Unsaturated Steroid Compounds

Abstract

The instant invention provides potent antiandrogen compounds, such as 3β-acetoxyandrost-1,5-diene-17-ethylene ketal and 3β-hydroxyandrost-1,5-diene-17-ethylene ketal, and methods for their use in the prevention and treatment of biological conditions mediated by androgen receptors. Thus, for example, compounds of the invention are useful in the prevention and treatment of prostrate cancer. Furthermore, it has been discovered that compounds of the invention are useful in the prevention and treatment of androgen-independent cancers such as androgen-independent prostrate cancer. Finally, inventive compounds may be used to treat antiandrogen induced withdrawal syndrome.

1 . A compound having the structure, 
       
         
           
           
               
               
           
         
         wherein K is —C(O)—, ═CR 1 —, or —CR 1 R 2 —, or 
       
       
         
           
           
               
               
           
         
         wherein K is ═CR 1 —, or 
       
       
         
           
           
               
               
           
         
         wherein K is ═CR 1 —, 
         or a pharmaceutically acceptable salt of the compound, and wherein, 
         A is ═CR 9 —; 
         E is ═CR 5 —; 
         G is —C(O)—, ═CR 3 —, or —CR 3 R 4 —; 
         R 1  is selected from the group consisting of —OR 11 , substituted and unsubstituted alkyl, substituted and unsubstituted alkene, substituted and unsubstituted alkyne, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted heterocyclylalkyl, —C(O)—R 12 , —C(O)—NR 12 R 13 , —C(O)—OR 12 , —C(S)—R 12 , —C(S)—OR 12 , —NR 12 R 13 , —NR 12 —C(O)—R 13 , —NR 12 —C(O)—OR 13 , —NR 12 —C(O)—NR 12 R 13 , and —S(O) 0-2 —R 12 ; 
         R 2  is selected from the group consisting of —H, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, and substituted and unsubstituted lower alkyne; 
         R 3  and R 5  are independently selected from the group consisting of —H, —F, —Cl, —Br, —I, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —CN, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH, substituted and unsubstituted lower alkoxy, and —S(O) 0-2 R 14 ; 
         R 4  is selected from the group consisting of —H, —F, —Cl, —Br, —I, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —CN, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH, substituted and unsubstituted lower alkoxy, and —S(O) 0-2 R 14 ; 
         R 7  and R 8  are independently selected from the group consisting of —H and substituted and unsubstituted lower alkyl group; 
         R 9  is selected from the group consisting of substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —OH, wherein R 9  and R 10  are not both —OH, substituted and unsubstituted lower alkoxy, and substituted and unsubstituted —S(O) 0-2  (lower alkyl), or R 9  and R 10 , together with the carbon to which they are attached, form a 5-, 6-, or 7-member heterocyclyl or cycloalkyl group; 
         R 11  is selected from the group consisting of —H, substituted and unsubstituted alkyl, substituted and unsubstituted alkene, substituted and unsubstituted alkyne, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted heterocyclylalkyl, —C(O)—R 12 , —C(O)—NR 12 R 13 , —C(O)—OR 12 , —C(S)—R 12 , —NR 12 R 13 , —S(O) 2 —R 12 , —S(O) 2 —OR 12 , and —P(O)(OR 12 )(OR 13 ) 0-1 ; 
         R 12  and R 13  are, at each occurrence, independently selected from the group consisting of —H, substituted and unsubstituted alkyl, substituted and unsubstituted alkene, substituted and unsubstituted alkyne, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heterocyclylalkyl; 
         R 14  and R 15  are, at each occurrence, independently selected from the group consisting of —H, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, substituted and unsubstituted C 6-10  aryl, and substituted and unsubstituted C 7-12  arylalkyl; 
         R and R′ are, at each occurrence, independently selected from the group consisting of —F, —Cl, —Br, —I, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —CN, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH, substituted and unsubstituted lower alkoxy, and —S(O) 0-2 R 14 ; and 
         n and n′ are independently 0, 1, or 2. 
       
     
     
         2 . The compound of  claim 1  having the structure 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2  wherein K is —C(OR 11 )R 2 —. 
     
     
         4 . The compound of  claim 2  having the structure 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1  having the structure 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 5  having the structure 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1  having the structure 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 7  having the structure 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound having the structure 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of the compound, wherein, 
         A is —C(O)—, ═CR 9 —, or —CR 9 R 10 —; 
         E is ═CR S —; 
         G is —C(O)—, ═CR 3 —, or —CR 3 R 4 —; 
         K is —C(O)—, ═CR 1 —, or —CR 1 R 2 —; 
         R 1  is selected from the group consisting of —OR 11 , substituted and unsubstituted alkyl, substituted and unsubstituted alkene, substituted and unsubstituted alkyne, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted heterocyclylalkyl, —C(O)—R 12 , —C(O)—NR 12 R 13 , —C(O)—OR 12 , —C(S)—R 12 , —C(S)—OR 12 , —NR 12 R 13 , —NR 12 —C(O)—R 13 , —NR 12 —C(O)—OR 13 , —NR 12 —C(O)—NR 12 R 13 , and —S(O) 0-2 —R 12 ; 
         R 2  is selected from the group consisting of —H, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, and substituted and unsubstituted lower alkyne; 
         R 3  and R 5  are independently selected from the group consisting of —H, —F, —Cl, —Br, —I, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —CN, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH, substituted and unsubstituted lower alkoxy, and —S(O) 0-2 R 14 ; 
         R 4  is selected from the group consisting of —H, —F, —Cl, —Br, —I, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —CN, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH, substituted and unsubstituted lower alkoxy, and —S(O) 0-2 R 14 ; 
         R 7  and R 8  are independently selected from the group consisting of —H and substituted and unsubstituted lower alkyl group; 
         R 9  and R 15  are independently selected from the group consisting of substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —OH, wherein R 9  and R 15  are not both —OH, substituted and unsubstituted lower alkoxy, and substituted and unsubstituted —S(O) 0-2  (lower alkyl), or R 9  and R 10 , together with the carbon to which they are attached, form a 5-, 6-, or 7-member heterocyclyl or cycloalkyl group; 
         R 11  is selected from the group consisting of —H, substituted and unsubstituted alkyl, substituted and unsubstituted alkene, substituted and unsubstituted alkyne, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted heterocyclylalkyl, —C(O)—R 12 , C(O)—NR 12 R 13 , —C(O)—OR 12 , —C(S)—R 12 , —NR 12 R 13 , —S(O) 2 —R 12 , —S(O) 2 —OR 12 , and —P(O)(OR 12 )(OR 13 ) 0-1 ; 
         R 12  and R 13  are, at each occurrence, independently selected from the group consisting of —H, substituted and unsubstituted alkyl, substituted and unsubstituted alkene, substituted and unsubstituted alkyne, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heterocyclylalkyl; 
         R 14  and R 15  are, at each occurrence, independently selected from the group consisting of —H, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, substituted and unsubstituted C 6-10  aryl, and substituted and unsubstituted C 7-12  arylalkyl; 
         R and R′ are, at each occurrence, independently selected from the group consisting of —F, —Cl, —Br, —I, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —CN, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH, substituted and unsubstituted lower alkoxy, and —S(O) 0-2 R 14 ; and 
         n and n′ are independently 0, 1, or 2. 
       
     
     
         10 . The compound of  claim 9  wherein A is —CR 9 R 10 —. 
     
     
         11 . The compound of  claim 9  wherein G is —CR 3 R 4 —. 
     
     
         12 . The compound of  claim 9  wherein K is —C(OR 11 )R 2 —. 
     
     
         13 . The compound of  claim 9  having the structure 
       
         
           
           
               
               
           
         
         wherein R is —H, alkyl or fluoroalkyl. 
       
     
     
         14 . The compound of  claim 13  wherein R is —H. 
     
     
         15 . The compound of  claim 9  having the structure 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 9  having the structure 
       
         
           
           
               
               
           
         
         wherein R is —H, alkyl or fluoroalkyl. 
       
     
     
         14 . The compound of  claim 13  wherein R is —H. 
     
     
         15 . The compound of  claim 9  having the structure 
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound having the structure 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of the compound, wherein the dotted line at the 15-position is an optional; double bond; 
         A is —C(O)—, ═CR 9 —, or —CR 9 R 10 —; 
         E is —C(O)— or —CR 5 R 6 — or, if a double bond is present at the 15-position, E is ═CR 5 —, wherein A and E are not both —C(O)—; 
         G is ═CR 3 —; 
         K is —C(O)—, ═CR 1 —, or —CR 1 R 2 —; 
         R 1  is selected from the group consisting of —OR 11 , substituted and unsubstituted alkyl, substituted and unsubstituted alkene, substituted and unsubstituted alkyne, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted heterocyclylalkyl, —C(O)—R 12 , —C(O)—NR 12 R 13 , —C(O)—OR 12 , —C(S)—R 12 , —C(S)—OR 12 , —NR 12 R 13 , —NR 12 —C(O)—R 13 , —NR 12 —C(O)—OR 13 , —NR 12 —C(O)—NR 12 R 13 , and —S(O) 0-2 —R 12 ; 
         R 2  is selected from the group consisting of —H, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, and substituted and unsubstituted lower alkyne; 
         R 3  and R 5  are independently selected from the group consisting of —H, —F, —Cl, —Br, —I, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —CN, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH, substituted and unsubstituted lower alkoxy, and —S(O) 0-2 R 14 ; 
         R 6  is selected from the group consisting of —H, —F, —Cl, —Br, —I, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —CN, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH, substituted and unsubstituted lower alkoxy, and —S(O) 0-2 R 14 ; 
         R 7  and R 8  are independently selected from the group consisting of —H and substituted and unsubstituted lower alkyl group; 
         R 9  and R 10  are independently selected from the group consisting of substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —OH, wherein R 9  and R 10  are not both —OH, substituted and unsubstituted lower alkoxy, and substituted and unsubstituted —S(O) 0-2  (lower alkyl), or R 9  and R 10 , together with the carbon to which they are attached, form a 5-, 6-, or 7-member heterocyclyl or cycloalkyl group; 
         R 11  is selected from the group consisting of —H, substituted and unsubstituted alkyl, substituted and unsubstituted alkene, substituted and unsubstituted alkyne, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted heterocyclylalkyl, —C(O)—R 12 , —C(O)—NR 12 R 13 , —C(O)—OR 12 , —C(S)—R 12 , —NR 12 R 13 , —S(O) 2 —R 12 , —S(O) 2 —OR 12 , and —P(O)(OR 12 )(OR 13 ) 0-1 ; 
         R 12  and R 13  are, at each occurrence, independently selected from the group consisting of —H, substituted and unsubstituted alkyl, substituted and unsubstituted alkene, substituted and unsubstituted alkyne, substituted and unsubstituted aryl, substituted and unsubstituted arylalkyl, substituted and unsubstituted heterocyclyl, and substituted and unsubstituted heterocyclylalkyl; 
         R 14  and R 15  are, at each occurrence, independently selected from the group consisting of —H, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, substituted and unsubstituted C 6-10  aryl, and substituted and unsubstituted C 7-12  arylalkyl; 
         R and R′ are, at each occurrence, independently selected from the group consisting of —F, —Cl, —Br, —I, substituted and unsubstituted lower alkyl, substituted and unsubstituted lower alkene, substituted and unsubstituted lower alkyne, —CN, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH, substituted and unsubstituted lower alkoxy, and —S(O) 0-2 R 14 ; and 
         n and n′ are independently 0, 1, or 2. 
       
     
     
         17 . The compound of  claim 16  having the structure 
       
         
           
           
               
               
           
         
         wherein, X and Y are independently selected from the group consisting of —NR 14 —, —O—, —S—, and substituted and unsubstituted C 1  alkyl, Z is substituted or unsubstituted C 2-4  alkyl or substituted or unsubstituted —(CR 14 R 15 ) 2-3 — and R 2  is —H or substituted or unsubstituted C 1-4  alkyl. 
       
     
     
         18 . The compound of  claim 16  wherein R 11  is selected from the group consisting of —H, substituted and unsubstituted alkyl, —C(O)—R 12 , —C(O)—NR 12 R 13 , and —C(O)—OR 12 . 
     
     
         19 . The compound of  claim 16  having the structure 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 16  having the structure 
       
         
           
           
               
               
           
         
         wherein R is —H, alkyl or fluoroalkyl. 
       
     
     
         21 . The compound of  claim 16  having the structure 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 16  having the structure 
       
         
           
           
               
               
           
         
         wherein R is —H, alkyl or fluoroalkyl.