(19) & (11) EP 2 301 628 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 30.03.2011 Bulletin 2011/13 A61P 37/06 (2006.01) (21) Application number: 10013062.4 (22) Date of filing: 13.10.2004 (84) Designated Contracting States: • Manivasakam, Palaniyandi AT BE BG CH CY CZ DE DK EE ES FI FR GB GR West Roxbury HU IE IT LI LU MC NL PL PT RO SE SI SK TR MA 02132 (US) Designated Extension States: • Hurst, Nicole AL HR LT LV MK Boston MA 02132 (US) (30) Priority: 15.10.2003 US 512415 P • Foley, Michael A. Chestnut Hill (62) Document number(s) of the earlier application(s) in MA (US) accordance with Art. 76 EPC: • Slavonic, Michael S. 09002049.6 / 2 070 550 Quincy 04809944.4 / 1 680 121 MA 02169 (US) • Smith, Brendan (71) Applicant: Zalicus Inc. Sommerville Cambridge, MA 02142 (US) MA 02118 (US) • Auspitz, Benjamin A. (72) Inventors: Cambridge • Keith, Curtis MA 02139 (US) Boston MA 02118 (US) (74) Representative: Bösl, Raphael Konrad • Borisy, Alexis Isenbruck Bösl Hörschler LLP Arlington Patentanwälte MA 02476 (US) Prinzregentenstrasse 68 • Zimmermann, Grant R. 81675 München (DE) Winchester MA 01890 (US) Remarks: •Jost-Price, Edward Roydon This application was filed on 01-20-2010 as a West Roxbury divisional application to the application mentioned MA 02132 (US) under INID code 62. (54) Methods and reagents for the treatment of immunoinflammatory disorders (57) The invention features, among others, a tetra- stituted pyrimidopyrimidine and a corticosteroid for use substituted pyrimidopyrimidine and a corticosteroid for ina method for treating an immunoinflammatory disorder. use in a method for treating an immunoinflammatory dis- order, as well as a composition comprising a tetra-sub- EP 2 301 628 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 301 628 A1 Description Background of the Invention 5 [0001] The invention relates to the treatment of immunoinflammatory disorders. [0002] Immunoinflammatory conditions are characterized by the inappropriate activation of the body’s immune de- fenses. Rather than targeting infectious invaders, the immune response targets and damages the body’s own tissues or transplanted tissues. The tissue targeted by the immune system varies with the disorder. For example, in multiple sclerosis, the immune response is directed against the neuronal tissue, while in Crohn’s disease the digestive tract is 10 targeted. Immunoinflammatory disorders affect millions of individuals and include conditions such as asthma, allergic intraocular inflammatory diseases, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anaemia, inflammatory dermatoses, inflammatory bowel or gastrointestinal disorders (e.g., Crohn’s disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, pruritis/inflammation, psoriasis, rheumatoid arthritis, cirrhosis, and systemic lupus ery- thematosus. 15 [0003] Current treatment regimens for immunoinflammatory disorders, transplanted organ rejection, and graft versus host disease typically rely on immunosuppressive agents. The effectiveness of these agents can vary and their use is often accompanied by adverse side effects. Thus, improved therapeutic agents and methods for the treatment of im- munoinflammatory conditions are needed. 20 Summary of the Invention [0004] The invention features a method for treating an immunoinflammatory disease by administering to a patient in need thereof certain tetra-substituted pyrimidopyrimidines, either alone or in combination with any of a number of com- panion compounds, including an antihistamine, a corticosteroid, rolipram, ibudilast, a tricyclic or tetracyclic antidepres- 25 sant, an SSRI, a non-steroidal anti-inflammatory drug, a non-steroidal immunophilin-dependent immunosuppressant, and an analog of any thereof, as described herein. [0005] Accordingly, in one aspect, the invention features a method of treating a patient having an immunoinflammatory disease by administering to the patient a tetra-substituted pyrimidopyrimidine in an amount and for duration to treat the patient. 30 [0006] In a related aspect, the invention features a method for treating a patient having an immunoinflammatory disorder by administering to the patient tetra-substituted pyrimidopyrimidine and an antihistamine simultaneously or within 14 days of each other in amounts sufficient to treat the patient. [0007] In another aspect, the invention features a method of decreasing proinflammatory cytokine secretion or pro- duction in a patient by administering to the patient a tetra-substituted pyrimidopyrimidine and an antihistamine simulta- 35 neously or within 14 days of each other in amounts sufficient to decrease proinflammatory cytokine secretion or production in the patient [0008] In another aspect, the invention features a composition that includes a tetra-substituted pyrimidopyrimidine and an antihistamine. A particularly desirable tetra-substituted pyrimidopyrimidine is dipyridamole. The composition may be formulated for topical or systemic administration. 40 [0009] In another aspect, the invention features a kit that includes: (i) a composition that includes a tetra-substituted pyrimidopyrimidine and an antihistamine; and (ii) instructions for administering the composition to a patient diagnosed with or at risk of developing an immunoinflammatory disorder. [0010] In a related aspect, the invention features a kit that includes: (i) an antihistamine; (ii) a tetra- substituted pyrim- idopyrimidine; and (iii) instructions for administering the tetra-substituted pyrimidopyrimidine and the antihistamine to a 45 patient diagnosed with or at risk of developing an immunoinflammatory disorder. [0011] In another aspect, the invention features a composition that includes a tetra-substituted pyrimidopyrimidine and a corticosteroid. Particularly desirable corticosteroids are prednisolone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone, and diflorasone. The composition may be formulated for topical or systemic administration (e.g., oral administration). One or both of the drugs may be present in the composition 50 in a low dosage or a high dosage, each of which is defined herein. [0012] In another aspect, the invention features a method of decreasing proinflammatory cytokine secretion or pro- duction in a patient by administering to the patient a tetra-substituted pyrimidopyrimidine and a corticosteroid simulta- neously or within 14 days of each other in amounts sufficient to decrease proinflammatory cytokine secretion or production in the patient 55 [0013] In a related aspect, the invention features a method for treating a patient diagnosed with or at risk of developing an immunoinflammatory disorder by administering to the patient a tetra-substituted pyrimidopyrimidine and a corticos- teroid simultaneously or within 14 days of each other in amounts sufficient to treat the patient. [0014] In another aspect, the invention features a kit that includes: (i) a composition that includes a tetra-substituted 2 EP 2 301 628 A1 pyrimidopyrimidine and a corticosteroid; and (ii) instructions for administering the composition to a patient diagnosed with or at risk of developing an immunoinflammatory disorder. [0015] In a related aspect, the invention features a kit that includes: (i) a tetra-substituted pyrimidopyrimidine; (ii) a corticosteroid; and (iii) instructions for administering the tetra-substituted pyrimidopyrimidine and the corticosteroid to a 5 patient diagnosed with or at risk of developing an immunoinflammatory disorder. [0016] In another aspect, the invention features a composition that includes tetra- substituted pyrimidopyrimidine and ibudilast. The composition may be formulated for topical or systemic administration. [0017] In another aspect, the invention features a method of decreasing proinflammatory cytokine secretion or pro- duction in a patient by administering to the patient tetra-substituted pyrimidopyrimidine and ibudilast simultaneously or 10 within 14 days of each other in amounts sufficient to decrease proinflammatory cytokine secretion or production in the patient. [0018] In a related aspect, the invention features a method for treating a patient diagnosed with or at risk of developing an immunoinflammatory disorder by administering to the patient tetra-substituted pyrimidopyrimidine and ibudilast si- multaneously or within 14 days of each other in amounts sufficient to treat the patient 15 [0019] In another aspect, the invention features a kit that includes: (i) a composition that includes tetra-substituted pyrimidopyrimidine and ibudilast; and (ii) instructions for administering the composition to a patient diagnosed with or at risk of developing an immunoinflammatory disorder. [0020] In a related aspect, the invention features a kit that includes: (i) tetra-substituted pyrimidopyrimidine; (ii) ibudilast; and (iii) instructions for administering the tetra-substituted pyrimidopyrimidine and the ibudilast to a patient diagnosed 20 with or at risk of developing an immunoinflammatory disorder. [0021] In another aspect, the invention features a composition that includes tetra- substituted pyrimidopyrimidine and rolipram. The composition may be formulated for topical or systemic administration. [0022] In another aspect, the invention features a method of decreasing proinflammatory cytokine secretion or pro- duction in a patient by administering to the patient a tetra-substituted pyrimidopyrimidine and rolipram simultaneously 25 or within 14 days of each other in amounts