Compounds and methods for treating transplant rejection

Abstract

The use of compounds of the formula and pharmaceutically acceptable salts thereof, alone or in combination for the treatment of transplant rejection, wherein the substituents are further defined in the application.

1 . A method for treating transplant rejection in a mammal comprising administering to said mammal an effective amount of a compound of formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof wherein:  
       Y is a bond or  
       
         
           
           
               
               
           
         
       
       R 1 , R 2 , R 3 , and R 4  are independently selected from the group consisting of hydrogen, hydroxy, C 1-10 alkyl, aryl, heteroaryl, C 1-10 alkaryl, and aryl C 1-10 alkyl, wherein all nonhydrogen and hydroxy substituents may optionally be substituted from one or more of the group selected from C 1-10 alkyl, halogen, nitro, amino, haloC 1-10 alkyl C 1-10 alkylamino, diC 1-10 alkylamino, acyl, and acyloxy;  
       Z is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alklynyl, hydroxyC 1-10 alkyl, aryl, heteroaryl, C 1-10 alkaryl, arylC 1-10 alkyl, heteroarylC 1-10 alkyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkylamino C 1-10 alkyl, carboxy C 1-10 alkyl, C 1-10 dialkylamino C 1-10 alkyl, aminoC 1-10 alkyl, heterocycle, heterocyclC 1-10 alkyl, R 7 NH, R 7 R 7 N, carboxy, carbohydrate group, carbohydrate lactone group, and an alditol group wherein all may optionally be substituted by one or more R 5 ;  
       R 5  is independently selected from the group selected from hydroxy, C 1-10 alkyl, C 1-10 alkoxy, halo, nitro, amino, cyano, C 1-10 alkylamino, di C 1-10 alkylamino, acyl, acyloxy, COOH, COOR 7 , OC(O)R 7 , CH(OH)R 7 , NHR 7 , NR 7 R 7 , C(O)NH 2 , C(O)NHR 7 , CONR 7 R 7 , NHC(O)O—R 7 , OSO 3 H, SO 3 H, SO 2 NHR 7 , SO 2 NR 7 R 7 , P(O)(OH)OR 7 , PO 2 H 2 P(O)(OH)R 7 , P(O)(OR 7 ) 2 , P(O)R 7 (OR 7 ), OPO 3 H, PO 3 H 2 , hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R 6 ;  
       R 6  is independently selected from the group consisting of hydroxy, C 1-10 alkyl, C 1-10 alkoxy, acyloxy, halo, nitro, amino, cyano, halo C 1-10 alkyl, C 1-10 alkylamino, di C 1-10 alkylamino, acyl, and acyloxy;  
       R 7  is independently selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkoxycarbonyl C 1-10 alkyl, aryl, carboxy C 1-10 alkyl, C 1-10 alkylcarboxy C 1-10 alkyl, C 1-10 alkylcarboxy C 1-10 aryl, heterocycle, heterocyclC 1-10 alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R 8 ; and  
       R 8  is independently selected from the group consisting of hydroxy, C 1-10 alkyl, C 1-10 alkoxy, acyloxy, halo, nitro, amino, cyano, and carboxy;  
       wherein two R 7  groups may come together to form a 4 to 7 membered ring.  
     
   
   
       2 . A method for treating transplant rejection in a mammal comprising administering to said mammal an effective amount of a compound of formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt wherein:  
       Y is a bond;  
       Z is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hydroxyC 1-10 alkyl, aryl, heteroaryl, C 1-10 alkaryl, aryl C 1-10 alkyl, heteroarylC 1-10 alkyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkylamino C 1-10 alkyl, carboxy C 1-10 alkyl, C 1-10 dialkylamino C 1-10 alkyl, aminoC 1-10 alkyl, heterocycle, heterocyclC 1-10 alkyl, R 7 NH, R 7 R 7 N, carbohydrate group, carbohydrate lactone group, and an alditol group wherein all may optionally be substituted by one or more R 5 ;  
       R 5  is independently selected from the group selected from hydroxy, C 1-10 alkyl, C 1-10 alkoxy, halo, nitro, amino, cyano, C 1-10 alkylamino, diC 1-10 alkylamino, acyl, acyloxy, COOH, COOR 7 , OC(O)R 7 , CH(OH)R 7 , NHR 7 , NR 7 R 7 , C(O)NH 2 , C(O)NHR 7 , CONR 7 R 7 , NHC(O)O—R 7 , OSO 3 H, SO 3 H, SO 2 NHR 7 , SO 2 NR 7 R 7 , P(O)(OH)OR 7 , PO 2 H 2 P(O)(OH)R 7 , P(O)(OR 7 ) 2 , P(O)R 7 (OR 7 ), OPO 3 H, PO 3 H 2 , hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R 6 ;  
       R 6  is independently selected from the group consisting of hydroxy, C 1-10 alkyl, C 1-10 alkoxy, acyloxy, halo, nitro, amino, cyano, halo C 1-10 alkyl, C 1-10 alkylamino, di C 1-10 alkylamino, acyl, and acyloxy;  
       R 7  is independently selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkoxycarbonyl C 1-10 aloyl, aryl, carboxy C 1-10 alkyl, C 1-10 alkylcarboxyC 1-10 alkyl, C 1-10 alkylcarboxy C 1-10 aryl, heterocycle, heterocyclC 1-10 alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R 8 ; and  
       R 8  is independently selected from the group consisting of hydroxy, C 1-10 alkyl, C 1-10 alkoxy, acyloxy, halo, nitro, amino, cyano, and carboxy;  
       wherein two R 7  groups may come together to form a 4 to 7 membered ring.  
     
   
   
       3 . The method of  claim 2 , wherein: 
 Z is selected from the group consisting of C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, and carboxy C 1-6 alkyl, wherein all may optionally be substituted by one or more R 5 ;    R 5  is independently selected from the group selected from hydroxy, amino, halo, COOH, COOR 7 , CH(OH)R 7 , NHR 7 , NR 7 R 1 , C(O)NH 2 , C(O)NHR 7 , CONR 7 R 7 , OSO 3 H, SO 3 H, SO 2 NHR 7 , SO 2 NR 7 R 7 , P(O)(OH)OR 7 , P(O)(OH)R 7 , P(O)HR 7 , P(OR 7 ) 2 , P(O)R 7 (OR 7 ), OPO 3 H, PO 3 H 2 , and hydroxymethyl, wherein when possible, all may be optionally substituted by one or more R 6 ;    R 6  is independently selected from the group consisting of hydroxy, C 1-10 alkyl, C 1-10 alkoxy, acyloxy, halo, nitro, amino, cyano, halo C 1-10 alkyl, C 1-10 alkylamino, di C 1-10 alkylamino, acyl, and acyloxy;    R 7  is independently selected from the group consisting of C 1-6 alkyl, C 2-10 alkenyl, C 2-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl C 1-6 alkyl, carboxy C 1-6 alkyl, and C 1-6 alkylcarboxy C 1-6 alkyl, wherein all may be optionally substituted by one or more R 8 ; and    R 8  is independently selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy, acyloxy, halo, amino, cyano, and carboxy.    
   
   
       4 . The method of  claim 3 , wherein: 
 Z is C 1-6 alkyl, optionally substituted by one or more R 5 ;    R 5  is independently selected from the group consisting of halo, COOH, COOR 7 , CONH 2 , CONHR 7 , CONR 7 R 7 , and amino;    R 7  is independently selected from the group consisting of C 1-6 alkyl, carboxy C 1-6 alkyl, C 1-6 alkoxycarbonylC 1-6 alkyl, and C 1-6 alkylcarboxy C 1-6 alkyl, wherein all may be optionally substituted by one or more R 8 ; and    R 8  is independently selected from the group consisting of hydroxy, halo, amino, and carboxy.    
   
   
       5 . The method of  claim 4 , wherein: 
 Z is C 1-6 alkyl, optionally substituted by one or more R 5 ; and    R 5  is COOH.    
   
   
       6 . The method of  claim 5 , wherein the compound or its pharmaceutically acceptable salt is selected from the group consisting of  
     
       
         
         
             
             
         
       
     
   
   
       7 . The method of  claim 6 , wherein the compound or its pharmaceutically acceptable salt is  
     
       
         
         
             
             
         
       
     
   
   
       8 . The method of  claim 2 , wherein: 
 Z is an alditol, optionally substituted with one or more R 5 ; and    R 5  is independently selected from the group consisting of halo, amino, carboxy, diC 1-6 alkylamino, and C 1-6 alkylamino.    
   
   
       9 . The method of  claim 8 , wherein the compound or its pharmaceutically acceptable salt is selected from the group consisting of  
     
       
         
         
             
             
         
       
     
   
   
       10 . The method of  claim 2 , wherein: 
 Z is a carbohydrate or a carbohydrate lactone, optionally substituted by one or more R 5 ; and    R 5  is independently selected from the group consisting of halo, amino, carboxy, diC 1-6 alkylamino, acyloxy, and C 1-6 alkylamino.    
   
   
       11 . The method of  claim 10 , wherein the compound or its pharmaceutically acceptable salt is selected form the group consisting of  
     
       
         
         
             
             
         
       
     
   
   
       12 . The method of  claim 2 , wherein: 
 Z is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, C 1-6 dialkylamino C 1-6 alkyl, and amino C 1-6 alkyl, wherein all may optionally be substituted by one or more R 5 ;    R 5  is independently selected from the group selected from hydroxy, C 1-10 alkyl, C 1-10 alkoxy, acyloxy, halo, nitro, amino, cyano, C 1-6 alkylamino, di C 1-6 alkylamino, acyl, acyloxy, COOH, COOR 7 , OC(O)R 7 , CH(OH)R 7 , NHR 7 , NR 7 R 7 , C(O)NH 2 , C(O)NHR 7 , CONR 7 R 7 , NHC(O)O—R 7 , OSO 3 H, SO 3 H, SO 2 NHR 7 , SO 2 NR 7 R 7 , P(O)(OH)OR 7 , P(O)HR 7 , P(O)(OH)R 7 , P(OR 7 ) 2 , P(O)R 7 (OR 7 ), OPO 3 H, PO 3 H 2 , hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R 6 ;    R 6  is independently selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy, acyloxy, halo, amino, cyano, haloC 1-6 alkyl, C 1-6 alkylamino, diC 1-6 alkylamino, acyl, and acyloxy;    R 7  is independently selected from the group consisting of C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkoxycarbonylC 1-10 alkyl, carboxy C 1-10 alkyl, C 1-6 alkylcarboxyC 1-6 alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R 8 ; and    R 8  is independently selected from the group consisting of hydroxy, halo, amino, and carboxy.    
   
   
       13 . The method of  claim 12 , wherein the compound or its pharmaceutically acceptable salt is selected form the group consisting of  
     
       
         
         
             
             
         
       
     
   
   
       14 . The method of  claim 2 , wherein: 
 Z is selected from the group consisting of C 1-6 alkyl, aryl, heteroaryl, C 1-6 alkaryl, arylC 1-6 alkyl, heteroaryl C 1-6 alkyl, heterocycle, and heterocyclC 1-6 alkyl, wherein all may optionally be substituted by one or more R 5 ;    R 5  is independently selected from the group selected from hydroxy, C 1-6 alkyl, C 1-6 alkoxy, acyloxy, halo, nitro, amino, cyano, C 1-6 alkylamino, di C 1-6 alkylamino, acyl, acyloxy, COOH, COOR 7 , OC(O)R 7 , CH(OH)R 7 , NHR 7 , NR 7 R 7 , C(O)NH 2 , C(O)NHR 7 , CONR 7 R 7 , NHC(O)O—R 7 , OSO 3 H, SO 3 H, SO 2 NHR 7 , SO 2 NR 7 R 7 , P(O)(OH)OR 7 , P(O)HR 7 , P(O)(OH)R 7 , P(OR 7 ) 2 , P(O)R 7 (OR 7 ), OPO 3 H, PO 3 H 2 , hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R 6 ;    R 6  is independently selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy, acyloxy, halo, amino, cyano, halo C 1-6 alkyl, C 1-6 alkylamino, di C 1-6 alkylamino, acyl, and acyloxy;    R 7  is independently selected from the group consisting of C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkoxycarbonylC 1-10 alkyl, aryl, carboxy C 1-6 alkyl, C 1-6 alkylcarboxyC 1-6 alkyl, C 1-6 alkylcarboxyC 1-6 aryl, heterocycle, heterocycl C 1-6 alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R 8 ; and    R 8  is independently selected from the group consisting of hydroxy, halo, amino, and carboxy; wherein two R 7  groups may come together to form a 4 to 7 membered ring.    
   
   
       15 . A method for treating transplant rejection in a mammal comprising administering to said mammal an effective amount of a compound of formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt wherein:  
       Y is  
       
         
           
           
               
               
           
         
       
       Z is selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkyl, hydroxyC 1-10 alkyl, aryl, heteroaryl, C 1-10 alkaryl, arylC 1-10 alkyl, heteroarylC 1-10 alkyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkylamino C 1-10 alkyl, carboxy C 1-10 alkyl, C 1-10 dialkylamino C 1-10 alkyl, aminoC 1-10 alkyl, heterocycle, heterocyclC 1-10 alkyl, R 7 NH, R 7 R 7 N, carboxy, carbohydrate group, carbohydrate lactone group, and an alditol group wherein all may optionally be substituted by one or more R 5 ;  
       R 5  is independently selected from the group selected from hydroxy, C 1-10 alkyl, C 1-10 alkoxy, halo, nitro, amino, cyano, C 1-10 alkylamino, di C 1-10 alkylamino, acyl, acyloxy, COOH, COOR 7 , OC(O)R 7 , CH(OH)R 7 , NR 7 , NR 7 R 7 , C(O)NH 2 , C(O)NHR 7 , CONR 7 R 7 , NHC(O)O—R 7 , OSO 3 H, SO 3 H, SO 2 NHR 7 , SO 2 NR 7 R 7 , P(O)(OH)OR 7 , PO 2 H 2 P(O)(OH)R 7 , P(O)(OR 7 ) 2 , P(O)R 7 (OR 7 ), OPO 3 H, PO 3 H 2 , hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R 6 ;  
       R 6  is independently selected from the group consisting of hydroxy, C 1-10 alkyl, C 1-10 alkoxy, acyloxy, halo, nitro, amino, cyano, halo C 1-10 alkyl, C 1-10 alkylamino, diC 1-10 alkylamino, acyl, and acyloxy;  
       R 7  is independently selected from the group consisting of C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkoxycarbonylC 1-10 alkyl, aryl, carboxy C 1-10 alkyl, C 1-10 akylcarboxyC 1-10 alkyl, C 1-10 alkylcarboxy C 1-10 aryl, heterocycle, heterocyclC 1-10 alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R 8 ; and  
       R 8  is independently selected from the group consisting of hydroxy, C 1-10 alkyl, C 1-10 alkoxy, acyloxy, halo, nitro, amino, cyano, and carboxy;  
       wherein two R 7  groups may come together to form a 4 to 7 membered ring.  
     
   
   
       16 . The method of  claim 15 , wherein: 
 Z is selected from the group consisting of C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, and carboxyC 1-6 alkyl, wherein all may optionally be substituted by one or more R 5 ;    R 5  is independently selected from the group selected from hydroxy, amino, halo, COOH, COOR 7 , CH(OH)R 7 , NHR 7 , NR 7 R 7 , C(O)NH 2 , C(O)NHR 7 , CONR 7 R 7 , OSO 3 H, SO 3 H, SO 2 NHR 7 , SO 2 NR 7 R 7 , P(O)(OH)OR 7 , P(O)(OH)R 7 , P(O)HR 7 , P(OR 7 ) 2 , P(O)R 7 (OR 7 ), OPO 3 H, PO 3 H 2 , and hydroxymethyl, wherein when possible, all may be optionally substituted by one or more R 6 ;    R 7  is independently selected from the group consisting of C 1-6 alkyl, C 2-10 alkenyl, C 2-6 alkylyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl C 1-6 alkyl, carboxyC 1-6 alkyl, and C 1-6 alkylcarboxy C 1-6 alkyl, wherein all may be optionally substituted by one or more R 8 ; and    R 8  is independently selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy, acyloxy, halo, amino, cyano, and carboxy.    
   
   
       17 . The method of  claim 16 , wherein: 
 Z is C 1-6 alkyl, optionally substituted by one or more R 5 ;    R 5  is independently selected from the group consisting of halo, COOH, COOR 7 CONH 2 , CONHR 7 , CONR 7 R 7 , and amino;    R 7  is independently selected from the group consisting of C 1-6 alkyl, carboxy C 1-6 alkyl, and C 1-6 alkylcarboxyC 1-6 alkyl, wherein all may be optionally substituted by one or more R 8 ; and    R 8  is independently selected from the group consisting of hydroxy, halo, amino, and carboxy.    
   
   
       18 . The method of  claim 17 , wherein: 
 Z is C 1-6 alkyl, optionally substituted by one or more R 5 ; and    R 5  is COOH.    
   
   
       19 . The method of  claim 18 , wherein the compound or its pharmaceutically acceptable salt is selected from the group consisting of  
     
       
         
         
             
             
         
       
     
   
   
       20 . The method of  claim 19 , wherein the compound or its pharmaceutically acceptable salt is  
     
       
         
         
             
             
         
       
     
   
   
       21 . The method of  claim 15 , wherein: 
 Z is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxyC 1-6 xalkyl, C 1-6 alkylaminoC 1-6 alkyl, and amino C 1-6 alkyl, wherein all may optionally be substituted by one or more R 5 ;    R 5  is independently selected from the group selected from hydroxy, C 1-6 alkyl, C 1-6 alkoxy, acyloxy, halo, nitro, amino, cyano, C 1-6 alkylamino, diC 1-6 alkylamino, acyl, acyloxy, COOH, COOR 7 ; OC(O)R 7 , CH(OH)R 7 , NHR 7 , NR 7 R 7 , C(O)NH 2 , C(O)NHR 7 , CONR 7 R 71  NHC(O)O—R 7 , OSO 3 H, SO 3 H, SO 2 NHR 7 , SO 2 NR 7 R 7 , P(O)(OH)OR 7 , P(O)HR 7 , P(O)(OH)R 7 , P(OR 7 ) 2 , P(O)R 7 (OR 7 ), OPO 3 H, PO 3 H 2 , hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R 6 ;    R 6  is independently selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy, acyloxy, halo, amino, cyano, haloC 1-6 alkyl, C 1-6 alkylamino, di C 1-6 alkylamino, acyl, and acyloxy;    R 7  is independently selected from the group consisting of C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkoxycarbonyl C 1-10 alkyl, carboxyC 1-6 alkyl, C 1-6 alkylcarboxyC 1-6 alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R 8 ; and    R 8  is independently selected from the group consisting of hydroxy, halo, amino, and carboxy.    
   
   
       22 . The method of  claim 21 , wherein the compound or its pharmaceutically acceptable salt is  
     
       
         
         
             
             
         
       
     
   
   
       23 . The method of  claim 15 , wherein: 
 Z is selected from the group consisting of C 1-6 alkyl, aryl, heteroaryl, C 1-6 alkaryl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl, heterocycle, and heterocyclC 1-6 alkyl, wherein all may optionally be substituted by one or more R 5 ;    R 5  is independently selected from the group selected from hydroxy, C 1-6 alkyl, C 1-6 alkoxy, acyloxy, halo, nitro, amino, cyano, C 1-6 alkylamino, diC 1-6 alkylamino, acyl, acyloxy, COOH, COOR 7 , OC(O)R 7 , CH(OH)R 7 , NHR 7 , NR 7 R 7 , C(O)NH 2 , C(O)NHR 7 , CONR 7 R 7 , NHC(O)O—R 7 , OSO 3 H, SO 3 H, SO 2 NHR 7 , SO 2 NR 7 R 7 , P(O)(OH)OR 7 , P(O)HR 7 , P(O)(OH)R 7 , P(OR 7 ) 2 , P(O)R 7 (OR 7 ), OPO 3 H, PO 3 H 2 , hydroxymethyl, and cyclic phosphate, wherein when possible, all may be optionally substituted by one or more R 6 ;    R 6  is independently selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy, acyloxy, halo, amino, cyano, haloC 1-6 alkyl, C 1-6 alkylamino, diC 1-6 alkylamino, acyl, and acyloxy;    R 7  is independently selected from the group consisting of C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkoxycarbonyl C 1-10 alkyl, aryl, carboxy C 1-10 alkyl, C 1-6 alkylcarboxyC 1-6 alkyl, C 1-6 alkylcarboxy C 1-6 aryl, heterocycle, heterocyclC 1-6 alkyl, and heteroaryl, wherein all may be optionally substituted by one or more R 8 ; and    R 8  is independently selected from the group consisting of hydroxy, halo, amino, and carboxy;    wherein two R 7  groups may come together to form a 4 to 7 membered ring.    
   
   
       24 . A method for treating transplant rejection in a mammal comprising administering to said mammal in combination a compound of  claim 1 ,  claim 2 , or  claim 15  and one or more compound selected from the group consisting of cyclosporin, tacrolimus (FK506), sirolimus (rapamycin), methotrexate, mycophenolic acid (mycophenolate mofetil), everolimus, azathiprine, steroids and NOX-100, said combination being administered in an amount effective to inhibit or modulate transplant rejection.  
   
   
       25 . A compound of the formula  
     
       
         
         
             
             
         
       
       or its pharmaceutically acceptable salt thereof.