Diarylspiro[2.4]heptenes as orally active, highly selective cyclooxygenase-2 inhibitors: Synthesis and structure-activity relationships

Article abstract of DOI:10.1021/jm950664x

A novel series of 5,6-diarylspiro[2.4]hept-5-enes was shown to provide highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. A study of structure-activity relationships in this series suggests that 3,4- disubstituted phenyl analogs are generally more selective than 4-substituted phenyl analogs and that replacement of the methyl sulfone group on the 6- phenyl ring with a sulfonamide moiety results in compounds with superior in vivo pharmacological properties, although with lower COX-2 selectivity. Several compounds have been shown to possess promising pharmacological properties in adjuvant-induced arthritis and edema analgesia models. The absence of gastrointestinal (GI) toxicity at 200 mpk of several selected compounds in rats and mice corresponds well with the weak potency for inhibition of COX-1 observed in the enzyme assay. Methyl sulfone 55 and sulfonamide 24 were shown to have superior in vivo pharmacological profiles, low GI toxicity, and good oral bioavailability and duration of action.

Full text of DOI:10.1021/jm950664x

J . Med. Chem. 1996, 39, 253-266
253
Dia r ylsp ir o[2.4]h ep ten es a s Or a lly Active, High ly Selective Cyclooxygen a se-2
In h ibitor s: Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s
Horng-Chih Huang,*,† J ames J . Li,† Danny J . Garland,† Timothy S. Chamberlain,† Emily J . Reinhard,†
Robert E. Manning,† Karen Seibert,‡ Carol M. Koboldt,‡ Susan A. Gregory,‡ Gary D. Anderson,‡
Amy W. Veenhuizen,‡ Yan Zhang,‡ William E. Perkins,‡ Earl G. Burton,§ J . Nita Cogburn,§
Peter C. Isakson,‡ and David B. Reitz†
Searle Research and Development, 700 North Chesterfield Parkway, St. Louis, Missouri 63198
Received September 7, 1995X
A novel series of 5,6-diarylspiro[2.4]hept-5-enes was shown to provide highly potent and selective
cyclooxygenase-2 (COX-2) inhibitors. A study of structure-activity relationships in this series
suggests that 3,4-disubstituted phenyl analogs are generally more selective than 4-substituted
phenyl analogs and that replacement of the methyl sulfone group on the 6-phenyl ring with a
sulfonamide moiety results in compounds with superior in vivo pharmacological properties,
although with lower COX-2 selectivity. Several compounds have been shown to possess
promising pharmacological properties in adjuvant-induced arthritis and edema analgesia
models. The absence of gastrointestinal (GI) toxicity at 200 mpk of several selected compounds
in rats and mice corresponds well with the weak potency for inhibition of COX-1 observed in
the enzyme assay. Methyl sulfone 55 and sulfonamide 24 were shown to have superior in
vivo pharmacological profiles, low GI toxicity, and good oral bioavailability and duration of
action.
In tr od u ction
whereas the inducible COX-2 isoform mediates inflam-
matory prostaglandin production.13-18 Selective inhibi-
tion of COX-2 thus offers an attractive target for the
design of antiinflammatory agents that avoid the GI
toxicity seen with current nonselective NSAIDs.
Our laboratories have reported the discovery of
several novel classes of potent and selective COX-2
inhibitors, e.g., the methyl sulfones 1 (SC-57666) and 2
(SC-58231) (Figure 1).19-21 Recently we communicated
our preliminary findings on 5,6-diarylspiro[2.4]hept-5-
enes.22 In this paper we report in detail on our study
of this series of orally active, potent, and selective COX-2
inhibitors.
Nonsteroidal antiinflammatory drugs (NSAIDs) such
as aspirin possess antiinflammatory, analgesic, and
antipyretic activities and have been widely used to treat
chronic inflammatory conditions such as arthritis.1 The
most common side effects associated with all currently
available NSAIDs are sometimes life-threatening gas-
trointestinal (GI) hemorrhage and ulceration.1,2 De-
creased renal function in some patients has also been
observed.3,4 Because of these problems, the pharma-
ceutical industry has been pursuing opportunities to
develop drugs that possess antiinflammatory activity
without the toxic side effects associated with known
NSAIDs.
Ch em istr y
In the early 1970s, it was reported that NSAIDs
prevent the production of prostaglandins (PGs) by
inhibiting the enzyme cyclooxygenase (COX), which
catalyzes the conversion of arachidonic acid to prosta-
glandin H2 (PGH2).5,6 For many years it was believed
that COX was a single enzyme (COX-1) constitutively
expressed in tissues such as gut and kidney. Recently,
a previously unknown, inducible isozyme associated
with inflammation was also identified (COX-2).7-10
Two structurally distinct experimental compounds
have been reported to inhibit PG production in inflam-
matory cells (DuP 697 and NS-398; see Figure 1).11,12
In contrast to other NSAIDs, these compounds do not
cause ulcers in the stomach or intestines of experimen-
tal animals at doses that exhibit antiinflammatory and
analgesic activities. It has since been reported that both
compounds are also selective COX-2 inhibitors.13-17
These observations support the hypothesis that the
constitutive COX-1 isozyme protects the GI tract,
Our initial goal in this study was to prepare the spiro-
[2.4]hept-5-ene 3 (Scheme 1), whose structure was
suggested by the good activity observed previously with
4,4-dimethylcyclopentene 2.19 As shown in Scheme 1,
one possible retrosynthetic disconnection of the cyclo-
propyl ring moiety in 3 leads to a diarylcyclopentenyl
diester (4). Further disconnection of the cyclopentene
ring (route A) gives a diaryldichlorobutene (5), which
in turn may be derived from the corresponding lactone.
Alternatively, disconnection of the double bond in the
cyclopentene ring of 4 (route B) leads to 6, a diketoma-
lonate which is readily accessible from the correspond-
ing bromoacetophenones and dimethyl malonate.
Since both synthetic routes required appropriately
substituted bromoacetophenones as starting materials,
several traditional methods (as illustrated in Scheme
2) were utilized to prepare the required bromoacetophe-
nones. The initial synthesis of diarylspiro[2.4]cyclo-
heptenes was accomplished according to route A of
Scheme 1, and is shown in Scheme 3. The preparation
of an early intermediate, the diaryl lactone 15, was
conveniently accomplished by the alkylation of 4-fluo-
rophenylacetic acid with bromide 10 and subsequent
ring closure of the resulting ester.23 DIBAL reduction
* To whom correspondence should be addressed.
† Department of Chemistry.
‡ Department of Inflammatory Diseases Research.
§ Department of Pharmacokinetics, Bioanalytical and Radiochem-
istry.
X Abstract published in Advance ACS Abstracts, December 15, 1995.
0022-2623/96/1839-0253$12.00/0 © 1996 American Chemical Society

254 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Huang et al.
F igu r e 1. Structures of some selective COX-2 inhibitors.
Sch em e 1
Sch em e 2a
a
Reagents: (a) CH3Li and then aqueous HCl (98%); (b) thionyl
chloride, reflux; (c) HN(OMe)Me (HCl salt), Et3N, CH2Cl2 (quan-
titative, steps b and c); (d) CH3MgBr (99%); (e) mCPBA (91%); (f)
Br2, HOAc (80-85%).
of lactone 15 in THF yielded diol 16, which was
converted to the corresponding dichloride 5 with thionyl
chloride in DMF. Cyclopentene ring formation was
achieved via double alkylation of dimethyl malonate
with dichloride 5 to give the key intermediate 4.24
Reduction of diester 4 with DIBAL yielded diol 17,
which was converted to ditosylate 18 and reductively
cyclized to give the target compound 3. Cyclopentadiene
analogs were also prepared by epoxidation of cyclopen-
tene 3 with mCPBA followed by AcOH-catalyzed epoxide
ring opening and subsequent dehydration to give cyclo-
pentadiene 19 (eq 1).
malonate 21 with an appropriate bromoacetophenone
(2-bromo-3′-chloro-4′-methoxyacetophenone (14) from
Scheme 2) gave the diketomalonate 22. McMurry
reductive cyclization (TiCl3 and Zn)25 of the diketone 22
yielded the key intermediate 23, which was carried
through a synthetic sequence similar to that shown in
Scheme 3 to give the spiro[2.4]cycloheptene 20.
Synthetic routes described above are not suitable for
the preparation of spiro[2.4]cycloheptene sulfonamides.
Thus, it appeared to us that the most effective access
to such compounds would be the direct conversion of
the existing methyl sulfones to the corresponding sul-
fonamides via a one-pot procedure recently developed
(eq 2).26 All of the sulfonamides reported in this paper
m
3
19
This initial synthesis of diarylspiro[2.4]cycloheptene
3 was lengthy and involved reduction of lactone 15 with
a large excess of DIBAL, which created serious problems
during aqueous workup of large-scale reactions. Fur-
thermore, our structure-activity relationship (SAR)
study was restricted by the limited commercial avail-
ability of substituted phenylacetic acids, one of the
starting materials in Scheme 3. An alternative syn-
thetic route (Scheme 1, route B) was therefore devel-
oped,20,22 which was utilized to prepare most of the
spiro[2.4]cycloheptene analogs reported in this paper.
The general procedure for the preparation of compounds
via this route is exemplified in Scheme 4 for the
synthesis of the 3-chloro-4-methoxyphenyl compound
20. The substituted bromoacetophenones needed for
this sequence were prepared according to Scheme 2.
Bromoacetophenone 10 was treated with dimethyl ma-
lonate and powdered K2CO3 in THF to give the ketoma-
lonate 21. Under similar conditions the treatment of
were prepared from the corresponding methyl sulfones
via this novel conversion. The general procedure for this
conversion is exemplified in eq 2 for the synthesis of
the 3-chloro-4-methoxyphenyl compound 24.
The construction of the cyclopentene ring of spiro[3.4]-
cyclooctene, spiro[4.4]cyclononene, and spiro[5.4]cyclo-
decene was again accomplished by McMurry coupling
of the corresponding diketo intermediates, as illustrated
in the synthesis of the spiro[2.4]cycloheptene analog 25
(Scheme 5). The starting exo-enone 26 was prepared
according to a published method by the condensation
of silyl enol ether 27 with the appropriate cyclic ketone

Diarylspiro[2.4]heptenes as COX-2 Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 255
Sch em e 3a
a
Reagents: (a) 10, Et3N, CH3CN (68%) and then TsOH, Et3N, molecular sieves, CH3CN, reflux (94%); (b) DIBAL, THF (quantitative);
(c) thionyl chloride, DMF; (d) dimethyl malonate, LiH, DMF (34% for steps c and d); (e) DIBAL, THF; (f) TsCl, pyridine (66% for steps e
and f); (g) NaI, Zn, DMF, 150 °C (85%).
Sch em e 4a
a
Reagents: (a) dimethyl malonate, K2CO3, KI, THF (63%); (b) 14, K2CO3, KI, THF (73%); (c) TiCl3, Zn, DME, reflux (50%).
(cyclobutanone in this example).27 The enone 26 was
then treated with titanium chloride and the silyl enol
ether of (4-methylthio)acetophenone (8) to give a dike-
tone methyl sulfide, which was oxidized to the sulfone
28.28 McMurry coupling of the diketone 28 gave the
desired spirocyclobutyl cyclopentene 25.
model.31,32 Compounds that expressed good oral anti-
inflammatory activity in this acute model were then
tested more extensively in vivo using the chronic
adjuvant-induced arthritis model and carrageenan-
induced hyperalgesia assay. Compounds showing the
most favorable in vivo pharmacological properties were
referred to more extensive GI toxicity assays and
pharmacokinetic studies.
Biology
All compounds were screened by assessing the selec-
tivity of the inhibitors toward human COX-2 and COX-
1.29,30 Compounds with sufficient potency and selectiv-
ity for COX-2 were advanced for assessment of oral
activity in the rat carrageenan-induced foot-pad edema
Resu lts a n d Discu ssion
In Vitr o a n d P r im a r y in Vivo Scr een in g Assa ys.
We theorized that the limited bioavailability (11%) and
relatively short duration of action (1.6 h in rats) of

256 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Huang et al.
Sch em e 5a
a
Reagents: (a) cyclobutanone, TiCl4, CH2Cl2 (98%) and then (CF3CO)2O, 4-DMAP, Et3N, CH2Cl2 (65%); (b) silyl enol ether of 8, TiCl4,
CH2Cl2 (81%); (c) mCPBA (97%); (d) TiCl3, Zn, DME, reflux (76%).
Ta ble 1. Comparison of Spiro[2.4]hept-5-ene 3 and
Cyclopentene 1
Ta ble 2. Comparison of Spiro[2.4]hept-5-enes A and
Spiro[2.4]hepta-4,6-dienes B
IC50, µM
oral bioavailability,b
half-life,b
no.a COX-2
COX-1
(po, 10 mpk, 24 h)
h (iv, 10 mpk)
1
3
0.026
0.008
>1000
11
58
1.6 h
2.3 h
5.4
a
All new compounds were identified by spectroscopic data and
b
confirmed by elemental analysis. For details, see the Experi-
mental Section.
IC50,b µM
selectivityc
ratio
no.a class
R
COX-2 COX-1
cyclopentene 1 may be due to the metabolic oxidation
of the potentially labile allylic methylene groups in the
cyclopentene ring (Table 1). It occurred to us that
substituents introduced at the 4-position of the cyclo-
pentene ring might exert sufficient steric hindrance to
shield the allylic methylene position from enzymatic
oxidation and thus slow down potential metabolic
degradation of the cyclopentene ring. Hence, 4,4-
dimethylcyclopentene 2 (Figure 1) and spiro[2.4]cyclo-
heptene 3 (Table 1) were chosen as our initial targets.
Although dimethylcyclopentene 2 was a potent and
selective COX-2 inhibitor (IC50 ) 15 nM and 18.3 µM
against COX-2 and COX-1, respectivley),19 it was less
active than cyclopentene 1 in adjuvant-induced arthritis
model (51% inhibtion and 75% inhibition at 10 mpk,
respectively). We therefore turned our attention to the
spiro[2.4]cycloheptene 3. As compared to 1, the potency
of spiro[2.4]cycloheptene 3 for inhibition of COX-2 was
enhanced 3-fold (IC50 ) 8 nM), while the potency for
inhibition of COX-1 was increased almost 200-fold (IC50
) 5.4 µM). This compound is nevertheless a very
selective COX-2 inhibitor with a selectivity ratio (IC50-
(COX-1/COX-2)) of 760. More importantly, as shown in
Table 1, inhibitor 3 has dramatically improved oral
bioavailability (58%) and a somewhat longer duration
of action (2.3 h in rats). Notwithstanding these im-
provements, it was essential for us to explore in depth
the structural changes leading to the observed enhance-
ment of COX-1 activity.
We hypothesized that the introduction of a spirocy-
clopropyl moiety into the cyclopentene ring had rigidi-
fied the central ring and restricted its conformational
mobility sufficiently to cause a dramatic enhancement
in COX-1 activity. On the basis of this assumption, one
might expect the spiral cyclopentadiene analogs to be
even less selective enzymatically than the corresponding
spiral cyclopentenes, due to still greater ring strain and
reduced flexibility. On the other hand, increasing the
size of the spiro ring should relieve ring strain in the
central cyclopentene ring and thus allow for greater
conformational mobility, consequently yielding a more
selective compound. These expectations were in fact
borne out by further experimentation. As shown in
3
19
20
29
A
B
A
B
4-fluoro
4-fluoro
3-chloro-4-methoxy 0.017
3-chloro-4-methoxy 0.027
0.0075
0.026
5.4
1.32
720
51
5880
125
>100
3.38
a
All new compounds were identified by spectroscopic data and
b
confirmed by elemental analysis. For details, see the Experi-
mental Section. c Selectivity ratio ) IC50(COX-1)/IC50(COX-2).
Ta ble 3. Ring Size Effect of the Spiro[2.4]hept-5-ene
IC50,b µM
carrageenan edemab,c
(po, 30 mpk, % inhibitn)
no.a
n
COX-2
COX-1
3
25
30
31
0
1
2
3
0.008
0.004
0.062
>100
5.4
>100
>100
>100
49
23
10
a
All new compounds were identified by spectroscopic data and
b
confirmed by elemental analysis. For details, see the Experi-
mental Section. c Rat carrageenan foot-pad edema test, oral dosing.
Table 2, cyclopentadiene 19 was less active toward the
COX-2 enzyme than 3 and also less selective, with IC50
values of 26 nM against COX-2 and 1.32 µM against
COX-1. This trend was even more pronounced in the
3-chloro-4-methoxy analogs 20 and 29. The introduction
of the additional double bond decreased the selectivity
ratio of cyclopentene 20 from 6000 to 125 for cyclopen-
tadiene 29. In vitro data of inhibitors with increased
ring sizes also supported our hypothesis (Table 3). The
spirocyclobutyl cyclopentene 25 showed greater COX-2
activity and was more selective for COX-2 than the
three-membered ring analog 3, displaying IC50 values
of 3.5 nM and >100 µM against COX-2 and COX-1,
respectively (Table 3). However, as the ring size was
increased further, the COX-2 activity diminished rapidly
(62 nM for spirocyclopentyl 30 and >100 µM for spiro-
cyclohexyl 31). Unfortunately, in vivo inhibition of
carrageenan-induced edema by the cyclobutyl compound

Diarylspiro[2.4]heptenes as COX-2 Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 257
Ta ble 4. Biological Properties of Some Selected Spiro[2.4]hept-5-enes
IC50,b µM
carrageenan edema,b,c
no.a
X
R
COX-2
COX-1
(30 mpk, % inhibitn)
3
32
33
34
35
36
37
38
39
40
41
42
43
20
24
44
45
46
47
48
49
50
51
52
53
54
55
56
4-fluoro
4-fluoro
CH3
NH2
CH3
NH2
CH3
CH3
NH2
CH3
NH2
CH3
NH2
CH3
NH2
CH3
NH2
CH3
NH2
CH3
CH3
NH2
CH3
NH2
CH3
NH2
CH3
CH3
CH3
NH2
0.008
0.003
0.001
0.001
0.0015
0.005
0.001
0.135
0.130
0.002
0.001
0.010
0.002
0.017
0.002
0.013
0.002
0.0025
0.0033
0.003
0.003
0.001
0.007
0.0015
0.022
0.033
0.006
0.004
5.4
0.33
3.1
0.14
4.04
0.57
0.005
49
60
4-chloro
4-chloro
4-methyl
4-methoxy
4-methoxy
4-trifluoromethoxy
4-trifluoromethoxy
4-trifluoromethyl
4-trifluoromethyl
3-fluoro-4-methoxy
3-fluoro-4-methoxy
3-chloro-4-methoxy
3-chloro-4-methoxy
3-bromo-4-methoxy
3-bromo-4-methoxy
3,4-methylenedioxy
3,4-difluoro
3,4-difluoro
3,4-dichloro
3,4-dichloro
3-chloro-4-fluoro
3-chloro-4-fluoro
2,4-difluoro
2,4-dichloro
3,5-dichloro-4-methoxy
3,5-dichloro-4-methoxy
0
>100
1.8
>100
0.5
>100
0.48
>100
2.8
20
35
46
30
40
42
47
21
>100
0.4
1.4
41
23
18
23
47
38
>100
0.92
>100
0.38
6.01
0.31
0.74
>100
>100
16.4
44
a
b
All new compounds were identified by spectroscopic data and confirmed by elemental analysis. For details, see the Experimental
Section. c Rat carrageenan foot-pad edema test, oral dosing.
25 was not as favorable as for the cyclopropyl compound
3 (23% and 49% inhibition at 30 mpk, respectively). We
therefore decided to retain the spiro[2.4]cycloheptene
moiety in all further compounds and focused our atten-
tion on the preparation of sulfonamide analogs.
have in fact conducted an extensive SAR using various
substituents to replace the 4′-fluoro group on the
5-phenyl ring, which has allowed us to identify com-
pounds with improved in vivo properties and greater
selectivity (Table 4).
In contrast to our previous observations,19 the sul-
fonamides in this series generally showed superior in
vivo pharmacological properties as compared with the
corresponding methyl sulfones. However, sulfonamides
also showed less selectivity for inhibition of the COX-2
enzyme (Table 4). For example, after the replacement
of the sulfone group in 3 with a sulfonamide moiety,
We initially focused our attention on the 4′-monosub-
stituted phenyl analogs. Replacing the 4′-fluoro sub-
stituent in compound 3 (IC50(COX-2/COX-1) ) 8 nM/
5.4 µM) with 4′-chloro, 4′-methyl, or 4′-methoxy groups
afforded inhibitors (33, 35, and 36) with greater potency
for inhibition of COX-2 (IC50 ) 1, 2, and 5 nM,
respectively). While the COX-1 activity did not change
significantly for the 4′-chloro and 4′-methyl compounds
(IC50 ) 3.1 and 4.04 µM for 33 and 35, respectively),
the COX-1 activity of the 4′-methoxy analog 36 was
enhanced quite dramatically (IC50 ) 0.57 µM). How-
ever, replacement of the 4′-methoxy substituent by a
4′-trifluoromethoxy group provided a selective inhibitor
(38) with weaker COX-2 potency (135 nM/>100 µM for
COX-2/COX-1). It was postulated that the electron-
donating character of a methoxy group might have
enhanced the COX-1 activity in the case of the 4′-
methoxy analog 36. Such electron-donating potential
should be reduced in compound 38 by the electron-
withdrawing character of the trifluoromethyl group. To
test this hypothesis, we prepared an analog with a
strongly electron-withdrawing substituent but without
a resonance-donating moiety. The 4′-trifluoromethyl
compound 40, which displayed IC50 values of 2 nM for
the COX-1 activity of 32 was increased 16-fold (IC50
)
0.33 µM), whereas the COX-2 activity was increased
only 3-fold (IC50 ) 3 nM). The selectivity ratio (IC50-
(COX-1/COX-2)) thus decreased from about 700 for 3
to only 100 for 32. In the acute carrageenan-induced
edema model, the sulfonamide 32 demonstrated better
oral antiinflammatory activity than did the methyl
sulfone 3 (60% inhibition vs 49% inhibition at 30 mpk,
respectively). Since in vivo activity depends on highly
complex physiological interactions, such activity is often
difficult to alter by rational synthesis. Selectivity, on
the other hand, is more likely to depend on well-defined
structural features amenable to optimization via a SAR
study. We therefore decided to retain the benzene-
sulfonamide moiety to improve in vivo pharmacological
properties and instead varied the 4′-fluorophenyl group
in order to obtain a higher degree of selectivity. We

258 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Huang et al.
Ta ble 5. In Vivo Pharmacological Properties of Selected Spirocyclopropyl Cyclopentenes
IC50, µM
AAb,c
% inhib/mpk
analgb,d
no.a
X
R
COX-2
COX-1
ED50, mpk
0.52
ED50, mpk
32.7
% inhib/mpk
55
42
20
24
3
41
50
43
32
3,5-dichloro-4-methoxy
3-fluoro-4-methoxy
3-chloro-4-methoxy
3-chloro-4-methoxy
4-fluoro
4-trifluoromethyl
3,4-dichloro
3-fluoro-4-methoxy
4-fluoro
CH3
CH3
CH3
NH2
CH3
NH2
NH2
NH2
NH2
0.006
0.010
0.017
0.002
0.008
0.001
0.001
0.002
0.003
>100
>100
>100
2.8
57/1
63/2
12/2
79/1
68/1
92/2
72/0.3
89/1
85/1
50/30
19/30
45/30
47/30
31/30
40/30
47/30
38/30
34/10
27.7
35.4
0.21
0.3
0.04
5.4
0.45
0.38
0.48
0.33
46.7
31.3
40.8
17.6
0.08
0.24
a
b
All new compounds were identified by spectroscopic data and confirmed by elemental analysis. Oral dosing. c Rat adjuvant arthritis
d
test. For details, see the Experimental Section. Rat carrageenan-induced analgesia test. For details, see the Experimental Section.
COX-2 and >100 µM for COX-1, was indeed a very
selective and active COX-2 inhibitor. Unfortunately, it
was a weak inhibitor of carrageenan-induced edema
(35% inhibition at 30 mpk). Some of the 4′-substituted
5-phenyl compounds in this series were converted to
sulfonamides. The increase in COX-1 activity of these
compounds ranged from 20-fold (4′-chloro analog 34) to
200-fold (4′-trifluoromethyl analog 41). The least selec-
tive 4′-methoxy-5-phenyl compound 37 showed high
potencies for both COX-1 and COX-2 (1 and 5 nM,
respectively). The most selective sulfonamide in this
series was the trifluoromethyl compound 41, displaying
a selectivity ratio (IC50(COX-1/COX-2)) of 500. This
compound also showed improved in vivo activity over
the corresponding sulfone 40 (46% inhibition in the
edema assay). Of the compounds prepared in this
study, the highly active compounds 3, 32, and 41 were
selected for further pharmacological studies (vide infra).
We next directed our attention to the preparation of
disubstituted phenyl analogs. While the 4′-methoxy-5-
phenyl compound 36 (the methyl sulfone) has high
potency for COX-1(IC50 ) 0.57 µM), the 3′-halo-4′-
methoxyphenyl sulfone compounds 42, 20, and 44 were
surprisingly selective for COX-2 (with IC50 values of 10,
17, and 13 nM for COX-2 and >100 µM for COX-1,
respectively). As previously suggested in rationalizing
the selectivity of the (trifluoromethoxy)phenyl analog
38, the electron-withdrawing 3′-halo moieties in these
compounds are likely to have balanced the electron-
donating potential of the methoxy group, thus yielding
selective COX-2 inhibitors. On the other hand, replace-
ment of the 3′-halo moiety with another oxygen should
not improve selectivity. The dioxymethylene analog 46
thus showed an IC50 value of 1.2 µM for COX-1.
However, the unique selectivity33 of the 3′-chloro-4′-
methoxyphenyl analog sulfonamide 24 (vide infra),
when compared with the corresponding 3′-fluoro and 3′-
bromo compounds 43 and 45, respectively, suggests that
the selectivity for COX-2 cannot be attributed solely to
the electronic effect of various substituents. The 3′-
bromo-4′-methoxyphenyl compound 44 demonstrated
poor in vivo activity (21% inhibition of acute edema at
30 mpk), and this compound was not pursued any
further. Both 3-fluoro-4-methoxyphenyl and 3′-chloro-
4′-methoxyphenyl analogs 42 and 20 displayed accept-
able inhibition in carrageenan edema assay (30% and
42%, respectively). The sulfonamides of these com-
pounds were also prepared to improve their in vivo
properties. However, COX-1 activities of the sulfona-
mides were again lowered to the sub-micromolar range
for fluoro and bromo analogs 43 and 45 (IC50 ) 0.48
and 0.4 µM, respectively). The 3′-chloro-4′-methoxy
compound 24 was still quite selective (selectivity ratio
) 1400), even though it had an IC50 of 2.8 µM against
COX-1. On the basis of this study, compounds 42, 43,
20, and 24 were chosen for further biological evaluation
(vide infra).
Several 3′,4′-dihalophenyl analogs (47-52) were also
prepared as both the methyl sulfones and the corre-
sponding sulfonamides. All the 3,4-dihalo compounds
(methyl sulfones 47, 49, and 51) were potent inhibitors
of COX-2 and either inactive or weakly active toward
COX-1. As with other analogs, the methyl sulfones
displayed weak in vivo activity, while the corresponding
sulfonamides showed high COX-1 activity. The 2′,4′-
dihalophenyl compounds 53 and 54 did not possess
favorable properties either. Among these, only the
dichlorophenyl analog 50 was chosen for further evalu-
ation. As an extension of this study, 3′,4′,5′-trisubsti-
tuted 5-phenyl compounds were also prepared. Among
these, the 3′,5′-dichloro-4′-methoxyphenyl compound 55
(COX-2 IC50 ) 6 nM, COX-1 IC50 > 100 µM) demon-
strated good oral activity in the edema assay (44% at
30 mpk). The corresponding sulfonamide 55 was also
very selective (4 nM and 16 µM for COX-2 and COX-1,
respectively). The sulfone 55 was selected for further
study on the basis of its significantly higher selectivity
ratio.
Secon d a r y in Vivo P h a r m a cologica l Stu d ies. A
number of COX-2 inhibitors prepared in this study were
advanced to secondary in vivo pharmacological studies
(Table 5). All of these analogs were potent and selective
COX-2 inhibitors that displayed good oral antiinflam-
matory activity in the acute edema assay. Table 5
summarizes the properties of these compounds, listed
in order of their selectivity toward COX-2. As expected,
the most selective inhibitors were the methyl sulfones.
The dichloromethoxyphenyl analog 55 was the most

Diarylspiro[2.4]heptenes as COX-2 Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 259
F igu r e 3. Plasma concentration of 55 after iv and oral
administration to the male rat. Compound 55 was adminis-
tered at 10 mpk in PEG-400:H2O, 2:1. The plasma half-life
was 9.2 h, and oral bioavailability was 58%.
F igu r e 2. Plasma concentration of 24 after iv and oral
administration to the male rat. Compound 24 was adminis-
tered at 10 mpk in PEG-400:H2O, 2:1. The plasma half-life
was 4 h, and oral bioavailability was 56%.
Ta ble 6. Gastric and Intestinal Toxicity Studies of Compounds
24 and 55
selective compound, with acceptable antiinflammatory
activity in the adjuvant-induced arthritis assay (ED50
) 0.52 mpk), and 55 was also more active than the
4-fluorophenyl analog 3 in the hyperalgesia assay. The
3′-fluoro- and 3′-chloro-4′-methoxyphenyl compounds 42
and 20 were potent and selective COX-2 inhibitors,
although each had shortcomings when assayed in vivo.
While the 3′-fluoro-4′-methoxyphenyl compound 42
showed weak analgesic activity (19% inhibition at 30
mpk), the 3′-chloro-4′-methoxyphenyl compound 20 was
only weakly active in the arthritis assay (12% inhibtion
at 2 mpk).
gastricb
dose,a
mpk (ig)
intestinalb
(rat)
no.
mouse
rat
24
24
55
55
20
200
20
1/10c
2/10c
0/10
0/6
0/6
0/6
0/6
0/6
0/6
not done
not done
200
1/10c
a
For experimental details, see ref 20. b Number of animals with
damage/number of animals treated. c Not signicant, compared with
the control group of animals.
With these observations in hand, we turned to the
sulfonamides in a search for improved in vivo properties.
The only sulfonamide having excellent COX-2 selectivity
(1400-fold) was the 3′-chloro-4′-methoxyphenyl analog
24. This compound was very potent in the adjuvant-
induced arthritis assay with an ED50 of 0.21 mpk, and
it also possessed good analgesic activity (ED50 ) 35.4
mpk). The 4′-(trifluoromethyl)phenyl analog 41 was the
most potent sulfonamide compound in the adjuvant-
induced arthritis assay (ED50 ) 0.04 mpk), although it
was only weakly active in the hyperalgesia assay, with
an ED50 of 46.7 mpk. The 3′-fluoro-4′-methoxyphenyl
analog 43 was another compound that was very potent
in the arthritis model (ED50 ) 0.08 mpk) but weakly
active in the hyperalgesia assay (ED50 ) 40.8 mpk). The
4-fluorophenyl compound 32 displayed good potency in
the adjuvant-induced arthritis assay (ED50 ) 0.24 mpk)
and also had the best analgesic activity (ED50 ) 17.6
mpk) from among all synthesized compounds in this
series; however, this compound displayed some acute
GI toxicity in mice at high doses (200 mpk).
P h a r m a cok in etics a n d Ga str oin testin a l Toxicity
Stu d ies. Because of their high selectivity for COX-2,
and superior in vivo pharmacological properties in the
secondary in vivo screening assays, compounds 55 and
24 were advanced further to the pharmacokinetics and
GI toxicity studies. As shown in Figures 2 and 3, the
peak plasma concentrations (Cmax) following a 10 mpk
oral solution dose to the rat were 1.0 µg/mL for 24 and
0.81 µg/mL for 55 and were reached at 1.0 and 2.0 h
(Tmax), respectively. Systemic availability of 24 and 55
following oral solution dose to the rat (10 mpk) was 56%
and 58%, respectively. Plasma elimination half-lives of
24 and 55 in the rat were 4.0 and 9.2 h, respectively.
With these promising pharmacokinetic data in hand,
we turned our attention to establishing a safety profile.
The compounds were evaluated in the acute gastric and
intestinal toxicity studies (Table 6). Both compounds
caused no lesions in the rat gastric study and no
significant damage in the mouse gastric toxicity assay
at oral doses up to 200 mpk. Compound 24 also caused
no intestinal damage in rats at a dose of 200 mpk. Our
studies have thus succeeded in identifying two com-
pounds which possess excellent antiinflammatory activ-
ity without the toxic effects associated with current
NSAIDs.
Con clu sion
We have designed and synthesized novel, highly
potent 5,6-diarylspiro[2.4]hept-5-enes as selective COX-2
inhibitors. Our SAR studies in this series suggest that
3′,4′-disubstituted phenyl analogs are generally more
selective than 4′-monosubstituted phenyl analogs. Fur-
thermore, replacement of the methyl sulfone group with
a sulfonamide moiety affords compounds with improved
in vivo pharmacological properties, although with lower
COX-2 selectivity. Several compounds have been shown
to possess promising pharmacological properties in
adjuvant-induced arthritis and edema analgesia models.
The absence of GI toxicity at 200 mpk of several selected
compounds in rats and mice corresponds well with the
weak potency for inhibition of COX-1 observed in the
enzyme assay. Methyl sulfone 55 and sulfonamide 2434
were shown to have superior in vivo pharmacological
profiles, low GI toxicity, and good oral bioavailability
and duration of action.
Exp er im en ta l Section
Unless otherwise stated, reactions were carried out under
nitrogen and in commercial grade solvents. Solvents were

260 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Huang et al.
evaporated on a Bu¨chi rotary evaporator at reduced pressure,
unless stated otherwise. Silica gel chromatography was
performed on either medium pressure liquid chromatography
(MPLC) or preparative high-performance liquid chromatog-
raphy (Waters Associates, Prep-500A or LC-2000), eluted with
EtOAc and hexane. All new compounds were fully character-
ized, and structures were assigned spectrally and confirmed
by elemental analysis. Purity of final products were checked
by elemental analyses, and the data are within (0.4% of the
theoretical values. Melting points were determined without
correction on a Thomas Hoover Unimelt apparatus. NMR
spectra were obtained on a Varian VXR-300 spectrometer at
300 MHz. Abbreviations used in NMR analyses are as
follows: s ) singlet, d ) doublet, t ) triplet, q ) quartet, m )
multiplet, br ) broad, dd ) doublet of doublets. High-
resolution mass spectra (HRMS) were obtained on a Finnigan
MAT 90 or VG model 250T spectrometer with FAB or EI
ionization. Elemental analyses were obtained from Galbraith
Laboratories, Inc.
P h a r m a cok in etics a n d Meta bolism Stu d y. Compounds
were administered to male Sprague-Dawley rats by tail vein
injection or gavage, with 4 animals/group. Multiple blood
samples were collected from each rat by retroorbital bleeding
into heparinized tubes. Bond Elut C-18 solid phase extraction
columns (Varian, 100 mg/1 mL) were activated with CH3CN,
methanol, and water. Columns were loaded with samples,
rinsed with water, rinsed with CH3CN:water (35:65), and
eluted with CH3CN. Acetonitrile extracts were concentrated
under nitrogen and resuspended in mobile phase. Acetonitrile
extracts were analyzed on a Beckman System Gold HPLC
system which included UV and radioisotope detectors. C-18
columns (Waters Novapak, 3.9 × 150 mm) were eluted
isocratically with 55:45 CH3CN:8.3 mM phosphate buffer, pH
7.2 (Sigma P-3288), at 1.0 mL/min, with UV monitoring at 232
nm. Terminal phase elimination half-life was calculated from
plasma concentration versus time data using the CSTRIP
computer program.36
Ch em istr y. Most of the compounds were prepared using
one of the three general procedure sequences described below.
Gen er a l P r oced u r e I (Rou te B). Preparation of diaryl-
spiro[2.4]cycloheptenes is illustrated below in the synthesis
of 5-(3′-chloro-4′-methoxyphenyl)-6-[4′-(methylsulfonyl)phenyl]-
spiro[2.4]hept-5-ene (20).
Step 1: 4-(Meth ylth io)a cetop h en on e (8). To a stirred
solution of 98.93 g (0.63 mol) of 4-(methylthio)benzonitrile in
1.2 L of THF under nitrogen at -78 °C was added 568 mL
(0.795 mol) of methyllithium (1.4 M in ethyl ether). The
resulting dark red solution was warmed to room temperature
and stirred for another 2.5 h. The reaction was slowly
quenched with 400 mL of 3 N HCl, and the resulting mixture
was stirred overnight at room temperature. The mixture was
concentrated to about 500 mL, diluted with EtOAc, and
washed with saturated Na2CO3 and brine. The extract was
dried (MgSO4) and concentrated to give 108.5 g (98.5%) of
desired acetophenone as a yellow solid: 1H NMR (CDCl3) δ
2.52 (s, 3H), 2.56 (s, 3H), 7.28 (d, J ) 8.6 Hz, 2H), 7.86 (d, J
) 8.6 Hz, 2H).
Step 2: 4-(Meth ylsu lfon yl)a cetop h en on e (9). To a
solution of 108.5 g (0.653 mol) of acetophenone 8 in 3 L of CH2-
Cl2 at 0 °C was added in portions 414 g (68%, 1.63 mol) of
mCPBA over a period of 1 h. The mixture was stirred at room
temperature overnight. To the cooled, white suspension was
added a solution of 124 g (0.653 mol) of sodium m-bisulfite in
300 mL of water, and the mixture was stirred at room
temperature for 1 h and then filtered. The filtrate was
concentrated to about 1 L and repeatedly washed carefully
with saturated NaHCO3 to remove 3-chlorobenzoic acid. The
extract was dried (MgSO4) and concentrated to give 117.33 g
(91%) of the desired product as a bright yellow solid: 1H NMR
(CDCl3) δ 2.67 (s, 3H), 3.08 (s, 3H), 8.05 (d, J ) 8.5 Hz, 2H),
8.14 (d, J ) 8.5 Hz, 2H).
Step 3: 2-Br om o-4′-(m eth ylsu lfon yl)acetoph en on e (10).
To a stirred solution of 11.91 g (60.5 mmol) of 4-(methylsul-
fonyl)acetophenone (9) in 133 mL of glacial AcOH and 0.11
mL of hydrochloric acid at ambient temperature was added a
solution of 8.22 g (51.4 mmol) of bromine in 9.3 mL of glacial
AcOH over a period of 3 h. The reaction mixture was diluted
with 500 mL of water and extracted with chloroform. The
combined extracts were dried (MgSO4) and concentrated to
give 15.7 g of crude bromoacetophenone 10 as a solid: 1H NMR
(CDCl3) δ 3.10 (s, 3H), 4.45 (s, 2H), 8.08 (d, J ) 9.0 Hz, 2H),
8.17 (d, J ) 9.0 Hz, 2H).
Step 4: 3′-Ch lor o-4′-m eth oxya cetop h en on e (13). To a
solution of 132.5 g (0.71 mol) of 3-chloro-4-methoxybenzoic acid
in 514 mL (7.05 mol) of thionyl chloride was added in portions
2.5 mL of DMF, and the resulting solution was stirred under
reflux for 4 h. The mixture was concentrated and dissolved
in 600 mL of CH2Cl2. To the resulting solution was added 83.1
g (0.85 mol) of N,O-dimethylhydroxyamine (HCl salt), and the
mixture was cooled to 0 °C. To the suspension was added
slowly 198 mL (1.4 mL) of triethylamine, and the mixture was
stirred at room temperature overnight. The resulting solution
was washed twice with 1 N KHSO4, NaHCO3, and brine. The
extract was dried (MgSO4) and concentrated to give 163.2 g
(quantitative) of desired benzamide 12 as a light brown oil:
Biology. P r ep a r a tion of COX-1 a n d COX-2 En zym es
a n d Bin d in g Assa y (IC50). Experimental details have been
published earlier.29,30
Ra t Ca r r a geen a n F oot-P a d Ed em a Test.1,31 The carra-
geenan foot edema test was performed with materials, re-
agents, and procedures essentially as described by Winter.32
Male Sprague-Dawley rats were selected in each group so that
the average body weight was as close as possible. Rats were
fasted with free access to water for over 16 h prior to the test.
The rats were dosed orally (1 mL) with compounds suspended
in vehicle (0.5% methyl cellulose and 0.025% Tween-20) or with
vehicle alone. One hour later a subplantar injection of 0.1 mL
of a 1% solution of carrageenan/sterile 0.9% saline was
administered. The volume of the injected foot was measured
with a displacement plethysmometer connected to a pressure
transducer with a digital indicator. Three hours after the
injection of the carrageenan, the volume of the foot was again
measured. The average foot swelling in a group of drug-
treated animals was compared with that of a group of placebo-
treated animals, and the percent inhibition of edema was
determined.
Ra t Ad ju va n t Ar th r itis Assa y.35 Arthritis was induced
in male Lewis rats (125-150 g; Harlan Sprague-Dawley,
Indianapolis, IN) by injection of 1 mg of Mycobacterium
butyricum (Difco Laboratories, Detroit, MI) in 50 uL of mineral
oil (Mallinkrodt, Paris, KY) into the right hind foot pad.
Fourteen days after injection of adjuvant, the contralateral left
foot-pad volume was measured with a water displacement
plethysmometer. Animals with paw volumes 0.37 mL greater
than normal paws were then randomized into treatment
groups. Compounds were prepared as a suspension in 0.5%
methyl cellulose (Sigma) and 0.025% Tween-20 (Sigma). Drug
administration was begun on day 15 postadjuvant injection
and continued until final assessment on day 25. Animals were
dosed twice daily by gavage at the indicated dosages in a
volume of 1.0 mL/day. During this period contralateral paw
volume measurements were taken intermittently. The typical
increase in contralateral paw volume measured on day 25
ranged from 1.4 to 1.9 mL.
R a t Ca r r a geen a n -In d u ced An a lgesia Test .31 Male
Sprague-Dawley rats were treated as previously described for
the Rat Carrageenan Foot-Pad Edema Test. Three hours after
the injection of carrageenan, the rats were placed in a special
Plexiglass container with a transparent floor having a high-
intensity lamp as a radiant heat source, positionable under
the floor. After an initial 20 min period, thermal stimulation
was begun on either the injected foot or the contralateral
uninjected foot. A photoelectric cell turned off the lamp and
timer when light was interrupted by paw withdrawal. The
time to withdrawal of the injected paw was then measured.
The withdrawal latency in seconds was determined for the
control and drug-treated groups, and percent inhibition of the
stimulus-induced decrease in withdrawal latency was deter-
mined.
Ga str ic a n d In testin a l Da m a ge Stu d y. The experimen-
tal details have been disclosed previously.31

Diarylspiro[2.4]heptenes as COX-2 Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 261
1H NMR (CDCl3) δ 3.35 (s, 3H), 3.56 (s, 3H), 3.94 (s, 3H), 6.93
(d, J ) 8.7 Hz, 1H), 7.68 (dd, J ) 2.2, 8.7 Hz, 1H), 7.82 (d, J
) 2.1 Hz, 1H).
resulting solution was stirred at -78 °C for 15 min and then
at room temperature overnight. The reaction was carefully
quenched sequentially with 15 mL of acetone, 30 mL of water
(caution: exothermic), and 90 mL of 10% NaOH. The aqueous
layer was extracted with EtOAc, and the combined extracts
were washed with saturated NaHCO3, 1 N HCl, water, and
brine. The extract was dried (MgSO4) and concentrated to give
11.8 g (quantitative) of crude diol as a colorless oil which was
used directly in next step: 1H NMR (CDCl3) δ 2.35 (s, 2H),
2.78 (d, J ) 10.5 Hz, 4H), 3.04 (s, 3H), 3.83 (s, 4H), 3.87 (s,
3H), 6.76 (d, J ) 8.7 Hz, 1H), 6.95 (dd, J ) 2.2, 8.7 Hz, 1H),
7.18 (d, J ) 2.1 Hz, 1H), 7.34 (d, J ) 1.8, 6.8 Hz, 2H), 7.77
(dd, J ) 1.8, 6.6 Hz, 2H).
To a solution of 11.8 g (26.8 mmol) of crude diarylcyclopen-
tenyl diol (obtained from above) in 92 mL of pyridine under
nitrogen at 0 °C was added 23 g (120 mmol) of p-toluenesul-
fonyl chloride in portions (exothermic), and the resulting dark
solution was stirred at room temperature overnight. The
mixture was concentrated to remove the pyridine, and the
residue was dissolved in EtOAc. The solution was washed
with water, 1 N HCl, NaHCO3, and brine. The extract was
dried (MgSO4), concentrated, and chromatographed to give
11.6 g (59% from diester) of ditosylate as a tan solid: 1H NMR
(CDCl3) δ 2.46 (s, 6H), 2.70 (d, J ) 15.1 Hz, 4H), 3.04 (s, 3H),
3.88 (s, 3H), 4.03 (s, 4H), 6.74 (d, J ) 8.7 Hz, 1H), 6.85 (dd, J
) 2.2, 8.7 Hz, 1H), 7.00 (d, J ) 2.0 Hz, 1H), 7.19 -7.25 (m,
2H), 7.35 (d, J ) 8.1 Hz, 4H), 7.7-7.82 (m, 6H). The ditosylate
was used in the next step to prepare the final product 20.
Under nitrogen, a solution of 11.6 g (15.9 mmol) of diaryl-
cyclopentenyl ditosylate in 260 mL of DMF was treated with
34.7 g (231 mmol) of NaI and 17.2 g (263 mmol) of zinc dust.
The resulting mixture was stirred at 150 °C for 3 h and
concentrated. The residue was dissolved in EtOAc, and the
solid was filtered off. The filtrate was washed with sodium
sulfite, water, and brine and then dried (MgSO4) and concen-
trated. The residue was chromatographed on silica gel to give
5.32 g (86%) of pale yellow solid, which was recrystallized to
give 2.32 g of the desired product 20 as a white solid: mp
140.0-140.5 °C; 1H NMR (CDCl3) δ 0.68 (s, 4H), 2.84-2.95
(m, 4H), 3.04 (s, 3H), 3.88 (s, 3H), 6.76 (d, J ) 8.5 Hz, 1H),
6.95 (dd, J ) 2.0, 8.5 Hz, 1H), 7.18 (d, J ) 2.0 Hz, 1H), 7.35
(dd, J ) 1.6, 6.7 Hz, 2H), 7.77 (dd, J ) 1.8, 6.6 Hz, 2H); HRMS
(EI) calcd for C21H21ClO3S 388.0900, found 388.0909. Anal.
(C21H21ClO3S) C, H, S.
To a stirred solution of 64.7 g (0.28 mol) of the resulting
benzamide 12 in 1 L of THF under nitrogen at -78 °C was
added 110 mL (3 M in ethyl ether, 0.3 mol) of methylmagne-
sium bromide. The resulting solution was warmed to room
temperature and stirred for another 3 h. The reaction was
slowly quenched with 3 N HCl and the mixture diluted with
EtOAc and washed with saturated NaHCO3 and brine. The
extract was dried (MgSO4) and concentrated to give 51.7 g
(99%) of the desired product 13 as an off-white solid: 1H NMR
(CDCl3) δ 2.55 (s, 3H), 3.97 (s, 3H), 6.96 (d, J ) 8.5 Hz, 1H),
7.86 (dd, J ) 2.2, 8.7 Hz, 1H), 7.98 (d, J ) 2.2 Hz, 1H).
St ep 5: 2-Br om o-3′-ch lor o-4′-m et h oxya cet op h en on e
(14). To a solution of 51.7 g (0.28 mol) of acetophenone 13 in
103 mL of glacial AcOH was added 1 mL of concentrated HCl.
To the resulting solution was added dropwise a solution of 14.5
mL (0.28 mol) of bromine in 20 mL of glacial AcOH over a
period of about 1.5 h, and the resulting dark solution was
stirred at room temperature for 2 h. The precipitate was
collected by filtration and washed with water. More solid was
collected from the filtrate. The combined solid was dried to
give 65 g (88%) of the desired product as a yellow solid: 1H
NMR (CDCl3) δ 3.99 (s, 3H), 4.37 (s, 2H), 6.99 (d, J ) 8.7 Hz,
1H), 7.91 (dd, J ) 2.4, 8.7 Hz, 1H), 8.03 (d, J ) 2.2 Hz, 1H).
Step 6: Dim eth yl 2-[2-[4-(Meth ylsu lfon yl)p h en yl]-2-
oxoeth yl]p r op a n ed ioa te (21). Under nitrogen, 161.8 g (87%
pure, 0.508 mol) of 2-bromoacetophenone 10 was added to a
suspension of 133.44 g (1.01 mol) of dimethyl malonate, 350.5
g (2.54 mol) of K2CO3 (powder; Aldrich), and 38.1 g (0.254 mol)
of KI in 450 mL of THF, and the resulting suspension was
stirred at room temperature for 6 h (exothermic, temperature
reached 40 °C in 30 min). The mixture was filtered and
concentrated, and the residue was recrystallized from EtOAc.
The mother liquor was concentrated and purified by silica gel
chromatography (Prep-500, Waters), eluting with 15% of
EtOAc in CH2Cl2, to give a total of 100 g (63.3%) of dimethyl
ketomalonate 21 as a white solid: 1H NMR (CDCl3) δ 3.07 (s,
3H), 3.64 (d, J ) 7.05 Hz, 2H), 3.78 (s, 6H), 4.09 (t, J ) 7.04
Hz, 1H), 8.05 (d, J ) 8.7 Hz, 2H), 8.15 (d, J ) 8.7 Hz, 2H).
Step 7: Dim eth yl 2-[2-(3-Ch lor o-4-m eth oxyp h en yl)-2-
oxoeth yl]-2-[2-[4-(m eth ylsu lfon yl)ph en yl]-2-oxoeth yl]pr o-
p a n ed ioa te (22). Under nitrogen, to a stirred suspension of
24 g (0.077 mol) of dimethyl ketomalonate 21, 42 g (0.3 mol)
of K2CO3 (powder; Aldrich), and 6 g (0.04 mol) of potassium
iodide in 85 mL of THF was added 30 g (0.114 mol) of
2-bromoacetophenone 14 in three portions over a 24 h period.
The mixture was filtered through a silica gel plug, eluted with
50% of EtOAc in hexane, and concentrated. The residue was
purified by silica gel chromatography (Prep-500, Waters),
eluting with 33% of EtOAc in hexane, to give 27.8 g (73%) of
dimethyl diketomalonate as a white solid. The material was
used directly in step 8 without further characterization.
Step 8: 1-[2-(3-Ch lor o-4-m eth oxyp h en yl)-4,4-d ica r bo-
m eth oxycyclopen ten -1-yl]-4-(m eth ylsu lfon yl)ben zen e (23).
To a vigorously stirred suspension of 38.4 g (0.249 mol) of
titanium(III) chloride in 400 mL of DME under nitrogen was
added 14 g (0.214 mol) of zinc dust (Aldrich), and the resulting
mixture was stirred under reflux for 1 h. To the dark solution
at reflux was added 27.8 g (0.054 mol) of dimethyl diketoma-
lonate 22, and the resulting mixture was stirred under reflux
for 1 h. The mixture was filtered, concentrated, diluted with
EtOAc, washed with water, saturated NaHCO3, and brine, and
then dried (MgSO4) and concentrated. The residue was
purified by silica gel chromatography to give 13 g (50%) of
diarylcyclopentenyl diester as a pale yellow solid: 1H NMR
(CDCl3) δ 3.04 (s, 3H), 3.5-3.6 (m, 4H), 3.80 (s, 6H), 3.88 (s,
3H), 6.77 (d, J ) 8.7 Hz, 1H), 6.95 (dd, J ) 2.2, 8.7 Hz, 1H),
7.19 (d, J ) 2.0 Hz, 1H), 7.35 (dd, J ) 1.8, 6.9 Hz, 2H), 7.79
(dd, J ) 1.8, 6.8 Hz, 2H).
The mother liquor from the recrystallization described above
was concentrated to give 3.0 g of pale yellow solid which was
used directly in the preparation of compound 24 using general
procedure II.
Gen er a l P r oced u r e II. Using a published procedure26 the
methylsulfonyl group in most of the compounds was converted
to a sulfonamidyl group as illustrated in the synthesis of
benzenesulfonamide 24.
4-[6-(3-Ch lor o-4-m eth oxyp h en yl)sp ir o[2.4]h ep t-5-en -5-
yl]ben zen esu lfon a m id e (24). Under nitrogen, a solution of
3.6 g (9.26 mmol) of 20 in 10 mL of THF at 0 °C was treated
with 6.3 mL (10.08 mmol) of propylmagnesium chloride (1.6
M in ether). The reaction mixture was stirred at ambient
temperature for 25 min, cooled to 0 °C, and treated with 16.5
mL (1.0 M in THF, 16.5 mmol) of tributylborane (or trieth-
ylborane). The resulting solution was stirred at ambient
temperature for 15 min and then at reflux for 18 h prior to
the addition of 7 g (85 mmol) of NaOAc, 18 mL of water, and
4 g (35 mmol) of hydroxylamine-O-sulfonic acid at 0 °C. The
resulting light orange mixture was stirred at ambient tem-
perature for 3.5 h, and the resulting aqueous phase was
extracted with EtOAc. The combined extracts were washed
with water and brine and then dried (MgSO4) and concen-
trated. The residue was chromatographed on silica gel to give
2.5 g (59%) of the desired product 24 as a white solid: mp
191.0-192.0 °C; 1H NMR (CDCl3) δ 0.63 (s, 4H), 2.84 (s, 4H),
3.83 (s, 3H), 5.74 (br s, 2H), 6.72 (d, J ) 8.5 Hz, 1H), 6.92 (dd,
J ) 2.0, 8.5 Hz, 1H), 7.15 (d, J ) 2.2 Hz, 1H), 7.24 (dd, J )
2.0, 6.9 Hz, 2H), 7.72 (dd, J ) 1.8, 6.7 Hz, 2H); HRMS (EI)
calcd for C20H20ClNO3S 389.0852, found 389.0869. Anal.
(C20H20ClNO3S‚0.05CH2Cl2) C, H, N, S.
Step 9: 5-(3-Ch lor o-4-m eth oxyp h en yl)-6-[4-(m eth ylsu l-
fon yl)p h en yl]sp ir o[2.4]h ep t-5-en e (20). To a solution of 13
g (27.2 mmol) of cyclopentenyl diester 23 in 200 mL of THF
under nitrogen at -78 °C was added 100 mL (150 mmol) of
DIBAL (1.5 M in toluene) over a period of 30 min. The

262 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Huang et al.
Gen er a l P r oced u r e III. Preparation of other spirocy-
cloalkyl diarylcyclopentenes (25, 30, and 31) is illustrated
below in the synthesis of diaryl spirocyclobutyl cyclopentene
25.
7.08 (t, J ) 8.0 Hz, 2H), 7.23 (t, J ) 8.0 Hz, 2H), 7.84 (d, J )
9.0 Hz, 2H), 7.91-7.99 (m, 2H).
Step 3: 6-(4-Flu or oph en yl)-7-[4-(m eth ylsu lfon yl)ph en yl]-
sp ir o[3.4]oct-6-en e (25). A solution of 18.3 g (51.4 mmol) of
methyl sulfide 28 in 200 mL of chloroform at 10 °C was slowly
treated with 35.6 g (ca. 103 mmol) of solid mCPBA (50-60%).
The reaction mixture was allowed to stir for 30 min and
treated with aqueous sodium bisulfite. The chloroform was
removed and the residue partitioned between EtOAc and
water. The EtOAc extract was washed three times with
saturated Na2CO3 and once with brine, dried (MgSO4), and
concentrated to give 19.27 g (97%) of the crude diketone
product as an oil: 1H NMR (CDCl3) δ 1.95-2.06 (m, 2H), 2.11
(t, J ) 7.0 Hz, 4H), 3.05 (s, 3H), 3.52 (s, 2H), 3.59 (s, 2H), 7.09
(t, J ) 9.0 Hz, 2H), 7.92-8.04 (m, 4H), 8.19 (d, J ) 9.0 Hz,
2H).
Step 1: 1-(4-Flu or oph en yl)-2-(cyclobu t-1-yliden e)eth an -
1-on e (26). Under nitrogen, 17.7 g (128 mmol) of 4-fluoroac-
etophenone (Aldrich) and 20.7 mL (192 mmol) of triethylamine
at ambient temperature were treated with 24.4 mL (192.3
mmol) of chlorotrimethylsilane and allowed to stir for 20 min
prior to the slow addition of a suspension of 30 g (200 mmol)
of NaI in 200 mL of CH3CN. The reaction mixture was stirred
for 3 h, poured into ice/water, and extracted with hexane. The
extracts were combined, dried (K2CO3), and concentrated to
give 27 g of the crude enol ether as an oil: 1H NMR (CDCl3)
δ 0.28 (s, 9H), 4.41 (d, J ) 2.0 Hz, 1H), 4.84 (d, J ) 2.0 Hz,
1H), 7.00 (d, J ) 8.0 Hz, 2H), 7.53-7.60 (m, 2H).
Under nitrogen, 11.0 g (100 mmol) of TiCl4 in 140 mL of
CH2Cl2 at 0 °C was slowly treated with a solution of 8.2 mL
(110 mmol) of cyclobutanone in 30 mL of CH2Cl2 prior to the
dropwise addition of a solution of 21.1 g (100 mmol) of the enol
ether obtained from above in 15 mL of CH2Cl2. The reaction
mixture was stirred for 15 min and then poured into 200 mL
of ice/water; the phases were separated. The aqueous phase
was extracted twice with 30 mL of CH2Cl2 and combined with
the original CH2Cl2 phase. The combined extracts were
washed three times with 120 mL of aqueous Na2CO3 and once
with brine. The extract was dried (MgSO4) and concentrated
to give 20.4 g (98%) of the crude alcohol as an oil: 1H NMR
(CDCl3) δ 1.53-1.70 (m, 1H), 1.80-1.94 (m, 1H), 1.99-2.10
(m, 2H), 2.17-2.31 (m, 2H), 3.31 (s, 2H), 7.10-7.19 (m, 2H),
7.95-8.03 (m, 2H).
Under nitrogen, 20.3 g (98 mmol) of the alcohol obtained
from above, 37 mL (260 mmol) of triethylamine, and 50 mg of
4-(dimethylamino)pyridine (DMAP) in 80 mL of CH2Cl2 at 0
°C was slowly treated with a solution of 16.6 mL (118 mmol)
of trifluoroacetic anhydride (TFAA) in 40 mL of CH2Cl2. The
reaction mixture was allowed to stir for 3 h at 0 °C and then
allowed to warm to ambient temperature to stir for an
additional 3 h prior to the addition of 200 mL of saturated
NaHCO3:water (1:1) and 300 mL of ether. The phases were
separated, and the aqueous phase was extracted twice with
100 mL of ether. The ether extracts were combined with the
original ether/CH2Cl2 phase, washed with brine, dried (Mg-
SO4), and concentrated. Purification by silica gel chromatog-
raphy (Waters Prep-500A) with EtOAc:hexane (2:98) gave 12.1
g (65%) of the desired enone 26 as an oil: 1H NMR (CDCl3) δ
2.11-2.24 (m, 2H), 2.95 (t, J ) 8.0 Hz, 2H), 3.19-3.29 (m, 2H),
2.68-2.74 (m, 1H), 7.05-7.16 (m, 2H), 7.84-7.97 (m, 2H).
Step 2: 1-(4-Flu or oph en yl)-2-[1-[2-[4-(m eth ylth io)ph en -
yl]-2-oxoeth yl]cyclobu t-1-yl]eth a n -1-on e (28). Under ni-
trogen, 11.0 g (66.2 mmol) of 4-(methylthio)acetophenone (8)
(from general procedure I, step 1) and 13.8 mL (99 mmol) of
triethylamine in 50 mL of CH3CN were treated with 12.6 mL
(99.3 mmol) of chlorotrimethylsilane at ambient temperature
and allowed to stir for 20 min prior to the slow addition of a
suspension of 14.9 g (99.4 mmol) of NaI in 60 mL of CH3CN.
The reaction mixture was stirred for 3 h, poured into ice/water,
and extracted with hexane. The extracts were combined, dried
(K2CO3), and concentrated to give 16 g of the crude enol ether
as an oil: 1H NMR (CDCl3) δ 0.26 (s, 9H), 2.48 (s, 3H), 4.39
(d, J ) 2.0 Hz, 1H), 4.87 (d, J ) 2.0 Hz, 1H), 7.20 (d, J ) 8.0
Hz, 2H), 7.50 (d, J ) 8.0 Hz, 2H).
Under nitrogen, 16.3 mL (149 mmol) of TiCl4 was slowly
added to a suspension of 19.5 g (298 mmol) of zinc dust in 500
mL of anhydrous THF at -78 °C. The resulting mixture was
allowed to warm to ambient temperature and then to stir at
reflux for 45 min. The reaction mixture was cooled to ambient
temperature prior to the addition of 19.27 g (49.6 mmol) of
neat diketone (obtained from above) by syringe. The reaction
mixture was allowed to stir at ambient temperature overnight,
filtered through Celite, and concentrated. The residue was
partitioned between EtOAc and water; the EtOAc phase was
washed with brine, dried (MgSO4), and concentrated. Purifi-
cation by silica gel chromatography (Waters Prep-500A) with
EtOAc:hexane (20:80) gave 13.5 g (76%) of the desired product
1
25 as a colorless solid: mp 123-124 °C; H NMR (CDCl3) δ
1.85-1.98 (m, 2H), 2.08 (t, J ) 7.0 Hz, 4H), 2.98 (s, 4H), 3.04
(s, 3H), 6.92 (t, J ) 9.0 Hz), 7.05-7.13 (m, 2H), 7.30 (t, J ) 8
Hz, 2H), 7.75 (t, J ) 8.0 Hz, 2H); MS (FAB) m/e 357 (M + H).
Anal. (C21H21FO2S) C, H, F, S.
P r ep a r a t ion of 5-(4-F lu or op h en yl)-6-[4-(m et h ylsu l-
fon yl)p h en yl]sp ir o[2.4]h ep t-5-en e (3) (Rou te A). Step
1: 3-(4-F lu or op h en yl)-4-[4-(m eth ylsu lfon yl)p h en yl]-5H-
fu r a n -2-on e (15). To a stirred solution of 4.45 g (28.9 mmol)
of 4-fluorophenylacetic acid (Aldrich) in 3.26 g (31.8 mmol) of
triethylamine and 275 mL of CH3CN was added 8.9 g (28.9
mmol) of 2-bromo-4′-(methylsulfonyl)acetophenone (10) (from
general procedure I, step 3) at ambient temperature. The
reaction mixture was stirred for 30 min, concentrated, and
partitioned between EtOAc and water. The organic phase was
dried (MgSO4) and concentrated. Purification by silica gel
chromatography with EtOAc:hexane (1:1) gave 6.87 g (68%)
of the desired ester as a colorless solid: 1H NMR (CDCl3) δ
3.08 (s, 3H), 3.79 (s, 2H), 5.35 (s, 2H), 7.06 (s, t, J ) 9.0 Hz,
2H), 7.32 (dd, J ) 6.0, 9.0 Hz, 2H), 8.06 (s, 4H).
Under nitrogen, 4.10 g (11.7 mmol) of the ester obtained
from above, 6.52 mL (46.8 mmol) of triethylamine, 4.89 g (25.7
mmol) of p-toluenesulfonic acid, and 12 g of 4 Å molecular
sieves were added to 117 mL of CH3CN and stirred at reflux
for 16 h. The reaction mixture was concentrated and the
residue partitioned between dichloromethane and water. The
CH2Cl2 layer was dried (MgSO4) and concentrated. Recrys-
tallization from hexane:EtOAc (2:1) gave 3.65 g (94%) of the
desired product 15 as a solid: mp 166-167 °C; 1H NMR
(CDCl3) δ 3.08 (s, 3H), 5.19 (s, 2H), 7.10 (t, J ) 9.0 Hz, 2H),
7.42 (dd, J ) 6, 9.0 Hz, 2H), 7.52 (d, J ) 9.0 Hz, 2H), 7.97 (d,
J ) 9.0 Hz, 2H); HRMS calcd for C17H13FO4S 332.0519, found
332.0501. Anal. (C17H13FO4S) C, H, O.
Under nitrogen, 7.2 mL (70.2 mmol) of TiCl4 in 100 mL of
CH2Cl2 at -78 °C was slowly treated with a solution of 12.1 g
(63.8 mmol) of enone 26 in 30 mL of CH2Cl2 followed by the
addition of a solution of silyl enol ether obtained from above
in 40 mL of CH2Cl2. The reaction mixture was stirred at -78
°C for 1 h, poured into a solution of 22 g of NaHCO3 in 160
mL of water, and filtered through Celite. The phases were
separated, and the aqueous phase was extracted twice with
40 mL of CH2Cl2. The extracts were combined with the
original CH2Cl2 phase, washed with brine, dried (MgSO4), and
concentrated. Purification by silica gel chromatography (Wa-
ters Prep-500A) with EtOAc:hexane (10:90) gave the desired
product 28 as an oil: 1H NMR (CDCl3) δ 1.91-2.04 (m, 2H),
2.11 (t, J ) 8.0 Hz, 4H), 2.49 (s, 3H), 3.48 (s, 2H), 3.49 (s, 2H),
Step 2: 2-(4-F lu or op h en yl)-3-[4-(m eth ylsu lfon yl)p h en -
yl]-1,4-d ih yd r oxy-2-bu ten e (16). To a solution of 3.08 g
(9.28 mmol) of furanone 15 in 93 mL of THF at -78 °C under
an atmosphere of nitrogen was added 20 mL (30 mmol) of
diisobutylaluminum hydride (DIBAL) (1.5 M in THF) over 10
min. The solution was stirred at -78 °C for 20 min, allowed
to warm to ambient temperature, and stirred overnight. An
additional 15 mL (22 mmol) aliquot of DIBAL was added, and
stirring was continued for 2 h. The reaction mixture was
cooled to -78 °C, treated dropwise with 25 mL of acetone,
warmed to room temperature, and slowly treated with 25 mL
of water. The mixture was stirred for 30 min prior to the
careful addition of 35 mL of 1.2 N NaOH. The mixture was
extracted with EtOAc, washed with 1 N HCl followed by brine,

Diarylspiro[2.4]heptenes as COX-2 Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 263
1
dried (MgSO4), and concentrated to give 3.8 g of the crude
desired diol 16 as a colorless oil: 1H NMR (CDCl3) δ 2.98 (s,
3H), 4.60 (d, J ) 6.0 Hz, 4H), 6.80 (t, J ) 9.0 Hz, 2H), 6.94-
7.02 (m, 2H), 7.22 (d, J ) 9.0 Hz, 2H), 7.65 (d, J ) 9.0 Hz,
2H).
Step 3: 2-(4-F lu or op h en yl)-3-[4-(m eth ylsu lfon yl)p h en -
yl]-1,4-d ich lor o-2-bu ten e (5). To a solution of 3.5 g (7.62
mmol) of crude 16 in 58 mL of DMF at 5 °C under an
atmosphere of nitrogen was added dropwise 1.52 mL (20.84
mmol) of thionyl chloride. The reaction mixture was stirred
at 5 °C for 22 h and at ambient temperature for an additional
8 h and then concentrated. The residue was partitioned
between EtOAc and water; the EtOAc phase was dried
(MgSO4) and concentrated to give the crude desired product
as a solid: 1H NMR (CDCl3) δ 3.00 (s, 3H), 4.55 (d, J ) 3.4
Hz, 4H), 6.86 (t, J ) 9.0 Hz, 2H), 6.75 (d, J ) 8.3 Hz, 2H),
7.45 (d, J ) 9.0 Hz, 2H).
Step 4: 1-[2-(4-F lu or op h en yl)-4,4-d ica r bom eth oxycy-
clop en ten -1-yl]-4-(m eth ylsu lfon yl)ben zen e (4). To a solu-
tion of 1.2 mL (10.5 mmol) of dimethyl malonate in 10 mL of
DMF under an atmosphere of nitrogen was added 215 mg (26.9
mmol) of lithium hydride in portions. The resulting suspen-
sion was stirred at ambient temperature for 20 min prior to
the addition of a solution of crude dichloride 5 in 10 mL of
DMF. The reaction mixture was stirred at ambient temper-
ature for 15 h, treated with another 150 mg (18.8 mmol) of
lithium hydride, and stirred for another 4 h. The mixture was
concentrated and partitioned between EtOAc and water; the
organic phase was dried (MgSO4) and concentrated. The
residue was chromatographed on silica gel to give 1.1 g (34%)
of the desired diester 4 as an oil: 1H NMR (CDCl3) δ 3.03 (s,
3H), 3.55 (s, 4H), 3.79 (s, 6H), 6.93 (t, J ) 9.0 Hz, 2H), 7.11
(dd, J ) 6, 9.0 Hz, 2H), 7.32 (d, J ) 9.0 Hz, 2H), 7.77 (d, J )
9.0 Hz, 2H).
Step 5: 1-[2-(4-F lu or op h en yl)-4,4-bis(h yd r oxym eth yl)-
cyclop en ten -1-yl]-4-(m eth ylsu lfon yl)ben zen e (17). Fol-
lowing a procedure similar to step 9 of general procedure I,
diester 4 was reduced to alcohol 17 as a colorless oil: 1H NMR
(CDCl3) δ 2.82 (d, J ) 5.0 Hz, 4H), 3.04 (s, 3H), 3.86 (d, J )
5.0 Hz, 4H), 6.94 (t, J ) 9.0 Hz, 2H), 7.11 (dd, J ) 5, 9.0 Hz,
2H), 7.33 (d, J ) 9.0 Hz, 2H), 7.77 (d, J ) 9.0 Hz, 2H).
Step 6: 1-[2-(4-F lu or op h en yl)-4,4-bis(tosylm eth yl)cy-
clop en ten -1-yl]-4-(m eth ylsu lfon yl)ben zen e (18). Follow-
ing a procedure similar to step 9 of general procedure I, diol
17 was converted to ditosylate 18 as a colorless solid: 1H NMR
(CDCl3) δ 2.46 (s, 6H), 2.73 (s, 3H), 3.04 (s, 3H), 4.05 (s, 4H),
6.85-7.0 (m, 4H), 7.20 (d, J ) 8.0 Hz, 2H), 7.34 (d, J ) 8.0
Hz, 4H), 7.75 (d, J ) 8.0 Hz, 6H).
Step 7: 5-(4-Flu or oph en yl)-6-[4-(m eth ylsu lfon yl)ph en yl]-
sp ir o[2.4]h ep t-5-en e (2). Following a procedure similar to
step 9 of general procedure I, ditosylate 18 was reductively
cyclized to 3 as a colorless solid: mp 140.5-142.0 °C; 1H NMR
(CDCl3) δ 0.69 (s, 4H), 2.92 (s, 4H), 3.04 (s, 3H), 6.93 (t, J )
9.0 Hz, 2H), 7.10 (dd, J ) 5, 9.0 Hz, 2H), 7.32 (d, J ) 8.0 Hz,
2H), 7.76 (d, J ) 8.0 Hz, 2H); HRMS calcd for C20H19FO2S
342.1090, found 342.1126. Anal. (C20H19FO2S) C, H, F, S.
2-(4-F lu or op h en yl)-3-[4-(m eth ylsu lfon yl)p h en yl]sp ir o-
[4.4]n on -2-en e (30). Following a procedure similar to the one
described in general procedure III, with the substitution of
cyclopentanone for cyclobutanone, the desired product was
obtained as a colorless solid: mp 142-143 °C; 1H NMR (CDCl3)
δ 1.72 (s, 8H), 2.83 (s, 4H), 3.04 (s, 3H), 6.93 (t, J ) 9.0 Hz,
2H), 7.10 (dd, J ) 5, 9.0 Hz, 2H), 7.31 (d, J ) 9.0 Hz, 2H),
7.76 (d, J ) 9.0 Hz, 2H); HRMS calcd for C22H23FO2S 370.1403,
found 370.1411. Anal. (C22H23FO2S) C, H, F, S.
2-(4-F lu or op h en yl)-3-[4-(m eth ylsu lfon yl)p h en yl]sp ir o-
[4.5]d ec-2-en e (31). Following a procedure similar to the one
described in general procedure III, with the substitution of
cyclohexanone for cyclobutanone, the desired product was
obtained as a colorless glass: 1H NMR (CDCl3) δ 1.41-1.63
(m, 10H), 2.72 (s, 4H), 3.03 (s, 3H), 6.92 (t, J ) 8.7 Hz, 2H),
7.05-7.12 (m, 2H), 7.31 (d, J ) 8.4 Hz, 2H), 7.75 (d, J ) 8.7
Hz, 2H); HRMS calcd for C23H25FO2S‚Li 391.1719, found
391.1690. Anal. (C23H25FO2S‚0.08C6H8) C, H, F, S.
converted to 32 as a colorless solid: mp 131.0-133.0 °C; H
NMR (CDCl3) δ 0.68 (s, 4H), 2.90 (s, 3H), 4.81 (s, 2H), 6.92 (t,
J ) 9.0 Hz, 2H), 7.11 (dd, J ) 6, 9.0 Hz, 2H), 7.27 (d, J ) 9.0
Hz, 2H), 7.74 (d, J ) 9.0 Hz, 2H); HRMS calcd for C19H18
-
FNO2S 344.1121, found 344.1122. Anal. (C19H18FNO2S‚0.1CH3-
CO2CH2CH3) C, H, N, S.
5-(4-Ch lor op h en yl)-6-[4-(m eth ylsu lfon yl)p h en yl]sp ir o-
[2.4]h ep t-5-en e (33). Following a procedure similar to the
one described in general procedure I, with the substitution of
2-bromo-4′-chloroacetophenone (Aldrich) for 2-bromo-3′-chloro-
4′-methoxyacetophenone (general procedure I, step 7), the
desired product was prepared as a white solid: mp 143.0-
145.0 °C; 1H NMR (CDCl3) δ 0.69 (s, 4H), 2.92 (s, 4H), 3.05 (s,
3H), 7.07 (d, J ) 8.7 Hz, 2H), 7.21 (d, J ) 8.7 Hz, 2H), 7.33 (d,
J ) 8.4 Hz, 2H), 7.77 (dd, J ) 8.7 Hz, 2H); MS (FAB) m/e 365
(100, M + Li). Anal. (C20H19ClO2S) C, H, Cl, S.
4-[6-(4-Ch lor op h en yl)sp ir o[2.4]h ep t-5-en -5-yl]ben zen e-
su lfon a m id e (34). Following a procedure similar to the one
described in general procedure II, 7.5 g (20.9 mmol) of 33 was
converted to crude sulfonamide. Purification by silica gel
chromatography gave 2.82 g (37%) of the desired product as a
1
white solid: mp 152.5-153.5 °C; H NMR (CDCl3) δ 0.68 (s,
4H), 2.91 (s, 4H), 4.85-5.05 (br s, 2H), 7.07 (d, J ) 8.4 Hz,
2H), 7.20 (d, J ) 8.4 Hz, 2H), 7.27 (d, J ) 8.1 Hz, 2H), 7.75 (d,
J ) 8.4 Hz, 2H); HRMS (EI) calcd for C19H18ClNO2S 359.0747,
found 359.0747. Anal. (C19H18ClNO2S) C, H, Cl, N, S.
5-(4-Meth ylp h en yl)-6-[4-(m eth ylsu lfon yl)p h en yl]sp ir o-
[2.4]h ep t-5-en e (35). Following a procedure similar to the
one described in general procedure I, with the substitution of
2-bromo-4′-methylacetophenone (Aldrich) for 2-bromo-3′-chloro-
4′-methoxyacetophenone (general procedure I, step 7), the
desired product was prepared as a white solid: mp 146-148
1
°C; H NMR (CDCl3) δ 0.67 (s, 4H), 2.32 (s, 3H), 2.91 (s, 4H),
3.03 (s, 3H), 7.04 (s, 4H), 7.34 (d, J ) 8.7 Hz, 2H), 7.74 (d, J
) 8.7 Hz, 2H); HRMS (EI) calcd for C21H22O2S 338.1341, found
338.1323. Anal. (C21H22O2S) C, H, S.
5-(4-Meth oxyph en yl)-6-[4-(m eth ylsu lfon yl)ph en yl]spir o-
[2.4]h ep t-5-en e (36). Following a procedure similar to the
one described in general procedure I, with the substitution of
2-bromo-4′-methoxyacetophenone (Aldrich) for 2-bromo-3′-
chloro-4′-methoxyacetophenone (general procedure I, step 7),
the desired product was prepared as a white solid: mp 170.2-
173.0 °C; 1H NMR (CDCl3) δ 0.67 (s, 4H), 2.91 (s, 4H), 3.04 (s,
3H), 3.79 (s, 3H), 6.77 (d, J ) 8.9 Hz, 2H), 7.07 (d, J ) 8.9 Hz,
2H), 7.35 (d, J ) 8.5 Hz, 2H), 7.75 (d, J ) 8.7 Hz, 2H); HRMS
(EI) calcd for C21H22O3S 354.1290, found 354.1317. Anal.
(C21H22O3S) C, H, S.
4-[6-(4-Met h oxyp h en yl)sp ir o[2.4]h ep t -5-en -5-yl]b en -
zen esu lfon a m id e (37). Following a procedure similar to the
one described in general procedure II, 200 mg (0.564 mmol) of
36 was converted to crude sulfonamide. Purification by silica
gel chromatography gave 96 mg (48%) of the desired product
as a white solid: 1H NMR (CDCl3) δ 0.67 (s, 4H), 2.90 (s, 4H),
3.78 (s, 3H), 4.86 (br s, 2H), 6.76 (d, J ) 8.9 Hz, 2H), 7.08 (d,
J ) 8.9 Hz, 2H), 7.30 (d, J ) 8.5 Hz, 2H), 7.73 (d, J ) 8.5 Hz,
2H). HRMS (EI) calcd for C20H21NO3S 355.1242, found
355.1250. Anal. (C20H21NO3S‚0.6H2O) C, H, N.
5-[4-(Tr iflu or om eth oxy)p h en yl]-6-[4-(m eth ylsu lfon yl)-
p h en yl]sp ir o[2.4]h ep t -5-en e (38). Following a procedure
similar to the one described in general procedure I, with the
substitution of 4′-(trifluoromethoxy)acetophenone (Aldrich) for
3′-chloro-4′-methoxyacetophenone (general procedure I, step
5), the desired product was prepared as a white solid: mp
126.0-127.0 °C; 1H NMR (CDCl3) δ 0.69 (s, 4H), 2.93 (s, 4H),
3.05 (s, 3H), 7.08 (d, J ) 8.7 Hz, 2H), 7.16 (d, J ) 8.7 Hz, 2H),
7.33 (d, J ) 8.4 Hz, 2H), 7.78 (d, J ) 8.1 Hz, 2H); HRMS (EI)
calcd for C21H19F3O3S 408.1007, found 408.1017. Anal.
(C21H19F3O3S‚0.12H2O) C, H, F, S.
4-[6-[4-(Tr iflu or om eth oxy)p h en yl]sp ir o[2.4]h ep t-5-en -
5-yl]ben zen esu lfon a m id e (39). Following a procedure simi-
lar to the one described in general procedure II, 1.80 g (4.4
mmol) of 38 was converted to crude sulfonamide. Purification
by silica gel chromatography gave 0.73 g (40%) of the desired
product as a white solid: mp 144.0-145.0 °C; 1H NMR (CDCl3)
δ 0.69 (s, 4H), 2.92 (s, 4H), 4.78 (br s, 2H), 7.08 (d, J ) 8.9 Hz,
2H), 7.16 (d, J ) 9.0 Hz, 2H), 7.28 (d, J ) 8.7 Hz, 2H), 7.76 (d,
4-[6-(4-F lu or op h en yl)sp ir o[2.4]h ep t-5-en -5-yl]ben zen e-
su lfon a m id e (32). Following general procedure II, 3 was

264 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Huang et al.
J ) 8.7 Hz, 2H); HRMS (EI) calcd for C20H18F3NO3S 409.0960,
found 409.0974. Anal. (C20H18F3NO3S‚0.29C3H6O2) C, H, N,
F, S.
tion of methyllithium to piperonylonitrile (Aldrich), see general
procedure I, Step 1] for 3′-chloro-4′-methoxyacetophenone
(general procedure I, step 5), the desired product was prepared
as a white solid: mp 110.5-111.5 °C; 1H NMR (CDCl3) δ 0.67
(s, 4H), 2.89 (br d, J ) 2.4 Hz, 4H), 3.05 (s, 3H), 5.94 (s, 2H),
6.55-6.67 (m, 2H), 6.70 (d, J ) 8.1 Hz, 1H), 7.36 (d, J ) 8.5
Hz, 2H), 7.76 (d, J ) 8.5 Hz, 2H); HRMS (EI) calcd for
C21H20O4S 368.1082, found 368.1077. Anal. (C21H20O4S) C,
H, S.
5-(3,4-Diflu or op h en yl)-6-[4-(m et h ylsu lfon yl)p h en yl]-
sp ir o[2.4]h ep t-5-en e (47). Following a procedure similar to
the one described in general procedure I with the substitution
of 3′,4′-difluoroacetophenone (Aldrich) for 3′-chloro-4′-meth-
oxyacetophenone (general procedure I, step 5), the desired
product was obtained as a white solid: mp 113-114 °C; 1H
NMR (CDCl3) δ 0.69 (s, 4H), 2.90 (s, 2H), 2.92 (s, 2H), 3.06 (s,
3H), 6.80-6.87 (m, 1H), 6.91-7.07 (m, 2H), 7.33 (d, J ) 8.0
Hz, 2H), 7.79 (d, J ) 8.0 Hz, 2H); HRMS calcd for C20H18F2O2S
360.0996, found 360.1014. Anal. (C20H18F2O2S) C, H, N, F,
S.
5-[4-(Tr iflu or om et h yl)p h en yl]-6-[4-(m et h ylsu lfon yl)-
p h en yl]sp ir o[2.4]h ep t -5-en e (40). Following a procedure
similar to the one described in general procedure I, with the
substitution of 4-(trifluoromethyl)acetophenone [prepared by
the addition of methyllithium to R,R,R-trifluoro-p-tolunitrile
(Aldrich), see general procedure I, step 1] for 3′-chloro-4′-
methoxyacetophenone (general procedure I, step 5), the desired
product was prepared as a white solid: mp 170.0-170.8 °C;
1H NMR (CDCl3) δ 0.70 (s, 4H), 2.95 (s, 4H), 3.05 (s, 3H), 7.24
(d, J ) 8.4 Hz, 2H), 7.31 (d, J ) 8.3 Hz, 2H), 7.49 (d, J ) 8.1
Hz, 2H), 7.78 (d, J ) 8.2 Hz, 2H); HRMS (EI) calcd for
C21H19F3O2S 392.1058, found 392.1080. Anal. (C21H19F3O2S)
C, H, F, S.
4-[6-[4-(Tr iflu or om eth yl)p h en yl]sp ir o[2.4]h ep t-5-en -5-
yl]ben zen esu lfon a m id e (41). Following a procedure similar
to the one described in general procedure II, 1.81 g (4.6 mmol)
of 40 was converted to crude sulfonamide. Purification by
silica gel chromatography gave 1.20 g (66%) of the desired
product as a white solid: mp 157.2-188.8 °C; 1H NMR (CDCl3)
δ 0.70 (s, 4H), 2.94 (s, 4H), 4.80 (s, 2H), 7.21-7.30 (m, 4H),
7.48 (d, J ) 8.5 Hz, 2H), 7.77 (d, J ) 8.3 Hz, 2H); HRMS (EI)
calcd for C20H18F3NO2S 393.1010, found 393.1045. Anal.
(C20H18F3NO2S‚0.07CH2Cl2) C, H, N, S.
5-(3-F lu or o-4-m et h oxyp h en yl)-6-[4-(m et h ylsu lfon yl)-
p h en yl]sp ir o[2.4]h ep t -5-en e (42). Following a procedure
similar to the one described in general procedure I, with the
substitution of 3′-fluoro-4′-methoxyacetophenone (Aldrich) for
3′-chloro-4′-methoxyacetophenone (general procedure I, step
5), the desired product was prepared as a white solid: mp
110.5-111.5 °C; 1H NMR (CDCl3) δ 0.68 (s, 4H), 2.85-2.95
(m, 4H), 3.05 (s, 3H), 3.87 (s, 3H), 6.77-6.94 (m, 3H), 7.35 (d,
J ) 8.4 Hz, 2H), 7.78 (d, J ) 8.7 Hz, 2H); HRMS (EI) calcd for
C21H21FO3S 372.1192, found 372.1187. Anal. (C21H21FO3S)
C, H, F, S.
4-[6-(3-F lu or o-4-m eth oxyp h en yl)sp ir o[2.4]h ep t-5-en -5-
yl]ben zen esu lfon a m id e (43). Following a procedure similar
to the one described in general procedure II, 1.40 g (3.76 mmol)
of 42 was converted to crude sulfonamide. Purification by
silica gel chromatography gave 0.88 g (63%) of the desired
product as a white solid: mp 153.0-154.0 °C; 1H NMR (CDCl3)
δ 0.68 (s, 4H), 2.89 (s, 4H), 3.87 (s, 3H), 4.79 (s, 2H), 6.75-
6.93 (m, 3H), 7.31 (d, J ) 8.7 Hz, 2H), 7.77 (d, J ) 8.4 Hz,
2H); HRMS (EI) calcd for C20H20FNO3S 373.1148, found
373.1172. Anal. (C20H20FNO3S) C, H, F, N.
5-(3-Br om o-4-m et h oxyp h en yl)-6-[4-(m et h ylsu lfon yl)-
p h en yl]sp ir o[2.4]h ep t -5-en e (44). Following a procedure
similar to the one described in general procedure I, with the
substitution of 3′-bromo-4′-methoxyacetophenone [prepared by
the addition of methylmagnesium bromide to 3-bromo-4-
methoxybenzaldehyde (Aldrich) followed by MnO2 oxidation
of the resulting alcohol] for 3′-chloro-4′-methoxyacetophenone
(general procedure I, step 5), the desired product was prepared
as a white solid: mp 89.5-91.8 °C; 1H NMR (CDCl3) δ 0.68 (s,
4H), 2.85-2.93 (m, 4H), 3.04 (s, 3H), 3.87 (s, 3H), 6.73 (d, J )
8.7 Hz, 1H), 6.97 (dd, J ) 2.5, 7.5 Hz, 1H), 7.3-7.4 (m, 3H),
7.78 (d, J ) 8.5 Hz, 2H); HRMS (EI) calcd for C21H21BrO3S
432.0395, found 432.0375. Anal. (C21H21BrO3S‚0.64CH2Cl2)
C, H, Br.
4-[6-(3-Br om o-4-m eth oxyp h en yl)sp ir o[2.4]h ep t-5-en -5-
yl]ben zen esu lfon a m id e (45). Following a procedure similar
to the one described in general procedure II, 3 g (6.92 mmol)
of 44 was converted to crude sulfonamide. Purification by
silica gel chromatography gave 1.32 g (44%) of the desired
product as a white solid: mp 187.5-189.8 °C; 1H NMR (CDCl3)
δ 0.67 (s, 4H), 2.89 (s, 4H), 3.87 (s, 3H), 4.76 (br s, 2H), 6.73
(d, J ) 8.5 Hz, 1H), 7.0 (dd, J ) 2.1, 8.5 Hz, 1H), 7.30 (d, J )
8.7 Hz, 2H), 7.37 (dd, J ) 2.1 Hz, 1H), 7.76 (d, J ) 8.7 Hz,
2H); HRMS (EI) calcd for C20H20BrNO3S 433.0347, found
433.0310. Anal. (C20H20BrNO3S) C, H, N.
4-[6-(3,4-Diflu or op h en yl)sp ir o[2.4]h ep t-5-en -5-yl]ben -
zen esu lfon a m id e (48). Following a procedure similar to the
one described in general procedure II, 880 mg (2.44 mmol) of
47 was converted to crude sulfonamide. Purification by silica
gel chromatography (MPLC) with EtOAc:hexane (1:5) as the
eluent followed by recrystallization from CH2Cl2/hexane gave
370 mg (42%) of the desired product as a white solid: mp 136-
1
137 °C; H NMR (CDCl3) δ 0.68 (s, 4H), 2.89 (s, 2H), 2.90 (s,
2H), 4.79 (s, 2H), 6.81-6.87 (m, 1H), 6.91-7.06 (m, 2H), 7.28
(d, J ) 8.0 Hz, 2H), 7.78 (d, J ) 8.0 Hz, 2H); MS (FAB) m/z
362 (M + H); HRMS calcd for C19H17F2NO2S 361.0948, found
361.0952. Anal. (C19H17F2NO2S‚0.29CH2Cl2) C, H, N, F, S.
5-(3,4-Dich lor op h en yl)-6-[4-(m et h ylsu lfon yl)p h en yl]-
sp ir o[2.4]h ep t-5-en e (49). Following a procedure similar to
the one described in general procedure I, with the substitution
of 2-bromo-3′,4′-dichloroacetophenone (Lancaster) for 2-bromo-
3′-chloro-4′-methoxyacetophenone (general procedure I, step
7), the desired product was prepared as a white solid: mp
1
107.5-108.5 °C; H NMR (CDCl3) δ 0.69 (s, 4H), 2.91 (d, J )
3.0 Hz, 4H), 3.05 (s, 3H), 6.90 (dd, J ) 1.9, 8.7 Hz, 1H), 7.24
(d, J ) 2.1 Hz, 1H), 7.27 (d, J ) 8.7 Hz, 1H), 7.33 (d, J ) 8.4
Hz, 2H), 7.80 (d, J ) 8.4 Hz, 2H); MS (FAB) m/z 399 (100, M
+ Li). Anal. (C20H18Cl2O2S‚0.08C6H14) C, H, Cl, S.
4-[6-(3,4-Dich lor op h en yl)sp ir o[2.4]h ep t-5-en -5-yl]ben -
zen esu lfon a m id e (50). Following a procedure similar to the
one described in general procedure II, 5.20 g (13.2 mmol) of
49 was converted to crude sulfonamide. Purification by silica
gel chromatography gave 1.40 g (27%) of the desired product
as a white solid: mp 162.0-163.0 °C; 1H NMR (CDCl3) δ 0.69
(s, 4H), 2.90 (d, J ) 2.1 Hz, 4H), 4.77 (s, 2H), 6.92 (dd, J )
2.1, 8.4 Hz, 1H), 7.23-7.32 (m, 4H), 7.78 (d, J ) 8.7 Hz, 2H);
HRMS (EI) calcd for C19H17Cl2NO2S 393.0357, found 393.0354.
Anal. (C19H17Cl2NO2S‚0.035C6H14]) C, H, N, Cl, S.
5-(3-Ch lor o-4-flu or oph en yl)-6-[4-(m eth ylsu lfon yl)ph en -
yl]sp ir o[2.4]h ep t-5-en e (51). Following a procedure similar
to the one described in general procedure I, with the substitu-
tion of 3′-chloro-4′-fluoroacetophenone (Lancaster) for 3′-chloro-
4′-methoxyacetophenone (general procedure I, step 5), the
desired product was prepared as a white solid: mp 128.0-
130.0 °C; 1H NMR (CDCl3) δ 0.69 (s, 4H), 2.91 (d, J ) 3.6 Hz,
4H), 3.05 (s, 3H), 6.9-7.02 (m, 2H), 7.19 (d, J ) 7.5 Hz, 1H),
7.33 (d, J ) 8.4 Hz, 2H), 7.79 (d, J ) 8.7 Hz, 2H); HRMS (EI)
calcd for C20H18ClFO2S 376.0700, found 376.0710. Anal.
(C20H18ClFO2S) C, H, F, Cl, S.
4-[6-(3-Ch lor o-4-flu or op h en yl)sp ir o[2.4]h ept-5-en -5-yl]-
ben zen esu lfon a m id e (52). Following a procedure similar
to the one described in general procedure II, 1.0 g (2.65 mmol)
of 51 was converted to crude sulfonamide. Purification by
silica gel chromatography gave 0.19 g (19%) of the desired
product as a white solid: mp 163.0-165.0 °C; 1H NMR (CDCl3)
δ 0.69 (s, 4H), 2.90 (d, J ) 2.7 Hz, 4H), 4.75 (br s, 2H), 6.70-
7.05 (m, 2H), 7.18-7.24 (m, 1H), 7.24-7.32 (m, 3H), 7.78 (d,
5-[6-[4-(Met h ylsu lfon yl)p h en yl]sp ir o[2.4]h ep t -5-en -5-
yl]-1,3-ben zod ioxole (46). Following a procedure similar to
the one described in general procedure I, with the substitution
of 3′,4′-(methylenedioxy)acetophenone [prepared by the addi-
J
) 8.7 Hz, 2H); HRMS (EI) calcd for C19H17ClFNO2S
377.0652, found 377.0639. Anal. (C19H17ClFNO2S‚0.018CH2-
Cl2) C, H, N, F, Cl, S

Diarylspiro[2.4]heptenes as COX-2 Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 265
5-(2,4-Diflu or op h en yl)-6-[4-(m et h ylsu lfon yl)p h en yl]-
sp ir o[2.4]h ep t-5-en e (53). Following a procedure similar to
the one described in general procedure I, with the substitution
of 2-chloro-2′,4′-difluoroacetophenone (Aldrich) for 2-bromo-
3′-chloro-4′-methoxyacetophenone (general procedure I, step
7), the desired product was prepared as a white solid: mp
116.0-117.5 °C; 1H NMR (CDCl3) δ 0.69 (s, 4H), 2.89 (s, 2H),
2.94 (s, 2H), 3.03 (s, 3H), 6.78 (t, J ) 8.4 Hz, 2H), 7.05 (q, J )
6.6 Hz, 2H), 7.28 (d, J ) 8.1 Hz, 2H), 7.74 (dd, J ) 1.8, 6.9 Hz,
Ack n ow led gm en t. We thank Dr. Eugene W. Lo-
gusch for helpful discussions and suggestions.
Refer en ces
(1) Lombardino, G. Nonsteroidal Antiinflammatory Drugs; Wiley
Interscience, J ohn Wiley & Sons: New York, 1985.
(2) Allison, M. C.; Howatson, A. G.; Torrance, C. J .; Lee, F. D.;
Russell, R. I. G. Gastrointestinal Damage Associated with the
Use of Non-Steroidal Antiinflammatory Drugs. N. Engl. J . Med.
1992, 327, 749-754.
2H); HRMS (EI) calcd for
C20H18F2O2S 360.0996, found
(3) Clive, D. M.; Stoff, J . S. Renal Syndromes Associated with
Nonsteroidal Antiinflammatory Drugs. N. Engl. J . Med. 1984,
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360.1010. Anal. (C20H18F2O2S‚0.22H2O) C, H, S.
5-(2,4-Dich lor op h en yl)-6-[4-(m et h ylsu lfon yl)p h en yl]-
sp ir o[2.4]h ep t-5-en e (54). Following a procedure similar to
the one described in general procedure I, with the substitution
of 2,2′,4′-trichloroacetophenone (Aldrich) for 2-bromo-3′-chloro-
4′-methoxyacetophenone (general procedure I, step 7), the
desired product was prepared as a white solid: mp 90.0-91.5
(4) Pirson, Y.; Van Ypersele de Strihou, C. Renal Side Effects of
Nonsteroidal Anti-Inflammatory Drugs: Clinical Relevance. Am.
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(5) Vane, J . R. Inhibition of Prostaglandin Synthesis as a Mecha-
nism of Action for Aspirin-Like Drugs. Nature (New Biol.) 1971,
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(6) Smith, J . B.; Willis, A. L. Aspirin Selectively Inhibits Prosta-
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1
°C; H NMR (CDCl3) δ 0.69 (s, 4H), 2.85 (s, 2H), 2.95 (s, 2H),
3.01 (s, 3H), 7.02 (d, J ) 8.1 Hz, 1H), 7.16 (d, J ) 2.1 Hz, 1H),
7.20 (d, J ) 8.4 Hz, 2H), 7.42 (d, J ) 2.1 Hz, 1H), 7.72 (d, J )
8.7 Hz, 2H); HRMS (EI) calcd for C20H18Cl2O2S 392.0405, found
392.0423. Anal. (C20H18Cl2O2S‚0.36H2O‚0.05C6H14) C, H, Cl,
S.
(7) Hla, T.; Neilson, K. Human Cyclooxygenase-2 cDNA. Proc. Natl.
Acad. Sci. U.S.A. 1992, 89, 7384-7388.
(8) 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.
(9) Kujubu, D. A.; Fletcher, B. S.; Varnum, C.; Lim, R. W.;
Herschman, H. TIS10, a Phorbol Ester Tumor Promoter-Induc-
ible mRNA from Swiss 3T3 Cells, Encodes a Novel Prostaglandin
Synthase/Cyclooxygenase Homologue. J . Biol. Chem. 1991, 266,
12866-12872.
5-(3,5-Dich lor o-4-m eth oxyph en yl)-6-[4-(m eth ylsu lfon yl)-
p h en yl]sp ir o[2.4]h ep t-5-en e (55). Under nitrogen, a mix-
ture of 41.4 g (0.200 mol) of 3-chloro-4-hydroxybenzoic acid,
75 mL (1.2 mol) of iodomethane, and 81.5 g (0.25 mol) of K2-
CO3 in 250 mL of DMF was stirred at 55 °C for 18 h. The
reaction mixture was filtered and concentrated. The residue
was dissolved in EtOAc, washed with water and brine, and
then dried (MgSO4) and concentrated. The residue was
dissolved in 84 mL of methanol and 84 mL of 2.5 N NaOH,
and the resulting mixture was stirred at reflux for 4 h. The
reaction mixture was concentrated. The residue was dissolved
in 600 mL of water, and the pH was adjusted to 2 with
concentrated HCl. The solution was extracted with EtOAc,
and the combined extracts were washed with brine, dried
(MgSO4), and concentrated to give 38.12 g (89%) of 3,5-
dichloro-4-methoxybenzoic acid as a white solid: 1H NMR
(CDCl3) δ 3.95 (s, 3H), 7.98 (s, 2H).
(10) The expression of this enzyme has been shown to be induced by
cytokines and endotoxins; see: Masferrer, J . L.; Seibert, K.;
Zweifel, B.; Needleman, P. Endogenous Glucocorticoids Regulate
an Inducible Cyclooxygenase Enzyme. Proc. Natl. Acad. Sci.
U.S.A. 1992, 89, 3917-3921.
(11) Gans, K. R.; Galbraith, W.; Roman, R. J .; Haber, S. B.; Kerr, J .
S.; Schmidt, W. K.; Smith, C.; Hewes, W. E.; Ackerman, N. R.
Anti-inflammatory and Safety Profile of DuP 697, a Novel Orally
Effective Prostaglandin Synthesis Inhibitor. J . Pharmacol. Exp.
Ther. 1989, 254, 180-187.
(12) Futaki, N.; Yoshikawa, K.; Hamasaka, Y.; Arai, I.; Higuchi, S.;
Iizuka, H.; Otomo, S. NS-398, A Novel Non-Steroidal Anti-
Inflammatory Drug with Potent Analgesic and Antipyretic
Effects, Which Causes Minimal Stomach Lesions. Gen. Phar-
macol. 1993, 24, 105-110.
(13) Isakson, P.; Seibert, K.; Masferrer, J .; Salvemini, D.; Lee, L.;
Needleman, P. Discovery of a Better Aspirin. Ninth International
Conference on Prostaglandins and Related Compounds, Flo-
rence, Italy, J une 1994.
Following a procedure similar to the one described in
general procedure I, with the substitution of 3,5-dichloro-4-
methoxybenzoic acid (obtained from above) for 3-chloro-4-
methoxybenzoic acid (general procedure I, step 4), an unex-
pected demethylated phenol product was isolated instead of
the expected product 55. The phenol product was recrystal-
(14) Futaki, N.; Takahashi, S.; Yokoyama, M.; Arai, I.; Huguchi, S.;
Otomo, S. NS-398, a New Anti-inflammatory Agent, Selectively
Inhibits Prostaglandin G/H Synthase/Cyclooxygenase (COX-2)
Activity In Vitro. Prostaglandins 1994, 47, 55-59.
1
lized as a white solid: mp 163.5-164.5 °C; H NMR (CDCl3)
(15) Masferrer, J . L.; Zweifer, B. S.; Manning, P. T.; Hauser, S. D.;
Leahy, K. M.; Smith, W. G.; Isakson, P. C.; Seibert, K. Selective
Inhibition of Inducible Cyclooxygenase 2 In Vivo Is Antiinflam-
matory and Nonulcerogenic. Proc. Natl. Acad. Sci. U.S.A. 1994,
91, 3228-3232.
δ 0.68 (s, 4H), 2.88 (br d, J ) 12.5 Hz, 4H), 3.05 (s, 3H), 5.83
(s, 2H), 7.02 (s, 2H), 7.35 (d, J ) 8.4 Hz, 2H), 7.81 (d, J ) 8.4
Hz, 2H); HRMS (EI) calcd for C20H18Cl2O3S 408.0354, found
408.0349. Anal. (C20H18Cl2O3S) C, H, Cl, S.
(16) Copeland, R. A.; Williams, J . M.; Giannaras, J .; Nurnberg, S.;
Covington, M.; Pinto, D.; Pick, S.; Trzaskos, J . M. Mechanism
of Selective Inhibition of the Inducible Isoform of Prostaglandin
G/H Synthase. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 11202-
1120.
(17) Copeland, R. A.; Williams, J . M.; Rider, N. L.; Van Dyk, D. E.;
Giannaras, J .; Nurnberg, S.; Covington, M.; Pinto, D.; Magolda,
R. L.; Trzaskos, J . M. Selective Time Dependent Inhibition of
Cyclooxygenase-2. Med. Chem. Res. 1995, 5, 384-393.
(18) Schoen, R. T.; Vender, R. J . Mechanisms of Nonsteroidal
Antiinflammatory Drug-Induced Gastric Damage. Am. J . Med.
1989, 86, 449-458.
(19) 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.; Veenjuizen, A.; Zhang, Y.; Isakson,
P. Novel 1,2-Diarylcyclopentenes Are Selective, Potent and
Orally Active Cyclooxygenase Inhibitors. Med. Chem. Res. 1995,
5, 351-363.
(20) Reitz, D. B.; Li, J . J .; Norton, M. B.; Reinhard, E. J .; Collins, J .
T.; Anderson, G. D.; Gregory, S.; Kobold, C. M.; Perkins, W. E.;
Seibert, K.; Isakson, P. C. Selective Cyclooxygenase Inhibitors:
Novel 1,2-Diarylcyclopentenes Are Potent and Orally Active
COX-2 Inhibitors. J . Med. Chem. 1994, 37, 3878-3881.
(21) Reitz, D. B.; Li, J . J .; Norton, M. B.; Reinhard, E. J .; Penick, M.
A.; Collins, J . T.; Logusch, E. W.; Garland, D. J .; Chamberlain,
T. S.; Huang, H.-C.; Isakson, P.; Seibert, K.; Kobold, C.; Gregory,
S.; Veenjuizen, A.; Zhang, Y.; Anderson, G.; Perkins, W.; Casler,
J .; Ponte, C. 208th National ACS Meeting, 1994; MEDI-271.
Under nitrogen, a mixture of 0.2 g (0.49 mmol) of the phenol
obtained from above, 91 mL (1.5 mmol) of iodomethane, and
0.32 g (1 mmol) of cesium carbonate in 6 mL of DMF was
stirred at 25 °C for 16 h. The reaction mixture was diluted in
EtOAc, washed with water and brine, and then dried (MgSO4)
and concentrated. The residue was recrystallized to give 0.18
g (90%) of the desired product 55 as a white solid: mp 107.0-
1
108.0 °C; H NMR (CDCl3) δ 0.69 (s, 4H), 2.89 (d, J ) 14 Hz,
4H), 3.05 (s, 3H), 3.89 (s, 3H), 7.04 (s, 2H), 7.34 (d, J ) 8.7
Hz, 2H), 7.82 (d, J ) 8.4 Hz, 2H); HRMS (EI) calcd for C21H20
-
Cl2O3S 422.0510, found 422.0513. Anal. (C21H20Cl2O3S‚0.67H2-
O) C, H, Cl, S.
4-[6-(3,5-Dich lor o-4-m et h oxyp h en yl)sp ir o[2.4]h ep t -5-
en -5-yl]ben zen esu lfon a m id e (56). Following a procedure
similar to the one described in general procedure II, with the
substitution of butyllithium instead of propylmagnesium
chloride, 423 mg (1 mmol) of 55 was converted to crude
sulfonamide. Purification by silica gel chromatography gave
87 mg (15%) of the desired product as a white solid: mp 94.5-
97.0 °C dec; 1H NMR (CDCl3) δ 0.68 (s, 4H), 2.83-2.95 (m,
4H), 3.89 (s, 3H), 4.81 (br s, 2H), 7.05 (s, 2H), 7.29 (d, J ) 8.5
Hz, 2H), 7.80 (d, J ) 8.6 Hz, 2H); HRMS (EI) calcd for C20H19
Cl2NO3S 423.0463, found 423.0455.
-

266 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Huang et al.
(22) Reitz, D. B.; Huang, H.-C.; Li, J .; Garland, D. J .; Manning, R.
E.; Anderson, G. D.; Gregory, S. A.; Koboldt, C. M.; Perkins, W.
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