
r-(4-F lu or op h en yl)-1,3-d ioxola n e-2-p r op a n ol (XIV). A
solution of 2-(2-bromoethyl)-1,3-dioxolane (1.76 mL, 15 mmol)
in THF (10 mL) was added over 10 min to a suspension of
magnesium turnings (410 mg, 16.5 mmol) in THF (10 mL).
After 20 min of stirring, the reaction mixture was cooled to
-70 °C and a solution of 4-fluorobenzaldehyde (1.07 mL, 10
mmol) in THF (10 mL) was added slowly. The reaction
mixture was stirred at -70 °C for 2 h and the reaction
quenched with aqueous ammonium chloride. The reaction
solution was allowed to warm to room temperature and
extracted with ethyl acetate. The organic layer was washed
with brine, dried (MgSO4), filtered, and concentrated. The
crude obtained as a white liquid (2.54 g) was chromatographed
(silica gel; hexane/ethyl acetate, 7/3) to give XIV as a colorless
oil (1.88 g, 83%): IR (CHCl3) 3416, 2883, 1606, 1510, 1140;
1H NMR (CDCl3) 7.32 (complex dd, J ) 9, 5 Hz, 2H), 7.03
(complex t, J ) 8 Hz, 2H), 4.90 (t, J ) 5 Hz, 1H), 4.72 (td, J
) 5, 4 Hz, 1H), 3.97 (m, 2H), 3.87 (m, 2H), 2.68 (d, J ) 4 Hz,
1H), 1.68-1.96 (complex band, 4H); MS (EI) 226 (M+). Anal.
(C12H15FO3‚0.2H2O) C, H.
3-(1,3-Dioxola n -2-yl)-1-(4-flu or op h en yl)p r op a n -1-on e
(XV). To a solution of XIV (1.75 g, 7.74 mmol) in methylene
chloride (100 mL) was added pyridinium chlorochromate (2.5
g, 11.6 mmol). After 3 h of stirring at room temperature, the
reaction mixture was diluted with ether and filtered through
a short silica gel column. The column was eluted with ether,
and the fractions containing the desired product (1.69 g, 96%)
were combined and concentrated as a white solid: mp (DSC)
69 °C; IR (KBr) 3431, 2897, 1684, 1597, 1509, 1439, 1412, 1365;
1H NMR (CDCl3) 8.01 (complex dd, J ) 9, 5 Hz, 2H), 7.12
(complex t, J ) 9 Hz, 2H), 5.01 (t, J ) 4 Hz, 1H), 3.97 (m, 2H),
3.87 (m, 2H), 3.08 (t, J ) 7 Hz, 1H), 2.13 (td, J ) 7, 4 Hz, 2H);
MS (DCI, NH3-PCI) 225 (MH+). Anal. (C12H13FO3) C, H.
1-(4-F lu or op h en yl)-3-(2-fu r a n yl)-2-p r op en -1-on e (XVI).
To a solution of 2-furaldehyde (4.15 mL, 50 mmol) and
4-fluoroacetophenone (6.16 mL, 50 mmol) in methanol (200
mL) was added sodium methoxide (2.85 g, 50 mmol) over 10
min. After 18 h of stirring at room temperature, the reaction
mixture was concentrated to remove the solvent, resuspended
in ethyl acetate (600 mL), and diluted with water. The organic
layer was separated, washed with brine, dried (MgSO4),
filtered, and concentrated. The crude solid (10.27 g) was
chromatographed (silica gel, hexane/ethyl acetate, 7/3) to give
XVI (8.9 g, 95%) as a white solid: mp (DSC) 72 °C; IR (KBr)
3433, 3107, 1662, 1604, 1589, 1554, 1506, 1475, 1410, 1390;
1H NMR (CDCl3) 8.06 (complex dd, J ) 9, 5 Hz, 2H), 7.60 (d,
J ) 15 Hz, 1H), 7.53 (d, J ) 2 Hz, 1H), 7.43 (d, J ) 15 Hz,
1H), 7.16 (complex t, J ) 9 Hz, 2H), 6.72 (d, J ) 3 Hz, 1H),
6.52 (complex dd, J ) 3, 2 Hz, 1H); MS (DCI, NH3-PCI) 217
(MH+). Anal. (C13H10FO) C, H.
1
5,5-Dim eth yl-1,3-d ioxa n e-2-p r op ion a ld eh yd e (X). To a
cold solution of oxalyl chloride (5.5 mL, 63.2 mmol) in meth-
ylene chloride (25 mL) at -78 °C was injected over 5 min
DMSO (10.2 mL, 0.14 mol). After 15 min of stirring, a solution
of IX (10 g, 57.5 mmol) in methylene chloride (100 mL) was
added over 10 min. The reaction solution was stirred for 1 h,
and triethylamine (40 mL, 0.2 mol) was added. After 1 h of
stirring at -70 °C, the reaction mixture was allowed to warm
to room temperature and stirred for 2 h. The reaction was
quenched with water and the mixture extracted with meth-
ylene chloride. The organic fractions were washed with
aqueous sodium bicarbonate and brine. After drying (Na2SO4),
filtration, and concentration, the crude mixture was chromato-
graphed (silica gel, hexane/ethyl acetate, 7/3) to give X (6.1 g,
61%) as a colorless liquid: IR (CHCl3) 3522, 2959, 2907, 2855,
2725, 2401, 1724, 1471, 1396, 1365, 1311; 1H NMR (CDCl3)
9.78 (t, J ) 2 Hz, 1H), 4.52 (t, J ) 5 Hz, 1H), 3.59 (d, J ) 11
Hz, 2H), 3.42 (d, J ) 11 Hz, 2H), 2.58 (td, J ) 7, 2 Hz, 2H),
1.99 (td, J ) 7, 5 Hz, 2H), 1.17 (s, 3H), 0.72 (s, 3H); MS (DCI,
NH3-PCI) 173 (MH+). Anal. (C9H16O3‚0.2H2O) C, H.
r-(4-F lu or op h e n yl)-5,5-d im e t h yl-1,3-d ioxa n e -2-p r o-
p a n ol (XI). To a cold solution of X (2 g, 11.62 mmol) in THF
(50 mL) at -70 °C was added over 5 min (4-fluorophenyl)-
magnesium bromide (8.7 mL, 2M solution in ether, 17.44
mmol). After 2 h of stirring at -70 °C, the reaction mixture
was allowed to warm to room temperature and stirred over-
night. The reaction was quenched with water and extracted
with ethyl acetate. The organic fractions were combined and
washed successively with water and brine. After drying
(MgSO4), filtration, and concentration, the crude compound
(3.5 g) was chromatographed to give XI (2.73 g, 87%) as a white
solid: mp (DSC) 84 °C; IR (KBr) 3449, 2963, 2862, 1604, 1508,
1471, 1396, 1365; 1H NMR (CDCl3) 7.32 (complex dd, J ) 9, 5
Hz, 2H), 7.02 (complex t, J ) 9 Hz, 2H), 4.70 (td, J ) 7, 3 Hz,
1H), 4.48 (t, J ) 5 Hz, 1H), 3.62 (d, J ) 11 Hz, 2H), 3.43 (d, J
) 11 Hz, 2H), 2.84 (d, J ) 3 Hz, 1H), 1.83-1.93 (complex band,
2H), 1.66-1.81 (complex band, 2H), 1.19 (s, 3H), 0.73 (s, 3H);
MS (DCI) 268 (M+). Anal. (C15H21FO3) C, H.
1-(4-Flu or op h en yl)-3-(5,5-d im eth yl-1,3-d ioxa n -2-yl)pr o-
p a n on e (XII). To a solution of XI (2.6 g, 10.7 mmol) in
methylene chloride (100 mL) was added pyridinium chloro-
chromate (3.5 g, 16.05 mmol). After being stirred at room
temperature for 3 h, the reaction mixture was diluted with
ether and filtered through a short silica gel column. The
column was eluted with ether, and the fractions containing
the desired product (XII) were combined and concentrated (2.2
g, 85%): mp (DSC) 65 °C; IR (KBr) 3443, 2957, 2909, 1682,
1589, 1508, 1469, 1439, 1414, 1396, 1369, 1315; 1H NMR
(CDCl3) 8.01 (complex dd, J ) 9, 5 Hz, 2H), 7.12 (complex t, J
) 9 Hz, 2H), 4.57 (t, J ) 5 Hz, 1H), 3.60 (d, J ) 11 Hz, 2H),
3.44 (d, J ) 11 Hz, 2H), 3.12 (t, J ) 7 Hz, 2H), 2.08 (td, J )
7, 5 Hz, 2H), 1.19 (s, 3H), 0.72 (s, 3H); MS (DCI, NH3-PCI)
267 (MH+). Anal. (C15H19FO3) C, H.
Eth yl 4-flu or o-γ,ú-d ioxoben zen eh ep ta n oa te (XVII). A
solution of XVI (4.35 g, 23.14 mmol) in ethanol (100 mL) and
concentrated HCl (25 mL) was heated at 80-85 °C for 24 h.
The solvent was removed under reduced pressure and redis-
solved in methylene chloride (800 mL). The organic layer was
separated and concentrated to give blackish solid (5.55 g). The
chromatography on silica gel using hexane/ethyl acetate (7/3)
gave XVIII (1.7 g, 28%) and XVII (2.12 g, 33%) in order of
elution.
XVII: mp (DSC) 73 °C; IR (KBr) 3441, 3074, 2986, 2957,
2907, 1728, 1703, 1672, 1595, 1506, 1479, 1414; 1H NMR
(CDCl3) 8.06 (m, 2H), 7.12 (t, J ) 8 Hz, 2H), 4.13 (q, J ) 7.5
Hz, 2H), 3.27 (t, J ) 7 Hz, 2H), 2.94 (t, J ) 7 Hz, 2H), 2.88 (t,
J ) 7 Hz, 2H) 2.62 (t, J ) 7 Hz, 2H), 1.25 (t, J ) 7.5 Hz, 3H);
MS (DCI, NH3-PCI) 281 (MH+). Anal. (C15H17FO4) C, H.
XVIII: mp (DSC) 43 °C; IR (KBr) 3433, 2990, 2930, 1898,
1724, 1686, 1653, 1635, 1603, 1591, 1556, 1500, 1479, 1439,
1417; 1H NMR (CDCl3) 7.57 (complex dd, J ) 9, 5 Hz, 2H),
7.04 (complex t, J ) 9 Hz, 2H), 6.46 (d, J ) 3 Hz, 1H), 6.10 (d,
J ) 3 Hz, 1H), 4.15 (q, J ) 7 Hz, 2H), 3.04 (t, J ) 8 Hz, 2H)
2.68 (t, J ) 8 Hz, 2H), 1.25 (t, J ) 7 Hz, 3H); MS (DCI, NH3-
PCI) 263 (MH+). Anal. (C15H15FO3) C, H.
1-[4-(Meth ylsu lfon yl)ph en yl]-3-(5,5-dim eth yl-1,3-dioxan -
2-yl)p r op a n on e (XIII). To a solution of XII (1.68 g, 6.3
mmol) in dimethylformamide (75 mL) was added methane-
sulfinic acid sodium (2.9 g, 28.4 mmol). The reaction mixture
was heated at 120-130 °C for 72 h. After cooling, the solvent
was removed under reduced pressure and the reaction mixture
diluted with water. The product was extracted with methylene
chloride and washed with brine. After drying (MgSO4),
filtration, and concentration, the crude solid (2.78 g) was
chromatographed (silica gel, hexane/ethyl acetate, 6/4) to give
XIII (1.62 g, 79%) as a white solid: mp (DSC) 104 °C; IR (KBr)
3431, 3013, 2953, 2868, 1686, 1655, 1649, 1572, 1508, 1473,
1437, 1398, 1363; 1H NMR (CDCl3) 8.15 (complex d, J ) 8 Hz,
2H), 8.06 (complex d, J ) 8 Hz, 2H), 4.58 (t, J ) 5 Hz, 1H),
3.60 (d, J ) 11 Hz, 2H), 3.44 (d, J ) 11 Hz, 2H), 3.17 (t, J )
7 Hz, 1H), 3.07 (s, 3H), 2.12 (td, J ) 7, 5 Hz, 2H), 1.18 (s, 3H),
Eth yl 4-(m eth ylsu lfon yl)-γ,ú-d ioxoben zen eh ep ta n oa te
(XIX). To a solution of XVII (870 mg, 3.1 mmol) in dimeth-
ylformamide (25 mL) was added methanesulfinic acid sodium

1,2-Diarylpyrroles as Inhibitors of Cyclooxygenase-2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1629
(1.27 g, 12.4 mmol). The reaction mixture was heated at 130-
135 °C for 30 h. After cooling, the solvent was removed under
reduced pressure and the reaction mixture diluted with water.
The product was extracted with ethyl acetate and washed with
brine. After drying (MgSO4), filtration, and concentration, the
crude dark brown solid (840 mg) was chromatographed (silica
gel, hexane/ethyl acetate, 1/1) to give XIX (270 mg, 26%) as a
white solid: mp (DSC) 97 °C; IR (KBr) 3435, 3024, 3009, 2980,
2924, 1730, 1707, 1682, 1653, 1635, 1595, 1572, 1471, 1435,
1-[4-[2-Meth yl-5-[4-(m eth ylsu lfon yl)p h en yl]-1H-p yr r ol-
1-yl]p h en yl]eth a n on e (8): mp (DSC) 182 °C; MIR 3106,
2922, 1685, 1602, 1592, 1510, 1416, 1351; 1H NMR (CDCl3)
8.02 (d, J ) 8 Hz, 2H), 7.48 (d, J ) 8 Hz, 2H), 7.25 (d, J ) 8
Hz, 2H), 7.17 (d, J ) 8 Hz, 2H), 6.52 (d, J ) 3 Hz, 1H), 6.17
(d, J ) 3 Hz, 1H), 3.0 (s, 3H), 2.64 (s, 3H), 2.17 (s, 3H); MS
(EI) 353 (M+). Anal. (C20H19NSO3‚1.0 H2O) C, H, N, S.
1-(3,4-Diflu or op h en yl)-2-Meth yl-5-[4-(m eth ylsu lfon yl)-
p h en yl]-1H-p yr r ole (9): mp (DSC) 151 °C; IR (KBr) 3427,
3084, 3011, 2916, 2282, 1612, 1591, 1552, 1520, 1469, 1439,
1414, 1305; 1H NMR (CDCl3) 7.72 (complex d, J ) 8 Hz, 2H),
7.22 (q, J ) 9 Hz, 1H), 7.20 (complex d, J ) 8 Hz, 2H), 7.02
(ddd, J ) 10, 7, 2 Hz, 2H), 6.94 (ddt, J ) 8, 4, 2 Hz, 1H), 6.48
(d, J ) 3 Hz, 1H), 6.12 (d, J ) 3 Hz, 1H), 3.01 (s, 3H), 2.13 (s,
3H); MS (EI) 347 (M+). Anal. (C18H15NSO2F2) C, H, N.
2-Eth yl-1-(4-flu or oph en yl)-5-[4-(m eth ylsu lfon yl)ph en yl]-
1H-p yr r ole (10): mp 119-120 °C; IR (KBr) 2968, 1590, 1509,
1424, 1315, 1301; 1H NMR (CDCl3) 7.70 (d, J ) 8 Hz, 2H),
7.06-7.32 (complex band, 6H), 6.54 (d, J ) 3 Hz, 1H), 6.15 (d,
J ) 3 Hz, 1H), 3.0 (s, 3H), 2.45 (q, J ) 7.5 Hz, 2H), 1.15 (t, J
) 7.5 Hz, 3H); HRMS calcd for M+ 343.1042, found 343.1047.
Anal. (C19H18NSO2F‚0.35H2O) C, H, N.
1
1404; H NMR (CDCl3) 8.15 (d, J ) 8 Hz, 2H), 8.06 (d, J ) 8
Hz, 2H), 4.12 (q, J ) 7.5 Hz, 2H), 3.32 (t, J ) 7 Hz, 2H), 3.1
(s, 3H), 2.96 (t, J ) 7 Hz, 2H), 2.86 (t, J ) 7 Hz, 2H) 2.62 (t,
J ) 7 Hz, 2H), 1.25 (t, J ) 7.5 Hz, 3H); MS (DCI, NH3-PCI)
341 (MH+). Anal. (C16H20SO6) C, H, S.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dia r ylp yr -
r oles. These compounds were synthesized as in Schemes 1-5
by condensing 1,4-diketones with the appropriate amines. The
procedure for the synthesis of 1 is described below as an
example.
1-(4-F lu or op h e n yl)-2-m e t h yl-5-[4-(m e t h ylsu lfon yl)-
p h en yl]-1H-p yr r ole (1). A mixture of VIIb (580 mg, 2.28
mmol), 4-fluoroaniline (0.24 mL, 2.5 mmol), and p-toluene-
sulfonic acid (30 mg) in toluene (50 mL) was refluxed for 20 h
using Dean-Stark apparatus. The reaction mixture was
cooled, filtered, and concentrated. The crude mixture (820 mg)
was chromatographed (silica gel, hexane/ethyl acetate, 7/3) to
give pure 1 (595 mg, 79%) as a white solid: mp (DSC) 157 °C;
IR (KBr) 3429, 3074, 2999, 1896, 1772, 1734, 1701, 1684, 1653,
1593, 1558, 1510, 1469, 1419; 1H NMR (CDCl3) 7.68 (d, J ) 8
Hz, 2H), 7.16 (d, J ) 8 Hz, 2H), 7.06-7.15 (complex band, 4H),
6.5 (d, J ) 3 Hz, 1H), 6.13 (d, J ) 3 Hz, 1H), 3.00 (s, 3H), 2.13
(s, 3H); MS (EI) 329 (M+). Anal. (C18H16NSO2F) C, H, N, S.
2-(4-F lu or op h e n yl)-5-m e t h yl-1-[4-(m e t h ylsu lfon yl)-
p h en yl]-1H-p yr r ole (2): mp (DSC) 206 °C; IR (KBr) 3427,
3098, 3049, 1593, 1564, 1523, 1496, 1439, 1412, 1385; 1H NMR
(CDCl3) 7.92 (complex d, J ) 8 Hz, 2H), 7.32 (complex d, J )
8 Hz, 2H), 6.97 (complex dd, J ) 9, 5 Hz, 2H), 6.87 (complex
t, J ) 9 Hz, 2H), 6.32 (d, J ) 3 Hz, 1H), 6.13 (d, J ) 3 Hz,
1H), 3.10 (s, 3H), 2.18 (s, 3H); MS (EI) 329 (M+). Anal.
(C18H16NSO2F) C, H, N, S.
1-[(4-F lu or op h en yl)m eth yl]-2-m eth yl-5-[4-(m eth ylsu l-
fon yl)p h en yl]-1H-p yr r ole (11): mp (DSC) 143 °C; IR (KBr)
3074, 3015, 2916, 1658, 1593, 1554, 1510, 1471, 1441, 1415,
1
1381; H NMR (CDCl3) 7.82 (d, J ) 8 Hz, 2H), 7.43 (d, J ) 8
Hz, 2H), 7.00 (t, J ) 8 Hz, 2H), 6.86 (m, 2H), 6.37 (d, J ) 3
Hz, 1H), 6.08 (d, J ) 3 Hz, 1H), 5.12 (s, 2H), 3.03 (s, 3H), 2.17
(s, 3H); MS (EI) 343 (M+). Anal. (C19H18NSFO2) C, H, N, S.
1-Cycloh exyl-2-m et h yl-5-[4-(m et h ylsu lfon yl)p h en yl]-
1H-p yr r ole (12): mp (DSC) 141 °C; IR (KBr) 3435, 3015,
2932, 2855, 1593, 1508, 1469, 1448, 1410, 1379; 1H NMR
(CDCl3) 7.93 (complex d, J ) 8 Hz, 2H), 7.47 (complex d, J )
8 Hz, 2H), 6.12 (d, J ) 3 Hz, 1H), 5.97 (d, J ) 3 Hz, 1H), 4.03
(tt, J ) 12, 3 Hz, 1H), 3.11 (s, 3H), 2.46 (s, 3H), 1.80-2.04
(complex band, 6H), 1.68 (broad d, J ) 10 Hz, 1H), 1.09-1.35
(complex band, 3H); MS (DCI, NH3-PCI) 318 (MH+). Anal.
(C18H23NSO2) C, H, N, S.
1-(1-Me t h y le t h y l)-2-m e t h y l-5-[4-(m e t h y ls u lfo n y l)-
p h en yl]-1H-p yr r ole (13): mp (DSC) 112 °C; IR (KBr) 1689,
1596, 1315, 1151, 957; 1H NMR (CDCl3) 7.95 (d, J ) 8 Hz,
2H), 7.48 (d, J ) 8 Hz, 2H), 6.12 (d, J ) 3 Hz, 1H), 5.97 (d, J
) 3 Hz, 1H), 4.52 (h, J ) 7 Hz, 1H), 3.1 (s, 3H), 2.46 (s, 3H),
2-(4-F lu or op h en yl)-1-[4-(m et h ylsu lfon yl)p h en yl]-1H -
p yr r ole (3): mp (DSC) 201 °C; MIR 3134, 1592, 1550, 1504,
1
1463, 1423, 1412, 1307; H NMR (CDCl3) 7.89 (complex d, J
) 8 Hz, 2H), 7.32 (complex d, J ) 8 Hz, 2H), 7.08 (complex
dd, J ) 9, 5 Hz, 2H), 6.97 (dd, J ) 3, 2 Hz, 1H), 6.96 (complex
t, J ) 9 Hz, 2H), 6.44 (dd, J ) 3, 2 Hz, 1H), 6.42 (t, J ) 3 Hz,
1H), 3.08 (s, 3H); MS (EI) 315 (M+). Anal. (C17H14NSFO2‚
0.2H2O) C, H, N, S.
1-(4-F lu or op h en yl)-2-[4-(m et h ylsu lfon yl)p h en yl]-1H -
p yr r ole (4): mp (DSC) 163 °C; IR (KBr) 3436, 3119, 3074,
1635, 1593, 1541, 1510, 1450, 1423, 1394, 1346; 1H NMR
(CDCl3) 7.76 (d, J ) 8 Hz, 2H), 7.27 (d, J ) 8 Hz, 2H), 7.16
(complex dd, J ) 9, 5 Hz, 2H), 7.08 (complex t, J ) 9 Hz, 2H),
6.95 (dd, J ) 2.5, 1.5 Hz, 1H), 6.58 (dd, J ) 3, 1.5 Hz, 1H),
6.40 (dd, J ) 3, 2.5 Hz, 1H), 3.05 (s, 3H); MS (EI) 315 (M+).
Anal. (C17H14NSFO2) C, H, N, S.
2-Met h yl-5-[4-(m et h ylsu lfon yl)p h en yl]-1-p h en yl-1H -
p yr r ole (5): mp (DSC) 148 °C; IR (KBr) 3431, 3063, 3015,
2997, 2918, 2231, 1593, 1550, 1508, 1498, 1468, 1419, 1386,
1350; 1H NMR (CDCl3) 7.65 (complex d, J ) 8 Hz, 2H), 7.35-
7.44 (complex band, 3H), 7.02-7.13 (complex band, 4H), 6.51
(d, J ) 3 Hz, 1H), 6.13 (d, J ) 3 Hz, 1H), 2.98 (s, 3H), 2.15 (s,
3H); MS (EI) 311 (M+). Anal. (C18H17NSO2) C, H, N, S.
2-Met h yl-5-[4-(m et h ylsu lfon yl)p h en yl]-1-[4-(t r iflu o-
r om eth yl)p h en yl]-1H-p yr r ole (6): mp (DSC) 130 °C; IR
(KBr) 3433, 3080, 3007, 2924, 1614, 1593, 1558, 1471, 1415,
1388, 1325, 1309; 1H NMR (CDCl3) 7.48 (m, 4H), 7.32 (d, J )
8 Hz, 2H), 7.15 (d, J ) 8 Hz, 2H), 6.52 (d, J ) 3 Hz, 1H), 6.17
(d, J ) 3 Hz, 1H), 3.0 (s, 3H), 2.17 (s, 3H); MS (EI) 378 (M+).
Anal. (C19H16NSO2F3) C, H, N, S.
2-Me t h yl-1-(4-m e t h ylp h e n yl)-5-[4-(m e t h ylsu lfon yl)-
p h en yl]-1H-p yr r ole (7): mp (DSC) 144 °C; IR (KBr) 3429,
3007, 2926, 1720, 1709, 1687, 1657, 1593, 1550, 1512, 1469,
1439, 1388; 1H NMR (CDCl3) 7.65 (d, J ) 8 Hz, 2H), 7.16 (m,
4H), 7.06 (d, J ) 8 Hz, 2H), 6.5 (d, J ) 3 Hz, 1H), 6.10 (d, J )
3 Hz, 1H), 3.0 (s, 3H), 2.40 (s, 3H), 2.13 (s, 3H); MS (EI) 325
(M+). Anal. (C19H19NSO2) C, H, N, S.
1.47 (d, J ) 7.5 Hz, 6H); MS (EI) 277 (M+). Anal. (C15H19
NSO2‚0.25H2O) C, H, N.
-
1-Bu tyl-2-m eth yl-5-[4-(m eth ylsu lfon yl)p h en yl]-1H-p yr -
r ole (14): mp (DSC) 79 °C; IR (KBr) 3420, 3020, 2932, 2874,
1595, 1510, 1471, 1417, 1375; 1H NMR (CDCl3) 7.90 (d, J ) 8
Hz, 2H), 7.52 (d, J ) 8 Hz, 2H), 6.20 (d, J ) 3 Hz, 1H), 5.97
(d, J ) 3 Hz, 1H), 3.88 (t, J ) 7.5 Hz, 2H), 3.1 (s, 3H), 2.32 (s,
3H), 1.5 (m, 2H), 1.2 (m, 2H), 0.82 (t, J ) 7.5 Hz, 3H); MS (EI)
291 (M+). Anal. (C16H21NSO2) C, H, N, S.
2-Me t h yl-5-[4-(m e t h ylsu lfon yl)p h e n yl]-1H -p yr r ole
(15): mp (DSC) 160 °C; IR (KBr) 3397, 2926, 1601, 1585, 1512,
1469, 1431, 1300; 1H NMR (CDCl3) 8.50 (broad s, 1H), 7.83
(complex d, J ) 8 Hz, 2H), 7.55 (complex d, J ) 8 Hz, 2H),
6.57 (t, J ) 3 Hz, 1H), 6.00 (t, J ) 3 Hz, 1H), 3.06 (s, 3H), 2.36
(s, 3H); MS (EI) 235 (M+). Anal. (C12H13NSO2) C, H, N, S.
2-(4-F lu or op h en yl)-1-[3-(p h en ylsu lfon yl)p h en yl]-1H -
p yr r ole (16): mp (DSC) 164 °C; IR (KBr) 3439, 3065, 2910,
2361, 2338, 1772, 1734, 1716, 1653, 1597, 1558, 1504, 1483,
1464; 1H NMR (CDCl3) 7.82 (dd, J ) 8, 2 Hz, 1H), 7.67 (d, J )
2 Hz, 1H), 7.53 (t, J ) 8 Hz, 1H), 7.42 (dd, J ) 8, 2 Hz, 1H),
7.06 (m, 2H), 6.84-6.96 (complex band, 3H), 6.42 (m, 2H), 2.92
(s, 3H); MS (EI) 315 (M+). Anal. (C17H14NSFO2‚0.25H2O) C,
H, N, S.
2-(4-Flu or op h en yl)-1-[4-(eth ylsu lfon yl)p h en yl]-1H-p yr -
r ole (17): mp (DSC) 168 °C; IR (KBr) 3435, 3130, 3067, 2970,
2926, 1902, 1734, 1716, 1684, 1653, 1593, 1552, 1505, 1464,
1423, 1410, 1334; 1H NMR (CDCl3) 7.85 (d, J ) 8 Hz, 2H),
7.70 (d, J ) 8 Hz, 1H), 7.07 (m, 2H), 6.96 (m, 3H), 6.42 (m,
2H), 3.13 (q, J ) 7.5 Hz, 1H), 1.27 (t, J ) 7.5 Hz, 3H); MS (EI)
329 (M+). Anal. (C18H16NSFO2) C, H, N, S.
2-(4-F lu or op h en yl)-1-[4-(p h en ylsu lfon yl)p h en yl]-1H -
p yr r ole (18): mp (DSC) 204 °C; IR (KBr) 3439, 3134, 3098,
1900, 1591, 1550, 1506, 1496, 1462, 1421, 1412, 1332; 1H NMR
(CDCl3) 7.96 (d, J ) 8 Hz, 2H), 7.88 (d, J ) 8 Hz, 2H), 7.50-

1630 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Khanna et al.
7.62 (complex band, 3H), 7.22 (d, J ) 8 Hz, 2H), 7.06 (m, 2H),
6.88-6.97 (complex band, 3H), 6.38 (m, 2H); MS (EI) 377 (M+).
Anal. (C22H16NSFO2‚0.5H2O) C, H, N.
through the reaction solution for 2 min. Hydrogen peroxide
(1.2 mL, 30% solution by wt, 10.5 mmol) was added and the
mixture stirred at room temperature for 1 h. The reaction
mixture was diluted with brine and extracted with ether. The
organic fractions were dried (MgSO4), filtered, and concen-
trated. The crude mixture (1 g) was chromatographed (silica
gel, hexane/ethyl acetate, 7/3) to give pure 27 (292 mg, 43%)
as a white solid: mp (DSC) 150 °C; IR (KBr) 3080, 3013, 2918,
1902, 1595, 1570, 1549, 1510, 1468, 1437, 1394; 1H NMR
(CDCl3) 7.76 (complex d, J ) 8 Hz, 2H), 7.26 (complex d, J )
8 Hz, 2H), 7.24 (complex dd, J ) 9, 4.8 Hz, 2H), 7.09 (complex
dd, J ) 9, 8 Hz, 2H), 6.80 (d, J ) 4 Hz, 1H), 6.52 (d, J ) 4 Hz,
1H), 3.02 (s, 3H); MS (EI) 383 (M+). Anal. (C18H13NSF4O2‚
0.5H2O) C, H, N.
1-[3-Ch lor o-4-(m e t h ylsu lfon yl)p h e n yl]-2-(4-flu or o-
p h en yl)-1H-p yr r ole (19): mp (DSC) 142 °C; IR (KBr) 3431,
2914, 1635, 1591, 1547, 1506, 1479, 1419, 1392, 1313; 1H NMR
(CDCl3) 8.05 (d, J ) 8 Hz, 1H), 7.38 (d, J ) 2 Hz, 1H), 7.13
(m, 2H), 6.92-7.06 (complex band, 3H), 6.42 (m, 2H), 3.27 (s,
3H); MS (EI) 349 (M+). Anal. (C17H13NSFClO2) C, H, N, S.
4-[2-(4-F lu or op h en yl)-1H -p yr r ol-1-yl]b en zen esu lfon -
a m id e (20): mp (DSC) 206 °C; IR (KBr) 3352, 3265, 3132,
3098, 1900, 1792, 1740, 1670, 1595, 1552, 1502, 1460, 1423,
1
1334; H NMR (CDCl3) 7.88 (complex d, J ) 8 Hz, 2H), 7.27
(complex d, J ) 8 Hz, 2H), 7.10 (complex dd, J ) 9, 5 Hz, 2H),
6.97 (m, 1H), 6.95 (complex t, J ) 9 Hz, 2H), 6.43 (dd, J ) 3,
2 Hz, 1H), 6.41 (t, J ) 3 Hz, 1H), 4.87 (broad s, 2H); MS (EI)
316 (M+). Anal. (C16H13N2SFO2) C, H, N, S.
2,2,2-Tr iflu or o-1-[1-(4-flu or op h e n yl)-2-m e t h yl-5-[4-
(m eth ylsu lfon yl) p h en yl]-1H-p yr r ol-3-yl]eth a n on e (28).
To a solution of 1 (800 mg, 2.43 mmol) in trifluoroacetic acid
(7 mL) was added trifluoroacetic anhydride (0.7 mL, 4.86
mmol), and the mixture was heated at 50 °C. After 3 h, the
reaction mixture was poured over ice and neutralized with
dilute ammonium hydroxide to pH ∼9. After extraction with
ethyl acetate, the organic layer was washed successively with
water and brine. The organic fractions were dried (MgSO4),
filtered, and concentrated, and the pale yellow crude solid (1.02
g) was chromatographed (silica gel, hexane/ethyl acetate, 7/3)
to give 28 (800 mg, 77%) as a white solid: mp (DSC) 196 °C;
IR (KBr) 3076, 3026, 2939, 2393, 1687, 1597, 1570, 1550, 1510,
4-[2-(4-F lu or op h en yl)-1H -p yr r ol-1-yl]-N-m et h ylb en -
zen esu lfon a m id e (21): mp (DSC) 174 °C; IR (KBr) 3439,
3265, 3130, 1736, 1595, 1550, 1504, 1462, 1421, 1325; 1H NMR
(CDCl3) 7.80 (complex d, J ) 8 Hz, 2H), 7.27 (complex d, J )
8 Hz, 2H), 7.10 (complex dd, J ) 9, 5 Hz, 2H), 6.96 (m, 1H),
6.94 (complex t, J ) 9 Hz, 2H), 6.37-6.44 (complex band, 2H),
4.43 (q, J ) 5 Hz, 1H), 2.70 (d, J ) 5 Hz, 3H). Anal. (C17H15N2-
SFO2‚0.25H2O) C, H, N.
4-[2-(4-F lu or op h en yl)-1H -p yr r ol-1-yl]-N,N-d im et h yl-
ben zen esu lfon a m id e (22): mp (DSC) 157 °C; IR (KBr) 3439,
3138, 1925, 1593, 1550, 1504, 1462, 1412, 1338; 1H NMR
(CDCl3) 7.82 (d, J ) 8 Hz, 2H), 7.27 (d, J ) 8 Hz, 2H), 7.07
(m, 2H), 6.86-7.94 (complex band, 3H), 6.40 (m, 2H), 2.72 (s,
6H); MS (EI) 344 (M+). Anal. (C18H17N2SFO2) C, H, N, S.
Eth yl 5-(4-flu or op h en yl)-1-[4-(m eth ylsu lfon yl)p h en yl]-
1H-p yr r ole-2-p r op a n oa te (23): mp (DSC) 127 °C; IR (KBr)
3406, 2920, 1716, 1684, 1653, 1635, 1599, 1577, 1558, 1506,
1471, 1425, 1305; 1H NMR (CDCl3) 7.92 (d, J ) 8 Hz, 2H),
7.35 (d, J ) 8 Hz, 2H), 6.97 (m, 2H), 6.85 (t, J ) 8 Hz, 2H),
6.32 (d, J ) 2 Hz, 1H), 6.13 (d, J ) 2 Hz, 1H), 4.13 (q, J ) 7.5
Hz, 2H), 3.1 (s, 3H), 2.78 (t, J ) 7.5 Hz, 2H), 2.54 (t, J ) 7.5
Hz, 2H), 1.25 (t, J ) 7.5 Hz, 3H); MS (EI) 415 (M+). Anal.
(C22H22NSFO4) C, H, N, S.
5-(4-F lu or op h en yl)-1-[4-(m et h ylsu lfon yl)p h en yl]-1H -
p yr r ole-2-p r op a n oic Acid (24). A suspension of 23 (300 mg,
0.72 mmol) in ethanol (10 mL) and 2 N NaOH (4.5 mL) was
stirred for 4 h. The clear solution obtained was concentrated
to remove ethanol, diluted with 1 N NaOH (200 mL), and
extracted with ether (200 mL). The aqueous layer was
separated, acidified with concentrated HCl, and extracted with
methylene chloride (2 × 350). The organic fractions were
concentrated and crystallized using methylene chloride to give
24 (198 mg, 69%) as a white solid: mp (DSC) 192 °C; IR (KBr)
3429, 3063, 2926, 1711, 1653, 1635, 1593, 1550, 1522, 1496,
1485, 1421, 1313; 1H NMR (CDCl3) 7.95 (d, J ) 8 Hz, 2H),
7.35 (d, J ) 8 Hz, 2H), 6.97 (m, 2H), 6.86 (t, J ) 8 Hz, 2H),
6.32 (d, J ) 2 Hz, 1H), 6.13 (d, J ) 2 Hz, 1H), 3.1 (s, 3H), 2.82
(t, J ) 7.5 Hz, 2H), 2.62 (t, J ) 7.5 Hz, 2H); MS (EI) 387 (M+).
Anal. (C20H18NSFO4‚1.0H2O) C, H, N, S.
Eth yl 1-(4-flu or op h en yl)-5-[4-(m eth ylsu lfon yl)p h en yl]-
1H-p yr r ole-2-p r op a n oa te (25): mp (DSC) 134 °C; IR (KBr)
3057, 2982, 2902, 1903, 1714, 1653, 1595, 1550, 1508, 1471,
1446, 1425, 1392; 1H NMR (CDCl3) 7.68 (d, J ) 8 Hz, 2H),
7.06-7.23 (complex band, 6H), 6.50 (d, J ) 2 Hz, 1H), 6.13 (d,
J ) 2 Hz, 1H), 4.10 (q, J ) 7.5 Hz, 2H), 3.0 (s, 3H), 2.76 (t, J
) 7.5 Hz, 2H), 2.53 (t, J ) 7.5 Hz, 2H), 1.24 (t, J ) 7.5 Hz,
3H); MS (EI) 415 (M+). Anal. (C22H22NSFO4) C, H, N, S.
1-(4-F lu or op h en yl)-5-[4-(m et h ylsu lfon yl)p h en yl]-1H -
p yr r ole-2-p r op a n oic a cid (26) was synthesized from 25
using the procedure described for 24: mp (DSC) 163 °C; IR
(KBr) 3078, 2926, 2365, 2334, 1711, 1653, 1593, 1510, 1469,
1427, 1307; 1H NMR (CDCl3) 7.68 (d, J ) 8 Hz, 2H), 7.06-
7.18 (complex band, 6H), 6.50 (d, J ) 2 Hz, 1H), 6.13 (d, J )
2 Hz, 1H), 3.0 (s, 3H), 2.76 (t, J ) 7.5 Hz, 2H), 2.56 (t, J ) 7.5
Hz, 2H); MS (EI) 387 (M+). Anal. (C20H18NSFO4‚0.2H2O) C,
H, N.
1
1481, 1427, 1379, 1309; H NMR (CDCl3) 7.76 (complex d, J
) 8 Hz, 2H), 7.26 (complex d, J ) 8 Hz, 2H), 7.14-7.22
(complex band, 4H), 6.95 (q, J ) 2 Hz, 1H), 3.04 (s, 3H), 2.50
(s, 3H); MS (EI) 425 (M+). Anal. (C20H15NSF4O3‚0.5H2O) C,
H, N.
1-[1-(4-F lu or op h en yl)-2-m eth yl-5-[4-(m eth ylsu lfon yl)-
p h en yl]-1H-p yr r ol-3-yl]eth a n on e (29). Acetyl chloride (120
µL, 1.67 mmol) was added slowly to a stirred slurry of
aluminum chloride (223 mg, 1.67 mmol) in methylene chloride
(15 mL) at -5 °C. After 30 min, a solution of 1 (500 mg, 1.52
mmol) in methylene chloride (20 mL) was added. The reaction
mixture was allowed to warm to room temperature and stirred
for 18 h. The reaction mixture was poured over ice-water
and extracted with methylene chloride. The organic fraction
was washed with brine, dried (MgSO4), filtered, and concen-
trated. The crude yellowish solid (570 mg) was chromato-
graphed (silica gel, hexane/ethyl acetate, 6/4) to give 29 (170
mg, 30%) as a white solid: mp (DSC) 211 °C; IR (KBr) 3072,
3013, 2924, 2205, 1905, 1709, 1649, 1595, 1568, 1552, 1510,
1477, 1425, 1390; 1H NMR (CDCl3) 7.74 (d, J ) 8 Hz, 2H),
7.24 (d, J ) 8 Hz, 2H), 7.14 (d, J ) 8 Hz, 4H), 6.88 (s, 1H),
3.04 (s, 3H), 2.51 (s, 3H), 2.42 (s, 3H); MS (EI) 371 (M+). Anal.
(C20H18NSFO3‚0.25H2O) C, H, N.
[1-(4-F lu or op h en yl)-2-m et h yl-5-[4-(m et h ylsu lfon yl)-
p h en yl]-1H-p yr r ol-3-yl]p h en ylm eth a n on e (30). Benzoyl
chloride (180 µL, 1.52 mmol) was added slowly to a stirred
slurry of aluminum chloride (223 mg, 1.67 mmol) in methylene
chloride (15 mL) at -10 °C. After 30 min, a solution of 1 (500
mg, 1.52 mmol) in methylene chloride (10 mL) was added. The
reaction mixture was allowed to warm to room temperature
and stirred for 20 h. The reaction mixture was poured over
ice-water and extracted with methylene chloride. The organic
fractions were washed with brine, dried (MgSO4), filtered, and
concentrated. The crude yellowish solid (570 mg) was chro-
matographed (silica gel, hexane/ethyl acetate, 6/4) to give 30
(54 mg, 8%) as a white solid: IR (KBr) 3061, 2924, 2363, 1917,
1772, 1734, 1717, 1699, 1684, 1635, 1597, 1577, 1568; 1H NMR
(CDCl3) 7.90 (d, J ) 8 Hz, 2H), 7.73 (d, J ) 8 Hz, 2H), 7.57 (t,
J ) 8 Hz, 1H), 7.50 (t, J ) 8 Hz, 2H), 7.14-7.27 (complex band,
6H), 6.76 (s, 1H), 3.02 (s, 3H), 2.45 (s, 3H); MS (EI) 433 (M+).
Anal. (C25H20NSFO3‚0.5H2O) C, H, N.
1-(4-F lu or op h e n yl)-2-m e t h yl-5-[4-(m e t h ylsu lfon yl)-
p h en yl]-3-[(tr iflu or om eth yl)su lfon yl]-1H-p yr r ole (31). To
a solution of 1 (10 g, 30.8 mmol) in methylene chloride (400
mL) at 0 °C were added aluminum chloride (4.6 g, 33.9 mmol)
and trifluoromethanesulfonic anhydride (8 mL, 46.2 mmol).
After 30 min, the reaction mixture was allowed to warm to
room temperature and refluxed for 72 h. The reddish orange
reaction mixture was cooled, poured over ice-water, and
extracted with methylene chloride. The organic fractions were
1-(4-Flu or op h en yl)-5-[4-(m eth ylsu lfon yl)p h en yl]-2-(tr i-
flu or om eth yl)-1H-p yr r ole (27). To a solution of 4 (550 mg,
1.75 mmol) in DMSO (10 mL) was added FeSO4‚7H20 (291 mg,
1.05 mmol). Excess of trifluoromethyl iodide gas was bubbled

1,2-Diarylpyrroles as Inhibitors of Cyclooxygenase-2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1631
washed with brine, dried (MgSO4), filtered, and concentrated.
The crude orange solid (16 g) was chromatographed (silica gel,
hexane/ethyl acetate 7/3) to give 31 (1.35 g, 10%) as a white
solid: mp 162-164 °C; 1H NMR (CDCl3) 7.78 (d, J ) 8 Hz,
2H), 7.22 (d, J ) 8 Hz, 2H), 7.19 (m, 4H), 6.92 (s, 1H), 3.04 (s,
3H), 2.40 (s, 3H). Anal. (C19H15NS2F4O4) C, H, N.
was added to a solution of 1 (500 mg, 2.87 mmol) in AcOH (5
mL). After being heated at 50 -55 °C for 60 min, the reaction
mixture was cooled and poured over ice. The solution was
made alkaline with 2 N NaOH and extracted with methylene
chloride. The organic fractions was washed with water and
brine, dried (MgSO4), filtered, and concentrated to give the
crude product (550 mg) as a yellowish liquid. Chromatography
(silica gel, methylene chloride/methanol/ammonium hydroxide,
90/10/1) gave 36 (259 mg, 23%) as a white solid: mp (DSC)
142 °C; IR (KBr) 3059, 3030, 2964, 2937, 2853, 2814, 1919,
1597, 1562, 1510, 1460, 1429, 1414, 1379; 1H NMR (CDCl3)
7.67 (d, J ) 8 Hz, 2H), 7.16 (d, J ) 8 Hz, 2H), 7.06-7.16
(complex band, 4H), 6.53 (s, 1H), 3.34 (s, 2H), 3.0 (s, 3H), 2.30
(s, 6H), 2.08 (s, 3H); MS (DCI, NH3-PCI) 387 (MH+). Anal.
(C21H23N2SFO2) C, H, N.
1-(4-F lu or op h e n yl)-2-m e t h yl-5-[4-(m e t h ylsu lfon yl)-
p h en yl]-1H-p yr r ole-3-ca r boxa ld eh yd e (32). To a solution
of 1 (1.55 g, 4.71 mmol) in dimethylformamide (3.65 mL, 47
mmol) and toluene (20 mL) was added over 10 min phospho-
rous oxychloride (3.5 mL, 37.7 mmol). After being stirred for
20 min, the reaction mixture was immersed in an oil bath at
∼70 °C and heated for 5 h. The reaction mixture was cooled,
poured into aqueous sodium acetate solution, and extracted
with ethyl acetate. The organic fractions were washed with
10% aqueous potassium carbonate and water. After drying
(Na2SO4), filtration, and concentration, the crude yellowish
liquid (2.06 g) was chromatographed (silica gel, hexane/ethyl
acetate, 6/4) to give 32 (1.2 g, 71%): mp (DSC) 155 °C; IR (KBr)
3071, 3022, 2926, 2739, 1938, 1730, 1672, 1599, 1556, 1510,
1-(4-F lu or op h e n yl)-2-m e t h yl-5-[4-(m e t h ylsu lfon yl)-
p h en yl]-1H-p yr r ol-3-yl]m eth yl Aceta te (37). To a solution
of 1 (500 mg, 2.87 mmol) in AcOH (5 mL), was added
formaldehyde (0.22 mL, 40% solution in water, 2.87 mmol).
After being heated at 50-55 °C for 90 min, the reaction
mixture was cooled and poured over ice. The solution was
made alkaline with 2 N NaOH and extracted with methylene
chloride. The organic fractions were washed with water and
brine, dried (MgSO4), filtered, and concentrated to give the
crude product (780 mg) as a yellowish liquid. Chromatography
(silica gel, hexane/ethyl acetate, 6/4) gave 37 (250 mg, 22%)
as a white solid: mp (DSC) 151 °C; IR (KBr) 3072, 2922, 1730,
1597, 1510, 1435, 1406, 1373; 1H NMR (CDCl3) 7.68 (d, J ) 8
Hz, 2H), 7.16 (d, J ) 8 Hz, 2H), 7.04-7.16 (complex band, 4H),
6.58 (s, 1H), 5.07 (s, 2H), 3.0 (s, 3H), 2.13 (s, 3H), 2.08 (s, 3H);
MS (EI) 401 (M+). Anal. (C21H20NSFO4) C, H, N.
1
1433, 1402, 1388; H NMR (CDCl3) 9.98 (s, 1H), 7.76 (d, J )
8 Hz, 2H), 7.22 (d, J ) 8 Hz, 2H), 7.14 (d, J ) 7 Hz, 4H), 6.92
(s, 1H), 3.02 (s, 3H), 2.42 (s, 3H); MS (EI) 357 (M+). Anal.
(C19H16NSFO3) C, H, N.
1-(4-F lu or op h e n yl)-2-m e t h yl-5-[4-(m e t h ylsu lfon yl)-
p h en yl]-1H-p yr r ole-3-ca r bon itr ile (33). To a cold solution
of 1 (750 mg, 2.28 mmol) in dimethylformamide (8 mL)-
acetonitrile (8 mL) at -78 °C was added chlorosulfonyl
isocyanate (200 µL, 2.28 mmol). The reaction mixture was
allowed to warm to 20 °C over 4 h, quenched by adding excess
water, and extracted with ethyl acetate. The organic fractions
were washed with brine, dried (MgSO4), filtered, and concen-
trated. The crude colorless liquid (0.77 g) was chromato-
graphed (silica gel, hexane/ethyl acetate, 6/4) to give the target
compound (620 mg, 77%) as a white solid: mp (DSC) 205 °C;
IR (KBr) 3076, 2930, 2220, 1720, 1709, 1687, 1657, 1601, 1560,
1-(4-F lu or op h e n yl)-2-m e t h yl-5-[4-(m e t h ylsu lfon yl)-
p h en yl]-1H-p yr r ole-3-m eth a n ol (38). To a solution of 32
(1.4 g, 3.9 mmol) in EtOH (30 mL) was added sodium
borohydride (297 mg, 7.84 mmol). After 3 h of refluxing, the
reaction mixture was cooled to room temperature and quenched
with drops of acetic acid. The solvent was removed under
reduced pressure and the residue redissolved in methylene
chloride. After the mixture was washed with 1 N HCl and
brine, the organic fractions were filtered, concentrated, and
chromatographed (silica gel, hexane/ethyl acetate, 1/1) to give
38 (1.4 g, 100%) as a white solid: mp (DSC) 148 °C; IR (KBr)
3069, 2993, 2916, 1890, 1593, 1558, 1510, 1471, 1435, 1375;
1H NMR (CDCl3) 7.68 (d, J ) 8 Hz, 2H), 7.15 (d, J ) 8 Hz,
2H), 7.04-7.16 (complex band, 4H), 6.58 (s, 1H), 4.62 (s, 2H),
1
1512, 1479, 1425, 1394; H NMR (CDCl3) 7.74 (d, J ) 8 Hz,
2H), 7.20 (d, J ) 8 Hz, 2H), 7.14 (d, J ) 7 Hz, 4H), 6.68 (s,
1H), 3.04 (s, 3H), 2.30 (s, 3H); MS (EI) 354 (M+). Anal.
(C19H15N2SFO2) C, H, N.
3-Br om o-1-(4-flu or op h en yl)-2-m eth yl-5-[4-(m eth ylsu l-
fon yl)p h en yl]-1H-p yr r ole (34). To a solution of 1 (3.3 g, 10
mmol) in THF (80 mL) at -70 °C was added over 10 min
N-bromosuccinimide (1.78 g, 10 mmol). The reaction mixture
was allowed to warm to 20 °C over 3 h and stirred for 18 h.
After dilution with aqueous sodium bicarbonate, the reaction
mixture was extracted with ethyl acetate. The organic frac-
tions were washed with water, dried (MgSO4), filtered, and
concentrated. The crude yellowish liquid (4.52 g) was chro-
matographed (silica gel, hexane/ethyl acetate, 7/3) to give 34
(3.6 g, 88%): mp (DSC) 157 °C; IR (KBr) 3115, 3078, 2920,
1639, 1595, 1510, 1414, 1381; 1H NMR (CDCl3) 7.70 (d, J ) 8
Hz, 2H), 7.16 (d, J ) 8 Hz, 2H), 7.12 (d, J ) 7 Hz, 4H), 6.53 (s,
1H), 3.04 (s, 3H), 2.10 (s, 3H); MS (EI) 407/409 (M+). Anal.
(C18H15NSBrFO2) C, H, N, Br.
3.0 (s, 3H), 2.12 (s, 3H); MS (EI) 359 (M+). Anal. (C19H18
-
NSFO3‚0.4H2O) C, H, N, S.
3-[(4-Ch lor oph en oxy)m eth yl]-1-(4-flu or oph en yl)-2-m eth -
yl-5-[4-(m eth ylsu lfon yl)p h en yl]-1H-p yr r ole (39). To a
solution of 38 (300 mg, 0.83 mmol), 4-chlorophenol (107 mg,
0.83 mmol), and triphenylphosphine (219 mg, 0.83 mmol) in
THF (20 mL) was added diethyl azodicarboxylate (132 µL, 0.83
mmol). The mixture was stirred at room temperature for 48
h. The solvent was removed under reduced pressure, and the
crude (830 mg) was chromatographed (silica gel, hexane/ethyl
acetate, 1/1) to give 39 (29 mg, 7%): mp (DSC) 145 °C; IR (KBr)
3071, 2922, 2872, 1716, 1653, 1595, 1579, 1510, 1490, 1435,
3-Ch lor o-1-(4-flu or op h en yl)-2-m eth yl-5-[4-(m eth ylsu l-
fon yl)p h en yl]-1H-p yr r ole (35). To a solution of 1 (1 g, 3.03
mmol) in THF (100 mL) at -70 °C was added over 10 min
N-chlorosuccinimide (488 mg, 3.65 mmol). The reaction
mixture was allowed to warm to 20 °C over 3 h and stirred for
18 h. More N-chlorosuccinimide (450 mg, 3.37 mmol) was
added, and the mixture was stirred for 6 h. After dilution with
aqueous potassium carbonate, the reaction mixture was
extracted with ethyl acetate. The organic fractions were
washed with water, dried (MgSO4), filtered, and concentrated.
The crude dark orange solid (1.3 g) was chromatographed
(silica gel, hexane/ethyl acetate, 1/1) to give 35 (107 mg,
1
1410; H NMR (CDCl3) 7.70 (d, J ) 8 Hz, 2H), 7.27 (d, J ) 8
Hz, 2H), 7.16 (d, J ) 8 Hz, 2H), 7.04-7.16 (complex band, 4H),
6.96 (d, J ) 8 Hz, 2H), 6.52 (s, 1H), 4.93 (s, 2H), 3.02 (s, 3H),
2.13 (s, 3H); MS (EI) 469 (M+). Anal. (C25H21NSClFO3‚
0.25H2O) C, H, N.
3-[(3-Ch lor oph en oxy)m eth yl]-1-(4-flu or oph en yl)-2-m eth -
yl-5-[4-(m eth ylsu lfon yl)p h en yl]-1H-p yr r ole (40). To a
solution of 38 (300 mg, 0.83 mmol), 3-chlorophenol (88 µL, 0.83
mmol), and triphenylphosphine (219 mg, 0.83 mmol) in THF
(20 mL) was added diethyl azodicarboxylate (132 µL, 0.83
mmol). The mixture was stirred at room temperature for 48
h. The solvent was removed under reduced pressure, and the
crude liquid (820 mg) was chromatographed (silica gel, hexane/
ethyl acetate, 7/3) to give 40 (75 mg, 19%): mp (DSC) 139 °C;
IR (KBr) 2922, 1716, 1684, 1653, 1593, 1558, 1539, 1510, 1477,
1435, 1361; 1H NMR (CDCl3) 7.68 (complex d, J ) 8 Hz, 2H),
7.23 (t, J ) 8 Hz, 1H), 7.19 (complex d, J ) 8 Hz, 2H), 7.17
(complex dd, J ) 9, 5 Hz, 2H), 7.12 (complex t, J ) 9 Hz, 2H),
7.04 (t, J ) 2 Hz, 1H), 6.96 (ddd, J ) 8, 2, 1 Hz, 1H), 6.92
1
10%): mp (DSC) 172 °C; H NMR (CDCl3) 7.70 (d, J ) 8 Hz,
2H), 7.17 (d, J ) 8 Hz, 2H), 7.12 (d, J ) 7 Hz, 4H), 6.48 (s,
1H), 3.02 (s, 3H), 2.10 (s, 3H); MS (EI) 363 (M+). Anal.
(C18H15NSClFO2) C, H, N.
1-(4-F lu or op h en yl)-N,N,2-t r im et h yl-5-[4-(m et h ylsu l-
fon yl)p h en yl]-1H-p yr r ole-3-m eth a n a m in e (36). To a solu-
tion of formaldehyde (0.21 mL, 40% solution in water, 2.87
mmol) in acetic acid (2 mL) was added cautiously dimeth-
ylamine (325 µL, 40% solution in water, 2.87 mmol). The
reaction mixture was allowed to cool to room temperature and

1632 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Khanna et al.
(4) Xie, W.; Chipman, J . G.; Robertson, D. L.; Erikson, R. L.;
Simmons, D. L. Expression of a Mitogen-Response Gene Encod-
ing Prostaglandin Synthase is Regulated by mRNA Splicing.
Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 2692-2696.
(ddd, J ) 8, 2, 1 Hz, 1H), 6.63 (s, 1H), 4.95 (s, 2H), 3.02 (s,
3H), 2.13 (s, 3H); MS (EI) 469 (M+). Anal. (C25H21NSClFO3)
C, H, N.
1-(4-F lu or op h e n yl)-2-m e t h yl-5-[4-(m e t h ylsu lfon yl)-
p h en yl]-r-(tr iflu or om eth yl)-1H-p yr r ole-3-m eth a n ol (41).
To a solution of 28 (310 mg, 0.73 mmol) in ethanol (10 mL)
and acetic acid (10 mL) in a Parr hydrogenation flask was
added 4% Pd on C (51 mg). The system was sealed, purged
with nitrogen (5 times) and hydrogen (5 times), and then
pressurized to 5 psi of hydrogen. After the reaction was run
on a shaker for 24 h, the system was vented, purged with
nitrogen, and filtered. The filtrate was concentrated, and the
crude (325 mg) was chromatographed (silica gel, hexane/ethyl
acetate, 6/4) to give 41 (270 mg, 87%): mp (DSC) 213 °C; IR
(KBr) 2918, 1720, 1691, 1657, 1597, 1547, 1510, 1439, 1302;
1H NMR (CDCl3) 7.70 (d, J ) 8 Hz, 2H), 7.18 (d, J ) 8 Hz,
2H), 7.04-7.16 (complex band, 4H), 6.65 (s, 1H), 5.05 (m, 1H),
3.02 (s, 3H), 2.51 (d, J ) 6 Hz, 1H), 2.13 (s, 3H); MS (EI) 427
(M+). Anal. (C20H17NSF4O3) C, H, N.
1-(4-F lu or op h e n yl)-2-m e t h yl-5-[4-(m e t h ylsu lfon yl)-
p h en yl]-3-(2,2,2-tr iflu or oeth yl)-1H-p yr r ole (42). To a so-
lution of 41 (325 mg, 0.76 mmol) in trifluoroacetic acid (5 mL)
and acetic acid (10 mL) in a Parr hydrogenation flask was
added 5% Pt on C (325 mg). The system was sealed, purged
with nitrogen (5 times) and hydrogen (5 times), and then
pressurized to 60 psi of hydrogen. After the reaction was run
on a shaker for 48 h, the system was vented, purged with
nitrogen, and filtered. The filtrate was concentrated, and the
residue was redissolved in methylene chloride and washed
with aqueous potassium carbonate and brine. After drying
(MgSO4), filtration, and concentration, the crude (320 mg) was
chromatographed (silica gel, hexane/ethyl acetate, 7/3) to give
42 (135 mg, 43%): mp (DSC) 151 °C; IR (KBr) 3427, 1597,
1510, 1354, 1257; 1H NMR (CDCl3) 7.70 (d, J ) 8 Hz, 2H),
7.18 (d, J ) 8 Hz, 2H), 7.04-7.14 (complex band, 4H), 6.50 (s,
1H), 3.28 (q, J ) 10.5 Hz, 2H), 3.02 (s, 3H), 2.08 (s, 3H); MS
(EI) 411 (M+). Anal. (C20H17NSF4O2‚0.25H2O) C, H, N.
3-[1-(3-Ch lor op h en oxy)-2,2,2-tr iflu or oeth yl]-1-(4-flu o-
r oph en yl)-2-m eth yl-5-[4-(m eth ylsu lfon yl)ph en yl]-1H-pyr -
r ole (43). To a solution of 41 (340 mg, 0.8 mmol), 3-chlo-
rophenol (85 µL, 0.8 mmol), and triphenylphosphine (209 mg,
0.8 mmol) in THF (20 mL) was added diethyl azodicarboxylate
(125 µL, 0.8 mmol). The mixture was stirred at room tem-
perature for 48 h. The solvent was removed under reduced
pressure, and the crude liquid (920 mg) was chromatographed
(silica gel, hexane/ethyl acetate, 6/4) to give 43 (40 mg, 9%):
IR (KBr) 2922, 1593, 1510, 1475, 1431, 1309; 1H NMR (CDCl3)
7.70 (complex d, J ) 8 Hz, 2H), 7.21 (t, J ) 8 Hz, 1H), 7.08-
7.20 (complex band, 6H), 7.00 (dd, J ) 8, 2 Hz, 1H), 6.97 (t, J
) 2 Hz, 1H), 6.86 (dd, J ) 8, 2 Hz, 1H), 6.64 (s, 1H), 5.42 (q,
J ) 6 Hz, 1H), 3.02 (s, 3H), 2.16 (s, 3H); MS (EI) 537 (M+).
Anal. (C26H20NSClF4O3) C, H, N.
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Inducible mRNA From Swiss 3T3 Cells, Encodes
a Novel
Prostaglandin Synthase/Cyclooxygenase Homologue. J . Biol.
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Selective Inhibition of Inducible Cyclooxygenase-2 In Vivo is
Antiinflammatory and Nonulcerogenic. Proc. Natl. Acad. Sci.
U.S.A. 1994, 91, 3228-3232. (b) Seibert, K.; Masferrer, J . L. Role
of Inducuble Cyclooxygenase (COX-2) in Inflammation. Receptor
1994, 4, 17-23.
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Inhibition of Prostaglandin Endoperoxide Synthase (Cyclooxy-
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flammatory Drugs. J . Biol. Chem. 1993, 268, 6610-6614. (b)
Mitchell, J . A.; Akarasereemont, P.; Thiemerman, C.; Flower,
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NOE experiments. The support of Physical Methodol-
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27), suugesting that the position C-3 on pyrrole ring must be
unoccupied.
J M970036A