US006005000A United States Patent (19) 11 Patent Number: 6,005,000 Hopper et al. (45) Date of Patent: Dec. 21, 1999 54) 5,5-DISUBSTITUTED-3, 4-DIHYDROXY-2(5H)- King and Burns, 1975, the Second conference on Vitamin C, FURANONES AND METHODS OF USE the New York Acadeny of Science, New York. THEREFOR Lafont et al., 1995, J. Clin Invest 95:1018–25. Mansuy et al., 1996, Biochem Biophys Res Comm 75 Inventors: Allen T. Hopper, Somerset, N.J.; John 135:1015-21. A. Ziemniak, Gwynedd Valley; Robert Mantri and Witiak, 1994, Curr Med Chem 1:328-55. E. Johnson, Collegeville, both of Pa. Marshall et al., 1986, J Org Chem 51:858–63. Maxwell, 1995, Drugs 49:345–61. 73 Assignee: Oxis International, Inc., Portland, Millar et al., 1996, J Org Chem 51:4726–8. Oreg. Nicolaou and Webber, 1984, J. Chem Soc, Chem Commun 350-1. 21 Appl. No.: 08/915,099 Nihiro et al., 1992, J Med Chem 35:1618–23. Nunes et al., 1995, Thromb Vasc Biol 15:156-65. 22 Filed: Aug. 20, 1997 Ochiai et al., 1991.J Am Chem Soc 113:1319–23. Related U.S. Application Data O'Sullivan et al., 1992, Biochem Biophys Res Comm 60 Provisional application No. 60/024,440, Aug. 22, 1996, and 187:1123-7. provisional application No. 60/024,586, Aug. 26, 1996. Rabinovici et al., 1993, J Appl Physiol 74:1791–802. Remacle et al., 1995, Mutat Res 316:103–22. 51) Int. Cl. ....................... C07D 307/62; A61K 31/375 Saeva et al., 1991, J Am Chem Soc 113:5333–7. 52 U.S. Cl. ............................................. 514/473; 549/315 Schank, 1972, Synthesis 176–90. 58 Field of Search .............................. 549/315; 514/473 Schreck et al., 1992, Free Rad Res Comms 17:221–37. Shimuzu et al., 1984, Pro Natl Acad Sci USA 81:689–93. 56) References Cited Silverman, 1992, The Organic Chemistry of Drug Design and Drug Action, Academic Press, San Diego, CA, 19-20. U.S. PATENT DOCUMENTS Steinberg, 1995, Lancet 346:36–8. 5,071,872 12/1991. Witiak et al. ........................... 514/465 Stork and Rychnovsky, 1987, JAm Chem Soc 109:1564–5. 5,095,126 3/1992 Witiak et al. ... 549/315 Sun, 1990, Free Rad Biol & Med 8:583–99. 5,185.366 2/1993 Witiak et al. ... ... 514/456 Triozzi et al., 1993, Int J Immunopharmac 15:47-54. 5,288,751 2/1994 Brooks et al. ... ... 514/438 Wang et al., 1996, Pharm Exp Therap 277:714–20. 5,298,526 3/1994 Witiak et al. ... ... 514/473 Wimalasena et al., 1994, Biochem Biophys Res Comm 5,399,721 3/1995 Hopper et al. ... ... 549/315 200:113-9. 5,504,107 4/1996 Mantri et al. ........................... 549/315 5,504,108 4/1996 Witiak et al. ........................... 514/473 Witiak et al., 1982, J Med Chem 25:90–3. 5,534,540 7/1996 Ulrich et al. ............................ 514/473 Witiak et al., 1986, J Med Chem 29:2170–4. Witiak et al., 1987, J Org Chem 52:2324-7. FOREIGN PATENT DOCUMENTS Witiak et al., 1987, Actual Chim Therap 15:41–62. 4–29985 1/1992 Japan. Witiak et al., 1988, J Med Chem 31:1437–45. WO95/32194 11/1995 WIPO. Witiak et al., 1992, in Trends in Medicinal chemistry '90, Proceeding of the XIth Internatinal Symposiumon Medici OTHER PUBLICATIONS nal Chemistry, Jerusalem, Israel, Sep. 2-7, Sarel et al eds. Alami et al., 1993, Tetrahedron Lett 34:6403–6. Blackwell Scientific Publicstions, Oxford, London:243-56. Berson and Greenbaum, 1958, JAm Chem Soc 80:653-6. Bisby et al., 1995, Free Rad Biol Med 20:411–20. Primary Examiner Bernard Dentz Boopathy and Baiasubramanian, 1968, Biochem J Attorney, Agent, or Firm-Klauber & Jackson 239:371-7. 57 ABSTRACT Brown, 1975, Organic Syntheses via Boranes, John Wiley and Sons, New York, 100, 178. The present invention relates to synthetic methods for the Buckle and Fenwick, 1989, J Chem Soc Perken Trans production of both optically active and racemic 5,5- 1477-82. disubstituted-3,4-dihydroxy-2(5H)-furanones; 5-(4-aryl)-3- Buffinton and Doe, 1995, Free Rad Biol Med 19:911-8. butynyl)-3,4-dihydroxy-2(5H)-furanones; 5-(2-arylthio) Bundy et al., 1995, J Med Chem 38:4161-3. ethyl-3,4-dihydroxy-2(5H)-furanones; and 5-(2-aryloxy) Coyle et al., 1993, Science 262:689–95. ethyl-3,4-dihydroxy-2(5H)-furanones. This invention DeJarlais et al., 1980, Synth Commun 10:653–60. further relates to the use of the above mentioned compounds Egan and Gale, 1985, J Biol Chem 260;11554–9. as anti-inflammatory agents through their action as mixed Evans et al., 1987, Biochem Pharm 36:2035-7. inhibitors of lipid peroxidation, 5-lipoxygenase, Frimer et al., 1995, J Org Chem 60:4510–20. cyclooxygenase-1 and cyclooxygenase-2. The invention fur Grisar et al., 1995, J Med Chem 38:453–8. ther relates to the use of Such compounds in the treatment of Gross et al., 1994, Hepato-Gastroenterol 41:320-7. chronic inflammatory disorderS Such as asthma, rheumatoid Halliwell, 1987, FASEB J 1:358-64. arthritis, inflammatory bowel disease, atherosclerosis, acute Halliwell, 1991, Drugs 42:569–605. respiratory distress Syndrome, and central nervous System Hopper et al. (1995) J. Org. Chem. 60:3334-41. disorderS Such as Alzheimer's and Parkinson's disease Hvoslef and Pedersen, 1979, Acta Chemica Scand B wherein reactive oxygen species and inflammatory media 33:503-11. tors are contributing deleterious factors. Kato et al., 1988, J Med Chem 31:793–8. Kerwin, 1995, J Med Chem 38:4343-62. 15 Claims, No Drawings 6,005,000 1 2 5,5-DISUBSTITUTED-3, 4-DIHYDROXY-2(5H)- Thus, there exists a need for new therapeutic agents which FURANONES AND METHODS OF USE exhibit activity as antioxidants and arachidonic acid metabo THEREFOR lism inhibitors. It is to this aim that the present invention is directed. This application claims priority from Provisional appli cations Ser. Nos. 60/024,440 filed on Aug. 22, 1996, and SUMMARY OF THE INVENTION 60/024,586 filed Aug. 26, 1996. FIELD OF THE INVENTION The present invention relates to 5-substituted and 5.5- The present invention relates generally to 5-Substituted disubstituted-3,4-dihydroxy-2(5H)-furanones of the general and 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones, 1O formula I methods of preparation therefor, and methods for their use. BACKGROUND OF THE INVENTION (I) The aci-reductone 4-(4-chlorophenyl)-2-hydroxytetronic R O acid compound (CHTA) possesses antilipidemic and anti 15 aggregatory properties which differ from those of the clas Sical phenoxyactetic acids as has been disclosed in Witiak et Aryl-(L) (CH2) 2 OH al., J. Med. Chem., 1988, 31:1434-1445 and Kamanna et al., Lipids, 1989, 24:25-32. Although unsubstituted-, 2-alkyl OH and 2-acyltetronic acids are frequently found in nature, the 2-hydroxy Substituted tetronic acid redox System is found wherein R is hydrogen, phenyl or lower alkyl, L is a linker only in Vitamin C and its closely related relatives moiety Selected from the group consisting of oxygen, Sulfur, (isoascorbic acid, erythroascorbic acid) and derivatives, and nitrogen, acetylene, a cis or trans carbon-carbon double the macrollide antibiotic, chlorothricin. bond, an ester, carbonate, urea, amide and carbamate; m is The antiaggregatory activities of 2-hydroxytetronic acid 25 aci-reductone compound (CHTA) are of interest since blood 0 or 1; n is 0 to 4; Aryl is a substituted or unsubstituted aryl platelets are involved in the genesis of atherosclerosis. group; with the proviso that when R is hydrogen, then either 2-Hydroxytetronic acid aci-reductones inhibit collagen m or n is not Zero, and the pharmaceutically acceptable Salts induced human platelet aggregation and Secretion of 'CI thereof. Serotonin in a concentration-dependent manner at equivalent In various preferred embodiments of the present doses, as reported in Witiak et al., J. Med. Chem., 1982, invention, these compounds are represented by four struc 25:90-93. The CHTA compound inhibits platelet function tural Subclasses of compounds. Thus, in one preferred by a similar mechanism, involving arachidonic acid release. embodiment, the compounds are 5,5-disubstituted-3,4- Redox analogues, Such as 2-hydroxytetronic acid, function dihydroxy-2(5H)-furanones of the structural formula Ia as antioxidants in membranes or interfere with free radical 35 processes involved in the biosynthetic elaboration of cyclic (Ia) prostaglandin endoperoxides (PGG and PGH), and, Subsequently, thromboxane A from arachidonic acid. The development of dual antioxidant-arachidonic acid (AA) metabolism inhibitors may provide added benefits 40 OH over existing drugs for the treatment of diseases associated with oxidative StreSS and inflammation. Numerous condi OH tions including asthma, rheumatoid arthritis, irritable bowel disease (IBD), adult respiratory distress syndrome (ARDS), atherosclerosis, ischemia/reperfusion injury, restenosis, neu 45 wherein R and Aryl are as hereinbefore defined. Most rodegenerative disorders and initiation and promotion of preferably, in the compounds of formula (Ia), R is a methyl, carcinogenesis correlate with abnormally high levels of 1-propyl or 2-methylpropyl group; and Aryl is a phenyl, or reactive oxygen species (ROS). Antioxidant-based therapies Substituted phenyl, such as 1,1'-biphenyl, 4-chlorophenyl or including both natural antioxidants (e.g., vitamin E, Vitamin 2-methylpropylphenyl group. C and SOD), and Synthetic antioxidants (e.g., 4-aryl-2- 50 In a Second preferred embodiment, the compounds are hydroxytetronic acids', 2-O-alkyl ascorbic acids, probucol 5-(aryl alkynyl)-3,4-dihydroxy-2(5H)-furanones of the and tirilazad meSylate) have been, or are currently being, structural formula Ib investigated for the treatment of a number of these condi tions.