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 method for treating a vascular proliferative disorder in a host comprising administering to a host an effective amount of the a compound of the formula I: selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof wherein: 
         R 1 , R 4 , and R 5  are each independently H, OH, lower alkoxy, NH 2 , NO 2 , N 3 , NHR 6 , halogen, or a phosphate ester salt moiety of the general formula (—OP(O)O − M + ) 2 , (—OP(O)(OR 9 )(O − M + ), or —OPO 3 R 7 R 8 ; 
         R 2  is H, OH, lower alkoxy, NH 2 , NO 2 , NHR 6 , or a phosphate ester salt moiety of the general formula (—O—P(O)(O − M + ) 2 , (—OP(O)(OR 9 )(O − M + ), or —OPO 3 R 7 R 8 , wherein NH 2  or OH may form a ring with R 1 ; 
         R 3  is H, lower alkoxy, or a phosphate ester salt moiety of the general formula (—OP(O)(O − M + ) 2 , (—OP(O)(OR 9 )(O − M + ), or —OPO 3 R 7 R 8 ; 
         R 6  is acylamino group; 
         R 7  is ammonium salt (NH 4   + ); 
         R 8  is lower alkyl, cycloalkyl, or aryl; 
         R 9  is alkyl, branched alkyl, benzyl, or aryl; and 
         M is a metal cation or salt, 
       
       provided that when R 1 , R 4 , and R 5  are H, R 2  is H, lower alkoxy, NH 2 , NO 2 , NHR 6 , or a phosphate ester salt moiety of the general formula (—OP(O)(OR 9 )(O − M + ) or —OPO 3 R 7 R 8 ; and 
       provided that when R 1 , R 2 , and R 5  are H, R 4  is H, lower alkoxy, NH 2 , NO 2 , NHR 6 , or a phosphate ester salt moiety of the general formula (—OP(O)(OR 9 )(O − M + ) or —OPO 3 R 7 R 8 ,
 2′,3′-dinitro-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-3A), 
 2′,3′-diamino-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-3B), 
 2′-serinamide-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-45), 
 2′-disodium phosphate-3′-hydroxy-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-1A), 
 2′-hydroxy-3′-disodium phosphate-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-2A), 
 3′,5′-dihydroxy-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-1B), 
 2′-hydroxy-3,3′,4,4′,5-pentamethoxy-(Z)-stilbene (ZSB-18), 
 2′-disodium phosphate-3,3′,4,4′,5-pentamethoxy-(Z)-stilbene (ZSB-19), 
 3′-hydroxy-3,4,4′,5,5′-pentamethoxy-(Z)-stilbene (ZSB-20), 
 3′-hydroxy-2′,3,4,4′,5-pentamethoxy-(Z)-stilbene (ZSB-27A), 
 3′-disodium phosphate-2′,3,4,4′,5-pentamethoxy-(Z)-stilbene (ZSB-27B), 
 2′,5′-dihydroxy-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-33A), 
 2′,5′-tetrasodium diphosphate-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-33B), 
 2′-hydroxy-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-46A), 
 2′-disodium phosphate-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-46B), 
 3′,5′-dinitro-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-13), 
 3′,5′-diamino-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-14), 
 3′,5′-diserinamide-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-15), 
 2′-nitro-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-39A), 
 2′-amino-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-39B), 
 2′-serinamide-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-45), 
 3′-hydroxy-5′-nitro-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-43), 
 3′-hydroxy-5′-amino-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-44), and 
 2′-amino-3′-hydroxy-3,4,4′,5-tetramethoxy-(Z)-stilbene (ZSB-48),  
 wherein said vascular proliferative disorder is selected from wet macular degeneration, diabetic retinopathy, retinopathy of prematurity, restenosis, and a cancer selected from leukemia, lung, colon, thyroid, melanoma, ovarian, renal, prostate, and breast cancer. 
 
     
     
       2. The method of  claim 1 , wherein said host is a mammal. 
     
     
       3. The method of  claim 2 , wherein said mammal is a human. 
     
     
       4. The method of  claim 1 , wherein said compound is administered systemically. 
     
     
       5. The method of  claim 1 , wherein said compound is administered orally. 
     
     
       6. The method of  claim 1 , wherein said compound is administered intravenously. 
     
     
       7. The method of  claim 1 , wherein said compound is administered topically. 
     
     
       8. The method of  claim 1 , wherein said compound is administered along with a carrier.