Method of preparing and use of prodrugs of betulinic acid derivatives

Abstract

A composition and method of preventing or inhibiting tumor growth and, more particularly, of treating a malignant tumor, using prodrugs of plant-derived compounds and derivatives is disclosed. In the method, a composition containing betulinic acid or a betulinic acid derivative is administered in a prodrug form to release betulinic acid or a betulinic acid derivative in vivo at the tumor site.

1 . (canceled)  
   
   
       2 . A composition for treating a tumor growth comprising: (a) a prodrug of betulinic acid or a derivative thereof having a formula  
     
       
         
         
             
             
         
       
       wherein R 1  is selected from the group consisting of hydrogen, CO(C 1 -C 6 alkyl)NR 4 R 5 , CO(C 1-3 alkyl)CO 2 R 4 , COCH(C 6 H 5 )NR 4 R 5 , CO(C 1 -C 6 alkyl), CO(C 1 -C 6 alkyl)CO 2 R 4 , CO(C 1-6 alkyl)O(CH 2 CH 2 O) n C 1-3 -alkyl, CH 2 OCO 2 C 1-6 alkyl, CH 2 OCOC 1-6 alkyl, PO(OH) 2 , and SO 3 H,  
       R 2  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, CH 2 C 6 H 5 , C 1 -C 6 alkylNR 4 R 5 , CH 2 OCOC 1 -C 6 alkyl, PO(OH) 2 , SO 3 H, CH(C 6 H 5 )NR 4 R 5 , (C 1 -C 6 alkyl)CO 2 R 4 , and (C 1 -C 6 alkyl)O(CH 2 CH 2 O) n C 1-3 alkyl,  
       R 4  and R 5 , independently, are selected from the group consisting of hydrogen, C 1 -C 6 alkyl, CO(C 1 -C 6 alkyl), and aryl, or R 4  and R 5  can be taken together to form a 5 to 7 membered ring,  
       and n is 1 to 10;  
       and pharmaceutically acceptable salts thereof,  
       and (b) an optional carrier.  
     
   
   
       3 . The composition of  claim 2  wherein at least one of R 1  and R 2  is hydrogen, and at least one of R 1  and R 2  is different from hydrogen.  
   
   
       4 . The composition of  claim 2  wherein R 1  and R 2  are selected from the group consisting of  
     
       
         
         
             
             
         
       
       wherein Ph is C 6 H 5 .  
     
   
   
       5 . The composition of  claim 2  wherein at least one of R 1  R 2  is PO(OH) 2  and the remaining R 1  or R 2  is hydrogen.  
   
   
       6 . The composition of  claim 2  wherein at least one of R 1  and R 2  is CH 2 OCOC(CH 3 ) 2 .  
   
   
       7 . The composition of  claim 2  wherein at least one of R 1  R 2  is SO 3 H and the remaining R 1  or R 2 , is hydrogen.  
   
   
       8 . A compound having a structure:  
     
       
         
         
             
             
         
       
       wherein R 1  is selected from the group consisting of hydrogen, CO(C 1 -C 6 alkyl)NR 4 R 5 , CO(C 1-3 alkyl)CO 2 R 4 , COCH(C 6 H 5 )NR 4 R 5 , CO(C 1 -C 6 alkyl), CO(C 1 -C 6 alkyl)CO 2 R 4 , CO(C 1-6 alkyl)O(CH 2 CH 2 O) n C 1-3 alkyl, CH 2 OCO 2 C 1-6 alkyl, CH 2 OCOC 1-6 alkyl, PO(OH) 2 , and SO 3 H,  
       R 2  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, CH 2 C 6 H 5 , C 1 -C 6 alkylNR 4 R 5 , CH 2 OCOC 1 -C 6 alkyl, PO(OH) 2 , SO 3 H, CH(C 6 H 5 )NR 4 R 5 , (C 1 -C 6 alkyl)CO 2 R 4 , and (C 1 -C 6 alkyl)O(CH 2 CH 2 O) n C 1-3 alkyl,  
       R 4  and R 5 , independently, are selected from the group consisting of hydrogen, C 1 -C 6 alkyl, CO(C 1 -C 6 alkyl), and aryl, or R 4  and R 5  can be taken together to form a 5 to 7 membered ring,  
       and n is 1 to 10;  
       with proviso that at least one of R 1  and R 2  is different from H;  
       and pharmaceutically acceptable salts thereof.  
     
   
   
       9 . (canceled)  
   
   
       10 . (canceled)  
   
   
       11 . A compound as described herein, and identified as compound 28a through 28i, and salts thereof.  
   
   
       12 . A method of treating a cancer sensitive to betulinic acid or a betulinic acid derivative comprising administering to an individual in need thereof a therapeutically effective amount of a compound of  claim 11 .  
   
   
       13 . The method of  claim 12  wherein the cancer is selected from the group consisting of a melanoma, a squamous tumor, a breast cancer, a colon cancer, a sarcoma, a human oral epidermal carcinoma, a hormone-dependent breast cancer, a prostate cancer, a lung cancer, a glioma, a melanoma, and a neuroblastoma.  
   
   
       14 . A method of treating a cancer sensitive to betulinic acid or a betulinic acid derivative comprising administering to an individual in need thereof a therapeutically effective amount of a prodrug of betulinic acid or a prodrug of a betulinic acid derivative.  
   
   
       15 . The method of  claim 14  wherein the cancer is selected from the group consisting of a melanoma, a squamous tumor, a breast cancer, a colon cancer, a sarcoma, a human oral epidermal carcinoma, a hormone-dependent breast cancer, a prostate cancer, a lung cancer, a glioma, a melanoma, and a neuroblastoma.  
   
   
       16 . The method of  claim 14  wherein the prodrug is administered topically, intravenously, or intraperitoneally.  
   
   
       17 . (canceled)  
   
   
       18 . (canceled)  
   
   
       19 . (canceled)  
   
   
       20 . A pharmaceutical composition comprising a compound of  claim 11  and a pharmaceutically acceptable carrier.  
   
   
       21 . A method of treating a cancer sensitive to betulinic acid or a betulinic acid derivative comprising administering to an individual in need thereof a therapeutically effective amount of a composition comprising a compound of  claim 11  and a carrier.  
   
   
       22 . (canceled)  
   
   
       23 . (canceled)  
   
   
       24 . (canceled)