Design of 5-(3,5-Di-tertbutyl-4-hydroxyphenyl)-1,3,4-thiadiazoles, -1,3,4-oxadiazoles, and -1,2,4-triazoles as Orally-Active, Nonulcerogenic Antiinflammatory Agents

Journal of Medicinal Chemistry

Volumn 36, Issue 8, 1993, Pages 1090-1099

  Mullican, Michael D ^a   Wilson, Michael W ^a   Connor, David T ^a   Kostlan, Catherine R ^a   Schrier, Denis J ^a   Dyer, Richard D ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,4 TRIAZOLE DERIVATIVE; 1,3,4 OXADIAZOLE DERIVATIVE; 1,3,4 THIADIAZOLE DERIVATIVE; ANTIINFLAMMATORY AGENT; ARACHIDONATE 5 LIPOXYGENASE; CARRAGEENAN; PROSTAGLANDIN SYNTHASE;

ANIMAL CELL; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; DISSOCIATION CONSTANT; DOSE RESPONSE; DRUG DESIGN; DRUG SYNTHESIS; ENZYME INHIBITION; INFLAMMATION; LEUKEMIA CELL; MALE; MAST CELL LEUKEMIA; NONHUMAN; ORAL DRUG ADMINISTRATION; PAW EDEMA; PRIORITY JOURNAL; RAT; STRUCTURE ACTIVITY RELATION;

EID: 0027221539     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm00060a017     Document Type: Article

References (37)

1. Presented in part by Wilson, M. W.; Mullican, M. D.; Kostlan, C. R.; Connor, D. T. Synthesis and Physical Chemical Properties of 3,5-Di-t-butyl-4-hydroxyphenyl-1,3,4-Thiadiazoles,-1,3,4-Oxadiazoles and -1,2,4-Triazoles. Abstracts, Thirteenth International Congress of Heterocyclic Chemistry, August 11–16, 1991, Corvallis, OR; Abstract P03-158.
2. Mullican, M. D.; Wilson, M. W.; Kostlan, C. R.; Connor, D. T.; Schrier, D. J.; Dyer, R. 5-(3,5-Di-tertbutyl-4-hydroxyphenyl)-1,3,4-Thiadiazoles,-1,3,4-Ozadiazolesand-1,2,4-Triazoles as Nonulcerogenic Antiinflammatory Agents. Discovery of CI-986. Abstracts for Papers, 203rd National Meeting of the American Chemical Society, San Francisco, CA, April 1992; American Chemical Society: Washington, D.C., 1992; MEDI 121.
3. Samuelsson, B. An Elucidation of the Arachidonic Acid Cascade: Discovery of Prostaglandins, Thromboxane and Leukotrienes. Drugs 1987, 33 (Suppl. 1), 2–9.
4. Lombardino, G. Nonsteroidal Antiinflammatory Drugs; Wiley Interscience, John Wiley & Sons: New York, 1985.
5. Samuelsson, B.; Borgeat, P.; Hammarstrom, S.; Murphy, R. C. Leukotrienes: A New Group of Biologically Active Compounds. Adv. Prostaglandin Thromboxane Res. 1980, 6, 1–18.
6. Samuelsson, B. Leukotrienes and Other Lipoxygenase Products. Prog. Lipid Res. 1986, 25, 13–18.
7. Schoen, R. T.; Vender, R. J. Mechanisms of Nonsteroidal Antiinflammatory Drug-Induced Gastric Damage. Am. J. Med. 1989, 86, 449–458.
8. Boughton-Smith, N. K.; Whittie, B. J. R. The Role of Leukotrienes in the Pathogenesis of Gastric Ulceration. Pharm. Res. Commun. 1988, 20, 919–934.
9. Flynn, D. L.; Belliotti, T. R.; Boctor, A. M.; Connor, D. T.; Kostlan, C. R.; Nies, D. E.; Ortwine, D. F.; Schrier, D. J.; Sircar, J. C. Styrylpyrazoles, Styrylisoxazoles, and Styrylisothiazoles. Novel 5-Lipoxygenase and Cyclooxygenase Inhibitors. J. Med. Chem. 1991, 34, 518–525.
10. Unangst, P. C.; Shrum, G. P.; Connor, D. T.; Dyer, R. D.; Schrier, D. J. Novel 1,2,4-Oxadiazoles and 1,2,4-Triazoles as Dual 5-Lipoxygenase and Cyclooxygenase Inhibitors. J. Med. Chem. 1992, 35, 3698.
11. Hidaka, T.; Hosoe, K.; Ariki, Y.; Takoe, K.; Yamashita, T.; Katsumi, I.; Kondo, H.; Yamashita, K.; Watanabe, K. Pharmacological Properties of a New Antiinflammatory Compound, α-(3,5-Di-tertbutyl-4-hydroxybenzylidene)-γ-butyrolactone (KME-4), and its Inhibitory Effects on Prostaglandin Synthetase and 5-Lipoxygenase. Jpn. J. Pharmacol. 1984, 36, 77–85.
12. Ikuta, H.; Shirota, H.; Kobayashi, Y.; Yamagishi, K.; Yamada, I.; Yamotsu, I.; Katayama, K. Synthesis and Antiinflammatory Activities of 3-(3,5-Di-tertbutyl-4-hydroxybenzylidene)pyrrolidin-2-ones. J. Med. Chem. 1987, 30, 1995–1998.
13. Koup, J. Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, personal communication.
14. Gehlen, H.; Blankenstein, G. Liebigs Ann. Chem. 1960, 638, 136–140.
15. Baron, M.; Wilson, C. 2-Substituted-1,3,4-oxa- and Thiadiazoline-S-thiones. J. Org. Chem. 1958, 23, 1021–1023.
16. Cohen, L. A. Electronic Control of Steric Hindrance in Hindered Phenols. J. Org. Chem. 1957, 22, 1333–1335.
17. Corey, E. J.; Gras, J. L.; Ulrich, P. A New General Method for Protection of the Hydroxyl Function. Tetrahedron Lett. 1976, 11, 809–812.
18. Jones, J. H.; Holtz, W. J.; Cragoe, E. J. Pyrazine Diuretics, VII N-Amido-3-Substituted Pyrazine Carboxamides. J. Med. Chem. 1969, 12, 285–287.
19. Kubota, S.; Uda, M. 1,2,4-Triazoles. IV. Tautomerism of 3,5-Disubstituted 1,2,4-Triazoles. Chem. Pharm. Bull. Jpn. 1975, 23, 955–966.
20. El-Khawass, S. M.; Habib, N. S. Synthesis of 1,2,4-Triazole, 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazole and 1,2,4-Triazole[3,4-b][1,3,4]-thiadiazine Derivatives of Benzotriazole. J. Heterocycl. Chem. 1989, 26, 177–181.
21. Hoggarth, E. Compounds Related to Thiosemicarbazide. Part II, 1-Benzoylthiosemicarbazides. J. Chem. Soc. 1949, 1163–1167.
22. Jacobsen, N. W.; McCarthy, B. L.; Smith, S. N-Aminopyrimidines: The Isomerization of 1-Aminobarbituric Acids to 2-(5-Oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) Aliphatic Acids. Aust. J. Chem. 1979, 32, 161–165.
23. Kress, T. J.; Costantine, S. M. A Convenient and General Synthesis of 2-Amino-1,3,4-thiadiazoles. Dehydration of Acylthiosemicar-bazides with Methanesulfonic Acid. J. Heterocycl. Chem. 1980, 17, 607–608.
24. Gompper, R.; Kutter, E.; Schmidt, R. R. Ketene Derivatives. VII. Reaction of ω,ω-Bis(alkylthio)quinone Methides. Chem. Ber. 1965, 98, 1374–1384.
25. Kubota, S.; Koida, Y.; Kosaka, T.; Kiuino, O. Structure on the Synthesis of 1,3,4-Thiadiazole Derivatives. II. Synthesis of 1,3,4-Thiadiazoline-5-Thione from Amidrazones and Carbon Disulfide. Chem. Pharm. Bull. 1970, 18, 1696–1698.
26. Audrieth, L. F.; Scott, E. S.; Kippur, P. S. Hydrazine Derivatives of the Carbonic and Thiocarbonic Acids. I. The Preparation and Properties of the Thiocarbohydrazide. J. Org. Chem. 1954, 19, 733–741.
27. Caution: Sodium hydrazide is explosive! Kosel, C.; Kauffmann, T.; Spaude, S.; Wolf, D. Chem. Ber. 1964, 97, 3436–3443.
28. Kosel, C. Dissertation, Technischen Hochschule Darmstadt, March 1962.
29. Dornow, A.; Fischer, K. Chem. Ber. 1966, 99, 72–80.
30. Winter, C. A.; Risley, E. A.; Nuss, G. W. “Carrageenin-Induced Edema in Hindpaw of the Rat as an Assay for Antiinflammatory Drugs.” Proc. Soc. Exp. Biol., N.Y. 1962, 111, 544–547.
31. Newbould, B. B. Chemotherapy of Arthritis Induced in Rats by Mycobacterial Adjuvant. Br. J. Pharmacol. 1963, 21, 127–136.
32. Dyer, R. D.; Kennedy, J.; Bornemeier, D.; Egloff, A. M.; Adamchak, M.; Chung, F.-Z.; Mullican, M.; Connor, D. T.; Schrier, D. J. Biochemical Pharmacology of CI-986, A Novel Inhibitor of Arachidonic Acid (AA) Metabolism. J. Cell. Biochem. 1991, Supplement 15E, 171, Abstract 0305.
33. Loewen, G.; Koup, J.; Schrier, D.; Baragi, V.; Tucker, E.; Thomas, D.; Okonkwo, G.; Jordan, H. Therapeutic Drug Monitoring of CI-986, A Novel Inhibitor of Arachidonic Acid Metabolism, During Pharmacological Screening in Rat Inflammation Models. J. Cell. Biochem. 1991, Supplement 15E, Abstract 313.
34. Schrier, D. J.; Baragi, V. M.; Connor, D. T.; Dyer, R. D.; Jordan, J. H.; Lesch, M. E.; Mullican, M. D.; Okonkwo, G.; Conroy, M. C. The Antiinflammatory Effects of CI-986, 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione, choline salt, a Novel Inhibitor of Arachidonic Acid Metabolism. J. Cell. Biochem. 1991, Supplement 15E, 175, Abstract 317.
35. Dyer, R. D.; Baragi, V. M.; Bornemeier, D.; Chung, F.-Z.; Connor, D. T.; Egloff, A. M.; Kennedy, J.; Mullican, M.; Vartanian, M.; Schrier, D. J. CI-986, A Novel Antiinflammatory Inhibitor of Arachidonic Acid (AA) Metabolism. Prostaglandins, Leukotrienes, Lipoxins & PAF: Final Program and Abstract Volume; Bailey, M., Ed.; Xlth Washington International Symposium, May 13–17, 1991, Abstract 153.
36. Bomemeier, D.; Kennedy, J.; Dawson, R. D. Cyclooxygenase (CO) Inhibition by CI-986 an In Vitro Inhibitor of Arachidonic Acid Metabolism. 75th Annual Meeting of the Federation of American Societies for Experimental Biology, Atlanta, GA, April 21–25, 1991. FASEB 1991, J5, Abstract 422.
37. Haky, J. E.; Young, A. M. Evaluation of a Simple HPLC Correction Method for the Estimation of the Octanol-Water Partition Coefficient of Organic Compounds. J. Liquid Chromatogr. 1984, 7, 625.