2,2-dimethyl-4,5-diaryl-3(2H)furanone derivatives as selective cyclo-oxygenase-2 inhibitors

Article abstract of DOI:10.1016/S0960-894X(00)00634-X

A series of 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-phenyl-3(2H)furanones was prepared and evaluated for their ability to inhibit cyclo-oxygenase-2 (COX-2).

Full text of DOI:10.1016/S0960-894X(00)00634-X

Bioorganic & Medicinal Chemistry Letters 11 (2001) 165±168
2,2-Dimethyl-4,5-diaryl-3(2H)furanone Derivatives as Selective
Cyclo-oxygenase-2 Inhibitors
Song Seok Shin, Min-Soo Noh, Young Joo Byun, Jin Kyu Choi, Ji Young Kim,
Kyung Min Lim, Jun-Yong Ha, Jin Kwan Kim, Chang Hoon Lee and Shin Chung*
Drug Discovery, Paci®c Corporation R&D Center, 314-1 Bora-ri, Kiheung-eup, Yongin-si, Kyounggi-do 449-900, South Korea
Received 29 September 2000; accepted 28 October 2000
AbstractÐA series of 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-phenyl-3(2H)furanones was prepared and evaluated for their
ability to inhibit cyclo-oxygenase-2 (COX-2) # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
large extent, there are still strong demands for a COX-2
inhibitor with improved ecacy and safety pro®les. For
example, a high daily dosing level of celecoxib would be a
metabolic burden for the elderly, who are often metaboli-
cally insucient. Recently, rofecoxib experienced negative
comment regarding its cardiovascular adverse e€ects.5
There are at least two kinds of cyclo-oxygenases.1
Cyclo-oxygenase-1 (COX-1) is constitutively expressed
in the gastro-intestinal tract and the kidney. COX-1 is
known to be responsible for the maintenance of physio-
logical homeostasis, such as gastrointestinal integrity
and renal function. Interruption of COX-1 activity can
lead to life-threatening gastro-intestinal toxicity of per-
foration, ulceration and bleeding. In the meantime,
cyclooxygenase-2 (COX-2) is induced upon in¯amma-
tory stimuli and is responsible for progression of
in¯ammation. Thus, selective inhibition of COX-2 over
COX-1 is useful for the treatment of in¯ammation and
in¯ammation-associated disorders with reduced gastro-
intestinal toxicities when compared with traditional non-
steroidal antiin¯ammatory drugs (NSAIDs).2
Phenyl sulfone-containing cis-1,2-diaryl-alkenes or their
structural equivalents are known to be a pharmacophore
for achieving selective COX-2 inhibition over COX-1.6 In
this paper will be presented a novel class of 2,2-dimethyl-
4,5-diaryl-3(2H)furanones (1), which are orally active,
highly potent and selective COX-2 inhibitors.
Synthesis
A synthetic route for 4,5-diaryl-3(2H)furanones (1) is
outlined in Scheme 1. 4-(Methylthio)benzaldehyde was
coupled with the in situ generated lithium acetylenide of
2 to a€ord diol 3. The benzylic hydroxyl group of 3 was
then smoothly oxidized to the corresponding ketone 4
with manganese dioxide (MnO2).7 The acyclic ketone 4
was cyclized to give 5-aryl-2,2-dimethyl-3(2H)-furanone
5 by using diethylamine as a catalyst in methanol as
described previously.8 The oxidation of 5 by OXONE was
followed by a halogenation reaction either with bromine
in acetic acid or with iodine, in the presence of a catalytic
amount of BTI ({bis(tri¯uoroacetoxy)iodo}benzene),9 to
a€ord the corresponding bromide or iodide compound 6,
respectively. The halide 6 was ®nally subjected to Suzuki
coupling reaction with an appropriate arylboronic acid to
give diaryl compound 1.10 Synthetic details for Scheme
1 can be found in ref 11.
Even though blockbuster COX-2 inhibitors such as cele-
coxib3 and rofecoxib4 are considered to have resolved the
gastro-intestinal toxicities of traditional NSAIDs to a
*Corresponding author. Tel.: +82-31-281-8340; fax: +81-31-284-3995;
e-mail: schung@paci®c.co.kr
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00634-X

166
S. S. Shin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 165±168
Scheme 1. Reaction conditions: (a) (i) n-BuLi (2.2 equiv)/THF, 78ꢀC; (ii) 4-(methylthio)benzaldehyde, 81%; (b) MnO2/CH2Cl2, 81%; (c) (Et2)NH/
CH3OH, 75%; (d) Oxone1/THF/CH3OH/H2O; (e) Br2/AcOH/CH2Cl2, 86% two steps or cat. BTI/I2/CCl4, 82% two steps; (f) arylboronic acid,
Pd(PPh3)4, aq NaHCO3/toluene±EtOH (3:1), Á.
Results and Discussion
ities were observed for some of the furanones, far
exceeding that of celecoxib (Table 3 and Fig. 1). Since
Compounds of this study were evaluated for their ability
to inhibit COX-2 and COX-1 by using freshly harvested
mouse peritoneal macrophages as described in the lit-
erature.12 The results of inhibition are summarized in
Table 1. As shown in Table 1, 4,5-diaryl-3(2H)furanone
derivatives inhibit COX-2 selectively over COX-1 and
most of the compounds possess COX-2/COX-1 selec-
tivity over 100-fold.
adjuvant arthritis is a more realistic animal model for
human arthritis than carrageenan-induced rat paw
edema, the pronounced activities of 3(2H)furanones in
adjuvant arthritis need to be addressed.15
When rats were orally administered once daily with
either 1h or 1o at 10 mg/kg/day for 4 weeks, there was
no detectable evidence of gastric toxicity upon autopsy
examinations of the stomach.16 Thus, the 3(2H)furan-
one derivatives could be drug candidates without gastric
adverse e€ects, which are frequently encountered with
traditional NSAIDs.
The in vivo oral antiin¯ammatory activities of 3(2H)-
furanone derivatives were evaluated by the inhibition of
carrageenan-induced rat paw edema according to the lit-
erature.13 Table 2 indicates that 3(2H)furanone deriva-
tives of this study are orally active with antiin¯ammatory
potency comparable to celecoxib.
Summary
When 3(2H)furanone derivatives were evaluated by
adjuvant arthritis test,14 impressively strong oral activ-
A novel class of 2,2-dimethyl-4,5-diaryl-3(2H)furanone
derivatives was synthesized and evaluated to be highly
selective and potent COX-2 inhibitors. The pronounced
oral antiin¯ammatory potency in adjuvant arthritis
Table 1. Inhibitory e€ects of 4,5-diaryl-2,2-dimethyl-3(2H)furanone
(1) derivatives on COX-1 and COX-2 (mouse macrophage method)
Table 2. Inhibition data of 3(2H)furanones for carrageenan-induced
paw edema in Sprague±Darley rats
IC50 (mg/mL)a
Compound
R
COX-2 COX-1 COX-2 selectivity
over COX-1
Compound
% Inhibitiona
1f
1g
1h
1o
32
32
36
34
31
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
H
2-CH3
2-OCH3
2-Cl
3-iso-Pr
3-Cl
3-CF3
0.05
0.3
0.1
0.3
3
20
50
50
30
2
3
5
50
3
3
3
20
5
20
50
60
67
500
167
1000
200
60
250
1000
100
150
100
667
100
667
167
93
Celecoxib
0.03
0.01
0.05
0.02
0.05
0.03
0.02
0.03
0.03
0.05
0.03
0.3
aPercent of inhibition at 3 mg/kg body weight by oral administration
and inhibition values were determined using ®ve animals/group.
3-F
3-COCH3
4-iso-Pr
4-n-Pr
Table 3. Therapeutic e€ects of the 3(2H)furanones on adjuvant
arthritis in Sprague±Darley rats
3-Cl, 5-Cl
2-F, 5-F
3-F, 4-F
3-F, 5-F
4-{CH(OH)CH3}
a
Compound
Adjuvant arthritis ED50 (mg/kg/day)
1g
1h
0.06
0.08
0.03
0.2
1p
Celecoxib
Rofecoxib
0.02
0.06
1.86
>100
1o
Celecoxib
>1667
aEach result is the average of at least two determinations.
aED50 values were determined using 7±8 animals/group per dose.

S. S. Shin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 165±168
167
Figure 1. Dose-dependent inhibition of adjuvant arthritis (therapeutic model).
The reaction solution was stirred at rt for 1 h. Then the reaction
was quenched by adding 20 mL of saturated aqueous sodium
thiosulfate solution. After removing the carbon tetrachloride
in vacuo, the resulting residue was extracted with CH2Cl2,
dried over MgSO4 and then concentrated in vacuo. The
resulting residue was chromatographed (SiO2, hexane/ethyl-
acetate, 2:1) to yield 69 mg (89%) of 4-bromo-2,2-dimethyl-5-
{4-(methylthio)phenyl}-3(2H)furanone as an oil. 1H NMR
(300 MHz, CDCl3): d 1.52 (s, 6H), 2.55 (s, 3H), 7.33 (d,
J=9.3 Hz, 2H), 8.15 (d, J=9.0 Hz, 2H); IR (cm 1): 1704,
1594, 1574, 1486, 1348, 1184, 1069.
would place 2,2-dimethyl-4,5-diaryl-3(2H)furanones in
a highly promising position for development of the next
generation anti-arthritic medications.
References and Notes
1. Hia, T.; Neilson, T. Proc. Natl. Acad. Sci. U.S.A. 1992, 89,
7384.
4-Bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)fur-
anone (6). 4-Bromo-2,2-dimethyl-5-{4-(methylthio)phenyl}-3-
(2H)furanone (42 mg) and 178 mg of Oxone were dissolved in
15 mL THF/15 mL ethanol/10 mL H2O and stirred overnight
at rt. Then the solvent was removed in vacuo. The resulting
residue was extracted and then dried over MgSO4. The organic
layer was concentrated under reduced pressure and the result-
ing residue was subjected to column chromatographic separa-
tion (SiO2, hexane/ethyl acetate, 2:1) to a€ord 45 mg (97%) of
desired 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-
3(2H)furanone. Mp, 196±196.5 ꢀC. 1H NMR (300 MHz,
CDCl3): d 1.57 (s, 6H), 3.11 (s, 3H), 8.11 (d, J= 8.7 Hz, 2H), 8.40
(d, J=8.7Hz, 2H). IR (cm 1): 2928, 1703, 1559, 1270, 1148,
1076, 847. MS (EI): 346 (m).
2. (a) Pairet, M.; Churchill, L.; Engelhardt, G. In New Targets
in In¯ammation: Inhibitors of COX-2 or Adhesion Molecules;
Bazan, N.; Botting, J.; Vane, J., Eds.; Kluwer Academic:
London, 1996; pp 23±38. (b) Reitz, D. B.; Seibert, K. Ann.
Rep. Med. Chem. 1995, 30, 179.
3. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Mal-
echa, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu,
S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gre-
gory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med.
Chem. 1997, 40, 1347.
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O'Neill, G. P.; Ouellet, M.; Percival, M. D.; Perrier, H.;
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thesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 7, pp 252±286. (b) Procter, G. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 7, pp 305±325.
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9. (a) Grimmett, M. R. Adv. Heterocycl. Chem. 1993, 57, 291.
(b) Merkushev, E. B. Synthesis 1988, 923.
A typical Suzuki coupling reaction is described as follows to
prepare 3(2H)furanone derivatives (1).
2,2-Dimethyl-4-(3-¯uorophenyl)-5-{4-(methylsulfonyl)phenyl}-
3(2H)furanone (1h). To a stirred solution of 4-bromo-2,2-
dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)furanone (6, 170
mg) in 30 mL toluene and 10 mL ethanol, were added 25 mg of
tetrakis(triphenylphosphine)palladium(0), 10 mL of saturated
aqueous sodium bicarbonate, and 100 mg of 3-¯uoroben-
zeneboronic acid. The reaction solution was stirred at 90 ꢀC
for 12 h. Then the solvent was removed under reduced pres-
sure. The resulting residue was extracted with CH2Cl2. The
organic layer was dried and concentrated in vacuo. Then the
residue was puri®ed by column chromatography (SiO2, hex-
ane/ethyl acetate) to yield 120 mg (68%) of 2,2-dimethyl-4-(3-
¯uorophenyl)-5-{4-(methylsulfonyl)-phenyl}-3(2H)furanone
(1h). Mp, 178±179 ꢀC. H NMR (300 MHz, CDCl3): d 1.58 (s,
1
6H), 3.08 (s, 3H), 7.05 (m, 3H), 7.33 (m, 1H), 7.83 (d, J=8.7 Hz,
2H), 7.95 (d, J=8.4 Hz, 2H). IR (cm 1): 3020, 1697, 1620, 1403,
1318, 1149, 958, 768. MS (FAB): 361 (m+1).
12. (a) Mitchell, J. A.; Akarasereenont, P.; Thiemermann, C.;
Flower, R. J.; Vane, J. R. Proc. Natl. Acad. Sci. U.S.A. 1994,
90, 11693. (b) Klein, T.; Nusing, R. M.; Pfeilschifter, J.; Ull-
rich, V. Biochem. Pharmacol. 1994, 48, 1605.
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chi, S.; Iizuka, H.; Otomo, S. Gen. Pharacol. 1993, 24, 105.
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47, 26.
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Chem. Soc. Jpn. 1988, 61, 3008.
11. Compounds of Scheme 1 were prepared as follows.
4-Bromo-2,2-dimethyl-5-{4-(methylthio)phenyl}-3(2H)furanone.
To a stirred solution of 2,2-dimethyl-5-{4-(methylthio)-
phenyl}-3(2H)furanone (5, 58mg) in 20 mL carbon tetra-
chloride, were added acetic acid (0.5mL) and bromine (0.1mL).

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S. S. Shin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 165±168
15. Even though the human daily dose for arthritic indica-
tions for a COX-2 inhibitor can be determined through human
clinical trials, a certain degree of correlation is available
between the human daily dose for arthritis and adjuvant arthritis
ED50 of COX-2 inhibitors, such as celecoxib, rofecoxib, valde-
coxib, meloxicam, and so on. Adjuvant arthritis ED50 may serve
as a measure for the human daily dose for arthritis. Since
3(2H)furanone derivatives 1g, 1h and 1o possess appreciably
higher activities of adjuvant arthritis than celecoxib, 1g, 1h
and 1o are likely to have daily arthritis doses far lower than
celecoxib, which could be translated into a reduced metabolic
burden to the elderly.
16. When 1h and 1o were orally administered to Sprague±
Darley rats at 10 mg/kg, quaque die for 13 weeks, there was
no observed evidence of renal anomalies. The renal functions
appeared normal as indicated by serum biochemistry (BUN and
creatinine) as well as histologic examinations of the kidneys.
Considering renal safety of 1h and 1o in Sprague±Darley rats, 1h
and 1o are not likely to have cardiovascular problems arising
at least from renal malfunctions.