Methods for treating inflammatory conditions or inhibiting JNK

Abstract

This invention is generally directed to methods for treating or preventing a disease or disorder comprising administering to a patient in need thereof an effective amount of a Jun N-terminal kinase (JNK) inhibitor, such as an isothiazoloanthrone, isoxazoloanthrone, isoindolanthrone, or derivative thereof having the general formula: and pharmaceutically acceptable salts thereof, wherein R o is —CH 2 —, —SO—, —O—, —SO 2 —, or —S—.

What is claimed is:  
     
         1 . A method for treating or preventing an inflammatory condition, comprising administering to a patient in need thereof an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein R 0  is —O—, —S—, —S(O)—, —S(O) 2 — or —CH 2 —;  
 the compound being (i) unsubstituted, (ii) monosubstituted and having a first substituent, or (iii) disubstituted and having a first substituent and a second substituent;  
 the first or second substituent, when present, being at the 3, 4, 5, 7, 8, 9, or 10 position;  
 wherein the first and second substituent, when present, are independently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c), (d), (e), or (f):  
                     
 wherein R 3  and R 4  are taken together and represent alkylidene or a heteroatom-containing alkylidene or R 3  and R 4  are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl; and  
 R 5  is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, or di-alkylaminoalkyl.  
 
     
     
         2 . The method of  claim 1 , wherein the compound is monosubstituted and has a first substituent selected from the group consisting of alkoxy, aryloxy, and a group represented by the formula (a), (c), (d), (e), or (f).  
     
     
         3 . The method of  claim 1 , wherein the compound is disubstituted.  
     
     
         4 . The method of  claim 3 , wherein the first and second substituent are independently alkoxy, aryloxy, or a group represented by the formula (a), (c), (d), (e), or (f).  
     
     
         5 . The method of  claim 1  wherein the treating or preventing comprises inhibiting JNK in vivo.  
     
     
         6 . The method of  claim 5  wherein inhibiting JNK in vivo comprises inhibiting TNF-α in vivo.  
     
     
         7 . The method of  claim 1  wherein the inflammatory condition is Type II diabetes or obesity.  
     
     
         8 . The method of  claim 1  wherein the inflammatory condition is 30 rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, asthma, bronchitis, allergic rhinitis, inflammatory bowel disease, irritable bowel syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, transplant rejection, hepatitis, endotoxin shock, psoriasis, eczema, dermatitis or multiple sclerosis.  
     
     
         9 . The method of  claim 1  wherein the inflammatory condition is hereditary obesity, dietary obesity, hormone related obesity or obesity related to the administration of medication.  
     
     
         10 . The method of  claim 1  wherein the inflammatory condition is Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition-related diabetes, ketosis-prone diabetes or ketosis-resistant diabetes.  
     
     
         11 . The method of  claim 1  wherein the inflammatory condition is otitis externa, acute otitis media, hearing loss, systemic lupus erythematosus, pancreatitis, peritonitis, sepsis, alcohol or toxin-induced liver disease, sclerosis, steatosis, ischemia-reperfusion injury, allergic rhinitis, an allergy, nephropathy, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary interstitial fibrosis, liver fibrosis, renal fibrosis, cystic fibrosis, wound-healing or burn-healing.  
     
     
         12 . A method for treating or preventing a disease responsive to JNK inhibition, comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound having the structure:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein R 0  is —O—, —S—, —S(O)—, —S(O) 2 — or —CH 2 —;  
 the compound being (i) unsubstituted, (ii) monosubstituted and having a first substituent, or (iii) disubstituted and having a first substituent and a second substituent;  
 the first or second substituent, when present, being at the 3, 4, 5, 7, 8, 9, or 10 position;  
 wherein the first and second substituent, when present, are independently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c), (d), (e), or (f):  
                     
 wherein R 3  and R 4  are taken together and represent alkylidene or a heteroatom-containing alkylidene, or R 3  and R 4  are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl; and  
 R 5  is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, or di-alkylaminoalkyl.  
 
     
     
         13 . A method for treating or preventing AIDS dementia complex, comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound having the structure:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein R 0  is —O—, —S—, —S(O)—, —S(O) 2 — or —CH 2 —;  
 the compound being (i) unsubstituted, (ii) monosubstituted and having a first substituent, or (iii) disubstituted and having a first substituent and a second substituent;  
 the first or second substituent, when present, being at the 3, 4, 5, 7, 8, 9, or 10 position;  
 wherein the first and second substituent, when present, are independently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c), (d), (e), or (f):  
                     
 wherein R 3  and R 4  are taken together and represent alkylidene or a heteroatom-containing alkylidene, or R 3  and R 4  are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl; and  
 R 5  is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono-alkylaminioalkyl, or di-alkylaminoalkyl.