2,3-Diarylpyran-4-ones: A new series of selective cyclooxygenase-2 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2004.02.028

A new series of cyclooxygenase-2 (COX-2) inhibitors with γ-pyrone as central scaffold unit has been synthesized and their biological activities were evaluated against cyclooxygenase inhibitory activity. The changes of physical properties of the molecules were performed according to the medicinal chemistry principles and moderate oral anti-inflammatory activity was obtained with this series of inhibitors.

Full text of DOI:10.1016/j.bmcl.2004.02.028

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2195–2198
2,3-Diarylpyran-4-ones: a new series of selective
cyclooxygenase-2 inhibitors
Yung Hyup Joo,* Jin Kwan Kim, Seon-Hwa Kang, Min-Soo Noh, Jun-Yong Ha,
Jin Kyu Choi, Kyung Min Lim and Shin Chung
Drug Discovery, AmorePacific Corporation R&D Center, Pharmaceutical & Health Research Institute,
314-1 Bora-ri, Kiheung-eup, Yongin-si, Kyounggi-do 449-729, South Korea
Received 24 November 2003; revised 5 February 2004; accepted 5 February 2004
Abstract—A new series of cyclooxygenase-2 (COX-2) inhibitors with c-pyrone as central scaffold unit has been synthesized and their
biological activities were evaluated against cyclooxygenase inhibitory activity. The changes of physical properties of the molecules
were performed according to the medicinal chemistry principles and moderate oral anti-inflammatory activity was obtained with this
series of inhibitors.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Even though selective COX-2 inhibitors are regarded to
have reduced the notorious GI toxicity of traditional
NSAIDs to a large extent, there appears to be some
room for improvement especially in renal and cardio-
vascularsafety. Next genaetrion selective COX-2
inhibitors are expected to address in more detail issues
relating to the cardio-renal safety.2
Traditional nonsteroidal anti-inflammatory drugs
(NSAIDs) inhibit both cyclooxygenase-1 (COX-1) and
cyclooxygenase-2 (COX-2). Even though NSAIDs are
effective in the management of inflammation and pain,
chronic use of NSAIDs has been associated with
unwanted adverse effects including gastrointestinal PUB
(perforation, ulceration, and bleeding), and renal toxic-
ity. Inhibition of constitutively expressed COX-1 inter-
rupts bodily homeostasis and is known to contribute
much to such adverse effects.1 On the otherhand, the
anti-inflammatory effect of NSAIDs appears to be orig-
inating from inhibition of COX-2, being induced upon
inflammatory stimuli. Therefore, selective inhibition of
COX-2 could be suitable to treat inflammation and
inflammation-associated disorders without incurring
adverse effects from inhibition of COX-1, which had been
the main theme fordevelopment of blockbusterselective
COX-2 inhibitors such as celecoxib and rofecoxib.
Previously, we reported that naturally occurring flavone
scaffold could be useful to achieve selective inhibition of
COX-2 overCOX-1. COX-2 inhibitors with the benzo-
pyran scaffold in Scheme 1 showed poor oral anti-
inflammatory activity despite their strong COX-2
inhibitory potency, though. The poor oral anti-inflam-
matory activity was ascribed to the poor oral bioavail-
ability due to the hydrophobic nature of the tricyclic
COX-2 inhibitors.3 In this article, will be discussed
N
O
Approach A
CH3
O
O
O
O
X
R
N
SO2CH3
O
O
F3C
N
Approach B
SO2CH3
N
X
O
O
H3C
R
SO2NH2
SO2CH3
SO2NH2
Valdecoxib
Celecoxib
Rofecoxib
SO2CH3
Keywords: Pyrone; Cyclooxygenase-2; Benzopyran.
* Corresponding author. Tel.: +82312805912; fax: +82312818391;
e-mail: yhjoo@amorepacific.com
Scheme 1. Approaches to improve oral bioavailability of 2,3-diphen-
ylbenzopyran derivatives.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.02.028

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Y. Hyup Joo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2195–2198
efforts to improve in vivo activity profiles of COX-2
inhibitors by truncating the benzopyran scaffold.
activities against COX-2 and COX-1 are summarized in
Table 1.
We reported that oral bioavailability of COX-2 inhibi-
tors with the benzopyran scaffold could be improved by
switching the phenyl moiety to 3-pyridyl group on the 3-
position of the benzopyran scaffold (Approach A of
Scheme 1). Given that the hydrophobic character of the
benzopyran scaffold contributes much to the poor oral
bioavailability,4 truncation of the benzopyran moiety
could lead to reduced hydrophobicity and subsequently
to improved bioavailability. In this regard, c-pyrone was
conceived as a replacement for the benzopyran scaffold
to improve oral bioavailability of COX-2 inhibitors
(Approach B of Scheme 1).
Most 2,3-diarylpyran-4-one 5 and 2,3-diarylpyran-4-
thione 9 showed modest COX-2 inhibitory activities,
which were considerably weaker than that of celecoxib.
Even though COX-1 IC50Õs were not quantified, most of
the pyrone COX-2 inhibitors in Table 1 did not show
notable inhibition at 10 lg/mL. In case of biphenyl
compounds 5j and 5p, were observed COX-1 inhibition
over50% at 10 lg/mL. However, these biphenyl com-
pounds showed COX-2 IC50Õs of 0.04 lg/mL, yielding
COX-2 selectivity overCOX-1 apporaching 100-fold.
When compared to previously reported benzopyran
derivatives,3 many of compounds 5 and 9 showed
somewhat reduced COX-2 inhibitory activity.
2. Synthesis
N
F
O
O
O
O
Y
2,3-Diarylpyran-4-one derivatives were synthesized as
outlined in Scheme 2. First, hetero-Diels–Alder reaction
of 4-(methylsulfonyl)benzaldehyde with DanishefskyÕs
diene (1) in the presence of zinc chloride gave dihydro-
pyran-4-one 2, which was followed by a-chlorination
with N-chlorosuccinimide (NCS) to afford dihydropy-
ran-4-one 3. Chloride compound 3 was subjected to
bromination using bromine/pyridine to obtain bromide
4, which was then transformed into desired 2,3-diaryl-
pyran-4-one 55 by Suzuki coupling6 with appropriate
aryl boronic acid. Reductive dechlorination of 5 was
effected by reaction with Zn/KI to give 8. Thione com-
pound 9 was prepared by reacting 5 with LawessonÕs
reagent in toluene at reflux.7
SO2CH3
SO2CH3
11 Y = H
12 Y = F
10
Compound 5b and 8b showed similarCOX-2 inhibitory
activities, suggesting that lack of the chloride on the
5-position of the pyrone scaffold does not seem to show
Table 1. In Vitro mCOX-2 and mCOX-1 enzyme inhibitory activities
of diarylpyran-4-one derivatives 5, 8, and 9
Compd ArmCOX-2
mCOX-1
(IC50, lg/mL)a (% inhibition
@ 10 lg/mL)a
5a
5b
5c
5d
5e
5f
Phenyl
0.39
0.56
2.39
0.54
0.37
0.56
0.55
0.49
0.93
0.04
0.28
2.68
0.27
9%b
0.66
<5
<5
19
<5
<5
<5
6
3. In vitro activities
4-Fluorophenyl
2-Fluorophenyl
3-Fluorophenyl
4-Chlorophenyl
3-Chlorophenyl
2,4-Difluorophenyl
3,4-Difluorophenyl
3,5-Difluorophenyl
4-Biphenyl
The diarylpyran-4-one analogs of this article were tested
fortheirability to inhibit COX-2 and COX-1 by using
freshly harvested mouse peritoneal macrophages as
described in the literature.8 The in vitro inhibitory
5g
5h
5i
20
<5
68
14
<5
<5
<5
<5
70
O
O
OCH3
5j
Cl
b
a
5k
5l
4-Ethylphenyl
4-Methoxyphenyl
3-Thienyl
82%
90%
O
O
TMSO
5m
5n
5o
5p
SO2CH3
Ar
3
SO2CH3
1
2
2-Thienyl
4-Methylphenyl
O
O
O
O
e
Cl
Ar
Cl
Br
d
c
(3-Fluoro-4-phenyl)- 0.04
phenyl
15~20%
SO2CH3
20~60%
SO2CH3
75%
O
O
5q
5r
4-Hydroxyphenyl
(3-Phenyl)phenyl
4-Benzyloxyphenyl
3-Pyridyl
Nab
Nab
Nab
2.55
0.77
0.33
0.03
0.5
17
<5
<5
<5
<5
<5
<5
13
8
5
4
SO2CH3
f
5s
60~80%
S
5t
Cl
Ar
8b
9b
10c
11c
12c
4-Fluorophenyl
4-Fluorophenyl
O
9
SO2CH3
0.5
0.01
12
79
Scheme 2. Reagents and conditions: (a) 4-(Methylsulfonyl)benzalde-
hyde, ZnCl2, benzene; (b) NCS, pyridine; (c) Br2, pyridine; (d)
ArB(OH)2 (6) orABr ꢀ(OCH3)3Liþ (7), Pd(PPh3)4, 2 M Na2CO3,
EtOH–H2O–Toluene; (e) KI, Zn, MeOH; (f) LawessonÕs reagent, tol-
uene; Ar ¼ substituted or unsubstituted aryl, heteroaryl.
Celecoxib
a Values are means of at least two measurements.
b Inhibition (%) @ 10 lg/mL (Na ¼ not active).
c See Ref. 3.

Y. Hyup Joo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2195–2198
2197
much effect on the COX-2 inhibitory activity. COX-2
inhibitory activity was quite insensitive to substitution in
the phenyl group on the 3-position of the c-pyrone
compared to that of benzopyran series, even though
presence of biphenyl moiety on the 3-position of the c-
pyrone appeared to improve in vitro COX-2 activity
significantly (5j and 5p). It is interesting to note that the
COX-2 inhibitors with biphenyl group on the 3-position
of c-pyrone showed COX-2 inhibitory activities not far
off that of celecoxib. Compound 5t containing 3-pyridyl
group showed COX-2 inhibitory activity significantly
reduced from those of compounds containing phenyl
group on the 3-position of c-pyrone, paralleling a prior
observation made with COX-2 inhibitors of the benzo-
pyran scaffold.3 Also thiocarbonyl compound 9 failed to
show notable improvement in COX-2 inhibitory activ-
ity.
though a short plasma half-life of 0.5 h was observed for
11 in male SD rats, consideration on the metabolic
stability of the benzopyran analogs yielded 12 as a
benzopyran COX-2 inhibitor with good oral absorption
and extended plasma half-life.3 The pyridine moiety of
11 and 12 was the key functionality forimprovement in
oral bioavailability. Flavonoid 11,12, and pyrone 5h
were quite similar with regards to COX-2 inhibitory
activity and lipophilicity. These compounds showed
COX-2 inhibitory activities around 0.5 lg/mL. Calcu-
lated log PÕs of 1.98, 2.14, and 2.24 were obtained for
11,12, and 5h, respectively.10 When 5h was orally
administered to male SD rats at 10 mg/kg, a plasma half-
life (T1=2) of 3.7 h was observed along with Tmax ¼ 4:0 h,
Cmax ¼ 5:1 lg/mL. The plasma half-life of 5h was
extended than that of flavonoid 11, and the anti-
inflammatory activity of pyrone 5h was improved from
the activity of flavonoid 11 and 12.
In conclusion, we prepared a new series of COX-2
inhibitors containing the c-pyrone scaffold, which was
evolved from the hydrophobic benzopyran scaffold
through rational modification to improve oral bio-
availability. The physico-chemical factors such as lipo-
philicity, molecularsize, and metabolic stability weer
appropriately modulated by truncating the benzopyran
structure. Pyrone 5h was obtained as an orally active
COX-2 inhibitorand selected as a lead compound for
further modifications.
4. In vivo anti-inflammatory activities
The oral anti-inflammatory activities for compounds of
this article were assessed by carrageenan-induced rat
paw edema9 using male SD rats. Reflecting their modest
COX-2 inhibitory activities, the anti-inflammatory
activities of c-pyrone COX-2 inhibitors were moderate.
Compound 5b and 5h were the most potent of the pyr-
one analogs despite theirmodest COX-2 inhibitoyr
activities (see Tables 1 and 2). In the meantime, biphenyl
containing COX-2 inhibitor 5j showed a relatively poor
oral anti-inflammatory activity for its COX-2 inhibitory
potency, suggesting a poor pharmacokinetic profile for
5j. It is notable that 5h showed an oral anti-inflamma-
tory activity close to that of celecoxib in the rat paw
edema.
References andnotes
1. (a) Fu, J.-Y.; Masferrer, J. L.; Seibert, K.; Raz, A.;
Needleman, P. J. Biol. Chem. 1990, 265, 16737; (b) Xie,
W.; Chipman, J. G.; Robertson, D. L.; Erikson, R. L.;
Simmons, D. L. Proc. Natl. Acad. Sci. USA 1991, 88,
2692; (c) DeWitt, D. L. Mol. Pharmacol. 1999, 55, 625.
2. (a) Mukherjee, D.; Nissen, S. E.; Topol, E. J. JAMA 2001,
286, 954; (b) Chiolero, A.; Maillard, M.; Burnier, M.
Expert Opin. Drug Saf. 2002, 1, 45.
Previously, benzopyran COX-2 inhibitors 11 and 12
were designed to overcome the poor oral bioavailability
of COX-2 inhibitors with the benzopyran scaffold. Even
3. Joo, Y. H.; Kim, J. K.; Kang, S.; Noh, M.; Ha, J.; Choi,
J. K.; Lim, K. M.; Lee, C. J.; Chung, S. Bioorg. Med.
Chem. Lett. 2003, 13, 413.
Table 2. Inhibition effect of diarylpyran-4-one derivatives 5 on car-
rageenan-induced rat paw edema
4. Possibility of tight crystal packing due to the fused
aromatic ring of benzopyran cannot be excluded for poor
oral bioavailability of 2,3-diarylbenzopyran analogs.
5. Selected compounds were prepared as follows. 2-{4-
(Methylsulfonyl)-phenyl}-2,3-dihydro-(4H)-pyran-4-one
(2): To a mixture of 4-(methylsulfonyl) benzaldehyde
(1.7 g, 9.2 mmol) and anhydrous ZnCl2 (0.6 g, 4.4 mmol)
in anhydrous benzene (50 mL) was added trans-1-methoxy-
3-(trimethylsilyloxy)-1,3-butadiene (1) (1.6 g, 9.34 mmol)
and the mixture stirred at room temperature for 24 h under
the argon atmosphere. The reaction mixture was washed
with 0.1 N aqueous HCl and the brine. The resulting
organic layer was dried and concentrated under reduced
pressure. The residue was subjected to flash chromatogra-
phy (SiO2, ethyl acetate/hexanes, 3:1) to yield the title
compound as a pale yellow solid (2.08 g, 90%). Mp;
154 ꢁ 155 °C: 1H NMR (CDCl3, 300 MHz) 8.03 ꢁ 8.00
(m, 2H), 7.64 ꢁ 7.61 (m, 2H), 7.50 (d, 1H, J ¼ 6:0 Hz),
5.59 ꢁ 5.51 (m, 2H), 3.08 (s, 3H), 2.91–2.68 (m, 2H):
IR(Neat); 3007, 2926, 1677, 1593, 1275, 1149, 750.
Compounds
Dose (mg/kg, po)
Swelling (%) inhibitiona
Indomethacin
Celecoxib
3
3
42
29
42
25
41
20
26
41
20
33
20
10
37
21
4
Celecoxib
11b
11b
12b
12b
12b
5b
10
10
30
3
10
30
3
5b
5g
10
3
5h
5h
3
10
10
10
10
5j
5k
5m
13
a Inhibition values were determined using five animals/group.
b See Ref. 3.

2198
Y. Hyup Joo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2195–2198
5-Chloro-2-{4-(methylsulfonyl)-phenyl}-2,3-dihydro-(4H)-
(0.018 g, 0.64 mmol) in toluene (2 mL) and ethanol
(2 mL) was added 2 M aqueous sodium carbonate
(0.2 mL), tetrakis (triphenylphosphine)palladium (0.004 g,
3 mol%) and the mixture was stirred at 100 °C for2 h.
After being concentrated under reduced pressure, the
residue was dissolved in CH2Cl2 (20 mL), washed with
water, and brine. The organic layer was dried and
concentrated under reduced pressure. The residue was
subjected to flash chromatography (SiO2, CH2Cl2/ethyl
acetate, 10:1) to yield the title compound as a pale yellow
pyran-4-one (3): To a solution of 2-{4-(methylsulfonyl)-
phenyl}-2,3-dihydro-(4H)-pyran-4-one (2) (0.17 g, 0.67
mmol) and pyridine (0.06 g, 0.74 mmol) in CHCl3 (15 mL)
was added NCS (0.1 g, 0.74 mmol) and the mixture was
refluxed for 12 h. The solution was cooled and washed with
1 N aqueous HCl, saturated NaHCO3, and brine. The
resulting organic layer was dried and concentrated under
reduced pressure. The residue was subjected to flash
chromatography (SiO2, hexane/ethyl acetate, 1:1) to yield
the title compound as a pale yellow solid (0.157 g, 82%).
1
solid (0.01 g, 25%). Mp; 196 ꢁ 197 °C: H NMR (CDCl3,
Mp; 227 ꢁ 229 °C: 1H NMR (CDCl3, 300 MHz)
d
300 MHz) d 8.21 (s, 1H), 7.87 ꢁ 7.85 (m, 2H), 7.48 ꢁ 7.45
(m, 2H), 7.17 ꢁ 7.12 (m, 2H), 7.06 ꢁ 7.00 (m, 2H), 3.05 (s,
3H): IR(KBr); 3076, 2927, 1647, 1510, 1315, 1163, 998,
837 cmꢀ1: MS(EI); 378 (Mþ): HRMS(EI); calcd for
C18H12O4 FSCl 378.0129, found: 378.0122.
8.04 ꢁ 8.01 (m, 2H), 7.75 (s, 1H), 7.63 ꢁ 7.60 (m, 2H), 5.62
(dd, 1H, J ¼ 5.1, 12.9 Hz), 3.08 (s, 3H), 3.00 ꢁ 2.91 (m, 2H):
IR(Neat); 3007, 2926, 1688, 1591, 1300, 1150, 1107 cmꢀ1
.
3-Bromo-5-chloro-2-{4-(methylsulfonyl)-phenyl}-(4H)-
pyran-4-one (4): To a solution of 5-chloro-2-{4-(methyl-
sulfonyl)-phenyl}-2,3-dihydro-(4H)-pyran-4-one (3) (0.064
g, 0.22 mmol) in pyridine (2 mL) was added bromine
(0.78 g, 0.5 mmol) and the mixture was stirred at
50 ꢁ 60 °C for 2 h. After cooling to room temperature,
the reaction mixture was washed with aqueous Na2S2O3
solution, 1 N aqueous HCl, satd NaHCO3, and brine. The
resulting organic layer was dried and concentrated under
reduced pressure to yield the title compound as a pale
yellow solid (0.06 g, 75%). Mp; 205 ꢁ 207 °C: 1H NMR
(CDCl3, 300 MHz) d 8.18 (s, 1H), 8.13 ꢁ 8.10 (m, 2H),
7.99 ꢁ 7.96 (m, 2H), 7.27 (s, 1H), 3.16 (s, 3H): IR(KBr);
6. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun.
1981, 11, 513; (b) Hoshino, Y.; Miyaura, N.; Suzuki, A.
Bull. Chem. Soc. Jpn. 1988, 61, 3008; (c) Watanabe, T.;
Miyaura, N.; Suzuki, A. Synlett 1992, 207.
7. Michael, P.; Cava, M. P.; Levinson, M. I. Tetrahedron
1985, 41, 5061.
8. Mtchell, J. A.; Akarasereenont, P.; Thiemermann, C.;
Flower, R. J.; Vane, J. R. Proc. Natl. Acad. Sci. USA
1994, 90, 11693.
9. Futaki, N.; Yoshikawa, K.; Hamasaka, Y.; Arai, I.;
Higuchi, S.; Iizuka, H.; Otomo, S. Gen. Pharmacol. 1993,
24, 105.
10. Calculated n-octanol/waterpatrition coefficients; C logP
was calculated by CrippenÕs fragmentation method11 using
Chemdraw Ultra 5.0 CambridgeSoft.
11. Ghose, A. K.; Crippen, G. M. J. Chem. Inf. Comput. Sci.
1987, 27, 21.
3007, 1651, 1276, 1152, 750 cmꢀ1
.
Chloro-3-(4-fluorophenyl)-2-{4-(methylsulfonyl)-phenyl}-
(4H)-pyran-4-one (5b): To a solution of 3-bromo-5-
chloro-2-{4-(methylsulfonyl)-phenyl}-(4H)-pyran-4-one
(4) (0.04 g, 0.11 mmol), 4-fluorophenylboronic acid