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 method of treating a mood disorder in a mammal, said method comprising administering to said mammal an effective amount of a kappa receptor antagonist selected from salvinorin C, D, E, or F, a C2 ester of salvinorin A, a tetrahydrofuranylethyl salvinorin, a salvinorin benzoate, a C1 reduced salvinorin, and a compound of any of formulas XXIa-XXId: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein 
         X 2  is selected from 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 C(O)—Y 1 ; 
         Z 2  is OR 2 , SR 2 , or NR 16 R 17 ; 
         Y 1  is selected from CH 3 , OR 11 , SR 11 , and NR 12 R 13 ; and 
         each of R 2 , R 11 , R 12 , R 13 , R 16 , and R 17  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 , and R 16  and R 17  combine to form a heterocyclic ring containing a nitrogen atom. 
       
     
     
         2 . The method of  claim 1 , wherein said mood disorder is a depressive disorder. 
     
     
         3 . The method of  claim 2 , wherein said depressive disorder is associated with major depression, bipolar disorder, dysthymia, drug withdrawal, or post-traumatic stress disorder. 
     
     
         4 . The method of  claim 1 , 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. 
     
     
         5 . 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. 
     
     
         6 . The method of  claim 5 , wherein said selective kappa receptor agonist is selected from salvinorin A, salvinorin B, a C2 ester of salvinorin A, a salvinorin benzoate, a C1 reduced salvinorin, and a compound of any of formulas XXIa-XXId: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein 
         X 2  is selected from 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 C(O)—Y 1 ; 
         Z 2  is OR 2 , SR 2 , or NR 16 R 17 ; 
         Y 1  is selected from CH 3 , OR 11 , SR 11 , and NR 12 R 13 ; and 
         each of R 2 , R 11 , R 12 , R 13 , R 16 , and R 17  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 , and R 16  and R 17  combine to form a heterocyclic ring containing a nitrogen atom. 
       
     
     
         7 . The method of  claim 6 , 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. 
     
     
         8 . 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. 
     
     
         9 . 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. 
     
     
         10 . The method of  claim 8 , wherein said selective kappa receptor partial agonist is selected from salvinorin C, D, E, or F, a C2 ester of salvinorin A, a tetrahydrofuranylethyl salvinorin, a salvinorin benzoate, a C1 reduced salvinorin, and a compound of any of formulas XXIa-XXId: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein 
         X 2  is selected from 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 C(O)—Y 1 ; 
         Z 2  is OR 2 , SR 2 , or NR 16 R 17 ; 
         Y 1  is selected from CH 3 , OR 11 , SR 11 , and NR 12 R 13 ; and 
         each of R 2 , R 11 , R 12 , R 13 , R 16 , and R 17  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 , and R 16  and R 17  combine to form a heterocyclic ring containing a nitrogen atom. 
       
     
     
         11 . The method of  claim 9 , wherein said selective kappa receptor partial agonist is selected from salvinorin C, D, E, or F, a C2 ester of salvinorin A, a tetrahydrofuranylethyl salvinorin, a salvinorin benzoate, a C1 reduced salvinorin, and a compound of any of formulas XXIa-XXId: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein 
         X 2  is selected from 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 C(O)—Y 1 ; 
         Z 2  is OR 2 , SR 2 , or NR 16 R 17 ; 
         Y 1  is selected from CH 3 , OR 11 , SR 11 , and NR 12 R 13 ; and 
         each of R 2 , R 11 , R 12 , R 13 , R 16 , and R 17  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 , and R 16  and R 17  combine to form a heterocyclic ring containing a nitrogen atom. 
       
     
     
         12 . The method of  claim 10 , wherein said selective kappa receptor partial agonist is 2-(O—(N-methyl)formamide)-salvinorin B. 
     
     
         13 . The method of  claim 11 , wherein said selective kappa receptor partial agonist is 2-(O—(N-methyl)formamide)-salvinorin B. 
     
     
         14 . The method of  claim 1 , wherein said kappa receptor antagonist is a compound described by the formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein 
         X 2  is selected from NR 16 R 17 , NH-acyl, NHC(O)NH-acyl, and NHC(O)Z 2 ; 
         Z 2  is OR 2 , SR 2 , or NR 16 R 17 ; 
         each of R 2 , R 16 , and R 17  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 , and R 16  and R 17  combine to form a heterocyclic ring containing a nitrogen atom. 
       
     
     
         15 . The method of  claim 5 , wherein said selective kappa receptor agonist is a compound described by the formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein 
         X 2  is selected from NR 16 R 17 , NH-acyl, NHC(O)NH-acyl, and NHC(O)Z 2 ; 
         Z 2  is OR 2 , SR 2 , or NR 16 R 17 ; 
         each of R 2 , R 16 , and R 17  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 , and R 16  and R 17  combine to form a heterocyclic ring containing a nitrogen atom. 
       
     
     
         16 . The method of  claim 8 , wherein said selective kappa receptor partial agonist is a compound described by the formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein 
         X 2  is selected from NR 16 R 17 , NHC(O)NH-acyl, and NHC(O)Z 2 ; 
         Z 2  is OR 2 , SR 2 , or NR 16 R 17 ; 
         each of R 2 , R 16 , and R 17  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 , and R 16  and R 17  combine to form a heterocyclic ring containing a nitrogen atom. 
       
     
     
         17 . The method of  claim 9 , wherein said selective kappa receptor partial agonist is a compound described by the formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein 
         X 2  is selected from NR 16 R 17 , NH-acyl, NHC(O)NH-acyl, and NHC(O)Z 2 ; 
         Z 2  is OR 2 , SR 2 , or NR 16 R 17 ; 
         each of R 2 , R 16 , and R 17  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 , and R 16  and R 17  combine to form a heterocyclic ring containing a nitrogen atom. 
       
     
     
         18 . 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 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  and X 5  together are described by formula IIa or IIb to complete a six-membered ring 
       
       
         
           
           
               
               
           
         
         X 6  is 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  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 N , 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.