Novel terphenyls as selective cyclooxygenase-2 inhibitors and orally active anti-inflammatory agents

Article abstract of DOI:10.1021/jm950878e

A novel series of terphenyl methyl sulfones and sulfonamides have been shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. The sulfonamide analogs 17 and 21 were found to be much more potent COX-2 inhibitors and orally active anti-inflammatory agents than the corresponding methyl sulfone analogs 16 and 20, respectively, albeit with some decrease in COX-2 selectivity. Structure-activity relationship studies have determined that incorporation of two fluorine atoms in the central phenyl group, as in 20 and 21, is extremely advantageous for both in vitro COX-2 potency and selectivity as well as in vivo activity. Several noticeable examples in the 1,2-diaryl-4,5-difluorobenzenesulfonamide series are 21a-c,k,l,n (COX-2, IC₅₀ = 0.002-0.004 μM), in which all have in vitro COX-1/COX-2 selectivity > 1000. In addition, sulfonamides 21a,b,d,g,j,m,n,q were shown to have greatly enhanced oral activity with more than 90% inhibition of prostaglandin E₂ production in the air pouch model of inflammation. Furthermore, sulfonamide 21b was found to be very active in the rat adjuvant-induced arthritis model (ED₅₀ = 0.05 mg/kg) and carrageenan-induced hyperalgesia assay (ED₅₀ = 38.7 mg/kg) with no indication of gastrointestinal toxicity in rats at doses as high as 200 mg/kg.

Full text of DOI:10.1021/jm950878e

1846
J . Med. Chem. 1996, 39, 1846-1856
Novel Ter p h en yls a s Selective Cyclooxygen a se-2 In h ibitor s a n d Or a lly Active
An ti-in fla m m a tor y Agen ts
J ames J . Li,*,† Monica B. Norton,† Emily J . Reinhard,† Gary D. Anderson,‡ Susan A. Gregory,‡ Peter C. Isakson,‡
Carol M. Koboldt,‡ J aime L. Masferrer,‡ William E. Perkins,‡ Karen Seibert,‡ Yan Zhang,‡ Ben S. Zweifel,‡ and
David B. Reitz†
Searle Research and Development, c/ o Monsanto Company, 700 Chesterfield Parkway North, St. Louis, Missouri 63198
Received December 4, 1995X
A novel series of terphenyl methyl sulfones and sulfonamides have been shown to be highly
potent and selective cyclooxygenase-2 (COX-2) inhibitors. The sulfonamide analogs 17 and 21
were found to be much more potent COX-2 inhibitors and orally active anti-inflammatory agents
than the corresponding methyl sulfone analogs 16 and 20, respectively, albeit with some
decrease in COX-2 selectivity. Structure-activity relationship studies have determined that
incorporation of two fluorine atoms in the central phenyl group, as in 20 and 21, is extremely
advantageous for both in vitro COX-2 potency and selectivity as well as in vivo activity. Several
noticeable examples in the 1,2-diaryl-4,5-difluorobenzenesulfonamide series are 21a -c,k ,l,n
(COX-2, IC50 ) 0.002-0.004 µM), in which all have in vitro COX-1/COX-2 selectivity >1000.
In addition, sulfonamides 21a ,b,d ,g,j,m ,n ,q were shown to have greatly enhanced oral activity
with more than 90% inhibition of prostaglandin E2 production in the air pouch model of
inflammation. Furthermore, sulfonamide 21b was found to be very active in the rat adjuvant-
induced arthritis model (ED50 ) 0.05 mg/kg) and carrageenan-induced hyperalgesia assay (ED50
) 38.7 mg/kg) with no indication of gastrointestinal toxicity in rats at doses as high as 200
mg/kg.
In tr od u ction
describe the design, synthesis, and structure-activity
relationship (SAR) studies of these terphenyl com-
pounds as selective COX-2 inhibitors, which ultimately
led to the identification of an anti-inflammatory agent
with a greatly improved safety profile.
Commercially available nonsteroidal anti-inflamma-
tory drugs (NSAIDs) are generally effective and widely
used for the treatment of inflammatory conditions.1-3
However, the disruption of beneficial prostaglandin (PG)
production by all currently used NSAIDs results in a
mechanism-based toxicity mainly in the gastrointestinal
(GI) tract and kidney4-6 and thus limits their thera-
peutic usefulness especially when long-term treatment
is involved. Recently an inducible cyclooxygenase (COX)
isozyme, now commonly known as COX-2, was discov-
ered and found to be expressed primarily in inflamed
tissues.7-10 As a result of this critical finding, a
substantial discovery effort has been underway in the
pharmaceutical industry to identify selective and orally
active COX-2 inhibitors11,12 because they may provide
the desired anti-inflammatory and analgesic profiles
without the deleterious side effects commonly associated
with the existing NSAIDs. Several distinct classes of
selective COX-2 inhibitors, e.g., 1-12 (Figure 1), have
appeared in the literature,13-24 and most of these
reported examples of selective COX-2 inhibitors dem-
onstrate potent anti-inflammatory activity in the rat
adjuvant-induced arthritis model along with exceptional
safety profiles in comparison with the current NSAIDs.
Ch em istr y
The general synthetic strategy employed to prepare
the terphenyl analogs was based on palladium(0)-
catalyzed aryl-aryl-coupling reactions. As shown in
Scheme 1, a series of 1,2-diarylbenzenes 16a -e were
prepared from 1,2-dibromobenzene (14) via sequential
Suzuki cross-coupling reactions.26 Two equivalents of
14 was used in the first coupling step to minimize the
formation of symmetrically bis-coupled product. The
arylboronic acid starting materials either were com-
mercially available or could be simply prepared in yields
of 60-80% from the corresponding aryl bromides in a
metal-halogen exchange reaction followed by addition
of trimethyl borate and subsequent hydrolysis. Prepa-
ration of 1,2-diaryl-4,5-difluorobenzenes 20a -o from
commercially available 1,2-dibromo-4,5-difluorobenzene
(18) was carried out in an analogous manner. Sulfon-
amide analogs 17a -e and 21a -o were prepared di-
rectly from the corresponding methyl sulfone analogs
16a -e and 20a -o, respectively, using the convenient
one-pot procedure recently reported by Huang et al.27
Due to difficulties in the preparation of pyridylboronic
acids, a modified procedure was used for the synthesis
of pyridyl analogs 20p ,q, as illustrated in Scheme 2.
Suzuki cross-coupling reaction of 13 and 18 gave aryl
bromide 22, which was converted to the arylboronic acid
23 via a Grignard intermediate. Subsequent Suzuki
cross-coupling reaction of 23 and 2-bromo-5-methyl-
pyridine followed by oxidation with Oxone (2KHSO5‚
KHSO4‚K2SO4) gave pyridyl analog 20p . For the syn-
thesis of 20q , the pyridyltin intermediate 25 was
The preliminary report25 that 16a (Figure 1) was
found to be a modestly selective COX-2 inhibitor has
prompted us to report our results on terphenyl COX-2
inhibitors. We have successfully identified a novel
series of 1,2-diaryl-4,5-difluorobenzenesulfonamides 21
which have greater in vitro COX-1/COX-2 enzyme
selectivity and vastly superior in vivo activity than what
was previously observed for 16a . In this article, we
† Department of Medicinal Chemistry.
‡ Department of Inflammatory Diseases Research.
X Abstract published in Advance ACS Abstracts, April 1, 1996.
0022-2623/96/1839-1846$12.00/0 © 1996 American Chemical Society

Novel Terphenyls as COX-2 Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9 1847
F igu r e 1. Representative examples of selective COX-2 inhibitors.
Sch em e 1a
a
Reagents: (a) 5 mol % Pd(PPh3)4, 2 M Na2CO3, ethanol, toluene, reflux; (b) m-CPBA; (c) 3-R1-4-R2-5-R3-C6H2B(OH)2, 5 mol % Pd(PPh3)4,
2 M Na2CO3, ethanol, toluene, reflux; (d) n-PrMgCl, 0 °C, BEt3, 0 °C to reflux; (e) NaOAc, H2O, H2NOSO3H, 0 °C to room temperature.
Sch em e 2a
Sch em e 3a
a
Reagents: (a) BBr3; (b) Tf2O, pyridine; (c) 13, 5 mol %
Pd(PPh3)4, K2CO3, toluene, reflux; (d) 4-FC6H4B(OH)2, 5 mol %
Pd(PPh3)4, K2CO3, toluene, reflux; (e) m-CPBA.
reaction with (4-fluorophenyl)boronic acid and subse-
quent m-CPBA oxidation produced 30 directly.
Analogs 32, 34, and 36 were prepared by an one-pot
reaction procedure using an equal molar ratio of 13, (4-
fluorophenyl)boronic acid, and 31, 33, or 35, respec-
tively, as shown in Scheme 4.31 Oxidation of the initial
mixture followed by purification provided the desired
compounds.
Scheme 5 shows the preparation of pyrazine 39.
Nucleophilic aromatic substitution of fluoride in 37 with
sodium methanesulfinate gave the (methylsulfonyl)-
benzil 38, which was reacted with ethylenediamine
followed by DDQ oxidation to provide pyrazine 39.
a
Reagents: (a) 13, 5 mol % Pd(PPh3)4, 2 M Na2CO3, ethanol,
toluene, reflux; (b) Mg, reflux, B(OCH3)3, 0 °C to room temperature,
10% NaOH, (c) 2-bromo-5-methylpyridine, 5 mol % Pd(PPh3)4, 2
M Na2CO3, ethanol, toluene, reflux; (d) Oxone; (e) n-PrMgCl, 0
°C, BEt3, 0 °C to reflux; (f) NaOAc, H2O, H2NOSO3H, 0 °C to room
temperature; (g) n-BuLi, (CH3)3SnCl, -78 °C to room temperature;
(h) 19, 5 mol % Pd(PPh3)4, toluene, reflux.
prepared from bromopyridine 2428 by treatment with
n-butyllithium in tetrahydrofuran at -78 °C followed
by addition of trimethyltin chloride. Stille cross-
coupling reaction29 of 19 and 25 gave the desired pyridyl
analog 20q.
Biologica l Resu lts a n d Discu ssion
Preparation of 1,2-diaryl-4,5-dichlorobenzene 30 is
shown in Scheme 3. Treatment of dichloroveratrole
(26)30 with tribromoborane gave the catechol 27, which
was converted to its ditriflate 28. A modified Suzuki
reaction of 28 with 13 gave 29; a second modified Suzuki
All compounds were initially evaluated for inhibitory
activity against both constitutive (COX-1) and inducible
(COX-2) forms of the human recombinant enzymes.14
IC50 values were determined, and these values are used
in all the following discussion of in vitro activity.

1848 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Li et al.
Sch em e 4a
Ta ble 1. In Vitro Inhibition of COX-1 and COX-2 Enzyme and
in Vivo Air Pouch Activity of Sulfones 16-e and Sulfonamides
17a -e
IC50 (µM)
air pouch
compda R1
R2
COX-2b COX-1b selectivityc (2 mg/kg)a
16a
17a
16b
17b
16c
17c
16d
17d
16e
17e
H
H
Cl
Cl
H
H
F
F
F
F
F
Cl
Cl
0.26
0.061
0.36
0.017
0.14
0.006
>100
19.0
>100
9.2
>100
3.9
>100
13.2
>100
8.2
>380
300
>280
540
63
68
NDa
NDd
50
>710
650
a
Reagents: (a) 13, 4-FC6H4B(OH)2, 5 mol % Pd(PPh3)4, 2 M
33
Na2CO3, ethanol, toluene, reflux; (b) m-CPBA.
CH3O >100
CH3O 0.033
11.4
0.019
NDd
400
NDd
34
F
Sch em e 5a
Cl CH3O
Cl CH3O
>9
430
NDd
45
a
b
See the Experimental Section. See Supporting Information
and ref 14. c Ratio of COX-1/COX-2. Not determined.
d
Ta ble 2. In Vitro Inhibition of COX-1 and COX-2 Enzyme
a
Reagents: (a) CH3SO2Na; (b) ethylenediamine; (c) DDQ.
Inhibitors with COX-2 IC50 < 0.5 µM and selectivity
ratio (IC50 of COX-1/IC50 of COX-2) of >300 were
subsequently measured for their oral activity in an acute
inflammation model, the foot-pad air pouch assay.32
Selected compounds with good activity in this assay
were further investigated in a chronic inflammation
model, the rat adjuvant-induced arthritis assay,21,33 and/
or an analgesic model, the rat carrageenan-induced
hyperalgesia assay.34 Finally, compounds possessing
the desired in vivo activity profiles were evaluated for
GI toxicity in the rat.35
In Vitr o Activity. One common feature of many of
the previously reported selective COX-2 inhibitors
(Figure 1) is 1,2-diaryl substitution to a central ring,
e.g., thiophene moiety for 1, pyrazole for 3, cyclopentene
for 5 and 6, spiro[2,4]heptene for 7 and 8, indene for 9
and 10, and benzofuran for 11 and 12. It seemed
reasonable to us that a phenyl group could serve as the
central ring and that it might also provide greater in
vivo stability relative to the cyclopentene moiety in
5.21,23 Thus, a series of simple terphenyls were pre-
pared, and a SAR investigation around the 4-fluoro-
phenyl moiety in 16a was initiated. Both methyl
sulfones 16 and corresponding sulfonamides 17 were
evaluated as potential selective COX-2 inhibitors, and
their COX-1 and COX-2 IC50s are summarized in Table
1. The methyl sulfones 16a -e were found to be modest
(16c, COX-2 ) 0.14 µM) to weak (16e, COX-2 ) 11.4
µM) COX-2 inhibitors, whereas the corresponding sul-
fonamides 17a -e were found to be more potent in both
COX-2 and COX-1 inhibition. For example, this trend
can be seen from the comparison of sulfone 16b (COX-2
) 0.36 µM, COX-1 > 100 µM) with sulfonamide 17b
(COX-2 ) 0.017 µM, COX-1 ) 9.24 µM). This observa-
tion is consistent with our earlier findings in the
cyclopentene COX-2 inhibitor series.21,23
a
b
See the Experimental Section. See Supporting Information
and ref 14.
In order to investigate the SAR of the central phenyl
group in 16a , several 1,2-diaryl-substituted terphenyl
analogs (20a , 30, 32, 34, 36, and 39) were prepared
(Scheme 1-5). As shown in Table 2, incorporation of
two fluorine atoms to the central phenyl ring gave the
4,5-difluorophenyl analog 20a (COX-2 ) 0.014 µM),
which is 18 times more potent than the simple terphenyl
16a (COX-2 ) 0.26 µM). Replacement of two fluorines

Novel Terphenyls as COX-2 Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9 1849
Ta ble 3. In Vitro Inhibition of COX-1 and COX-2 Enzyme and in Vivo Air Pouch Activity of Sulfones 20-q and Sulfonamides 21a -q
IC50 (µM)
air pouch
compda
R1
R2
R3
COX-2b
COX-1b
selectivityc
(2 mg/kg)a
20a
21a
20b
21b
20c
21c
20d
21d
20e
21e
20f
21f
20g
21g
20h
21h
20i
21i
20j
21j
20k
21k
20l
21l
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
F
F
F
F
F
H
H
Cl
0.014
0.004
0.010
0.002
0.005
0.002
0.021
0.013
0.019
0.013
>100
0.021
0.013
0.005
0.34
>100
5.7
>7100
1400
NDd
99
54
94
44
88
37
96
28
90
NDd
36
66
98
0
24
0
0
47
97
1
83
27
88
51
96
53
93
64
NDd
2
>100
>10 000
Cl
5.5
2750
CH3
CH3
F
F
Cl
Cl
Cl
Cl
CH3
CH3
CH3O
CH3O
>100
3.7
>20 000
1850
>4750
1700
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
>100
22.5
>100
18.9
>100
>100
>100
10.9
>100
>100
>100
17.9
>100
1.7
>100
17.0
>100
16.5
>100
14.6
>100
3.9
>5250
1450
NDd
4750
>7700
2200
>300
>1500
>300
550
0.065
0.34
OCH2CH2O
OCH2CH2O
OCH2O
0.032
0.012
0.004
0.007
0.004
0.013
0.003
0.023
0.005
0.006
0.003
0.008
0.006
52.3
>8300
OCH2O
400
CH3
CH3
CH3
CH3
CH3
CH3
Cl
Cl
(CH3)2N
(CH3)2N
see Scheme 2
see Scheme 2
see Scheme 2
see Scheme 2
H
H
Cl
Cl
CH3
CH3
CH3
CH3
Cl
>14 300
4250
>7700
5500
>4300
2900
20m
21m
20n
21n
20o
21o
20p
21p
>16 600
1300
>100
0.59
>100
>100
>100
265
>12 500
100
Cl
2
0.33
0.17
0.051
0.9
>300
>600
5200
56
65
100
98
20q
21q
indomethacinb
0.1
0.1
a
b
d
See the Experimental Section. See Supporting Information and ref 14. c Ratio of COX-1/COX-2. Not determined.
in the central ring in 20a with chlorine atoms was found
to have a deleterious effect on COX-2 potency, as can
be seen by comparing 4,5-dichlorophenyl analog 30
(COX-2 ) 0.24 µM) with 20a . Analog 32 (COX-2 )
0.083 µM), in which 1,3-benzodioxole was used as the
central ring, proved to be less potent than 20a but more
potent than 30. Several other phenyl surrogates such
as tetrafluorobenzene in 34, naphthalene in 36, and
pyrazine in 39 were also investigated as possible
replacements for the central phenyl group in 16a ;
however, all were found to be essentially inactive
against COX-2 enzyme (COX-2 > 100 µM). The lack of
activity observed for 34 and 39 suggests that the COX-2
binding interactions might be very sensitive to both
electronic and steric properties of the positions adjacent
to the 1,2-diaryl groups.
On the basis of our investigation with central ring
surrogates (vide supra), an extensive SAR study was
conducted around the 1,2-diaryl-4,5-difluorobenzene
sulfones 20a -q and sulfonamides 21a -q. Table 3
summarizes both COX-1 and COX-2 enzyme data; the
nonselective COX inhibitor indomethacin is provided as
a reference compound. Similar to our previous observa-
tion for 20a , sulfones 20b-e in the 1,2-diaryl-4,5-
difluorobenzene series were found to be more potent and
more selective COX-2 inhibitors than the corresponding
simple terphenyl sulfones 16b-e, respectively. For
example, 20b (COX-2 ) 0.010 µM) is 36 times more
potent than 16b (COX-2 ) 0.36 µM). Furthermore,
sulfonamides 21a -e (Table 3) were found to be more
potent COX-2 inhibitors than sulfonamides 17a -e
(Table 2). Within the 1,2-diaryl-4,5-difluorobenzene
series (Table 3), most of the methyl sulfones 20 were
found to be highly (e.g., 20c COX-2 ) 0.005 µM) to
modestly potent (e.g., 20h COX-2 ) 0.34 µM) COX-2
inhibitors with IC50 values generally ranging from 0.010
to 0.025 µM. On the other hand, COX-1 activity appears
to be insensitive to the various 4-fluorophenyl replace-
ments that were investigated, since sulfones 20a -q
were all found to be essentially inactive against the
COX-1 enzyme (COX-1 > 100 µM). Replacement of the
methyl sulfone moiety in 20a -q with a sulfonamide
group resulted in a series of even more potent COX-2
inhibitors (21a -q), which is consistent with our previ-
ous observations for cyclopentene COX-2 inhibitors.21,23
Several noticeable examples were found to have COX-2
potency in the low-nanomolar range, e.g., 21b,c (COX-2
) 0.002 µM), 21l,n (COX-2 ) 0.003 µM), and 21a ,j,k

1850 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Li et al.
be clearly seen from Table 3, the sulfonamides 21a -q
were found to be generally superior in oral activity
relative to the corresponding methyl sulfones 20a -q.
Moreover, 4,5-difluorobenzenesulfonamides 21 are sub-
stantially more orally active than the corresponding
unsubstituted benzenesulfonamides 17 in the air pouch
model, e.g., 21d inhibits 96%, while 17d inhibits only
34%. Several noteworthy examples are 21a ,b ,d ,g,j,
m ,n ,q which inhibit more than 90% of the prostaglandin
E2 production in the air pouch model of inflammation,
an efficacy comparable to the reference compound
indomethacin (Table 3). The exact reason for the
superior in vivo activity observed for 4,5-difluoroben-
zenesulfonamides 21 (vs 17) is not known, although one
might speculate that it is a combination of increased in
vitro binding affinity and metabolic stability.
F igu r e 2. Dose-response curve of adjuvant-induced arthritis
assay of 17a , 21b, and indomethacin in Lewis rats (see the
Experimental Section for assay procedure).
On the basis of its COX-2 potency (COX-2 ) 0.002
µM) and air pouch activity (94% at 2 mg/kg), sulfon-
amide 21b was selected for further in vivo evaluation.
In subsequent testing, 21b was shown to be slightly
more potent than indomethacin in the rat adjuvant-
induced arthritis model (ED50 ) 0.05 vs 0.11 mg/kg),
as shown in Figure 2; however, it was found to be less
active in the analgesic assay (ED50 ) 38.7 vs 4.4 mg/
kg), as shown in Figure 3. A rat GI toxicity study was
conducted to assess the safety of 21b. When 21b was
administered intragastrically at 200 mg/kg, no gastric
lesions were observed after 5 h and no intestinal damage
was detected after 72 h. For the purpose of comparison,
the nonselective COX inhibitor indomethacin was used
in a positive control group, and it caused severe bleeding
and/or death at doses as low as 16 mg/kg.
F igu r e 3. Dose-response curve of carrageenan-induced hy-
peralgesia assay of 17a , 21b, and indomethacin in Sprague-
Dawley rats (see the Experimental Section for assay proce-
dure).
Con clu sion
We have discovered a series of novel terphenyl
compounds that are selective COX-2 inhibitors and
orally active anti-inflammatory agents. Replacement
of the methyl sulfone moiety in 16 and 20 with a
sulfonamide group as in 17 and 21, respectively, was
found to provide a more potent COX-2 inhibitor with
greatly enhanced in vivo activity, albeit with some
decrease in COX-2 selectivity. SAR studies have indi-
cated that central ring substituents play an important
role in COX-2 potency, and only 1,2-diaryl-4,5-disub-
stituted benzenes, e.g., 16, 17, 20, 21, 30, and 32, were
found to be potent COX-2 inhibitors. Other modifica-
tions, e.g., at the 3- and 6-positions of the central ring,
resulted in a loss of COX-2 activity (COX-2 >100 µM).
Incorporation of two fluorine atoms in the central ring
of simple terphenylsulfonamides 17 provided 1,2-diaryl-
4,5-difluorobenzenesulfonamides 21, which are very
potent (COX-2 ) 0.002-0.051 µM) and highly selective
(COX-1/COX-2 > 1000) COX-2 inhibitors; of particular
significance is the dramatic increase in the oral activity
associated with this change. Sulfonamide 21b was
found to be very active in the rat adjuvant-induced
arthritis model (ED50 ) 0.05 mg/kg) and carrageenan-
induced hyperalgesia assay (ED50 ) 38.7 mg/kg). Fur-
thermore, no indication of GI toxicity was observed
when 21b was administered intragastrically at 200 mg/
kg. Development of selective and orally active terphenyl
COX-2 inhibitors such as sulfonamide 21b could there-
fore provide a new generation of NSAIDs with greatly
reduced GI toxicity.
(COX-2 ) 0.004 µM). The increased COX-1 activity
(COX-1 ) 3-20 µM) observed for sulfonamides 21a -q
caused an overall decrease in COX-1/COX-2 enzyme
selectivity relative to methyl sulfones 20a -q (COX-1
> 100 µM), respectively. Nevertheless, sulfonamides
21a -q are very potent and highly selective COX-2
inhibitors with a COX-1/COX-2 enzyme selectivity ratio
generally >1000.
In Vivo Activity. To assess the oral activity of
terphenyl COX-2 inhibitors, selected methyl sulfones 16
and sulfonamides 17 were evaluated in an acute inflam-
mation model, i.e., the air pouch assay. As shown in
Table 1, inhibition values range from 34% to 68% at 2
mg/kg. The most active analog (17a ) in this assay was
further evaluated in vivo and found to have modest
potency (ED50 ) 1.5 mg/kg, Figure 2) in the rat
adjuvant-induced arthritis assay. However, 17a was
subsequently found to display weak activity (ED50 > 50
mg/kg, Figure 3) in the analgesic assay.
Benzodioxole methyl sulfone 32 (Table 2) was simi-
larly evaluated in the air pouch model and found to be
inactive (0% inhibition at 2 mg/kg). The corresponding
sulfonamide analog of 32 was also tested and found to
be weakly active (26% inhibition at 2 mg/kg).
Since simple terphenyls 16 and 17 and benzodioxole
32 were considered to have insufficient oral activity for
further development, our attention was focused on the
more potent 4,5-difluorobenzene methyl sulfone (20a -
q) and sulfonamide (21a -q) COX-2 inhibitors. As can

Novel Terphenyls as COX-2 Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9 1851
hexane (3:7) gave 16.2 g (73%) of the title compound 15 as a
Exp er im en ta l Section
1
colorless solid: mp 168.2-169.5 °C; H NMR (CDCl3) δ 3.12
Gen er a l. Expression and purification of recombinant hu-
man COX-1 and COX-2 enzymes,14 in vitro COX-1 and COX-2
enzyme assays,14 rat adjuvant-induced arthritis,21,33 rat GI
toxicity study,35 general chemistry method,21 and preparation
of arylboronic acids,21 preparation of sulfonamides from cor-
responding methyl sulfones21,27 have been described previously.
Air P ou ch Mod el of In fla m m a tion .32 Male Lewis rats
(175-200 g; Charles River Laboratories) were used, and the
rats were fasted with free access to water at 24 h prior to
experiment. Air cavities were produced by subcutaneous
injection of 20 mL of sterile air into the intrascapular area of
the back at 24 h prior to experiment. Each test compound
suspended in 0.5% methyl cellulose, and 0.025% Tween-20
(Sigma) was administered intragastrically at 2 mg/kg in a
volume of 5 mL/kg 2 h prior to carrageenan injection. Inflam-
mation was then induced by injecting 2 mL of 1% carrageenan
into the rat air pouch with animals sacrificed at 3 h after
injection. Pouch exudates were collected, washed, and assayed
for PGE2 by specific ELISAs (Cayman Chemical Co.).
Ca r r a geen a n -In d u ced Hyp er a lgesia in th e Ra t.34 Male
Sprague-Dawley rats (195-250 g; Charles River Laboratories)
were used, and the rats were fasted with free access to water
at least 16 h prior to experiments. The test compound
suspended in 1 mL of 0.5% methyl cellulose and 0.025%
Tween-20 (Sigma) was dosed orally via an 18-G gavage needle
at 2 h prior to induction of inflammation. Inflammation was
then induced by injection of 0.1 mL of 1% carrageenan
suspension in 0.9% sterile saline via a 27-G needle into the
plantar tissue of the right hind foot pad. After 3 h, a radiant
heat source was positioned under the paw, and the latency of
paw withdraw was measured. The inhibition values were
determined on the basis of an average of five Sprague-Dawley
rats.
(s, 3H), 7.23-7.33 (m, 2H), 7.40 (dt, J ) 2, 8 Hz, 1H), 7.61 (d,
J ) 8 Hz, 2H), 7.70 (dd, J ) 2, 8 Hz, 1H), 8.01 (d, J ) 9 Hz,
2H).
16e. Under nitrogen, to a stirred solution of 4.0 g (12.8
mmol) of 15 and 2.9 g (15.4 mmol) of (3-chloro-4-methoxy-
phenyl)boronic acid in a mixed solvent of 35 mL of toluene,
35 mL of ethanol, and 35 mL of 2 M Na2CO3 was added 1 g
(0.86 mmol) of Pd(PPh3)4. After refluxing with vigorous
stirring for 3 h, the solvent was removed in vacuo. The residue
was dissolved in ethyl acetate, washed with water and brine,
and dried over MgSO4. Purification by silica gel chromatog-
raphy (Waters PrepLC 500A) with ethyl acetate/hexane (1:3)
gave 3.4 g (70%) of the title compound 16e as a colorless
solid: mp 161.5-162.3 °C; 1H NMR (CDCl3) δ 3.05 (s, 3H),
3.88 (s, 3H), 6.75 (d, J ) 9 Hz, 1H), 6.87 (dd, J ) 2, 9 Hz, 1H),
7.17 (d, J ) 2 Hz, 1H), 7.34 (d, J ) 9 Hz, 2H), 7.37-7.51 (m,
4H), 7.82 (d, J ) 8 Hz, 2H); MS (EI) m/ z (rel intensity) 372
(100), 243 (24); HRMS calcd for M+ 372.0587, found 372.0557.
Anal. (C20H17ClO3S) C, H, Cl.
1-(4-F lu or op h en yl)-2-[4-(m et h ylsu lfon yl)p h en yl]b en -
zen e (16a ). Following general procedure A described for 16e,
15 was reacted with (4-fluorophenyl)boronic acid to give the
title compound 16a as a colorless solid: mp 178.0-179.0 °C;
1H NMR (CDCl3) δ 3.05 (s, 3H), 6.93 (t, J ) 8 Hz, 2H), 7.03-
7.09 (m, 2H), 7.32 (d, J ) 8 Hz, 2H), 7.38-7.50 (m, 4H), 7.80
(d, J ) 8 Hz, 2H); MS (FAB) m/ z 333 (M + Li)+. Anal.
(C19H15FO2S) C, H, F.
2-Ch lor o-1-flu or o-4-[2-[4-(m e t h ylsu lfon yl)p h e n yl]-
p h en yl]ben zen e (16b). Following general procedure A de-
scribed for 16e, 15 was reacted with (3-chloro-4-fluorophenyl)-
boronic acid to give the title compound 16b as a colorless
solid: mp 179.5-181.1 °C; 1H NMR (CDCl3) δ 3.06 (s, 3H),
6.86-6.93 (m, 1H), 6.98 (t, J ) 8 Hz, 1H), 7.19 (dd, J ) 2, 7
Hz, 1H), 7.33 (d, J ) 8 Hz, 2H), 7.38-7.53 (m, 4H), 7.84 (d, J
) 9 Hz, 2H); MS (FAB) m/ z 367 (M + Li)+; HRMS calcd for
M+ 360.0387, found 360.0401. Anal. (C19H14ClFO2S) C, H,
F.
Gen er a l P r oced u r e A for P r ep a r a tion of Meth yl Su l-
fon e An a logs 16a -e. 2-Chloro-1-methoxy-4-[2-[4-(methyl-
sulfonyl)phenyl]phenyl]benzene (16e) is described as a typical
example.
4-Br om o-2-ch lor oa n isole. Under nitrogen, to a stirred
suspension of 10.0 g (48 mmol) of 4-bromo-2-chlorophenol and
5.4 g (38 mmol) of K2CO3 powder in 75 mL of acetone was
added 7.3 mL (77 mmol) of dimethyl sulfate. The mixture was
heated at reflux for 2 h and cooled to ambient temperature.
The inorganic salts were removed by filtration, and the organic
solvent was removed in vacuo. The residue was dissolved in
ethyl acetate, washed with water and brine, and dried over
MgSO4. Concentration in vacuo gave 10.2 g (96%) of 4-bromo-
2-chloroanisole as a colorless solid: mp 68.5-70.5 °C; 1H NMR
(CDCl3) δ 3.88 (s, 3H), 6.80 (d, J ) 9 Hz, 1H), 7.33 (dd, J ) 2,
9 Hz, 1H), 7.50 (d, J ) 2 Hz, 1H).
(3-Ch lor o-4-m eth oxyp h en yl)bor on ic Acid . Following
the literature procedure described for 13,21 10.2 g (46.2 mmol)
of 4-bromo-2-chloroanisole was converted to (3-chloro-4-meth-
oxyphenyl)boronic acid: 1H NMR (CDCl3) δ 3.83 (s, 3H), 6.57
(s, 2H), 6.83 (d, J ) 8 Hz, 1H), 7.64 (dd, J ) 2, 8 Hz, 1H), 7.77
(d, J ) 2 Hz, 1H).
1-Br om o-2-[4-(m eth ylsu lfon yl)ph en yl]ben zen e (15). Un-
der nitrogen, to a stirred solution of 12.0 g (71.4 mmol) of 1321
and 17.0 mL (140.9 mmol) of 1,2-dibromobenzene (14) in a
mixed solvent of 150 mL of toluene, 150 mL of ethanol, and
150 mL of 2 M Na2CO3 was added 5 g (4.3 mmol) of Pd(PPh3)4.
After refluxing with vigorous stirring for 3 h, the solvent was
removed in vacuo. The residue was dissolved in ethyl acetate,
washed with water and brine, and dried over MgSO4. Puri-
fication by silica gel plug with ethyl acetate/hexane (5:95) gave
an oil residue which was dissolved in 200 mL of CH2Cl2. To
this solution was slowly added 53.0 g (153 mmol) of 3-chloro-
peroxybenzoic acid (m-CPBA, 50%), and the reaction was
continued for 30 min at ambient temperature. The excess
m-CPBA was quenched by adding 7.7 g of Na2SO3 at 0 °C,
and the mixture was stirred for 10 min at ambient tempera-
ture. Most of the solvent was removed in vacuo; the residue
was dissolved in ethyl acetate, washed with saturated NaHCO3
twice, and dried over MgSO4. Purification by silica gel
chromatography (Waters PrepLC 500A) with ethyl acetate/
1-(4-Ch lor op h en yl)-2-[4-(m et h ylsu lfon yl)p h en yl]ben -
zen e (16c). Following general procedure A described for 16e,
15 was reacted with (4-chlorophenyl)boronic acid to give the
title compound 16c as a colorless solid: mp 180.2-180.6 °C;
1H NMR (CDCl3) δ 3.06 (s, 3H), 7.04 (d, J ) 8 Hz, 2H), 7.21
(d, J ) 8 Hz, 2H), 7.33 (d, J ) 9 Hz, 2H), 7.38-7.51 (m, 4H),
7.81 (d, J ) 8 Hz, 2H); MS (EI) m/ z (rel intensity) 342 (34),
228 (100); HRMS calcd for M+ 342.0481, found 342.0484. Anal.
(C19H15ClO2S) C, H, Cl.
2-F lu or o-1-m et h oxy-4-[2-[4-(m et h ylsu lfon yl)p h en yl]-
p h en yl]b en zen e (16d ). 3-(F lu or o-4-m et h oxyp h en yl)-
bor on ic Acid . Following the literature procedure described
for 13,21 4-bromo-2-fluoroanisole was converted to (3-fluoro-
4-methoxyphenyl)boronic acid: 1H NMR (CDCl3) δ 3.75 (s, 3H),
6.80 (d, J ) 8 Hz, 1H), 7.36-7.48 (m, 2H).
16d . Following general procedure A described for 16e, 15
was reacted with (3-fluoro-4-methoxyphenyl)boronic acid to
give the title compound 16d as a colorless solid: mp 136.2-
1
136.6 °C; H NMR (CDCl3) δ 3.06 (s, 3H), 3.87 (s, 3H), 6.72-
6.89 (m, 3H), 7.31-7.51 (m, 6H), 7.81 (d, J ) 9 Hz, 2H); MS
(EI) m/ z (rel intensity) 356 (100), 262 (28), 246 (22); HRMS
calcd for M+ 356.0882, found 356.0881. Anal. (C20H17FO3S)
C, H, F.
4-[2-(4-Flu or oph en yl)ph en yl]ben zen esu lfon am ide (17a).
Following the literature procedure,21,27 16a was converted to
the title compound 17a as a colorless solid: mp 187.3-188.2
°C; 1H NMR (CDCl3) δ 4.83 (s, 2H), 6.92 (t, J ) 9 Hz, 2H),
7.02-7.11 (m, 2H), 7.27 (d, J ) 9 Hz, 2H), 7.36-7.50 (m, 4H),
7.78 (d, J ) 8 Hz, 2H); MS (EI) m/ z (rel intensity) 327 (75),
245 (100); HRMS calcd for M+ 327.0729, found 327.0743. Anal.
(C18H14NFO2S) C, H, N.
4-[2-(3-C h lo r o -4-flu o r o p h e n y l)p h e n y l]b e n z e n e -
su lfon a m id e (17b). Following the literature procedure,21,27
16b was converted to the title compound 17b as a colorless
solid: mp 192.5-193.2 °C; 1H NMR (CDCl3) δ 4.86 (s, 2H),
6.68-6.76 (m, 1H), 6.81 (t, J ) 9 Hz, 1H), 7.06 (d, J ) 8 Hz,
2H), 7.17-7.32 (m, 5H), 7.63 (d, J ) 8 Hz, 2H); MS (FAB) m/ z

1852 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Li et al.
368 (M + Li)+; HRMS calcd for M+ 361.0340, found 361.0338.
1-(3-Ch lor o-4-flu or op h en yl)-4,5-d iflu or o-2-[4-(m eth yl-
su lfon yl)p h en yl]ben zen e (20b). Following general proce-
dure B described for 20e, 19 was reacted with (3-chloro-4-
fluorophenyl)boronic acid to give the title compound 20b as a
Anal. (C18H13NClFO2S) C, H, N.
4-[2-(4-Ch lor oph en yl)ph en yl]ben zen esu lfon am ide (17c).
Following the literature procedure,21,27 16c was converted to
the title compound 17c as a colorless solid: mp 206.2-207.0
1
colorless solid: mp 172.2-172.5 °C; H NMR (CDCl3) δ 3.05
1
(s, 3H), 6.82-6.89 (m, 1H), 6.99 (t, J ) 9 Hz, 1H), 7.14 (dd, J
) 2, 8 Hz, 1H), 7.20-7.32 (m, 4H), 7.84 (d, J ) 8 Hz, 2H); MS
(EI) m/ z (rel intensity) 396 (22), 282 (100), 262 (25); HRMS
calcd for M+ 396.0199, found 396.0203. Anal. (C19H12ClF3O2S)
C, H, F.
°C; H NMR (CDCl3) δ 4.77 (s, 2H), 7.04 (d, J ) 9 Hz, 2H),
7.16-7.31 (m, 4H), 7.36-7.51 (m, 4H), 7.80 (d, J ) 9 Hz, 2H);
MS (EI) m/ z (rel intensity) 343 (100), 262 (21), 228 (82); HRMS
calcd for M+ 343.0434, found 343.0434. Anal. (C18H14NClO2S)
C, H, N.
1,2-Diflu or o-4-(4-flu or o-3-m eth ylp h en yl)-5-[4-(m eth yl-
su lfon yl)p h en yl]b en zen e (20c). (4-F lu or o-3-m et h yl-
p h en yl)bor on ic Acid . Following the literature procedure
described for 13,21 5-bromo-2-fluorotoluene was converted to
(4-fluoro-3-methylphenyl)boronic acid: 1H NMR (CDCl3) δ 2.39
(d, J ) 2 Hz, 3H), 7.13 (t, J ) 9 Hz, 1H), 7.99-8.08 (m, 2H).
20c. Following general procedure B described for 20e, 19
was reacted with (4-fluoro-3-methylphenyl)boronic acid to give
the title compound 20c as a colorless solid: mp 167.2-167.5
4-[2-(3-F lu o r o -4-m e t h o x y p h e n y l)p h e n y l]b e n ze n e -
su lfon a m id e (17d ). Following the literature procedure,21,27
16d was converted to the title compound 17d as a colorless
1
solid: mp >143 °C dec; H NMR (CDCl3) δ 3.96 (s, 3H), 4.90
(s, 2H), 6.74-6.90 (m, 3H), 7.29 (d, J ) 9 Hz, 2H), 7.35-7.48
(m, 4H), 7.79 (d, J ) 9 Hz, 2H); MS (FAB) m/ z 364 (M + Li)+;
HRMS calcd for M+ 357.0835, found 357.0809. Anal. (C19H16
-
FNO3S‚0.27H2O) C, H, N.
4-[2-(3-C h lo r o -4-m e t h o x y p h e n y l)p h e n y l]b e n ze n e -
su lfon a m id e (17e). Following the literature procedure,21,27
16e was converted to the title compound 17e as a colorless
solid: mp 179.5-180.2 °C; 1H NMR (CDCl3) δ 3.87 (s, 3H),
4.76 (s, 2H), 6.75 (d, J ) 9 Hz, 1H), 6.86 (dd, J ) 2, 9 Hz, 1H),
7.20 (d, J ) 3 Hz, 1H), 7.29 (d, J ) 9 Hz, 2H), 7.35-7.47 (m,
4H), 7.79 (d, J ) 8 Hz, 2H); MS (EI) m/ z (rel intensity) 373
(100), 243 (29); HRMS calcd for M+ 373.0539, found 373.0587.
Anal. (C19H16NClO3S) C, H, N.
Gen er a l P r oced u r e B for P r ep a r a tion of Meth yl Su l-
fon e An a logs 20a -o. 1-(3-Chloro-4-methoxyphenyl)-4,5-di-
fluoro-2-[4-(methylsulfonyl)phenyl]benzene (20e) is described
as a typical example.
1
°C; H NMR (CDCl3) δ 2.19 (d, J ) 2 Hz, 3H), 3.04 (s, 3H),
6.71-6.78 (m, 1H), 6.84 (t, J ) 9 Hz, 1H), 6.92 (dd, J ) 2, 8
Hz, 1H), 7.18-7.32 (m, 4H), 7.81 (d, J ) 8 Hz, 2H); MS (FAB)
m/ z 383 (M + Li)+; HRMS calcd for M+ 376.0745, found
376.0752. Anal. (C20H15F3O2S) C, H, F.
1,2-Diflu or o-4-(3-flu or o-4-m eth oxyp h en yl)-5-[4-(m eth -
ylsu lfon yl)p h en yl]ben zen e (20d ). Following general pro-
cedure B described for 20e, 19 was reacted with (3-fluoro-4-
methoxyphenyl)boronic acid (see 16d) to give the title compound
20d as a colorless solid: mp 159.2-159.7 °C; 1H NMR (CDCl3)
δ 3.05 (s, 3H), 3.87 (s, 3H), 6.63-6.85 (m, 3H), 7.16-7.32 (m,
4H), 7.82 (d, J ) 8 Hz, 2H); MS (EI) m/ z (rel intensity) 392
(49), 298 (48), 269 (100), 249 (79); HRMS calcd for M+
392.0694, found 392.0683. Anal. (C20H15F3O3S‚0.02 hexane)
C, H.
1-Br om o-4,5-d iflu or o-2-[4-(m e t h ylsu lfon yl)p h e n yl]-
ben zen e (19). Under nitrogen, to a stirred solution of 12.3 g
(73.2 mmol) of 1321 and 40.0 g (147.1 mmol) of 1,2-dibromo-
4,5-difluorobenzene (18) in a mixed solvent of 160 mL of
toluene, 160 mL of ethanol, and 160 mL of 2 M Na2CO3 was
added 5 g (4.3 mmol) of Pd(PPh3)4. After refluxing with
vigorous stirring for 3 h, the solvent was removed in vacuo.
The residue was dissolved in ethyl acetate, washed with water
and brine, and dried over MgSO4. Purification by silica gel
plug with ethyl acetate/hexane (0:100 to 10:90) gave an oil
residue which was dissolved in 350 mL of CH2Cl2. To this
solution was then slowly added 59 g (220 mmol) of m-CPBA
(64%), and the reaction was continued for 30 min at ambient
temperature. The mixture was then diluted with 500 mL of
CH2Cl2, washed with 5% NaOH, and dried over MgSO4.
Purification by silica gel chromatography (Waters PrepLC
500A) with ethyl acetate/hexane (1:4) gave 17.4 g (68%) of 19
1-(3,5-Dich lor o-4-m e t h oxyp h e n yl)-4,5-d iflu or o-2-[4-
(m et h ylsu lfon yl)p h en yl]b en zen e (20f). 4-Br om o-2,6-
d ich lor oa n isole. Following the methylation procedure de-
scribed for 16e, 4-bromo-2,6-dichlorophenol was methylated
to give 4-bromo-2,6-dichloroanisole as a colorless solid: mp
1
67.0-68.0 °C; H NMR (CDCl3) δ 3.88 (s, 3H), 7.45 (s, 2H).
(3,5-Dich lor o-4-m eth oxyp h en yl)bor on ic Acid . Follow-
ing the literature procedure described for 13,21 4-bromo-2,6-
dichloroanisole was converted to (3,5-dichloro-4-methoxyphenyl)-
boronic acid: 1H NMR (CDCl3) δ 3.83 (s, 3H), 7.73 (s, 2H).
20f. Following general procedure B described for 20e, 19
was reacted with (3,5-dichloro-4-methoxyphenyl)boronic acid
to give the title compound 20f as a colorless solid: mp 175.5-
175.8 °C; 1H NMR (CDCl3) δ 3.04 (s, 3H), 3.89 (s, 3H), 6.97 (s,
2H), 7.19-7.36 (m, 4H), 7.87 (d, J ) 8 Hz, 2H); MS (FAB) m/ z
449 (M + Li)+; HRMS calcd for M+ 442.0009, found 442.0018.
Anal. (C20H14Cl2F2O3S) C, H.
1
as a colorless solid: mp 158.5-159.5 °C; H NMR (CDCl3) δ
3.12 (s, 3H), 7.13-7.21 (m, 1H), 7.50-7.60 (m, 3H), 8.02 (d, J
) 9 Hz, 2H).
1,2-Diflu or o-4-(3-m eth yl-4-m eth oxyp h en yl)-5-[4-(m eth -
ylsu lfon yl)p h en yl]ben zen e (20g). 4-Br om o-2-m eth yla n i-
sole. Following the methylation procedure described for 16e,
4-bromo-2-methylphenol was methylated to give 4-bromo-2-
methylanisole as a colorless solid: mp 65.0-66.0 °C; 1H NMR
(CDCl3) δ 2.18 (s, 3H), 3.80 (s, 3H), 6.67 (d, J ) 9 Hz, 1H),
7.22-7.28 (m, 2H).
(3-Meth yl-4-m eth oxyp h en yl)bor on ic Acid . Following
the literature procedure described for 13,21 4-bromo-2-methyl-
anisole was converted to (3-methyl-4-methoxyphenyl)boronic
acid: 1H NMR (CDCl3) δ 2.33 (s, 3H), 3.92 (s, 3H), 6.96 (d, J
) 8 Hz, 1H), 7.98 (s, 1H), 8.03 (d, J ) 8 Hz, 1H).
20e. Under nitrogen, to a stirred solution of 4.4 g (12.8
mmol) of 19 and 3.1 g (16.7 mmol) of (3-chloro-4-methoxy-
phenyl)boronic acid (see 16e) in a mixed solvent of 37 mL of
toluene, 37 mL of ethanol, and 37 mL of 2 M Na2CO3 was
added 1 g (0.86 mmol) of Pd(PPh3)4. After refluxing with
vigorous stirring for 10 h, the solvent was removed in vacuo.
The residue was dissolved in ethyl acetate, washed with water
and brine, and dried over MgSO4. Purification by silica gel
chromatography (Waters PrepLC 500A) with ethyl acetate/
hexane (3:7) gave 4.5 g (95%) of the title compound 20e as a
1
colorless solid: mp 147.5-148.5 °C; H NMR (CDCl3) δ 3.05
(s, 3H), 3.88 (s, 3H), 6.75 (d, J ) 9 Hz, 1H), 6.83 (dd, J ) 2, 9
Hz, 1H), 7.10 (d, J ) 2 Hz, 1H), 7.17-7.32 (m, 4H), 7.83 (d, J
) 9 Hz, 2H); MS (EI) m/ z (rel intensity) 408 (33), 294 (52),
279 (63), 251 (100); HRMS calcd for M+ 408.0399, found
408.0396. Anal. (C20H15ClF2O3S‚0.27EtOAc) C, H, F.
20g. Following general procedure B described for 20e, 19
was reacted with (3-methyl-4-methoxyphenyl)boronic acid to
give the title compound 20g as a colorless solid: mp 160.5-
161.5 °C; 1H NMR (CDCl3) δ 2.11 (s, 3H), 3.04 (s, 3H), 3.79 (s,
3H), 6.63 (d, J ) 9 Hz, 1H), 6.74 (dd, J ) 2, 9 Hz, 1H), 6.85 (d,
J ) 2 Hz, 1H), 7.15-7.27 (m, 3H), 7.30 (d, J ) 8 Hz, 1H), 7.80
(d, J ) 8 Hz, 2H); MS (FAB) m/ z 395 (M + Li)+; HRMS calcd
for M+ 388.0945, found 388.0940. Anal. (C21H18F2O3S) C, H,
F.
1,2-Diflu or o-4-(3,4-d im e t h oxyp h e n yl)-5-[4-(m e t h yl-
su lfon yl)p h en yl]ben zen e (20h ). (3,4-Dim eth oxyp h en yl)-
bor on ic Acid . Following the literature procedure described
for 13,21 1-bromo-3,4-dimethoxybenzene was converted to (3,4-
1,2-Diflu or o-4-(4-flu or op h en yl)-5-[4-(m eth ylsu lfon yl)-
p h en yl]ben zen e (20a ). Following general procedure B de-
scribed for 20e, 19 was reacted with (4-fluorophenyl)boronic
acid to give the title compound 20a as a colorless solid: mp
1
172.8-173.5 °C; H NMR (CDCl3) δ 3.05 (s, 3H), 6.94 (t, J )
8 Hz, 2H), 6.98-7.06 (m, 2H), 7.21-7.31 (m, 4H), 7.81 (d, J )
8 Hz, 2H); MS (FAB) m/ z 369 (M + Li)+; HRMS calcd for M+
362.0588, found 362.0586. Anal. (C19H13F3O2S) C, H, F.

Novel Terphenyls as COX-2 Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9 1853
dimethoxyphenyl)boronic acid: 1H NMR (CDCl3) δ 3.98 (s, 3H),
4.02 (s, 3H), 7.02 (d, J ) 9 Hz, 1H), 7.69 (s, 1H), 7.86 (d, J )
9 Hz, 1H).
(dd, J ) 2, 8 Hz, 1H), 6.86 (s, 1H), 6.95 (d, J ) 8 Hz, 1H),
7.16-7.26 (m, 3H), 7.29 (d, J ) 9 Hz, 1H), 7.79 (d, J ) 9 Hz,
2H); MS (FAB) m/ z 379 (M + Li)+; HRMS calcd for M+
372.0996, found 372.0978. Anal. (C20H18F2O2S) C, H, F.
1,2-Diflu or o-4-(4-ch lor o-3-m eth ylp h en yl)-5-[4-(m eth yl-
su lfon yl)p h en yl]b en zen e (20n ). (4-Ch lor o-3-m et h yl-
p h en yl)bor on ic Acid . Following the literature procedure
described for 13,21 5-bromo-2-chlorotoluene was converted to
(4-chloro-3-methylphenyl)boronic acid: 1H NMR (DMSO-d6) δ
2.31 (s, 3H), 7.35 (d, J ) 8 Hz, 1H), 7.59 (d, J ) 8 Hz, 1H),
7.71 (s, 1H), 8.10 (br s, 2H).
20n . Following general procedure B described for 20e, 19
was reacted with (4-chloro-3-methylphenyl)boronic acid to give
the title compound 20n as a colorless solid: mp 151.5-152.2
°C; 1H NMR (CDCl3) δ 2.29 (s, 3H), 3.05 (s, 3H), 6.73 (dd, J )
2, 8 Hz, 1H), 6.98 (d, J ) 2 Hz, 1H), 7.16 (d, J ) 9 Hz, 1H),
7.19-7.32 (m, 4H), 7.82 (d, J ) 9 Hz, 2H); MS (FAB) m/ z 399
(M + Li)+; HRMS calcd for M+ 392.0449, found 392.0437.
Anal. (C20H15ClF2O2S) C, H, F.
20h . Following general procedure B described for 20e, 19
was reacted with (3,4-dimethoxyphenyl)boronic acid to give the
title compound 20h as a colorless solid: mp 140.0-141.0 °C;
1H NMR (CDCl3) δ 3.04 (s, 3H), 3.61 (s, 3H), 3.86 (s, 3H), 6.48
(d, J ) 2 Hz, 1H), 6.65 (dd, J ) 2, 8 Hz, 1H), 6.75 (d, J ) 8 Hz,
1H), 7.17-7.29 (m, 2H), 7.31 (d, J ) 8 Hz, 2H), 7.81 (d, J ) 8
Hz, 2H); MS (FAB) m/ z 411 (M + Li)+; HRMS calcd for M+
404.0894, found 404.0893. Anal. (C21H18F2O4S‚0.24H2O) C,
H.
1,2-Diflu or o-4-[3,4-(eth ylen ed ioxy)p h en yl]-5-[4-(m eth -
ylsu lfon yl)p h en yl]ben zen e (20i). [3,4-(Eth ylen ed ioxy)-
p h en yl]bor on ic Acid . Following the literature procedure
described for 13,21 3,4-(ethylenedioxy)bromobenzene was con-
verted to [3,4-(ethylenedioxy)phenyl]boronic acid: 1H NMR
(CDCl3) δ 4.27-4.36 (m, 4H), 6.97 (d, J ) 9 Hz, 1H), 7.67-
7.72 (m, 2H).
20i. Following general procedure B described for 20e, 19
was reacted with [3,4-(ethylenedioxy)phenyl]boronic acid to
give the title compound 20i as a colorless solid: mp 82.0-
2-Ch lor o-4-[4,5-d iflu or o-2-[4-(m eth ylsu lfon yl)p h en yl]-
p h en yl]-N,N-d im eth yla n ilin e (20o). 4-Br om o-2-ch lor o-
N,N-d im eth yla n ilin e. Under nitrogen, to a stirred solution
of 12.8 g (62 mmol) of 4-bromo-2-chloroaniline in 200 mL of
DMF were added 42.8 g (310 mmol) of K2CO3 powder and 11.6
mL (186 mmol) of CH3I. After heating at 100 °C with vigorous
stirring overnight, most of the DMF was removed in vacuo,
and the residue was dissolved in ethyl acetate. The ethyl
acetate layer was washed with water five times and dried over
Na2SO4. Purification by silica gel chromatography (Waters
PrepLC 500A) with ethyl acetate/hexane (5:95) gave 11.3 g
(78%) of 4-bromo-2-chloro-N,N-dimethylaniline as a colorless
liquid: 1H NMR (CDCl3) δ 2.79 (s, 6H), 6.92 (d, J ) 9 Hz, 1H),
7.25-7.34 (m, 1H), 7.49 (d, J ) 2 Hz, 1H).
[3-Ch lor o-4-(N,N-d im eth yla m in o)p h en yl]bor on ic Acid .
Following the literature procedure described for 13,21 4-bromo-
2-chloro-N,N-dimethylaniline was converted to [3-chloro-4-
(N,N-dimethylamino)phenyl]boronic acid: 1H NMR (CDCl3) δ
2.93 (s, 6H), 7.12 (d, J ) 8 Hz, 1H), 8.01 (d, J ) 8 Hz, 1H),
8.12 (s, 1H).
1
83.0 °C; H NMR (CDCl3) δ 3.05 (s, 3H), 4.21-4.26 (m, 4H),
6.43 (dd, J ) 2, 8 Hz, 1H), 6.61 (d, J ) 2 Hz, 1H), 6.68 (d, J )
8 Hz, 1H), 7.14-7.24 (m, 2H), 7.31 (d, J ) 8 Hz, 2H), 7.81 (d,
J ) 8 Hz, 2H); MS (FAB) m/ z 409 (M + Li)+; HRMS calcd for
M
C, H.
+ 402.0737, found 402.0749. Anal. (C21H16F2O4S‚0.17hexane)
5-[4,5-Diflu or o-2-[4-(m et h ylsu lfon yl)p h en yl]p h en yl]-
1,3-b en zod ioxole (20j). (1,3-Ben zod ioxol-5-yl)b or on ic
Acid . Following the literature procedure described for 13,21
5-bromo-1,3-benzodioxole was converted to (1,3-benzodioxol-
5-yl)boronic acid: 1H NMR (CDCl3) δ 5.98 (s, 2H), 6.88 (t, J )
8 Hz, 1H), 7.26-7.41 (m, 2H), 7.80 (br s, 2H).
20j. Following general procedure B described for 20e, 19
was reacted with (1,3-benzodioxol-5-yl)boronic acid to give the
title compound 20j as a colorless solid: mp 110.0-111.0 °C;
1H NMR (CDCl3) δ 3.05 (s, 3H), 5.95 (s, 2H), 6.47-6.52 (m,
2H), 6.67 (d, J ) 9 Hz, 1H), 7.16-7.24 (m, 2H), 7.32 (d, J ) 9
Hz, 2H), 7.82 (d, J ) 9 Hz, 2H); MS (FAB) m/ z 395 (M + Li)+;
HRMS calcd for M+ 388.0581, found 388.0569. Anal.
(C20H14F2O4S) C, H.
1,2-Diflu or o-4-(4-m eth ylp h en yl)-5-[4-(m eth ylsu lfon yl)-
p h en yl]ben zen e (20k ). Following general procedure B de-
scribed for 20e, 19 was reacted with (4-methylphenyl)boronic
acid to give the title compound 20k as a colorless solid: mp
147.0-148.0 °C; 1H NMR (CDCl3) δ 2.32 (s, 3H), 3.05 (s, 3H),
6.92 (d, J ) 8 Hz, 2H), 7.03 (d, J ) 8 Hz, 2H), 7.17-7.32 (m,
4H), 7.79 (d, J ) 8 Hz, 2H); MS (FAB) m/ z 365 (M + Li)+;
HRMS calcd for M+ 358.0839, found 358.0831. Anal.
(C20H16F2O2S) C, H.
1-(3-Ch lor o-4-m eth ylp h en yl)-4,5-d iflu or o-2-[4-(m eth yl-
su lfon yl)p h en yl]ben zen e (20l). (3-Ch lor o-4-m eth ylp h en -
yl)bor on ic Acid . Following the literature procedure de-
scribed for 13,21 4-bromo-2-chlorotoluene was converted to (3-
chloro-4-methylphenyl)boronic acid: 1H NMR (CDCl3) δ 2.47
(s, 3H), 7.37 (d, J ) 8 Hz, 1H), 7.98 (d, J ) 8 Hz, 1H), 8.08 (s,
1H).
20l. Following general procedure B described for 20e, 19
was reacted with (3-chloro-4-methylphenyl)boronic acid to give
the title compound 20l as a colorless solid: mp 138.0-139.0
°C; 1H NMR (CDCl3) δ 2.34 (s, 3H), 3.05 (s, 3H), 6.75 (dd, J )
2, 8 Hz, 1H), 7.03-7.10 (m, 2H), 7.18-7.26 (m, 2H), 7.29 (d, J
) 8 Hz, 2H), 7.83 (d, J ) 8 Hz, 2H); MS (FAB) m/ z 399 (M +
Li)+; HRMS calcd for M+ 392.0449, found 392.0440. Anal.
(C20H15ClF2O2S) C, H.
1,2-Diflu or o-4-(3,4-d im eth ylp h en yl)-5-[4-(m eth ylsu lfo-
n yl)p h en yl]ben zen e (20m ). (3,4-Dim eth ylp h en yl)bor on -
ic Acid . Following the literature procedure described for 13,21
4-bromo-o-xylene was converted to (3,4-dimethylphenyl)boronic
acid: 1H NMR (CDCl3) δ 2.19 (s, 6H), 7.07 (d, J ) 8 Hz, 1H),
7.45-7.54 (m, 2H), 7.84 (br s, 2H).
20o. Following general procedure B described for 20e, 19
was reacted with [3-chloro-4-(N,N-dimethylamino)phenyl]-
boronic acid to give the title compound 20o as a colorless
solid: mp 129.0-130.0 °C; 1H NMR (CDCl3) δ 2.81 (s, 6H),
3.05 (s, 3H), 6.76-6.91 (m, 2H), 7.08 (d, J ) 2 Hz, 1H), 7.17-
7.26 (m, 2H), 7.31 (d, J ) 9 Hz, 2H), 7.83 (d, J ) 9 Hz, 2H);
MS (FAB) m/ z 428 (M + Li)+; HRMS calcd for M+ 421.0715,
found 421.0719. Anal. (C21H18NClF2O2S) C, H, N.
2-[4,5-Diflu or o-4′-(m et h ylsu lfon yl)-[1,1′-b ip h en yl]-2-
yl]-5-m eth ylp yr id in e (20p ). 1-Br om o-4,5-d iflu or o-2-[4-
(m eth ylth io)p h en yl]ben zen e (22). Following the first step
in general procedure B described for 20e, the reaction was
worked up prior to the m-CPBA oxidation. Purification by
silica gel chromatography (Waters PrepLC 500A) with ethyl
acetate/hexane (2:98) gave 22 as a colorless solid: mp 53.5-
1
54.5 °C; H NMR (CDCl3) δ 2.53 (s, 3H), 7.10-7.19 (m, 1H),
7.29 (s, 4H), 7.45-7.53 (m, 1H).
[4,5-Diflu or o-2-[(4-m et h ylt h io)p h en yl]p h en yl]b or on -
ic Acid (23). Under nitrogen, to a mixture of 3.87 g (12.3
mmol) of 22 and 300 mg (12.3 mmol) of Mg turnings in 12 mL
of anhydrous THF was added 1 mL of dibromoethane. The
mixture was heated at reflux for 5 h and cooled to 0 °C followed
by the addition of 2.8 mL (24.6 mmol) of trimethyl borate and
stirring overnight. After 10 mL of 10% NaOH was added, the
solution was stirred for 3 h, acidified to pH 4, extracted with
ethyl acetate three times, and dried over MgSO4. Concentra-
tion in vacuo gave 2.7 g (78%) of 23 as a pale yellow semisolid.
20p . Under nitrogen, to a stirred solution of 2.7 g (9.6
mmol) of 23 and 1.7 g (9.8 mmol) of 2-bromo-5-methylpyridine
in a mixed solvent of 25 mL of toluene, 25 mL of ethanol, and
25 mL of 2 M Na2CO3 was added 1 g (0.86 mmol) of Pd(PPh3)4.
After refluxing with vigorous stirring for 48 h, the solvent was
removed in vacuo. The residue was dissolved in ethyl acetate,
washed with water and brine, and dried over Na2SO4. Puri-
fication by silica gel plug with ethyl acetate/hexane (15:85)
gave a semisolid residue which was then dissolved in a mixed
solvent of 15 mL of THF and 15 mL of CH3OH. To this
20m . Following general procedure B described for 20e, 19
was reacted with (3,4-dimethylphenyl)boronic acid to give the
title compound 20m as a colorless solid: mp 125.1-125.8 °C;
1H NMR (CDCl3) δ 2.16 (s, 3H), 2.23 (s, 3H), 3.04 (s, 3H), 6.69

1854 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Li et al.
mixture was slowly added a solution of 3.5 g (5.7 mmol) of
Oxone in 15 mL of H2O, and the reaction was continued for 3
h at ambient temperature. The excess Oxone was quenched
by adding 2 g of Na2SO3, and the mixture was stirred for 30
min. Most of the solvent was removed in vacuo; the residue
was dissolved in ethyl acetate, washed with brine, and dried
over Na2SO4. Purification by silica gel chromatography (MPLC)
with ethyl acetate/hexane (45:55) gave 1.0 g (29%) of the title
compound 20p as a colorless foam: 1H NMR (CDCl3) δ 2.32
(s, 3H), 3.05 (s, 3H), 6.76 (d, J ) 8 Hz, 1H), 7.17-7.36 (m,
4H), 7.53 (t, J ) 9 Hz, 1H), 7.82 (d, J ) 9 Hz, 2H), 8.42 (s,
1H); MS (FAB) m/ z 360 (M+H)+; HRMS calcd for (M+H)+
360.0870, found 360.0885. Anal. (C19H15NO2SF2) C, H, N, F.
5-[4,5-Diflu or o-4′-(m et h ylsu lfon yl)-[1,1′-b ip h en yl]-2-
colorless solid: mp >70 °C dec; 1H NMR (CDCl3) δ 3.87 (s,
3H), 4.84 (s, 2H), 6.75 (d, J ) 9 Hz, 1H), 6.82 (dd, J ) 2, 9 Hz,
1H), 7.14 (d, J ) 2 Hz, 1H), 7.16-7.28 (m, 4H), 7.81 (d, J ) 8
Hz, 2H); MS (EI) m/ z (rel intensity) 409 (22), 279 (28), 251
(100), 231 (20); HRMS calcd for M+ 409.0351, found 409.0340.
Anal. (C19H14ClF2NO3S) C, H, N.
4-[2-(3,5-D ic h lo r o -4-m e t h o x y p h e n y l)-4,5-d iflu o r o -
p h en yl]ben zen esu lfon a m id e (21f). Following the literature
procedure,21,27 20f was converted to the title compound 21f as
a colorless solid: mp 145.5-146.0 °C; 1H NMR (CDCl3) δ 3.89
(s, 3H), 4.78 (s, 2H), 6.98 (s, 2H), 7.18-7.29 (m, 4H), 7.85 (d,
J ) 8 Hz, 2H); MS (FAB) m/ z 450 (M + Li)+; HRMS calcd for
(M+H)+ 444.0039, found 444.0052. Anal. (C19H13NCl2F2O3S)
C, H, N.
yl]-2-m et h ylp yr id in e
(20q ).
2-Met h yl-5-(t r im et h yl-
4-[4,5-Diflu or o-2-(3-m eth yl-4-m eth oxyp h en yl)p h en yl]-
ben zen esu lfon a m id e (21g). Following the literature pro-
cedure,21,27 20g was converted to the title compound 21g as a
sta n n yl)p yr id in e (25). Under nitrogen, to a stirred solution
of 5.2 g (30 mmol) of 2428 in 300 mL of anhydrous THF at -78
°C was added 14 mL (35 mmol) of n-BuLi (2.5 M in hexanes).
After 10 min, 7.2 g (36 mmol) of trimethyltin chloride in 5 mL
of anhydrous THF was added and the solution was allowed to
warm to ambient temperature and stirred overnight. Most of
the THF was removed in vacuo; the residue was dissolved in
ethyl acetate, washed with brine, and dried over Na2SO4.
Purification by silica gel chromatography (Waters PrepLC
500A) with ethyl acetate/hexane (1:3) gave 2.0 g (29%) of 25
as a yellow oil: 1H NMR (CDCl3) δ 0.31 (s, 9H), 2.52 (s, 3H),
7.11 (d, J ) 8 Hz, 1H), 7.65 (dd, J ) 2, 8 Hz, 1H), 8.49 (s, 1H).
20q.29 Under nitrogen, to a stirred solution of 200 mg (0.6
mmol) of 19 and 300 mg (1.2 mmol) of 25 in 5 mL of toluene
was added 100 mg (0.1 mmol) of Pd(PPh3)4. After refluxing
for 16 h, the solvent was removed in vacuo. The residue was
dissolved in ethyl acetate, washed with water and brine, and
dried over Na2SO4. Purification by silica gel chromatography
(MPLC) with ethyl acetate/hexane (1:1) gave 70 mg (32%) of
the title compound 20q as a pale brown solid: mp 141.0-142.5
1
colorless solid: mp 120.0-121.8 °C; H NMR (CDCl3) δ 2.11
(s, 3H), 3.79 (s, 3H), 4.84 (s, 2H), 6.63 (d, J ) 9 Hz, 1H), 6.74
(dd, J ) 2, 9 Hz, 1H), 6.88 (d, J ) 2 Hz, 1H), 7.13-7.28 (m,
4H), 7.78 (d, J ) 8 Hz, 2H); MS (FAB) m/ z 396 (M + Li)+;
HRMS calcd for M+ 389.0897, found 389.0921. Anal. (C20H17
NF2O3S) C, H, N.
-
4-[4,5-Diflu or o-2-(3,4-d im et h oxyp h en yl)p h en yl]b en -
zen esu lfon a m id e (21h ). Following the literature proce-
dure,21,27 20h was converted to the title compound 21h as a
1
colorless solid: mp 157.0-158.0 °C; H NMR (CDCl3) δ 3.61
(s, 3H), 3.86 (s, 3H), 4.77 (s, 2H), 6.46 (d, J ) 2 Hz, 1H), 6.65
(dd, J ) 2, 8 Hz, 1H), 6.75 (d, J ) 8 Hz, 1H), 7.16-7.30 (m,
4H), 7.79 (d, J ) 8 Hz, 2H); MS (FAB) m/ z 412 (M + Li)+;
HRMS calcd for M+ 405.0846, found 405.0870. Anal. (C20H17
-
NF2O4S‚0.35H2O) C, H, N.
4-[4,5-Diflu or o-2-[3,4-(eth ylen ed ioxy)p h en yl]p h en yl]-
ben zen esu lfon a m id e (21i). Following the literature proce-
dure,21,27 20i was converted to the title compound 21i as a
colorless solid: mp 107.0-108.0 °C; 1H NMR (CDCl3) δ 4.22-
4.26 (m, 4H), 4.75 (s, 2H), 6.43 (dd, J ) 2, 8 Hz, 1H), 6.62 (d,
J ) 2 Hz, 1H), 6.68 (d, J ) 8 Hz, 1H), 7.13-7.30 (m, 4H), 7.80
(d, J ) 8 Hz, 2H); MS (FAB) m/ z 410 (M + Li)+; HRMS calcd
for M+ 403.0690, found 403.0697. Anal. (C20H15NO4F2S) C,
H, N.
1
°C; H NMR (CDCl3) δ 2.52 (s, 3H), 3.04 (s, 3H), 7.02 (d, J )
8 Hz, 1H), 7.19-7.32 (m, 5H), 7.82 (d, J ) 8 Hz, 2H), 8.24 (s,
1H); MS (FAB) m/ z 360 (M+H)+; HRMS calcd for (M+H)+
360.0870, found 360.0862. Anal. (C19H15NO2SF2‚0.33H2O) C,
H, N.
4-[4,5-Diflu or o-2-(4-flu or op h e n yl)p h e n yl]b e n ze n e -
su lfon a m id e (21a ). Following the literature procedure,21,27
20a was converted to the title compound 21a as a colorless
solid: mp 190.2-191.5 °C; 1H NMR (CDCl3) δ 4.77 (s, 2H),
6.94 (t, J ) 8 Hz, 2H), 6.98-7.06 (m, 2H), 7.17-7.28 (m, 4H),
7.79 (d, J ) 8 Hz, 2H); MS (FAB) m/ z 370 (M + Li)+; HRMS
calcd for M+ 363.0541, found 363.0576. Anal. (C18H12NF3O2S)
C, H, N.
4-[2-(1,3-Be n zod ioxol-5-yl)-4,5-d iflu or op h e n yl]b e n -
zen esu lfon a m id e (21j). Following the literature proce-
dure,21,27 20j was converted to the title compound 21j as a
1
colorless solid: mp 142.0-143.0 °C; H NMR (CDCl3) δ 4.83
(s, 2H), 5.95 (s, 2H), 6.49-6.54 (m, 2H), 6.69 (d, J ) 8 Hz,
1H), 7.15-7.30 (m, 4H), 7.81 (d, J ) 8 Hz, 2H); MS (EI) m/ z
389 (18), 251 (100), 231 (43); HRMS calcd for M+ 389.0533,
found 389.0517. Anal. (C19H13NF2O4S‚0.19H2O) C, H, N.
4-[4,5-Diflu or o-2-(4-m e t h ylp h e n yl)p h e n yl]b e n ze n e -
su lfon a m id e (21k ). Following the literature procedure,21,27
20k was converted to the title compound 21k as a colorless
solid: mp 103.0-104.0 °C; 1H NMR (CDCl3) δ 2.32 (s, 3H),
4.81 (s, 2H), 6.93 (d, J ) 8 Hz, 2H), 7.04 (d, J ) 8 Hz, 2H),
7.16-7.29 (m, 4H), 7.78 (d, J ) 9 Hz, 2H); MS (EI) m/ z 359
(26), 279 (33), 278 (41), 264 (100), 251 (36), 119 (62), 80 (70),
64 (56); HRMS calcd for M+ 359.0792, found 359.0777. Anal.
(C19H15NF2O2S) C, H, N.
4-[2-(3-Ch lor o-4-flu or op h e n yl)-4,5-d iflu or op h e n yl]-
ben zen esu lfon a m id e (21b). Following the literature pro-
cedure,21,27 20b was converted to the title compound 21b as a
1
colorless solid: mp 162.5-162.8 °C; H NMR (CDCl3) δ 4.80
(s, 2H), 6.81-6.88 (m, 1H), 6.99 (t, J ) 9 Hz, 1H), 7.15-7.28
(m, 5H), 7.83 (d, J ) 8 Hz, 2H); MS (FAB) m/ z 404 (M + Li)+;
HRMS calcd for M+ 397.0151, found 397.0152. Anal. (C18H11
NClF3O2S) C, H, N.
-
4-[4,5-Diflu or o-2-(4-flu or o-3-m et h ylp h en yl)p h en yl]-
ben zen esu lfon a m id e (21c). Following the literature pro-
cedure,21,27 20c was converted to the title compound 21c as a
4-[2-(3-Ch lor o-4-m eth ylph en yl)-4,5-diflu or oph en yl]ben -
zen esu lfon a m id e (21l). Following the literature proce-
dure,21,27 20l was converted to the title compound 21l as a
1
colorless solid: mp 151.5-152.0 °C; H NMR (CDCl3) δ 2.18
(d, J ) 2 Hz, 3H), 4.84 (s, 2H), 6.70-6.78 (m, 1H), 6.83 (t, J )
9 Hz, 1H), 6.94 (dd, J ) 2, 8 Hz, 1H), 7.15-7.29 (m, 4H), 7.79
(d, J ) 8 Hz, 2H); MS (FAB) 384 (M + Li)+; HRMS calcd for
M+ 377.0697, found 377.0720. Anal. (C19H14NF3O2S) C, H,
N.
1
colorless solid: mp 139.0-140.0 °C; H NMR (CDCl3) δ 2.33
(s, 3H), 4.81 (s, 2H), 6.74 (dd, J ) 2, 8 Hz, 1H), 7.04 (d, J ) 8
Hz, 1H), 7.12 (d, J ) 2 Hz, 1H), 7.17-7.25 (m, 4H), 7.80 (d, J
) 8 Hz, 2H); MS (FAB) m/ z 400 (M + Li)+; HRMS calcd for
4-[4,5-Diflu or o-2-(3-flu or o-4-m eth oxyp h en yl)p h en yl]-
ben zen esu lfon a m id e (21d ). Following the literature pro-
cedure,21,27 20d was converted to the title compound 21d as a
M
+ 393.0402, found 393.0400. Anal. (C19H14NO2F2ClS) C, H,
N.
4-[4,5-Diflu or o-2-(3,4-d im e t h ylp h e n yl)p h e n yl]b e n -
1
colorless solid: mp 132.2-132.8 °C; H NMR (CDCl3) δ 3.87
zen esu lfon a m id e (21m ). Following the literature proce-
dure,21,27 20m was converted to the title compound 21m as a
(s, 3H), 4.85 (s, 2H), 6.71-6.85 (m, 3H), 7.15-7.27 (m, 4H),
7.81 (d, J ) 9 Hz, 2H); MS (EI) m/ z (rel intensity) 393 (32),
298 (21), 282 (25), 269 (100), 249 (46); HRMS calcd for M+
393.0646, found 393.0647. Anal. (C19H14NO3SF3) C, H, N.
4-[2-(3-Ch lor o-4-m eth oxyp h en yl)-4,5-d iflu or op h en yl]-
ben zen esu lfon a m id e (21e). Following the literature pro-
cedure,21,27 20e was converted to the title compound 21e as a
1
colorless solid: mp 132.8-133.9 °C; H NMR (CDCl3) δ 2.16
(s, 3H), 2.22 (s, 3H), 4.83 (s, 2H), 6.68 (dd, J ) 2, 8 Hz, 1H),
6.88 (s, 1H), 6.94 (d, J ) 8 Hz, 1H), 7.15-7.28 (m, 4H), 7.77
(d, J ) 8 Hz, 2H); MS (FAB) m/ z 380 (M + Li)+; HRMS for
M+ 373.0948, found 373.0972. Anal. (C20H17NF2O2S) C, H,
N.

Novel Terphenyls as COX-2 Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9 1855
4-[2-(4-Ch lor o-3-m eth ylph en yl)-4,5-diflu or oph en yl]ben -
zen esu lfon a m id e (21n ). Following the literature proce-
dure,21,27 20n was converted to the title compound 21n as a
m-CPBA (70%) was added, and the reaction mixture was
stirred overnight at ambient temperature. The excess m-
CPBA was quenched by adding Na2SO3 at 0 °C, and the
mixture was stirred for 30 min at ambient temperature. The
solution was diluted with CH2Cl2, washed with water and
brine, and dried over Na2SO4. Purification by silica gel
chromatography (MPLC) with ethyl acetate/hexane (3:7) gave
505 mg (33%) of 30 as a colorless solid: mp 143.5-144.5 °C;
1H NMR (CDCl3) δ 3.05 (s, 3H), 6.95 (d, J ) 9 Hz, 2H), 6.99-
7.07 (m, 2H), 7.30 (d, J ) 9 Hz, 2H), 7.52 (d, J ) 9 Hz, 2H),
7.83 (d, J ) 9 Hz, 2H); MS (CI) m/ z 395 (M+H)+; HRMS calcd
for (M + Li)+ 401.0157, found 401.0142. Anal. (C19H13O2-
SFCl2) C, H, F, Cl.
1
colorless solid: mp 141.5-142.8 °C; H NMR (CDCl3) δ 2.29
(s, 3H), 4.89 (s, 2H), 6.73 (dd, J ) 2, 8 Hz, 1H), 7.00 (d, J ) 2
Hz, 1H), 7.15 (d, J ) 8 Hz, 1H), 7.17-7.27 (m, 5H), 7.80 (d, J
) 9 Hz, 1H); MS (FAB) m/ z 400 (M + Li)+; HRMS for M+
393.0402, found 393.0416. Anal. (C19H14NF2ClO2S) C, H, N.
4-[2-[3-Ch lor o-4-(N,N-d im et h yla m in o)p h en yl]-4,5-d i-
flu or op h en yl]ben zen esu lfon a m id e (21o). Following the
literature procedure,21,27 20o was converted to the title com-
1
pound 21o as a colorless solid: mp 193.0-194.0 °C; H NMR
(CDCl3) δ 2.83 (s, 6H), 4.80 (s, 2H), 6.79 (dd, J ) 2, 9 Hz, 1H),
6.87-6.95 (m, 1H), 7.13 (d, J ) 2 Hz, 1H), 7.17-7.29 (m, 4H),
7.82 (d, J ) 8 Hz, 2H); MS (FAB) m/ z 429 (M + Li)+; HRMS
for M+ 422.0667, found 422.0667. Anal. (C20H17N2ClF2O2S‚
0.27H2O) C, H, N.
5-(4-F lu or op h en yl)-6-[4-(m et h ylsu lfon yl)p h en yl]-1,3-
ben zod ioxole (32). Under nitrogen, to a stirred solution of
4.0 g (14.3 mmol) of 5,6-dibromo-1,3-benzodioxole (31), 2.87 g
(17.2 mmol) of 13,21 and 2.4 g (17.2 mmol) of (4-fluorophenyl)-
boronic acid in a mixed solvent of 70 mL of toluene, 40 mL of
ethanol, and 30 mL of 2 M Na2CO3 was added 1 g (0.86 mmol)
of Pd(PPh3)4. After refluxing with vigorous stirring overnight,
the solvent was removed in vacuo. The residue was dissolved
in ethyl acetate, washed with water and brine, and dried over
Na2SO4. Purification by silica gel plug with hexane gave a
semisolid residue which was dissolved in 30 mL of CH2Cl2. To
this mixture was then slowly added 12 g (38.2 mmol) of
m-CPBA (55%) at -10 °C, and the reaction was continued for
30 min at ambient temperature. The excess m-CPBA was
quenched by adding 4 g of Na2SO3 at -10 °C, and the mixture
was stirred for 30 min at ambient temperature. The solvent
was removed in vacuo, and the residue was dissolved in ethyl
acetate, washed with water and brine, and dried over Na2SO4.
Purification by silica gel chromatography (MPLC) with ethyl
acetate/hexane (1:4) followed by reversed phase chromatog-
raphy (Waters Delta Prep 3000) with acetonitrile/water/TFA
(45:55:0.05) gave 200 mg of the title compound 32 as a colorless
solid: mp 173.0-174.0 °C; 1H NMR (CDCl3) δ 3.04 (s, 3H),
6.06 (s, 2H), 6.86-6.92 (m, 4H), 6.96-7.03 (m, 2H), 7.23-7.27
(m, 2H), 7.76 (d, J ) 9 Hz, 2H); MS (FAB) m/ z 377 (M + Li)+;
4-[4,5-Diflu or o-2-(5-m et h ylp yr id in -2-yl)p h en yl]b en -
zen esu lfon a m id e (21p ). Following the literature proce-
dure,21,27 20p was converted to the title compound 21p as a
colorless foam: 1H NMR (CDCl3) δ 2.55 (s, 3H), 4.91 (s, 2H),
6.81 (d, J ) 8 Hz, 1H), 7.18-7.31 (m, 3H), 7.35 (d, J ) 8 Hz,
1H), 7.50-7.59 (m, 1H), 7.82 (d, J ) 9 Hz, 2H), 8.47 (s, 1H);
MS (FAB) m/ z 361 (M+H)+; HRMS calcd for (M + Li)+
367.0904, found 367.0904. Anal. (C18H14N2O2SF2‚0.13hexane)
C, H, N.
4-[4,5-Diflu or o-2-(6-m et h ylp yr id in -3-yl)p h en yl]b en -
zen esu lfon a m id e (21q). Following the literature proce-
dure,21,27 20q was converted to the title compound 21q as a
colorless solid: mp >96 °C dec; 1H NMR (CDCl3) δ 2.55 (s,
3H), 5.10 (s, 2H), 7.09 (d, J ) 8 Hz, 1H), 7.20-7.28 (m, 4H),
7.32 (dd, J ) 2, 9 Hz, 1H), 7.81 (d, J ) 9 Hz, 2H), 8.21 (d, J )
2 Hz, 1H); MS (FAB) m/ z 361 (M+H)+; HRMS calcd for
(M+H)+ 361.0822, found 361.0823. Anal. (C18H14N2O2SF2) C,
H, N, F.
1,2-Dich lor o-4-(4-flu or op h en yl)-5-[4-(m eth ylsu lfon yl)-
p h en yl]ben zen e (30). 1,2-Dich lor oca tech ol (27). Under
nitrogen, to a stirred solution of 5.75 g (27.8 mmol) of
dichloroveratrole (26)30 in 200 mL of CH2Cl2 was added 83.4
mL (83.4 mmol) of BBr3 (1.0 M in CH2Cl2) at 0 °C, and the
reaction was continued for 2 h at ambient temperature. After
most of the solvent was removed in vacuo, the residue was
dissolved in ethyl acetate, washed with brine, and dried over
Na2SO4. Recrystallization from ethyl acetate/hexane (5:95)
gave 5.0 g (96%) of 27 as a gray solid: mp 113.0-114.5 °C; 1H
NMR (CDCl3) δ 5.18 (s, 2H), 6.98 (s, 2H).
1,2-Dich lor o-4,5-b is[(t r iflu or om e t h yl)su lfon yl]b e n -
zen e (28). Under nitrogen, to a stirred solution of 3.72 g (20.8
mmol) of 27 in 40 mL of CH2Cl2 were added 8.4 mL (104 mmol)
of pyridine and 9.0 mL (53.5 mmol) of triflic anhydride at 0
°C, and the reaction was continued for 7 days at ambient
temperature. The mixture was poured into ice-water and
extracted with CH2Cl2, and the combined extracts were dried
over Na2SO4. Purification by silica gel plug with ethyl acetate/
hexane (5:95) gave 7.9 g (86%) of 28 as a yellow oil: 1H NMR
(CDCl3) δ 7.62 (s, 2H).
1,2-Dich lor o-4-[4-(m e t h ylt h io)p h e n yl]-5-[(t r iflu or o-
m eth yl)su lfon yl]ben zen e (29). Under nitrogen, to a stirred
solution of 7.9 g (17.8 mmol) of 28, 3.0 g (18 mmol) of 13,21
and 7.4 g (54 mmol) of anhydrous K2CO3 powder in 90 mL of
toluene was added 5 g (4.3 mmol) of Pd(PPh3)4. After refluxing
with vigorous stirring for 48 h, the solution was diluted with
CH2Cl2, washed with water and brine, and dried over MgSO4.
Purification by silica gel plug with ethyl acetate/hexane (5:95
to 30:70) gave 4.8 g (56%) of 29 as a colorless solid: 1H NMR
(CDCl3) δ 2.54 (s, 3H), 7.33 (s, 4H), 7.50 (s, 1H), 7.56 (s, 1H).
30. Under nitrogen, to a stirred solution of 1.64 g (3.93
mmol) of 29, 1.1 g (7.9 mmol) of (4-fluorophenyl)boronic acid,
and 1.6 g (11.6 mmol) of anhydrous K2CO3 powder in 20 mL
of toluene was added 480 mg (0.42 mmol) of Pd(PPh3)4. The
mixture was heated at reflux with vigorous stirring for 7 days
and cooled to ambient temperature. The solution was diluted
with ethyl acetate, washed with water, and dried over MgSO4.
Purification by silica gel plug with ethyl acetate/hexane (5:
95) gave an oil residue which was dissolved in 15 mL of
CH2Cl2. After cooling down to 0 °C, 1.4 g (11.8 mmol) of
HRMS calcd for M+ 370.0675, found 370.0680. Anal. (C20H15
-
FO4S‚0.25H2O) C, H.
1,2,3,4-Te t r a flu or o-5-(4-flu or op h e n yl)-6-[4-(m e t h yl-
su lfon yl)p h en yl]ben zen e (34). Following the procedure
described for 32, 34 was isolated as a colorless solid: mp
134.0-135.0 °C; 1H NMR (CDCl3) δ 3.05 (s, 3H), 6.91-7.03
(m, 4H), 7.26 (d, J ) 9 Hz, 2H), 7.84 (d, J ) 9 Hz, 2H); MS
(FAB) m/ z 405 (M + Li)+; HRMS calcd for M+ 398.0400, found
398.0393.
2-(4-F lu or op h en yl)-3-[4-(m eth ylsu lfon yl)p h en yl]n a p h -
th a len e (36). Following the procedure described for 32, 36
was isolated as a colorless solid: mp 147.0-148.0 °C; 1H NMR
(CDCl3) δ 3.08 (s, 3H), 6.97 (d, J ) 9 Hz, 2H), 7.11-7.19 (m,
2H), 7.41 (d, J ) 8 Hz, 2H), 7.53-7.60 (m, 2H), 7.84 (d, J ) 8
Hz, 2H), 7.87-7.94 (m, 4H); MS (FAB) m/ z 383 (M + Li)+;
HRMS calcd for M+ 376.0933, found 376.0940.
2-(4-F lu or op h en yl)-3-[4-(m eth ylsu lfon yl)p h en yl]p yr a -
zin e (39). 4-F lu or o-4′-(m eth ylsu lfon yl)ben zil (38). Under
nitrogen, to a stirred solution of 11.7 g (47.5 mmol) of 37 in
80 mL of DMF was added 4.8 g (47.0 mmol) of CH3SO2Na.
The mixture was heated at reflux with vigorous stirring for 3
h and then cooled to ambient temperature. The solution was
diluted with ethyl acetate, washed with water, and dried over
Na2SO4. Purification by silica gel chromatography (Waters
PrepLC 500A) with ethyl acetate/hexane (1:4) gave 1.8 g (12%)
of 38 as a colorless solid: 1H NMR (CDCl3) δ 3.10 (s, 3H), 7.18-
7.24 (m, 2H), 8.01-8.20 (m, 6H).
39. A stirred solution of 1.8 g (5.9 mmol) of 38 in 5 mL of
ethylenediamine was heated at 60 °C for 3 h and then cooled
to ambient temperature. Concentration in vacuo gave an oil
residue which was dissolved in 10 mL of CH2Cl2. To this
solution was added 3.3 g (14.5 mmol) of DDQ at -10 °C, and
the reaction was continued for 5 h at ambient temperature.
The excess DDQ was then quenched by adding Na2SO3 at 0
°C, and the mixture was stirred for 30 min at ambient
temperature. The solution was diluted with CH2Cl2, washed
with water and brine, and dried over Na2SO4. Purification
by silica gel chromatography (MPLC) with ethyl acetate/

1856 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Li et al.
(20) Reitz, D. B.; Li, J . J .; Norton, M. B.; Reinhard, E. J .; Huang,
H.-C.; Penick, M. A.; Collins, J . T.; Garland, D. J .; Seibert, K.;
Kobold, C. M.; Gregory, S. A.; Veenhuizen, A.; Zhang, Y.;
Isakson, P. C. Novel 1,2-Diarylcyclopentenes Are Selective,
Potent and Orally Active Cyclooxygenase Inhibitors. Med. Chem.
Res. 1995, 5, 351-363.
hexane (3:7) gave 400 mg (23%) of 39 as a pale brown solid:
mp 141.0-142.0 °C; 1H NMR (CDCl3) δ 3.06 (s, 3H), 7.04 (t, J
) 9 Hz, 2H), 7.19-7.25 (m, 2H), 7.67 (d, J ) 8 Hz, 2H), 7.91
(d, J ) 8 Hz, 2H), 8.66 (dd, J ) 1, 8 Hz, 2H); MS (FAB) m/ z
329 (M + H)+; HRMS calcd for M+ 328.0682, found 328.0685.
(21) Li, J . J .; Anderson, G. D.; Burton, E. G.; Cogburn, J . N.; Collins,
J . T.; Garland, D. J .; Gregory, S. A.; Huang, H.-C.; Isakson, P.
C.; Koboldt, C. M.; Logusch, E. W.; Norton, M. B.; Perkins, W.
E.; Reinhard, E. J .; Seibert, K.; Veenhuizen, A. W.; Zhang, Y.;
Reitz, D. B. 1,2-Diarylcyclopentenes as Selective Cyclooxy-
genase-2 Inhibitors and Orally Active Anti-inflammatory Agents.
J . Med. Chem. 1995, 38, 4570-4578.
(22) Reitz, D. B.; Huang, H.-C.; Li, J . J .; Garland, D. J .; Manning, R.
E.; Anderson, G. D.; Gregory, S. A.; Kobold, C. M.; Perkins, W.
E.; Seibert, K.; Isakson, P. C. Selective Cyclooxygenase Inhibi-
tors: Novel 4-Spiro 1,2-Diarylcyclopentenes Are Potent and
Orally Active COX-2 Inhibitors. Bioorg. Med. Chem. Lett. 1995,
5, 867-872.
Su p p or tin g In for m a tion Ava ila ble: Summary of in vitro
and in vivo assays (5 pages). Ordering information can be
found on any current masthead page.
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J M950878E