Thienopyridinone derivatives as macrophage migration inhibitory factor inhibitors

Abstract

Inhibitors of macrophage migration inhibitory factor having a thienopyridinone backbone are provided which have utility in the treatment of a variety of disorders, including the treatment of pathological conditions associated with macrophage migration inhibitory factor activity. The inhibitors of macrophage migration inhibitory factor have the following structures: including forms such as stereoisomers, free forms, pharmaceutically acceptable salts or esters thereof, solvates, or combinations of such forms, wherein n, R 1 , R 2 , R 3 , X, and Y are as defined herein. Compositions comprising an inhibitor of macrophage migration inhibitory factor in combination with a pharmaceutically acceptable carrier are also provided, as well as methods for use of the same.

1 . A compound having a structure selected from the group consisting of structure (I), structure (II), and structure (III):  
       
         
           
           
               
               
           
         
       
       or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 R 1  is selected from the group consisting of hydrogen, C 1-8  alkyl, —(CH 2 ) x -(C 6-18  aryl), and —(CH 2 ) x -(5-7 membered heterocycle), wherein x is 0 to 4, and wherein R 1  is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, keto, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino, and di-(C 1-6  alkyl)amino;  
 R 2  is selected from the group consisting of −C(═O)-(C 1-6  alkyl), —NO, —NO 2 , —CONH 2 , —C(═O)—NH(C 1-6  alkyl), —C(═O)—N(C 1-6  alkyl) 2 , —C(═O)—NH—(5-7 membered heterocycle), —C(═O)-(5-7 membered heterocycle), —C(═O)—N[(CH 2 ) 2 ] 2 N—CH 3 , —CN, —C(═O)O-(C 1-6  alkyl), and —OC(═O)-(C 1-6  alkyl);  
 R 3  is selected from the group consisting of C 1-8  alkyl, —(CH 2 ) y -(C 6-18  aryl), and —(CH 2 ) y -(5-7 membered heterocycle), wherein y is 0 to 4, and wherein R 3  is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxy, —C(═O)-(C 1-6  alkyl), —CN, —C(═O)O-(C 1-6  alkyl), —OC(═O)-(C 1-6  alkyl), keto, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino, and di-(C 1-6  alkyl)amino;  
 X is selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino, and di-(C 1-6  alkyl)amino;  
 Y is selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino, and di-(C 1-6  alkyl)amino; and  
 n is 0, 1, or 2.  
 
     
     
         2 . The compound of  claim 1 , wherein R 3  is selected from the group consisting of thiophenyl, furanyl, 4-hydroxyphenyl, 4-methoxyphenyl, and 5-F-thiophenyl.  
     
     
         3 . The compound of  claim 1 , wherein R 2  is selected from the group consisting of —C(═O)OCH 2 CH 3 , —C(═O)OCH(CH 3 ) 2 , and —CN.  
     
     
         4 . The compound of  claim 1 , wherein X is hydrogen.  
     
     
         5 . The compound of  claim 1 , wherein Y is hydrogen.  
     
     
         6 . The compound of  claim 1 , wherein n is 1.  
     
     
         7 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         8 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         9 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         10 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         11 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof  
       
     
     
         12 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         13 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         14 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         15 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         16 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         17 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         18 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         19 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         20 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         21 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         22 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         23 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         24 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         25 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         26 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         27 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         28 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         29 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         30 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         31 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         32 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         33 . The compound of  claim 1 , having a structure:  
       
         
           
           
               
               
           
         
         or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof.  
       
     
     
         34 . A pharmaceutical composition for treating a disease or disorder wherein macrophage migration inhibitory factor is pathogenic, the pharmaceutical composition comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier or diluent.  
     
     
         35 . The pharmaceutical composition of  claim 34 , further comprising a drug for treating the disease or disorder, wherein the drug has no measurable macrophage migration inhibitory factor inhibiting activity.  
     
     
         36 . The pharmaceutical composition of  claim 34 , further comprising a drug selected from the group consisting of a nonsteroidal anti-inflammatory drug, an anti-infective drug, a beta stimulant, a steroid, an antihistamine, an anticancer drug, an asthma drug, a sepsis drug, an arthritis drug, and an immunosuppressive drug.  
     
     
         37 . A method for treating a disease or disorder wherein macrophage migration inhibitory factor is pathogenic, comprising administering to a patient in need thereof an effective amount of a compound having a structure selected from the group consisting of structure (I), structure (II), and structure (III):  
       
         
           
           
               
               
           
         
       
       or a stereoisomer, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 R 1  is selected from the group consisting of hydrogen, C 1-8  alkyl, —(CH 2 ) x -(C 6-18  aryl), and —(CH 2 ) x -(5-7 membered heterocycle), wherein x is 0 to 4, and wherein R 1  is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, keto, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino, and di-(C 1-6  alkyl)amino;  
 R 2  is selected from the group consisting of —C(═O)-(C 1-6  alkyl), —NO, —NO 2 , —CONH 2 , —C(═O)—NH(C 1-6  alkyl), —C(═O)—N(C 1-6  alkyl) 2 , —C(═O)—NH-(5-7 membered heterocycle), —C(═O)-(5-7 membered heterocycle), —C(═O)—N[(CH 2 ) 2 ] 2 N—CH 3 , —CN, —C(═O)O-(C 1-6  alkyl), and —OC(═O)-(C 1-6  alkyl);  
 R 3  is selected from the group consisting of C 1-8  alkyl, —(CH 2 ) y -(C 6-18  aryl), and —(CH 2 ) y -(5-7 membered heterocycle), wherein y is 0 to 4, and wherein R 3  is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxy, —C(═O)-(C 1-6  alkyl), —CN, —C(═O)O-(C 1-6  alkyl), —OC(═O)-(C 1-6  alkyl), keto, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino, and di-(C 1-6  alkyl)amino;  
 X is selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino, and di-(C 1-6  alkyl)amino;  
 Y is selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino, and di-(C 1-6  alkyl)amino; and  
 n is 0, 1, or 2;  
 whereby macrophage migration inhibitory factor is inhibited.  
 
     
     
         38 . The method of  claim 37 , wherein the disease or disorder is selected from the group consisting of inflammation, septic shock, arthritis, cancer, acute respiratory distress syndrom, an inflammatory disease, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, asthma, an autoimmune disorder, diabetes, asthma, multiple sclerosis, Cushing's disease, cardiovascular disease, restenosis, and atherosclerosis.