Treatment of graft versus host disease in transplant patients

Abstract

The present invention relates to a method of treating patients who undergo hematopoietic stem cell transplantation (HSCT) with peripheral blood mobilized stem cells for hematological malignancies and for whom the risk for severe acute graft versus host disease (GVHD) is considerable.

1 . A method of treating and/or preventing graft versus host disease (GVHD) in a patient undergoing hematopoietic stem cell transplantation (HSCT), which method comprises:
 (i) Administering to the patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof;   (ii) Conditioning said patient thereby destroying substantially all bone marrow and the immune system; and   (iii) Transplanting hematopoietic stem cells from a donor to said patient;   wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is   
       
         
           
           
               
               
           
         
         wherein
 R 2  is H, halogen, trihalomethyl, C 1-4 alkoxy, C 1-7 alkyl, phenethyl or benzyloxy; 
 R 3  is H, halogen, CF 3 , OH, C 1-7 alkyl, C 1-4 alkoxy, benzyloxy, phenyl or C 1-4 alkoxymethyl; 
 each of R 4  and R 5 , independently is H or a residue of formula (a) 
 
       
       
         
           
           
               
               
           
         
         
           wherein each of R 8  and R 9 , independently, is H or C 1-4 alkyl optionally substituted by halogen; 
           and n is an integer from 1 to 4; and 
           R 6  is hydrogen, halogen, C 1-7 alkyl, C 1-4 alkoxy or trifluoromethyl. 
         
       
     
     
         2 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (II), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         or the compound of formula (I) is a phosphate derivative of formula (IIa), or a pharmaceutically acceptable salt thereof or a phosphate derivative of formula (IIb), or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (II) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of GVHD in a patient who was first conditioned thereby destroying substantially all bone marrow and the immune system, and who then received a hematopoietic stem cell transplantation (HSCT) from a donor,
 wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is   
       
         
           
           
               
               
           
         
         wherein
 R 2  is H, halogen, trihalomethyl, C 1-4 alkoxy, C 1-7 alkyl, phenethyl or benzyloxy; 
 R 3  is H, halogen, CF 3 , OH, C 1-7 alkyl, C 1-4 alkoxy, benzyloxy, phenyl or C 1-4 alkoxymethyl; 
 each of R 4  and R 5 , independently is H or a residue of formula (a) 
 
       
       
         
           
           
               
               
           
         
         
           wherein each of R 8  and R 9 , independently, is H or C 1-4 alkyl optionally substituted by halogen; 
           and n is an integer from 1 to 4; and 
         
       
       R 6  is hydrogen, halogen, C 1-7 alkyl, C 1-4 alkoxy or trifluoromethyl. 
     
     
         5 . The compound for use in accordance to  claim 4 , wherein said compound is a compound of formula (II), (IIa) or (IIb) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 1  wherein said conditioning is selected from:
 Reduced Intensity Conditioning (RIC and 
 Myeloablative Conditioning. 
 
     
     
         7 . The method of  claim 1  wherein said conditioning is a high dose chemotherapy comprising one or more agents selected from fludarabin, busulphan, methotrexate, cyclosporin A and cyclophosphamide. 
     
     
         8 . The method of  claim 1  wherein said conditioning is a total body irradiation (TBI) according to national guidelines. 
     
     
         9 . The method of  claim 1  wherein hematopoietic stem cell transplantation (HSCT) is carried out immediately after conditioning, or 0-1 day after conditioning, or 1-8 days, or 1-10 days after conditioning. 
     
     
         10 . The method of  claim 1 , wherein treatment of the patient with a compound of formula (I) is commenced 5 days before conditioning, or 3 days before conditioning or 1 day before conditioning.