Methods and reagents for the treatment of immunoinflammatory disorders

Abstract

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, either alone or in combination with one or more additional agents. The invention also features a composition containing a tetra-substituted pyrimidopyrimidine in combination with one or more additional agents.

1 . A composition comprising a tetra-substituted pyrimidopyrimidine and a second drug selected from the group consisting of tricyclic and tetracyclic antidepressants; selective serotonin reuptake inhibitors (SSRIs); rolipram; ibudilast; non-steroidal anti-inflammatory drugs (NSAIDs); COX-2 inhibitors; biologics; small molecule immunomodulators; disease-modifying anti-rheumatic drugs (DMARDs); xanthines; anticholinergic compounds; beta receptor agonists; bronchodilators; non-steroidal immunophilin-dependent immunosuppressants, vitamin D analogs; psoralens; retinoids; and 5-amino salicylic acids, with the proviso that when said tetra-substituted pyrimidopyrimidine is dipyridamole, said second drug is not methotrexate or aspirin.  
     
     
         2 . The composition of  claim 1 , wherein said tetra-substituted pyrimidopyrimidine is dipyridamole.  
     
     
         3 . The composition of  claim 1 , wherein said tetra-substituted pyrimidopyrimidine is mopidamole, dipyridamole monoacetate, 2,6-di-(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxy-4,8-di-piperidinopyrimidopyrimidine, 2,6-bis-(2,3-dimethyoxypropoxy)-4,8-di-piperidinopyrimidopyrimidine, 2,6-bis[N,N-di(2-methoxy)ethyl]-4,6-di-piperidinopyrimidopyrimidine, or 2,6-bis(diethanolamino)-4,8-di-4-methoxybenzylaminopyrimidopyrimidine.  
     
     
         4 . The composition of  claim 1 , wherein said tricyclic antidepressant is nortryptiline, amoxapine, or desipramine.  
     
     
         5 . The composition of  claim 1 , wherein said SSRI is paroxetine or fluoxetine.  
     
     
         6 . The composition of  claim 1 , wherein said NSAID is naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylsalicylic acid, fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac, or tolmetin.  
     
     
         7 . The composition of  claim 1 , wherein said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib.  
     
     
         8 . The composition of  claim 1 , wherein said biologic is adelimumab, etanercept, or infliximab.  
     
     
         9 . The composition of  claim 1 , wherein said DMARD is methotrexate or leflunomide.  
     
     
         10 . The composition of  claim 1 , wherein said xanthine is theophylline.  
     
     
         11 . The composition of  claim 1 , wherein said anticholinergic compound is ipratropium or tiotropium.  
     
     
         12 . The composition of  claim 1 , wherein said beta receptor agonist is ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol scetate, salmeterol xinafoate, or terbutaline.  
     
     
         13 . The composition of  claim 1 , wherein said vitamin D analog is calcipotriene or calcipotriol.  
     
     
         14 . The composition of  claim 1 , wherein said psoralen is methoxsalen.  
     
     
         15 . The composition of  claim 1 , wherein said retinoid is acitretin or tazoretene.  
     
     
         16 . The composition of  claim 1 , wherein said 5-amino salicylic acid is mesalamine, sulfasalazine, balsalazide disodium, or olsalazine sodium.  
     
     
         17 . The composition of  claim 1 , wherein said small molecule immunomodulator is VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcasan, mycophenylate, or merimepodib.  
     
     
         18 . The composition of  claim 1 , wherein said composition is formulated for topical administration.  
     
     
         19 . The composition of  claim 1 , wherein said composition is formulated for systemic administration.  
     
     
         20 . The composition of  claim 1 , wherein said tetra-substituted pyrimidopyrimidine or said second drug is present in said composition in a low dosage.  
     
     
         21 . The composition of  claim 1 , wherein said tetra-substituted pyrimidopyrimidine or said second drug is present in said composition in a high dosage.  
     
     
         22 . The composition of  claim 1 , wherein said composition further comprises an NSAID, COX-2 inhibitor, biologic, small molecule immunomodulator, DMARD, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, non-steroidal immunophilin-dependent immunosuppressant, vitamin D analog, psoralen, retinoid, or 5-amino salicylic acid.  
     
     
         23 . A method for treating a patient diagnosed with or at risk of developing an immunoinflammatory disorder, said method comprising administering to the patient a tetra-substituted pyrimidopyrimidine and a second drug selected from the group consisting of tricyclic and tetracyclic antidepressants; selective serotonin reuptake inhibitors; rolipram; ibudilast; NSAIDs; COX-2 inhibitors; biologics; small molecule immunomodulators; DMARDs; xanthines; anticholinergic compounds; beta receptor agonists; bronchodilators; non-steroidal immunophilin-dependent immunosuppressants, vitamin D analogs; psoralens; retinoids; and 5-amino salicylic acids, with the proviso that when said tetra-substituted pyrimidopyrimidine is dipyridamole, said second drug is not methotrexate or aspirin, wherein said tetra-substituted pyrimidopyrimidine and said second drug are administered simultaneously or within 14 days of each other in amounts sufficient to treat said patient.  
     
     
         24 . The method of  claim 23 , wherein said immunoinflammatory disorder is rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, polymylagia rheumatica, giant cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, ankylosing spondylitis, cirrhosis, or psoriatic arthritis.  
     
     
         25 . The method of  claim 23 , wherein said tetra-substituted pyrimidopyrimidine and said second drug are administered simultaneously.  
     
     
         26 . The method of  claim 23 , wherein said tetra-substituted pyrimidopyrimidine is dipyridamole.  
     
     
         27 . The method of  claim 23 , wherein said tetra-substituted pyrimidopyrimidine is mopidamole, dipyridamole monoacetate, 2,6-di-(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxy-4,8-di-piperidinopyrimidopyrimidine, 2,6-bis-(2,3-dimethyoxypropoxy)-4,8-di-piperidinopyrimidopyrimidine, 2,6-bis[N,N-di(2-methoxy)ethyl]-4,6-di-piperidinopyrimidopyrimidine, or 2,6-bis(diethanolamino)-4,8-di-4-methoxybenzylaminopyrimidopyrimidine.  
     
     
         28 . The method of  claim 23 , wherein said tricyclic antidepressant is nortryptiline, amoxapine, or desipramine.  
     
     
         29 . The method of  claim 23 , wherein said SSRI is paroxetine or fluoxetine.  
     
     
         30 . The method of  claim 23 , wherein said NSAID is naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylsalicylic acid, fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac, or tolmetin.  
     
     
         31 . The method of  claim 23 , wherein said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib.  
     
     
         32 . The method of  claim 23 , wherein said biologic is adelimumab, etanercept, or infliximab.  
     
     
         33 . The method of  claim 23 , wherein said DMARD is methotrexate or leflunomide.  
     
     
         34 . The method of  claim 23 , wherein said xanthine is theophylline.  
     
     
         35 . The method of  claim 23 , wherein said anticholinergic compound is ipratropium or tiotropium.  
     
     
         36 . The method of  claim 23 , wherein said beta receptor agonist is ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol scetate, salmeterol xinafoate, or terbutaline.  
     
     
         37 . The method of  claim 23 , wherein said vitamin D analog is calcipotriene or calcipotriol.  
     
     
         38 . The method of  claim 23 , wherein said psoralen is methoxsalen.  
     
     
         39 . The method of  claim 23 , wherein said retinoid is acitretin or tazoretene.  
     
     
         40 . The method of  claim 23 , wherein said 5-amino salicylic acid is mesalamine, sulfasalazine, balsalazide disodium, or olsalazine sodium.  
     
     
         41 . The method of  claim 23 , wherein said small molecule immunomodulator is VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcasan, mycophenylate, or merimepodib.  
     
     
         42 . The method of  claim 23 , wherein said composition is formulated for topical administration.  
     
     
         43 . The method of  claim 23 , wherein said composition is formulated for systemic administration.  
     
     
         44 . The method of  claim 23 , wherein said tetra-substituted pyripyrimyrimidine or said second drug is administered in a low dosage.  
     
     
         45 . The method of  claim 23 , wherein said tetra-substituted pyrimidopyrimidine or said second drug is is administered in a high dosage.  
     
     
         46 . The method of  claim 23 , wherein said method further comprises administering a third drug selected from an NSAID, COX-2 inhibitor, biologic, small molecule immunomodulator, DMARD, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, non-steroidal immunophilin-dependent immunosuppressant, vitamin D analog, psoralen, retinoid, and 5-amino salicylic acid, wherein said tetra-substituted pyrimidopyrimidine, said second drug, and said third drug are administered simultaneously or within 14 days of each other in amounts sufficient to treat said patient.  
     
     
         47 . A kit comprising: 
 (i) a composition comprising a tetra-substituted pyrimidopyrimidine and a second drug selected from the group consisting of tricyclic and tetracyclic antidepressants; selective serotonin reuptake inhibitors; rolipram; ibudilast; NSAIDs; COX-2 inhibitors; biologics; small molecule immunomodulators; DMARDs; xanthines; anticholinergic compounds; beta receptor agonists; bronchodilators; non-steroidal immunophilin-dependent immunosuppressants, vitamin D analogs; psoralens; retinoids; and 5-amino salicylic acids, with the proviso that when said tetra-substituted pyrimidopyrimidine is dipyridamole, said second drug is not methotrexate or aspirin; and    (ii) instructions for administering said composition to a patient diagnosed with or at risk of developing an immunoinflammatory disorder.    
     
     
         48 . A kit comprising: 
 (i) a tetra-substituted pyrimidopyrimidine;    (ii) a second drug selected from the group consisting of tricyclic and tetracyclic antidepressants; selective serotonin reuptake inhibitors; rolipram; ibudilast; NSAIDs; COX-2 inhibitors; biologics; small molecule immunomodulators; DMARDs; xanthines; anticholinergic compounds; beta receptor agonists; bronchodilators; non-steroidal immunophilin-dependent immunosuppressants, vitamin D analogs; psoralens; retinoids; and 5-amino salicylic acids, with the proviso that when said tetra-substituted pyrimidopyrimidine is dipyridamole, said second drug is not methotrexate or aspirin; and    (iii) instructions for administering said tetra-substituted pyrimidopyrimidine and said second drug to a patient diagnosed with or at risk of developing an immunoinflammatory disorder.    
     
     
         49 . A kit comprising: 
 (i) a drug selected from the group consisting of tricyclic and tetracyclic antidepressants; selective serotonin reuptake inhibitors; rolipram; ibudilast; NSAIDs; COX-2 inhibitors; biologics; small molecule immunomodulators; DMARDs; xanthines; anticholinergic compounds; beta receptor agonists; bronchodilators; non-steroidal immunophilin-dependent immunosuppressants, vitamin D analogs; psoralens; retinoids; and 5-amino salicylic acids; and    (ii) instructions for administering said drug and a tetra-substituted pyrimidopyrimidine a patient diagnosed with or at risk of developing an immunoinflammatory disorder, with the proviso that when said tetra-substituted pyrimidopyrimidine is dipyridamole, said second drug is not methotrexate or aspirin.    
     
     
         50 . A kit comprising: 
 (i) a tetra-substituted pyrimidopyrimidine; and    (ii) instructions for administering said pyrimidopyrimidine and a second drug selected from the group consisting of tricyclic and tetracyclic antidepressants; selective serotonin reuptake inhibitors; rolipram; ibudilast; NSAIDs; COX-2 inhibitors; biologics; small molecule immunomodulators; DMARDs; xanthines; anticholinergic compounds; beta receptor agonists; bronchodilators; non-steroidal immunophilin-dependent immunosuppressants, vitamin D analogs; psoralens; retinoids; and 5-amino salicylic acids, with the proviso that when said tetra-substituted pyrimidopyrimidine is dipyridamole, said second drug is not methotrexate or aspirin to a patient diagnosed with or at risk of developing an immunoinflammatory disorder, with the proviso that when said tetra-substituted pyrimidopyrimidine is dipyridamole, said second drug is not methotrexate or aspirin.    
     
     
         51 . The kit of  claim 50 , wherein said tetra-substituted pyrimidopyrimidine is dipyridamole.  
     
     
         52 . The kit of  claim 50 , wherein said tetra-substituted pyrimidopyrimidine is mopidamole, dipyridamole monoacetate, 2,6-di-(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxy-4,8-di-piperidinopyrimidopyrimidine, 2,6-bis-(2,3-dimethyoxypropoxy)-4,8-di-piperidinopyrimidopyrimidine, 2,6-bis[N,N-di(2-methoxy)ethyl]-4,6-di-piperidinopyrimidopyrimidine, or 2,6-bis(diethanolamino)-4,8-di-4-methoxybenzylaminopyrimidopyrimidine.  
     
     
         53 . The kit of  claim 50 , wherein said immunoinflammatory disorder is rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, polymylagia rheumatica, giant cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, ankylosing spondylitis, cirrhosis, or psoriatic arthritis.