Indolylmaleimide derivatives

Abstract

Provided are compounds of formula I which have interesting pharmacological properties.

1 - 10 . (canceled)  
     
     
         11 . A method for preventing or treating T-cell mediated inflammatory or autoimmune diseases in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R a  is H; CH 3 ; CH 2 —CH 3 ; or isopropyl,  
 R b  is H; halogen; C 1-6 alkoxy; or C 1-6 alkyl, and either  
 I. R is a radical of formula (a)  
                     wherein    R 1  is piperazin-1-yl optionally substituted by CH 3  in position 3 or 4; or 4,7-diaza-spiro [2.5] oct-7-yl;    R 2  is Cl; Br; CF 3 ; or CH 3 ; and    
 R 3  is H; CH 3 ; or CF 3 ; R 2  being other than CH 3  or Cl when R 3  is H, R a  is H or CH 3 , R b  is H and R 1  is 4-methyl-1-piperazinyl; or  
 II. R is a radical of formula (b)  
                     wherein    R 4  is piperazin-1-yl substituted in positions 3 and/or 4 by CH 3 ; or 4,7-diaza-spiro[2.5] oct-7-yl; R a  being other than H or CH 3  when R 4  is 4-methyl-1-piperazinyl; or    
 III. R is a residue of formula (c)  
                     wherein    R 14  is piperazin-1-yl optionally substituted by CH 3  in position 3 and/or 4 or in position 3 by ethyl, phenyl-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl or halogeno-C 1-4 alkyl; or 4,7-diaza-spiro [2.5] oct-7-yl;    R 15  is halogen; CF 3 ; or CH 3 ; R 15  being other than CH 3  when R 16  is CH 3 , R a  is H or CH 3 , R b  is H and R 14  is 4-methyl-1-piperazinyl; and    R 16  is H; CH 3 ; CH 2 —CH 3 ; or CF 3 ; R 16  being other than H when R 15  is Cl, R a  is H or CH 3 , R b  is H and R 14  is 4-methyl-1-piperazinyl; or    
 IV. R is a radical of formula (d)  
                     wherein    
 R 8  is 1-piperazinyl, 3-methyl-piperazin-1-yl or 4-benzyl-piperazin-1-yl; or  
 V. R is a radical of formula (e)  
                     wherein    R 9  is 4,7-diaza-spiro[2.5] oct-7-yl; or 1-piperazinyl substituted in position 3 by methyl or ethyl and optionally in position 4 by methyl;    or a pharmaceutically acceptable salt thereof.    
 
     
     
         12 . The method according to  claim 11  for preventing or treating CNS diseases, cancer, infectious diseases, rheumatoid arthritis, multiple sclerosis, diabetes type I or II, asthma, cutaneous manifestations of immunologically-mediated disorders or illnesses, psoriasis, inflammatory bowel disease, Crohn's disease or ulcerative colitis  
     
     
         13 . The method according to  claim 12  for preventing or treating psoriasis.  
     
     
         14 . The method according to  claim 12  wherein the compound of formula I is administered by the topical route to the skin or to the eye.  
     
     
         15 . The method according to  claim 11  wherein the compound is selected from 3-[3-(4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione, 3-[5-chloro-6-methyl-2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-4-(1H-indol-3-yl)-pyrrole-2,5-dione and 3-(1H-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidin-4-yl]pyrrole-2,5-dione or a salt thereof.  
     
     
         16 . The method according to  claim 15  wherein the compound is 3-[3-(4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione or a salt thereof.  
     
     
         17 . The method according to  claim 15  wherein the compound is the acetate salt of 3-[3-(4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione.  
     
     
         18 . The method according to  claim 12  comprising co-administration, concomitantly or in sequence, of a therapeutically effective amount of a compound of formula I in free form or in pharmaceutically acceptable salt form, and a second drug substance, said second drug substance being an immunosuppressant, immunomodulatory, anti-inflammatory, antiproliferative or anti-diabetic drug.