Salvinorin derivatives and uses thereof

Abstract

The invention features salvinorin compositions that are selective for kappa opioid receptors; methods of treating mania by using a selective kappa receptor agonist; and methods of treating mood disorders, such as depressive disorders and manic disorders, using salvinorin compositions.

1 . A compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein 
 A is selected from  
                     
 each of the bonds between C 1  and C 6 , C 2  and C 3 , and C 3  and C 4  is, independently, selected from a single bond or a double bond, provided that no carbon atom is part of more than one double bond;  
 X 1  is selected from H, O, S, O—R 1 , O-acyl, OC(O)Z 1 , S—R 1 , S-acyl, SC(O)Z 1 , NR 14 R 15 , NH-acyl, NHC(O)NH-acyl, and NHC(O)Z 1 ;  
 X 2  is selected from O—R 2 , O-acyl, OC(O)Z 2 , S—R 2 , S-acyl, SC(O)Z 2 , NR 16 R 17 , NH-acyl, NHC(O)NH-acyl, and NHC(O)Z 2 ;  
 X 3  is selected from CH 2 O—R 3 , CH 2 O-acyl, CH 2 S—R 3 , CH 2 S-acyl, CH 2 NH-acyl, CH 2 NHC(O)NH-acyl, CH 2 NHC(O)Z 5 , CH 2 NR 29 R 30 , NH-acyl, NHC(O)NH-acyl, NR 31 R 32 , NHC(O)Z 5 , and C(O)—Y 1 ;  
 X 4  is selected from C(O)—OR 4 , CH 2 X 8  and C(O)—NR 5 R 6 ;  
 X 5  is selected from H, O—R 7 , O-acyl, NH-acyl, NHC(O)NH-acyl, and NR 8 R 9 , or X 4  and X 5  together are described by formula IIa or IIb to complete a six-membered ring  
                     
 X 6  is selected from O, S, and NR 10 ;  
 X 7  is selected from O—R 18 , O-acyl, OC(O)Z 3 , S—R 18 , S-acyl, SC(O)Z 3 , NR 19 R 20 , NH-acyl, NHC(O)NH-acyl, and NHC(O)Z 3 ;  
 X 8  is selected from O—R 21 , O-acyl, OC(O)Z 4 , S—R 21 , S-acyl, SC(O)Z 4 , NR 22 R 23 , NH-acyl, NHC(O)NH-acyl, and NHC(O)Z 4 ;  
 Y 1  is selected from CH 3 , OR 11 , SR 11 , and NR 12 R 13 ;  
 Z 1  is OR 1 , SR 1 , or NR 14 R 15 ;  
 Z 2  is OR 2 , SR 2 , or NR 16 R 17 ;  
 Z 3  is OR 18 , SR 18 , or NR 19 R 20 ;  
 Z 4  is OR 21 , SR 21 , or NR 22 R 23 ;  
 Z 5  is OR 24 , SR 24 , or NR 25 R 26 ; and  
 each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 29 , R 30 , R 31 , and R 32  is, independently, selected from H, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 2-7  heterocyclyl, C 6-12  aryl, C 7-14  alkaryl, C 3-10  alkheterocyclyl, and C 1-8  heteroalkyl, or one or more of R 5  and R 6 , R 8  and R 9 , R 12  and R 13 , R 14  and R 15 , R 16  and R 17 , R 19  and R 20 , R 22  and R 23 , R 25  and R 26 , R 29  and R 30 , and R 31  and R 32  combine to form a heterocyclic ring containing a nitrogen atom; with the proviso that the compound of formula I is not salvinorin A, B, C, D, E, or F; a C 2  ester of salvinorin A; a tetrahydrofuranylethyl salvinorin; a salvinorin benzoate; or a C, reduced salvinorin.  
 
   
   
       2 . The compound of  claim 1 , wherein said compound is further described by formulas IVa or IVb:  
     
       
         
         
             
             
         
       
     
     wherein 
 A, X 2 , X 6 , and Y 1  are as defined in  claim 1 .  
 
   
   
       3 . The compound of  claim 1 , wherein said compound is further described by formulas VIa or VIb:  
     
       
         
         
             
             
         
       
     
     wherein 
 W 3  is selected from O—R 3 , O-acyl, S—R 3 , S-acyl, NH-acyl, NHC(O)NH-acyl, NHC(O)Z 5 , and NR 29 R 30 ; and A, X 2 , and X 6  are as are as defined in  claim 1 .  
 
   
   
       4 . The compound of  claim 1 , wherein said compound is further described by formulas VIIc or VIId:  
     
       
         
         
             
             
         
       
     
     wherein 
 J 3  is selected from NH-acyl, NHC(O)NH-acyl, NR 31 R 32 , NHC(O)Z 5 ; and A, X 2 , X 6 , Z 5 , R 31 , and R 32  are as defined in  claim 1 .  
 
   
   
       5 . The compound of  claim 1 , wherein said compound is further described by formulas IXa or IXb:  
     
       
         
         
             
             
         
       
     
     wherein 
 A, X 2 , X 6 , and Y 1  are as defined in  claim 1 .  
 
   
   
       6 . The compound of  claim 1 , wherein said compound is further described by formulas XIa or XIb:  
     
       
         
         
             
             
         
       
     
     wherein 
 W 3  is selected from O—R 3 , O-acyl, S—R 3 , S-acyl, NH-acyl, NHC(O)NH-acyl, NHC(O)Z 5 , and NR 29 R 30 ; and A, X 2 , X 6 , Z 5 , R 3 , R 29 , and R 30  are as defined in  claim 1 .  
 
   
   
       7 . The compound of  claim 1 , wherein said compound is further described by formulas XXIIIa or XXIIIb:  
     
       
         
         
             
             
         
       
     
     wherein 
 J 3  is selected from NH-acyl, NHC(O)NH-acyl, NR 31 R 32 , NHC(O)Z 5 ; and A, X 2 , X 6 , Z 5 , R 31 , and R 32  are as defined in  claim 1 .  
 
   
   
       8 . The compound of  claim 1 , wherein said compound is further described by formula XX:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 2 , X 3 , X 6 , and A are as defined in  claim 1 .  
 
   
   
       9 . The compound of  claim 8 , wherein said compound is further described by formula XXIa:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 2  and X 3  are as defined in  claim 1 .  
 
   
   
       10 . The compound of  claim 8 , wherein said compound is further described by formula XXIb:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 2  and X 3  are as defined in  claim 1 .  
 
   
   
       11 . The compound of  claim 8 , wherein said compound is further described by formula XXIc:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 2  and X 3  are as defined in  claim 1 .  
 
   
   
       12 . The compound of  claim 8 , wherein said compound is further described by formula XXId:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 2  and X 3  are as defined in  claim 1 .  
 
   
   
       13 . The compound of claims  9 - 12 , wherein X 2  is selected from NR 16 R 17 , NH-acyl, NHC(O)NH-acyl, and NHC(O)Z 2 ; X 3  is selected from CH 2 O—R 3 , CH 2 O-acyl, CH 2 S—R 3 , CH 2 S-acyl, CH 2 NH-acyl, CH 2 NHC(O)NH-acyl, CH 2 NHC(O)Z 5 , CH 2 NR 29 R 30 , NH-acyl, NHC(O)NH-acyl, NR 31 R 32 , and NHC(O)Z 5 ; and R 3 , R 16 , R 17 , R 29 , R 30 , R 31 , R 32 , Z 2 , and Z 5  are as defined in  claim 1 .  
   
   
       14 . A compound of formula XIX:  
     
       
         
         
             
             
         
       
     
     wherein 
 said compound is substantially pure;  
 each of the bonds between C 1  and C 6 , C 2  and C 3 , and C 3  and C 4  is, independently, selected from a single bond or a double bond, provided that no carbon atom is part of more than one double bond;  
 X 1  is selected from H, O, S, O—R 1 , O-acyl, OC(O)Z 1 , S—R 1 , S-acyl, SC(O)Z 1 , NR 14 R 15 , NH-acyl, NHC(O)NH-acyl, and NHC(O)Z 1 ;  
 X 2  is selected from H, O, S, O—R 2 , O-acyl, OC(O)Z 2 , S—R 2 , S-acyl, SC(O)Z 2 , NR 16 R 17 , NH-acyl, NHC(O)NH-acyl, and NHC(O)Z 2 ;  
 X 3  is selected from CH 2 O—R 3 , CH 2 O-acyl, CH 2 NH-acyl, CH 2 NHC(O)NH-acyl, and C(O)—Y 1 ;  
 X 6  is selected from O, S, and NR 10 ;  
 X 7  is selected from 0, O—R 18 , O-acyl, OC(O)Z 3 , S—R 18 , S-acyl, SC(O)Z 3 , NR 19 R 20 , NH-acyl, NHC(O)NH-acyl, and NHC(O)Z 3 ;  
 Y 1  is selected from CH 3 , OR 11 , and NR 12 R 13 ;  
 Z 1  is OR 1 , SR 1 , or NR 14 R 15 ;  
 Z 2  is OR 2 , SR 2 , or NR 16 R 17 ;  
 Z 3  is OR 18 , SR 18 , or NR 19 R 20 ; and  
 each of R 1 , R 2 , R 3 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20  is, independently, selected from H, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 2-7  heterocyclyl, C 6-12  aryl, C 7-14  alkaryl, C 3-10  alkheterocyclyl, and C 1-8  heteroalkyl, or one or more of R 12  and R 13 , R 14  and R 15 , R 16  and R 17 , and R 19  and R 20 , combine to form a heterocyclic ring containing a nitrogen atom; with the proviso that the compound of formula XIX is not 1,2-dihyroxy-episalvinorin.  
 
   
   
       15 . The compound of  claim 14 , wherein said compound is further described by formula XIXa:  
     
       
         
         
             
             
         
       
     
     wherein 
 X 2  and X 3  are as defined are as defined in  claim 14 .  
 
   
   
       16 . The compound of  claim 14 , wherein said compound is selected from episalvinorin A, episalvinorin B, episalvinorin C, episalvinorin D, episalvinorin E, episalvinorin F, 1-hydroxy-2-acetyl-episalvinorin, 1-acetyl-2-hydroxy-episalvinorin, 1,2-diacetyl-episalvinorin, and 2-methoxymethyl-episalvinorin B.  
   
   
       17 . The compound of claims  1  or  14 , wherein said compound is a selective kappa receptor partial agonist.  
   
   
       18 . A method of treating a mood disorder in a mammal, said method comprising administering to said mammal an effective amount of a kappa receptor antagonist of  claim 1 , salvinorin C, D, E, or F, a C 2  ester of salvinorin A, a tetrahydrofuranylethyl salvinorin, a salvinorin benzoate, or a C 1  reduced salvinorin.  
   
   
       19 . The method of  claim 18 , wherein said mood disorder is a depressive disorder.  
   
   
       20 . The method of  claim 19 , wherein said depressive disorder is associated with major depression, bipolar disorder, dysthymia, drug withdrawal, or post-traumatic stress disorder.  
   
   
       21 . The method of  claim 18 , wherein said mood disorder is a schizoaffective disorder, schizophrenia, anxiety disorder, panic disorder, post traumatic stress disorder, phobic disorder, borderline personality disorder, schizoid disorder, or schizotypal disorder.  
   
   
       22 . A method of treating mania in a mammal in need thereof, said method comprising administering to said mammal an effective amount of a selective kappa receptor agonist.  
   
   
       23 . The method of  claim 22 , wherein said selective kappa receptor agonist is a compound of  claim 1 , salvinorin A, salvinorin B, a C 2  ester of salvinorin A, a salvinorin benzoate, or a C 1  reduced salvinorin.  
   
   
       24 . The method of  claim 23 , wherein said selective kappa receptor agonist is 2-propionyl-salvinorin B, 2-butanoyl-salvinorin B, 2-methoxy-salvinorin B, episalvinorin B, 2-methoxymethyl-episalvinorin B, episalvinorin A, 2-methoxymethyl-salvinorin B, 2-(O-formamide)-salvinorin B, 2-n-butoxy-salvinorin B, 2-allyloxy-salvinorin B, 2-ethoxy-salvinorin B, 2-propoxy-salvinorin B, 2-benzyloxy-salvinorin B, 2-(N-ethylamino)-salvinorin, or 2-(N,N-dimethylamino)-salvinorin.  
   
   
       25 . A method for treating bipolar disorder in a mammal in need thereof, said method comprising administering to said mammal an effective amount of a selective kappa receptor partial agonist.  
   
   
       26 . A method for stabilizing the mood of a mammal diagnosed with a mood disorder, said method comprising administering to said mammal an effective amount of a selective kappa receptor partial agonist.  
   
   
       27 . The method of claims  25  or  26 , wherein said selective kappa receptor partial agonist is a compound of  claim 1 , salvinorin C, D, E, or F, a C 2  ester of salvinorin A, a tetrahydrofuranylethyl salvinorin, a salvinorin benzoate, or a C 1  reduced salvinorin.  
   
   
       28 . The method of  claim 27 , wherein said selective kappa receptor partial agonist is 2-(O—(N-methyl)formamide)-salvinorin B.