3,4-Diaryl-5-hydroxyfuranones: Highly selective inhibitors of cyclooxygenase-2 with aqueous solubility

Article abstract of DOI:10.1016/S0960-894X(03)00046-5

The introduction of a hydroxyl group into the 5-position of the diaryl furanone system provides highly selective inhibitors of cyclooxygenase-2. These molecules can be converted into their sodium salts which are water soluble, facilitating intravenous formulation. These salts show excellent potency in rat models of pain, fever and inflammation.

Full text of DOI:10.1016/S0960-894X(03)00046-5

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1195–1198
3,4-Diaryl-5-hydroxyfuranones: Highly Selective Inhibitors of
Cyclooxygenase-2 with Aqueous Solubility
W. Cameron Black,* Christine Brideau, Chi-Chung Chan, Stella Charleson,
Wanda Cromlish, Robert Gordon, Erich L. Grimm, Gregory Hughes, Serge Leger,
Chun-Sing Li, Denis Riendeau, Michel Therien, Zhaoyin Wang, Li-Jing Xu
and Petpiboon Prasit
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Quebec, Canada H9R 4P8
Received 26 September 2002; accepted 26 November 2002
Abstract—The introduction of a hydroxyl group into the 5-position of the diaryl furanone system provides highly selective inhibi-
tors of cyclooxygenase-2. These molecules can be converted into their sodium salts which are water soluble, facilitating intravenous
formulation. These salts show excellent potency in rat models of pain, fever and inflammation.
# 2003 Elsevier Science Ltd. All rights reserved.
Selective inhibitors of cyclooxygenase-2 (COX-2) have
been demonstrated to be clinically effective anti-
inflammatory and analgesic drugs with reduced gastro-
intestinal toxicity as compared to NSAIDs.1 This
improved safety profile is attributable to the lack of
inhibition of COX-1, which plays a role in cytoprotec-
tion of the GI tract. There is currently interest in the
identification of a COX-2 inhibitor suitable for par-
enteral administration. One such molecule is parecoxib,
a prodrug which requires metabolic activation to give
the active drug, valdecoxib.2 There could be an advan-
tage to a COX-2 inhibitor with intrinsic water-solubility
that could be administered orally or intravenously
without having to resort to a prodrug approach. The
5-hydroxyfuranones described here have the potential to
fulfil such a role.
Extensive exploration of the furanone template has
revealed that the introduction of alkyl substituents at
the 5-position of the ring provides enhanced selectivity
over COX-1.8 Furthermore, the 2-phenyl substituent
can be replaced with a wide variety of groups, in many
cases improving both potency and selectivity of the
resulting inhibitors.9
Phenylsulfone- and phenylsulfonamide-containing tri-
cyclic molecules have proved to be a fertile area for the
discovery of selective inhibitors of COX-2. A number of
central ring templates have been successfully devel-
oped.3 Among these are the furanone of rofecoxib,4 the
trifluoromethyldiazole of celecoxib,5 the chloropyridine
of etoricoxib,6 and the isoxazole ring of valdecoxib.7
We wish to report that the introduction of a hydroxyl
group into the 5-position of the furanone ring provides
compounds with beneficial biological and physical
properties. Alkoxy substituents in this position provide
potent and highly selective inhibitors of COX-2.
Hydroxyl-substituted furanones, while being somewhat
*Corresponding author. Fax: +1-514-428-4939; e-mail: blackc@
merck.com
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00046-5

1196
W. C. Black et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1195–1198
less potent than their alkoxy analogues, are also highly
selective for COX-2. Furthermore these compounds can
be readily converted into water-soluble salts.
large amount of a circulating metabolite, which was sub-
sequently identified to be the demethylated material 3.
In an attempt to limit this route of metabolism, several
alkyl ether substituents on the furanone ring were eval-
uated (Table 1). Increasing the size of the alkyl group
gave a gradual reduction in the COX-2 activity. Phar-
macokinetic evaluation showed that although the larger
alkyl groups were successful at reducing the amount of
the circulating metabolite 3, the overall oral bioavail-
ability decreased dramatically. The trifluoroethyl deri-
vative 7 provided an exception to this trend. It exhibited
reasonable COX-2 activity and an oral bioavailability in
rats of 35%. However, it gave only modest efficacy in
the rat paw edema assay and was not pursued further.
The majority of the compounds listed in Table 1 were
prepared using the route outlined in Scheme 1. a-Bromo
ketone A was prepared by known methods.10 The bro-
mide was displaced by the triethylammonium salt of an
arylacetic acid to provide the corresponding ester, which
underwent an intramolecular aldol condensation in the
presence of DBU. If oxygen was rigourously excluded,
the intermediate 5-methyl furanone B could be isolated.
However, exposure to air in the presence of the base led
to rapid oxidation of the ring, providing the desired
hydroxyfuranone C.11 In practice, the cyclization and
oxidation were accomplished in one step by treating the
ester with DBU followed by passing a stream of air
through the dark solution using a gas diffusion tube.
Alkyl ethers D were formed by heating a solution of the
hydroxyfuranone with the appropriate alcohol in the
presence of sulfuric acid.
The 5-hydroxyfuranone template was chosen for further
study and the nature of the aryl group at the 3-position
of the furanone ring was evaluated. Previous experience
in other series had shown that aryl groups with para
substituents increase potency against COX-1 while meta
substituents decrease COX-1 potency.4 In the hydro-
xyfuranone series, this trend was difficult to ascertain,
since little or no inhibition was observed in the COX-1
assays for most compounds. However, the 4-thio-
methoxy substituent 11 did result in a significant
increase in COX-1 activity. Other lipophilic substituents
in the 4-position of the phenyl were well-tolerated. The
4-chlorophenyl derivative 9 was found to have the best
overall profile of COX-2 potency and antiinflammatory
activity. The more polar hydroxyphenyl derivative 13
was inactive in the COX-2 assays, consistent with the
requirement for a lipophilic group in this position of the
inhibitor. Halogen substituents in the ortho or meta
positions of this ring led to reduced potency in the COX-
2 assays (14–16, 19), with the exception of a meta chloro
substituent, which appeared particularly well-tolerated
(17 and 18). Several heterocyclic groups were explored as
phenyl replacements, without success (21–23).
The initial 5-hydroxy-5-methylfuranone 3 (Table 1) was
found to have only modest activity in the COX-2 CHO
cell assay.12 However, its complete lack of activity
against COX-1 in the sensitive U937 microsome assay13
justified further study. It was found that the potency of
3 in the COX-2 whole blood assay14 was relatively good,
implying a small protein shift in this protein-rich assay.
Pharmacokinetics in rats showed high drug exposure
(60 mM Cmax following a 20 mg/kg oral dose) and a low
clearance (2.6 mL/min). This prompted us to evaluate
the compound in our standard model of in vivo anti-
inflammatory activity, the rat paw edema assay15 where
it proved to be equally efficacious to rofecoxib.
Since the chemical behaviour of this hydroxyfuranone
was reminiscent of a weak acid (vide infra), it was trea-
ted with diazomethane, leading to the methyl ether 4.
This derivative was found to be 5-fold more potent than
3 in the CHO assay, and nearly 15-fold more potent in
the COX-2 whole blood assay. While the undesired
COX-1 activity of 4 was greater than that of 3, its
selectivity profile was markedly superior to that of
rofecoxib and celecoxib, particularly in the critical
whole blood assays. Pharmacokinetic evaluation
showed modest plasma concentrations of 4, but also a
Previous studies in the 5,5-dimethylfuranone series had
found that oxygen and sulfur substituents in the 3-posi-
tion were well-tolerated and provided potent and selec-
tive inhibitors of COX-2.9 In the case of the
hydroxyfuranones, it was surprising to see that such
substitution gave inactive compounds (24 and 25).
These hydroxyfuranones have several distinctive char-
acteristics compared to other furanone derivatives we
have encountered in the COX-2 program. Their lack of
potency against COX-1 is remarkable, with undetect-
able activity under our assay conditions in many cases.
While most furanone derivatives have limited aqueous
solubility, the hydroxyfuranones are freely soluble in
aqueous base. This can be explained by the formation of
the salt of an open chain isomer under basic conditions
(Scheme 2). This salt can be isolated as an amorphous
solid which contains none of the corresponding cyclic
1
alkoxide by H NMR analysis. At neutral or acidic pH,
the molecule exists exclusively in the cyclic form as evi-
denced by 1H NMR and IR analysis. The aqueous
solubilities of 26 and 27 are >100 mg/mL, but decrease
rapidly as the solution is acidified below pH 8.3.16
A
Scheme 1.

W. C. Black et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1195–1198
Table 1. In vitro and rat paw edema data for diarylalkoxy- and diarylhydroxyfuranones
1197
Entry
R
Ar
COX-2
COX-1
Human whole blood
CHO cells
(IC50, mM)
Human whole blood
(IC50, mM)
U937 microsomes
(IC50, mM)
Rat paw edema
(ED50, mg/kg)
(IC50, mM)
1
2
3
4
5
6
7
8
Rofecoxib
Celecoxib
0.02
0.5
1.0
1.8
0.1
0.5
0.8
0.4
1.2
1.7
1.7
1.7
4.3
1.7
0.05
>100
14
10
3
>10
>100
105
19
6.3
1.5
3.2
1.8
2.8
0.002
0.38
0.069
H
Me
Et
iPr
4-F-Ph
4-F-Ph
4-F-Ph
4-F-Ph
4-F-Ph
Ph
4-Cl-Ph
4-Br-Ph
4-MeS-Ph
4-iPr-Ph
4-HO-Ph
3-F-Ph
3,4-F2-Ph
3,5-F2-Ph
3-Cl-4-F-Ph
3,4-Cl2-Ph
2,4-Cl2-Ph
2-Np
57
CF3CH2–
0.32
0.16
0.11
0.14
0.31
0.41
>5
0.25
0.20
0.55
0.11
0.07
1.2
6.4
1.5
1.4
1.6
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
>90
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
101
7
>100
38
>100
>300
>10
>100
>300
>100
81
35
>100
30
>100
>100
>100
>10
>10
>33
12.8
6.3
13.4
2.2
>10
>10
>90
0.85
7.5
3.2
75
1.9
0.45
1.9
0.11
0.65
>5
>10
2-Thienyl
3-Thienyl
2-Benzothiophene
SPh
>33
24
3.2
>10
>33
O-(3,4-F2-Ph)
>5
compound 9 shows aqueous solubility due to the for-
mation of an open-chain salt. This solubility allows for
the preparation of stable aqueous solutions that may be
suitable for intravenous formulation.
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100 mg/mL solution of 26 in water was allowed to stand
at room temperature for 8 weeks without evidence of
decomposition.
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class of cyclooxygenase-2 inhibitors. Furthermore,

1198
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