Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-06-04
1998-09-22
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514465, 514653, 549407, 549438, A61K 31355, A61K 3136
Patent
active
058114386
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to the provision of compounds having potent anti-inflammatory and anti-oxidant activity. The invention is further directed to compositions containing the compounds of the present invention for use in pharmaceutical applications. The present invention is also directed to various methods of using the compounds and compositions of the present invention in pharmaceutical applications including: 1) the treatment of inflammatory disorders including ocular inflammation associated with ophthalmic disease and ophthalmic surgery; 2) the prevention of corneal haze following ocular surgery; 3) tissue preservation including cornea preservation during transplantation procedures; and 4) as an adjunct to heart disease therapy.
Inflammation from cellular stress can cause excessive tissue damage. Numerous biochemical pathways are known to lead to inflammation. In general, the cyclooxygenase system produces prostaglandins, while the lipoxygenase system produces leukotrienes, "HETEs" and "HPETEs". Such agents have been associated with inflammation. See generally, Goodman and Gilman's The Pharmacological Basis of Therapeutics, pages 600-617, Pergman Press, NY (1990). Therapies designed to inhibit the production of these types of agents are therefore of great interest.
Non-steroidal anti-inflammatory agents (NSAIA) have been used for the treatment of inflammatory disorders. The following references may be referred to for further background concerning this use of NSAIAs: Anti-inflammatory and Anti-rheumatic drugs. Boca Raton, Fla., CRC Press, (1985). delivery to the appropriate site of action and side effects (Goodman and Gilman's The Pharmacological Basis of Therapeutics, pages 638-669, Pergman Press, NY (1990)).
Free radical molecules also play a major role in inflammation. These unstable chemical moieties lead to the oxidation of tissue resulting in damage. Such oxidative stress and damage has been described in Biochemical Pharmacology, 32(14), 2283-2286 (1983) and Free Radicals in Biology and Medicine, 4, 225-261 (1988). Agents that act as anti-oxidants can protect against oxidative damage. Such protection has been the subject of numerous scientific publications, including the following:
The combination of anti-oxidant activity with other pharmacologically significant activities in a single molecule is discussed in JP 010484 A2 and EP 387771 A2; and compounds with cyclooxygenase/5-Lipoxygenase and anti-oxidant activity are discussed in Drug Research, 39(II) Number 10, pages 1242-1250 (1989). However, these references do not disclose the compounds of the present invention.
Ocular inflammation is a condition which generally affects the patient with scratchiness, itchiness and/or red eye. Ocular inflammation can be initiated by various insults. For example, ocular inflammation can result from allergic response to various allergens, trauma to the eye, dry eye and surgical complications. Various anti-inflammatory therapies are currently in use for the treatment of ocular inflammation including the topical administration of diclofenac.
Ocular surgery can result in various post-surgical complications to the eye. Such complications generally include: 1) loss of vascular blood barrier function; 2) tissue edema including conjunctiva swelling, conjuctiva congestion and corneal haze; 3) cataract formation; and 4) loss of membrane integrity including decrease in docosahexanenoic acid levels in membrane phospholipids.
As stated above, vitrectomy surgery can induce a variety of post-surgical complications. Many of these complications are further potentiated in diabetic patients who are at risk for many ocular pathologies. Posterior segment surgery due to the severity of the surgical procedure can cause extensive tissue damage at both the acute and chronic phases of the recovery process. The acute phase of the postsurgical period is characterized by both ocular neovascularization and tissue edema. This is caused by breakdown of the blood aqueous and blood retinal barrier functio
REFERENCES:
patent: 4374258 (1983-02-01), Horner et al.
patent: 4988728 (1991-01-01), Gerson et al.
patent: 5084575 (1992-01-01), Kreft, III et al.
patent: 5424321 (1995-06-01), Hellberg et al.
patent: 5607966 (1997-03-01), Hellberg et al.
patent: 5643943 (1997-07-01), Gamache et al.
Bazan, H., "Response of Inflammatory Lipid Mediators following Corneal Injury", Lipid Mediators In Eye Inflammation New Trends Lipid Mediators Res. Basel Karger, vol. 5, pp. 1-11 (1990).
Bellavite, P., "The Superoxide-Forming Enzymatic System Of Phagocytes", Free Radical Biology & Medicine, vol. 4, pp. 225-261 (1988).
Bonne, C. et al., 2-(2-Hydroxy-4-methylphenyl)aminothiazole Hydrochloride as a Dual Inhibitor of Cyclooxygenase/Lipoxygenase and a Free Radical Scavenger, Drug Research, vol. 39(II), No. 10, pp. 1242-1250 (1989).
Campbell, W., "Lipid-Derived Autacoids: Eicosanoids And Platelet-Activiating Factor", Goodman and Gilman's The Pharmacological Basis of Therapeutics, Pergman Press, NY, pp. 600-617 (1990).
Chow, C., "Vitamin E And Oxidative Stress", Free Radical Biology & Medicine, vol. II, pp. 215-232 (1991).
Cohen, N. et al., "Lewis Acid Mediated Nucleophilic Substitution Reactions of 2-Alkoxy-3,4-dihydro-2H-Ibenzopyrans: Regiochemistry and Utility in the Synthesis of 3,4-Dihydro-2H-1-benzopyran-2-carboxylic Acids", Journal of Organic Chemistry, vol. 54, pp. 3282-3292 (1989).
Derwent AN 95-403834 Abstract.
Duchstein, H. et al., "Activiated Species of Oxygen: A Challenge to Modern Pharmaceutical Chemistry", Archives of Pharmacology, vol. 325, pp. 129-146 (1992).
Duniec, Z. et al.; "Antioxidant properties of some chemicals vs their influence on cyclooxygenase and lipoxidase activities", Biochemical Pharmacology, vol. 32, No. 14, pp. 2283-2286 (1983).
Gifford, H., "On The Treatment Of Sympathetic Ophthalmia By Large Doses Of Salicylate Of Sodium, Aspirin, Or Other Salicylic Compounds", Ophthalmoscope, vol. 8, pp. 257-259 (1910).
Goa, K. et al., "Ocular Diclofenac", Drugs & Aging, vol. 2(6), pp. 473-486 (1992).
Graff, G. et al., oxyphenyl!Ethanone(AHR-5333): A Selective Human Blood Neutrophil 5-Lipoxygenase Inhibitor", Prostaglandins, vol. 38, No. 4, pp. 473-496 (1989). Human Disease: An Overview", Methods in Enzymology, vol. 186, pp. 1-85 (1990).
Hammond et al., "2,3-Dihydro-5-benzofuranols as Antioxidant-Based Inhibitors of Leukotriene Biosynthesis", J. Med. Chem., vol. 32, pp. 1006-1020 (1989).
Hutchinson et al., "Drug Discovery and Development through the Genetic Engineering of Antibiotic-Producing Microorganisms", Journal of Medicinal Chemistry, vol. 32, No. 5, pp. 907-918 (1989).
Insel, P., "Analgesic-Antipyretics And Antiinflammatory Agents: Drugs Employed In The Treatment Of Rheumatoid Arthritis And Gout", Goodman and Gilman's The Pharmacological Basis of Therapeutics, Pergman Press, NY, pp. 638-669 and 681 (1990).
Momsen, W. et al., "Lipid Structural Reorganization Induced by the Pancreatic Lipase Cofactor, Procolipase", Biochemistry, vol. 34, pp. 7271-7281 (1995).
Nelson, P., "Cyclooxygenase Inhibitors", CRC Handbook of Eicosanoids: Prostaglandins and Related Lipids, vol. II, Drugs Acting Via the Eicosanoids, CRC Press, Boca Raton, FL, pp. 59-133 (1989).
Pearce et al., "Inhibitors of Cholesterol Biosynthesis. 2. Hypocholesterolemic and Antioxidant Activities of Benzopyran and Tetrahydronaphthalene Analogues of the Tocotrienols", Journal of Medicinal Chemistry, vol. 37, No. 4, pp. 526-541 (1994).
Petty, M., et al.; "Protective effects of an .alpha.-tocopherol analogue against myocardial reperfusion injury in rats", European Journal of Pharmacology, vol. 210, pp. 85-90 (1992).
Rainsford, K.D., editor, Inflammation and Mechanism and Actions of Traditional Drugs, vol. 1 Anti-inflammatory and Anti-rheumatic drugs, Boca Raton, FL, CRC Press, pp. 54-68, 79-87, 120-126 and 140-144 (1985).
Sies, H., et al., "Role of tocopherols in the protection of biological systems against oxidative damage", Journal of Photochemistry and Photobiology, vol. 8, pp. 211-224 (1991).
Skoog,
Gamache Daniel A.
Garner William H.
Graff Gustav
Hellberg Mark R.
Nixon Jon C.
Alcon Laboratories Inc.
Brown Gregg C.
Mayo Michael C.
Owens Amelia
LandOfFree
Esters and amides of non-steroidal anti-inflammatory carboxylic does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Esters and amides of non-steroidal anti-inflammatory carboxylic , we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Esters and amides of non-steroidal anti-inflammatory carboxylic will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1622061