USOO56O7966A United States Patent (19) 11) Patent Number: 5,607,966 Hellberg et al. (45) Date of Patent: Mar. 4, 1997 54 ESTERS AND AMIDES OF NON-STEROIDAL Insel, P.; "Analgesic-Antipyretics and Antiinfmammatory ANTI-NFLAMMATORY CARBOXYLC Agents'; Goodman and Gilman's The Pharmacological ACDS WHICH MAYBE USED AS Basis of Therapeutics; Pergman Press, New York (1990) ANTI-OXEDANTS, 5-LPOXYGENASE 638-669, 681. NHBTORS AND NON-STEROIDAL "Antioxidant properties of some chemicals vs their influence ANTI-NFLAMMATORY PRODRUGS on cyclooxygenase and lipoxidase activities'; Biochemical Pharmacology 32 (14) (1983) 2283-2286. (75) Inventors: Mark R. Hellberg, Arlington; Gustav Bellavite, P.; "The Superoxide-Forming Enzymatic System Graf, Cleburne, both of Tex. of Phagocytes'; Free Radical Biology & Medicine 4 (1988) 255-261. 73) Assignee: Alcon Laboratories, Inc., Fort Worth, Duchstein and Gurka; "Activated Species of Oxygen'; Tex. Archives of Pharmacology 325 (1992) 129-146. Sies and Murphy, "Role of tocopherols in the protection of 21 Appl. No.: 362,718 biological systems against oxidative damage'; Journal of Photochemistry and Photobiology 8 (1991) 211-224. 22 Filed: Dec. 23, 1994 Chow, C.; “Vitamin E and Oxidative Stress'; Free Radical (51) Int. Cl. .......................... CO7D 311/04; A01K 31/35 Biology & Medicine 11 (1991) 215-232. 52 U.S. Cl. .......................... 514/458; 514/.465; 514/653; Petty, et al.; "Protective Effects of an O-tocopherol analogue 549/407; 549/438: 564/172 against myocardial reperfusion injury in rats'; European Journal of Pharmacology 210 (1992) 85–90. 58 Field of Search ..................................... 549/407,438; Bonne, et al., 564/172; 514/458, 465, 653 '2-(2-Hydroxy-4-methylphenyl)aminothiazole Hydro (56) References Cited chloride as a Dual Inhibitor of Cyclooxygenase/Lipoxygen zse and a Free Radical Scavenger"; Drug Research 39 II, Nr. U.S. PATENT DOCUMENTS 10 (1989) 1242-1245. 4,374,258 2/1983 Horner .................................... 549,407 Nelson, P.; "Cyclooxygenase Inhibitors'; CRC Handbook of 4,988,728 1/1991 Gerson et al. ... ... 514f448 Eicosanoids: Prostaglandins, and Related Lipids, vol. II 5,084.575 1/1992 Kreft, III et al. ....................... 54.6/172 Drugs Acting Via the Eicosanoids; CRC Press, Boca Raton, FL (1989) 59-133. FOREIGN PATENT DOCUMENTS Cohen, et al.; "Lewis Acid Mediated Nucleophilic Substi 24,043-A 10/987 European Pat. Off. tution Reactions'; Journal of Organic Chemistry 54 (1989) 279867-A 8/1988 European Pat. Off.. 3282-3292. 345592-A 12/1989 European Pat. Off.. Lambda, et al.; "Spectroscopic detection of lipid peroxida 380367-A 8/1990 European Pat. Off. tion products and structural changes in a sphingomyelin O387771 9/1990 European Pat. Off. ...... CO7D 311/72 model system”; Biochimica et Biophysica Acta 1081 (1991) O527458A1 2/993 European Pat. Off. ...... CO7C 233/22 81-87. 0525360A2 2/1993 European Pat. Off. ... C07C 235/34 Skoog and Beck; "Methods of Isolating Leukocytes'; Blood 34O7507A1 9/1985 Germany. 11 (1956) 436-454. 3904674-A 8/1990 Germany. Graff and Anderson; "1-4-3-4- 64-40484A2 10/1989 Japan ......................... COTD 49/052 BIS(4-Fluorophenyl)hydroxymethyl)-1-peperidinyl)pro WO95/29.906 - 1/1995 WIPO poxy-3-methoxyphenyl)ethanone (AHR-5333)”; Prostag OTHER PUBLICATIONS landins 38 No. 4 (1989) 473-497. Hammond et al., "2,3-Dihydro-5-benzofuranols as Bazan. H.; "Response of Inflammatory Lipid Mediators Antiooxidant-Based Inhibitors of Leukotriene Biosynthe following Corneal Injury'; Lipid Mediators in Eye Inflam sis', J. Med. Chem., vol. 32, pp. 1006-1020 (1989). mation. Hutchinson et al., “Drug Discovery and Development New Trends Lipid Mediators Res. Basel Karger vol. 5 (1990) through the Genetic Engineering of Antibiotic-Producing 1-11. Microorganisms”, Journal of Medicinal Chemistry, vol. 32, Primary Examiner-Robert Gerstl No. 5, pp. 907–918 (1989). Attorney, Agent, or Firm-Michael C. Mayo; Gregg C. Tseng, C., et al., "Inhibition of in Vitro Prostaglandin and Brown Leukotriene Biosyntheses by Chinnamoyl-3-phenethylamine and N-Acyidopamine 57 ABSTRACT Derivatives', Chem. Pharm. Bull, vol. 40, No. 2, pp. 396-400 (1992). Compounds having anti-inflammatory and anti-oxidant Campbell, W.; "Lipid-Derived Autacoids'; Goodman and activity are disclosed. The compounds are useful in prevent Gilman's The Pharmacological Basis of Therapeutics, Perg ing and treating inflammatory disorders through several man Press, New York (1990) 600-617. mechanisms. Methods of treatment employing these prop Gifford, H.; "The Treatment of Sympathetic Ophthalmia', erties of the compounds and corresponding pharmaceutical Ophthalmoscope 8 (1910) 257-259. compositions are disclosed. Goa and Chrisp, "Ocular Diclofenac'; Drugs & Aging 206) (1992) 473–486. 33 Claims, No Drawings 5,607,966 1. 2 ESTERS AND AMDES OF NON-STEROIDAL erences do not disclose the compounds of the present ANTI-NFLAMMATORY CARBOXYLIC invention. ACDS WHICH MAY BE USED AS The present invention is directed to the provision of new ANTI-OXIDANTS, 5-LPOXYGENASE compounds that have both potent anti-inflammatory activity NHIBITORS AND NON-STEROIDAL and potent anti-oxidant activity in a single molecule. The use ANTI-NFLAMMATORY PRODRUGS of a single chemical entity with potent anti-inflammatory and potent anti-oxidant activity provides increased protec tion relative to the use of a compound with singular activity. BACKGROUND OF THE INVENTION The use of a single agent having both activities over a 10 combination of two different agents provides uniform deliv The present invention is directed to the provision of ery of an active molecule, thereby simplifying issues of drug compounds having potent anti-inflammatory and anti-oxi metabolism, toxicity and delivery. dant activity. The invention is further directed to composi tions containing the compounds of the present invention for SUMMARY OF THE INVENTION use in pharmaceutical applications. The invention is also 15 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. reduce cellular damage. Additionally, the compounds of the Inflammation from cellular stress can cause excessive 20 present invention also exhibit other anti-inflammatory activ tissue damage. Numerous biochemical pathways are known ity 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 "FFPETEs”. steroidal anti-inflammatory agent (NSAIA) moiety and an Such agents have been associated with inflammation. See 25 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, New tage of these individual efficacies. In addition, the present York (1990). Therapies designed to inhibit the production of invention improves upon these individual efficacies by pro these types of agents are therefore of great interest. viding greater drug delivery to the targettissues by means of Non-steroidal anti-inflammatory agents (NSAIA) have 30 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); advantages of the present invention will be apparent to those Nature, New Biology volume 231, page 232 (1971); 35 skilled in the art based on the following description. FASEB Journal, volume 1, page 89 (1987); and The NSAIA component of the compounds provides anti Inflammation and Mechanisms and Action of Traditional inflammatory activity. The use of these NSAIAs will provide Drugs, Vol. I Anti-inflammatory and Anti-rheumatic inhibition of cyclooxygenase, an important enzyme involved drugs. Boca Raton, Fla., CRC Press, (1985). in the prostaglandin/inflammation pathway. The compounds However, there are some problems associated with NSAIA also include an anti-oxidant component. As oxidative stress treatment including delivery to the appropriate site of action has been implicated in inflammatory responses, the presence and side effects (Goodman and Gilman's The Pharmaco logical Basis of Therapeutics, pages 638-669, Pergman of an anti-oxidant will further help treat the target tissue. Press, New York (1990)). The compounds of the present invention also exhibit Free radical molecules also play a major role in inflam 45 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 oxidative stress efficacy against 5-lipoxygenase, an enzyme known to be and damage has been described in Biochemical Pharmacol involved in inflammation. ogy, 32(14), 2283-2286 (1983) and Free Radicals