Salvinorin derivatives and uses thereof
AssigneeThe McLean Hospital Corporation
InventorsCecile Beguin, William Carlezon, Bruce Cohen, Minsheng He, David Lee, Michele Richards, Lee-Yuan Liu-Chen
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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.
Claims29
A compound of formula I:
- wherein
- A is selected from
- each of the bonds between C1 and C6, C2 and C3, and C3 and C4 is, independently, selected from a single bond or a double bond, provided that no carbon atom is part of more than one double bond;
- X1 is selected from H, O, S, O—R1, O-acyl, OC(O)Z1, S—R1, S-acyl, SC(O)Z1, NR14R15, NH-acyl, NHC(O)NH-acyl, and NHC(O)Z1;
- X2 is selected from O—R2, O-acyl, OC(O)Z2, S—R2, S-acyl, SC(O)Z2, NR16R17, NH-acyl, NHC(O)NH-acyl, and NHC(O)Z2;
- X3 is selected from CH2O—R3, CH2O-acyl, CH2S—R3, CH2S-acyl, CH2NH-acyl, CH2NHC(O)NH-acyl, CH2NHC(O)Z5, CH2NR29R30, NH-acyl, NHC(O)NH-acyl, NR31R32, NHC(O)Z5, and C(O)—Y1;
- X4 is selected from C(O)—OR4, CH2X8 and C(O)—NR5R6;
- X5 is selected from H, O—R7, O-acyl, NH-acyl, NHC(O)NH-acyl, and NR8R9, or X4 and
- X5 together are described by formula IIa or IIb to complete a six-membered ring
- X6 is selected from O, S, and NR10;
- X7 is selected from O—R18, O-acyl, OC(O)Z3, S—R18, S-acyl, SC(O)Z3, NR19R20, NH-acyl, NHC(O)NH-acyl, and NHC(O)Z3;
- X8 is selected from O—R21, O-acyl, OC(O)Z4, S—R21, S-acyl, SC(O)Z4, NR22R23, NH-acyl, NHC(O)NH-acyl, and NHC(O)Z4;
- Y1 is selected from OR11, SR11, and NR12R13;
- Z1 is OR1, SR1, or NR14R15;
- Z2 is OR2, SR2, or NR16R17;
- Z3 is OR18, SR18, or NR19R20;
- Z4 is OR21, SR21, or NR22R23;
- Z5 is OR24, SR24, or NR25R26;
- and
- each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R29, R30, R31, and R32 is, independently, selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-7 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, and C1-8 heteroalkyl, or one or more of R5 and R6, R8 and R9, R12 and R13, R14 and R15, R16 and R17, R19 and R20, R22 and R23, R25 and R26, R29 and R30, and R31 and R32 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 C2 ester of salvinorin A;
- a tetrahydrofuranylethyl salvinorin;
- a salvinorin benzoate;
- or a C1 reduced salvinorin.
A compound of formula XIX:
- wherein
- said compound is substantially pure;
- each of the bonds between C1 and C6, C2 and C3, and C3 and C4 is, independently, selected from a single bond or a double bond, provided that no carbon atom is part of more than one double bond;
- X1 is selected from H, O, S, O—R1, O-acyl, OC(O)Z1, S—R1, S-acyl, SC(O)Z1, NR14R15, NH-acyl, NHC(O)NH-acyl, and NHC(O)Z1;
- X2 is selected from H, O, S, O—R2, O-acyl, OC(O)Z2, S—R2, S-acyl, SC(O)Z2, NR16R17, NH-acyl, NHC(O)NH-acyl, and NHC(O)Z2;
- X3 is selected from CH2O—R3, CH2O-acyl, CH2NH-acyl, CH2NHC(O)NH-acyl, and C(O)—Y1;
- X6 is selected from O, S, and NR10;
- X7 is selected from O, O—R18, O-acyl, OC(O)Z3, S—R18, S-acyl, SC(O)Z3, NR19R20, NH-acyl, NHC(O)NH-acyl, and NHC(O)Z3;
- Y1 is selected from OR11 and NR12R13;
- Z1 is OR1, SR1, or NR14R15;
- Z2 is OR2, SR2, or NR16R17;
- Z3 is OR18, SR18, or NR19R20;
- and
- each of R1, R2, R3, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 is, independently, selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-7 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, and C1-8 heteroalkyl, or one or more of R12 and R13, R14 and R15, R16 and R17, and R19 and R20, 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.
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.
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.
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.
Dependencies are inferred from the claim text.