3-(2-Methoxytetrahydrofuran-2-yl)pyrazoles: A novel class of potent, selective cyclooxygenase-2 (COX-2) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2004.09.073

The synthesis of a series of novel 3-(2-methoxytetrahydrofuran-2-yl) pyrazoles and their in vitro cyclooxygenase-2 (COX-2) inhibitory activity in human whole blood (HWB) are reported. A series of 3-(2-methoxytetrahydrofuran-2- yl)pyrazoles (4-10) was synthesized. The compounds were evaluated for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in human whole blood (HWB). The compound, 5-(4-methanesulfonylphenyl)- 3-(2-methoxytetrahydrofuran-2-yl)-1-p-tolyl-1H-pyrazole 5 showed potent and selective COX-2 inhibition (IC₅₀ for COX-1: >100 μM and COX-2: 1.2 μM).

Full text of DOI:10.1016/j.bmcl.2004.09.073

Bioorganic & Medicinal Chemistry Letters 14 (2004) 6049–6052
3-(2-Methoxytetrahydrofuran-2-yl)pyrazoles: a novel class
of potent, selective cyclooxygenase-2 (COX-2) inhibitors
Ramani R. Ranatunge,*, Richard A. Earl, David S. Garvey, David R. Janero,
L. Gordon Letts, Allison M. Martino, Madhavi G. Murty, Stewart K. Richardson,
David J. Schwalb, Delano V. Young and Irina S. Zemtseva
NitroMed Inc., 125 Spring St., Lexington, MA 02421, USA
Received 16 March 2004; revised 22 September 2004; accepted 24 September 2004
Available online 14 October 2004
Abstract—A series of 3-(2-methoxytetrahydrofuran-2-yl)pyrazoles (4–10) was synthesized. The compounds were evaluated for their
ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in human whole blood (HWB). The compound,
5-(4-methanesulfonylphenyl)-3-(2-methoxytetrahydrofuran-2-yl)-1-p-tolyl-1H-pyrazole 5 showed potent and selective COX-2 inhi-
bition (IC50 for COX-1: >100lM and COX-2: 1.2lM).
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
tive inhibitors intrinsically lack anti-thrombotic activity,
and some cardiovascular liabilities have been associated
preclinically with them.9 Thus, there is still a need for
novel, selective, and potent COX-2 inhibitors with an
improved profile compared to current COX-2 inhibitors.
Here we report the synthesis and COX inhibitory profile
of a novel series of pyrazoles (I) containing a five-mem-
bered cyclic ether, some of which potently and selec-
tively inhibit COX-2.
A new generation of anti-inflammatory drugs, celecoxib
(CelebrexTM),1 rofecoxib(Vioxx Ò),2 and valdecoxib
(BextraÒ),3 is being widely prescribed to treat acute or
chronic inflammation by providing symptomatic pain
relief. The high cyclooxygenase-2 (COX-2) versus cyclo-
oxygenase-1 (COX-1) selectivity demonstrated by these
compounds explains their superiority over other
NSAIDs in reducing gastrointestinal (GI) side effects.4,5
However, emerging evidence suggests that adverse reac-
tions such as GI irritation or ulceration and renal liabil-
ities are associated with prolonged use of COX-2
selective inhibitors. These adverse reactions have been
attributed, at least in part, to COX-1 inhibition occur-
ring with long-term exposure or at higher doses.6
COX-2 selective inhibitors are also known to suppress
synthesis of prostacyclin, a potent vasodilator, gastro-
protectant, and platelet inhibitor, via inhibition of
endothelial COX-2. COX-2 selective inhibitors do not
inhibit production of thromboxane, a vasoconstrictor,
and promoter of platelet aggregation, which is synthe-
sized in platelets by COX-1.7,8 Therefore, COX-2 selec-
H3C
O
O
CF3
N N
O
O
S
S
O
H3C
O
H2N
Celecoxib
Rofecoxib
OCH3
O
X
N
N
N
O
CH3
Keywords: Cyclooxygenase-2 (COX-2); Pyrazole; Tetrahydrofuran-2-yl.
*
O
Corresponding author. Tel.: +1 781 266 4139; fax: +1 781 274
8080; e-mail: ramani@nitromed.com
S
H2N
O
H3CO2S
Following the senior author, contributors appear in alphabetical
order.
I
Valdecoxib
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.09.073

6050
R. R. Ranatunge et al. / Bioorg. Med. Chem. Lett. 14 (2004) 6049–6052
O
O
X
X
CH3
N
N
OTBDMS
N
N
N
3
a
OCH3
S
S
2
1
c
b
O
OCH3
O
X
X
N
N
OH
N
N
3
c
4 X = -H
5 X = -CH3
6 X = -CF3
7 X = -F
8 X = -Cl
9 X = -Br
10 X = -CN
O
S
S
3
O
Scheme 1. Reagents and conditions: (a) TBDMSO(CH2)3MgBr, THF; (b) TBAF, THF; (c) Oxone, MeOH/H2O, rt.
Table 1. In vitro human whole blood COX-1 and COX-2 inhibition by
1-(2-methoxytetrahydrofuran-2-yl)pyrazole derivatives
2. Chemistry
The pyrazole containing COX-2 inhibitor, celecoxib has
a 1,5-diaryl substitution pattern as well as a trifluoro-
methyl group at C-3. Our recent studies suggested that
COX-2 selectivity and potency may be enhanced by
modifying the C-3 substituent of the central pyrazole
ring to incorporate alkyl, alkenyl, ketone, and oxime
groups.10,11 During the course of this work, we observed
formation of the cyclic ethers (4–10) and found that they
functioned as COX-2 selective inhibitors.
OCH3
X
N
O
N
H3CO2S
Compd
X
% inhibition HWBa
COX-1 COX-2
10lM
The synthesis of compounds 4–10 was adapted from our
earlier work (Scheme 1).11 Weinrebamides 1 were
prepared from the reaction of corresponding methyl
esters11,12 with N,O-dimethylhydroxylamine hydrochlo-
ride in the presence of trimethylaluminum.11,13,14a The
reaction of 1 with the Grignard reagent prepared from
(3-bromopropoxy) tert-butyldimethylsilane (1equiv)
and magnesium turnings (2.2equiv) gave 2 in good yield.
Deprotection of the TBDMS group with TBAF gave the
hydroxyketones 3. Oxidation of the sulfide (3) was
accompanied by simultaneous cyclization to give the
cyclic acetals 4–10. It has been reported that a solution
of OxoneÒ (1equiv) is useful for the deprotection of a
TBDMS group from alcohols.15 In our studies, the use
of excess OxoneÒ (3equiv) promoted the one-pot depro-
tection, oxidation and cyclization to afford compounds
4–10 directly from 2 in good yield (Scheme 1).16
100lM
1lM
4
–H
20
55
50
25
60
72
0
65
90
70
75
80
84
25
30
55
25
40
25
13
30
5
–CH3
–CF3
–F
6
7
8
–Cl
–Br
9
10
–CN
Celecoxib
Rofecoxib
65b
75
100
100
50
75
a Percent inhibition of COX-1 (100lM) or COX-2 (10 and 1lM) in
human whole blood (HWB). Average percent inhibition using blood
from two donors. Assays were performed on duplicate blood sam-
ples, each of which was assayed in duplicate by enzyme-linked
immunoassay (EIA), as described in Refs. 11, 17–19.
b COX-1 inhibition at 30lM celecoxib.
10 and 1lM. For the most potent and selective COX-
2 inhibitors, the IC50Õs were then determined (Table 2).
3. Biology
The inhibition of the COX-1 and COX-2 isoforms by 3-
(2-methoxytetrahydrofuran-2-yl)pyrazole derivatives 4–
10 in human whole blood (HWB) is presented in Table
1, together with comparative data for celecoxiband
rofecoxib.17–19 As an initial in vitro screen, compounds
were assayed against COX-1 at 100lM and COX-2 at
In general, lipophilic or electron-rich substituents (4–7)
were preferred at the C4 phenyl ring over electron defi-
cient ones (8–10). Thus, the presence of a 4-chloro or 4-
bromo substituent increased COX-1 inhibition and
weakened COX-2 inhibition at the lower screening con-
centration (1lM). In the presence of a cyano group (10),

R. R. Ranatunge et al. / Bioorg. Med. Chem. Lett. 14 (2004) 6049–6052
6051
Table 2. IC50 for 1-(2-methoxytetrahydrofuran-2-yl)pyrazole deriva-
tive 5
4. Jackson, L. M.; Hawkey, C. J. Exp. Opin. Invest. Drugs
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Med. 1999, 340, 1888–1899.
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28S–32S.
Compound
IC50 (lM)
COX-1
COX-2
Celecoxib
Rofecoxib
5
14
40
>100a
1.2
0.3
1.2a
8. Mukherjee, D.; Nissen, S. E.; Topol, E. J. JAMA 2001,
286, 954–959.
a Average of three blood donors.
9. de Gaetano, G.; Donati, M. B.; Cerletti, C. Trends Pharm.
Sci. 2003, 24, 245–246.
COX-1 inhibitory activity was abrogated, and the po-
tency for COX-2 was reduced with no difference at the
two screening concentrations. The unsubstituted (4), tri-
fluoromethyl- (6) and fluoro-substituted (7) compounds
showed less COX-1 and COX-2 inhibition than celec-
oxib. The best substituent found on C-4 of the phenyl
ring, a C-4 methyl is not particularly surprising or unex-
pected since it is also found in celecoxibat the 5-position
of the central pyrazole ring. Thus, the most potent and
selective COX-2 inhibitor was the 4-methyl substituted
derivative (5), with activity (IC50Õs for COX-1:
>100lM and COX-2 = 1.2lM in HWB) comparable
to celecoxiband rofecoxib( Table 2).
10. Bandarage, R. R.; Augustyniak, M. E.; Bandarage, U. K.;
Cochran, E. D.; Earl, R. A.; Garvey, D. S.; Janero, D. R.;
Letts, L. G.; Marek, P.; Martino, A. M.; Murty, M. G.;
Richardson, S. K.; Schroeder, J. D.; Shumway, M. J.;
Tam, S. W.; Trocha, A. M.; Young, D. V. #314, 224th
ACS National Meeting, Boston, MA, August 18–22,
2002.
11. Ranatunge, R. R.; Augustyniak, M. E.; Bandarage, U. K.;
Earl, R. A.; Ellis, J. L.; Garvey, D. S.; Janero, D. R.;
Letts, L. G.; Martino, A. M.; Murty, M. G.; Richardson,
S. K.; Schroeder, J. D.; Shumway, M. J.; Tam, S. W.;
Trocha, A. M.; Young, D. V. J. Med. Chem. 2004, 47,
2180–2193.
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Tojo, T.; Ochi, T.; Shimojo, F.; Senoh, H.; Matsuo, M.
Chem. Pharm. Bull. 1997, 45, 1475–1481.
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1997, 38, 2685–2688.
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moto, K. J. Org. Chem. 1994, 59, 74–79; (b) Handrick, G.
R.; Atkinson, E. R. Tetrahedron Lett. 1981, 22, 3815.
15. Sabitha, G.; Syamala, M.; Yadav, J. S. Org. Lett. 1999, 1,
1701–1703.
In summary, we have prepared a series of novel 3-(2-
methoxytetrahydrofuran-2-yl)pyrazole COX-2 inhibi-
tors, from which compound 5 was identified as a highly
selective and potent COX-2 inhibitor with IC50Õs for
COX-1: >100lM and COX-2 = 1.2lM in HWB (Table
2). The reported identification of 5 invites further explo-
ration of cyclic substituents at C3 of the pyrazole-con-
taining COX-2 selective inhibitors, an area which so
far has received very little attention.
16. Spectral data for compounds 4–10.
5-(4-Methanesulfonylphenyl)-3-(2-methoxytetrahydrofu-
ran-2-yl)-1-phenyl-1H-pyrazole (4). White solid. Yield
1
71%. Mp 63–66°C. H NMR d 7.86 (d, J = 8.4Hz, 2H),
7.22–7.51 (m, 7H), 6.67 (s, 1H), 4.00–4.28 (m, 2H), 3.27 (s,
3H), 3.06 (s, 3H), 2.32–2.58 (m, 1H), 1.95–2.32 (m, 3H).
13C NMR d 153.5, 141.5, 140.0, 139.6, 135.8, 129.3, 129.2,
128.2, 127.6, 125.7, 107.5, 106.5, 68.2, 50.1, 44.5, 38.7,
24.4. MS m/z 367 (MÀOCH3), 457 (M+OAc). Anal. Calcd
(C21H22N2O4S): C, 63.30; H, 5.56; N, 7.03. Found: C,
63.27; H, 5.42; N, 6.80.
Acknowledgements
The authors wish to thank Dr. Radha Iyengar for help-
ful comments and suggestions.
References and notes
5-(4-Methanesulfonylphenyl)-3-(2-methoxytetrahydrofu-
ran-2-yl)-1-p-tolyl-1H-pyrazole (5). White foam. Yield
65%. Mp 65–68°C. H NMR d 7.85 (d, J = 8.5Hz, 2H),
7.41 (dd, J = 1.8 and 6.8Hz, 2H), 7.12–7.19 (m, 4H), 6.45
(s, 1H), 4.02–4.21 (m, 2H), 3.27 (s, 3H), 3.06 (s, 3H), 2.40–
2.50 (m, 1H), 2.37 (s, 3H), 2.12–2.28 (m, 2H), 1.97–2.12
(m, 1H). 13C NMR d 153.2, 141.4, 139.8, 138.2, 137.1,
135.9, 129.8, 129.3, 127.6, 125.6, 107.2, 106.5, 68.1, 50.0,
44.4, 38.7, 24.4, 21.3. MS m/z 381 (MÀOCH3). Anal.
Calcd (C22H24N2O4S): C, 64.06; H, 5.86; N, 6.79. Found:
C, 64.33; H, 6.03; N, 6.51.
1
1. Penning, T. D.; Tally, J. J.; Bertenshaw, S. R.; Carter, J.
S.; Collins, P. W.; Doctor, S.; Graneto, M. J.; Lee, L. F.;
Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier,
D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn,
J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.;
Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson,
P. C. J. Med. Chem. 1997, 40, 1347–1365.
2. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charleson,
S.; Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchin-
son, A. W.; Gauthier, J. Y.; Gordon, R.; Guay, J.;
Gresser, M.; Kargman, S.; Kennedy, B.; Leblanc, Y.;
Leger, S.; Mancini, J.; OÕNeill, G. P.; Ouellet, M.; Percival,
M. D.; Perrier, H.; Riendeau, D.; Rodger, I.; Tagari, P.;
Therien, M.; Vikers, P.; Wong, E.; Xu, L.-J.; Young, R.
N.; Zamboni, R.; Boyce, S.; Rupniak, N.; Forrest, M.;
Visco, D.; Patrick, D. Bioorg. Med. Chem. Lett. 1999, 9,
1773–1778.
5-(4-Methanesulfonylphenyl)-3-(2-methoxytetrahydrofu-
ran-2-yl)-1-(4-trifluoromethyl-phenyl)-1H-pyrazole
(6).
White solid. Yield 78%. Mp 120–123°C. 1H NMR d
7.94 (d, J = 8.3Hz, 2H), 7.64 (d, J = 8.6Hz, 2H), 7.40–7.51
(m, 4H), 6.71 (s, 1H), 4.03–4.28 (m, 2H), 3.29 (s, 3H), 3.11
(s, 3H), 2.40–2.55 (m, 1H), 1.95–2.30 (m, 3H). 13C NMR
d 154.5, 142.3, 141.9, 140.6, 135.5, 130.0 (JC–F = 33.2),
129.5, 128.0, 126.5, 125.5, 122.0, 108.7, 106.4, 68.4, 50.2,
44.5, 38.8, 24.5. MS m/z 467 (MH+), 489 (MNa+), 435
(MÀOCH3). Anal. Calcd (C22H21F3N2O4S): C, 56.65; H,
4.54; N, 6.01; F, 12.22; S, 6.87. Found: C, 56.46; H, 4.50;
N, 5.83; F, 11.98; S, 6.69.
3. Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.;
Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers,
R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert,
K. J. Med. Chem. 2000, 43, 775–777.

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R. R. Ranatunge et al. / Bioorg. Med. Chem. Lett. 14 (2004) 6049–6052
1-(4-Fluoro-phenyl)-5-(4-methanesulfonylphenyl)-3-(2-meth-
2.32–2.50 (m, 1H), 2.10–2.30 (m, 2H), 1.92–2.10 (m, 1H).
13C NMR d 154.0, 141.6, 140.3, 138.6, 135.6, 132.4, 129.4,
127.8, 127.1, 121.9, 108.0, 106.4, 68.3, 50.1, 44.5, 38.8,
24.4. MS m/z 445/447 (MÀOCH3), 535/537 (M+OAc).
Anal. Calcd (C21H21BrN2O4S1/4mol H2O): C, 52.34; H,
4.50; N, 5.81. Found: C, 52.48; H, 4.54; N, 5.42.
4-[5-(4-Methanesulfonylphenyl)-3-(2-methoxytetrahydro-
furan-2-yl)-pyrazol-1-yl]-benzecarbonitrile (10). White
solid. Yield 65%. Mp 148–150°C. 1H NMR d 7.94 (d,
J = 8.2Hz, 2H), 7.65 (d, J = 8.4Hz, 2H), 7.40–7.48 (m,
4H), 6.69 (s, 1H), 4.00–4.20 (m, 2H), 3.27 (s, 3H), 3.10 (s,
3H), 2.40–2.52 (m, 1H), 2.00–2.30 (m, 3H).13C NMR d
155.0, 142.9, 141.9, 140.9, 135.4, 133.3, 129.5, 128.1, 125.6,
118.1, 111.5, 109.2, 106.3, 68.4, 50.2, 44.5, 38.8, 24.4. MS
m/z 392 (MÀOCH3). Anal. Calcd (C22H21N3O4S): C,
62.40; H, 5.00; N, 9.92. Found: C, 62.19; H, 4.83; N,
9.76.
oxytetrahydrofuran-2-yl)-1H-pyrazole (7). White foam.
Yield 69%. 1H NMR d 7.88 (dd, J = 1.8 and 6.7Hz,
2H), 7.42 (dd, J = 1.8 and 8.6Hz, 2H), 7.24–7.34 (m, 2H),
7.04–7.15 (m, 2H), 6.66 (s, 1H), 4.08–4.50 (m, 2H), 3.27 (s,
3H), 3.07 (s, 3H), 2.35–2.51 (m, 1H), 1.91–2.58 (m, 3H).
13C NMR d 163.6, 160.3, 153.6, 141.6, 140.1, 135.7, 129.2,
127.7, 116.3, 116.0, 107.5, 106.4, 68.2, 50.0, 44.4, 38.7,
24.3. MS m/z 385 (MÀOCH3). Anal. Calcd
(C21H21FN2O4S): C, 60.56; H, 5.08; N, 6.73. Found: C,
60.61; H,5.12; N, 6.45.
1-(4-Chloro-phenyl)-5-(4-methanesulfonylphenyl)-3-(2-meth-
oxytetrahydrofuran-2-yl)-1H-pyrazole (8). White foam.
1
Yield 65%. Mp 65–68°C. H NMR d 7.91 (d, J = 8.3Hz,
2H), 7.44 (d, J = 8.3Hz, 2H), 7.18–7.37 (m, 4H), 6.68
(s, 1H), 4.00–4.22 (m, 2H), 3.27 (s, 3H), 3.09 (s, 3H),
2.30–2.52 (m, 1H), 1.98–2.30 (m, 3H). 13C NMR d 153.9,
141.6, 140.3, 138.1, 135.6, 133.9, 129.43, 129.39, 127.8,
126.8, 107.9, 106.4, 68.3, 50.1, 44.5, 38.8, 24.4. MS m/z
401 (MÀOCH3), 491 (M+OAc). Anal. Calcd
(C21H21ClN2O4S): C, 58.26; H, 4.89; N, 6.47, S, 7.41; Cl,
8.19. Found: C, 58.03; H, 4.90; N, 6.20; S, 7.11; Cl, 8.10.
1-(4-Bromo-phenyl)-5-(4-methanesulfonylphenyl)-3-(2-meth-
oxytetrahydrofuran-2-yl)-1H-pyrazole (9). White solid.
17. Young, J. M.; Panah, S.; Satchawatcharaphong, C.;
Cheung, P. S. Inflamm. Res. 1996, 45, 246–253.
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Young, D. V.; Zemtseva, I. S. Bioorg. Med. Chem. 2004,
12, 1357–1366.
1
Yield 76%. Mp 68–70°C. H NMR d 7.90 (d, J = 8.4Hz,
2H), 7.31–7.53 (m, 4H), 7.18 (dd, J = 1.9 and 6.7Hz, 2H),
6.66 (s, 1H), 4.00–4.25 (m, 2H), 3.27 (s, 3H), 3.08 (s, 3H),