Compounds Having CRTH2 Antagonist Activity

Abstract

Compounds of general formula (II) wherein W is chloro or fluoro; R 1 is phenyl optionally substituted with one or more substituents, selected from halo, —CN, —C 1 -C 6 alkyl, —SOR 3 , —SO 2 R 3 , —SO 2 N(R 2 ) 2 , —N(R 2 ) 2 , —NR 2 C(O)R 3 , —CO 2 R 2 , —CONR 2 R 3 , —NO 2 , —OR 2 , —SR 2 , —O(CH 2 ) p OR 2 , or —O(CH 2 ) p O(CH 2 ) q OR 2 wherein each R 2 is independently hydrogen, —C 1 -C 6 alkyl, —C—C 8 cycloalkyl, aryl or heteroaryl; each R 3 is independently, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, aryl or heteroaryl; p and q are each independently an integer from 1 to 3; and R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with aryl, aryl, (CH 2 ) m OC(═O)C 1 -C 6 alkyl, ((CH 2 ) m O) n CH 2 CH 2 X, (CH 2 ) m N(R 5 ) 2 or CH((CH 2 ) m O(C═O)R 6 ) 2 ; m is 1 or 2; n is 1-4; X is OR 5 or N(R 5 ) 2 ; R 5 is hydrogen or methyl; and R 6 is C 1 -C 18 alkyl; and their pharmaceutically acceptable salts, hydrates, solvates, complexes or prodrugs are useful in orally administrable compositions for the treatment of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.

1 . A method for the treatment of a disease or condition mediated by PGD 2  or other agonists at the CRTH2 receptor, comprising administering to a patient in need of such treatment a suitable amount of a compound of general formula (II): 
       
         
           
           
               
               
           
         
       
       wherein
 W is chloro or fluoro; 
 R 1  is phenyl optionally substituted with one or more substituents, selected from halo, —CN, —C 1 -C 6  alkyl, —SOR 3 , —SO 2 R 3 , —SO 2 N(R 2 ) 2 , —N(R 2 ) 2 , —NR 2 C(O)R 3 , —CO 2 R 2 , —CONR 2 R 3 , —NO 2 , —OR 2 , —SR 2 , —O(CH 2 ) p OR 2 , or —O(CH 2 ) p O(CH 2 ) q OR 2  wherein
 each R 2  is independently hydrogen, —C 1 -C 6  alkyl, —C 3 -C 8  cycloalkyl, aryl or heteroaryl; 
 each R 3  is independently, —C 1 -C 6  alkyl, —C 3 -C 8  cycloalkyl, aryl or heteroaryl; 
 p and q are each independently an integer from 1 to 3; and 
 
 R 4  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkyl substituted with aryl, aryl, (CH 2 ) m OC(═O)C 1 -C 6 alkyl, ((CH 2 ) m O) n CH 2 CH 2 X, (CH 2 ) m N(R 5 ) 2  or CH((CH 2 ) m O(C═O)R 6 ) 2 ; 
 m is 1 or 2; 
 n is 1-4; 
 X is OR 5  or N(R 5 ) 2 ; 
 R 5  is hydrogen or methyl; and 
 R 6  is C 1 -C 18  alkyl; 
 
       or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof. 
     
     
         2 . The method of  claim 1 , wherein W is fluoro. 
     
     
         3 . The method of  claim 1 , wherein the phenyl group R 1  is unsubstituted or is substituted with a single halo substituent. 
     
     
         4 . The method of  claim 3 , wherein the halo substituent is fluoro or chloro. 
     
     
         5 . The method of  claim 4 , wherein the fluoro or chloro substituent is at the 4-position of the phenyl group R′. 
     
     
         6 . The method of  claim 1 , wherein the compound of general formula (II) is selected from the group consisting of:
 (3-{[2-(Benzenesulfonyl)pyridin-3-yl]-methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid;   [5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid; and   [3-({2-[(4-Chlorobenzene)sulfonyl]pyridin-3-yl}methyl)-5-fluoro-2-methylindol-1-yl]-acetic acid.   
     
     
         7 . The method of  claim 1 , wherein the disease or condition is asthma, including allergic asthma, bronchial asthma, intrinsic, extrinsic, exercise-induced, drug-induced and dust-induced asthma, treatment of cough, including chronic cough associated with inflammatory and secretory conditions of the airways and iatrogenic cough, acute and chronic rhinitis, including rhinitis medicamentosa, vasomotor rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, nasal polyposis, acute viral infection including common cold, infection due to respiratory syncytial virus, influenza, coronavirus and adenovirus, atopic dermatitis, contact hypersensitivity (including contact dermatitis), eczematous dermatitis, phyto dermatitis, photo dermatitis, sebhorroeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosis et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme, cellulitis, panniculitis, cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; blepharitis conjunctivitis, especially allergic conjunctivitis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory disorders affecting the retina, ophthalmitis, bronchitis, including infectious and eosinophilic bronchitis, emphysema, bronchiectasis, farmer's lung, hypersensitivity pneumonitis, idiopathic interstitial pneumonias, complications of lung transplantation, vasculitic and thrombotic disorders of the lung vasculature, pulmonary hypertension, food allergies, gingivitis, glossitis, periodontitis, oesophagitis including reflux, eosinophilic gastroenteritis, proctitis, pruris ani, celiac disease, food-related allergies, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other CRTH2-mediated diseases, for example autoimmune diseases such as hyper IgE syndrome, Hashimoto's thyroiditis, Graves' disease, Addison's disease, idiopathic thrombocytopaenic purpura, eosinophilic paschiitis, antiphospholipid syndrome and systemic lupus erythematosus, AIDS, leprosy, Sezary syndrome, paraneoplastic syndrome, mixed and undifferentiated connective tissue diseases, inflammatory myopathies including dermatomyositis and polymyositis, polymalgia rheumatica, juvenile arthritis, rheumatic fever, vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, temporal arteritis, myasthenia gravis, acute and chronic pain, neuropathic pain syndromes, central and peripheral nervous system complications of malignant, infectious or autoimmune processes, low back pain, familial Mediterranean Fever, Muckle-Wells syndrome, Familial Hibernian fever, Kikuchi disease, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, as well as rheumatoid arthritis, Still's disease, ankylosing spondylitis, reactive arthritis, undifferentiated spondarthropathy, psoriatic arthritis, septic arthritis and other infection-related arthopathies and bone disorders and osteoarthritis, acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, calcium paptite related tendon syndrome and synovial inflammation, Behcet's disease, primary and secondary Sjogren's syndrome systemic sclerosis and limited scleroderma, hepatitis, cirrhosis of the liver, cholecystitis, pancreatitis, nephritis, nephritic syndrome, cystitis and Hunner's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvo-vaginitis, Peyronie's disease, erectile dysfunction, Alzheimer's disease and other dementing disorders, pericarditis, myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid, ischaemic reperfusion injuries, endocarditis, valvulitis, aortitis, phlebitis, thrombosis, treatment of common cancers and fibrotic conditions such as idiopathic pulmonary fibrosis including cryptogenic fibrosing alveolitis, keloids, excessive fibrotic scarring/adhesions post surgery, liver fibrosis including that associated with hepatitis B and C, uterine fibroids, sarcoidosis, including neurosarcoidosis, scleroderma, fibrosis associated with RA, atherosclerosis, including cerebral atherosclerosis, vasculitis, myocardial fibrosis resulting from myocardial infarction, cystic fibrosis, restenosis, systemic sclerosis, Dupuytren's disease, fibrosis complicating anti-neoplastic therapy and chronic infection including tuberculosis and aspergillosis and other fungal infections, CNS fibrosis following stroke or the promotion of healing without fibrotic scarring. 
     
     
         8 . The method of  claim 7 , wherein the condition to be treated or prevented is allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mastocytosis, autoimmune disease, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, fibrotic diseases caused/exacerbated by Th2 immune responses, idiopathic pulmonary fibrosis or hypertrophic scars. 
     
     
         9 . The method of  claim 7 , further comprising administering one or more additional active agents selected from the group consisting of:
 other CRTH2 antagonists, Suplatast tosylate, β2 adrenoreceptor agonists, methylxanthines, mast cell stabilisers, muscarinic receptor antagonists, antihistamines, α 1  and α 2  adrenoreceptor agonists, modulators of chemokine receptor function, leukotriene antagonists, leukotriene biosynthesis inhibitors, 5-lipoxygenase activating protein inhibitors, N-(5-substituted)-thiophene-2-alkylsolfonamides, 2,6-di-tert-butylphenol hydrazones, methoxytetrahydropyrans, pyridinyl-substituted-2-cyanonaphthalene compounds, 2-cyanoquinoline compounds, indole and quinoline compounds, phosphodiesterase inhibitors, anti-IgE antibody therapies, anti-infectives, anti-fungals, immunosuppressants, immunotherapy agents,   corticosteroids, drugs which promote Th1 cytokine response, other antagonists of PGD 2  acting at other receptors such as DP antagonists, drugs that modulate cytokine production, TNF receptor immunoglobulin molecules, inhibitors of other TNF isoforms, non-selective COX-1/COX-2 inhibitors, COX-2 inhibitors, low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquine, d-penicillamine, auranofin, parenteral or oral gold, drugs that modulate the activity of Th2 cytokines IL-4 and IL-5, PPAR-γ agonists, anti-RSV antibodies and agents that may be used to treat rhinovirus infection.   
     
     
         10 . The method of  claim 1 , wherein the compound is (3-{[2-(Benzenesulfonyl)pyridin-3-yl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid. 
     
     
         11 . The method of  claim 1 , wherein the disease is allergic asthma. 
     
     
         12 . The method of  claim 1 , wherein the disease is perennial allergic rhinitis. 
     
     
         13 . The method of  claim 1 , wherein the disease is seasonal allergic rhinitis. 
     
     
         14 . The method of  claim 1 , wherein the disease is atopic dermatitis. 
     
     
         15 . The method of  claim 9 , wherein said one or more additional active agents is the leukotriene antagonist montelukast.