Functionalized stilbene derivatives as improved vascular targeting agents

Abstract

Novel stilbenoid compounds and their prodrug forms are disclosed, which serve as potent vascular targeting agents useful for the treatment of solid tumor cancers and other diseases associated with unwanted neovascularization. The novel stilbenoid compounds are tubulin-binding stilbenoid analogs structurally related to combretastatin A-1 and combretastatin A-4. The prodrug forms serve as potent vascular targeting agents (VTAs) useful for the treatment of solid tumor cancers and diseases associated with retinal neovascularization.

What is claimed is: 
     
       1. A compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 4  and R 5  is independently H, OH, lower alkoxy, NH 2 , NO 2 , N 3 , NH—R 6 , halogen, a phosphate ester salt moiety of the general formula (—O—P(O)(O − M + ) 2  or (—OP(O)(OR 9 )(O − M + ); or —OPO 3 R 7 R 8 ; 
 R 2  is H, OH, lower alkoxy, NH 2 , NO 2 , NH—R 6 , or phosphate ester salt moiety of the general formula (—O—P(O)(O − M + ) 2  or (—OP(O)(OR 9 )(O − M + ); or —OPO 3 R 7 R 8 , wherein NH 2  or OH may cyclize with R 1 ; 
 R 3  is H, lower alkoxy, or phosphate ester salt moiety of the general formula (—O—P(O)(O − M + ) 2  or (—OP(O)(OR 9 )(O − M + ); or —OPO 3 R 7 R 8 ; 
 R 6  is an acylamino group; 
 R 7  is an ammonium salt (NH 4   + ); 
 R 8  is lower alkyl, cycloalkyl, or aryl; 
 R 9  is an alkyl or branched alkyl substituent, or a benzyl or aryl group; and 
 M is a metal cation or salt, 
 
       wherein at least one of R 1 , R 2 , R 3  R 4  or R 5  is a phosphate ester salt moiety of the general formula (—OP(O)(OR 9 )(O − M − ). 
     
     
       2. The compound of  claim 1 , wherein:
 R 1 , R 4  and R 5  are independently H, OH or NHR 6 ;   R 2  is H, or a phosphate ester salt moiety of the general formula (—OP(O)(OR 9 )(O − M + ) 2 , wherein M is a metal cation or salt such as Na, K and Li; or has the formula —OPO 3 R 7 R 8 ;   R 3  is lower alkoxy; and   R 6  is an acylamino group.   
     
     
       3. The compound of  claim 1  or  2 , wherein said acylamino group is serineamide. 
     
     
       4. A pharmaceutical composition comprising the compound of  claim 1  as active component, and a pharmaceutically acceptable carrier. 
     
     
       5. A compound of the formula: 
       
         
           
           
               
               
           
         
       
     
     
       6. A compound of the formula: 
       
         
           
           
               
               
           
         
       
     
     
       7. A compound of the formula: 
       
         
           
           
               
               
           
         
       
     
     
       8. A compound of the formula: 
       
         
           
           
               
               
           
         
       
     
     
       9. A compound of the formula: 
       
         
           
           
               
               
           
         
       
     
     
       10. A compound of formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is a phosphate ester salt moiety of the general formula (—P(O)(O − M + ) 2 ), wherein M is a metal cation or salt such as Na, K and Li, —PO 3 R 2 R 3 —, or an alkyl sulfonate; 
 R 2  is an alkyl group or an ammonium salt (NH 4   + ); and 
 R 3  is an alkyl group, an aryl group or a cycloalkyl. 
 
     
     
       11. The compound of  claim 10 , wherein
 R 1  is a phosphate ester salt moiety of the general formula —PO 3 R 2 R 3 ;   R 2  is an ammonium salt (NH 4   + ); and   R 3  is an alkyl group.   
     
     
       12. A pharmaceutical composition comprising a compound 10 as active component and a pharmaceutically acceptable carrier.