Diphenylethylene compounds and uses thereof

Abstract

The present invention relates to Diphenylethylene Compounds and compositions comprising a Diphenylethylene Compound. The present invention also relates to methods for preventing or treating various diseases and disorders by administering to a subject in need thereof one or more Diphenylethylene Compounds. In particular, the invention relates to methods for preventing or treating cancer or an inflammatory disorder by administering to a subject in need thereof one or more Diphenylethylene Compounds. The present invention further relates to articles of manufacture and kits comprising one or more Diphenylethylene Compounds.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate or hydrate thereof, 
 wherein: 
 R 1  and R 2  are independently —H, —CN, —COOH, —C(O)-lower alkyl, —C(O)O-lower alkyl, —C(O)—N(R 9 ) 2 , substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle;  
 each occurrence of R a , R b , R c  and R d  is independently —H, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 ;  
 R 3  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 , or R 3  with either R a  or with R 4 , together form —O—C(R 16 R 17 )—O—;  
 R 4  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 ;  
 R 5  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —-N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 ;  
 R 6  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 ;  
 R 7  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 ;  
 R 8  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 , or R 8  with either R c  or with R 7 , together form —O—C(R 16 R 17 )—O—;  
 each occurrence of R 9  is independently —H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted cycloalkyl;  
 each occurrence of R 10  is independently substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted lower hydroxyalkyl, or R 10  and a nitrogen to which it is attached form a substituted or unsubstituted heterocycle, or R 10  is —H where appropriate;  
 each occurrence of R 16  and R 17  is independently —H or halogen; and  
 with the proviso that if one of R 3  or R 5  is H, then the other is not substituted or unsubstituted lower alkyl or substituted or unsubstituted alkoxy and if one of R 6  or R 8  is H, then the other is not substituted or unsubstituted lower alkyl or substituted or unsubstituted alkoxy.  
 
 
     
     
         2 . A compound of  claim 1 , wherein R 3  and R 5  are alkoxy.  
     
     
         3 . A compound of  claim 2 , wherein R 3  and R 5  are methoxy.  
     
     
         4 . A compound of  claim 2 , wherein R 7  is alkoxy.  
     
     
         5 . A compound of  claim 2 , wherein R 3 , R 5  and R 7  are methoxy.  
     
     
         6 . A compound of  claim 1 , wherein R 1  is —H and R 2  is —CN.  
     
     
         7 . A compound of  claim 1 , wherein R 1  is —CN and R 2  is —H.  
     
     
         8 . A compound of  claim 1 , wherein R 8  is —NH 2 .  
     
     
         9 . A compound of  claim 1 , wherein the compound is the E isomer.  
     
     
         10 . A compound of  claim 1 , wherein the compound is the Z isomer.  
     
     
         11 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate or hydrate thereof, 
 wherein: 
 R 1  and R 2  are independently —CN, —COOH, —C(O)-lower alkyl, —C(O)O-lower alkyl, —C(O)—N(R 9 ) 2 , substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle;  
 each occurrence of R a , R b , R c  and R d  is independently —H, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 ;  
 R 3  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 , or R 3  with either R a  or with R 4 , together form —O—C(R 16 R 17 )—O—;  
 R 4  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 ;  
 R 5  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 ;  
 R 6  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 ;  
 R 7  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 ;  
 R 8  is —H, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, halogen, cyano, —NO 2 , —OH, —OPO(OH) 2 , —N(R 9 ) 2 , —OC(O)—R 10 , —OC(O)—R 10 —N(R 10 ) 2 , —C(O)N(R 10 ) 2 , —NHC(O)—R 10 , —NHS(O) 2 —R 10 , —S(O) 2 —R 10 , —NHC(O)NH—R 10 , —NHC(O)N(R 10 ) 2 , —NHC(O)NHSO 2 —R 10 , —NHC(O)—R 10 —N(R 10 ) 2 , —NHC(O)CH(R 10 )(N(R 9 ) 2 ) or —NHC(O)—R 10 —NH 2 , or R 8  with either R c  or with R 7 , together form —O—C(R 16 R 17 )—O—;  
 each occurrence of R 9  is independently —H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted cycloalkyl;  
 each occurrence of R 10  is independently substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted lower hydroxyalkyl, or R 10  and a nitrogen to which it is attached form a substituted or unsubstituted heterocycle, or R 10  is —H where appropriate; and  
 each occurrence of R 16  and R 17  is independently —H or halogen.  
 
 
     
     
         12 . A compound or a pharmaceutically acceptable salt, hydrate or solvate thereof having the structure:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein said composition is suitable for parenteral, transdermal, mucosal, nasal, buccal, rectal, sublingual, or oral administration to a subject.  
     
     
         15 . A method for inhibiting cancer cell proliferation comprising contacting a cancer cell with an effective amount of the compound of  claim 1 .  
     
     
         16 . The method of  claim 15 , wherein the cancer cell is of the head, neck, eye, mouth, throat, esophagus, chest, bone, lung, colon, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas or brain.