2444 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Mitsumori et al.
tent, and Selective Prostaglandin D2 Receptor Antagonists. J .
Med. Chem. 1997, 40, 3504-3507. (b) Arimura, A.; Yasui, K.;
Kishino, J .; Asanuma, F.; Hasegawa, S.; Kakudo, S.; Ohtani, M.;
ylam in o)bicyclo[2.2.1]h ept-2-yl]-6-oxoh eptan oic Acid (47).
To a solution of 1.04 g (3.70 mmol) of 1-bromo-5-(tert-butyldim-
ethylsilyloxy)pentane in 6.5 mL of Et2O and 9 mL of THF was
added 90.0 mg (3.70 mmol) of Mg turnings and a catalytic
amount of I2. The mixture was refluxed for 1 h and cooled in
an ice/water bath. To this solution was added a solution of
0.580 g (1.23 mmol) of 47a in 9 mL of THF. The reaction
mixture was stirred for 15 min at 0 °C and then was allowed
to reach room temperature. After being stirred for 4.5 h, the
mixture was quenched with a saturated NH4Cl solution and
extracted with AcOEt. The organic layer was washed with
brine, dried over Na2SO4, and evaporated. The residue was
purified by column chromatography on silica gel to give 0.547
g (73%) of the alcohol derivative as a colorless solid. This
alcohol derivative (0.300 g, 0.489 mmol) was treated with J ones
reagent to give 47 (0.220 g, 88%) as an amorphous solid. 1H
NMR (CDCl3): δ 1.10-2.25 (m, 19H), 2.94 (m, 1H), 4.12 (s,
3H), 5.53 (d, J ) 7.2 Hz, 1H), 7.39 (m, 1H), 7.50-7.62 (m, 3H),
7.96 (d, J ) 7.5 Hz, 1H), 8.13 (s, 1H). IR (CHCl3): 3367, 3025,
2955, 1711, 1634, 1600, 1584, 1468, 1454, 1440, 1415, 1342,
Arita, H. Prevention of Allergic Inflammation by
a Novel
Prostaglandin Receptor Antagonist, S-5751. J . Pharmacol. Exp.
Ther. 2001, 298, 411-419. (c) Matsuoka, T.; Hirata, M.; Tanaka,
H.; Takahashi, Y.; Murata, T.; Kabashima, K.; Sugimoto, Y.;
Kobayashi, T.; Ushikubi, F.; Aze, Y.; Eguchi, N.; Urade, Y.;
Yoshida, N.; Kimura, K.; Mizoguchi, A.; Honda, Y.; Nagai, H.;
Narumiya, S. Prostaglandin D2 as a Mediator of Allergic Asthma.
Science 2000, 287, 2013-2017.
(5) (a) Coleman, R. A.; Kennedy, I.; Humphrey, P. P. A.; Bunce, K.;
Lumleym, P. In Comprehensive Medicinal Chemistry; Emmet,
J . C., Ed.; Pergamon Press: Oxford, 1989; Vol. 3, pp 643-714.
(b) Hirata, M.; Kakizuka, A.; Aizawa, M.; Ushikubi, F.; Naru-
miya, S. Molecular characterization of a mouse prostaglandin
D2 receptor and functional expression of the cloned gene. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 11192-11196. (c) Caldwell, A,
G.; Harris, C, J .; Stepney, R.; Whittaker, N. Hydantoin Pros-
taglandin Analogues, Potent and Selective Inhibitors of Platelet
Aggregation J . Chem. Soc., Chem. Commun. 1979, 13, 561-562.
(d) Barraclough, P.; Brockwell, M.; Caldwell, A. G.; Demaine,
D. A.; Harris, C. J .; Richard King, W.; Stepney, R. J .; Wharton,
C. J .; Whittle, B. J . R. Synthesis and Inhibitory Activity on
Platelet Aggregation of 13′-Aza and Other ω-Chain Modified
BW245C Analogues. Arch. Pharm. (Weinheim, Ger.) 1994, 327,
307-317. (e) Barraclough, P.; Bolofo, M. L.; Giles, H.; Gillam,
J .; Harris, C. J .; Kelly, M. G.; Leff, P.; McNeill, A.; Robertson,
A. D.; Stepney, R. J .; Whittle, B. J . R. Synthesis of Hexahydro-
cyclopentimidazol-2-(1H)-one Derivatives Displaying Selective
DP-Receptor Agonist Properties. Bioorg. Med. Chem. 1996, 4,
81-90. (f) Caldwell, A. G. J apan Patent Kokai 59-157072, 1984.
(g) Caldwell, A. G. European Patent 126849 A1, 1984.
1317, 1222, 1189, 1157 cm-1. [R]25.0 +1.2° (c 1.00, CHCl3).
D
Anal. (C27H31NO7S‚0.2H2O) C, H, N, S.
Ack n ow led gm en t. The authors thank Drs. Hitoshi
Arita and Kenji Kawada for their encouragement and
helpful discussions throughout this study. We also
thank Ms. Yoko Furue and Ms. Maki Hattori for their
technical support.
(6) For important recent knowledge of PGD2 receptor, see the
following. (a) Gervais, F. G.; Cruz, R. P. G.; Chateauneuf, A.;
Gale, S.; Sawyer, N.; Nantel, F.; Metters, K. M.; O’Neill, G. P.
Selective Modulation of Chemokinesis, Degranulation, and Apo-
tosis in Eosinophils through the PGD2 receptors CRTH2 and DP.
J . Allergy Clin. Immunol, 2001, 108, 982-988. (b) Fujitani, Y.;
Kanaoka, Y.; Aritake, K.; Uodome, N.; Okazaki-Hatake, K.;
Urade, Y. Pronounced Eosinophilic Lung Inflammation and Th2
Cytokine Release in Human Lipocalin-Type Prostaglandin D
Synthase Transgenic Mice. J . Immunol. 2002, 168, 443-449.
(7) (a) Narisada, M.; Ohtani, M.; Watanabe, F.; Uchida, K.; Arita,
H.; Doteuchi, M.; Hanasaki, K.; Kakushi, H.; Otani, K.; Hara,
S. Synthesis and in Vitro Activity of Various Derivatives of a
Novel Thromboxane Receptor Antagonist, (()-(5Z)-7-[3-endo-
[(Phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-exo-yl]heptenoic Acid.
J . Med. Chem. 1988, 31, 1847-1854. (b) Ohtani, M.; Matsuura,
T.; Watanabe, F.; Narisada, M. Enantioselective Synthesis of
S-1452, an Orally Active Potent Thromboxane A2 Receptor
Antagonist J . Org. Chem. 1991, 56, 2122-2127. (c) Kishino, J .;
Hanasaki, K.; Nagasaki, T.; Arita, H. Kinetic studies on ste-
reospecific recognition by the thromboxane A2/prostaglandin H2
receptor of the antagonist, S-145. Br. J . Pharmacol. 1991, 103,
1883-1888. (d) Yasui, K.; Asanuma, F.; Furue, Y.; Arimura, A.
Involvement of thromboxane A2 in antigen-induced nasal block-
age in guinea pigs. Int. Arch. Allergy Immunol. 1997, 112, 400-
405. (e) Arimura, A.; Asanuma, F.; Matsumoto, Y.; Kurosawa,
A.; J yoyama, H.; Nagai, H. Effect of the selective thromboxane
A2 receptor antagonist, S-1452, on antigen-induced sustained
bronchial hyperresponsiveness. Eur. J . Pharmacol. 1994, 260,
201-209.
(8) (a) Adams, R.; Marvel, C. S. Benzenesulfonyl chloride. Org.
Synth. 1941, 1, 84-87. (b) Bartlett, P. D.; Knox, L. H. D,L-10-
Camphorsulfonyl chloride, Org. Synth. 1973, 5, 196-198. (c)
Suter, C. M. Studies in the Diphenyl Ether Series. II. Prepara-
tion and Structure of Some Sulfonic Acids and Related Deriva-
tives. J . Am. Chem. Soc. 1931, 53, 1112-1116. (d) Morgan, M.
S.; Cretcher, L. H. A Kinetic Study of Alkylation by Ethyl
Arylsulfonates. J . Am. Chem. Soc. 1948, 70, 375-378. (e)
Mortlock, A. A.; Bath, C.; Butlin, R. J .; Heys, C.; Hunt, S. J .;
Reid, A. C.; Sumner, N. F.; Tang, E. K.; Whiting, E.; Wilson, C.;
Wright, N. D. N-Methyl-2-(4-(2-methylpropyl)phenyl)-3-(3-meth-
oxy-5-methylpyrazin-2-ylsulfamoyl)benzamide; One of a Class
of Novel Benzenesulfonamides Which Are Orally-Active, ETA-
Selective Endothelin Antagonists. Bioorg. Med. Chem. Lett.
1997, 7, 1399-1402. (f) Hamada, T.; Yonemitsu, U. An Improved
Synthesis of Arylsulfonyl Chlorides from Aryl Halides. Synthesis
1986, 4, 852-854. (g) Tamura, Y.; Watanabe, F.; Nakatani, T.;
Yasui, K.; Fuji, M.; Komurasaki, T.; Tsuzuki, H.; Maekawa, R.;
Yoshioka, T.; Kawada, K.; Sugita, K.; Ohtani, M. Highly Selec-
tive and Orally Active Inhibitors of Type IV Collagenase (MMP-9
and MMP-2): N-Sulfonylamino Acid Derivatives. J . Med. Chem.
1998, 41, 640-649.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails with spectral data. This material is available free of
Refer en ces
(1) (a) Narumiya, S.; Sugimoto, Y.; Ushikubi, F. Prostanoid recep-
tors: structures, properties, and functions. Physiol. Rev. 1999,
79, 1193-1226. (b) Resul, B.; Stjernschantz, J .; No, K.; Liljebris,
C.; Sele´n, G.; Astin, M.; Karlsson, M.; Bito, L. Z. Phenyl-
Substituted Prostaglandins: Potent and Selective Antiglaucoma
Agents. J . Med. Chem. 1993, 36, 243-248. (c) Liljebris, C.; Resul,
B.; Hacksell, V. Palladium Catalyzed Syntheses of Phenyl-
Substituted PGF2R Analogues: Potential Antiglaucoma Agens.
Bioorg. Med. Chem. Lett. 1993, 3, 241-244. (d) Nickolson, R.
C.; Town, M. H.; Vorbru¨ggen, H. Prostacyclin-Analogs. Med. Res.
Rev. 1985, 5, 1-53. (e) Poletto, J . F.; Bernady, K. F.; Kupter,
D.; Partidge, R.; Weiss, M. J . Prostaglandins and Congeners.
Synthesis of Simplified Prostaglandins. Inhibition of Gastric Acid
Secretion by 2-(ω-Carboxyalkyl)-3-alkylcycloalkanones. J . Med.
Chem. 1975, 18, 359-362. (f) Ferreira, S. H.; Moncada, S.; Vane,
J . R. Indomethacin and Aspirin Abolish Prostaglandin Release
from the Spleen. Nature (London), New Biol. 1971, 231, 237-
239. (g) Miller, T. A. Protective Effects of Prostaglandins against
Gastric Mucosal Damage: Current Knowledge and Proposed
Mechanisms. Am. J . Physiol. 1983, 245, G601-G623.
(2) Lewis, R. A.; Soter, N. A.; Diamond, P. T.; Austen, K. F.; Oates,
J . A.; Roberts, L. J ., II. Prostaglandin D2 generation after
activation of rat and human mast cells with anti-IgE. J .
Immunol. 1982, 129, 1627-1631.
(3) (a) Flower, R. J .; Harvey, E. A.; Kingston, W. P. Inflammatory
effects of prostaglandin D2 in rat and human skin. Br. J .
Pharmacol. 1976, 56, 229-233. (b) Doyle, W. J .; Boehm, S.;
Skoner, D. P. Physiologic responses to intranasal dose-response
challenges with histamine, methacholine, bradykinin, and pros-
taglandin in adult volunteers with and without nasal allergy.
J . Allergy Clin. Immunol. 1990, 86, 924-935. (c) J ohnston, S.
L.; Freezer, N. J .; Ritter, W.; O’Toole, S.; Howarth, P. H.
Prostaglandin D2-induced bronchoconstriction is mediated only
in part by the thromboxane prostanoid receptor. Eur. Respir. J .
1995, 8, 411-415. (d) Woodward, D. F.; Hawley, S. B.; Williams,
L. S.; Ralston, T. R.; Protzman, C. E.; Spada, C. S.; Nieves, A.
L. Studies on the ocular pharmacology of prostaglandin D2.
Invest. Ophthalmol. Visual Sci. 1990, 31, 138-146. (e) Emery,
D. L.; Djokic, T. D.; Graf, P. D.; Nadel, J . A. Prostaglandin D2
causes accumulation of eosinophils in the lumen of the dog
trachea. J . Appl. Physiol. 1989, 67, 959-962. (f) Boie, Y.; Sawyer,
N.; Slipetz, D. M.; Metters, K. M.; Abramovitz, M. Molecular
cloning and characterization of the human prostanoid DP
receptor. J . Biol. Chem. 1995, 270, 18910-18916.
(4) (a) Tsuri, T.; Honma, T.; Hiramatsu, Y.; Okada, T.; Hashizume,
H.; Mitsumori, S.; Inagaki, M.; Arimura, A.; Yasui, K.; Asanuma,
F.; Kishino, J .; Ohtani, M. Bicyclo[2.2.1]heptane and 6,6-
Dimethylbicyclo[3.1.1]heptane Derivatives: Orally Active, Po-
(9) Nakayama, J .; Tanuma, M.; Honda, Y.; Hoshino, M. Reaction
of Arylmethanesulfonyl and Styrylmethanesulfonyl Chlorides
with Triethylamine. Tetrahedron Lett. 1984, 25, 4553-4556.