1062
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M. D.; Perrier, H.; Prasit, P.; Rodger, I. J. Pharmacol Exp.
Ther. 1999, 290, 551.
concentrated. The residue was dissolved in methanol and solid
potassium carbonate was added, and the resulting mixture was
stirred at room temperature for 1 h. Water was added to dis-
solve the solids and the mixture was extracted twice with ethyl
acetate. The combined organics were washed with brine, dried
(MgSO4) and concentrated. Chromatography of the residue
(silica gel; ethyl acetate/dichloromethane, 4:1, v/v) provided
4. 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.; Rodgers, 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.; Zhanng, Y. Y.; Isakson, P. C. J. Med.
Chem. 1997, 40, 1347.
5. Leblanc, Y.; Roy, P.; Boyce, S.; Brideau, C.; Chan, C. C.;
Charleson, S.; Gordon, R.; Grimm, E.; Guay, J.; Leger, S.; Li,
C. S.; Riendeau, D.; Visco, D.; Wang, Z.; Webb, J.; Xu, L. J.;
Prasit, P. Bioorg. Med. Chem. Lett. 1999, 9, 2207.
1
the title compound as a white solid (100 mg, 67%). H NMR
(300 MHz, acetone-d6): d 3.14 (s, 3H), 4.39 (t, 1H, J=5.6 Hz),
4.65 (d, 2H, J=5.6 Hz), 7.41 (dd, 1H, J=0.8, 8.1 Hz), 7.59 (d,
2H, J=8.7 Hz), 7.69 (dd, 1H, J=2.3, 8.1 Hz), 7.93 (d, 2H,
J=8.7 Hz), 8.00 (d, 1H, J=2.4 Hz), 8.44 (m, 1H), 8.75 (d, 1H,
J=2.4 Hz).
6. Riendeau, D.; Percival, M. D.; Boyce, S.; Brideau, C.;
Charleson, S.; Cromlish, W.; Ethier, D.; Evans, J.; Falgueyret,
J. P.; Ford-Hutchinson, A. W.; Gordon, R.; Greig, G.; Gres-
ser, M.; Guay, J.; Kargman, S.; Leger, S.; Mancini, J. A.;
O’Neill, G.; Ouellet, M.; Rodger, I. W.; Therien, M.; Wang,
Z.; Webb, J. K.; Wong, E.; Xu, L.; Young, R. N.; Zamboni,
R.; Prasit, P.; Chan, C. C. Br. J. Pharmacol. 1997, 121, 105.
7. Dallob, A.; De Lepeleire, I.; Van Hecken, A.; Porras, A.;
Depre, M.; Mukhopadhyay, S.; Flynn, M.; Wildonger, L.;
Gottesdiener, K.; Tanaka, W.; De Schepper, P. Inflamm. Res.
1999, 48, s130.
15. 5-Chloro-2-(2-methyl-5-pyridinyl-N-oxide)-3-(4-methylsul-
fonylphenyl)pyridine (M2). A mixture of etoricoxib (389 mg,
1.08 mmol) and m-chloroperoxybenzoic acid (57–86%,
330 mg) in dichloromethane (10 mL) was stirred at room tem-
perature for 30 min and then diluted with ethyl acetate. The
organics were washed with 1 N NaOH (3ꢃ), brine, dried
(MgSO4) and concentrated. The residual solid was suspended
in ethyl acetate, stirred vigorously for 1 h and then filtered to
provide the title compound as a white solid (250 mg, 62%). 1H
NMR (300 MHz, acetone-d6): d 2.34 (s, 3H), 3.15 (s, 3H), 6.91
(dd, 1H, J=1.7, 8.1 Hz), 7.25 (d, 1H, J=8.1 Hz), 7.67 (d, 2H,
J=8.6 Hz), 7.97 (d, 2H, J=8.6 Hz), 8.02 (d, 1H, J=2.4 Hz),
8.24 (d, 1H, J=1.7 Hz), 8.74 (d, 1H, J=2.4 Hz).
8. Rushmore, T. Presented at the Second Annual Land
O’Lakes Conference on Drug Metabolism, Marrimac, WI,
USA, 1999.
16. Nicoll-Griffith, D.; Yergey, J.; Trimble, L.; Williams, H.;
Rasori, R.; Zamboni, R. Drug Metab. Disp. 1992, 20, 383.
17. Nicoll-Griffith, D. A.; Falgueyret, J. P.; Silva, J. M.; Morin,
P. E.; Trimble, L.; Chan, C. C.; Clas, S.; Leger, S.; Wang, Z.;
Yergey, J. A.; Riendeau, D. Drug Metab. Disp. 1999, 27, 403.
18. 2-(2-Carboxy-5-pyridinyl)-5-chloro-3-(4-methylsulfonylphe-
nyl)pyridine (M3). To a solution of etoricoxib (200 mg,
0.56 mmol) in t-butanol (2 mL) and water (4 mL) at 90 ꢄC was
added solid KMnO4 (264 mg, 1.67 mmol) portionwise over
30 min. The mixture was stirred for 15 h at 90 ꢄC and then
cooled to room temperature. The mixture was filtered through
a plug of Celite, washing with ethyl acetate, and the filtrate
was acidified with 1 N HCl. The organic layer was separated,
dried (MgSO4) and concentrated to provide a white solid. The
suspended solid was stirred vigorously in ether and then fil-
tered to provide the title compound as a white solid (40 mg,
18%). 1H NMR (300 MHz, acetone-d6): d 3.14 (s, 3H), 7.63 (d,
2H, J=8.6 Hz), 7.94–8.00 (m, 3H), 8.05–8.09 (m, 2H), 8.60
(dd, 1H, J=0.8, 2.1 Hz), 8.81 (d, 1H, J=2.3 Hz).
19. McIntosh, I. S.; Kassahun, K.; Shou, M.; Slaughter, D.
E.; Agrawal, N.; Rodrigues, A. D. unpublished results.
20. Chauret, N.; Gauthier, A.; Martin, J.; Nicoll-Griffith,
D. A. Drug Metab. Disp. 1997, 25, 1130.
21. Silva, J. M.; Morin, P. E.; Day, S.; Kennedy, B. P.; Pay-
ette, P.; Rushmore, T.; Yergey, J. A.; Nicoll-Griffith, D. A.
Drug Metab. Disp. 1998, 26, 490.
22. Acocella, G.; Pagani, V.; Marchetti, M.; Baroni, G. C.;
Nicolis, F. B. Chemotherapy 1971, 16, 356.
23. Brideau, C.; Kargman, S.; Liu, S.; Dallob, A. L.; Ehrich,
E. W.; Rodger, I. W.; Chan, C. C. Inflamm. Res. 1996, 45, 68.
9. Nicoll-Griffith, D. A.; Silva, J.; Chauret, N.; Day, S.;
Leblanc, Y.; Roy, P.; Yergey, J.; Dixit, R.; Patrick, D. Drug
Metab. Disp. 2001, 29, 159.
10. Friesen, R. W.; Brideau, C.; Chan, C. C.; Charleson, S.;
Deschenes, D.; Dube, D.; Ethier, D.; Fortin, R.; Gauthier,
J. Y.; Girard, Y.; Gordon, R.; Greig, G. M.; Riendeau, D.;
Savoie, C.; Wang, Z.; Wong, E.; Visco, D.; Xu, L. J.; Young,
R. Y. Bioorg. Med. Chem. Lett. 1998, 8, 2777.
11. Riendeau, D.; Percival, M. D.; Brideau, C.; Charleson, S.;
Dube, D.; Ethier, D.; Falgueyret, J. P.; Friesen, R.; Greig, G.;
Guay, J.; Mancini, J.; Ouellet, M.; Wong, E.; Xu, L.; Boyce,
S.; Visco, D.; Girard, Y.; Prasit, P.; Zamboni, R.; Gresser, M.;
Ford-Hutchinson, A. W.; Young, R. N.; Chan, C. C. JPET
2001, 296, 558.
12. Chauret, N.; Nicoll-Griffith, D. A.; Friesen, R.; Li, C.;
Trimble, L.; Dube, D.; Fortin, R.; Girard, Y.; Yergey, J. Drug
Metab. Disp. 1995, 23, 1325.
13. Nicoll-Griffith, D. A.; Yergey, J. A.; Trimble, L. A.; Silva,
J. M.; Li, C.; Chauret, N.; Gauthier, J. Y.; Grimm, E.; Leger,
S.; Roy, P.; Therien, M.; Wang, Z.; Prasit, P.; Zamboni, R.;
Young, R. N.; Brideau, C.; Chan, C. C.; Mancini, J.; Rien-
deau, D. Bioorg. Med. Chem. Lett. 2000, 10, 2683.
14. 5-Chloro-2-(2-hydroxymethyl-5-pyridinyl)-3-(4-methylsul-
fonyl)phenylpyridine (M1).
A solution of M2 (150 mg,
0.40 mmol) in acetic anhydride (5 mL) was heated at reflux for
15 min and then cooled to room temperature. Ethanol and 1 N
NaOH were added and the mixture was stirred for 15 min. The
mixture was extracted twice with ethyl acetate and the com-
bined organics were washed with brine, dried (MgSO4) and