Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 1. Thiazolone and oxazolone series

Journal of Medicinal Chemistry

Volumn 42, Issue 7, 1999, Pages 1151-1160

  Song, Yuntao ^a   Connor, David T ^a   Doubleday, Robert ^a   Sorenson, Roderick J ^a   Sercel, Anthony D ^a   Unangst, Paul C ^a   Roth, Bruce D ^a   Gilbertsen, Richard B ^a   Chan, Kam ^a   Schrier, Denis J ^a   Guglietta, Antonio ^a   Bornemeier, Dirk A ^a   Dyer, Richard D ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3,5 DI TERT BUTYLPHENOL; 5 (3,5 DI TERT BUTYL 4 HYDROXYBENZYLIDENE) 2 (METHOXYAMINO)THIAZOL 4 ONE; 5 (3,5 DI TERT BUTYL 4 HYDROXYBENZYLIDENE) 2 METHOXYIMINO 4 THIAZOLONE; CYCLOOXYGENASE 2 INHIBITOR; OXAZOLONE; PHENOL DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CONCENTRATION RESPONSE; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; FOOT PAD; GASTROINTESTINAL MUCOSA; MALE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; CARRAGEENAN; CELL LINE; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITORS; CYCLOOXYGENASE INHIBITORS; DINOPROSTONE; EDEMA; GASTRIC MUCOSA; HUMANS; HYPERALGESIA; ISOENZYMES; MALE; MEMBRANE PROTEINS; MICE; OXAZOLES; PHENOLS; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES; RATS; RATS, SPRAGUE-DAWLEY; STOMACH ULCER; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

EID: 0033535514     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9805081     Document Type: Article

References (37)

1. Presented in part: (a) Song, Y.; Connor, D. T.; Sorenson, K. J.; Doubleday, R.; Sercel, A. D.; Unangst, P. C.; Gilbertsen, R. B.; Chan, K.; Bornemeier, D. A.; Dyer, R. D. 2,6-Di-tert-butylphenols: A New Class of Potent and Selective COX-2 Inhibitor. Poster presentation at the 8th International Conference of the Inflammation Research Association, Hershey, PA, October 1996; Abstract P86.
2. (b) Song, Y.; Connor, D. T.; Sorenson, R. J.; Doubleday, R.; Sercel, A. D.; Unangst, P. C.; Gilbertsen, R. B.; Chan, K.; Bornemeier, D. A.; Dyer, R. D. 2,6-Di-tert-butylphenols: A New Class of Potent and Selective COX-2 Inhibitor. Inflamm. Res. Suppl. 2 1997, 46, S141-S142.
3. (c) 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. Novel Di-tert-butylphenols as Selective COX-2 Inhibitors and Orally Active and Safe Antiinflammatory Agents. Poster presentation at the 213th ACS National Meeting, San Francisco, CA, Apr 13-17, 1997; Abstract 073.
4. Ferreira, S. H.; Moncada, S.; Vane, J. R. Indomethacin and Aspirin Abolish Prostaglandin Release from the Spleen. Nature (New Biol.) 1971, 237, 237-239.
5. Miller, T. A. Protective Effects of Prostaglandins against Gastric Mucosal Damage: Current Knowledge and Proposed Mechanisms. Am. J. Physiol. 1983, 245, G601-G623.
6. Allison, M. C.; Howatson, A. G.; Torrance, C. J.; Lee, F. D.; Russell, R. I. Gastrointestinal Damage Associated with the Use of Nonsteroidal Antiinflammatory Drugs. N. Engl. J. Med. 1992, 327, 749-754.
7. Kujubu, D. A.; Fletcher, B. S.; Varnum, B. C.; Lim, R. W.; Herschman, H. R. TIS10, A Phorbol Ester Tumor Promoter-inducible mRNA from Swiss 3T3 Cells, Encodes a Novel Prostaglandin Synthase/Cyclooxygenase Homologue. J. Biol. Chem. 1991, 266, 12866-12872.
8. (a) Hla, T.; Neilson, K. Human Cyclooxygenase-2 cDNA. Proc Natl. Acad. Sci. U.S.A. 1992, 89, 7384-7388.
9. (b) Kujubu, D. A.; Herschman, H. R. Dexamethasone Inhibits Mitogen Induction of the TIS10 Prostaglandin Synthase/Cyclooxygenase Gene. J Biol. Chem. 1992, 267, 7991-7994.
10. (a) Seibert, K.; Zhang, Y.; Leahy, K.; Hauser, S.; Masferrer, J.; Perkins, W.; Lee, L.; Isakson, P. Pharmacological and Biochemical Demonstration of the Role of Cyclooxygenase 2 in Inflammation and Pain. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 12013-12017.
11. (b) Isakson, P.; Seibert, K.; Masferrer, J.; Salvemini, D.; Lee, L.; Needleman, P. Discovery of a Better Aspirin. In Advances in Prostaglandin, Thromboxane, and Leukotriene Research; Samuelson, B., Ed.; Raven Press, Ltd.: New York, 1995; Vol. 23, p 49-54.
12. (a) Masferrer, J. L.; Zweifel, B. S.; Manning, P. T.; Hauser, S. D.; Leahy, K M.; Smith, W. G.; Isakson, P. C.; Seibert, K. Selective Inhibition of Inducible Cyclooxygenase 2 in vivo Is Antiinflammatory and Nonulcerogenic. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3228-3232.
13. (b) Futaki, N.; Yoshikawa, K.; Hamasaka, Y.; Arai, I.; Higuchi, S.; Iizuka, H.; Otomo, S. NS-398, a Novel Nonsteroidal Antiinflammatory Drug with Potent Analgesic and Antipyretic Effects, Which Causes Minimal Stomach Lesions. Gen. Pharmacol. 1993, 24, 105-110.
14. Chan, C. C.; Boyce, S.; Brideau, C.; Ford-Hutchinson, A. W.; Gordon, R.; Guay, D.; Hill, R. G.; Li, C. S.; Mancini, J.; Penneton, M.; Prasit, P.; Rasori, R.; Riendeau, D.; Roy, P.; Tagari, P.; Vickers, P.; Wong, E.; Rodger, I. W. Pharmacology of a Selective Cyclooxygenase-2 Inhibitor, L-745,337: a Novel Nonsteroidal Antiinflammatory Agent with an Ulcerogenic Sparing Effect in Rat and Nonhuman Primate Stomach. J. Pharmacol. Exp. Ther. 1995, 274, 1531-1537.
15. (a) Thiazolones: 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. 1894, 37, 322-328.
16. (b) 1,3,4-Thiadiazoles: Mullican, M. D.; Wilson, M. W.; Connor, D. T.; Kostlan, C. R.; Schrier, D. J.; Dyer, R. D. Design of 5-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1,3,4-thiadiazoles, 1,3,4-oxadiazoles, and -1,2,4-triazoles as Orally-Active, Nonulcerogenic Antiinflammatory Agents. J. Med. Chem. 1993, 36, 1090-1099.
17. Mitchell, J. A.; Akarasereenont, P.; Thiemermann, C.; Flower, R. J.; Vane, J. R. Selectivity of Nonsteroidal Antiinflammatory Drugs as Inhibitors of Constitutive and Inducible Cyclooxygenase. Proc. Natl. Acad. Sci. U.S.A. 1994, 90, 11693-11697.
18. The structure of 20 was confirmed by X-ray crystallography.
19. For the preparation of 4a,b,e,f,q-s, 9, 10, 11e, 12c, 16a-d, 17a,b, 18a-e, and 19a,b, see ref of 10a.
20. For the preparation of 12a,b, see: Cetenko, W. A.; Connor, D. T.; Sircar, J. C.; Sorenson, R. J.; Unangst, P. C; Warner-Lambert Co. Preparation of 3,5-Di-tertiarybutyl-4-hydroxyphenylmethylene Derivatives of 2-Substituted Thiazolidinones, Oxazolidinones, and Imidazolidinones as Antiinflammatory Agents. Eur. Pat. Appl. EP 449216, 1991.
21. For the preparation of 13, see: Imai, N.; Shiraishi, T.; Katsumi, I.; Yamashita, K.; Ariki, Y.; Yamashita, T.; Kanegafuchi Chemical Industry Co., Ltd. Diisopropylbenzylidene-substituted Heterocycles. Jpn. Kokai Tokkyo Koho, JP 62029570, 1987.
22. For the preparation of 14 and 15, see: Cetenko, W. A.; Connor, D. T.; Sorenson, R. J.; Unangst, P. C.; Stabler, S. R.; Warner-Lambert Co. Preparation of (Arylmethylenyl)thiazolidinones, -Imidazolidinones and -Oxazolidinones as Antiinflammatory Agents and Antiallergy Agents. Eur. Pat. Appl. EP 343643, 1989.
23. For a review, see: Tsai, A. L.; Kulmacz, R. J. Prostaglandin H synthase: Current Concept of Mechanisms of Reaction and of Inhibition by Nonsteroidal Antiinflammatory Agents. In Recent Adv. Mol. Biochem. Res. Proteins, Proc. IUBMB Symp. Protein Struct. Funct.; Wei, Y. H., Chen, C. S., Su, J. C., Ed.; World Sci.: Singapore, Singapore, 1993; pp 29-37.
24. (a) Goodwin, D. C.; Gunthers, M. R.; Hsi, L. C.; Crews, B. C.; Eling, T. E.; Mason, R. P.; Marnett, L. J. Nitric Oxide Trapping of Tyrosyl Radicals Generated During Prostaglandin Endoperoxide Synthase Turnover. Detection of the Radical Derivative of Tyrosine 385. J. Biol. Chem. 1998, 273, 8903-8909.
25. (b) Tsai, A. L.; Palmer, G.; Xiao, G.; Swinney, D. C.; Kulmacz, R. J. Structural Characterization of Arachidonyl Radicals Formed by Prostaglandin H Synthase-2 and Prostaglandin H Synthase-1 Reconstituted with Mangano Protoporphyrin IX. J. Biol. Chem. 1998, 273, 3888-3894.
26. (c) Xiao, G.; Tsai, A. L.; Palmer, G.; Boyar, W. C.; Marshall, P. J.; Kulmacz, R. J. Analysis of Hydroperoxide-Induced Tyrosyl Radicals and Lipoxygenase Activity in Aspirin-Treated Human Prostaglandin H Synthase-2. Biochemistry 1997, 36, 1836-1845.
27. Lazer, E. S.; Wong, H. C.; Possanza, G. J.; Graham, A. G.; Farina, P. R. Antiinflammatory 2,6-Di-tert-butyl-4-(2-arylethenyl)phenols. J. Med. Chem. 1989, 32, 100-104.
28. Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution. J. Org. Chem. 1978, 43, 2923-2925.
29. (a) Percival, M. D.; Ouellet, M.; Vincent, C. J.; Yergey, J. A.; Kennedy, B. P.; O'Neill, G. P. Purification and Characterization of Recombinate Human Cyclooxygenase-2. Arch. Biochem. Biophys. 1994, 315, 111-118.
30. (b) Barnett, J.; Chow, J.; Ives, D.; Chiou, M.; Mackenzie, R.; Osen, E.; Nguyen, B.; Tsing, S.; Bach, C.; Freire, J.; Chan, H.; Sigal, E.; Ramesha, C. Purification, Characterization and Selective Inhibition of Human Prostaglandin G/H Synthase 1 and 2 Expressed in the Baculovirus System. Biochin. Biophys. Acta 1994, 1209, 130-139.
31. Winter, C. A.; Risley, E. A.; Nuss, G. W. Carrageenin-Induced Edema in Hind Paw of the Rat as an Assay for Antiinflammatory Drugs. Proc. Soc. Exp. Biol. Med. 1962, 111, 544-547.
32. Koster, R.; Anderson, M.; Debeer, E. Acetic Acid for Analgesic Screening. Fed. Proc. 1968, 18, 412.
33. Cahoy, R. P. Process for Manufacturing 3,5-Di-tert-butyl-4-hydroxybenzaldehyde by Formylation of 2,6-Di-tert-butylphenol. U.S. Patent 4,009,210, 1977.
34. Newman, M. S.; Lee, L. F. The Synthesis of Arylacetylenes. 3,5-Di-tert-butylphenylacetylene. J. Org. Chem. 1972, 37, 4468-4469.
35. Paal, C. Zur Kenntniss des p-Oxybenzaldehyds. Chem. Ber. 1895, 28(3), 2407-2414.
36. Laurie, A.; Shroyer, W.; Lorberau, C.; Eaton, S. S.; Eaton, G. R. Steric Effects of Meta Substituents in Substituted Tetraphenylporphyrin Complexes of Ruthenium, Indium, Titanium, and Gallium. J. Org. Chem. 1980, 45, 4296-4303.
37. Compound 6a is commercially available from SALOR, Milwaukee, WI.