Triptolide derivatives for modulation of apoptosis and immunosuppression

Abstract

Variously substituted carbonate and carbamate derivatives of triptolide compounds have good aqueous solubility and convert to biologically active compounds in vivo, at a rate which can be modulated by varying the substitution on the prodrug. The prodrugs are useful as immunosuppressive, anti-inflammatory and anticancer agents.

1 . A method of inducing cell death, comprising administering to a subject in need of such treatment, in a pharmaceutically acceptable vehicle, an effective amount of a triptolide prodrug, or a pharmaceutically acceptable salt thereof, having the structure I: 
       
         
           
           
               
               
           
         
       
       where
 X 1  is OR 1 , and X 2  and X 3  are H; and 
 OR 1  is O—(C═O)—Z, where Z is selected from the group consisting of: —OR 2 , —O—Y—(C═O)—OR 3 , —O—Y—NR 4 R 5 , —NR 4 R 5 , —NR 3 —Y—(C═O)—OR 3 , and —NR 3 —Y—NR 4 N 5 ; 
 wherein 
 Y is a divalent alkyl, alkenyl or alkynyl group having up to six carbon atoms; 
 R 2  is selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, and acyloxyalkyl; 
 each R 3  is independently selected from hydrogen and R 2 ; and 
 R 4  and R 5  are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, and acyloxyalkyl, or R 4  and R 5  taken together form a 5- to 7-member heterocyclic ring whose ring atoms are selected from the group consisting of carbon, nitrogen, oxygen and sulfur, wherein said ring atoms include at most 3 heteroatoms. 
 
     
     
         2 . The method of  claim 1 , wherein OR 1  is-selected from the group consisting of:
 O—(C═O)—NR 4 R 5 , O—(C═O)—NR 3 —Y—(C═O)—OR 3 , and O—(C═O)—NR 3 —Y—NR 4 N 5 .   
     
     
         3 . The method of  claim 1 , wherein Z is —NR 4 R 5 . 
     
     
         4 . The method of  claim 1 , wherein each of the groups defined as R 2 , R 3 , R 4 , and R 5 , when selected from alkyl, alkenyl, and alkynyl, have up to six carbon atoms, with the proviso that R 2  is not alkyl; when defined as cycloalkyl, have 3 to 7 carbon atoms; when defined as cycloalkenyl, have 5 to 7 carbon atoms; and when selected from aralkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, and acyloxyalkyl, have alkyl components with up to six carbon atoms. 
     
     
         5 . The method of  claim 4 , wherein each of R 2 , R 3 , R 4 , and R 5  is independently selected from the group consisting of alkyl having up to six carbon atoms, aryl, aralkyl, and alkoxyalkyl. 
     
     
         6 . The method of  claim 5 , wherein R 2  has up to six carbon atoms. 
     
     
         7 . The method of  claim 1 , wherein said treatment is treatment of leukemia. 
     
     
         8 . The method of  claim 1 , wherein said treatment is treatment of a solid tumor selected from the group consisting of pancreatic cancer and melanoma. 
     
     
         9 . A method of effecting immunosuppression, comprising administering to a subject in need of such treatment, in a pharmaceutically acceptable vehicle, an effective amount of a compound having the structure I as defined in  claim 1 . 
     
     
         10 . The method of  claim 9 , wherein said immunosuppression comprises inhibition of transplant rejection. 
     
     
         11 . The method of  claim 10 , wherein said immunosuppression comprises inhibition of a kidney transplant rejection. 
     
     
         12 . The method of  claim 10 , wherein said immunosuppression comprises inhibition of a bone marrow transplant rejection. 
     
     
         13 . The method of  claim 9 , wherein said immunosuppression comprises inhibition of graft-versus-host disease (GVHD). 
     
     
         14 . The method of  claim 9 , wherein said immunosuppression comprises treatment of an autoimmune disease. 
     
     
         15 . The method of  claim 14 , wherein said autoimmune disease is selected from the group consisting of Addison's disease, autoimmune hemolytic anemia, autoimmune thyroiditis, Crohn's disease, diabetes (Type I), Graves' disease, Guillain-Barre syndrome, systemic lupus erythematosus (SLE), lupus nephritis, multiple sclerosis, myasthenia gravis, psoriasis, primary biliary cirrhosis, rheumatoid arthritis and uveitis, asthma, atherosclerosis, Type I diabetes, psoriasis, and various allergies.