Indolylmaleimide derivatives

Abstract

Provided are compounds of formula (I) which are useful in the treatment and/or prevention of diseases or disorders mediated by T lymphocytes and/or PKC, e.g. acute or chronic rejection of organ or tissue allo- or xenografts, graft versus host diseases, atherosclerosis, vascular occlusion due to vascular injury such as angioplasty, restenosis, obesity, syndrome X, impaired glucose tolerance, polycystic ovary syndrome, hypertension, heart failure, chronic obstructive pulmonary disease, CNS diseases such as Alzheimer disease or amyotrophic lateral sclerosis, cancer, infectious diseases such as AIDS, septic shock or adult respiratory distress syndrome, ischemia/reperfusion injury e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, or traumatic shock, e.g. traumatic brain injury. The compounds of formula I are also useful in the treatment and/or prevention of T-cell mediated acute or chronic inflammatory disease or disorders or autoimmune diseases e.g. rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or II and the disorders associated therewith, e.g. angiopathy, diabetic proliferative retinopathy, diabetic macular edema, nephropathy, neuropathy and dawn phenomenon, respiratory diseases such as asthma or inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contract dermatitis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis), inflammatory eye diseases, e.g. Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis.

1 . 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  
 Ill. 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 8  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 salt thereof.  
 
     
     
         2 . A compound according to  claim 1  which is selected from 3-[5-chloro-6-methyl-2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-4-( 1H-indol-3-yl)-pyrrole-2,5-dione, 3-[3-(4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dion and 3-(1H-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidin-4-yl]pyrrole-2,5-dio salt thereof.  
     
     
         3 . A process for the preparation of a compound of formula I according to  claim 1 , which process comprises reacting a compound of formula II  
       
         
           
           
               
               
           
         
       
       wherein R a  and R b  are as defined in  claim 1 , 
 with a compound of formula III  
   R—CH 2 —CO—NH 2    (III)  
 wherein R is as defined in  claim 1 ,  
 and, where required, converting the resulting compound of formula I obtained in free form to a salt form or vice versa, as appropriate.  
 
     
     
         4 . A compound of formula I according to  claim 1 , in free form or in a pharmaceutically acceptable salt form for use as a pharmaceutical.  
     
     
         5 . A pharmaceutical composition comprising a compound of formula I according to  claim 1  or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable diluent or carrier therefor.  
     
     
         6 . A compound of formula I according to  claim 1  or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for use in the treatment or prevention of disorders or diseases mediated by T lymphocytes and/or PKC or GSK-3β.  
     
     
         7 . A compound of formula I according to  claim 1  or a pharmaceutically acceptable salt thereof for use in combination with an immunosuppressant, immunomodulatory, anti-inflammatory, antiproliferative or anti-diabetic drug.  
     
     
         8 . A combination comprising a) a compound of formula I in free form or in pharma-ceutically acceptable salt form, and b) at least one second agent selected from an immunosuppressant, immunomodulatory, anti-inflammatory, antiproliferative and anti-diabetic drug.  
     
     
         9 . A method for preventing or treating disorders or diseases mediated by T lymphocytes and/or PKC or GSK-3β in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound of formula I according to  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         10 . A method according to  claim 9  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.