New cyclooxygenase-2/5-lipoxygenase inhibitors. 1. 7-tert-butyl-2,3- dihydro-3,3-dimethylbenzonfuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: Discovery and variation of the 5-keto substituent

Journal of Medicinal Chemistry

Volumn 41, Issue 7, 1998, Pages 1112-1123

  Janusz, John M ^a   Young, Patricia A ^a   Ridgeway, James M ^a   Scherz, Michael W ^a   Enzweiler, Kevin ^a   Wu, Laurence I ^a   Gan, Lixian ^a   Darolia, Renuka ^a   Matthews, Randall S ^a   Hennes, Duane ^a   Kellstein, David E ^a   Green, Shelley A ^a   Tulich, Jennifer L ^a   Rosario Jansen, Theresa ^a   Magrisso, I Jack ^a   Wehmeyer, Kenneth R ^a   Kuhlenbeck, Deborah L ^a   Eichhold, Thomas H ^a   Dobson, Roy L M ^a   Sirko, Steven P ^a   Farmer, Ralph W ^a   more..

^a PROCTER AND GAMBLE PHARMACEUTICALS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

7 TERT BUTYL 2,3 DIHYDRO 3,3 DIMETHYLBENZOFURAN DERIVATIVE; ANALGESIC AGENT; ARACHIDONATE 5 LIPOXYGENASE; CARRAGEENAN; CYCLOOXYGENASE 2 INHIBITOR; LEUKOTRIENE B4; LIPOXYGENASE INHIBITOR; NAPROXEN; NONSTEROID ANTIINFLAMMATORY AGENT; PHENYLQUINONE; PROSTAGLANDIN SYNTHASE; TEBUFELONE; UNCLASSIFIED DRUG;

ADJUVANT ARTHRITIS; ANALGESIC ACTIVITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG SAFETY; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HUMAN CELL; MALE; MAST CELL LEUKEMIA; MOUSE; NONHUMAN; ORAL DRUG ADMINISTRATION; PAIN; PAW EDEMA; RAT; STRUCTURE ACTIVITY RELATION; THROMBOCYTE;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ARACHIDONATE 5-LIPOXYGENASE; BENZOFURANS; BLOOD PLATELETS; CARRAGEENAN; CYCLOOXYGENASE INHIBITORS; EDEMA; HUMANS; MALE; RATS; RATS, INBRED LEW; RATS, SPRAGUE-DAWLEY;

EID: 15444344804     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970679q     Document Type: Article

References (33)

1. Lombardino, J. G. Nonsteroidal Antiinflammatory Drugs;Wiley-Interscience, John Wiley & Sons: New York, 1985.
2. Asako, H.; Kubes, P.; Wallace, J.; Gaginella, T.; Wolf, R. E.; Granger, N. Indomethacin-induced Leukocyte Adhesion in Mesenteric Venules: Role of Lipoxygenase Products. Am. J. Physiol. 1992, 262 (5), G903-G908.
3. Moore, G. G. I.; Swingle, K. F. 2,6-Di-tert-butyl-4-(2′-thenoyl)-phenol (R-830): A Novel Nonsteroidal Antiinflammatory Agent with Antioxidant Properties. Agents Actions 1982, 12, 674-683.
4. Hidaka, T.; Hosoe, K.; Ariki, Y.; Takeo, K.; Yamashita, T.; Katsumi, I.; Kondo, H.; Yamashita, K.; Watanabe, K. Pharmacological Properties of a New Antiinflammatory Compound, α-(3,5-Di-Tert-Butyl-4-Hydroxybenzylidene)-γ-Butyrolactone (KME-4), and Its Inhibitory Effects on Prostaglandin Synthetase and 5-Lipoxygenase. Jpn. J. Pharmacol. 1984, 36, 77-85.
5. Katayama, K.; Shirota, H.; Kobayashi, S.; Terato, K.; Ikuta, H.; Yamatsu, I. In Vitro Effect of N-Methoxy-3-(3,5-di-tert-butyl-4-hydroxy-benzylidene)-2-pyrrolidone (E-5110), a Novel Nonsteroidal Antiinflammatory Agent, on Generation of Some Inflammatory Mediators. Agents Actions 1987, 21, 269-271.
6. Unangst, P. C.; Connor, D. T.; Cetenko, W. A.; Sorenson, R. J.; Kostlan, C. R.; Sircar, J. C.; Wright, C. D.; Schrier, D. J.; Dyer, R. D. Synthesis and Biological Evaluation of 5[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]oxazoles, -thiazoles, and -imidazoles: Novel Dual 5-Lipoxygenase and Cyclooxygenase Inhibitors with Antiinflammatory Activity. J. Med. Chem. 1994, 37, 322-328.
7. Swingle, K. F.; Bell, R. L.; Moore, G. G. I. Antiinflammatory activity of antioxidants. In Antiinflammatory and Anti-Rheumatic Drugs; Rainsford, K. D., Ed.; CRC Press: Boca Raton, FL, 1985; Vol. III, pp 105-126.
8. (a) Futaki, N.; Yoshikawa, K.; Hamasaka, Y.; Arai, I.; Higuchi, S.; Iizuka, H.; Otomo, S. NS-398, A Novel Non-Steroidal Antiinflammatory Drug with Potent Analgesic and Antipyretic Effects, Which Causes Minimal Stomach Lesions. Gen. Pharmacol. 1993, 24, 105-110.
9. (b) Futaki, N.; Takahashi, S.; Yokoyama, M.; Arai, I.; Higuchi, S.; Otomo, S. NS-398, A New Antiinflammatory Agent, Selectively Inhibits Prostaglandin G/H Synthase/Cyclooxygenase (COX-2) Activity in Vitro. Prostaglandins 1994, 47, 55-59.
10. Reitz, D. B.; Li, J. J.; Norton, M. B.; Reinhard, E. J.; Collins, J. T.; Anderson, G. D.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Isakson, P. C. Selective Cyclooxygenase Inhibitors: Novel 1,2-Diarylcyclopentenes are Potent and Orally Active COX-2 Inhibitors. J. Med. Chem. 1994, 37, 3878-3881.
11. Sietsema, W. K.; Kelm, G. R.; Deibel, R. M.; Doyle, M. J.; Loomans, M. E.; Smyth, R. E.; Kinnett, G. O.; Eichhold, T. H.; Farmer, R. W. Absorption, Bioavailability, and Pharmacokinetics of Tebufelone in the Rat. J. Pharm. Sci. 1993, 82, 610-612.
12. Weisman, S. M.; Doyle, M. J.; Wehmeyer, K. R.; Hynd, B. A.; Eichhold, T. H.; Clear, R. M.; Coggeshall, C. W.; Kuhlenbeck, D. L. Effects of Tebufelone (NE-11740), a New Antiinflammatory Drug, on Arachidonic Acid Metabolism. Agents Actions 1994, 41, 156-163.
13. Loomans, M. E.; Matthews, R. S.; Miller, J. A. Novel Antiinflammatory agents. Pharmaceutical compositions and methods for reducing inflammation. U.S. Patent 4,708,966, 1987.
14. A similar metabolite was observed for butylated hydroxytoluene (BHT); see: Wiebe, L. I.; Mercer, J. R.; Ryan, A. J. Urinary Metabolites of 3,5-Di-(1-[13C]methyl-1-methylethyl)-4-hydroxytoluene (BHT-13C) in Man. Drug Metab. Dispos. 1978, 6, 296-302.
15. Miller, J. A.; Matthews, R. S. A Short, Efficient Synthesis of tert-Butyl-Hydroxylated Di-tert-butylphenols. J. Org. Chem. 1992, 57, 2514-2516.
16. Stanetty, P.; Koller, H.; Pürstinger, G. 2,3-Dihydro-7-benzofurancarbonsauren. Monatsh. Chem. 1990, 121, 883-891.
17. Hudec, T. T. Process for the preparation of certain substituted aromatic compounds. U.S. Patent 4,982,006, 1991.
18. Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. The Invention of Radical Reactions. 32. Radical Deoxygenations, Dehalogenations, and Deaminations with Dialkyl Phosphites and Hypophosphorous Acid as Hydrogen Sources. J. Org. Chem. 1993, 58, 6838-6842.
19. Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Hypophosphorous Acid and its Salts: New Reagents for Radical Chain Deoxygenation, Dehalogenation and Deamination. Tetrahedron Lett. 1992, 33, 5709-5712.
20. (a) Gibson, T. W.; Echler, R. S. Process for the Preparation of 2-alkyl-4-acyl-6-tert-butylphenol compounds. U.S. Patent 5,126, 487,1992.
21. (b) Nishinaga, A.; Shimizu, T.; Toyoda, Y.; Matsuura, T. Oxygenation of 2,6-Di-tert-butylphenols Bearing an Electron-Withdrawing Group in the 4-Position. J. Org. Chem. 1982, 47, 2278-2285.
22. Nahm, S.; Weinreb, S. M. AT-Methoxy-N-Methylamides as Effective Acylating Agents. Tetrahedron Lett. 1981, 22, 3815-3818.
23. Ito, Y.; Hirao, T.; Saegusa, T. Synthesis of αβ-Unsaturated Carbonyl Compounds by Palladium(II)-Catalyzed Dehydrosilylation of Silyl Enol Ethers. J. Org. Chem. 1978, 43, 1011-1013.
24. Kajigaeshi, S.; Kakinami, T.; Moriwaki, M.; Fujisaki, S.; Maeno, K.; Okamoto, T. α-Chlorination of Aromatic Acetyl Derivatives with Benzyltrimethylammonium Dichloroiodate. Synthesis 1988, 545-546.
25. Mukaiyama, T. The Directed Aldol Reaction. Org. React. 1982, 28, 203-335.
26. As an example, compound 30 inhibited paw edema by 34% while tebufelone inhibited paw edema by 47% in the same experiment, for a CPE index of 0.72.
27. Ortiz de Montellano, P. R.; Correia, M. A. Suicidal Destruction of Cytochrome P-450 During Oxidative Drug Metabolism. Annu. Rev. Pharmacol. Toxicol. 1983, 23, 481-503.
28. Satoh, H.; Inada, I.; Hirata, T.; Maki, Y. Indomethacin produces gastric antral ulcers in the refed rat. Gastroenterology 1981, 81, 719-725.
29. Battistini, B.; Botting, R.; Bakhle, Y. S. COX-1 and COX-2: Toward the Development of More Selective NSAIDS. Drug News Perspect. 1994, 7, 501-512.
30. Katsumi, I.; Kondo, H.; Yamashita, K.; Hidaka, T.; Hosoe, K.; Yamashita, T.; Watanabe, K. Studies on Styrene Derivatives. I. Synthesis and Antiinflammatory Activities of a-Benzylidene-γ-butyrolactone Derivatives. Chem. Pharm. Bull. 1986, 34, 121-129.
31. Sercel, A. D.; Song, Y.; Belliotti, T.; Beylin, V. G.; Connor, D. T.; Marlatt, M. E.; Sorenson, R. J.; Unangst, P. C.; Gilbertsen, R. B.; Chan, K.; Schrier, D. J.; Laemont, K.; Okonkwo, G. C.; Guglietta, A.; Bornemeier, D. A.; Dyer, R. D. SAR Studies of Substituted Di-tert-butyl phenols as Selective COX-2 Inhibitors. 213th ACS National Meeting, April 1997; Med. Chem. Poster #72.
32. For recent reports on COX-2-selective di-tert-butylphenol inhibitors, see: (a) Song, Y.; Connor, D. T.; Doubleday, R.; Sorenson, R. J.; Sercel, A. D.; Unangst, P. C.; Cornell, W.; Gilbertsen, R. B.; Chan, K.; Schrier, D. J.; Laemont, K.; Okonkwo, G. C.; Guglietta, A.; Bornemeier, D. A.; Dyer, R. D. Synthesis and SAR Studies of Novel Di-tert-butylphenols as Selective PGHS-2 Inhibitors. 213th ACS National Meeting, April 1997; Med. Chem. Poster #73. (b) Song, Y.; Connor, D. T.; Sercel, A. D.; Sorenson, R. J.; Doubleday, R.; Unangst, P. C.; Roth, B. D.; Cornell, W.; Gilbertsen, R. B.; Chan, K.; Schrier, D. J.; Laemont, K.; Okonkwo, G. C.; Guglietta, A.; Bornemeier, D. A.; Dyer, R. D. Substituted Di-tert-butylphenols: A New Class of Potent and Selective PGHS-2 Inhibitor. 213th ACS National Meeting, April 1997; Med. Chem. Poster #74.
33. For recent reports on COX-2-selective di-tert-butylphenol inhibitors, see: (a) Song, Y.; Connor, D. T.; Doubleday, R.; Sorenson, R. J.; Sercel, A. D.; Unangst, P. C.; Cornell, W.; Gilbertsen, R. B.; Chan, K.; Schrier, D. J.; Laemont, K.; Okonkwo, G. C.; Guglietta, A.; Bornemeier, D. A.; Dyer, R. D. Synthesis and SAR Studies of Novel Di-tert-butylphenols as Selective PGHS-2 Inhibitors. 213th ACS National Meeting, April 1997; Med. Chem. Poster #73. (b) Song, Y.; Connor, D. T.; Sercel, A. D.; Sorenson, R. J.; Doubleday, R.; Unangst, P. C.; Roth, B. D.; Cornell, W.; Gilbertsen, R. B.; Chan, K.; Schrier, D. J.; Laemont, K.; Okonkwo, G. C.; Guglietta, A.; Bornemeier, D. A.; Dyer, R. D. Substituted Di-tert-butylphenols: A New Class of Potent and Selective PGHS-2 Inhibitor. 213th ACS National Meeting, April 1997; Med. Chem. Poster #74.