New cyclooxygenase-2/5-lipoxygenase inhibitors. 1. 7-tert-butyl-2,3- dihydro-3,3-dimethylbenzonfuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: Discovery and variation of the 5-keto substituent

Article abstract of DOI:10.1021/jm970679q

A series of 5-keto-substituted 7-tert-butyl-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were prepared and evaluated as potential nonsteroidal antiinflammatory and analgesic agents. Interest in this class of compounds arose when a DHDMBF was found to be

Full text of DOI:10.1021/jm970679q

1112
J . Med. Chem. 1998, 41, 1112-1123
New Cyclooxygen a se-2/5-Lip oxygen a se In h ibitor s. 1.
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth ylben zofu r a n Der iva tives a s Ga str oin testin a l
Sa fe An tiin fla m m a tor y a n d An a lgesic Agen ts: Discover y a n d Va r ia tion of th e
5-Keto Su bstitu en t
J ohn M. J anusz,* Patricia A. Young, J ames M. Ridgeway, Michael W. Scherz, Kevin Enzweiler, Laurence I. Wu,
Lixian Gan, Renuka Darolia, Randall S. Matthews, Duane Hennes, David E. Kellstein, Shelley A. Green,
J ennifer L. Tulich, Theresa Rosario-J ansen, I. J ack Magrisso, Kenneth R. Wehmeyer, Deborah L. Kuhlenbeck,
Thomas H. Eichhold, Roy L. M. Dobson, Steven P. Sirko, and Ralph W. Farmer
Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040
Received October 7, 1997
A series of 5-keto-substituted 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs)
were prepared and evaluated as potential nonsteroidal antiinflammatory and analgesic agents.
Interest in this class of compounds arose when a DHDMBF was found to be an active metabolite
of the di-tert-butylphenol antiinflammatory agent tebufelone. We have now found that a variety
of 5-keto-substituted DHDMBFs have good in vivo antiinflammatory and analgesic activity
after oral administration. These compounds inhibit both cyclooxygenase (COX) and 5-lipoxy-
genase (5-LOX) in vitro. The cyclooxygenase inhibition was found to be selective for the
cyclooxygenase-2 isoform, and this combination of COX-2/5-LOX inhibition may be responsible
for the gastrointestinal safety of compounds such as 30.
In tr od u ction
tert-butylphenol class.10-12 Among the metabolites of
tebufelone was the dihydrodimethylbenzofuran 813 (Chart
1). Although 8 is no longer a phenol and is not an
antioxidant, it nonetheless displays antiinflammatory
activity equivalent to tebufelone in the rat carrageenan
paw edema assay. Herein we report that the antiin-
flammatory activity of this new class of agents is general
and that certain of these compounds are dual COX/5-
LOX inhibitors, some with >50-fold selectivity for COX-
2. This combination of two potential mechanisms for
reduced GI side effects may be responsible for the GI
safety displayed by these compounds.
Nonsteroidal antiinflammatory drugs (NSAIDs) are
widely used for the treatment of pain, inflammation,
and fever.1 The mechanism of action of these drugs is
proposed to involve the inhibition of cyclooxygenase
(COX) which converts arachidonic acid to proinflamma-
tory prostaglandins. However, since prostaglandins are
also cytoprotective, common mechanism-based side ef-
fects of NSAID use are gastric ulceration and nephro-
toxicity.
In recent years, several approaches have been pro-
posed to minimize the toxicities of NSAIDs. Among
these is the development of dual cyclooxygenase/5-
lipoxygenase (COX/5-LOX) inhibitors. LTB4, one of the
leukotrienes formed from arachidonic acid by 5-LOX,
has been proposed to play a role in the formation of
gastric ulcers.2
The di-tert-butylphenol class of antiinflammatory
agents is one source of dual COX/5-LOX inhibitors.
Representative compounds include R-830 (1),3 KME-4
(2),4 E-5110 (3),5 and CI-1004 (4)6 (Chart 1). The
antioxidant and radical scavenging properties of these
compounds have been proposed to be relevant to their
antiinflammatory efficacy and low ulcerogenic poten-
tial.7
Another approach to gastrointestinal (GI) safe NSAIDs
involves selective inhibition of COX isozymes: COX-1,
thought to be the constitutive form essential for normal
gastric and kidney function, and COX-2, an isozyme that
is upregulated during inflammation. Selective inhibi-
tors of COX-2 such as NS-398 (5) and SC-57666 (6)
(Chart 1) have indeed been found to have reduced GI
side effects in animal models.8,9
Ch em istr y
The original six-step route14 to the requisite DHD-
MBF starting material 12 was inconvenient for scale-
up, so an improved synthesis was devised. The key
reaction was the free radical cyclization of â-methallyl
2,4-dibromo-6-tert-butylphenyl ether to the desired 2,3-
dihydrobenzofuran nucleus (Scheme 1).15 Thus, 2,4-
dibromo-6-tert-butylphenol (9)16 was allylated with 3-chlo-
ro-2-methylpropene. The resulting ether 10 underwent
a 5-exo-trig radical cyclization reaction under the influ-
ence of various radical reaction initiators and reduc-
tants. Operationally, aqueous hypophosphorus acid17,18
proved to be a superior hydrogen source over either
n-Bu3SnH or (TMS)3SiH, both of which required exten-
sive chromatography to remove Sn- or Si-based byprod-
ucts. This cyclization reaction was carried out on multi-
kilogram quantities, with yields ranging from 60% to
70%, and provided 5-bromo-7-tert-butyl-2,3-dihydro-3,3-
dimethylbenzofuran (11) as a 70:30 mixture with 12.
Debromination of 11 to 12 was reliably achieved by
transfer hydrogenation of this mixture with cyclohexene
in refluxing EtOH in the presence of 10% Pd on charcoal
and an acid scavenger such as K2CO3.
The di-tert-butylphenol tebufelone (7) (Chart 1) was
previously identified as a promising member of the di-
S0022-2623(97)00679-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/10/1998

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 1
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1113
Ch a r t 1
Sch em e 1
The acetylated analogue 13 was the starting material
for four analogues (Scheme 4). Bromination of the
trimethylsilyl enol ether with N-bromosuccinimide fol-
lowed by reaction with potassium thioacetate gave the
thioester 43 (method I). Chlorination of 13 was ac-
complished by reaction with benzyltrimethylammonium
dichloroiodate.22 Subsequent substitution reactions
provided the amine 40 (method J ) and ester 42 (method
K). Mukaiyama aldol reaction23 of 13 with acetone
provided the alcohol 45 (method L).
Resu lts a n d Discu ssion
In Vivo Activity. The carrageenan paw edema
(CPE) assay was the primary screen used to assess in
vivo antiinflammatory activity. Compounds were tested
for their ability to inhibit paw swelling relative to
tebufelone (positive control) after a single oral screening
dose (50 mg/kg). The CPE data in Table 1 are given in
terms of a CPE index which is the ratio of a compound’s
percent inhibition of paw edema versus control to
tebufelone’s percent inhibition of paw edema versus
control.24 At the 50 mg/kg screening dose, both naprox-
en, a marketed nonsteroidal antiinflammatory agent,
and tebufelone exhibited about the same antiinflam-
matory activity. While uncertainties about bioavail-
ability complicate the interpretation of the CPE results,
the bioavailability of 30 was quite good (62%) in the rat.
The prototypical DHDMBF 8 had activity equivalent
to tebufelone. The parent unsubstituted DHDMBF 12
was inactive. A series of aliphatic and cyclic ketones
were prepared to determine chain length and size
limitations. Activity was observed for ketones with two
to five carbons in the chain (compounds 13 and 15-18)
with the exception of the tert-butyl ketone 21. The two-
carbon alcohol 14, however, was inactive. The six-
carbon ketone 19 was inactive, although the longer
dioxa ketone 20 retained activity. Among cycloalkyl
ketones, the cyclopropyl and cyclopentyl compounds 22
and 23 were active while the cyclohexyl ketone 24 was
not. Systems with extended conjugation were investi-
gated with the synthesis of aromatic ketones. The
phenyl ketone 25 was active, while 2- and 4-halogenated
versions 26 and 27 were not. Terminally unsaturated
compounds such as tebufelone and the corresponding
DHDMBF 8 were among the most active compounds but
have the potential to inhibit liver enzymes.25 The
cyclopropyl group offered an alternative terminating
group with some of the characteristics of terminal
The 5-keto derivatives of the dihydrobenzofurans
were generally prepared by Friedel-Crafts acylation of
12 with an appropriately activated carboxylic acid. An
acylation method developed for the large-scale prepara-
tion of tebufelone proved to be a convenient and quite
general method here.19 Addition of trifluoroacetic an-
hydride (TFAA) at -20 °C to a 1:1.1 mixture of 12 and
the appropriate carboxylic acids gave the desired ke-
tones generally in modest to good isolated yields (Scheme
2, method A). Reduction of ketone 13 with NaBH4
provided the corresponding alcohol 14. The TFAA
reaction failed for preparation of the dioxa acid-derived
compound 20, but the addition of 5-lithio DHDMBF to
the Weinreb amide20 of the oxa acid (method B) was
successful. Preparation of compound 31 involved the
oxidation of the trimethylsilyl enol ether (LDA, TMSCl)
of 30 with palladium acetate and benzoquinone (method
C).21
The preparations of several sulfur-, nitrogen-, and
chlorine-containing analogues are shown in Scheme 3.
The sulfide 33 was prepared by the TFAA method and
then subsequently oxidized with m-chloroperbenzoic
acid to the sulfoxide 34 and sulfone 35 (method D). The
sulfoxide 37 and the sulfone 38 were prepared similarly
from the sulfide 36 (method F) which, in turn, was
prepared by ammonolysis/alkylation of the thioacetyl
compound 43 (method E). The amine 39 and sulfide
41 were prepared via substitution reactions of 47
(method G), itself prepared via the TFAA reaction. The
â-chloro ketone 44 was prepared by addition of HCl to
the olefin 46 (method H) which also derives from the
TFAA-mediated acylation.

1114 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
J anusz et al.
Sch em e 2
Sch em e 3
unsaturation. A series of three cyclopropylalkyl ketones
(28-30) were prepared and were active with the curious
exception of the middle compound in the series, 29. The
4-cyclopropylbutanoyl compound 30 proved to be of
particular interest (vide infra), and several analogues
of 30 were prepared. The trans R,â-unsaturated deriva-
tive 31 proved inactive. The terminally branched
compound 32 formally derived by addition of hydrogen
across the unsubstituted cyclopropyl bond, was also
inactive. In contrast, some heteroatoms could be incor-
porated into the cyclopropylbutanoyl side chain with
retention of activity: the sulfide 36 (but not the corre-
sponding sulfoxide 37 and sulfone 38) was active as was
the amine 40 (but less active than tebufelone). These
results prompted us to prepare other heteroatom-
containing analogues. In general, these analogues

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 1
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1115
Sch em e 4
would be more hydrophilic and perhaps have somewhat
greater water solubility than the extremely hydrophobic
all-carbon analogues. Among sulfur-containing ana-
logues, the sulfide and sulfoxide 33 and 34 were active,
the latter compound’s activity contrasting with the
inactivity of the sulfoxide 37. The sulfone 35 was
inactive, consistent with the results for the sulfone 38.
The thioether 41 was active as was the thioester 43. In
contrast, the corresponding ester 42 was inactive. The
â-halo and â-hydroxy compounds 44 and 45 were active
as was the R,â-unsaturated analogue 46.
Most of the active compounds from the CPE assay
were evaluated for analgesic activity in the mouse
phenylquinone-induced abdominal constriction (PAC)
assay. The correlation of antiinflammatory and anal-
gesic activity was generally good. All the compounds
active in the CPE assay had an ED50 of <35 mg/kg or
g50% inhibition at 70 mg/kg in the PAC assay with the
exception of compounds 18 and 33. Compound 30 was
the most potent analogue with an ED50 of 11 mg/kg.
Selected compounds were progressed to subsequent
testing tiers for additional assessment of safety and
efficacy. Table 2 shows some of these data for compound
30 in comparison to a standard NSAID, naproxen.
Compound 30 was active in the therapeutic rat adjuvant
arthritis assay with an ED50 of 6.6 mg/kg. The acute
ulcerogenic dose (UD50) was much higher, with no GI
lesions observed at oral doses up to 1000 mg/kg. Thus,
the therapeutic index for 30 is much greater than that
of the benchmark NSAID, naproxen. Additional testing
confirmed the high GI safety for compound 30: in a
refed rat antral damage model,26 its UD50 was greater
than that for naproxen and nabumetone, and no GI
damage was seen in 13-day studies in dogs and rats at
doses up to 200 mg/kg/day, po (data not shown).
In Vitr o Resu lts. The lack of GI toxicity for com-
pound 30 prompted us to probe the in vitro pharmacol-
ogy of the dihydrodimethylbenzofurans. With the dis-
covery of COX-2 (well after our program began), we
examined the potency and selectivity for inhibition of
human platelet-derived COX-1 and recombinant human
COX-2, as well as RBL lipoxygenase, as possible expla-
nations for the observed in vivo antiinflammatory
activity and GI safety. Thirteen compounds in three
groups (active, less active, or inactive in the CPE assay)
were tested (Table 3). Among the seven compounds
which were active in the CPE assay, all were potent
inhibitors of COX-1 and/or COX-2 with IC50 values < 1
µM. Compound 31 was also a potent inhibitor in vitro
but was inactive in the CPE assay perhaps due to
bioavailability and/or metabolism effects. Among the
six compounds that were inactive or less active in the
CPE assay, all were weak inhibitors of COX-1 and
COX-2 with IC50 values > 1 µM except for compound
31, discussed above, and compound 19. Compound 19,
while still potent against COX-2 (IC50 ) 0.09 µM) had
little activity against COX-1 (IC50 > 10 µM). The
compounds tested were moderately COX-2-selective
with IC50 ratios from 1 to >111. The most selective
compound was analogue 19, mentioned above. A trend
for increasing COX-2 selectivity with increasing chain
length was noted in comparing analogues 16, 18, and
19 where the selectivity ranges from 1 to 50 to >111.
The IC50 values for two benchmark compounds were
determined for comparison. The marketed NSAID
ibuprofen was a modestly selective COX-1 inhibitor,27
while SC-57666 (Searle) was a highly selective (>100-
fold) COX-2 inhibitor,9 results consistent with literature
reports. The 5-keto dihydrodimethylbenzofurans con-

1116 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
J anusz et al.
Ta ble 1. Structure, Synthetic Methods, and in Vivo Activity of Dihydrodimethylbenzofurans
compd
R
method
yield, %
mp, °C
formula
CPE indexa
PAC assayb
7, tebufelone
naproxen
8
1.00c
1.06c
0.94
0.31
0.92
0.00
1.14
1.16
1.25
0.92
0.40
0.52
0.30
0.67
0.65
0.36
0.72
0.52
0.00
1.06
0.18
0.72
0.18
0.36
1.77
1.01
0.00
0.62
0.04
0.00
0.32e
0.38e
0.70
0.21
0.95
1.20
0.49e
1.22
26
1.3
CO(CH2)3CCH
H
COMe
CH(OH)Me
COEt
COPr
CO-i-Pr
COBu
COpentyl
COCH2O(CH2)2OMe
CO-t-Bu
CO-c-Pr
CO-c-pentyl
CO-c-hexyl
COphenyl
CO-4-F-phenyl
CO-2-Cl-phenyl
COCH2-c-Pr
CO(CH2)2-c-Pr
CO(CH2)3-c-Pr
CO-E-CHdCHCH2-c-Pr
CO(CH2)3CHMe2
COCH2SMe
COCH2SOMe
COCH2SO2Me
COCH2SCH2-c-Pr
COCH2SOCH2-c-Pr
COCH2SO2CH2-c-Pr
CO(CH2)2NMe2
COCH2N(Me)CH2-c-Pr
CO(CH2)2SMe
COCH2OAc
ref 13
Scheme 1
NTd
NT
78%
NT
20
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
75
57
96
67
66
61
41
27
8
47
76
34
26
29
12
36
100
9
53
56
22
11
32
68
37
61
59
14
29
34
31
51
42
21
86
oil
86-87
oil
oil
oil
oil
54-56
oil
oil
oil
61-63
62-63
131-132
oil
98-100
117-118
62-63
oil
33-34
76-77
41-42
oil
96-97
112-113
oil
C14H20
O
A
A
A
A
A
A
A
B
A
A
A
A
A
A
A
A
A
A
C
A
A
D
D
E
C
C
C
C
C
C
C
16H22O2
16H24O2
17H24O2
18H26O2
18H26O2
19H28O2
20H30O2
85%
22
38%
NT
NT
NT
85%
56%
NT
34
NT
NT
NT
58%
11
C19H28O4
19H28O2
C18H24O2
C
C
C
C
C
C
20H28O2
21H30O2
21H24O2
21H23O2F
21H23O2Cl
C19H26O2
C20H28O2
C21H30O2
C21H28O2
C21H32O2
C17H24O2S
C17H24O3S
C17H24O4S
C20H28O2S
C20H28O3S
C20H28O4S
C19H29NO2
C21H31NO2
C18H26O2S
C18H24O4
C18H24O3S
C19H27O2Cl
C19H28O3
C19H26O2
NT
NT
35%
20
NT
54%
NT
NT
NT
NT
NT
NT
64%
16
F
F
107-108
84-86
oil
G
J
G
K
I
H
L
A
oil
80-81
83-84
61-63
87-88
86-88
56-58
COCH2SAc
COCH2C(Cl)Me2
COCH2C(OH)Me2
COCHdCMe2
NT
50%
a
CPE index, carrageenan paw edema index, is defined as the ratio of the reduction in paw volume for test compounds relative to
tebufelone. A value of >1 means more active than tebufelone, <1 means less active; dose ) 50 mg/kg po. Bold faced values are statistically
b
greater than vehicle control and not statistically different from tebufelone. See Experimental Section for complete details. PAC,
phenylquinone-induced abdominal constriction assay. Values are ED50’s in bold or the percent reduction of constrictions at a po dose of
70 mg/kg. Maximal percent reduction is ∼90%. See Experimental Section for complete details. c Percent inhibition of paw swelling for a
d
50 mg/kg po dose was 51.1 ( 10.0 for tebufelone (33-75%, n ) 65) and 54% for naproxen (44-64%, n ) 2). NT, not tested. e Activity is
statistically greater than vehicle control but less than tebufelone.
Ta ble 2. Additional Efficacy and Safety Testing
group is not required for in vivo antiinflammatory
activity although it often improves potency. A similar
trend is observed for in vitro COX inhibition.29 In
contrast, until recently, 5-LOX inhibition was thought
to be associated with the antioxidant properties of the
phenol. A recent report6 has shown that 5-LOX (and
COX) activity can be retained in the absence of the
phenolic group, although in this case the resulting dual
inhibitor lacked antiinflammatory activity. Our com-
pounds appear to be the first nonphenolic compounds
related to di-tert-butylphenols which are both dual
inhibitors of COX and 5-LOX in vitro and good antiin-
flammatory/analgesic agents in vivo.
adjuvant arthritis acute GI safety therapeutic index
compd
30
ED50, mg/kg
UD50, mg/kg
(UD50/ED50)
6.6
1.9
>1000
>152
16.3
naproxen
31
sistently showed low micromolar IC50 values as inhibi-
tors of 5-LOX.
It is interesting to compare the above results with
related results in the di-tert-butylphenol series. There
are conflicting literature reports on the importance of
the phenolic group for biological activity. In the CPE
assay, acetylation of the phenol or replacement with a
methoxy group provides compounds with equivalent or
slightly reduced activity28 or with greatly reduced
potency.7 Replacement of the phenolic group with
hydrogen reduced7 or eliminated6 antiinflammatory
activity. Together these data suggest that the phenolic
Con clu sion s
5-Substituted dihydrodimethylbenzofurans represent
a new class of antiinflammatory/analgesic agents. De-
spite the lack of antioxidant properties, these com-

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 1
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1117
Ta ble 3. In Vitro Activity of Dihydrodimethylbenzofurans
TLC analysis showed the reaction to be complete. The solids
were removed by filtration, and the acetone was evaporated
to give a dark oil. This oil partially decomposed to starting
material when stored at 23 °C over a period of 24 h. When
stored at -20 °C, no decomposition was detected by NMR after
56 h. Immediately before use, the oil was dissolved in hexanes
(100 mL) and stirred with silica gel (80 g). The slurry was
filtered through a pad of Celite and eluted with additional
hexanes (6 × 100 mL). The filtrate was evaporated to give 77
g (94%) of 10 as a yellow oil suitable for the next reaction: 1H
NMR δ 1.39 (s, 9 H), 1.90 (s, 3 H), 4.48 (s, 2 H), 5.03 (s, 1 H),
5.21 (s, 1 H), 7.41 (d, J ) 2.4 Hz, 1 H), 7.58 (d, J ) 2.4 Hz, 1
H); 13C NMR δ 19.50, 30.47, 35.69, 75.61, 112.06, 116.51,
118.80, 129.82, 134.00, 140.42, 147.02, 154.23.
IC50, µMa
5-LOXb
compd
COX-1
COX-2
COX-1/COX-2
IC50, µM
Active in CPE
0.015
0.095
0.04
8
0.06
0.095
2.00
0.15
7.00
0.65
1.00
0.25
4
1
50
21.4
31.8
1.6
10
6
16
18
25
30
36
44
8.5
12
5
8
NT
8
0.007
0.22
0.40
0.10
0.10
7, tebufelone
2.5
3
Less Active in CPEc
2.5
40
30
12
NT
7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth ylben zofu r a n (12).
A mixture of aqueous hypophosphorus acid (550 g) and toluene
(5 × 500 mL) was cautiously evaporated on a rotovap to
provide azeotropically dried hypophosphorus acid as a clear
liquid (275 g, 4.16 mol). In a 5-L three-neck flask, equipped
with Ar inlet, submersed N2 inlet, reflux condenser, and
magnetic stirrer, were placed dioxane (3000 mL), 10 (50.3 g,
0.14 mol), the anhydrous hypophosphorus acid (275 g, 4.16
mol), and Et3N (585 mL, 4.16 mol). The mixture was degassed
by bubbling with N2 for 30 min and then was maintained
under an N2 atmosphere. A solution of azobis(isobutyrylni-
trile) (AIBN; 20 mL of a 0.7 M solution in degassed dioxane)
was added via syringe, and the stirred solution was brought
to reflux. Every 0.5 h, an additional 20 mL of the AIBN
solution was injected. After 3 h, TLC indicated complete
consumption of starting material, and addition of AIBN was
discontinued. The reaction was allowed to reflux for an
additional 14 h and then was allowed to cool to 24 °C. The
reaction mixture was twice extracted with a mixture of brine
(250 mL) and 1 N HCl (100 mL). The organic layer was dried
over MgSO4, filtered, and evaporated to give 41.2 g of a yellow
oil admixed with a white solid. This was triturated with
hexanes (300 mL), and the insolubles were filtered off, rinsed
with fresh hexanes (50 mL), and discarded. The combined
filtrates were evaporated to give 27.4 g (75%) of a clear-yellow
oil. NMR analysis showed the product to consist of a 30:70
mixture of 12 and its 5-bromo derivative 11.
In a 250-mL round-bottom flask, equipped with magnetic
stir bar, reflux condenser, and N2 inlet, were suspended a 15-g
sample of this crude product and 10% Pd on charcoal (3.94 g)
in absolute EtOH (70 mL). K2CO3 (8.8 g, 63.5 mmol) was
added, and the mixture was degassed by bubbling with N2 for
15 min. Cyclohexene (33 mL) was added, and the mixture was
heated at reflux for 8 h. The reaction mixture was allowed to
cool to 23 °C and was filtered through a pad of Celite.
Evaporation of the solvent at reduced pressure provided a dark
oil, which was taken up in hexanes (50 mL), stirred with fresh
silica gel (5 g), filtered, and evaporated to yield 12 as a dark-
yellow oil, of sufficient purity for subsequent reactions: 1H
NMR δ 1.30 (s, 6 H), 1.36 (s, 9 H), 4.18 (s, 2 H), 6.94 (t, J )
7.0 Hz, 1 H), 7.05 (dd, J ) 7.0, 1.4 Hz, 1 H), 7.08 (dd, J ) 7.0,
1.4 Hz, 1 H); 13C NMR δ 27.46, 29.32, 34.36, 41.32, 83.62,
119.91, 120.24, 124.59, 133.02, 136.91, 157.02; IR 2858, 1590,
1460 cm-1; MS m/z 205 (MH+).
Inactive in CPE
19
31
32
37
38
>10
0.09
0.25
4.5
4.0
2.0
>111
NT
NT
15
NT
NT
0.8
3.2
3.3
5
15
20
5
2.5
Benchmarks
30
<0.3
ibuprofen
6, SC-57666
3
30
0.1
>100
a
COX testing was done by testing duplicate samples in dupli-
b
cate. 5-LOX testing was done by testing single samples in
triplicate. c Activity is statistically less than tebufelone but greater
than vehicle.
pounds are potent inhibitors of COX and 5-LOX with
moderate selectivity for COX-2.30 This combination of
COX-2 selectivity and 5-LOX inhibition may be respon-
sible for the high GI safety observed in this class. In
the companion paper, the scope of this lead was inves-
tigated by varying the dihydrobenzofuran “core”.
Exp er im en ta l Section
Gen er a l P r oced u r es. Reagents and solvents were gener-
ally used as received from the commercial supplier. Dry THF
and dry Et2O were obtained by distillation from sodium/
benzophenone ketyl under a N2 atmosphere. Dry hexanes,
CH2Cl2, and DMF were obtained by distillation from CaH2
under a N2 atmosphere. Reactions were routinely performed
under a N2 atmosphere in oven-dried glassware. Melting
points were determined with an electrothermal heating block
and are uncorrected. 1H and 13C NMR spectra were recorded
at 300 and 75 MHz, respectively, on either a Bruker AC300
or a Nicolet QE300 spectrometer. NMR spectra were recorded
in CDCl3 unless indicated otherwise, and chemical shifts are
reported relative to tetramethylsilane (δ ) 0.00). Infrared
spectra were recorded on a Perkin-Elmer instrument as a neat
thin film on NaCl windows, unless indicated otherwise.
Routine mass spectra were obtained using chemical ionization
with NH3 or CH4 gas. Elemental microanalyses were per-
formed by Oneida Laboratories, Inc. (Whitesboro, NY) or in-
house at P&G Pharmaceuticals in Norwich, NY. High-
resolution mass spectral data were obtained using EI as the
ionization method. HPLC was performed on a Spectra Physics
system using a 300-mm C18 reverse-phase column and iso-
cratic elution with 9:1 MeOH-H2O and a flow rate of 1 mL/
min. Low- and medium-pressure column chromatographies
were performed using Merck silica gel 60 (270-400 mesh).
TLC was performed on 250-µm precoated Merck silica gel 60
F254 glass-backed plates. Preparative TLC was performed
using 20- × 20-cm 1500-µm precoated Analtech silica gel GF
plates. Spots were visualized under 254-nm UV light or by
staining with phosphomolybdate spray reagent.
For 11: 1H NMR δ 1.36 (s, 6 H), 1.39 (s, 9 H), 4.26 (s, 2 H),
7.11 (d, J ) 1.8 Hz, 1 H), 7.22 (d, J ) 1.8 Hz, 1 H); 13C NMR
δ 27.30, 29.04, 34.24, 41.65, 83.93, 112.26, 122.97, 127.60,
135.21, 139.23, 156.21; IR 2958, 2870, 1441 cm-1; MS m/z 283
(MH+).
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)eth a n -1-on e (13). Meth od A. To a solution of 12 (2.0
g, 9.8 mmol) and acetic acid (0.56 mL, 9.8 mmol) at 0 °C was
added trifluoroacetic anhydride (1.5 mL, 9.8 mmol). The
reaction mixture was cooled to -20 °C and allowed to slowly
warm to room temperature overnight. The reaction was
monitored by TLC (2% EtOAc/hexanes). The reaction was
quenched with H2O (20 mL), and the aqueous layer was
extracted with CH2Cl2 (3×). The combined organic layers were
washed with water and brine and dried over MgSO4 to provide
a yellow oil (3.1 g). Medium-pressure chromotography (2%
2-ter t-Bu t yl-4,6-d ib r om op h en yl 2-Met h yla llyl E t h er
(10). In a 3-L three-neck flask, equipped with Ar inlet and
magnetic stirrer, were placed 9 (70.0 g, 226 mmol), K2CO3 (37.6
g, 276 mmol), NaI (3.38 g, 22.6 mmol), â-methallyl chloride
(33.9 mL, 339 mmol), and acetone (1500 mL). The reaction
mixture was vigorously stirred at 23 °C for 56 h. Subsequent

1118 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
J anusz et al.
EtOAc/hexanes) gave 1.37 g (57%) of 13 as a white solid: mp
86-87 °C; 1H NMR δ 1.20 (s, 6 H), 1.25 (s, 9 H), 2.38 (s, 3 H),
4.15 (s, 2 H), 7.50 (d, J ) 1.7 Hz, 1 H), 7.60 (d, J ) 1.7 Hz, 1
H); 13C NMR δ 26.33, 27.49, 29.04, 34.10, 40.97, 84.65, 120.82,
126.73, 130.57, 132.55, 137.59, 162.50, 197.10; IR 2959, 2874,
1674, 1596 cm-1; MS m/z 247 (MH+). Anal. (C16H22O2) C, H.
(()-7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-(1-h yd r oxy-
eth yl)d ih yd r oben zofu r a n (14). To a solution of 13 (463 mg,
1.88 mmol) in absolute EtOH (5 mL) was added NaBH4 (75
mg, 1.98 mmol). The reaction mixture was allowed to stir at
23 °C for 18 h. The solvent was evaporated, and the oily
residue was partitioned between water and EtOAc. The
aqueous layer was extracted twice with EtOAc, and the
combined organic layers were dried over MgSO4, filtered, and
evaporated to provide 450 mg (96%) of 14 as a faint-yellow
oil: 1H NMR δ 1.33 (s, 3 H), 1.34 (s, 3 H), 1.39 (s, 9 H), 1.51
(d, J ) 7.2 Hz, 3 H), 4.86 (q, J ) 7.2 Hz, 1 H); 13C NMR δ
24.02, 24.79, 27.34, 29.10, 33.96, 41.28, 70.61, 83.76, 116.84,
117.24, 133.22, 137.34, 137.56, 155.99; IR 3408, 2959, 2869,
1456 cm-1; MS m/z 249 (MH+). Anal. (C16H24O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)p r op a n -1-on e (15): method A; 1H NMR δ 1.22 (t, J ) 7
Hz, 6 H), 1.38 (s, 6 H), 1.40 (s, 9 H), 2.95 (q, J ) 7 Hz, 2 H),
4.30 (s, 2 H), 7.63 (d, J ) 1.7 Hz, 1 H), 7.80 (d, J ) 1.7 Hz, 1
H); 13C NMR δ 8.57, 27.48, 29.04, 31.33, 34.09, 40.98, 84.60,
120.48, 126.27, 130.21, 132.75, 137.50, 162.00, 199.7; IR 2960,
1676, 1598, 1456 cm-1; MS m/z 261 (MH+). Anal. (C17H24O2)
C, H.
(s, 3 H), 3.62 (t, J ) 4.4 Hz, 2 H), 3.75 (t, J ) 4.3 Hz, 2 H),
4.30 (s, 2 H), 4.76 (s, 2 H), 7.72 (d, J ) 1.9 Hz, 1 H), 7.74 (d,
J ) 1.9 Hz, 1 H); 13C NMR δ 27.5, 29.1, 34.2, 41.1, 58.9, 70.7,
72.0, 74.2, 84.7, 120.7, 126.4, 128.4, 133.1, 137.8, 162.0, 195.1,
231; IR (CDCl3) 2960, 1689, 1597, 1456 cm-1; MS m/z 321
(MH+); HRMS (EI, MH+) calcd for C19H28O4 320.1988, found
320.1987; HPLC 96.7%.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-2,2-d im eth ylp r op a n -1-on e (21): method A; 1H NMR δ
1.30 (s, 6 H), 1.38 (s, 9 H), 1.41 (s, 9 H), 4.29 (s, 2 H), 7.55 (d,
J ) 1.7 Hz, 1 H), 7.76 (d, J ) 1.7 Hz, 1 H); 13C NMR δ 27.57,
28.72, 29.21, 34.20, 41.15, 43.70, 84.51, 121.56, 127.13, 129.92,
132.09, 136.99, 160.14, 206.24; IR 2959, 1664, 1593, 1456 cm-1
;
MS m/z 289 (MH+). Anal. (C19H28O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)cyclop r op ylm eth a n on e (22): method A; mp 61-63 °C;
1H NMR δ 0.98 (m, 2 H), 1.20 (m, 2 H), 1.38 (s, 6 H), 1.44 (s,
9 H), 2.65 (m, 1 H), 4.34 (s, 2 H), 7.70 (d, J ) 1.7 Hz, 1 H),
7.85 (d, J ) 1.7 Hz, 1 H); 13C NMR δ 11.06, 16.54, 27.52, 29.07,
34.14, 41.02, 84.62, 120.54, 126.29, 131.25, 132.54, 137.50,
162.30, 197.80; IR 2959, 2869, 1660, 1597, 1455 cm-1; MS m/z
273 (MH+). Anal. (C18H24O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)cyclop en tylm eth a n on e (23): method A; mp 62-63 °C;
1H NMR δ 1.33 (s, 6 H), 1.40 (s, 9 H), 1.50-1.80 (m, 4 H), 1.90
(m, 4 H), 3.70 (m, 1 H), 4.30 (s, 2 H), 7.66 (d, J ) 1.5 Hz, 1 H),
7.81 (d, J ) 1.5 Hz, 1 H); 13C NMR δ 26.30, 27.51, 29.09, 30.25,
40.99, 45.88, 84.61, 120.92, 126.75, 130.13, 132.64, 137.45,
161.0, 201.62; IR 2957, 2869, 1669, 1595, 1454 cm-1; MS m/z
301 (MH+). Anal. (C20H28O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
1
n yl)bu ta n -1-on e (16): method A; H NMR δ 1.00 (t, J ) 7
Hz, 1 H), 1.35 (s, 6 H), 1.42 (s, 9 H), 1.75 (m, J ) 7 Hz, 2 H),
2.88 (t, J ) 7 Hz, 2 H), 4.30 (s, 2 H), 7.62 (d, J ) 1.7 Hz, 1 H),
7.80 (d, J ) 1.7 Hz, 1 H); 13C NMR δ 14.00, 18.11, 27.55, 29.14,
34.16, 40.14, 41.05, 84.66, 120.62, 126.39, 130.53, 132.78,
137.55, 162.03, 199.11; IR 2959, 1673, 1596, 1455 cm-1; MS
m/z 275 (MH+), 231. Anal. (C18H26O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)-2-m eth ylp r op a n -1-on e (17): method A; 1H NMR δ 1.15
(d, J ) 7 Hz, 6 H), 1.25 (s, 6 H), 1.35 (s, 9 H), 3.47 (m, 1 H),
4.25 (s, 2 H), 7.60 (d, J ) 1.7 Hz, 1 H), 7.80 (d, J ) 1.7 Hz, 1
H); 13C NMR δ 19.37, 27.39, 29.03, 34.01, 34.60, 40.90, 84.51,
120.74, 126.45, 129.30, 132.67, 137.45, 161.28, 202.70; IR 2963,
1671, 1595, 1455 cm-1; MS m/z 275 (MH+). Anal. (C18H26O2)
C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)cycloh exylm eth a n on e (24): method A; mp 131-132 °C;
1H NMR δ 1.38 (s, 6 H), 1.40 (s, 9 H), 1.45-1.60 (m, 5 H), 1.75
(m, 1 H), 1.87 (m, 4 H), 3.20 (m, 1 H), 4.30 (s, 2 H), 7.62 (d, J
) 1.5 Hz, 1 H), 7.80 (d, J ) 1.5 Hz, 1 H); 13C NMR δ 25.85,
25.92, 27.51, 29.06, 29.65, 34.10, 41.01, 45.22, 84.62, 120.70,
126.51, 129.44, 132.76, 137.54, 161.5, 202.61; IR 2929, 1669,
1593, 1452 cm-1; MS m/z 315 (MH+). Anal. (C21H30O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)p h en ylm eth a n on e (25): method A; 1H NMR δ 1.32 (s, 6
H), 1.38 (s, 9 H), 4.35 (s, 2 H), 7.44-7.55 (m, 4 H), 7.64 (d, J
) 1.7 Hz, 1 H), 7.65 (d, J ) 1.7 Hz, 1 H), 7.78 (d, J ) 1.5 Hz,
1 H); 13C NMR δ 27.51, 29.10, 34.14, 41.02, 84.65, 122.90,
128.02, 128.98, 129.56, 130.19, 131.54, 132.70, 137.43, 138.74,
161.41, 195.78; IR 2958, 1650, 1595 cm-1; MS m/z 309 (MH+).
Anal. (C21H24O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)p en ta n -1-on e (18): method A; mp 54-56 °C; 1H NMR δ
0.91 (t, J ) 7.7 Hz, 3 H), 1.35-1.45 (s, 19 H), 1.75 (m, 2 H),
2.91 (t, J ) 7.7 Hz, 2 H), 4.28 (s, 2 H), 7.65 (d, J ) 1.5 Hz, 1
H), 7.78 (d, J ) 1.5 Hz, 1 H); 13C NMR δ 13.92, 22.48, 26.85,
27.49, 29.06, 34.11, 37.89, 40.99, 84.61, 120.56, 126.37, 130.43,
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)(4′-flu or op h en yl)m eth a n on e (26): method A; mp 98-
1
100 °C; H NMR δ 1.36 (s, 15 H), 4.34 (s, 2 H), 7.16 (m, 2 H),
7.48 (d, J ) 1.8 Hz, 1 H), 7.60 (d, J ) 1.7 Hz, 1 H), 7.79 (m, 2
H); 13C NMR δ 27.6, 29.2, 34.3, 41.1, 84.8, 122.9 (115.4, 115.1,
d, J ) 22.5 Hz), 128.9, 130.1, 132.9 (132.3, 132.2, d, J ) 7.5
Hz), 135.2, 137.6, 161.6 (166.6, 163.2, d, J ) 255 Hz), 194.6;
IR (KBr) 2957, 2882, 1655, 1599 cm-1; MS m/z 327 (MH+).
Anal. (C21H23FO2) C, H, F.
132.73, 137.51, 161.5, 199.32; IR 2958, 1674, 1596, 1457 cm-1
;
MS m/z 289 (MH+). Anal. (C19H28O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
1
n yl)h exa n -1-on e (19): method A; H NMR δ 0.90 (m, 3 H),
1.30-1.45 (s, 19 H), 1.73 (m, 2 H), 2.92 (t, J ) 7.7 Hz, 2 H),
4.31 (s, 2 H), 7.63 (d, J ) 1.5 Hz, 1 H), 7.78 (d, J ) 1.5 Hz, 1
H); 13C NMR δ 13.89, 22.47, 24.39, 27.48, 29.06, 31.58, 34.10,
38.14, 40.98, 84.60, 120.56, 126.36, 130.43, 136.5, 137.0, 161.5,
199.0; IR 2958, 1672, 1589, 1553, 1535, 1455 cm-1; MS m/z
303 (MH+). Anal. (C20H30O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)(2′-ch lor op h en yl)m eth a n on e (27): method A; mp 117-
1
118 °C; H NMR δ 1.30 (s, 9 H), 1.32 (s, 6 H), 4.32 (s, 2 H),
7.30-7.47 (m, 4 H), 7.51 (d, J ) 1.6 Hz, 1 H), 7.61 (d, J ) 1.6
Hz, 1 H); 13C NMR δ 27.47, 28.95, 34.06, 40.88, 84.36, 122.67,
126.39, 128.80, 129.24, 129.42, 129.82, 130.46, 131.09, 132.52,
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)-1-oxo-3,6-d ioxa h ep ta n e (20). Meth od B. To 1.0 g (3.5
mmol) of 11 in 2 mL of ether and 18 mL of hexanes at -78 °C
was added 4.4 mL (7.1 mmol) of 1.6 M t-BuLi. After 30 min
at -78 °C, the in situ generated aryllithio species was added
to 0.9 g (5.3 mmol) of N-methyl-N-methoxy(methoxyethoxy)-
acetamide in 10 mL of Et2O at -78 °C in a slow steady stream.
The resulting solution was allowed to slowly reach room
temperature, and the reaction was then quenched with H2O.
The reaction mixture was then diluted with 200 mL of Et2O,
washed with H2O (3 × 30 mL), dried over MgSO4, and filtered,
and the solvent was evaporated. Purification by flash chro-
matography (60% EtOAc/hexanes) afforded 90 mg (8.4%) of
20 as a yellow oil: 1H NMR δ 1.34 (s, 6 H), 1.35 (s, 9 H), 3.38
137.84, 139.32, 162.41, 193.87; IR 2959, 1654, 1592, 1458 cm-1
;
MS m/z 343 (MH+). Anal. (C21H23ClO2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-2-cyclop r op yleth a n -1-on e (28): method A; mp 62-63
°C; 1H NMR δ 0.20 (m, 2 H), 0.59 (m, 2 H), 1.16 (m, 1 H), 1.35
(s, 6 H), 1.38 (s, 9 H), 2.83 (d, J ) 6.8 Hz, 1 H), 4.31 (s, 2 H),
7.62 (d, J ) 1.8 Hz, 1 H), 7.77 (d, J ) 1.8 Hz, 1 H); 13C NMR
δ 4.5, 7.0, 27.5, 29.0, 34.1, 41.0, 43.5, 84.6, 120.6, 126.5, 130.2,
132.8, 137.5, 161.5, 198.7; IR 2959, 2870, 1674, 1596, 1455
cm-1; MS m/z 287 (MH+). Anal. (C19H26O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
1
n yl)-3-cyclop r op ylp r op a n -1-on e (29): method A; H NMR
δ -0.01 (m, 2 H), 0.38 (m, 2 H), 0.69 (m, 1 H), 1.35 (s, 9 H),

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 1
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1119
1.30 (s, 6 H), 1.55 (q, J ) 7.5 Hz, 2 H), 2.95 (t, J ) 7.5 Hz, 2
H), 4.21 (s, 2 H), 7.54 (d, J ) 1.7 Hz, 1 H), 7.75 (d, J ) 1.7 Hz,
1 H); 13C NMR δ 4.58, 10.73, 22.55, 27.49, 29.07, 34.12, 38.27,
40.98, 84.71, 120.58, 126.40, 130.45, 132.62, 137.51, 161.49,
199.21; IR 2959, 2869, 1874, 1596, 1455 cm-1; MS m/z 301
(MH+). HRMS (EI, MH+) calcd for C20H28O2 301.2167, found
301.2130; HPLC 96.6%. Anal. (C20H28O2) C, H; C: calcd,
79.96; found, 78.92. H: calcd, 9.39; found, 8.95.
1 H); 13C NMR δ 0.01, 6.07, 20.42, 29.41, 29.55, 176.04; IR
2932, 1709 cm-1; MS m/z 129 (MH+).
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-4-cyclop r op ylbu ta n -1-on e (30): method A; mp 33-34
1
°C; H NMR δ -0.03 (m, 2 H), 0.41 (m, 2 H), 0.69 (q, J ) 7.5
Hz, 1 H), 1.29 (m, 2 H), 1.34 (s, 6 H), 1.37 (s, 9 H), 1.83 (m, 2
H), 2.95 (t, J ) 7.5 Hz, 2 H), 4.29 (s, 2 H), 7.62 (d, J ) 1.7 Hz,
1 H), 7.72 (d, J ) 1.7 Hz, 1 H); 13C NMR δ 4.42, 10.72, 24.89,
27.59, 29.15, 34.21, 34.39, 38.02, 41.09, 84.71, 120.65, 126.49,
130.49, 132.82, 137.62, 161.49, 199.45; IR 2958, 1674, 1596,
1455 cm-1; MS m/z 315 (MH+). Anal. (C21H30O2) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)-4-cyclop r op ylbu ta n -1-on e (30). 4-Cyclop r op ylbu -
ta n -1-ol. Caution: Neat AlMe3 is extraordinarily pyrophoric,
and this reaction should be carried out only by well-trained
technical personnel! Particular attention should be paid to
the Aldrich Technical Bulletin accompanying commercial
AlMe3, describing proper techniques for handling air- and
moisture-sensitive reagents. This reaction was performed with
a sand-filled secondary container underneath the reaction
vessel and large quantities of dry ice at hand to smother any
spill to allow time for personnel to evacuate should the
necessity arise. In a 12-L four-neck flask, equipped with
mechanical stirrer, 1-L addition funnel, efficient steel-coil
condensor funnel and 4-mm bore gas outlet, internal ther-
mometer, and ice bath, were placed 5-hexen-1-ol (378.6 g, 3.78
mol), CH2I2 (1265 g, 4.73 mol), and CH2Cl2 (2200 mL). The
reaction flask was purged with N2 for 0.5 h, and then neat
AlMe3 (approximately 600 g, 8.3 mol) was transferred via
cannula into the addition funnel. The AlMe3 was added
dropwise to the stirred reaction mixture. Caution: Strong
exotherm and gas (CH4) evolution! The temperature rose to
40 °C during the addition. After approximately 150 g of AlMe3
had been added, the exotherm and gas evolution subsided, and
the remainder AlMe3 was added over the course of 45 min,
along with a 100-mL CH2Cl2 rinse of the addition funnel. The
reaction mixture was heated at reflux for 10 h. Completion
(E)-1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zo-
fu r a n yl)-4-cyclop r op yl-2-b u t en -1-on e (31). Met h od C.
Lithium diisopropylamide (4.0 mL, 8.0 mmol, 2.0 M solution
in heptane-THF-ethylbenzene) was added dropwise to a
solution of 30 (1.26 g, 4.0 mmol) in 20 mL of anhydrous THF
at -78 °C. The resulting solution was stirred at -78 °C for
15 min, and chlorotrimethylsilane (1.0 mL, 8.0 mmol) was
introduced. The reaction mixture was stirred at -78 °C for
10 min, warmed to 0 °C, stirred for 1 h, quenched with H2O,
and extracted with Et2O. The extract was dried over anhy-
drous Na2SO4 and concentrated to give 1.90 g of a yellowish
oil, which was added under argon to a clear-brown solution of
palladium acetate (0.89 g, 4.0 mmol) and benzoquinone (0.43
g, 4.0 mmol) in 40 mL of CH3CN. The resulting dark solution
was stirred for 18 h and filtered through a short column of
silica gel. The filtrate was diluted with 100 mL of H2O and
extracted with 10% EtOAc/hexanes. The extract was washed
with H2O and brine, dried over anhydrous MgSO4, and
concentrated to afford 1.36 g of the crude product as a brown
oil. Purification by flash column chromatography on silica gel
(1% f 2% Et2O/hexanes) gave 0.70 g (56%) of 31 as a colorless
1
solid: mp 76-77 °C; H NMR δ 0.14 (m, 2 H), 0.52 (m, 2 H),
0.85 (m, 1 H), 1.33 (s, 6 H), 1.36 (s, 9 H), 2.19 (t, J ) 6.3 Hz,
2 H), 4.29 (s, 2 H), 7.09-6.91 (m, 2 H), 7.61 (d, J ) 1.8 Hz, 1
H), 7.76 (d, J ) 1.8 Hz, 1 H); 13C NMR δ 4.37, 9.41, 27.5, 29.2,
34.2, 37.3, 41.1, 84.7, 121.1, 126.1, 127.0, 131.3, 132.9, 137.7,
147.0, 161.4, 189.7; IR 2959, 1665, 1619, 1592, 1455 cm-1; MS
m/z 313 (MH+). Anal. (C21H28O2) C, H.
1
of the reaction was confirmed by H NMR analysis of a 1-mL
aliquot. The reaction mixture was diluted to a volume of 12
L with fresh CH2Cl2 and then transferred via glass tube siphon
into a stirred mixture of 50% NaOH (1.8 L, 22.7 mol) in ice
(10 L). The organic phase was separated and the aqueous
phase extracted with CH2Cl2 (3 × 2 L). The combined organic
phases were dried (MgSO4), filtered, and evaporated to provide
the title compound as a yellow oil (442.8 g, 102%) which was
used without further purification: 1H NMR δ -0.08 (m, 2 H),
0.31 (m, 2 H), 0.58 (m, 1 H), 1.13 (q, J ) 6.8 Hz, 2 H), 1.36 (m,
2 H), 1.50 (m, 2 H), 3.41 (s, 1 H), 3.50 (t, J ) 6.8 Hz, 2 H).
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-5-m eth ylh exa n -1-on e (32): method A; mp 41-42 °C; 1H
NMR δ 1.06 (d, J ) 6.7 Hz, 6 H), 1.28 (m, 1 H), 1.55 (s, 6 H),
1.57 (s, 9 H), 1.72 (m, 2 H), 1.76 (m, 2 H), 2.90 (t, J ) 7.3 Hz,
2 H), 4.31 (s, 2 H), 7.62 (d, J ) 1.8 Hz, 1 H), 7.78 (d, J ) 1.8
Hz, 1 H); 13C NMR δ 22.5, 22.6, 27.5, 27.9, 29.2, 34.2, 38.5,
38.8, 41.1, 84.7, 120.6, 126.4, 130.6, 132.9, 137.6, 161.4, 199.3;
IR (KBr) 2957, 1675, 1597 cm-1; MS m/z 317 (MH+), 301, 246,
231. Anal. (C21H32O2) C, H.
4-Cyclop r op ylbu ta n oic Acid . In a 500-mL three-neck
flask, equipped with mechanical stirrer, addition funnel, and
an internal thermometer, was placed a solution of 4-cyclopro-
pylbutan-1-ol (20 g, 175 mmol), in acetone (100 mL). The
solution was cooled to 0 °C, and J ones reagent (prepared by
the careful addition of concentrated H2SO4 (40 mL) to a
solution of CrO3 (35 g, 350 mmol) in H2O (75 mL)) was added
dropwise at a rate such that the temperature of the reaction
mixture did not exceed 10 °C. The reaction was monitored by
TLC (hexane-EtOAc, 19:1); after approximately two-thirds of
the J ones reagent had been added, the reaction was judged
complete and was quenched by the addition of 2-propanol (10
mL). The pH was adjusted to above pH 10 with 4 N NaOH,
and the reaction mixture was partitioned between H2O (200
mL) and EtOAc (4 × 100 mL). The organic phase was
separated, washed with H2O and brine, dried (MgSO4), filtered,
and evaporated to provide 3-cyclopropylpropyl 4-cyclopropyl-
butyrate (7.22 g). The aqueous phase was acidified with
concentrated H2SO4 to pH 2 and extracted with EtOAc (6 ×
100 mL). The organic phases were dried (MgSO4), filtered,
and evaporated to provide the title compound as a colorless
oil (12.1 g, 54.2%). The ester (7.2 g) was hydrolyzed with
aqueous 2 N NaOH (32 mL) in MeOH (30 mL) at 23 °C.
Workup as above provided 4-cyclopropylbutan-1-ol (3.45 g) and
the title compound (3.20 g) as colorless oils. The combined
yield of the desired acid was 15.3 g (68.2%): 1H NMR δ -0.08
(m, 2 H), 0.28 (m, 2 H), 0.61 (m, 1 H), 1.20 (m, 2 H), 1.75
(quintet, J ) 7.7 Hz, 2 H), 2.35 (t, J ) 7.7 Hz, 2 H), 10.80 (bs,
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
1
n yl)-3-th ia bu ta n -1-on e (33): method A; H NMR δ 1.30 (s,
6 H), 1.35 (s, 9 H), 2.15 (s, 3 H), 3.70 (s, 2 H), 4.25 (s, 2 H),
7.60 (d, 1 H), 7.75 (d, 1 H); 13C NMR δ 15.9, 27.5, 29.0, 34.1,
38.8, 41.0, 84.7, 121.3, 127.2, 128.3, 132.9, 137.7, 161.9, 193.1.
Anal. (C17H24O2S) C, H, S.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-3-su lfin ylbu ta n -1-on e (34). Meth od D. Compound 33
(1.08 g, 3.7 mmol) was dissolved in CH2Cl2 (8 mL) in a flame-
dried flask under argon and then cooled in an ice/H2O bath.
mCPBA (85%, 826 mg, 4.1 mmol) was added carefully, and
the reaction mixture was stirred for 45 min. The reaction
mixture was then poured into saturated NaHCO3, separated,
and extracted twice with CH2Cl2. The organic extracts were
combined and evaporated. The crude product was purified by
filtration flash chromatography with 10% and then 50%
EtOAc/hexanes followed by crystallization from EtOAc/hex-
anes to give 363 mg (32%) of 34 as a white powder: mp 96-
97 °C; 1H NMR δ 1.30 (s, 6 H), 1.35 (s, 9 H), 2.75 (s, 3 H), 4.10
(d, 1 H), 4.30 (s, 2 H), 4.50 (d, 1 H), 7.60 (d, 1 H), 7.75 (d, 1 H);
13C NMR δ 27.5, 28.9, 34.2, 39.7, 40.9, 62.3, 84.9, 121.5, 127.5,
129.2, 133.4, 138.2, 163, 190.1; MS m/z 309 (MH+), 247. Anal.
(C17H24O3S) C, H, S.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-3-su lfon ylbu ta n -1-on e (35). Meth od D. Compound 34
(500.1 mg, 1.62 mmol) was dissolved in 8 mL of CH2Cl2 in a

1120 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
J anusz et al.
dry flask under argon. mCPBA (∼75%, 467.6 mg, 2.03 mmol)
was added, and the reaction mixture was allowed to stir at
room temperature. After 2.5 h, the reaction mixture was
poured into dilute sodium bisulfite and extracted with CH2-
Cl2. The organics were washed with another portion of
bisulfite and then 2 × 35 mL of 0.5 N NaHCO3. The combined
organics were dried over molecular sieves; then the solvent
was evaporated. Flash chromatography with 10% and then
50% EtOAc/hexanes followed by crystallization from EtOAc/
hexanes gave 354.9 mg (67.5%) of white crystals: mp 112-
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-3-su lfon yl-4-cyclop r op ylbu ta n -1-on e (38). Meth od
F . To a stirring solution of 36 (0.4 g, 1.2 mmol) in 11 mL of
acetone at 0 °C was added mCPBA (1.0 g, 6.0 mmol). The
resulting solution was allowed to warm to room temperature
over 12 h and was monitored by TLC until conversion to
sulfone was about complete. The reaction was quenched with
aqueous sodium bisulfite and diluted with H2O. The organic
layer was extracted with 100 mL of CH2Cl2 and washed with
saturated NaHCO3 and brine (3 × 100 mL). The organic layer
was dried over anhydrous MgSO4, filtered, and evaported.
Purification by flash chromatography in 16% EtOAc/hexanes
resulted in 0.3 g (59%) of 38 as a white solid: mp 84-86 °C;
1H NMR δ 0.53 (m, 2 H), 0.75 (m, 2 H), 1.28 (m, 1 H), 1.36 (s,
6 H), 1.37 (s, 9 H), 3.23 (d, J ) 6.8 Hz, 2 H), 4.35 (s, 2 H), 4.61
(s, 2 H), 7.63 (d, J ) 1.8 Hz, 1 H), 7.80 (d, J ) 1.9 Hz, 1 H);
13C NMR δ 4.2, 4.3, 27.3, 27.4, 28.8, 34.1, 40.8, 58.4, 84.9,
122.0, 128.0, 129.0, 133.4, 138.1, 163.1, 187.6; IR (KBr) 2957,
2907, 1672, 1593 cm-1; MS m/z 365 (MH+), 247. Anal.
(C20H28O4S) C, H, S.
1
113 °C; H NMR δ 1.40 (s, 16 H), 3.15 (s, 3 H), 4.40 (s, 2 H),
4.60 (s, 2 H), 7.70 (d, 1 H), 7.80 (d, 1 H); 13C NMR δ 27.8, 29.2,
34.5, 41.2, 42.0, 61.4, 85.3, 122.5, 128.4, 129.2, 133.8, 138.5,
163.5, 187.7; MS m/z 325 (MH+), 247. Anal. (C17H24O4S1) C,
H, S.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)-3-th ia -4-cyclop r op ylbu ta n -1-on e (36). 1-(7-ter t-Bu -
tyl-2,3-dih ydr o-3,3-dim eth yl-5-ben zofu r an yl)-2-m er capto-
1-eth a n on e. Meth od E. A stirring solution of 43 (0.5 g, 1.6
mmol) in 20 mL of MeOH was purged with argon for 30 min
at room temperature. Then NH3 gas was bubbled in for 60
min. The resulting yellow solution was stirred for 30 min until
completion by TLC, diluted with Et2O (150 mL), and washed
with H2O. The organic layer was dried over anhydrous
MgSO4, filtered, and evaporated to give a yellow oil. Purifica-
tion by flash chromatography (12% EtOAc/hexanes) resulted
in 0.3 g (67%) of the title compound as a light-yellow solid:
mp 42-44 °C; 1H NMR δ 1.34 (s, 6 H), 1.35 (s, 9 H), 2.14 (t, J
) 7.2 Hz, 1 H), 3.90 (d, J ) 7.2 Hz, 2 H), 4.31 (s, 2 H), 7.60 (d,
J ) 1.8 Hz, 1 H), 7.75 (d, J ) 1.8 Hz, 1 H); 13C NMR δ 28.2,
29.7, 31.5, 34.9, 41.7, 85.5, 121.9, 127.7, 128.9, 133.9, 138.6,
162.8, 194.2; MS m/z 279 (MH+), 280, 318. Anal. (C16H22O2S)
C, H, S.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)-3-th ia -4-cyclop r op ylbu ta n -1-on e (36). To 1-(7-tert-
butyl-2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-2-mercapto-1-
ethanone (0.2 g, 0.7 mmol) in 3 mL of MeOH was added
NaOMe (0.1 g, 1.8 mmol). The resulting solution was stirred
at 0 °C for 15 min at which time bromomethylcyclopropane
(0.2 g, 1.8 mmol) was added via syringe. The reaction mixture
was allowed to warm to room temperature over 16 h, and the
reaction was followed by TLC until no starting material was
present. The organic layer was diluted with 100 mL of Et2O
and washed with H2O. The organic layer was dried over
MgSO4, filtered, and evaporated. Flash chromatography with
5% EtOAc/hexanes resulted in 0.1 g (37%) of 36 as an orange
oil: 1H NMR δ 0.20 (bd d, 2 H), 0.51 (bd d, 2 H), 0.96 (m, 1 H),
1.33 (s, 6 H), 1.39 (s, 9 H), 2.48 (d, J ) 7.0 Hz, 2 H), 3.59 (s, 2
H), 4.26 (s, 2 H), 7.61 (d, J ) 1.5 Hz, 1 H), 7.77 (d, J ) 1.5 Hz,
1 H); 13C NMR δ 5.2, 10.5, 27.4, 28.9, 34.0, 36.4, 37.4, 40.8,
84.5, 121.2, 127.1, 128.4, 132.7, 137.5, 161.6, 193.4; IR (KBr)
2958, 1654, 1594 cm-1; MS m/z 333 (MH+), 247. Anal.
(C20H28O2S) C, H, S.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-3-(d im et h yla m in o)p r op a n -1-on e (39). Met h od G.
Compound 12 (2.45 g, 12.0 mmol) and 3-chloropropionic acid
(1.3 g, 12.0 mmol) were reacted with trifluoroacetic anhydride
in the usual way (method A). Purification of the crude product
by flash chromatography on silica gel (1% EtOAc/hexanes)
gave 0.85 g (35%) of a light-yellow oil, which was dissolved in
20 mL of acetone and reacted for 18 h with Me2NH (6 mL,
33.0 mmol, 33% ethanolic solution). The reaction mixture was
evaporated. The residue was purified by flash chromatography
on silica gel (10% EtOAc/hexanes f 10% MeOH/CHCl3) to give
0.50 g (14%) of 39 as a brown oil: 1H NMR δ 1.29 (s, 6 H),
1.32 (s, 9 H), 2.26 (s, 6 H), 2.72 (t, J ) 7.4 Hz, 2 H), 3.07 (t, J
) 7.4 Hz, 2 H), 4.26 (s, 2 H), 7.58 (d, J ) 1.8 Hz, 1 H), 7.74 (d,
J ) 1.8 Hz, 1 H); 13C NMR δ 27.4, 28.9, 34.0, 36.3, 40.8, 45.2,
54.6, 84.5, 120.5, 126.3, 130.1, 132.7, 137.5, 161.6, 197.6; IR
2958, 1671, 1595 cm-1; MS m/z 304 (MH+). Anal. (C19H29
NO2 ‚0.25H2O) C, H, N; H: calcd, 9.66; found 9.15.
-
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-2-(N-m eth yl-N-(cyclop r op ylm eth yl)a m in o)eth a n -1-
on e (40). 1-(7-ter t-Bu tyl-2,3-d ih yd r o-3,3-d im eth yl-5-ben -
zofu r a n yl)-2-ch lor oeth a n -1-on e. Meth od J . A mixture of
benzyltrimethylammonium dichloroiodate (31.70 g, 91.0 mmol),
13 (12.35 g, 50.2 mmol), 300 mL of 1,2-dichloroethane, and
120 mL of MeOH was heated at reflux for 13 h. The reaction
mixture was cooled to room temperature and concentrated in
vacuo; 5% aqueous sodium bisulfite solution (125 mL) was
added to the residue obtained. This mixture was extracted
with Et2O; the extract was washed with aqueous NaHCO3
solution and brine, dried over anhydrous MgSO4, and concen-
trated to produce 14.09 g (100%) of the title compound as a
1
reddish solid: mp 76-77 °C; H NMR δ 1.32 (s, 6 H), 1.34 (s,
9 H), 4.32 (s, 2 H), 4.63 (s, 2 H), 7.61 (d, J ) 1.8 Hz, 1 H), 7.74
(d, J ) 1.8 Hz, 1 H).
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)-3-su lfin yl-4-cyclop r op ylbu ta n -1-on e (37). Meth od F .
To a stirring solution of 36 (0.3 g, 0.8 mmol) in 10 mL of CH2-
Cl2 was added mCPBA (0.2 g, 0.8 mmol). The resulting
solution was stirred at -23 °C for 2 h, at which time no
starting material was present by TLC. The reaction was
quenched with aqueous sodium bisulfite and diluted with H2O.
The organic layer was extracted with 100 mL of CH2Cl2 and
washed with saturated NaHCO3 (3 × 100 mL). The organic
layer was dried over anhydrous MgSO4, filtered, and evapo-
rated to yield a brown oil. Purification by flash chromatog-
raphy in 25% EtOAc/hexanes and further recrystallization
from hexanes resulted in 0.2 g (61%) of 37 as a white solid:
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-2-(N-m eth yl-N-(cyclop r op ylm eth yl)a m in o)eth a n -1-
on e (40). 1-(7-tert-Butyl-2,3-dihydro-3,3-dimethyl-5-benzo-
furanyl)-2-chloroethan-1-one (1.47 g, 5.2 mmol) was added in
portions to a solution of NaI (0.86 g, 5.8 mmol) in acetone.
The reaction mixture was stirred for 0.5 h and filtered through
a short column of Celite to give a solution of 1-(7-tert-butyl-
2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-2-iodoethan-1-one in
acetone, which was immediately reacted for 0.5 h with N-
methyl-N-(cyclopropylmethyl)amine (1.50 g, 17.6 mmol). The
reaction mixture was evaporated, and the residue was dis-
solved in EtOAc; this solution was washed with aqueous
NaHCO3 solution and brine, dried over anhydrous Na2SO4, and
concentrated to give 1.92 g of the crude product. Purification
by flash chromatography on silica gel (20% f 25% EtOAc/
hexanes) produced 0.50 g (29%) of 40 as a yellow oil: 1H NMR
δ 0.38 (m, 2 H), 0.51 (m, 2 H), 0.94 (m, 1 H), 1.33 (s, 6 H), 1.35
(s, 9 H), 2.43 (s, 3 H), 2.44 (d, J ) 6.6 Hz, 2 H), 3.86 (s, 2 H),
4.28 (s, 2 H), 7.67 (d, J ) 1.8 Hz, 1 H), 7.86 (d, J ) 1.8 Hz, 1
H); 13C NMR δ 3.7, 8.7, 27.4, 28.9, 34.0, 40.9, 42.7, 62.4, 62.8,
1
mp 107-108 °C; H NMR δ 0.41 (m, 2 H), 0.73 (m, 2 H), 1.28
(m, 1 H), 1.35, (s, 6 H), 1.37 (s, 9 H), 2.87 (m, 2 H), 4.37 (s, 2
H), 4.40 (d, J ) 14.5 Hz, 1 H), 4.45 (d, J ) 14.5 Hz, 1 H), 7.63
(d, J ) 1.9 Hz, 1 H), 7.78 (d, J ) 1.9 Hz, 1 H); 13C NMR δ 4.3,
5.4, 27.4, 28.7, 34.1, 40.8, 58.21, 59.4, 84.8, 121.5, 127.5, 129.2,
133.3, 138.1, 163.5, 190.5; IR (KBr) 2963, 1667, 1597, 1457
cm-1; MS m/z 349 (MH+), 333, 247. Anal. (C20H28O3S‚0.25H2O)
C, H, S.

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 1
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1121
84.5, 120.7, 126.5, 129.4, 132.6, 137.4, 161.5, 196.0; IR 2959,
chromatography on silica gel (10% EtOAc/hexanes) afforded
0.31 g (51%) of 43 initially as a yellowish oil which upon
storage in a refrigerator became a light-yellow solid: mp 61-
63 °C; 1H NMR δ 1.33 (s, 6 H), 1.35 (s, 9 H), 2.38 (s, 3 H), 4.30
(s, 2 H), 4.36 (s, 2 H), 7.64 (d, J ) 1.8 Hz, 1 H), 7.80 (d, J )
1.8 Hz, 1 H); 13C NMR δ 27.5, 29.0, 30.1, 34.2, 36.2, 41.0, 84.7,
121.2, 127.0, 128.6, 133.1, 137.8, 162.2, 191.8, 194.3; IR 2960,
1694, 1597 cm-1; MS m/z 321 (MH+). Anal. (C18H24O3S) C,
H, S.
2871, 1673, 1596 cm-1; MS m/z 330 (MH+). Anal. (C21H31
NO2‚1.33H2O) C, H, N; H: calcd, 9.60; found, 8.76.
-
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)-3-m eth ylth ia p r op a n -1-on e (41). Meth od G. Com-
pound 12 was reacted with 3-chloropropionic acid and triflu-
oroacetic anhydride in the usual manner (method A). The
crude product was purified by flash chromatography on silica
gel (0.5% EtOAc/hexanes) to give 1.55 g (35%) of 1-(7-tert-butyl-
2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-3-chloropropan-1-
one as a colorless oil. To a solution of this oil (0.76 g, 2.6 mmol)
in 15 mL of MeOH was added sodium thiomethoxide (0.54 g,
6.4 mmol). The reaction mixture was stirred for 5 h and
evaporated. The residue was dissolved in Et2O; the resulting
solution was washed with H2O and brine, dried over anhydrous
MgSO4, and concentrated to give 1.40 g of the crude product
as a syrup. Purification by flash chromatography on silica gel
(1 f 2% EtOAc/hexanes) yielded 0.78 g (34% for two steps) of
41 as a light-yellow solid: mp 80-81 °C; 1H NMR δ 1.34 (s, 6
H), 1.36 (s, 9 H), 2.15 (s, 3 H), 2.88 (t, J ) 7.4 Hz, 2 H), 3.22
(t, J ) 7.4 Hz, 2 H), 4.30 (s, 2 H), 7.61 (d, J ) 1.8 Hz, 1 H),
7.76 (d, J ) 1.8 Hz, 1 H); 13C NMR δ 15.8, 27.4, 28.7, 28.9,
34.0, 38.1, 40.9, 84.6, 120.5, 126.3, 129.9, 132.9, 137.6, 161.6,
197.0; IR 2959, 1673, 1595, 1455 cm-1; MS m/z 307 (MH+).
Anal. (C18H26O2S) C, H, S.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)-2-a cetoxyeth a n -1-on e (42). Meth od K. A mixture of
1-(7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-2-chlo-
roethan-1-one, described in the preparation of 40 (1.12 g, 4.0
mmol), formamidine acetate (0.50 g, 4.8 mmol), and 10 mL of
EtOH was heated at reflux for 19 h. The reaction mixture
was cooled to room temperature and concentrated in vacuo.
The residue was treated with aqueous Na2CO3 solution, and
the resulting mixture was extracted with EtOAc. The extract
was washed with brine, dried over anhydrous Na2SO4, and
concentrated to give 1.2 g of a dark-brown oil. Purification
by flash chromatography on silica gel (5% EtOAc/hexanes)
gave 0.38 g (31%) of 42 as a light-green solid: mp 83-84 °C;
1H NMR δ 1.35 (s, 6 H), 1.37 (s, 9 H), 2.23 (s, 3 H), 4.33 (s, 2
H), 5.31 (s, 2 H), 7.56 (d, J ) 1.8 Hz, 1 H), 7.71 (d, J ) 1.8 Hz,
1 H); 13C NMR δ 20.6, 27.5, 29.0, 34.2, 41.0, 65.8, 84.7, 120.4,
126.1, 127.5, 133.3, 138.0, 162.3, 170.5, 190.7; IR 2959, 1749,
1694, 1599 cm-1; MS m/z 305 (MH+). Anal. (C18H24O4) C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-3-ch lor o-3-m eth ylbu ta n -1-on e (44). Meth od H.
A
solution of 46 (9.4 g, 32.7 mmol) in 1 M ethereal HCl (80 mL)
was stirred for 24 h at room temperature. The reaction was
quenched with H2O (80 mL) and the mixture extracted with
CH2Cl2 (3×). The combined extracts were washed with H2O
and brine, dried over MgSO4, and evaporated to provide a tan
solid (11.2 g). This solid was recrystallized twice from hexanes
1
to provide 44 (3.54 g 33%): mp 87-88 °C; H NMR δ 1.37 (s,
6 H), 1.40 (s, 9 H), 1.83 (s, 6 H), 3.50 (s, 2 H), 4.33 (s, 2 H),
7.64 (d, J ) 1.7 Hz, 1 H), 7.83 (d, J ) 1.7 Hz, 1 H); 13C NMR
δ 27.55, 29.09, 32.48, 34.19, 41.01, 51.91, 68.48, 84.75, 120.96,
126.79, 130.59, 132.98, 137.64, 161.96, 195.18; IR 2980, 1675,
1594 cm-1; MS m/z 323 (MH+). Anal. (C19H27O2Cl) C, H, Cl.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-3-h yd r oxy-3-m eth ylbu ta n -1-on e (45). Meth od L. To
a solution of 13 (1.07 g, 3.19 mmol) in dry CH2Cl2 (65 mL) at
-78 °C were added i-Pr2NEt (0.97 mL, 5.6 mmol) and then
trimethylsilyl triflate (1.1 mL, 5.6 mmol). The solution was
stirred at -78 °C for 10 min, brought to 23 °C for 45 min, and
then cooled to -78 °C. Acetone (0.54 mL, 7.3 mmol) and TiCl4
(1 M, 4.3 mmol, 4.3 mL) were added sequentially via syringe.
The reaction, judged complete by TLC (15% EtOAc/hexanes)
after 1 h, was warmed to 23 °C and the solvent evaporated.
The resulting dark oil was dissolved in MeOH (25 mL) and
stirred with 1 N HCl (4.3 mL) for 30 min. The MeOH was
removed, the H2O was extracted with CH2Cl2 (3 × 20 mL),
and the organic layers were washed with NaHCO3, dried
(MgSO4), and evaporated to a gummy orange solid (1.10 g).
This solid was taken up in hexanes, filtered to remove
insoluble i-Pr2NEt HCl, and evaporated to an oil. This oil was
purified by medium-pressure chromatography to give 276 mg
(21%) of 45 as a white solid: mp 86-88 °C; 1H NMR δ 1.30 (s,
6 H), 1.33 (s, 9 H), 1.35 (s, 9 H), 3.10 (s, 2 H), 4.35 (s, 2 H),
7.10 (d, J ) 1.5 Hz, 1 H), 7.75 (d, J ) 1.5 Hz, 1 H); 13C NMR
δ 27.51, 29.00, 29.53, 34.15, 40.97, 47.81, 69.87, 84.76, 120.72,
126.53, 130.53, 133.07, 137.77, 162.17, 200.51; IR 3464, 2963,
1721, 1656, 1594 cm-1; MS m/z 305 (MH+). Anal. (C19H28O3)
C, H.
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-b en zofu r a -
n yl)-3-m eth yl-2-bu ten -1-on e (46): method A; mp 56-58; 1H
NMR δ 1.33 (s, 6 H), 1.36 (s, 9 H), 2.05 (s, 3 H), 2.18 (s, 3 H),
4.35 (s, 2 H), 6.70 (s, 1 H), 7.60 (d, J ) 1.7 Hz, 1 H), 7.77 (d,
J ) 1.7 Hz, 1 H); 13C NMR δ 21.04, 27.61, 27.86, 29.21, 34.24,
41.13, 84.68, 120.89, 121.64, 132.43, 126.65, 132.86, 137.50,
154.28, 161.21, 190.84; IR 2958, 1797, 1659, 1614 cm-1; MS
m/z 287 (MH+). Anal. (C19H26O2) C, H.
Biologica l P r oced u r es. 1. Ca r r a geen a n -In d u ced P a w
Ed em a (CP E) Assa y. After a 16-h food fast, left hindpaw
volumes of 180-200-g rats (male Sprague-Dawley rats ob-
tained from Charles River Laboratories) were measured using
a Ugo Basile model 7150 plethysmometer (Stoelting Inc., Wood
Dale, IL). Immediately thereafter, animals (N ) 7/group) were
dosed orally with vehicle (5 mL/kg), tebufelone (positive
control), or test compound at 50 mg/kg. Solid test compounds
were micronized with 25% microcrystalline cellulose (Avicel,
FMC, Philadelphia, PA) and subsequently suspended in a
vehicle of 0.25% methylcellulose (4000 cpi) and 1% Tween 80
(both from Sigma) in double-distilled water. Compounds
which were oils were added directly to the vehicle and vortexed
vigorously to suspend; 1 h later, 50 λ of a 1% suspension of
carrageenan lambda (Sigma) in physiological saline was
injected into the plantar surface of the left hindpaw to induce
inflammation. Paw edema was allowed to develop for 4 h, and
posttreatment paw volumes were determined. The percent
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)-2-th ioa cetoxyeth a n -1-on e (43). 1-(7-ter t-Bu tyl-2,3-
d ih yd r o-3,3-d im eth yl-5-ben zofu r a n yl)-2-br om oeth a n -1-
on e. Meth od I. A solution of 13 (2.46 g, 10.0 mmol) in 25
mL of anhydrous THF was added dropwise to LDA (6.0 mL,
12.0 mmol, 2.0 M solution in heptane-THF-ethylbenzene) at
-78 °C. The resulting solution was stirred at -78 °C for 15
min, and chlorotrimethylsilane (1.5 mL, 12.0 mmol) was
introduced. The reaction mixture was stirred at -78 °C for
15 min, warmed to room temperature, stirred for 1.5 h,
quenched with H2O, and extracted with Et2O. The extract was
dried over anhydrous Na2SO4 and concentrated in vacuo; the
residue was dissolved in 25 mL of anhydrous THF and reacted
at 0 °C with N-bromosuccinimide (1.78 g, 10.0 mmol). The
resulting yellowish solution was kept at 0 °C for 0.5 h, warmed
to room temperature, stirred for 0.5 h, quenched with H2O,
and extracted with Et2O. The extract was dried over anhy-
drous MgSO4 and concentrated in vacuo. Purification of the
residue by flash chromatography on silica gel (5% f 20% Et2O/
hexanes) afforded 2.85 g (88%) of the title compound as a
1
yellowish solid: mp 54-56 °C; H NMR δ 1.36 (s, 6 H), 1.38
(s, 9 H), 4.34 (s, 2 H), 4.40 (s, 2 H), 7.64 (d, J ) 1.8 Hz, 1 H),
7.80 (d, J ) 1.8 Hz, 1 H).
1-(7-ter t-Bu t yl-2,3-d ih yd r o-3,3-d im et h yl-5-ben zofu r a -
n yl)-2-th ioa cetoxyeth a n -1-on e (43). A mixture of 1-(7-tert-
butyl-2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-2-bromoethan-
1-one (0.63 g, 1.9 mmol) and potassium thioacetate (0.22 g,
1.9 mmol) in 10 mL of anhydrous acetone was heated at reflux
for 2 h. The acetone was evaporated, and the residue was
partitioned between Et2Oand H2O; the ethereal layer was dried
over anhydrous MgSO4 and evaporated. Purification by flash

1122 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
J anusz et al.
inhibition (%I) of paw edema by each compound was calculated
using the following formula:
10 min. The cell pellet was washed once with the same volume
of phosphate-buffered saline, and the suspension was again
centrifuged. The platelets were suspended in 5 volumes of 50
mM Tris-HCl buffer (pH 7.5) and subjected to sonication for 3
× 20 s at 4 °C. The suspension was centrifuged at 5000g for
10 min. The supernatant was further centrifuged at 100,000g
for 60 min. The pellet (microsomes) was suspended in 5 mL
of 50 mM Tris-HCl buffer (pH 7.5) and stored in 500-µL
aliquots at -70 °C. This fraction was used as the source of
COX-1.
%I ) [(C - T)/C] × 100
where C is the average difference in paw volume (posttreat-
ment - pretreatment) in the control (vehicle) group and T is
the average difference in test compound-treated animals.
Statistical analysis comparing paw volume ratios (post/pre)
across treatment groups was performed using either least-
squares or robust (M-test) one-way analysis of variance
(ANOVA). Variability in the percent inhibition of paw swelling
in either controls or test compounds affected the statistical
significance such that similar CPE values may or may not be
statistically different from controls.
2. P h en ylqu in on e-In d u ced Abd om in a l Con str iction
(P AC) Assa y. Male CD-1 mice (18-22 g; Harlan Laboratories)
were food-deprived for 4 h and orally dosed with vehicle (10
mL/kg), tebufelone (positive control, 70 mg/kg), or test com-
pound at 10, 40, and 70 mg/kg (N ) 6/group). Dosing solutions
were prepared as described for the CPE assay; 1 h later, 10
mL/kg of a 0.02% solution of phenylquinone (Sigma) was
injected intraperitoneally, and abdominal constrictions were
counted for the ensuing 10 min. Results are expressed as
percent inhibition of writhing using the formula indicated in
the CPE methodology above. Maximal inhibition was about
90%. Statistical analysis comparing responses across treat-
ment groups was performed using either least-squares or
robust ANOVA, and ED50 values were determined using
regression analysis.
3. Th er a p eu tic Ad ju va n t Ar th r itis Assa y. After base-
line paw volumes were measured using a mercury plethys-
mometer, male Lewis rats (190-210 g; Charles River, Portage,
MI) were injected subcutaneously into the base of the tail with
an 8 mg/mL suspension of Mycobacterium butyricum (Difco,
Detroit, MI) in mineral oil at a dose volume of 0.5 mL/kg. On
day 14, paw volumes were again determined, and animals
were randomly divided into treatment groups (N ) 6). From
days 14 to 28, animals were orally dosed with vehicle (5 mL/
kg/day), tebufelone (1, 3, or 10 mg/kg/day, positive control), or
test compound (3, 10, or 30 mg/kg/day). Dosing solutions were
prepared as described for the CPE assay. On day 28, paw
volumes and animal weights were measured, and animals
were euthanized. For graphical representation, data are
expressed as percent inhibition of paw volume increase from
days 14 to 28 using the formula:
COX-2 En zym e: Recombinant human COX-2 was obtained
from Sf9 cells infected with recombinant baculovirus carrying
COX-2 cDNA. Briefly, Sf9 cells (1 × 107) were seeded in 75-
cm2 tissue culture flasks in 20 mL of complete TNF-FH
medium. Cells were allowed to attach for 1 h. The medium
was removed, and 4 mL of Grace’s medium containing recom-
binant virus at a multiplicity of infection of about 10 was
added. After the cells were incubated for 1 h at 27 °C, the
medium was removed and 20 mL of fresh TNM-FH medium
was added. The cells were allowed to grow continuously for
72 h. The cells were then collected by centrifugation at 5000g
for 10 min. The cells were then suspended in 1.0 mL of 50
mM Tris-HCl (pH 7.5) and sonicated for 2 × 10 s at 0 °C. The
crude homogenate was centrifuged at 10000g for 10 s. The
supernatant was then stored at -80 °C and was used as the
source of COX-2
b. En zym e Assa y P r otocol. Cyclooxygenase enzyme
activity, either COX-1 or COX-2, was assayed by the ability
of the enzyme to convert arachidonic acid (AA) to prostaglandin
H2 (PGH2), which was then reduced to prostaglandin F2R
(PGF2R) by SnCl2 added during the reaction. The reaction
mixture contained AA (33 µM), SnCl2 (0.5 mg/mL), inhibitor
(5-keto dihydromethylbenzofurans or controls) at various
concentrations (compounds were dissolved in DMSO at the 1
mg/mL level and then diluted with DMSO to provide working
stock solutions; an aliquot of the appropriate DMSO working
stock solution was then added to the enzyme preparation to
give the desired concentration of inhibitor), and the enzyme
in 0.5 mL of 50 mM Tris-HCl buffer (pH 7.5). The amounts of
COX-1 and COX-2 enzyme activities used for the assay were
adjusted to give comparable conversion of AA to PGH2. The
reaction was initiated by the addition of the enzyme prepara-
tion and was allowed to continue for 5 min at 37 °C. The
reaction was terminated by the addition of 40 µL of 1 N HCl.
The reaction mixture was neutralized by the addition of 60
µL of 1 M Tris base. A portion (30 µL) of the reaction mixture
was diluted to 1 mL with enzyme immunoassay (EIA) buffer,
and 50 µL of the diluted sample was assayed for PGF2R by
EIA. Duplicate samples were run for each inhibitor concen-
tration including the zero concentration sample. Each sample
was assayed for immunoreactive PGF2R in duplicate. The EIA
was carried out in 96-microwell plates precoated with protein
A (1 mg/well) which served to capture the antibody molecules.
Appropriately diluted PGF2R antibodies, samples, or standards
and PGF2R-horseradish peroxidase conjugate were added to
each well. Incubation was allowed to proceed for 1 h. After
unbound materials were removed by washing, the bound
enzyme activity was determined by adding substrate (3,3′,5,5′-
tetramethylbenzidine plus H2O2). The concentrations of the
unknown samples were determined from the standard curve.
The dose-dependent inhibition curve for COX-1 and COX-2 for
each compound was constructed by plotting the percent
inhibition of PGF2R production versus the concentration of the
NoPAIN analogue using the FigP software package (BioSoft,
Cambridge, U.K.). The concentration that gives 50% inhibition
(IC50) was calculated for each analogue. The ratio of the IC50
for COX-1 versus COX-2 (IC50 COX-1/IC50 COX-2) provides an
indication of the specificity of the inhibition. A ratio that is
greater than 1 indicates specificity for COX-2, while a ratio
less than 1 indicates a greater specificity for COX-1.
%I ) [(C - T)/(C - H)] × 100
where C is the average difference in paw volume (day 28 -
day 14) in the control (vehicle) group, T is the average
difference in test compound-treated animals, and H is the
average difference in healthy (nonadjuvant-injected) animals.
For statistical analysis, the mean of the right and left paw
volumes on day 28 was compared across groups using an
ANOVA. ED50 values were calculated using linear regression
of paw volumes vs log(dose).
4. Acu te Ga str ic Sa fety. Rats weighing 180-200 g (N )
6/group) were dosed orally once with vehicle (5 mL/kg),
naproxen (50 mg/kg), or test compound (200, 500, and 1000
mg/kg) and euthanized 4 h later using CO2 asphyxiation. In
a separate study, naproxen was tested in a dose-response of
20, 50, and 100 mg/kg and found to have a UD50 of 31 mg/kg.
Dosing solutions were prepared as described for the CPE
assay. Stomachs were removed, cut open along the greater
curvature, rinsed clean in physiological saline, and spread out
on cards. Both the length and the area of hemorrhagic lesions
were measured using the Image Pro Plus analysis program
(Media Cybernetics, Silver Spring, MD), and both parameters
were statistically compared across treatment groups using a
nonparametric method (Wilcoxon rank-sum test).
5. Hu m a n COX-1/COX-2 Isola ted En zym e Assa ys. a .
En zym e Isola tion . COX-1 En zym e: Outdated human plate-
let concentrate (1 unit) was obtained from local hospitals/blood
banks. The platelet suspension was centrifuged at 1000g for
6. RBL-2H3 In ta ct Cell Assa y for LTB4 In h ibition . Rat
basophilic leukemia cells (RBL-2H3) were grown overnight in
spinner culture in S-MEM (minimum essential media for
suspension culture) with 16% fetal bovine serum, L-glutamine

New Cyclooxygenase-2/ 5-Lipoxygenase Inhibitors. 1
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1123
(11) Weisman, S. M.; Doyle, M. J .; Wehmeyer, K. R.; Hynd, B. A.;
Eichhold, T. H.; Clear, R. M.; Coggeshall, C. W.; Kuhlenbeck,
D. L. Effects of Tebufelone (NE-11740), a New Antiinflamma-
tory Drug, on Arachidonic Acid Metabolism. Agents Actions 1994,
41, 156-163.
(12) Loomans, M. E.; Matthews, R. S.; Miller, J . A. Novel Antiin-
flammatory agents. Pharmaceutical compositions and methods
for reducing inflammation. U.S. Patent 4,708,966, 1987.
(13) A similar metabolite was observed for butylated hydroxytoluene
(BHT); see: Wiebe, L. I.; Mercer, J . R.; Ryan, A. J . Urinary
Metabolites of 3,5-Di-(1-[13C]methyl-1-methylethyl)-4-hydroxy-
toluene (BHT-13C) in Man. Drug Metab. Dispos. 1978, 6, 296-
302.
(2 mM), and penicillin/streptomycin (100 U/100 µg/mL) to a
density of 2.0 × 106 cells/mL. LTB4 inhibitory activity was
assayed for 10 min at 37 °C with controls/test agents (25 µL
preincubated with 1.0 × 107 cells/sample for 30 min at 37 °C)
in 5-mL reaction volumes consisting of assay buffer (140 mM
NaCl, 5 mM KCl, 0.6 mM MgCl2, 2 mM CaCl2, 5 mM glucose,
and 5 mM HEPES, pH 7.4) and 10 µM calcium ionophore
A23187. The reaction was quenched with EDTA, and samples
were centrifuged. Sample supernatant was removed and
stored in 25% methanol at -70 °C until quantitative analysis
by a stable-isotope-based high-performance liquid chromatog-
raphy/electrospray mass spectrometry/mass spectrometry (LC/
MS/MS) method. The samples were prepared for analysis by
spiking a known volume with LTB4-d4, mixing, and performing
solid-phase extraction on octadecylsilane (ODS) cartridges.
Chromatographic isolation of LTB4 and LTB4-d4 from matrix
components was performed on a Waters Symmetry ODS
column (2.1 mm × 150 mm) with a mobile phase of methanol/1
mM ammonium acetate/formic acid (78/22/0.1; v/v/v) at a flow
rate of 0.25 mL/min. The MS/MS detection utilized a selected-
reaction-monitoring scheme where LTB4 and the LTB4-d4 were
monitored using parent-to-daughter transitions of m/z 354.3
f 301.0 and m/z 358.3 f 305.0. The methodology was able
to detect LTB4 at the 100 pg/mL level with an accuracy of 100
( 10%.
(14) Miller, J . A.; Matthews, R. S. A Short, Efficient Synthesis of tert-
Butyl-Hydroxylated Di-tert-butylphenols. J . Org. Chem. 1992,
57, 2514-2516.
(15) Stanetty, P.; Koller, H.; Pu¨rstinger, G. 2,3-Dihydro-7-benzo-
furancarbonsauren. Monatsh. Chem. 1990, 121, 883-891.
(16) Hudec, T. T. Process for the preparation of certain substituted
aromatic compounds. U.S. Patent 4,982,006, 1991.
(17) Barton, D. H. R.; J ang, D. O.; J aszberenyi, J . C. The Invention
of Radical Reactions. 32. Radical Deoxygenations, Dehalogena-
tions, and Deaminations with Dialkyl Phosphites and Hypo-
phosphorous Acid as Hydrogen Sources. J . Org. Chem. 1993, 58,
6838-6842.
(18) Barton, D. H. R.; J ang, D. O.; J aszberenyi, J . C. Hypophospho-
rous Acid and its Salts: New Reagents for Radical Chain
Deoxygenation, Dehalogenation and Deamination. Tetrahedron
Lett. 1992, 33, 5709-5712.
(19) (a) Gibson, T. W.; Echler, R. S. Process for the Preparation of
2-alkyl-4-acyl-6-tert-butylphenol compounds. U.S. Patent 5,126,
487, 1992. (b) Nishinaga, A.; Shimizu, T.; Toyoda, Y.; Matsuura,
T. Oxygenation of 2,6-Di-tert-butylphenols Bearing an Electron-
Withdrawing Group in the 4-Position. J . Org. Chem. 1982, 47,
2278-2285.
Ack n ow led gm en t. We would like to thank Profes-
sor Daniel Tai of the University of Kentucky for the in
vitro COX-1/COX-2 inhibition data.
(20) Nahm, S.; Weinreb, S. M. N-Methoxy-N-Methylamides as Ef-
fective Acylating Agents. Tetrahedron Lett. 1981, 22, 3815-3818.
(21) Ito, Y.; Hirao, T.; Saegusa, T. Synthesis of R,â-Unsaturated
Carbonyl Compounds by Palladium(II)-Catalyzed Dehydrosilyl-
ation of Silyl Enol Ethers. J . Org. Chem. 1978, 43, 1011-1013.
(22) Kajigaeshi, S.; Kakinami, T.; Moriwaki, M.; Fujisaki, S.; Maeno,
K.; Okamoto, T. R-Chlorination of Aromatic Acetyl Derivatives
with Benzyltrimethylammonium Dichloroiodate. Synthesis 1988,
545-546.
Refer en ces
(1) Lombardino, J . G. Nonsteroidal Antiinflammatory Drugs; Wiley-
Interscience, J ohn Wiley & Sons: New York, 1985.
(2) Asako, H.; Kubes, P.; Wallace, J .; Gaginella, T.; Wolf, R. E.;
Granger, N. Indomethacin-induced Leukocyte Adhesion in Me-
senteric Venules: Role of Lipoxygenase Products. Am. J . Physiol.
1992, 262 (5), G903-G908.
(3) Moore, G. G. I.; Swingle, K. F. 2,6-Di-tert-butyl-4-(2′-thenoyl)-
phenol (R-830): A Novel Nonsteroidal Antiinflammatory Agent
with Antioxidant Properties. Agents Actions 1982, 12, 674-683.
(4) Hidaka, T.; Hosoe, K.; Ariki, Y.; Takeo, K.; Yamashita, T.;
Katsumi, I.; Kondo, H.; Yamashita, K.; Watanabe, K. Pharma-
cological Properties of a New Antiinflammatory Compound,
R-(3,5-Di-Tert-Butyl-4-Hydroxybenzylidene)-γ-Butyrolactone
(KME-4), and Its Inhibitory Effects on Prostaglandin Syn-
thetase and 5-Lipoxygenase. J pn. J . Pharmacol. 1984, 36, 77-
85.
(5) Katayama, K.; Shirota, H.; Kobayashi, S.; Terato, K.; Ikuta, H.;
Yamatsu, I. In Vitro Effect of N-Methoxy-3-(3,5-di-tert-butyl-4-
hydroxy-benzylidene)-2-pyrrolidone (E-5110), a Novel Nonste-
roidal Antiinflammatory Agent, on Generation of Some Inflam-
matory Mediators. Agents Actions 1987, 21, 269-271.
(6) Unangst, P. C.; Connor, D. T.; Cetenko, W. A.; Sorenson, R. J .;
Kostlan, C. R.; Sircar, J . C.; Wright, C. D.; Schrier, D. J .; Dyer,
R. D. Synthesis and Biological Evaluation of 5[[3,5-Bis(1,1-
dimethylethyl)-4-hydroxyphenyl]methylene]oxazoles, -thiazoles,
and -imidazoles: Novel Dual 5-Lipoxygenase and Cyclooxyge-
nase Inhibitors with Antiinflammatory Activity. J . Med. Chem.
1994, 37, 322-328.
(7) Swingle, K. F.; Bell, R. L.; Moore, G. G. I. Antiinflammatory
activity of antioxidants. In Antiinflammatory and Anti-Rheu-
matic Drugs; Rainsford, K. D., Ed.; CRC Press: Boca Raton, FL,
1985; Vol. III, pp 105-126.
(8) (a) 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. (b) Futaki, N.; Takahashi, S.;
Yokoyama, M.; Arai, I.; Higuchi, S.; Otomo, S. NS-398, A New
Antiinflammatory Agent, Selectively Inhibits Prostaglandin G/H
Synthase/Cyclooxygenase (COX-2) Activity in Vitro. Prostaglan-
dins 1994, 47, 55-59.
(23) Mukaiyama, T. The Directed Aldol Reaction. Org. React. 1982,
28, 203-335.
(24) As an example, compound 30 inhibited paw edema by 34% while
tebufelone inhibited paw edema by 47% in the same experiment,
for a CPE index of 0.72.
(25) Ortiz de Montellano, P. R.; Correia, M. A. Suicidal Destruction
of Cytochrome P-450 During Oxidative Drug Metabolism. Annu.
Rev. Pharmacol. Toxicol. 1983, 23, 481-503.
(26) Satoh, H.; Inada, I.; Hirata, T.; Maki, Y. Indomethacin produces
gastric antral ulcers in the refed rat. Gastroenterology 1981, 81,
719-725.
(27) Battistini, B.; Botting, R.; Bakhle, Y. S. COX-1 and COX-2:
Toward the Development of More Selective NSAIDS. Drug News
Perspect. 1994, 7, 501-512.
(28) Katsumi, I.; Kondo, H.; Yamashita, K.; Hidaka, T.; Hosoe, K.;
Yamashita, T.; Watanabe, K. Studies on Styrene Derivatives. I.
Synthesis and Antiinflammatory Activities of R-Benzylidene-γ-
butyrolactone Derivatives. Chem. Pharm. Bull. 1986, 34, 121-
129.
(29) Sercel, A. D.; Song, Y.; Belliotti, T.; Beylin, V. G.; Connor, D. T.;
Marlatt, M. E.; Sorenson, R. J .; Unangst, P. C.; Gilbertsen, R.
B.; Chan, K.; Schrier, D. J .; Laemont, K.; Okonkwo, G. C.;
Guglietta, A.; Bornemeier, D. A.; Dyer, R. D. SAR Studies of
Substituted Di-tert-butylphenols as Selective COX-2 Inhibitors.
213th ACS National Meeting, April 1997; Med. Chem. Poster
#72.
(30) For recent reports on COX-2-selective di-tert-butylphenol inhibi-
tors, see: (a) Song, Y.; Connor, D. T.; Doubleday, R.; Sorenson,
R. J .; Sercel, A. D.; Unangst, P. C.; Cornell, W.; Gilbertsen, R.
B.; Chan, K.; Schrier, D. J .; Laemont, K.; Okonkwo, G. C.;
Guglietta, A.; Bornemeier, D. A.; Dyer, R. D. Synthesis and SAR
Studies of Novel Di-tert-butylphenols as Selective PGHS-2
Inhibitors. 213th ACS National Meeting, April 1997; Med. Chem.
Poster #73. (b) Song, Y.; Connor, D. T.; Sercel, A. D.; Sorenson,
R. J .; Doubleday, R.; Unangst, P. C.; Roth, B. D.; Cornell, W.;
Gilbertsen, R. B.; Chan, K.; Schrier, D. J .; Laemont, K.;
Okonkwo, G. C.; Guglietta, A.; Bornemeier, D. A.; Dyer, R. D.
Substituted Di-tert-butylphenols: A New Class of Potent and
Selective PGHS-2 Inhibitor. 213th ACS National Meeting, April
1997; Med. Chem. Poster #74.
(9) Reitz, D. B.; Li, J . J .; Norton, M. B.; Reinhard, E. J .; Collins, J .
T.; Anderson, G. D.; Gregory, S. A.; Koboldt, C. M.; Perkins, W.
E.; Seibert, K.; Isakson, P. C. Selective Cyclooxygenase Inhibi-
tors: Novel 1,2-Diarylcyclopentenes are Potent and Orally Active
COX-2 Inhibitors. J . Med. Chem. 1994, 37, 3878-3881.
(10) Sietsema, W. K.; Kelm, G. R.; Deibel, R. M.; Doyle, M. J .;
Loomans, M. E.; Smyth, R. E.; Kinnett, G. O.; Eichhold, T. H.;
Farmer, R. W. Absorption, Bioavailability, and Pharmacokinetics
of Tebufelone in the Rat. J . Pharm. Sci. 1993, 82, 610-612.
J M970679Q