Salvinorin derivatives and uses thereof
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 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 ;
A is selected from
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 6 is O;
Z 2 is OR 2 , SR 2 , or NR 16 R 17 ;
Z 5 is OR 24 , SR 24 , or NR 25 R 26 ; and
each of R 2 , R 3 , R 16 , R 17 , R 24 , R 25 , R 26 , R 29 , and R 30 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 16 and R 17 , R 25 and R 26, and R 29 and R 30 combine to form a heterocyclic ring containing a nitrogen atom and wherein said compound is a selective kappa receptor antagonist, a selective kappa receptor partial agonist, or a selective kappa receptor agonist.
2. The compound of formulas VIIc or VIId:
wherein
J 3 is selected from NH-acyl, NHC(O)NH-acyl, NR 31 R 32 , NHC(O)Z 5 ;
A is selected from
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 6 is O;
Z 2 is OR 2 , SR 2 , or NR 16 R 17 ;
Z 5 is OR 24 , SR 24 , or NR 25 R 26 ; and
each of R 2 , R 16 , R 17 , R 24 , R 25 , R 26 , 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 16 and R 17 , R 25 and R 26, and R 31 and R 32 combine to form a heterocyclic ring containing a nitrogen atom and wherein said compound is a selective kappa receptor antagonist, a selective kappa receptor partial agonist, or a selective kappa receptor agonist.
3. The compound of 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 ;
A is selected from
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 6 is O;
Z 2 is OR 2 , SR 2 , or NR 16 R 17 ;
Z 5 is OR 24 , SR 24 , or NR 25 R 26 ; and
each of R 2 , R 3 , R 16 , R 17 , R 24 , R 25 , R 26 , R 29 , and R 30 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 16 and R 17 , R 25 and R 26, and R 29 and R 30 combine to form a heterocyclic ring containing a nitrogen atom and wherein said compound is a selective kappa receptor antagonist, a selective kappa receptor partial agonist, or a selective kappa receptor agonist.
4. The compound of formulas XXIIIa or XXIIIb:
wherein
J 3 is selected from NH-acyl, NHC(O)NH-acyl, NR 31 R 32 , NHC(O)Z 5 ;
A is selected from
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 6 is O;
Z 2 is OR 2 , SR 2 , or NR 16 R 17 ;
Z 5 is OR 24 , SR 24 , or NR 25 R 26 ; and
each of R 2 , R 16 , R 17 , R 24 , R 25 , R 26 , 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 16 and R 17 , R 25 and R 26 , and R 31 and R 32 combine to form a heterocyclic ring containing a nitrogen atom and wherein said compound is a selective kappa receptor antagonist, a selective kappa receptor partial agonist, or a selective kappa receptor agonist.
5. The compound of any of formulas XXIa-XXId:
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 ;
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 ;
Z 5 is OR 24 , SR 24 , or NR 25 R 26 ; and
each of R 3 , R 16 , R 17 , R 29 , R 30 , R 31 , 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 16 and R 17 , R 29 and R 30 , and R 31 and R 32 combine to form a heterocyclic ring containing a nitrogen atom.
6. The compound of formula XIXa:
wherein
X 2 is selected from H, O, S, O—R 2 , O-acyl, OC(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 ;
Y 1 is selected from OR 11 and NR 12 R 13 ;
Z 2 is OR 2 , SR 2 , or NR 16 R 17 ; and
each of R 2 , R 3 , 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 compound selected from selected from
8. A compound of any of formulas XXIa-XXJd:
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 ;
X 3 is C(O)—Y 1 ;
Z 2 is OR 2 , SR 2 , or NR 16 R 17 ;
Y 1 is selected from 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.
9. A compound of any of formulas XXIa-XXId:
and pharmaceutically acceptable salts thereof, wherein
X 2 is selected from S—R 2 , S-acyl and SC(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 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.
10. 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.
11. A compound selected from:
12. The compound of claim 11 , wherein said compound is:
13. A compound described by the formula:
and pharmaceutically acceptable salts thereof, wherein
X 2 is selected from S—R 2 , S-acyl and SC(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.