Small molecule modulators of prb inactivation

Abstract

The present invention provides a small molecule treatment of diseases/conditions caused by a virus carrying a viral oncoprotein. In one embodiment, the virus which carries the viral oncoprotein is HPV. The small molecule useful herein includes thiadiazolin-3,5-dione compounds having an optionally substituted aryl group bound to one nitrogen atom of said thiadiazolin-3,5-dione compound. The small molecules may also be administered with a compound which inhibits binding of HPV E6 to p53. In one embodiment, the thiadiazolin-3,5-dione compound has formula (I), or a pharmaceutically acceptable salt, prodrug, solvate, or metabolite thereof, wherein R 1 and R 2 are defined herein.

What is claimed is: 
     
         1 . A composition for treating a human papilloma virus (HPV) mediated disease, said composition comprising (i) a thiadiazolin-3,5-dione compound comprising an optionally substituted aryl group bound to one nitrogen atom of said thiadiazolin-3,5-dione compound; and (ii) a compound which inhibits binding of HPV E6 to p53. 
     
     
         2 . The composition according to  claim 1 , said thiadiazolin-3,5-dione compound is of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycle; 
 R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; 
 
         or a pharmaceutically acceptable salt, prodrug, solvate, or metabolite thereof. 
       
     
     
         3 . The composition according to  claim 2 , wherein R 1  is: 
       
         
           
           
               
               
           
         
         wherein, R 3  to R 7  are, independently, selected from the group consisting of H, optionally substituted alkyl, halogen, optionally and substituted alkoxy. 
       
     
     
         4 . The composition according to  claim 3 , wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The composition according to  claim 4 , wherein one of R 3  to R 7  is alkyl or alkoxy. 
     
     
         6 . The composition according to  claim 2 , wherein R 2  is C 1  to C 6  alkyl or of the structure: 
       
         
           
           
               
               
           
         
         wherein, R 8  to R 12  are, independently, selected from the group consisting of H, optionally substituted alkyl, halogen, and optionally substituted alkoxy. 
       
     
     
         7 . The composition according to  claim 6 , wherein R 8 , R 9 , R 11 , and R 12  are H and R 10  is alkoxy. 
     
     
         8 . The composition according to  claim 1 , wherein said compound of formula (I) is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The composition according to  claim 1 , wherein said compound which inhibits binding of HPV E6 to p53 is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The composition according to  claim 1 , further comprising a chemotherapeutic. 
     
     
         11 . A method for preventing disruption of pRb/E2F complexes, said method comprising administering a compound of formula (I) or a composition of  claim 1  to a patient in need thereof, wherein said compound of formula (I) is of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycle; 
 R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; 
 
         or a pharmaceutically acceptable salt, prodrug, solvate, or metabolite thereof. 
       
     
     
         12 . A method for preventing interaction between pRb and a viral oncoprotein, said method comprising administering a compound of formula (I) or a composition of  claim 1  to a patient in need thereof, wherein said compound of formula (I) is of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycle; 
 R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; 
 
         or a pharmaceutically acceptable salt, prodrug, solvate, or metabolite thereof. 
       
     
     
         13 . A method for preventing or a disease caused by a virus carrying a viral oncoprotein containing a LxCxE motif, said method comprising administering a compound of formula (I) or a composition of  claim 1  to a patient in need thereof, wherein said compound of formula (I) is of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycle; 
 R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; 
 
         or a pharmaceutically acceptable salt, prodrug, solvate, or metabolite thereof. 
       
     
     
         14 . The method according to  claim 13 , wherein said viral oncoprotein is E1a from adenovirus, E7 from HPV, or T-antigen from simian virus 40. 
     
     
         15 . A method for preventing or treating neoplastic disease, said method comprising administering a compound of formula (I) or a composition of  claim 1  to a patient in need thereof, wherein said compound of formula (I) is of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycle; 
 R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; 
 
         or a pharmaceutically acceptable salt, prodrug, solvate, or metabolite thereof. 
       
     
     
         16 . The method according to  claim 15 , wherein said patient is infected with HPV or said neoplastic disease is caused by HPV infection. 
     
     
         17 . A method for preventing HPV-E7 mediated E2F displacement from pRb or disrupting pRb/HPV-E7 complexes, said method comprising administering a compound of formula (I) or a composition of  claim 1  to a patient in need thereof, wherein said compound of formula (I) is of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycle; 
 R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; 
 
         or a pharmaceutically acceptable salt, prodrug, solvate, or metabolite thereof. 
       
     
     
         18 . A method for preventing or treating genital warts or neoplastic disease caused by human papilloma virus, adenovirus, or SV40, said method comprising administering a compound of formula (I) or a composition of  claim 1  to a patient in need thereof, wherein said compound of formula (I) is of the structure: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycle; 
 R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; 
 
         or a pharmaceutically acceptable salt, prodrug, solvate, or metabolite thereof. 
       
     
     
         19 . The method according to  claim 18 , further comprising administering a chemotherapeutic. 
     
     
         20 . The method according to  claim 18 , further comprising treating said patient with radiation.