Novel Methods for the Treatment of Inflammatory Diseases

Abstract

Methods of inhibiting the cytokine or biological activity of Macrophage Migration Inhibitory Factor (MIF) comprising contacting MIF with a compound of formula (I) are provided. The invention also relates to methods of treating diseases or conditions where MIF cytokine or biological activity is implicated comprising administration of compounds of formula (I), either alone or as a part of combination therapy. Novel compounds of formula (I) are also provided for.

1 .- 46 . (canceled) 
     
     
         47 . A compound of formula (I), or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         X and X′ taken together form —C(R 5 )═N—; 
         Y is —C(R 5 )— and taken together with the carbon atom bearing the phenyl group forms a double bond and R 1  is absent; 
         Y′ is —N(R 5 )—; 
         Z forms a covalent single bond between X′ and Y′; 
         R 2  and R 4  are independently selected from hydrogen and C 1-3 alkyl; 
         R 3  is selected from C 1-3 alkyl and (A) m R 12 ; 
         —C(R 5 )— is selected from —C(H)— and —C(C 1-20 alkyl)-; 
         —N(R 5 )— is —N(C 2-20 alkyl)-; 
         m is 0; 
         R 12  is selected from the group consisting of OH, SH, NH 2 , halo, NO 2 , C(R 17 ) 3 , OC(R 17 ) 3  and CN; and 
         R 17  is independently selected from hydrogen and halogen. 
       
     
     
         48 . A compound of formula (I), or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         X and X′ taken together form —C(R 5 )═N—; 
         Y is —C(R 5 )— and taken together with the carbon atom bearing the phenyl group forms a double bond and R 1  is absent; 
         Y′ is —N(R 5 )—; 
         Z forms a covalent single bond between X′ and Y′; 
         R 2  and R 4  are independently selected from hydrogen and C 1-3 alkyl; 
         R 3  is selected from C 1-3 alkyl and (A) m R 12 ; 
         —C(R 5 )— is selected from —C(H)— and —C(C 1-20 alkyl)-; 
         —N(R 5 )— is selected from —N(alkyl)- wherein alkyl is selected from the group consisting of ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, cyclopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1-propylpropyl, 2-propylpropyl and cyclohexyl; 
         m is 0; 
         R 12  is selected from the group consisting of OH, SH, NH 2 , halo, NO 2 , C(R 17 ) 3 , OC(R 17 ) 3  and CN; 
         R 17  is independently selected from hydrogen and halogen; and 
         wherein each alkyl may be optionally substituted. 
       
     
     
         49 . The compound according to  claim 47  or  claim 48 , or a pharmaceutically acceptable salt thereof, wherein
 Y is —CH—; and 
 X is —CH—. 
 
     
     
         50 . The compound according to  claim 47  or  claim 48 , or a pharmaceutically acceptable salt thereof, wherein R 3  is OC(R 17 ) 3 . 
     
     
         51 . The compound according to  claim 47  or  claim 48 , or a pharmaceutically acceptable salt thereof, wherein R 3  is C 1-3 alkyl. 
     
     
         52 . The compound according to  claim 47  or  claim 48 , or a pharmaceutically acceptable salt thereof, wherein R 3  is —CH 3  or —OCH 3 . 
     
     
         53 . The compound according to  claim 47  or  claim 48 , or a pharmaceutically acceptable salt thereof, wherein N(R 5 )— is —N(3-methylbutyl). 
     
     
         54 . A compound wherein the compound is 4-(4-methoxyphenyl)-1-(3-methylbutyl)-1H-pyrazole or a pharmaceutically acceptable salt thereof. 
     
     
         55 . A pharmaceutical composition comprising a compound according to any one of  claims 47 ,  48 , or  54 , and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         56 . The pharmaceutical composition according to  claim 55  further comprising a glucocorticoid.