Novel use of pyrrolopyridine derivatives for preventing or treating inflammatory diseases

Abstract

The present invention relates to a pharmaceutical composition for preventing and/or treating inflammatory disease, the composition comprising a pyrrolopyridine-derivative compound as an active ingredient; the compound represented by Chemical Formula 1 according to the present invention, enantiomers thereof or pharmaceutically acceptable salts thereof, which have excellent inhibitory activity against not only protein kinases but also inflammatory factors and inflammatory cytokines; therefore a pharmaceutical composition comprising the same as an active ingredient may be useful in prevention, treatment and/or improvement of inflammatory disease, in particular but not limited to inflammatory bowel disease, rheumatoid arthritis, or lupus.

1 . A method of preventing or treating an inflammatory disease in a patient in need thereof, the method comprising administering to the patient a compound represented by Chemical Formula 1: 
       
         
           
           
               
               
           
         
         or an isomer, pharmaceutically acceptable salt, or pharmaceutical composition thereof, wherein: 
         R 1  is C 1 -C 3  alkoxy; 
         R 2  and R 3  are each independently hydrogen, straight chain or branched chain C 1 -C 10  alkyl, or C 3 -C 6  cycloalkyl; and 
         R 4  is haloalkyl. 
       
     
     
         2 . The method of  claim 1 , wherein the method of preventing or treating an inflammatory disease comprises one or more of:
 (a) reducing pro-inflammatory cytokines in the patient;   (b) increasing differentiation of regulatory T cells (T reg ) in the patient; and   (c) decreasing pro-inflammatory T cells in the patient.   
     
     
         3 . A method of reducing pro-inflammatory cytokines in a patient in need thereof, the method comprising administering to the patient a compound represented by Chemical Formula 1: 
       
         
           
           
               
               
           
         
         or an isomer, pharmaceutically acceptable salt, or pharmaceutical composition thereof, wherein: 
         R 1  is C 1 -C 3  alkoxy; 
         R 2  and R 3  are each independently hydrogen, straight chain or branched chain C 1 -C 10  alkyl, or C 3 -C 6  cycloalkyl; and 
         R 4  is haloalkyl. 
       
     
     
         4 . The method of  claim 2 , wherein the pro-inflammatory cytokine is selected from one or more of NO, IFN-γ, IL-1α, IL-1β, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, IL-17A, IL-22, IL-23, KC, MIP-1a, MIP-1b, GM-CSF, and TNF-α. 
     
     
         5 . A method of increasing differentiation of regulatory T cells (T reg ) in a patient in need thereof, the method comprising administering to the patient a compound represented by Chemical Formula 1: 
       
         
           
           
               
               
           
         
         or an isomer, pharmaceutically acceptable salt, or pharmaceutical composition thereof, wherein: 
         R 1  is C 1 -C 3  alkoxy; 
         R 2  and R 3  are each independently hydrogen, straight chain or branched chain C 1 -C 10  alkyl, or C 3 -C 6  cycloalkyl; and 
         R 4  is haloalkyl. 
       
     
     
         6 . A method of decreasing pro-inflammatory T cells in a patient in need thereof, the method comprising administering to the patient a compound represented by Chemical Formula 1: 
       
         
           
           
               
               
           
         
         or an isomer, pharmaceutically acceptable salt, or pharmaceutical composition thereof, wherein: 
         R 1  is C 1 -C 3  alkoxy; 
         R 2  and R 3  are each independently hydrogen, straight chain or branched chain C 1 -C 10  alkyl, or C 3 -C 6  cycloalkyl; and 
         R 4  is haloalkyl. 
       
     
     
         7 . The method of  claim 2 , wherein the pro-inflammatory T cells are Th17. 
     
     
         8 . The method of  claim 1 , wherein R 1  is methoxy. 
     
     
         9 . The method of  claim 1 , wherein, R 2  is a straight chain or branched chain C 1 -C 5  alkyl. 
     
     
         10 . The method of  claim 1 , wherein, R 2  is a C 3 -C 4  cycloalkyl. 
     
     
         11 . The method of  claim 1 , wherein, R 3  is hydrogen. 
     
     
         12 . The method of  claim 1 , wherein, R 4  is trifluoromethyl. 
     
     
         13 . The method of  claim 1 , wherein the compound represented by Chemical Formula 1 is:
 (1) (4-((−4-ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-6-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidine-1-yl) methanone;   (2) (3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b] pyridine-6-yl)amino)phenyl)(4-morpholinopiperidine-1-yl)methanone;   (3) (4-(4-(isopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-6-ylamino)-3-methoxyphenyl)(4-morpholinopiperidine-1-yl)methanone;   (4) (S)-(4-((4-(2-butylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidine-1-yl)-methanone; or   (5) (4-((4-(cyclopropylamino)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b] pyridine-6-yl)3-methoxyphenyl) (4-morpholinopiperidine-1-yl)methanone.   
     
     
         14 . The method of  claim 1 , wherein the compound represented by Chemical Formula 1 is (4-((−4-ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-6-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidine-1-yl) methanone. 
     
     
         15 . The method of  claim 1 , wherein the inflammatory disease is selected from graft versus host disease (GvHD), obstructive airway disease, chronic obstructive pulmonary disease, allergy, systemic lupus erythematosus, scleroderma, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), atopic dermatitis, psoriasis, anaphylaxis, dermatitis, diabetic retinosis, retinitis, macular degeneration, uveitis, conjunctivitis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, osteoporosis, diabetes, diabetic kidney disease, nephritis, Sjogren's syndrome, autoimmune pancreatitis, periodontal disease, alopecia areata, chronic pelvic inflammatory disease, endometriosis, rhinitis, tonsilitis, otitis media, sore throat, cystitis, chronic prostatitis, diseases and conditions of the eye such as ocular allergy, keratoconjunctivitis sicca, vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), polychondritis, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Becker's/Duchenne muscular dystrophy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, leptospirosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, diabetes (Type 1 diabetes or Type 2 diabetes), appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, dacryoadenitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, vaginitis, vasculitis, and vulvitis. 
     
     
         16 . The method of  claim 1 , wherein the inflammatory disease is selected from inflammatory bowel disease, rheumatoid arthritis, lupus, psoriasis, atopic dermatitis, graft versus host disease (GvHD), acute lung injury, alopecia areata, diabetes, and/or osteoarthritis. 
     
     
         17 . The method of  claim 1 , wherein the compound represented by Chemical Formula 1 prevents and/or inhibits or otherwise favorably impacts protein kinase activity. 
     
     
         18 . The method of  claim 1 , wherein the method comprises conjointly administering a compound represented by Chemical Formula 1, or an isomer, pharmaceutically acceptable salt, or pharmaceutical composition thereof and at least one additional active ingredient. 
     
     
         19 . The method of  claim 18 , wherein at least one additional active ingredient is selected from gamma globulin, phosphodiesterase inhibitors (e.g., apremilast), IRAK4 inhibitors, belimumab, tacrolimus, rapamycin, mycophenolate mofetil, interferon, paracetamol, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), celecoxib, and colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, betamethasone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Araya®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-JAK/STAT inhibitors such as tofacitinib, baricitinib, and GLPG0634, antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®), “anti-IL-6” agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) optionally in combination with lenalidomide (Revlimid®), or any combination(s) thereof. 
     
     
         20 . The pharmaceutical composition of  claim 1 , further comprising excipients, disintegrating agents, sweetening agents, lubricants, and/or flavoring agents.