Selective glucocorticoid receptor agonists

Abstract

This invention is directed to a method for treating an inflammatory condition, treating haematological and other malignancies, causing immunosuppression, or preventing or treating transplant rejection in man or other animals which comprises administering to a patient a compound that has the structure of Formula (I) or Formula (II) as defined below, or a pharmaceutically acceptable derivative thereof or pro-drug therefor, wherein R=NH 2 , NHR 1 , NHOR 2 , NHNHR 2 , NHCOR 2 , and R 1 =C (1-4) alkyl, C (3-6) cycloalkyl, C n , where n=1-3, R 2 =methyl, ethyl, R 3 =alkyl, cycloalkyl, substituted alkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, or substituted hetreoaryl; wherein R 4 , R 5 =C (1-4) alkyl. Novel compounds according to Formula (III), wherein R 6 and R 7 are any of H, CH 3 CO, CH 3 CH 2 CO, CH 3 CH 2 CH 2 CO provided that R 6 and R 7 are not both H, or Formula (IV), wherein R 8 and R 9 are any of H, CH 3 CO, CH 3 CH 2 CO or CH 3 CH 2 CH 2 CO, having use in such methods, are also described.

1 . A method for treating an inflammatory condition, treating haematological and other malignancies, causing immunosuppression, or preventing or treating transplant rejection in man or other animals which comprises administering to a patient a compound that has the structure of Formula I or Formula II as defined below, or a pharmaceutically acceptable derivative thereof or pro-drug therefor  
       
         
           
           
               
               
           
         
       
       Wherein 
 R=NH 2 , NHR 1 , NHOR 2 , NHNHR 2 , NHCOR 2 ,  
                     
 and R 1 =C (1-4) alkyl, C (3-6) cycloalkyl,  
                     
  where n=1-3,  
 R 2 =methyl,ethyl,  
 R 3 =alkyl, cycloalkyl, substituted alkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, or substituted hetreoaryl;  
 OR  
                     
 Wherein R 4 ,R 5 =C (1-4)  alkyl.  
 
     
     
         2 . A method according to  claim 1  wherein the compound has the structure of Formula I wherein R is NHR 1  and R 1  is methyl, ethyl, propyl, cyclopropyl, butyl, cyclobutyl or  
       
         
           
           
               
               
           
         
       
       and n=1.  
     
     
         3 . A method according to  claim 2  wherein the compound is Compound G, K, or M.  
     
     
         4 . A method according to  claim 1  wherein the compound has the structure of Formula I where R is  
       
         
           
           
               
               
           
         
       
       and R 3  is alkyl, preferably C (1-6) alkyl, most preferably propyl or hexyl.  
     
     
         5 . A method according to  claim 4  wherein the compound is Compound H or T.  
     
     
         6 . A method according to  claim 1  wherein the compound has the structure of formula I where R is  
       
         
           
           
               
               
           
         
       
       and R 3  is  
       
         
           
           
               
               
           
         
       
       where n=1-6, preferably n=1.  
     
     
         7 . A method according to  claim 6  wherein the compound is Compound I.  
     
     
         8 . A method according to  claim 1  wherein the compound has the structure of formula I where R is  
       
         
           
           
               
               
           
         
       
       and R 3  is a benzyl or a substituted benzyl group, preferably halobenzyl, most preferably fluorobenzyl.  
     
     
         9 . A method according to  claim 8  wherein the compound is Compound N or S.  
     
     
         10 . A method according to  claim 1  wherein the compound has a structure according to Formula II and R  5  and/or R  6  is methyl and/or ethyl.  
     
     
         11 . A method according to  claim 10  wherein the compound is Compound A  
     
     
         12 . A method according to any preceding claim wherein the compounds are administered to a patient to induce apoptosis in pro-inflammatory cells and/or malignant cells.  
     
     
         13 . A compound as defined in Formula III or Formula IV below:  
       
         
           
           
               
               
           
         
       
       Wherein R 6  and R 7  are any of H, CH 3 CO, CH 3 CH 2 CO, CH 3 CH 2 CH 2 CO provided that R 6  and R 7  are not both H,  
       OR  
       
         
           
           
               
               
           
         
       
       Wherein R 8  and R 9  are any of H, CH 3 CO, CH 3 CH 2 CO or CH 3 CH 2 CH 2 CO.  
     
     
         14 . A compound according to Formula I or II as defined in any of  claims 1  to  11 , or a pharmaceutically acceptable derivative thereof or pro-drug therefor, or a compound according to Formula II or IV as claimed in  claim 13 , for use as a medicine.  
     
     
         15 . A compound as claimed in  claim 14  for use in treating an inflammatory condition, for treating haematological or other malignancies, for causing immunosuppression or for the prevention or treatment of transplant rejection,  
     
     
         16 . Use of compound according to Formula I or II as defined in any of  claims 1  to  11 , or a pharmaceutically acceptable derivative thereof or pro-drug therefor, or a compound according to Formula III or IV as claimed in  claim 13 , in the manufacture of a medicament for treatment of an inflammatory condition, for treating haematological or other malignancies, causing immunosuppression or preventing or treating transplant rejection.  
     
     
         17 . A pharmaceutical composition which comprises a compound according to Formula I or II as defined in any of  claims 1  to  11 , or a pharmaceutically acceptable derivative thereof or pro-drug therefor, or a compound according to Formula II or IV as claimed in  claim 13 , and a pharmaceutically acceptable carrier.  
     
     
         18 . A pharmaceutical composition according to  claim 17  for use in the treatment of an inflammatory condition, for treating haematological or other malignancies, causing immunosuppression or the prevention or treatment of transplant rejection.  
     
     
         19 . Use of a composition according to  claim 17  in the manufacture of a medicament for the treatment of an inflammatory condition, for treating haematological or other malignancies, causing immunosuppression or the prevention or treatment of transplant rejection.  
     
     
         20 . Use of a composition according to  claim 17  in the manufacture of a medicament for inducing apoptosis in target cells.  
     
     
         21 . Use of a compound according to Formula I or II as defined in any of  claims 1  to  11 , or a pharmaceutically acceptable derivative thereof or pro-drug therefor, or a compound according to Formula III or IV as claimed in  claim 13 , in the manufacture of a medicament for inducing apoptosis in target cells.  
     
     
         22 . A method of inducing apoptosis in target cells, which comprises administering to the target cells or to the vicinity in which the target cells are located a Compound according to Formula I or II as defined in any of  claims 1  to  11  or a pharmaceutically acceptable derivative thereof or pro-drug therefore, or a compound according to Formula III or IV as claimed in  claim 13.