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United States Patent (19) 11 Patent Number: 5,750,564 Hellberg Et Al

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United States Patent (19) 11 Patent Number: 5,750,564 Hellberg Et Al USOO5750564A United States Patent (19) 11 Patent Number: 5,750,564 Hellberg et al. 45 Date of Patent: May 12, 1998 (54) ANTI-OXDANT ESTERS OF NON Duchstein and Gurka: “Activated Species of Oxygen: A STERODAL ANTI-NFLAMMATORY challenge to Modern Pharmaceutical Chemistry"; Archives AGENTS of Pharmacology; vol. 325; pp. 129-146 (1992). Sies and Murphy, "Role of tocopherols in the protection of 76 Inventors: Mark Hellberg, 52211 Overridge Dr. biological systems against oxidative damage": Journal of Arlington, Tex. 76017; Pete Delgado, Photochemistry and Photobiology; vol. 8, pp. 211-218 4315 N. Segura Ct. Fort Worth. Tex. (1991). 76132; Jon C. Nixon, 1616 Hastings Chow, C.; “Vitamin E and Oxidative Stress'; Free Radical Biology & Medicine; vol. 11; pp. 215-232 (1991). Dr. Mansfield, Tex. 76132 Petty, et al.; "Protective effects of an oc-tocopherol analogue against myocardial reperfusion injury in rats": European (21) Appl. No.: 526,913 Journal of Pharmacology; vol. 210; pp. 85-90 (1992). Bonne. et al.; (22 Filed: Sep. 12, 1995 "2-(2-Hydroxy-4-methylphenyl)aminothiazole Hydro (51) Int. Cl. ........................ A61K 3/34; A61K 31/35 chloride as a Dual Inhibitor of Cyclooxygenase/Lipoxygen 52 U.S. Cl. .......................... 514/469; 54.6/174: 548/510; zse and a Free Radical Scavenger"; Drug Research 39 II. 549/23: 549/57; 549/410; 549/467: 549/470; No. 10; pp. 1242–1245 (1989). 514/311: 514/415: 514/432; 514/443; 514/456; Nelson, P.; "Cyclooxygenase Inhibitors": CRC Handbook of 514/914 Eicosanoids. Prostaglandins, and Related Lipids, vol. II Drugs Acting Via the Eicosanoids; CRC Press, Boca Raton, 58 Field of Search ..................................... 549/467.470; FL; pp. 59-133 (1989). 514/469, 914 Cohen, et al.; "Lewis Acid Mediated Nucleophilic Substi tution Reactions'; Journal of Organic Chemistry; vol. 54: 56 References Cited pp. 3282-3292 (1989). Lamba, et al.; "Spectroscopic detection of lipid peroxidation U.S. PATENT DOCUMENTS products and structural changes in a sphingomyelin model 4,523,024 6/1985 Shiono et al. .......................... 549/407 system”; Biochinica et Biophysica Acta; vol. 1081; pp. 4.550,022 10/1985 Garabedian et al. A a 181-187 (1991). 4,681,890 7/1987 Kanehira et al. .. Skoog and Beck; "Studies on the Fibrinogen. Dextran and 4,857,516 8/1989 Terao et al. ... 514/OO Phytohemagglutinin Methods of Isolating Leukocytes"; 4.975,419 12/1990 Newton et al. 514/6 Blood; vol. 11; pp. 436-454 (1956). 4,988,728 1/1991 Gerson et al. ..... 514448 Graf and Anderson; "1-4-3-4- 5,084.575 1/1992 Kreft, III et al. .. 54672 BIS(4-Fluorophenyl)hydroxymethyl-1-peperidinyl pro 5,424,321 6/1995 Hellberg et al. ........................ 514/337 poxy-3-methoxyphenylethanone (AHR-5333): A Selec tive Human Blood Neutrophil 5-Lipoxygenase Inhibbitor"; FOREIGN PATENT DOCUMENTS Prostaglandins; vol. 38; No. 4; pp. 473-497 (1989). 0 183869 A1 6/1986 European Pat. Off. Bazan. H.; "Response of Inflammatory Lipid Mediators 345593 12/1989 European Pat. Off. following Corneal Injury"; Lipid Mediators in Eye inflam 0.387 771 9/1990 European Pat. Off. ...... CO7D 311/72 mation New Trends Lipid Mediators Res. Basel Karger vol. 0.525 360A2 2/1993 European Pat. Off. ...... CO7C 235/34 5 (1990) 1-11. 0.640609 A1 3/1995 European Pat. Off. Vane, J.; "Inflammation and the mechanism of action of 0.645 383 A1 3/1995 European Pat. Off.. anti-inflammatory drugs"; FASEBJournal; vol. 1, pp. 89-96 0 719 760 A 7/1996 European Pat. Off.. (1987). 58072579 4/1983 Japan. Derwent Publications Ltd., AN 93-297401 Jul. 1993. 64-40484A2 of 1989 Japan ......................... COD 4911052 WO 96/20187 Derwent Publications Ltd., AN 87-246978, Jul. 1987. A 7/1996 WIPO. Derwent Publications Ltd., AN 85-027830, Dec. 1984, Derwent Publications Ltd., AN 84-007991, Nov. 1983. OTHER PUBLICATIONS Hammond et al., "Antioxidant-Based Inhibitors of Leukot riene Biosynthesis. The Discovery of 6-1-2-(Hydroxym Campbell, W.; "Lipid-Derived Autacoids"; Goodman and ethyl)phenyl-1-propen-3-yl)-2, Gilman's The Pharmacological Basis of Therapeutics. Perg 3-dihydro-5-benzofuranol, a. Potent Topical man Press, New York; pp. 600-617 (1990). Antiinflammatory Agent". Journal of Medicinal Chemistry, Gifford, H: "The Treatment of Sympathetic Ophthalmia"; vol. 33. No. 3, pp. 908-918 (1990). Ophthalmoscope; vol. 8; pp. 257-259 (1910). Primary Examiner-Johann Richter Goa and Chrisp; "Ocular Diclofenac"; Drugs & Aging; vol. Assistant Examiner-Laura L. Stockton 2; No. 6; pp. 473-486 (1992). Attorney, Agent, or Firm-Michael C. Mayo Insel, P.; "Analgesic-Antipyretics and Antiinfmammatory Agents'; Goodman and Gilman's The Pharmacological 57 ABSTRACT Basis of Therpeutics; Pergman Press, New York; pp. 638-669, 681 (1990). Compounds having anti-inflammatory and anti-oxidant Duniec. et al.; "Antioxidant properties of some chemicals vs activity are disclosed. The compounds are useful in prevent their influence on cyclooxygenase and lipoxidase activities"; ing and treating inflammatory disorders through several Biochemical Pharmacology; vol. 32; No. 14; pp. 2283-2286 mechanisms. Methods of treatment employing these prop (1983). erties of the compounds and corresponding pharmaceutical Bellavite, P.; "The Superoxide-Forming Enzymatic System compositions are disclosed. of Phagocytes'; Free Radical Biology & Medicine; vol. 4; pp. 255-261 (1988). 30 Claims, No Drawings 5,750,564 1. 2 ANTI-OXDANT ESTERS OF NON. and potent anti-oxidant activity in a single molecule. The use STERODAL ANTI-NFLAMMATORY of a single chemical entity with potent anti-inflammatory AGENTS and potent anti-oxidant activity provides increased protec tion relative to the use of a compound with singular activity. BACKGROUND OF THE INVENTION 5 The use of a single agent having both activities over a The present invention is directed to the provision of combination of two different agents provides uniform deliv compounds having potent anti-inflammatory and anti ery of an active molecule, thereby simplifying issues of drug oxidant activity. The invention is further directed to com metabolism, toxicity and delivery. positions containing the compounds of the present invention for use in pharmaceutical applications. The invention is also 10 SUMMARY OF INVENTION directed to methods of using the compounds and composi The present invention provides new compounds having tions of the present invention to prevent and treat inflam potent anti-inflammatory and anti-oxidant activity. The dual matory disorders including ocular inflammation associated therapeutic efficacies act in a complementary manner to with ophthalmic disease and ophthalmic surgery. 15 reduce cellular damage. Additionally, the compounds of the Inflammation from cellular stress can cause excessive present invention exhibit 5-lipoxygenase inhibitory activity tissue damage. Numerous biochemical pathways are known not present in the individual agents. to lead to inflammation. In general, the cyclooxygenase The compounds of the present invention are useful as system produces prostaglandins, while the lipoxygenase cytoprotective agents. These compounds include a non system produces leukotrienes. "HETEs” and “HPETEs." 20 steroidal anti-inflammatory agent (NSAIA) moiety and an Such agents have been associated with inflammation. See anti-oxidant moiety. In order to provide effective therapy for generally, Goodman and Gilman's The Pharmacological inflammatory disorders, the present invention takes advan Basis of Therapeutics, pages 600-617. Pergman Press, NY tage of these individual efficacies. In addition, the present (1990). Therapies designed to inhibit the production of these invention improves upon these individual efficacies by pro types of agents are therefore of great interest. 25 viding greater drug delivery to the targettissues by means of Non-steroidal anti-inflammatory agents (NSAIA) have administering a single drug having multiple therapeutic been used for the treatment of inflammatory disorders. The actions. Finally, the compounds of the present invention following references may be referred to for further back exhibit therapeutic properties which are not present in the ground concerning this use of NSAIAS: individual moieties of the compounds. These and other Ophthalmoscope, volume 8, page 257 (1910); 30 advantages of the present invention will be apparent to those FASEB Journal, volume 1. page 89 (1987); and skilled in the art based on the following description. Inflammation and Mechanisms and Actions of Traditional The NSAIA component of the compounds provides anti Drugs, vol. I Anti-inflammatory and Anti-rheumatic inflammatory activity. The use of these NSAIAs will provide drugs. Boca Raton, Fla., CRC Press, (1985). inhibition of cyclooxygenase, an important enzyme involved However, there are some problems associated with NSAIA 35 in the prostaglandin/inflammation pathway. The compounds treatment including delivery to the appropriate site of action also include an anti-oxidant component. As oxidative stress and side effects (Goodman and Gilman's The Pharmaco has been implicated in inflammatory responses, the presence logical Basis of Therapeutics, pages 638-669, Pergman of an anti-oxidant will further help treat the target tissue. Press, NY (1990)). The compounds of the present invention also exhibit Free radical molecules also play a major role in inflam properties present only in the combined molecule, not in the mation. These unstable chemical moieties lead to the oxi individual components. One such property is the inhibitory dation of tissue resulting in damage. Such
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