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(12) Patent Application Publication (10) Pub. No.: US 2004/0110734 A1 Sackeyflo Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0110734 A1 Sackeyflo Et Al US 2004O110734A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0110734 A1 Sackeyflo et al. (43) Pub. Date: Jun. 10, 2004 (54) COMBINATIONS FOR THE TREATMENT OF (22) Filed: Nov. 19, 2003 NFLAMMATORY DISORDERS Related U.S. Application Data (76) Inventors: Robyn Sackeyflo, Ann Arbor, MI (US); Jason Fong, Philadelphia, PA (US); (63) Continuation of application No. 10/191,149, filed on Nicole Hurst, Boston, MA (US); Jul. 9, 2002. Palaniyandi Manivasakam, Brighton, MA (US); Edward Roydon Jost-Price, (60) Provisional application No. 60/304,089, filed on Jul. West Roxbury, MA (US); Grant 9, 2001. Zimmermann, Somerville, MA (US); Curtis Keith, Boston, MA (US); Alexis Publication Classification Borisy, Boston, MA (US) 51)1) Int. Cl.Cl." ..................... A61K 31/573573; A61K 31/553;55 Correspondence Address: A61K 31/554 CLARK & ELBING LLP (52) U.S. Cl. ..................... 514/171; 514/221; 514/211.13 101 FEDERAL STREET BOSTON, MA 02110 (US) (57) ABSTRACT The invention features methods and compositions for the (21) Appl. No.: 10/716,823 treatment of immunonflammatory disorders. US 2004/0110734 A1 Jun. 10, 2004 COMBINATIONS FOR THE TREATMENT OF SUMMARY OF THE INVENTION NFLAMMATORY DISORDERS 0008 We have discovered that the combination of amox CROSS-REFERENCE TO RELATED apine (2-cloro-11(1-piperazinyl)dibenzb,f1,4oxapine) APPLICATIONS and prednisolone (also known as 1-dehydrocortisol, 1-de 0001. This application is a continuation of U.S. Utility hydrohydrocortisone; 1,4-pregnadiene-11beta, 17alpha,21 application Ser. No. 10/191,149, filed Jul. 9, 2002, which triol-3,20-dione; and 11beta, 17alpha,21-trihydroxy-1,4- claims the benefit of U.S. Provisional Application Serial No. pregnadiene-3,20-dione) brings about Substantial 60/304,089, filed Jul. 9, 2001, each of which is hereby suppression of TNFC. levels induced in peripheral blood incorporated by reference. mononuclear cells (PBMCs). BACKGROUND OF THE INVENTION 0009 Amoxapine is a tricyclic antidepressant (TCA). 0002 The invention relates to the treatment of inflam Based on the ability of amoxapine to act in concert with matory disorders. prednisolone to inhibit TNFC. levels, one skilled in the art will recognize that other TCAS can also be used in the 0003) Inflammation occurs when tissues are injured by present invention. Structural analogs of amoxapine that are Viruses, bacteria, trauma, chemicals, heat, cold or any other not tricyclic antidepressants can also be used. Exemplary harmful Stimulus. Chemicals including bradykinin, hista Structural analogs include, for example, clothiapine, perlap mine, Serotonin and others are released, attracting tissue ine, fluperlapine, and dibenz, (b,f)(1,4)oxazepine, 2-chloro macrophages and white blood cells to localize in an area to 11-(4-methyl-1-piperazinyl)-, monohydrochloride. engulf and destroy foreign Substances. During this process, chemical mediatorS Such as TNFC. are released, giving rise 0010 Prednisolone is a corticosteroid. Based on the to inflammation. Inflammatory disorders are those in which shared Structural features and apparent mechanism of action the inflammation is Sustained or chronic. One example of an among the corticosteroid family, one skilled in the art will inflammatory disorder is Osteoarthritis. recognize that other corticosteroids can be used in combi nation with amoxapine or other TCAS to treat inflammatory 0004 Immunoinflammatory disorders (e.g., rheumatoid disorders. arthritis, psoriasis, ulcerative colitis, Crohn's disease, Stroke-induced brain cell death, ankylosing spondylitis, 0011. Accordingly, the invention features a method for fibromyalgia, and autoimmune diseaseS Such as asthma, treating a patient having an inflammatory disorder, by multiple Sclerosis, type I diabetes, Systemic lupus erythe administering to the patient (i) a TCA (e.g., amoxapine); and matosus, Scleroderma, Systemic Sclerosis, and Sjögren's (ii) a corticosteroid (e.g., prednisolone) Simultaneously or Syndrome) are inflammatory disorders characterized by dys within 14 days of each other, in amounts sufficient to regulation of the immune System and inappropriate mobili suppress TNFC. levels sufficiently to produce a therapeutic Zation of body's defenses against its own healthy tissue. benefit to the patient. In one embodiment, the two com pounds are amoxapine and prednisolone. 0005 One percent of humans world-wide are afflicted with rheumatoid arthritis, a relentleSS, progressive disease 0012. The invention also features a method for treating a causing Severe Swelling, pain, and eventual deformity and patient having an inflammatory disorder by administering to destruction of joints. According to the Arthritis Foundation, the patient (i) clothiapine, perlapine, fluperlapine, or dibenz rheumatoid arthritis currently affects over two million (b,f)(1,4)oxazepine, 2-chloro-11-(4-methyl-1-piperazinyl)-, Americans, of which women are three times more likely to monohydrochloride; and (ii) a corticosteroid (e.g., predniso be afflicted. Rheumatoid arthritis is characterized by inflam lone) simultaneously or within 14 days of each other, in mation of the lining of the joints and/or other internal organs, amounts sufficient to suppress TNFC. levels sufficiently to and the presence of elevated numbers of lymphocytes and produce a therapeutic benefit to the patient. high levels of proinflammatory cytokines. 0013 Preferably, the two compounds of the invention are 0006 Treatment of rheumatoid arthritis generally administered within ten days of each other, more preferably includes administration of (i) non-steroidal anti-inflamma within five days of each other, and most preferably within tory drugs (NSAIDs, e.g., detoprofen, diclofenac, diflunisal, twenty-four hours of each other, or Simultaneously. The etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, disorder treated according to the invention can be, for ketoprofen, meclofenameate, mefenamic acid, meloxicam, example, rheumatoid arthritis, pSoriasis, ulcerative colitis, nabumeone, naproxen Sodium, Oxaprozin, piroXicam, Sulin Crohn's disease, Stroke-induced brain cell death, ankylosing dac, tolmetin, celecoxib, rofecoxib, aspirin, choline Salicy spondylitis, and fibromyalgia, asthma, multiple Sclerosis, late, Salsalte, and Sodium and magnesium Salicylate); (ii) type I diabetes, Systemic lupus erythematosus, Scleroderma, Steroids (e.g., cortisone, dexamethasone, hydrocortisone, Systemic Sclerosis, or Sjögren's Syndrome. methylprednisolone, prednisolone, prednisone, triamcino lone); (iii) DMARDS, i.e., disease modifying antirheumatic 0014. In the above-described treatment method, both drugs (e.g., cycloSporine, azathioprine, methotrexate, compounds are preferably provided together in a pharma leflunomide, cyclophosphamide, hydroxychloroquine, Sul ceutical composition that also includes a pharmaceutically fasalazine, D-penicillamine, minocycline, and gold); or (iv) acceptable carrier. recombinant proteins (e.g., ENBRELF) (etanercept, a 0015 The invention also features a pharmaceutical com soluble TNF receptor) and REMICADE(E) (infliximab) a position that includes (i) a TCA (e.g., amoxapine); and (ii) chimeric monoclonal anti-TNF antibody). a corticosteroid (e.g., prednisolone), along with a pharma 0007. There is a need to develop new regimens for the ceutically acceptable carrier, diluent, or excipient. treatment of rheumatoid arthritis, and other inflammatory 0016. The invention also features a method for identify disorders. ing compounds useful for treating a patient having an US 2004/0110734 A1 Jun. 10, 2004 inflammatory disorder. The method includes the steps of: 0020. In preferred embodiments, each X is, indepen contacting immune cells in vitro with (i) a TCA or a dently, H, Cl, or F;Y is (CH), Z is C; A is (CH); and each corticosteroid; and (ii) a candidate compound, and deter B is, independently, H, Cl, or F. mining whether the immune response is modulated relative 0021 Exemplary tricyclic antidepressants include, for to (a) immune cells contacted with the TCA or corticosteroid example, amoxapine, 8-hydroxyamoxapine, 7-hy but not contacted with the candidate compound, and (b) droxyamoxapine, loxapine, loxapine Succinate, loxapine immune cells contacted with the candidate compound but hydrochloride, 8-hydroxyloxapine, amitriptyline, clomi not with the TCA or corticosteroid. A candidate compound pramine, doxepin, imipramine, trimipramine, desipramine, that, when combined with the TCA or corticosteroid, modul nortriptyline, and protriptyline. lates the immune response to a greater degree than controls, 0022. By “corticosteroid” is meant any naturally occur is a compound that is potentially useful for treating a patient ring or Synthetic Steroid hormone which can be derived from having an inflammatory disorder. cholesterol and is characterized by a hydrogenated cyclo pentanoperhydrophenanthrene ring System. Naturally occur 0017 Compounds useful in the invention include those ring corticosteriods are generally produced by the adrenal described herein in any of their pharmaceutically acceptable cortex. Synthetic corticosteriods may be halogenated. Func forms, including isomerS Such as diastereomers and enanti tional groups required for activity include a double bond at omers, Salts, Solvates, and polymorphs thereof, as well as A4, a C3 ketone, and a C20 ketone. Corticosteroids may racemic mixtures of the compounds described herein. have glucocorticoid and/or mineralocorticoid activity. 0018) By “tricyclic antidepressant” or “TCA” is meant a 0023 Exemplary
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