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||||||||||| US005478848A United States Patent (19) 11 Patent Number: 5,478,848 Aune 45) Date of Patent: Dec. 26, 1995 54) INHIBITION OF ARTHRITIS BYL-TYPE Kong et al., Second Messenger Phosphoproteins 13, CALCIUM CHANNEL ANTAGONSTS 117-130 (1991). NIMODIPINE, NISOLDIPINE AND Olsen et al., Biochem. Biophys. Res. Commun. 162,448-455 NFEDIPINE (1989). Dayer and Demczuk, Cytokines and Other Mediators in 75) Inventor: Thomas M. Aune, Hamden, Conn. Rheumatoid Arthritis, Springer Seminars in Immunopathol ogy, pp. 1-27 (Springer-Verlag 1984). 73) Assignee: Bayer Corporation, Pittsburgh, Pa. Gay and Koopman, Current Opinion in Rheumatology 1, 8-14 (1989). (21) Appl. No.: 188464 Brennan et al., The Lancet Jul. 29, 224-247 (1989). Taurog et al., Meth. Enzymol. 162, 339-355 (1988). (22 Filed: Jan. 26, 1994 Otterness and Bliven et al., Nonsteroidal Anti-Inflammatory (51 Int. Cl. .................. A61K 31/44 Drugs, pp. 111-252 (1985). 52 U.S. Cl. ............ 514/356; 514/355 Ward, Am. J. Med., pp. 3-9 (1984). Triggle and Janis, Structure and Physiology if the Slow (58) Field of Search ...................................... 514/355, 356 Inward Calcium Channel, pp. 51-70 (1987). (56) References Cited Godfraind et al., Pharmacol. Rev. 38, 321-416 (1986). Janis and Triggle, Drug Dev. Res. 4, 257-274 (1984). U.S. PATENT DOCUMENTS Schramm et al., Nature 303, 535-537 (1983). Re. 33,963 6/1992 Hegasy ......... ... 424/78.24 Scriabine, Rational Drug Therapy 21, 1-17 (1987). 3,932,645 1/1976 Meyer et al. ........................... 424/266 Chen et al., Science 239, 1024 (1988). 4,154,839 5/1979 Wehinger et al. ...................... 424/266 Scriabine, Structure and Physiology of the Slow Inward 4,537,898 8/1985 Hoff et al. .............................. 514/356 Calcium Channel, pp. 51-70 (1987). 4,600,778 7/1986 Teller et al. ............................ 54.6/249 Jeurissen et al., Arthritis and Rheumatism 34, 961–972 4,783,337 11/1988 Wong et al. ............................ 424/468 (1991). 4,788,205 11/1988 Cooper et al. .......................... 514/333 4,857,312 8/1989 Hegasy et al. ... ... 514/344 Yocum et al., Annals of Internal Medicine 109,863–869 4,892,730 1/1990 Hegasy ..... ... 424/80 (1988). 4,892,741 1/1990 Ohm et al. .............................. 424/479 Rau et al., Arthritis and Rheumatism 34, 1236-1244 (1991). 4,981,683 1/1991 Hegasy et al. ............................ 424/80 4,988,717 1/1991 Wehinger et al. ...................... 514/356 Primary Examiner-T. J. Criares OTHER PUBLICATIONS 57 ABSTRACT Gay and Gay, Rheumatol. Int. 9, 105-113 (1989). The present invention comprises new methods for treating Kouri et al., Scand. J. Immunol. 19, 359-364 (1984). rheumatoid arthritis. It has been found that the L-type Burmester et al., Scand. J. Immunol. 17, 68-82 (1983). calcium channel antagonists are effective in treating arthri Baumgarten and Villereal, J. Biol. Chem. 267, 1524-10530 tis. Nimodipine, nisoldipine, and nifedipine, are examples of (1992). specific compounds useful in the present invention. Bernini et al., J. Cardiovasc. Pharmacol. 18, 42-45 (1991). Hijioka et al., Mol. Pharmacol., 4, 435-440 (1992). 8 Claims, 1 Drawing Sheet U.S. Patent Dec. 26, 1995 5,478,848 100 2 8O E 55 6O E s 40 o nimodipine 2 Sl o nisoldipine o 20 o nifedipine CC Verapamil 10 OO L-type calcium channel antagonist (mg/kg/day, i.p.) FIG. 1 5,478,848 1. 2 NHIBITION OF ARTHRETS BY LTYPE arthritis because of problems with toxicity. A certain level of CALCUM CHANNEL ANTAGONSTS toxicity is also associated with the use of NSAIDs. Otterness NIMODIPINE, NISOLDIPINE AND and Bliven, Nonsteroidal Anti-inflammatory Drugs 111-252 NIFEDIPNE (1985). The most common and perhaps most severe side effect is gastrointestinal bleeding. For example, ulceration of BACKGROUND OF THE INVENTION the upper gastrointestinal tract leading to gastrointestinal bleeding is common with therapeutic doses of indomethacin 1. Field of the Invention used in the treatment of rheumatoid arthritis. This is also the This invention relates to methods of using L-type calcium case for other NSAIDs. channel antagonists to treat arthritis. 10 Methotrexate has recently been approved for the treat 2. Description of the Prior Art ment of severe, active rheumatoid arthritis. Hepatic fibrosis Rheumatoid arthritis is a debilitating disease of the con and cirrhosis have been reported in patients being treated for nective tissue. It most often manifests itself through inflam rheumatoid arthritis with methotrexate, however. There has mation and thickening of the synovial membranes, the sacs also been evidence of progressive dose-related hepatic that hold the fluid (synovial fluid) that lubricates the joints. 15 changes during extended periods of treatment that correlates It generally causes irreversible damage to the joint capsule with ethanol ingestion. and the articular cartilage. There is evidence that suggests Indomethacin was introduced in 1963 to treat rheumatoid that an autoimmune mechanism may play a role in the arthritis. Although it is widely used because of its efficacy, disease. toxicity often limits its use. From 35 to 50 percent of patients Synovium is composed of two cell types termed type A 20 receiving standard therapeutic doses of indomethacin expe synoviocytes and type B synoviocytes. (Gay and Gay, rience untoward side effects, and about 20 percent are forced Rheumatol Int. 9, 105-113 (1989); Kouri et al., Scand. J. to discontinue its use. Immunol 19, 359-364 (1984); Burmester et al., Scand. J. The drug sulindac was developed in an attempt to find an Immunol. 17, 68-82 (1983)). Type A synoviocytes resemble effective, but less toxic alternative to indomethacin. It is only tissue macrophages and type B synoviocytes resemble fibro 25 half as potent as indomethacin, however, and has toxic side blasts. Certain examples of tissue macrophage-like cells and effects of its own. fibroblasts possess calcium channels that resemble L-type In view of the foregoing, alternative methods for the calcium channels. Baumgarten and Villereal, J. Biol. Chem. treatment of rheumatoid arthritis are desirable. 267, 10524-10530 (1992); Bernini et al., J. Cardiovasc. 30 Pharmacol. 18, 42-45 (1991); Hijioka et al., Mol. Pharma SUMMARY OF THE INVENTION col. 41, 435-440 (1992); Kong et al., Second Messenger Phosphoproteins 13, 117-130 (1991); Olsen et at. Biochem. An object of the present invention is to provide a new and Biophys. Res. Commun. 162,448-455 (1989). The evidence useful method for treating arthritis in mammals that is both that suggests that certain macrophage- or fibroblast-like cells safe and effective. The present invention comprises a novel have L-type calcium channels includes: 1) electrophysi 35 method for the treatment of arthritis in mammals. It has been ologic studies, 2) inhibition of calcium currents by selective found that L-type calcium channel antagonists are effective L-type calcium channel antagonists, and 3) activation of agents for treating arthritis. Dihydropyridines, phenylalka calcium currents by selective L-type calcium channel ago mines, and benzothiazepines are particular classes of L-type nists. In rheumatoid arthritis, type A cells and type B cells calcium channel antagonists that are useful in the methods of participate in the inflammatory process. 40 the present invention. Specific compounds that are useful in A hallmark of rheumatoid arthritis is the formation of a the invention are the dihydropyridines nimodipine, nisol "pannus,' which results from massive proliferation of syn dipine, and nifedipine as well as the phenyl-alkylamine oviocytes. Synoviocytes are known to release inflammatory verapamil and the benzothiazepine diltiazem. Effective dos cytokines and other mediators as well as proteases and other 45 ages range from about 1 mg antagonist/day to about 1 g enzymes that contribute to the tissue destruction associated antagonist/day. with rheumatoid arthritis. Dayer and Demczuk, Cytokines and Other Mediators in Rheumatoid Arthritis, Springer BRIEF DESCRIPTION OF THE DRAWINGS Seminars in Immunopathology. 1-27 (Springer-Verlag FIG. 1 displays the inhibition of adjuvant-induced arthri 1984); Gay and Koopman, Current Opinion in Rheumatol 50 ogy 1, 8-14 (1989); Brennan et al., The Lancet Jul. 29, tis by nimodipine, nisoldipine, nifedipine, and verapamil. 224-247 (1989). Adjuvant-induced arthritis is an experimental disease DETALED DESCRIPTION OF THE unique to laboratory rats. It occurs after inoculation with an INVENTION oily emulsion or suspension of material possessing Freund's 55 The Ca' channel antagonists known as the 1,4-dihydro type adjuvant activity. Adjuvant-induced arthritis is a pyridines (DHPs) have been shown to be highly potent and widely-used model for studying the physiology, biochemis specific inhibitors of Ca” entry into excitable cells through try, and pharmacology of inflammation as well as a model of L-type Ca' channels. Scriabine, Receptor Biochem, and cell-mediated autoimmune disease, human arthritis, and Method. 9, 51-70 (1987); Triggle and Janis, Receptor Bio chronic pain. Taurog et al., Meth. Enzymol 162, 339-355 60 chem. and Method. 9, 29-50 (1987); Godfraind et al., (1988). As a model system, adjuvant arthritis has predicted Pharmacol. Rev. 38, 321-416 (1986); Janis and Triggle, clinical potency and efficacy for non-steroidal anti-inflam Drug Dev. Res. 4, 257-274 (1984); Schramm et al., Nature matory drugs NSAIDs used for rheumatoid arthritis. This is 303535-537 (1983); Scriabine, Rational Drug Therapy 21, also the case for immunosuppressive agents, such as 1-7 (1987). More recently, a number of investigators have cyclosporin, and cytotoxic agents such as cyclophosphamide 65 also demonstrated that certain non-excitable cells also con or methotrexate. Except for methotrexate, this latter class of tain DHP-sensitive Ca' channels that appear to be similar drugs is not widely used for the treatment of rheumatoid to L-type channels. Hijioka et al., supra; Chen et al., Science 5,478,848 3 4 239, 1024 (1988); Kong et al., supra; Olsen et al., supra; and Baumgarten et al., supra.