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.
The application is a continuation-in-part of U.S. Ser. No. 11/079,825, filed Mar. 14, 2005, which claims benefit of U.S. Provisional Application Nos. 60/552,669, filed Mar. 12, 2004, and 60/630,903, filed Nov. 24, 2004, each of which is incorporated herein by reference.
BACKGROUND OF THE INVENTIONThe invention relates to the treatment of depressive disorders and mania.
Stressors that cause symptoms of depression increase the activation of cAMP response element-binding protein (CREB) in the nucleus accumbens. CREB activation results in the activation of the prodynorphin gene, which encodes the opioid peptide dynorphin. Dynorphin is an agonist of the kappa opioid receptors in the brain, and enhances symptoms of depression. It has been shown that kappa receptor antagonists can act as antidepressants by mediating a disinhibition of dopamine release in the nucleus accumbens. See Pliakas et al., J. Neurosci. 21:7397 (2001); and Mague et al., J Pharmacol Exp. Ther. 305:323 (2003). It has been shown that antimanic/antipsychotic drugs increase the activity of dynorphinergic neurons, which have their effects through kappa receptors (Ma et al., Neuroscience 121:991 (2003).
The diterpene salvinorin A, derived from Salvia divinorum, has recently been shown to be a high affinity and selective kappa opioid receptor agonist. See Roth et al., Proc. Natl. Acad. Sci. USA 99:11934 (2002); and Butelman et al., Psychopharmacology 172:220 (2004).
New compounds which are highly selective for kappa opioid receptors over mu and delta opioid receptors and which have kappa antagonist, kappa partial agonist, or kappa agonist activity are needed to provide improved methods for the treatment of affective disorders and other conditions for which kappa opioid receptor signaling plays a role in the pathogenesis of disease.
SUMMARY OF THE INVENTIONThe invention is based on the discovery of compounds that are selective for kappa opioid receptors. The modulation of activity at kappa opioid receptors can be useful for the treatment of mood disorders. For example, the compounds exhibiting antagonist activity at kappa receptors are useful for the treatment of depressive disorders, among other conditions. The compounds exhibiting partial agonist activity at kappa receptors are useful for the treatment of bipolar disorder, e.g., as mood stabilizers, among other conditions. The compounds exhibiting full agonist activity at kappa receptors are useful for the treatment of the manic phase of bipolar disorder, among other conditions.
In a first aspect, the invention features a compound of formula I.
In formula I, 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 CH3, 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 C, reduced salvinorin.
Compounds of formula I include those described by formulas IIIa and IIIb.
In formulas IIIa and IIIb, A, X2, X4, X5, and Y1 are as defined above.
Desirably, compounds of formulas IIIa and IIIb are further described by any one of formulas IVa or IVb.
In formulas IVa and IVb, A, X2, X6, and Y1 are as defined above.
Compounds of formula I further include those described by formulas Va and Vb.
In formulas Va and Vb, W3 is selected from O—R3, O-acyl, S—R3, S-acyl, NH-acyl, NHC(O)NH-acyl, NHC(O)Z5, and NR29R30. A, X2, X4, X5, Z5, R3, R29, and R30 are as defined above.
Desirably, compounds of formulas Va and Vb are further described by any one of formulas VIa or VIb.
In formulas VIa and VIb, A, X2, X6, and W3 are as defined above.
Compounds of formula I further include those described by formulas VIIa and VIIb.
In formulas VIIa and VIIb, J3 is selected from NH-acyl, NHC(O)NH-acyl, NR31R32, NHC(O)Z5. A, X2, X4, X5, Z5, R31, and R32 are as defined above.
Desirably, compounds of formulas VIIa and VIIb are further described by any one of formulas VIIc or VIId.
In formulas VIIc and VIId, A, X2, X6, and J3 are as defined above.
Compounds of formula I also include those described by formulas VIIIa and VIIIb.
In formulas VIIIa and VIIIb, A, X2, X4, X5, and Y1 are as defined above.
Desirably, compounds of formulas VIIIa and VIIIb are further described by any one of formulas IXa or IXb.
In formulas IXa and IXb, A, X2, X6, and Y1 are as defined above.
Compounds of formula I include those described by formulas Xa and Xb.
In formulas Xa and Xb, W3 is selected from O—R3, O-acyl, S—R3, S-acyl, NH-acyl, NHC(O)NH-acyl, NHC(O)Z5, and NR29R30. A, X2, X4, X5, Z5, R3, R29, and R30 are as defined above.
Desirably, compounds of formulas Xa and Xb are further described by any one of formulas XIa or XIb.
In formulas XIa and XIb, A, X2, X6, and W3 are as defined above.
Compounds of formula I include those described by formulas XXIIa and XXIIb.
In formulas XXIIa and XXIIb, J3 is selected from NH-acyl, NHC(O)NH-acyl, NR31R32, NHC(O)Z5. A, X2, X4, X5, Z5, R31, and R32 are as defined above.
Desirably, compounds of formulas XXIIa and XXIIb are further described by any one of formulas XXIIIa or XXIIIb.
In formulas XXIIIa and XXIIIb, A, X2, X6, and J3 are as defined above. Compounds of formula I further include those described by formula XII.
In formula XII, A, X4, X5, R1, R2, and Y1 are as defined above.
Desirably, compounds of formula XII are further described by any one of formulas XIIIa, XIIIb, XIIIc, or XIIId.
In formulas XIIIa, XIIIb, XIIIc, and XIIId, A, X6, R1, R2, and Y1 are as defined above.
Compounds of formula I also include those described by formula XIV.
In formula XIV, A, X4, X5, R1, R2, and R3 are as defined above.
Desirably, compounds of formula XIV are further described by any one of formulas XVa, XVb, XVc, or XVd.
In formulas XVa, XVb, XVc, or XVd, A, X6, R1, R2, and R3 are as defined above.
Compounds of formula I include those described by formula XVI.
In formula XVI, A, X1, X2, X4, X5, and Y1 are as defined above.
Desirably, compounds of formula XVI are further described by formula XVIIa.
In formula XVIIa, A, X1, X2, X6, and Y1 are as defined above.
Compounds of formula I further include those described by formulas XVIIIa, XVIIIb, XVIIIc, or XVIIId.
In formulas XVIIIa, XVIIIb, XVIIIc, and XVIIId, Y2 is selected from OR4 and NR5R6; and X1, X2, X3, X6, R5, R6, and R7 are as defined above.
Compounds of formula I include those described by formula XX.
In formula XX, X2, X3, X6, and A are as defined above.
Desirably, compounds of formula XX are further described by any one of formulas XXIa-XXId.
In formula XXIa, XXIb, XXIc, and XXId, X2 and X3 are as defined above. Desirably, X2 is selected from NR16R17, NH-acyl, NHC(O)NH-acyl, and NHC(O)Z2 and 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-acryl, NR31R32, and NHC(O)Z5, where R3, R16, R17, R29, R30, R31, R32, Z2, and Z5 are defined as above.
The invention also features a substantially pure compound of formula XIX.
In formula XIX, 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, NHC(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 CH3, 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, R1, 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. Desirably, the compound of formula XIX 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.
Compounds of formula XIX include those described by formula XIXa.
In formulas XIXa, X2 and X3 are as defined above in formula XIX.
Any of the compounds described herein can be a selective kappa antagonist, a selective kappa receptor partial agonist, or a selective kappa agonist.
The invention features a method for treating a mood disorder in a mammal, e.g., a human patient, by administering an effective amount of a selective kappa receptor antagonist of formula I, salvinorin C, D, E, or F, a C2 ester of salvinorin A, a tetrahydrofuranylethyl salvinorin, a salvinorin benzoate, or a C1 reduced salvinorin. These compounds are particularly useful for treating depressive disorders and disorders associated with depression, such as major depression, dysthymia, bipolar disorder (manic depression), drug withdrawal, and post traumatic stress disorder; however, any psychologic or psychiatric disorder having symptoms that include abnormalities of mood, such as schizoaffective disorder, schizophrenia, anxiety disorder, panic disorder, post traumatic stress disorder, phobic disorder, borderline personality disorder, schizoid disorder, or schizotypal disorder, are amenable to treatment according to the present methods.
The invention features a method for treating bipolar disorder in a mammal, e.g., a human patient, in need thereof, by administering an effective amount of a selective kappa receptor partial agonist.
The invention further features a method for stabilizing the mood of a mammal, e.g., a human patient, diagnosed with a mood disorder by administering an effective amount of a selective kappa receptor partial agonist.
The selective kappa receptor partial agonist can be a compound of formula I, salvinorin C, D, E, or F, a C2 ester of salvinorin A, a tetrahydrofuranylethyl salvinorin, a salvinorin benzoate, or a C1 reduced salvinorin. Desirably, the selective kappa receptor partial agonist is 2-(O—(N-methyl)formamide)-salvinorin B.
The invention features a method for treating mania in a mammal, e.g., a human patient, in need thereof, by administering an effective amount of a selective kappa receptor agonist. Selective kappa receptor agonists are particularly useful for treating mania associated with bipolar disorder, acute mania, and chronic mania. The mania can occur in a single episode or be recurring. The selective kappa receptor agonist can be a compound of formula I, salvinorin A, or salvinorin B, a C2 ester of salvinorin A, a salvinorin benzoate, or a C1 reduced salvinorin. Desirably, the 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.
The selective kappa receptor antagonists, partial agonists, or agonists can be administered systemically, including, for example, by intravenous, intramuscular, or subcutaneous injection, orally, or by topical or transdermal application, provided that the kappa receptor antagonist is capable of penetrating the blood-brain barrier sufficiently to be effective. Alternatively, the kappa-selective compounds can be centrally administered using, for example, by an intrathecal, intracerebroventricular, or intraparenchemal injection.
The methods and compositions described herein can also be used to generate information useful, for example, for increasing investment in a company or increasing consumer demand for the methods and/or compositions.
The invention therefore features a method of increasing consumer demand for a pharmaceutical composition (e.g., the articles of the invention) or therapeutic regimen (e.g., the administration of articles of the invention) described herein. The method includes the step of disseminating information about the pharmaceutical composition or therapeutic regimen.
The invention further features a method of increasing investment in a company seeking governmental approval for the sale of a pharmaceutical composition and/or therapeutic regimen described herein. The method includes the steps of i) disseminating information about the pharmaceutical composition or therapeutic regimen and ii) disseminating information about the intent of the company to market the pharmaceutical composition or therapeutic regimen.
Consumer demand for a pharmaceutical composition described herein can be increased by disseminating information about the utility, efficacy, or safety of the pharmaceutical composition. Consumers include health maintenance organizations, hospitals, doctors, and patients. Typically, the information will be disseminated prior to a governmental approval for the sale of a composition or therapeutic regimen of the invention.
A company planning to sell a pharmaceutical composition described herein can increase investment therein by disseminating information about the company's intention to seek governmental approval for the sale of and disseminating information about the pharmaceutical composition and/or therapeutic regimen of the invention. For example, the company can increase investment by disseminating information about in vivo studies conducted, or planned, by the company, including, without limitation, information about the toxicity, efficacy, or dosing requirements of a pharmaceutical composition or therapeutic regimen of the invention. The company can also increase investment by disseminating information about the projected date of governmental approval of a pharmaceutical composition or therapeutic regimen of the invention.
Information can be disseminated in any of a variety of ways, including, without limitation, by press release, public presentation (e.g., an oral or poster presentation at a trade show or convention), on-line posting at a web site, and mailing. Information about the pharmaceutical composition or therapeutic regimen can include, without limitation, a structure, diagram, figure, chemical name, common name, tradename, formula, reference label, or any other identifier that conveys the identity of the pharmaceutical composition or therapeutic regimen of the invention to a person.
By “in vivo studies” is meant any study in which a pharmaceutical composition or therapeutic regimen of the invention is administered to a mammal, including, without limitation, non-clinical studies, e.g., to collect data concerning toxicity and efficacy, and clinical studies.
By “projected date of governmental approval” is meant any estimate of the date on which a company will receive approval from a governmental agency to sell, e.g., to patients, doctors, or hospitals, a pharmaceutical composition or therapeutic regimen of the invention. A governmental approval includes, for example, the approval of a drug application by the Food and Drug Administration, among others.
As used herein “substantially pure” refers to a composition containing a compound described herein which possesses the S configuration at C8 and which contains less than 10%, 5%, 2%, 1%, 0.05%, or 0.01% (w/w) of the corresponding epimer possessing the R configuration at C8 (e.g., greater than 90% episalvinorin A and less than 10% salvinorin A). The amount of R and S C8 isomers present in the mixture can be determined using chromatographic methods. The stereochemical configuration of each component in the mixture can be determined using NMR techniques.
By “selective kappa antagonist” is meant any chemical compound which has affinity for the kappa opioid receptor, substantially no agonist activity, and produces less than 15% of the maximal response in comparison to dynorphin A. The selective kappa antagonist has more than 100, 200, 300, 500, 700, 1,000, or 2,000 fold greater affinity for kappa opioid receptors than for each of the mu and delta opioid receptors. Affinities for the various opioid receptor subtypes are determined using standard in vitro assays. For example, the binding assays may utilize guinea pig brain membranes or stably transfected Chinese Hamster Ovary (CHO) cells expressing each of the three opioid receptors.
By “selective kappa receptor partial agonist” is meant any chemical compound which has affinity for the kappa opioid receptor and agonist activity, but produces only a partial (i.e., submaximal) response of between 15% and 85% in comparison to dynorphin A, an endogenous neurotransmitter of the kappa opioid receptor. The selective kappa partial agonist has more than 100, 200, 300, 500, 700, 1,000, or 2,000 fold greater affinity for kappa opioid receptors than for each of the mu and delta opioid receptors. Affinities for the various opioid receptor subtypes are determined using standard in vitro assays. For example, the binding assays may utilize guinea pig brain membranes or stably transfected Chinese Hamster Ovary (CHO) cells expressing each of the three opioid receptors.
By “selective kappa receptor agonist” is meant any chemical compound which has affinity for the kappa opioid receptor and agonist activity, and produces at least 85% of the maximal response in comparison to dynorphin A, an endogenous neurotransmitter of the kappa opioid receptor. The selective kappa agonist has more than 100, 200, 300, 500, 700, 1,000, or 2,000 fold greater affinity for kappa opioid receptors than for each of the mu and delta opioid receptors. Affinities for the various opioid receptor subtypes are determined using standard in vitro assays. For example, the binding assays may utilize guinea pig brain membranes or stably transfected Chinese Hamster Ovary (CHO) cells expressing each of the three opioid receptors.
The term “administration” or “administering” refers to a method of giving a dosage of a pharmaceutical composition to a patient, where the method is, e.g., topical, transdermal, oral, intravenous, intraperitoneal, intracerebroventricular, intrathecal, or intramuscular. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, site of administration, and severity of the symptoms being treated.
By “depressive disorder” is meant any psychologic or psychiatric disorder which is associated with symptoms of depression. Treatable depressive disorders can be characterized by an inhibition or reduction of dopaminergic function in the nucleus accumbens, e.g., major depression, dysthymia, bipolar disorder (manic depression), drug withdrawal, and post-traumatic stress disorder.
By “effective amount” is meant is meant an amount of a compound of the invention which has a therapeutic effect, e.g., which prevents, reduces, or eliminates the depression, mania, mood fluctuations, or reduces CREB activation. This amount, an effective amount, can be routinely determined by one of skill in the art, by animal testing and/or clinical testing, and will vary, depending on several factors, such as the particular disorder to be treated and the particular compound of the invention used. This amount can further depend upon the subject's weight, sex, age and medical history.
By salvinorin A, B, C, D, E, and F is meant the compounds identified below.
By “C2 ester of salvinorin A” is meant a compound of formula A:
wherein R is a chemical moiety of formula R′—C(O)— in which R′ is C1-8 alkyl.
By “C1 reduced salvinorin” is meant the reduced salvinorin compounds, shown below, including both C8 isomers.
By “tetrahydrofuranylethyl salvinorin” is meant the furan reduced compounds, compounds a-e, shown below.
As used herein “salvinorin benzoate” refers to the benzoyl derivatives shown below.
In the generic descriptions of compounds of this invention, the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alkyl group containing from 1 to 7 carbon atoms or C1-8 alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range. For example, an alkyl group from 1 to 8 carbon atoms includes each of C1, C2, C3, C4, C5, C6, C7, and C8. A C1-8 heteroalkyl, for example, includes from 1 to 7 carbon atoms in addition to one or more heteroatoms. Other numbers of atoms and other types of atoms may be indicated in a similar manner.
As used herein, the terms “alkyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 6 ring carbon atoms, inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. The C1-8 alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, cyano, nitrilo, NH-acyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C1-8 alkyls include, without limitation, methyl; ethyl; n-propyl; isopropyl; cyclopropyl; cyclopropylmethyl; cyclopropylethyl; n-butyl; iso-butyl; sec-butyl; tert-butyl; cyclobutyl; cyclobutylmethyl; cyclobutylethyl; n-pentyl; cyclopentyl; cyclopentylmethyl; cyclopentylethyl; 1-methylbutyl; 2-methylbutyl; 3-methylbutyl; 2,2-dimethylpropyl; 1-ethylpropyl; 1,1-dimethylpropyl; 1,2-dimethylpropyl; 1-methylpentyl; 2-methylpentyl; 3-methylpentyl; 4-methylpentyl; 1,1-dimethylbutyl; 1,2-dimethylbutyl; 1,3-dimethylbutyl; 2,2-dimethylbutyl; 2,3-dimethylbutyl; 3,3-dimethylbutyl; 1-ethylbutyl; 2-ethylbutyl; 1,1,2-trimethylpropyl; 1,2,2-trimethylpropyl; 1-ethyl-1-methylpropyl; 1-ethyl-2-methylpropyl; and cyclohexyl.
By “C2-8 alkenyl” is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 8 carbon atoms. A C2-8 alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members. The C2-8 alkenyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, cyano, nitrilo, NH-acyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C2-8 alkenyls include, without limitation, vinyl; allyl; 2-cyclopropyl-1-ethenyl; 1-propenyl; 1-butenyl; 2-butenyl; 3-butenyl; 2-methyl-1-propenyl; 2-methyl-2-propenyl; 1-pentenyl; 2-pentenyl; 3-pentenyl; 4-pentenyl; 3-methyl-1-butenyl; 3-methyl-2-butenyl; 3-methyl-3-butenyl; 2-methyl-1-butenyl; 2-methyl-2-butenyl; 2-methyl-3-butenyl; 2-ethyl-2-propenyl; 1-methyl-1-butenyl; 1-methyl-2-butenyl; 1-methyl-3-butenyl; 2-methyl-2-pentenyl; 3-methyl-2-pentenyl; 4-methyl-2-pentenyl; 2-methyl-3-pentenyl; 3-methyl-3-pentenyl; 4-methyl-3-pentenyl; 2-methyl-4-pentenyl; 3-methyl-4-pentenyl; 1,2-dimethyl-1-propenyl; 1,2-dimethyl-1-butenyl; 1,3-dimethyl-1-butenyl; 1,2-dimethyl-2-butenyl; 1,1-dimethyl-2-butenyl; 2,3-dimethyl-2-butenyl; 2,3-dimethyl-3-butenyl; 1,3-dimethyl-3-butenyl; 1,1-dimethyl-3-butenyl and 2,2-dimethyl-3-butenyl.
By “C2-8 alkynyl” is meant a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 8 carbon atoms. A C2-8 alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The C2-8 alkynyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, cyano, nitrilo, NH-acyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C2-8 alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-hexene-1-ynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl; 1-methyl-2-propynyl; 1-methyl-2-butynyl; 1-methyl-3-butynyl; 2-methyl-3-butynyl; 1,2-dimethyl-3-butynyl; 2,2-dimethyl-3-butynyl; 1-methyl-2-pentynyl; 2-methyl-3-pentynyl; 1-methyl-4-pentynyl; 2-methyl-4-pentynyl; and 3-methyl-4-pentynyl.
By “C2-7 heterocyclyl” is meant a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of 2 to 7 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, cyano, nitrilo, NH-acyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom. A nitrogen atom in the heterocycle may optionally be quaternized. Preferably when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Heterocycles include, without limitation, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, without limitation, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.
By “C6-12 aryl” is meant an aromatic group having a ring system comprised of carbon atoms with conjugated n electrons (e.g., phenyl). The aryl group has from 6 to 12 carbon atoms. Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The aryl group may be substituted or unsubstituted. Exemplary substituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.
By “C7-14 alkaryl” is meant an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms.
By “C3-10 alkheterocyclyl” is meant an alkyl substituted heterocyclic group having from 7 to 14 carbon atoms in addition to one or more heteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2-tetrahydrofuranylmethyl).
By “C1-8 heteroalkyl” is meant a branched or unbranched alkyl, alkenyl, or alkynyl group having from 1 to 8 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, cyano, nitrilo, NH-acyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and carboxyl groups. Examples of C1-8 heteroalkyls include, without limitation, methoxymethyl and ethoxyethyl.
By “halide” is meant bromine, chlorine, iodine, or fluorine.
By “fluoroalkyl” is meant an alkyl group that is substituted with a fluorine.
By “perfluoroalkyl” is meant an alkyl group consisting of only carbon and fluorine atoms.
By “carboxyalkyl” is meant a chemical moiety with the formula —(R) —COOH, wherein R is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-7 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-8 heteroalkyl.
By “hydroxyalkyl” is meant a chemical moiety with the formula —(R) —OH, wherein R is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-7 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-8 heteroalkyl.
By “alkoxy” is meant a chemical substituent of the formula —OR, wherein R is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-7 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-8 heteroalkyl.
By “aryloxy” is meant a chemical substituent of the formula —OR, wherein R is a C6-12 aryl group.
By “alkylthio” is meant a chemical substituent of the formula —SR, wherein R is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-7 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-8 heteroalkyl.
By “arylthio” is meant a chemical substituent of the formula —SR, wherein R is a C6-12 aryl group.
By “quaternary amino” is meant a chemical substituent of the formula —(R) —N(R′)(R″)(R′″)+, wherein R, R′, R″, and R′″ are each independently an alkyl, alkenyl, alkynyl, or aryl group. R may be an alkyl group linking the quaternary amino nitrogen atom, as a substituent, to another moiety. The nitrogen atom, N, is covalently attached to four carbon atoms of alkyl and/or aryl groups, resulting in a positive charge at the nitrogen atom.
By “acyl” is meant a chemical moiety with the formula R—C(O)—, wherein R is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C2-7 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, C1-8 heteroalkyl (including amino acid acyls), or the acyl is a fatty acid acyl.
By “amino acid acyl” is meant a chemical moiety with the formula R—C(O)—, wherein R—C(O)— is selected from natural and unnatural amino acids.
By “fatty acid acyl” is meant a chemical moiety with the formula R—C(O)—, wherein R is a partially-saturated straight chain or branched hydrocarbon group having from 14 to 26 carbon atoms. Fatty acid acyls are derived from fatty acids including, without limitation, those occurring naturally in the brain. For example, fatty acids having 16 carbon atoms and 0, 1 or 2 double bonds (C16:0; C16:1 and C16:2), those with 18 carbon atoms and 1, 2 or 3 double bonds (C18:1; C18:2; and C18:3), those with 20 carbon atoms and 1, 2 or 4 double bonds (C20:1; C20:2; and C20:4) and those with 22 carbon atoms and 4, 5 or 6 double bonds (C22:4; C22:5 and C22:6). The fatty acids can be substituted or unsubstituted. Exemplary substituents include hydroxyl, halide, methyl, ethyl, propyl, isopropyl, butyl, and pentyl groups. Desirably, the fatty acid acyl is 4, 7, 10, 13, 16, 19 docosahexanoyl.
Because the compounds of the invention are highly selective for the kappa opioid receptor, they can be used in the methods of the invention to treat conditions for which kappa opioid receptor signaling plays a role in the pathogenesis of disease without directly influencing signaling at other receptors and producing unwanted side-effects.
Other features and advantages of the invention will be apparent from the following Detailed Description, the drawings, and the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
We have made compounds that are useful for the treatment of depression and/or mania. The compounds are described by formulas I-XXI. These compounds can be prepared as described in Examples 1-28.
Assays
To determine their affinity for specific opioid receptors, the compounds described herein can be characterized in radioligand receptor binding assays, using ligands that are specific for the mu, delta and kappa receptors. For example, the binding assays may utilize guinea pig brain membranes or stably transfected Chinese Hamster Ovary (CHO) cells expressing each of the three opioid receptors, as described in Example 29.
To determine their efficacy (e.g., agonist, partial agonist, antagonist) at a specific opioid receptor, compounds can be characterized by [35S]GTPγS binding assay, as described in Example 30.
A symptom of clinical depression that can be modeled in rats is despair, a feeling of hopelessness. Symptoms of despair can be induced in rats using the forced swim test (FST), as described in Example 31, a highly validated model used to study antidepressant treatments.
Mania-like symptoms can be induced in rodents by the administration of psychomotor stimulant drugs such as cocaine or amphetamine. Psychostimulants produce a range of behaviors in animals that appear similar to mania, including hyperactivity, heightened sensory awareness and alertness, and changes in sleep patterns. Psychostimulant-induced hyperactivity is mediated by increased dopaminergic transmission in striatal regions. Based on this information, psychostimulant-induced hyperactivity in rodents has become a standard model for the screening of antimanic drugs. The mania-like effects of these psychomotor stimulants can be studied in behavioral assays that quantify locomotor activity (“open field activity”) or the function of brain reward systems (“place conditioning” or “intracranial self-stimulation (ICSS)) (see Example 32). The Antimanic-like effects of salvinorin derivatives can be identified by the ability of these agents to reduce, attenuate, or block the stimulant or rewarding effects of cocaine or amphetamine in these assays. For further details see, for example, Einat and Belmaker Animal models of bipolar disorder: From a single episode to progressive cycling models; In: “Contemporary Issues in Modeling Psychopathology” Myslobodsky M, Weiner I (Eds.), 2000; London: Kluver Academic, New York, pp 165-179.
Therapy
The compounds described herein can be used for the treatment of mania, depressive disorders. Compounds of formula I can be particularly useful for treating major depression, dysthymia, bipolar disorder (manic depression), and post traumatic stress disorder; however, any psychologic or psychiatric disorder having symptoms that include abnormalities of mood or emotion are amenable to treatment according to the present methods. For example, the compounds can be used to treat disorders of mood, including, without limitation, Depression, Bipolar Disorder, Schizoaffective Disorder, Schizophrenia and other psychotic disorders, Anxiety Disorders, Panic Disorder, Traumatic Stress Disorders, Phobic Disorders, and Personality Disorders with abnormal mood, such as Borderline Personality Disorder, Schizoid and Schizotypal Disorders. For example, compounds having antagonist activity at kappa opioid receptors are useful for the treatment of depression; compounds having partial agonist activity at kappa opioid receptors are useful as mood stabilizers for the treatment of, for example, bipolar disorder; and compounds having agonist activity at kappa opioid receptors are useful for the treatment of mania.
The invention features a method of treating depressive disorders or mania by administering a compound having any of formulas I-XIX. The compounds of the invention may be administered with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form. Administration may be transdermal, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracistemal, intraperitoneal, intracerebroventricular, intrathecal, intranasal, aerosol, by suppositories, or oral administration.
Therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops, or aerosols.
Methods well known in the art for making formulations are found, for example, in “Remington: The Science and Practice of Pharmacy” (20th ed., ed. A. R. Gennaro, 2000, Lippincott Williams & Wilkins). Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Nanoparticulate formulations (e.g., biodegradable nanoparticles, solid lipid nanoparticles, liposomes) may be used to control the biodistribution of the compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycolate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. The concentration of the compound in the formulation will vary depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration.
The compound may be optionally administered as a pharmaceutically acceptable salt, such as a non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry. Examples of acid addition salts include organic acids such as acetic, lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as tannic acid, carboxymethyl cellulose, or the like; and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid, or the like. Metal complexes include calcium, zinc, iron, and the like.
Administration of compounds in controlled release formulations is useful where the compound of formula I has (i) a narrow therapeutic index (e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD50) to median effective dose (ED50)); (ii) a narrow absorption window in the gastro-intestinal tract; or (iii) a short biological half-life, so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.
Many strategies can be pursued to obtain controlled release in which the rate of release outweighs the rate of metabolism of the therapeutic compound. For example, controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including, e.g., appropriate controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose and sorbitol), lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc).
Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium.
Pharmaceutical formulations of compounds of formulas I-XIX can include isomers such as diastereomers and enantiomers, mixtures of isomers, including racemic mixtures, salts, solvates, and polymorphs thereof.
The formulations can be administered to patients in therapeutically effective amounts. For example, an amount is administered which prevents, reduces, or eliminates the depression, mania, mood fluctuations, or reduces CREB activation, respectively. Typical dose ranges are from about 0.001 μg/kg to about 2 mg/kg of body weight per day. Desirably, a dose of between 0.001 μg/kg and 1 mg/kg of body weight, or 0.005 μg/kg and 0.5 mg/kg of body weight, is administered. The exemplary dosage of drug to be administered is likely to depend on such variables as the type and extent of the condition, the overall health status of the particular patient, the formulation of the compound, and its route of administration. Standard clinical trials may be used to optimize the dose and dosing frequency for any particular compound.
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are performed, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.
Where the specification refers to a position of the salvinorin ring system, the position is identified according to the numbering system provided below.
The synthesis of compounds of the invention may require selective protection and deprotection of alcohols, amines, and carboxylic acid functional groups in the salvinorin starting material. For example, commonly used protecting groups for amines include carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m-nitrophenyl. Other commonly used protecting groups for amines include amides, such as formamides, acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, and tert-butylsulfonyl amides. Examples of commonly used protecting groups for carboxylic acids include esters, such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl, 2-(trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl, ortho-esters, and halo-esters. Examples of commonly used protecting groups for alcohols include ethers, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P-nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (including methoxy-trityls), and silyl ethers. Protecting groups can be chosen such that selective conditions (e.g., acidic conditions, basic conditions, catalysis by a nucleophile, catalysis by a lewis acid, or hydrogenation) are required to remove each, exclusive of other protecting groups in a molecule. The conditions required for the addition of protecting groups to amine, alcohol, and carboxylic acid functionalities and the conditions required for their removal are provided in detail in “T. W. Green and P. G. M. Wuts: Protective Groups in Organic Synthesis” (2nd ed., 1991, John Wiley & Sons) and “P. J. Kocienski: Protecting Groups” (1994 Georg Thieme Verlag); each of which is incorporated herein by reference.
EXAMPLE 1 Modifications at C2 C2 modified salvinorin derivatives can be prepared, for example, from salvinorin B using the general procedures described below, among others. For example, the stereochemistry at C2 can be inverted using a Mitsunobu reaction (PPh3+DIAD+NuH, where NuH is, for example, an arylalcohol, cyclic imide, or carboxylic acid, among others) (see Scheme 1A). Alternatively; the hydroxy group at C2 can be acylated using an acyl halide or a carboxylic acid and an activating agent (see Scheme 1B); can be alkylated using an alkyl halide (see Scheme 1C); can be converted to a carbamate (see Scheme 1D); or can be converted to an amine (see Scheme 1E). The amine of Scheme 1E can be converted to an amide (see Scheme 1F). These methods can also be used to make analogous modifications at C1, C12, C17, and C4, when these positions are substituted by hydroxyl groups.
General Protocol: To a CH2Cl2 solution of salvinorin B (1 equivalent), triphenylphosphine (3 equivalents), and the nucleophile (3 equivalents) was added diisopropylazodicarboxylate (3 equivalents) (DEAD may also be used) dropwise and the reaction was stirred at room temperature (3.5 hours). Saturated NaHCO3 was added to the reaction mixture. The organic layer washed with brine, dried (MgSO4), and concentrated in vacuo. The crude material was purified by column chromatography (SiO2; EtOAc—CH2Cl2) to obtain the desired product.
General Protocol: To a pyridine solution of salvinorin B (1 equivalent) was added the acyl chloride (5 equivalents) and the solution was stirred at room temperature (5 minutes). Ice cold water (2-5 mL) and CH2Cl2 (2-5 mL) were added to the reaction mixture. The organic layer was concentrated in vacuo and then purified by column chromatography (SiO2; EtOAc-hexanes) to obtain the desired product.
General Protocol: To a stirred MeCN solution of salvinorin B (1 equivalent) was added Ag2O (10 equivalents) and the alkyl halide (20 equivalents). The reaction mixture was concentrated and crude was purified by column chromatography (SiO2; CH2Cl2-EtOAc or EtOAc-hexanes) to obtain the desired product.
General Protocol: To a cloudy solution of salvinorin B (1 equivalent) and DMAP (catalytic amount) in pyridine was added the alkyl isocyanate (8-15 equivalents). The reaction mixture was stirred at room temperature (18 hours). The solution was concentrated in vacuo and the residue was purified by column chromatography (SiO2; 1:2, EtOAc:hexanes) to obtain the desired product.
General Protocol: To a cold (0° C.) suspension of salvinorin B (1 equivalent) in CH2Cl2 was added pyridine (excess) and trifluoromethanesulfonic anhydride (excess) and the reaction solution was stirred at 0° C. for 20 minutes. The reaction solution washed with 1 N HCl (2 mL), brine (2 mL), dried (MgSO4) and evaporated. A solution of the triflate (1 equivalent) in amine (excess) was then stirred at a temperature of between 25° C. and 60° C. for a period of between 1.5 to 18 hours. In select cases CH2Cl2 was added. The solution was concentrated in vacuo and the residue was purified by column chromatography (SiO2; 9:1, CH2Cl2:EtOAc) to obtain the desired product.
General Protocol: A CH2Cl2 solution of triethylamine (1.25 equivalent) and the acyl chloride or anhydride (1.25 equivalent) was added to the C(2) salvinorin amine (1 equivalent). The reaction solution was stirred at room temperature until completion. The reaction was concentrated and the residue was purified by column chromatography (SiO2; 9:1, CH2Cl2:EtOAc) to obtain the desired product.
EXAMPLE 2 Modifications at C4 C4 modified salvinorin derivatives can be prepared, for example, from salvinorin A using the general procedures shown in Scheme 2, among others. First, the methoxy group is removed using LiI/pyridine. The resulting carboxylic acid group can be reduced to hydroxymethyl using borane, converted to an amide using an amine and an activating reagent, or converted to an ester using an alcohol and an activating reagent. The carboxylic acid can be activated, for example, by formation of an active ester, such as nitrophenylesters, N-hydroxysuccinimidyl esters, or others as described in Chem. Soc. Rev. 12:129, 1983 and Angew. Chem. Int. Ed. Engl. 17:569, 1978. The activated acid can then be reacted with a preselected amine or alcohol to produce the desired amide or ester, respectively. Analogous modification can be made at C1-7 carboxylic acid for compounds in which the lactone ring is opened (see Example 5).
The furan ring can be hydrogenated using the general procedures shown in Scheme 3, among others. Using H2/Pt/C the furan ring is hydrogenated without disruption of the lactone ring. When more stringent conditions, H2/Pd/C, are employed, the reduction of the furan ring is accompanied by cleavage of the lactone ring and reduction of the C12 position. See Valdes et al., J. Org. Chem. 49:4716 (1984); and Koreeda et al., Chem. Lett. 2015 (1990).
The C1 ketone of salvinorin A can be reduced using the general procedure shown in Scheme 4, among others. See Valdes et al., J. Org. Chem. 49:4716 (1984); and Koreeda et al., Chem. Lett. 2015 (1990).
The lactone ring of salvinorin derivatives can be opened using the general procedure shown in Scheme 5, among others.
The C8 epimerization of salvinorin derivatives can be achieved under basic conditions as shown in Scheme 6 and reported, for 1,2-dihyroxy-episalvinorin, by Valdes et al., J. Org. Chem. 49:4716 (1984); and Valdes et al., Org. Lett. 3:3935 (2001).
To a cold (0° C.) solution of salvinorin A (153.0 mg, 0.35 mmol) in MeOH (3 mL) and CH2Cl2 (3 mL) was added K2CO3 (98 mg, 0.71 mmol) and the mixture was stirred at 0° C. (20 minutes). Water (5 mL) and CH2Cl2 (5 mL) were added to the reaction mixture. The organic layer was concentrated in vacuo and then purified by column chromatography (SiO2; 4:1, CH2Cl2:EtOAc) to obtain 66 mg (48%) of pure 1 as a white solid: Rf 0.23 (1:1, EtOAc:hexanes); 1H NMR (CDCl3) δ 1.10 (s, 3H), 1.49 (s, 3H), 1.51-1.69 (m, 3H), 1.77-1.82 (m, 1H), 2.02-2.10 (m, 2H), 2.14-2.20 (m, 1H), 2.17 (s, 1H), 2.45-2.50 (m, 1H), 2.55 (dd, 1H), 2.71 (dd, 1H), 3.60 (d, 1H), 3.72 (s, 3H), 4.05-4.12 (m, 1H), 5.57 (dd, 1H), 6.38 (s, 1H), 7.40-7.42 (m, 2H); 13C NMR (CDCl3) 15.2, 16.5, 18.1, 34.5, 35.4, 38.1, 42.6, 43.5, 51.3, 51.9, 53.1, 63.8, 71.9, 74.3, 108.3, 125.3, 139.3, 143.8, 171.1, 171.8, 208.9 ppm.
EXAMPLE 8 Synthesis of 2-propionyl-salvinorin B (Compound 2)
To a pyridine (400 μL) solution of salvinorin B (6.2 mg, 16 μmol) was added propionyl chloride (10 μL, 115 μmol) and the solution was stirred at room temperature (5 minutes). Ice cold water (2 mL) and CH2Cl2 (2 mL) were added to the reaction mixture. The organic layer was concentrated in vacuo and then purified by column chromatography (SiO2; 1:2, EtOAc:hexanes) to obtain 4.3 mg (61%) of pure 2 as a white solid: Rf 0.54 (1:1, EtOAc:hexanes); 1H NMR (CDCl3) δ 1.11 (s, 3H), 1.18 (t, 3H), 1.45 (s, 3H), 1.52-1.67 (m, 4H), 1.77-1.82 (m, 1H), 2.06 (dd, 1H), 2.17 (s, 1H), 2.26-2.33 (m, 2H), 2.46 (q, 2H), 2.47-2.54 (m, 1H), 2.72-2.78 (m, 1H), 3.72 (s, 3H), 5.15 (dd, 1H), 5.51 (dd, 1H), 6.37 (d, 1H), 7.38-7.40 (m, 2H); 13C NMR (CDCl3) 9.0, 15.2, 16.4, 18.2, 27.2, 30.8, 35.5, 38.2, 42.1, 43.4, 51.4, 51.9, 53.6, 64.1, 72.0, 74.8, 108.4, 125.3, 139.4, 143.7, 171.1, 171.6, 173.4, 202.0 ppm. HRMS (ES+) calcd for C24H31O8 [M+H+]: 447.2019, found: 447.2023.
EXAMPLE 9 Synthesis of 2-butyryl-salvinorin B (Compound 3)
Compound 3 (2.7 mg, 36%) was prepared as a white solid from salvinorin B (6.3 mg, 16 mmol), pyridine (400 mL), and butyryl chloride (8 mL, 81 mmol) utilizing method A: Rf 0.46 (1:1, EtOAc:hexanes); 1H NMR (CDCl3) d 0.99 (t, J=7.2 Hz, 3H), 1.12 (s, 3H), 1.45 (s, 3H), 1.53-1.69 (m, 4H), 1.70 (q, J=7.2 Hz, 2H), 1.76-1.82 (m, 1H), 2.07 (dd, J=3.0, 11.4 Hz, 1H), 2.17 (s, 1H), 2.27-2.33 (m, 2H), 2.37-2.47 (m, 2H), 2.52 (dd, J=5.1, 13.5 Hz, 1H), 2.72-2.78 (m, 1H), 3.73 (s, 3H), 5.15 (dd, J=9.9, 9.9 Hz, 1H), 5.52 (dd, J=5.4, 11.7 Hz, 1H), 6.38 (dd, J=0.6, 1.8 Hz, 1H), 7.39-7.41 (m, 2H); 13C NMR (CDCl3) 13.6, 15.2, 16.4, 18.2, 18.4, 30.9, 35.5, 35.8, 38.2, 42.1, 43.4, 51.4, 51.9, 53.7, 64.2, 72.0, 74.8, 108.4, 125.3, 139.5, 143.7, 171.1, 171.6, 172.6, 201.9 ppm; HRMS (ES+) calcd for C25H33O8 [M+H+]: 461.2175, found: 461.2179.
EXAMPLE 10 Synthesis of 2-methoxy-salvinorin B (Compound 4)
To a MeCN (800 μL) solution of salvinorin B (4.5 mg, 12,mol) was added Ag2O (32 mg, 0.14 mmol) and MeI (17 μL, 0.27 mmol) and the mixture was stirred at 40° C. for 4 days. The reaction mixture was concentrated and the crude product was purified by column chromatography (SiO2; 9:1, CH2Cl2:EtOAc) to obtain 3.6 mg (77%) of pure 4 as a white solid: Rf 0.30 (9:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.11 (s, 3H), 1.48 (s, 3H), 1.53-1.72 (m, 4H), 1.77-1.82 (m, 1H), 2.02-2.19 (m, 4H), 2.35-2.43 (m, 1H), 2.57 (dd, 1H), 2.66 (dd, 1H), 3.46 (s, 3H), 3.72 (s, 3H), 5.56 (dd, 1H), 6.38 (dd, 1H), 7.39-7.42 (m, 2H); 13C NMR (CDCl3) 15.2, 16.4, 18.2, 32.0, 35.6, 38.3, 42.1, 43.7, 51.6, 51.8, 53.9, 58.1, 64.3, 72.0, 83.1, 108.3, 125.5, 139.3, 143.7, 171.1, 171.8, 206.2 ppm. HRMS (ES+) calcd for C22H29O7 [M+H+]: 405.1913, found: 405.1908.
EXAMPLE 11 Synthesis of Episalvinorin B (Compound 5)
K2CO3 (200 mg) was added to a solution of salvinorin A (200 mg) in MeOH (25 mL) at room temperature. The mixture was stirred for 20 minutes. TLC (1:1, EtOAc:Hexanes) showed complete consumption of the starting material and a new lower Rf spot. The reaction mixture was diluted with 50 mL of water and pH was adjusted to 7.0 followed by extraction with EtOAc (2×50 mL). The organic layer was dried (Na2SO4) and concentrated to afford a white solid. The white solid was further purified by column (1:1, EtOAc:Hexane) to give the pure compound 5 (Yield: 91 mg, 50.4%). 1H NMR: (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.41 (d, J=1.5 Hz, 1H), 6.37 (s, 1H), 5.31 (dd, J=4.5, 11.4 Hz, 1H), 4.01 (t, 1H), 3.69 (s, 3H), 3.60 (d, J=3.3 Hz, 1H), 2.72 (dd, J=3, 13.5 Hz, 1H), 2.47-2.38 (m, 3H), 2.23 (s, 1H), 2.18 (d, J=1.8 Hz, 1H), 2.07-1.82 (m, 3H), 1.64 (s, 3H), 1.56-41 (m, 2H), 1.06 (s, 3H). 13C NMR (70.5 MHz, CDCl3): δ 209.2, 173.4, 172.1, 143.6, 139.6, 123.5, 108.4, 74.4, 70.0, 63.6, 52.3, 51.6, 48.2, 45.2, 42.6, 34.5, 34.2, 33.8, 24.6, 17.5, 15.3.
EXAMPLE 12 Synthesis of 2-methoxymethyl-episalvinorin B (Compound 6)
10 mg of compound 5 was dissolved in 5 mL of anhydrous CH2Cl2 to which was added a catalytic amount of DMAP (1 mg), N,N-Diisopropylethylamine (2 eq) and MOM-Cl (2 eq) at room temperature and the reaction was stirred for 48 hours. After completion of the reaction, water was added (10 mL) to the reaction mixture followed by extraction with EtOAc (2×10 mL). The organic layer was dried (Na2SO4) and concentrated to afford a crude mixture. The crude mixture was further purified by column chromatography (1:2, EtOAC:Hexanes) to give the pure compound 6. 1H NMR (300 MHz, CDCl3): δ 7.41 (d, 2H), 6.38 (t, 1H), 5.30 (d, J=10.8 Hz, 1H), 4.697 (s, 2H), 4.06 (dd, J=7.2, 12.3 Hz, 1H), 3.69 (s, 3H), 3.37 (s, 3H), 2.68 (dd, J=3.3, 13.2 Hz, 1H), 2.46-2.31 (m, 3H), 2.24-2.11 (m, 3H), 2.02-1.82 (m, 2H), 1.65 (s, 3H), 1.59-1.41 (m, 3H), 1.26 (s, 3H). 13C NMR (70.5 MHz, CDCl3): δ 206.0, 171.5, 172.2, 143.6, 139.5, 123.6, 108.4, 95.8, 78.2, 70.1, 64.3, 55.8, 53.1, 51.6, 48.3, 45.4, 42.0, 34.8, 34.0, 32.5, 24.6, 17.6, 15.3.
EXAMPLE 13 Synthesis of Episalvinorin A (Compound 7)
10 mg of compound 5 was dissolved in 5 mL of anhydrous CH2Cl2 to which was added catalytic amount of DMAP (1 mg), pyridine (2 eq) and acetic anhydride (2 eq) at room temperature and the reaction was stirred for 1 hour. After completion of the reaction, water was added (10 mL) to the reaction mixture followed by extraction with EtOAc (2×10 mL). The organic layer was dried (Na2SO4) and concentrated to afford a crude mixture. The crude mixture was further purified by column chromatography (1:2, EtOAC:Hexanes) to give the pure compound 7. Yield: quantitative. 1H NMR (300 MHz, CDCl3): δ 7.43 (d, J=1.5 Hz, 1H), 7.38 (d, J=1.5 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 5.26 (dd, J=1.8, 12 Hz), 5.11 (t, 1H), 3.70 (s, 3H), 2.75 (t, 1H), 2.46 (d, J=2.7 Hz, 1H), 2.39-2.14 (m, 7H), 2.06-1.89 (m, 1H), 1.63 (s, 3H), 1.57-1.46 (m, 2H), 1.26 (m, 1H), 1.07 (s, 3H). 13C NMR (70.5 MHz, CDCl3): δ 202.3, 173.3, 171.8, 169.7, 143.5, 139.7, 123.4, 108.5, 75.2, 70.0, 64.0, 52.9, 51.7, 48.001, 45.2, 42.2, 34.7, 34.0, 30.7, 24.6, 20.5, 17.6, 15.2. The stereochemistry of 7 was confirmed by using H—H COSY, HMQC, and HMBC spectroscopies.
EXAMPLE 14 Synthesis of 2-methoxymethyl-salvinorin B (Compound 8)
10 mg of compound 1 was dissolved in 5 mL of anhydrous CH2Cl2 to which was added a catalytic amount of DMAP (1 mg), N,N-Diisopropylethylamine (2 eq) and MOM-Cl (2 eq) at room temperature and the reaction was stirred for 48 hours. After completion of the reaction, water was added (10 mL) to the reaction mixture followed by extraction with EtOAc (2×10 mL). The organic layer was dried (Na2SO4) and concentrated to afford a crude mixture. The crude mixture was further purified by column chromatography (1:2, EtOAc:Hexane) to give the pure compound 8. 1H-NMR: (300 MHz, CDCl3) δ 7.41 (d, 2H), 6.39 (d, J=0.6 Hz, 1H), 5.55 (dd, J=5.1, 11.7 Hz, 1H), 4.72 (q, 2H), 4.14 (dd, J=7.2, 12 Hz, 1H), 3.72 (s, 3H), 3.39 (s, 3H), 2.69 (dd, J=3.6, 13.5 Hz, 1H), 2.54 (dd, J=5.1, 13.2 Hz, 1H), 2.38-2.32 (m, 1H), 2.27-2.03 (m, 4H), 1.81-1.53 (m, 5H), 1.47 (s, 3H), 1.26 (s, 3H), 1.21 (s. 3H). 13C-NMR: (70.5 MHz, CDCl3) δ 205.8, 171.8, 171.2, 143.7, 139.4, 125.3, 108.3, 95.7, 77.8, 71.9, 64.3, 55.8, 53.9, 51.9, 51.5, 43.6, 41.9, 38.2, 35.5, 32.6, 18.1, 16.4, 15.2.
EXAMPLE 15 Synthesis of 2-(O-formamide)-salvinorin B (Compound 9)
To a cloudy solution of salvinorin B (17.4 mg, 45 μmol) in CH2Cl2 (2 mL) was added trichloroacetylisocyanate (20 μL, 0.17 mmol) and the solution was stirred at room temperature (10 minutes) under argon. Al2O3 (activated, 450 mg) was added and the mixture was stirred at room temperature (3 hours). The reaction mixture was concentrated to ˜0.5 mL and then purified by column chromatography (SiO2; 1:1, EtOAc:hexanes) to obtain 17.6 mg (91%) of pure 9 as a white solid: Rf 0.15 (1:1, EtOAc:hexanes); 1H NMR (CDCl3) δ 1.12 (s, 3H), 1.46 (s, 3H), 1.53-1.72 (m, 3H), 1.77-1.82 (m, 1H), 2.04-2.09 (m, 1H), 2.14-2.40 (m, 3H), 2.16 (s, 1H), 2.54 (dd, J=5.1, 13.2 Hz, 1H), 2.74 (dd, J=3.3, 13.2 Hz, 1H), 3.73 (s, 3H), 4.78 (br s, 2H), 5.08 (dd, J=7.5, 12.3 Hz, 1H), 5.53 (dd, J=5.1, 11.7 Hz, 1H), 6.38 (s, 1H), 7.38-7.41 (m, 2H); 13C NMR (CDCl3) 15.2, 16.4, 18.2, 31.0, 35.5, 38.2, 42.1, 43.4, 51.4, 51.9, 53.6, 64.1, 72.0, 75.5, 108.4, 125.3, 139.4, 143.7, 155.3, 171.1, 171.6, 203.0 ppm.
EXAMPLE 16 Synthesis of 2-(O—(N-methyl)formamide)-salvinorin B (Compound 10)
Compound 10 (11.0 mg, 68%) was prepared as a white solid from salvinorin B (14.1 mg, 36 μmol), DMAP (catalytic amount), pyridine (700 μL), and methyl isocyanate (32 μL, 540 μmol) utilizing the method of Scheme 1D. Rf 0.10 (1:2, EtOAc:hexanes); 1H NMR (CDCl3) δ 1.11 (s, 3H), 1.46 (s, 3H), 1.54-1.72 (m, 3H), 1.77-1.81 (m, 1H), 2.05-2.10 (m, 1H), 2.15-2.37 (m, 3H), 2.18 (s, 1H), 2.55 (dd, J=5.1, 13.5 Hz, 1H), 2.75 (dd, J=3.6, 13.2 Hz, 1H), 2.83 (d, J=4.8 Hz, 3H), 3.73 (s, 3H), 4.83-4.84 (m, 1H), 5.10 (dd, J=7.5, 12.0 Hz, 1H), 5.53 (dd, J=5.1, 11.7 Hz, 1H), 6.38 (s, 1H), 7.39-7.41 (m, 2H); 13C NMR (CDCl3) 15.2, 16.4, 18.1, 27.7, 31.1, 35.4, 38.2, 42.0, 43.4, 51.4, 52.0, 53.6, 64.0, 72.1, 75.2, 108.4, 125.2, 139.5, 143.7, 155.7, 171.1, 171.7, 203.5 ppm; HRMS (ES+) calcd for C23H30NO8 [M+H+]: 448.1971, found: 448.1981.
EXAMPLE 17 Synthesis of 2-(N-methylamino)-salvinorin (Compound 11)
Compound 11 (3.7 mg, 29%) was prepared as a white solid from salvinorin B (12.2 mg, 31 μmol), CH2Cl2 (1.5 mL), trifluoromethanesulfonic anhydride (25 μL, 149 μmol), pyridine (25 μL, 309 μmol), and ethylamine (2.0 N in THF, 1.5 mL) utilizing method Scheme 1E. Rf 0.42 (4:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.09 (s, 3H), 1.45 (s, 3H), 1.53-1.66 (m, 4H), 1.72-1.76 (m, 1H), 1.82-1.88 (m, 1H), 2.07-2.16 (m, 2H), 2.27 (s, 3H), 2.29-2.40 (m, 1H), 2.48 (dd, J=5.7, 13.5 Hz, 1H), 2.97 (s, 1H), 3.05-3.07 (m, 1H), 3.13 (dd, J=3.3, 13.5 Hz, 1H), 3.69 (s, 3H), 5.54 (dd, J=5.1, 11.7 Hz, 1H), 6.37-6.38 (m, 1H), 7.40-7.41 (m, 2H); 13C NMR (CDCl3) 15.2, 16.2, 18.1, 32.2, 34.6, 34.9, 38.4, 43.0, 43.4, 50.6, 51.4, 59.5, 67.1, 72.0, 79.6, 108.4, 125.6, 139.4, 143.7, 171.6, 173.1, 211.4 ppm; HRMS (ES+) calcd for C22H30NO6 [M+H+]: 404.2073, found: 404.2065.
EXAMPLE 18 Synthesis of 2-(2′-(N,N-dimethylamino)acetate) salvinorin B (Compound 12)
Compound 12 (4.8 mg, 51%) was prepared as a white solid from salvinorin B (7.8 mg, 20 μmol), N,N-dimethylglycine (6.3 mg, 61 μmol), DMAP (0.6 mg, 5 μmol), 1.0 M DCC in CH2Cl2 (60 μL), and CH2Cl2 (2 mL) using the method of Scheme 1B. Rf 0.07 (4:1, CH2Cl2:EtOAc); 1H NMR(CDCl3) δ 1.11 (s, 3H), 1.45 (s, 3H), 1.54-1.67 (m, 3H), 1.78-1.82 (m, 2H), 2.07 (dd, J=2.7, 10.7 Hz, 1H), 2.18 (s, 1H), 2.29-2.37 (m, 2H), 2.40 (s, 6H), 2.50 (dd, J=5.4, 13.2 Hz, 1H), 2.76 (t, J=8.4 Hz, 1H), 3.30 (d, J=16.7 Hz, 1H), 3.35 (d, J=16.7 Hz, 1H), 3.73 (s, 3H), 5.21 (t, J=10.2, 1H), 5.53 (dd, J=5.3, 11.9 Hz, 1H), 6.38 (s, 1H), 7.39-7.42 (m, 2H); 13C NMR (CDCl3) 15.2, 16.4, 18.1, 30.8, 35.5, 38.2, 42.1, 43.3, 45.3, 51.4, 52.0, 53.6, 60.0, 64.1, 72.0, 75.1, 108.4, 125.2, 139.4, 143.7, 169.7, 171.1, 171.5, 201.5 ppm; HRMS (ES+) calcd for C25H34NO8 [M+H+]: 476.2284, found: 476.2277.
EXAMPLE 19 Synthesis of C(2) Ethers
Compounds 13-17, 71, and 72 were prepared using the method of Scheme 1C.
Compound 73 was prepared as follows: to a solution of salvinorin B (150.0 mg, 0.38 mmol, 1 eq), PPh3 (300.0 mg, 1.15 mmol, 3 eq), and 4-nitrobenzoic acid (192.5 mg, 1.15 mmol, 3 eq) in CH2Cl2 (30 mL) was added diisopropylazodicarboxylate (230 μL, 1.15 mmol, 3 eq) dropwise. The reaction solution was stirred at room temperature (3.5 hours). Saturated NaHCO3 (30 mL) was added. The organic layer washed with brine (30 mL), dried (MgSO4) and concentrated. The residue was purified by column chromatography (SiO2; 19:1, CH2Cl2:EtOAc) to obtain the 4-nitrobenzoate as a white solid. K2CO3 (52.5 mg, 0.38 mmol, 1 eq) was added to a cold (0° C.) suspension of the intermediate in MeOH (10 mL). The reaction mixture was stirred at 0° C. (10 minutes) and was concentrated. CH2Cl2 (10 mL) and aqueous 1 N HCl (10 mL) were added to the residue. The organic layer washed with brine (10 mL), dried (MgSO4), and concentrated. The reaction solution was concentrated and the residue was purified by column chromatography (SiO2; 9:1, CH2Cl2:EtOAc to 4:1, CH2Cl2:EtOAc) to obtain the desired product (95.5 mg, 64%) as a white solid: Rf 0.53 (4:1, CH2Cl2:EtOAc).
EXAMPLE 20 Synthesis of C(2) Amines and Related Structures
Compounds 18, 19, 75, 76, 77, and 79 were prepared using the method of Scheme 1E.
Compounds 80, 82, 83, and 84 were prepared using the method of Scheme 1F.
Compound 78 was prepared as follows: sodium azide (21.9 mg, 0.34 mmol, 1.1 eq) was added to a cold (0° C.) solution of 79 (129.0 mg, 0.31 mmol, 1 eq) in DMF (2 mL). The reaction mixture was stirred at 0° C. (1 hour). EtOAc (20 mL) and H2O (20 mL) were added to the reaction mixture. The organic layer was washed with saturated NaHCO3 (20 mL), brine (20 mL), dried (MgSO4), and volatiles were evaporated. The residue was purified by column chromatography (SiO2; 2:1, hexanes:EtOAc) to obtain the desired product (63.1 mg, 50%) as a white solid: Rf 0.36 (2:1, hexanes:EtOAc); HRMS (ES+) calcd for C21H26N3O6 [M+H+]: 416.1821, found: 416.1824.
Compound 74 was prepared as follows: A CH2Cl2 (1 mL) solution of PPh3 (20.9 mg, 0.080 mmol, 1.1 eq) was added to a CH2Cl2 (1 mL) solution of 78 (30.0 mg, 0.072 mmol, 1 eq). The reaction mixture was stirred at room temperature (1.5 hours). EtOAc (20 mL) and H2O (20 mL) were added to the reaction mixture. The organic layer washed with saturated NaHCO3 (20 mL), brine (20 mL), dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2; 2:1, hexanes:EtOAc) to obtain the desired product (63.1 mg, 50%) as a white solid: Rf 0.36 (2:1, hexanes:EtOAc).
Compound 81 was prepared as follows: a CH2Cl2 solution of triethylamine (3 μL, 0.022 mmol, 1.25 eq) and the acyl chloride or anhydride (2 μL, 0.022 mmol, 1.25 eq) was added to 11 (7.0 mg, 0.017 mmol, 1 eq). The reaction solution was stirred at room temperature (10 minutes). The reaction was concentrated and the residue was purified by column chromatography (SiO2; 4:1, CH2Cl2:EtOAc) to obtain the desired product (5.7 mg, 71%) as a white solid: Rf 0.25 (4:1, CH2Cl2:EtOAc).
Compound 85 was prepared as follows: Trichloroacetylisocyanate (9 μL, 0.077 mmol, 5 eq) was added to a CH2Cl2 (1 mL) solution of 74 (6.0 mg, 0.015 mmol, 1 eq). The reaction mixture was stirred at room temperature (5 minutes). The reaction solution was concentrated and the residue was purified by column chromatography (SiO2; 4:1, CH2Cl2:EtOAc) to obtain the desired product (4.7 mg, 53%) as a white solid: Rf 0.53 (19:1, CH2Cl2:MeOH).
EXAMPLE 21 Synthesis of C(2) Carbamates
Compound 20, 86, 87, and 88 was prepared using the method of Scheme 1D.
EXAMPLE 22 Synthesis of C(2) Esters
Compounds 21-27 and 89-92 were prepared using the method of Scheme 1B.
Compounds 93 and 94 were prepared using the method of Scheme 1A.
Compound 28 was prepared from salvinorin B according to the following procedure: To a cold (0° C.) suspension of salvinorin B (8.8 mg, 23 mmol) and succinic anhydride (5.6 mg, 56 mmol) was added DBU (10 mL, 68 mmol) dropwise. The reaction mixture was stirred at 0° C. (15 minutes), washed with aqueous 3% citric acid, saturated aqueous NaHCO3, brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography (SiO2; 19:1, CH2Cl2:MeOH) to obtain 5.4 mg (49%) of pure 28 as a colorless oil.
EXAMPLE 23 Synthesis of C(2) Carbonates
To a solution of Salvinorin-B (15 mg, 1 equivalent) in dry dichloromethane (2 mL), was added alkyl chloroformate (5 equivalents) followed by DMAP (5 mg) and the mixture stirred at room temperature for 15 hours. TLC was used to monitor the progress of the reaction. After the reaction was complete the reaction mixture was diluted with dichloromethane, washed with water, and dried over anhydrous Na2SO4. The organic solvent was removed under vacuum. The resulting crude product was purified by column chromatography (20% ethyl acetate in hexane as the eluent) to obtain 2-substituted salvinorin carbonate as a colorless solid.
EXAMPLE 24 Synthesis of C(4) Derivatives
To a solution of Salvinorin A (0.5 g, 1.15 mmol, 1 eq) in dry pyridine (10 mL), was added lithium iodide (0.76 g, 5.70 mmol, 5 equivalents). The reaction mixture was wrapped with an aluminum foil and heated to reflux for 36 hours. The volatiles were removed under vacuum, and the residue was quenched with ice and treated with 5% aqueous HCl until slightly acidic followed by extraction with ethyl acetate. The organic layer washed with water, dried over anhydrous Na2SO4, and purified by column chromatography over silica gel (mobile phase: ethyl acetate/hexane followed by ethyl acetate, and finally by 10% methanol in ethyl acetate). Eluting sequentially were epi-Salvinorin A (25 mg, 5%), recovered Salvinorin A (20 mg, 4%), epi-demethyl Salvinorin (31, 100 mg, 23%) and demethyl Salvinorin (32, 150 mg, 33%), respectively. Compound 31: 1H NMR (CDCl3, 300 MHz): 1.14 (s, 3H, CH3), 1.46 (s, 3H, CH3), 1.65 (m, 1H), 1.90 (m, 1H), 2.05 (s, 1H), 2.10 (m, 1H), 2.18 (s, 3H, CH3), 2.30 (m, 1H), 2.50 (dd, J=4 Hz, 12 Hz, 1H), 2.80 (dd, J=5 Hz, 10 Hz, 1H), 5.20 (dd, J=8 Hz, 10.2 Hz, 1H), 5.50 (dd, J=6 Hz, 8.5 Hz, 1H), 6.38 (s, 1H), 7.40 (s, 1H), 7.41 (s,1H); 13CNMR (CDCl3, 75 MHz): 15.19, 16.42, 18.10, 20.55, 30.59, 35.44, 38.07, 42.02, 43.30, 51.29, 53.36, 63.95, 72.08, 74.90, 108.35, 125.13, 139.43, 143.73, 170.00, 171.27, 175.75, 201.87. Compound 32: 1H NMR(CDCl3, 300 MHz): 1.10 (s, 3H, CH3), 1.50 (m, 2H), 1.64 (s, 3H, CH3), 1.76 (m, 1H), 1.85 (m, 1H), 2.05 (m, 1H), 2.16 (s, 3H, CH3), 2.20 (m, 1H), 2.35 (m, 2H), 2.47 (d, J=3 Hz, 1H), 2.80 (dd, J=3 Hz, 5.1 Hz, 1H), 5.10 (dd, J=7.8 Hz, 10 Hz, 1H), 5.30 (d, J=12 Hz, 1H), 6.38 (s, 1H), 7.38 (s, 1H), 7.44 (s,1H); 13CNMR (CDCl3, 75 MHz): 15.26, 17.52, 20.53, 24.60, 30.51, 33.82, 34.71, 42.14, 45.18, 47.86, 52.65, 63.90, 70.10, 75.11, 108.50, 123.28, 139.71, 143.58, 169.91, 173.71, 176.20, 202.35.
C(4) Esters
To a solution of the acid (31 or 32, 1 equivalent) in dry dichloromethane was added corresponding alcohol (1.5 equivalents), DCC (1.5 equivalents) and DMAP (catalytic amount). The reaction mixture was stirred at room temperature for 15 hours under an inert atmosphere, followed by quenching with water and filtration to remove the insoluble white solid. The reaction mixture was then diluted with dichloromethane and washed with saturated ammonium chloride solution and dried over anhydrous sodium sulfate. Volatiles were removed under vacuum and the crude reaction mixture was purified by chromatography on silica gel with 25% ethyl acetate in hexane as the eluent to obtain pure esters.
C(4) Amides
To a solution of the acid (31 or 32, 1 equivalent) in dry DMF was added the corresponding amine or amino acid (2.0 equivalents), HOBt (1.5 equivalents) and EDCI (1.5 equivalents). The reaction mixture was stirred at room temperature for 24 hours under an inert atmosphere. Volatiles were removed under vacuum. The reaction mixture was then diluted with ethyl acetate, washed with water and saturated ammonium chloride solution, and dried over anhydrous sodium sulfate. Volatiles were removed under vacuum and the crude reaction mixture was purified by chromatography on silica gel with ethyl acetate in hexane (gradient ratio as needed) as the eluent to obtain pure amides.
EXAMPLE 25 Synthesis of Tetrahydrofuranyl Derivatives
Salvinorin A (9.0 mg, 21 mmol) in EtOAc (10 mL) was hydrogenated in the presence of 5% Pt/C (catalytic amount) at room temperature (3 days). The solution was concentrated in vacuo and the residue was purified by column chromatography (SiO2; 19:1, CH2Cl2:MeOH) to obtain 3.5 mg (36%) of pure 62 as a white solid: Rf 0.50 (19:1, CH2Cl2:MeOH).
EXAMPLE 26 Synthesis of C(17) Derivatives
Synthesis of compound 66: To a solution of Salvinorin A (43 mg, 100 mmol) in 5 mL of dry THF under inert atmosphere was added lithium tri-t-butoxyaluminohydride (0.5 M, 0.6 ml, 600 mmol) and the mixture heated to reflux for 8 hours. The reaction mixture was cooled in an ice bath and quenched with dilute HCl and stirred at room temperature for 30 minutes. Volatiles were removed under vacuum and the reaction mixture extracted with chloroform, washed with water, and dried. The crude product was purified by column chromatography on a silica gel column (25% ethyl acetate in hexane) to obtain 10 mg of unreacted starting material followed by 30 mg (60% Yield) of compound 66 as a colourless solid. 1H NMR (CDCl3, 300 MHz): 1.08 (s, 3H, CH3), 1.40 (s, 3H, CH3), 2.15 (s, 3H, CH3), 2.80 (m, 2H), 3.71 (s, 3H, COOCH3), 4.80 (d, J=9 Hz, 1H), 4.90 (d, J=12 Hz, 1H), 6.38 (d, J=0.3 Hz, 1H), 7.38 (m, 2H); 13C NMR (CDCl3, 75 MHz): 15.00, 16.74, 17.68, 20.61, 30.89, 35.69, 38.85, 42.41, 44.76, 51.81, 52.23, 53.72, 65.44, 66.30, 75.06, 94.19, 108.80, 126.21, 139.12, 143.07, 169.90, 171.90, 202.49.
Synthesis of compound 67: To a solution of compound 66 (4 mg, 10 mmol) in 1 mL of dry MeOH under inert atmosphere was added trimethylsilylchloride (0.1 ml, 80 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. Volatiles were removed under vacuum and the reaction mixture was extracted with methylene chloride, washed with water, and dried. The crude product was purified by column chromatography on a silica gel column (25% ethyl acetate in hexane) to obtain 3.2 mg (78% Yield) of compound 67 as a colourless oil. 1H NMR (CDCl3, 300 MHz): 1.08 (s, 3H, CH3), 1.40 (s, 3H, CH3), 2.80 (m, 2H), 3.71 (s, 3H, COOCH3), 3.50 (s, 3H), 4.80 (d, J=9 Hz, 1H), 4.90 (d, J=12 Hz, 1H), 6.38 (d, J=0.3 Hz, 1H), 7.38 (m, 2H).
EXAMPLE 27 Synthesis of Lactone Ring Cleaved Derivatives
Synthesis of compound 68: To a solution of Salvinorin A (21.5 mg, 50 mmol) in dry THF (5 ml) was added lithium aluminium hydride (1 M in THF, 0.15 ml, 150 mmol) at 0° C. and the mixture stirred at room temperature for 4 hours. The reaction was quenched with dilute HCl until slightly acidic according to pH paper. Volatiles were removed under vacuum and the product extracted with chloroform (3×10 mL), washed with water and dried. The crude product was purified by column chromatography (silica gel/ethyl acetate and 3% ethyl acetate in methanol) to afford 10 mg (60% yield) of compound 68. 1H NMR (CD3OD, 300 MHz): 1.07 (s, 3H, CH3), 1.20 (m, 2H), 1.34 (s, 3H, CH3), 1.50 (m, 1H), 1.80 (m, 2H), 3.10 (m, 1H), 3.30 (m, 1H), 3.70 (m, 1H), 4.10 (s, 1H), 4.65 (d, J=9 Hz, 1H), 4.85 (d, J=11 Hz, 1H), 6.35 (s, 1H), 7.32 (d, J=1.8 Hz, 1H), 7.36 (s, 1H); 13C NMR (CDCl3, 75 MHz): 16.75, 18.47, 19.56, 29.76, 37.54, 38.52, 42.23, 47.15, 50.69, 55.07, 58.92, 62.85, 67.62, 70.18, 73.93, 95.71, 110.06, 128.85, 140.38, 144.10.
Synthesis of compound 69: A solution of salvinorin A (14 mg, 32 mmol) in methylamine (2.0 M in THF, 2 mL) was stirred at room temperature (18 hours). The solution was concentrated in vacuo and the residue was purified by column chromatography (SiO2; 19:1, CH2Cl2:MeOH) to obtain 9.1 mg (67%) of pure 66 as a white solid: Rf 0.14 (19:1, CH2Cl2:MeOH).
EXAMPLE 28 Synthesis of C(1) Deoxy Derivatives
Synthesis of compound 70: To a solution of Salvinorin A (21.5 mg, 50 mmol) in 1.5 mL methanol was added Ba(OH)2 (17 mg, 100 mmol) with stirring at room temperature. The reaction mixture turned a deep red color and after 1 hour the reaction was quenched with ice, neutralized with dilute HCl, and extracted with chloroform (2×10 ml). The organic layer was dried over anhydrous sodium sulfate and the crude product was purified by column chromatography (silica gel/20% ethyl acetate in Hexane) to obtain 14 mg (75%) of compound 70. 1H NMR (CDCl3, 300 MHz): 1.68 (s, 3H, CH3), 1.75 (s, 3H, CH3), 2.0 (m, 2H), 2.25 (m, 1H), 2.50 (m, 1H), 3.00 (m, 1H), 3.10 (m, 1H), 3.83 (s, 3H, COOCH3), 5.40 (dd, J=2.4 Hz, 7.5 Hz, 1H), 6.40 (d, J=0.7 Hz, 1H), 6.92 (s, 1H), 6.98 (s, 1H), 7.40 (m, 1H), 7.48 (m, 1H); 13C NMR (CDCl3, 75 MHz): 21.91, 24.98, 28.35, 30.20, 36.80, 37.70, 42.28, 44.90, 52.59, 70.87, 108.42, 124.57, 128.19, 139.61, 139.93, 143.64, 145.64, 157.50, 165.37, 173.10, 180.74.
EXAMPLE 29 Radioligand Binding AssaysCompounds can be characterized in radioligand receptor binding assays, using ligands that are specific for the mu, delta and kappa receptors. The binding assays may utilize guinea pig brain membranes or stably transfected Chinese Hamster Ovary (CHO) cells expressing each of the three opioid receptors. Membranes can be isolated from CHO cells that stably express either the human mu, delta or kappa opioid receptors. At approximately 80% confluence, the cells are harvested by the use of a cell scraper. The cells and media from the plates are centrifuged at 200×g for 10 mm at 4° C.; resuspended in 50 mM Tris-HCl, pH 7.5; homogenized by the use of a Polytron; centrifuged at 48,000×g for 20 mm at 4° C.; and resuspended in 50 mM Tris-HCl, pH 7.5, at a protein concentration of 5-10 mg/ml, as determined by the Bradford method. The membranes are stored frozen, at −80° C. until use.
Cell membranes are incubated at 25° C. with the radiolabeled ligands in a final volume of 1 ml of 50 mM Tris-HCl, pH 7.5. Incubation times of 60 minutes are used for the mu-selective peptide [3H]DAMGO and the kappa-selective ligand [3H]Diprenorphine, and 4 hours of incubation for the delta-selective antagonist [3H]naltrindole. Nonspecific binding is measured by inclusion of 1 μM naloxone. The binding can be terminated by filtering the samples through Schleicher & Scheull No. 32 glass fiber filters using a Brandel 48-well cell harvester. The filters are subsequently washed three times with 3 mL of cold 50 mM Tris-HCl, pH 7.5, and can be counted in 2 ml of Ecoscint A scintillation fluid. For [3H]Diprenorphine binding, the filters are soaked in 0.1% polyethylenimine for at least 30 minutes before use. IC50 values can be calculated by a least squares fit to a logarithm-probit analysis. Ki values of unlabeled compounds are calculated from the equation Ki=(IC50)/1+S where S=(concentration of radioligand)/(Kd of radioligand). Cheng and Prusoff, Biochem. Pharmacol. 22:3099 (1973). Alternatively, guinea pig brain membranes can be prepared and used as previously described in Neumeyer, et al., J. Med. Chem. 43:114 (2000). For further details see Huang et al., J. Pharmacol. Exp. Ther. 297:688 (2001); and Zhu et al., J. Pharmacol. Exp. Ther. 282:676 (1997). Other buffers may be used in the binding assay.
EXAMPLE 30 [35S]GTPγS Binding AssaysMembranes from the CHO cell lines, expressing either the mu, delta or kappa receptor, are incubated with 12 concentrations of each compound for 60 minutes at 30° C. in a final volume of 0.5 ml of assay buffer (50 mM Tris-HCl, 3 mM MgCl2, 0.2 mM EGTA, 100 mM NaCl, pH 7.5) containing 3 μM GDP and 0.08 nM [35S]GTPγS. Basal binding can be determined in the presence of GDP and the absence of test compounds, and nonspecific binding can be determined by including 10 μM unlabeled [35S]GTPγS. The incubation can be terminated by filtration under vacuum through glass fiber filters, followed by three washes with 3 ml ice-cold 50 mM Tris-HCl, pH 7.5. Samples can be allowed to equilibrate overnight and can be counted in 2 ml Ecoscint A scintillation fluid for 2 minutes in a liquid scintillation counter.
For [35S]GTPγS binding assays, percent stimulation of [35S]GTPγS binding is defined as [(stimulated binding-basal binding) basal binding]×100. Percent stimulation is plotted as a function of compound concentration (log scale), and EC50 and Emax values are determined by linear regression analysis. All data is compared across conditions using ANOVA and non-paired two-tailed Student's tests. For further details see Huang et al., J. Pharmacol. Exp. Ther. 297:688 (2001); and Zhu et al., J. Pharmacol. Exp. Ther. 282:676 (1997).
EXAMPLE 31 Forced Swim Test (FST)The FST is a two day procedure in which rats swim under conditions in which escape is not possible. On the first day, the rats are forced to swim for 15 minutes. The rats initially search for an escape from the water, but eventually adopt a posture of immobility in which they make only the movements necessary to keep their heads above water. Upon re-testing one day later, latencies to become immobile (an indicator of how rapidly the rats “give up” in response to a familiar stressor) are decreased, which is inferred as despair. Standard antidepressants such as desipramine (DMI) and fluoxetine (FLX) extend latencies to become immobile. Drug efficacy in this animal model is predictive of antidepressant efficacy in humans. The FST has been described by Mague et al., J. Pharmacol. Exp. Ther. 305:323 (2003).
Salvinorin A produces depressive-like effects in the forced swim test in rats without affecting locomotor activity (see
Intracranial self-stimulation (ICSS) is highly sensitive to the function of brain reward systems. In this assay, rodents respond to self-administer rewarding electrical stimulation through electrodes implanted within the limbic system. Changes in the rewarding efficacy of the stimulation shift the rate-frequency functions: leftward shifts (reflecting decreases in ICSS thresholds) imply that the stimulation is more rewarding as a result of a treatment, whereas rightward shifts (reflecting increases in thresholds) imply that it is less rewarding. The effects of many types of treatments on ICSS have been described. Most drugs of abuse decrease the amount of stimulation required to sustain responding: this is indicated by leftward shifts in rate-frequency functions and decreased ICSS thresholds. Conversely, agents that block drug reward (dopamine or kappa-opioid receptor agonists) increase the amount of stimulation required to sustain responding: this is indicated by rightward shifts in rate-frequency functions, and increased ICSS thresholds. Thus ICSS is sensitive to manipulations that increase or decrease reward.
Considering that mania is typically associated with increases in reward-driven behavior, the ICSS test may be a reasonable model of mania. Thus drugs that reduce the rewarding effects of the electrical stimulation may have some efficacy in the treatment of mania or related states.
We have found that intraperitoneal administration of 1.0 mg/kg of salvinorin A (a dose with depressive-like effects as demonstrated in the forced swim test (FST) in rats) significantly elevates ICSS thresholds (see
The affinities (Ki), potencies (EC50) and efficacies of test compounds on human kappa opioid receptor were measured. 2-methoxymethyl-salvinorin B was found to be seven times more potent than salvinorin A. The results are summarized in Table 1.
1Percent of the maximal effect of U50,488H.
2N.A. is No Affinity.
The C(4) position of a salvinorin derivative can be converted to a methyl ketone using the general procedure shown in Scheme 6, among others.
The preparation of C(2) esters, alcohol, and ethers with natural configuration at C(2) (202a-206a) and unnatural configuration 201b-206b (the “2-epi” compounds, compound number designated with a ‘b’) were prepared (Scheme 7). Standard acylation conditions (Ac2O or propionyl chloride, Et3N, CH2Cl2) were then used to yield esters 203b and 204b, respectively. Salvinorin analogues 205b and 206b were readily obtained by O-alkylation of 202b with methyl and ethyl iodide, respectively.
The synthetic routes to C(2) amines and amides 207-217 are depicted in Scheme 8.
-
- NaN3, DMF, 53% yield for the preparation of 29; (e) PPh3; (f) H2O, THF, 35%, over three steps; (g) NaN3, DMSO, 29-48% yield; (h) SOCl2, Et3N, ClCH2CH2Cl, 70% yield; (i) TMSCl, NaI, CH3CN, 16% yield.
Scheme 9 describes the modifications at the C(18) position.
Further synthetic details are provided below.
Method A: To a CH2Cl2 solution of 1 (1 equiv) was added Et3N (2 equiv) and the acyl chloride (2 equiv) or Ac2O (2 equiv) and the solution was stirred at room temperature (10-240 min). The reaction was concentrated in vacuo and the residue was purified by column chromatography (SiO2; EtOAc13 CH2Cl2) to obtain the desired product.
Method B: To a stirred CH3CN solution of 1 (1 equiv) was added Ag2O (10 equiv) and the alkyl halide (20 equiv) and the reaction was stirred (60° C., 3 d). The reaction mixture was concentrated and crude was purified by column chromatography (SiO2; EtOAc-hexanes) to obtain the desired product.
Method C: To a cold (0° C.) suspension of 1 (1 equiv) in CH2Cl2 was added pyridine (excess) and trifluoromethanesulfonic anhydride (excess) and the reaction solution was stirred at 0° C. (1 h). The reaction solution washed with aqueous 1 N HCl (2 mL), brine (2 mL), dried (MgSO4) and evaporated. A solution of the triflate (1 equiv) in amine (excess) was then stirred (0-60° C., 10 min-18 h). In select cases, CH2Cl2 was added. The solution was concentrated in vacuo and the residue was purified by column chromatography (SiO2; CH2Cl2-EtOAc or CH2Cl2-CH3OH) to obtain the desired product.
Method D: To a solution of 218 (as a mixture of C(8)-epimers), EDCI (1.2-2 equiv), and DMAP (catalytic amount) in CH2Cl2 was added the amine (1.3-2.4 equiv), and the reaction was stirred at room temperature (5-60 min). The solution was concentrated in vacuo, and the residue was purified by column chromatography (SiO2; EtOAc-hexanes) to obtain the desired product.
Method E: To a cold (0° C.) solution of 222 (1 equiv) in CH2Cl2 was added excess pyridine and trifluoromethanesulfonic anhydride. The reaction solution was stirred at 0° C. for 5 min, quenched with aqueous 1 N HCl (1 mL), washed with brine (1 mL), dried (MgSO4), and evaporated to dryness. The crude triflate (1 equiv) was taken up in a THF solution of the amine (excess) and stirred at room temperature (5-10 min). The solution was concentrated in vacuo, and the residue was purified by column chromatography (SiO2; CH2Cl2-CH3OH) to obtain the desired product.
Synthesis of 2-epi-salvinorin A (201b). To a CH2Cl2 (2 mL) suspension of salvinorin B (50.0 mg, 0.13 mmol), PPh3 (100.0 mg, 0.38 mmol), and AcOH (22 μL, 0.38 mmol) was added diisopropylazodicarboxylate (75 μL, 0.38 mmol) dropwise. The opaque solution was stirred at room temperature (18 h). The reaction was concentrated and the residue was purified by column chromatography (SiO2; 19:1, CH2Cl2:EtOAc) and crystallization from CH3OH to obtain the desired product (21.1 mg, 38% yield) as a white solid: Rf 0.25 (19:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.09 (s, 3H), 1.40-1.48 (m, 1H), 1.46 (s, 3H), 1.56-1.68 (m, 2H), 1.77-1.82 (m, 1H), 2.08-2.22 (m, 3H), 2.13 (s, 3H), 2.28-2.39 (m, 1H), 2.45 (dd, J=5.3, 13.3 Hz, 1H), 2.53 (s, 1H), 2.89 (dd, J=3.7, 12.8 Hz, 1H), 3.71 (s, 3H), 4.84-4.86 (m, 1H), 5.54 (dd, J=5.2, 11.9 Hz, 1H), 6.37-6.38 (m, 1H), 7.40-7.41, (m, 2H); 13C NMR (CDCl3) 15.2, 16.1, 18.1, 20.9, 30.9, 35.0, 38.6, 43.0, 43.5, 50.9, 51.4, 51.9, 61.7, 72.1, 76.5, 108.3, 125.5, 139.2, 143.7, 169.3, 171.2, 172.1, 204.3 ppm; HRMS (ES+) calcd for C23H29O8 [M+H+]: 433.1862, found: 433.1849.
Synthesis of 2-epi-salvinorin B (202b). To a CH2Cl2 (30 mL) solution of salvinorin B (150.0 mg, 0.38 mmol), PPh3 (300.0 mg, 1.15 mmol), and 4-nitrobenzoic acid (192.5 mg, 1.15 mmol) was added diisopropylazodicarboxylate (230 μL, 1.15 mmol) dropwise. The reaction solution was stirred at room temperature (3.5 h). Saturated aqueous NaHCO3 (30 mL) was added. The organic layer washed with brine (30 mL), dried (MgSO4) and concentrated. The residue was purified by repeated column chromatography (SiO2; 19:1, CH2Cl2:EtOAc) to obtain the 4-nitrobenzoate intermediate as a white solid. K2CO3 (52.5 mg, 0.38 mmol, 1 equiv) was added to a cold (0° C.) suspension of the intermediate in CH3OH (10 mL). The reaction mixture was stirred at 0° C. (10 min) and was concentrated. CH2Cl2 (10 mL) and aqueous 1 N HCl (10 mL) were added to the residue. The organic layer washed with brine (10 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography (SiO2; 9:1, CH2Cl2:EtOAc to 4:1, CH2Cl2:EtOAc) to obtain the desired product (95.5 mg, 64%) as a white solid: Rf 0.53 (4:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.09 (s, 3H), 1.44 (s, 3H), 1.55-1.78 (m, 4H), 2.03-2.20 (m, 3H), 2.27-2.37 (m, 1H), 2.51 (dd, J=5.2, 13.3 Hz, 1H), 2.84 (s, 1H), 3.05 (dd, J=3.6, 13.2 Hz, 1H), 3.71 (s, 3H), 4.02-4.06 (m, 1H), 5.55 (dd, J=5.1, 11.7 Hz, 1H), 6.38-6.39 (m, 1H), 7.40-7.42 (m, 2H); 13C NMR (CDCl3) 15.0, 16.2, 18.1, 32.9, 34.9, 38.4, 42.5, 43.4, 50.0, 51.4, 51.7, 60.2, 72.0, 74.0, 108.4, 125.5, 139.4, 143.7, 171.4, 172.9, 208.6 ppm; HRMS (ES+) calcd for C21H27O7 [M+H+]: 391.1757, found: 391.1767.
Synthesis of 2-epi-salvinorin B propionate (203b). Compound 203b (5.9 mg, 65%) was prepared as a white solid from 202b (8.0 mg, 21 μmol), Et3N (5.7 μL, 42 μmol), and propionyl chloride (3.6 μL, 42 μmol) utilizing method A: Rf 0.40 (19:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.10 (s, 3H), 1.16 (t, J=7.8 Hz, 3H), 1.38-1.42 (m, 1H), 1.47 (s, 3H), 1.57-1.68 (m, 2H), 1.79-1.82 (m, 1H), 2.05-2.22 (m, 3H), 2.29-2.49 (m, 4H), 2.52 (s, 1H), 2.89 (dd, J=3.6, 13.2 Hz, 1H), 3.71 (s, 3H), 4.84-4.86 (m, 1H), 5.54 (dd, J=4.9, 11.6 Hz, 1H), 6.37-6.38 (m, 1H), 7.40-7.41 (m, 2H); 13C NMR (CDCl3) 9.1, 15.2, 16.0, 18.1, 27.5, 30.9, 35.0, 38.7, 43.1, 43.5, 51.0, 51.4, 51.8, 61.7, 72.0, 76.4, 108.3, 125.5, 139.2, 143.7, 171.2, 172.2, 172.9, 204.5 ppm; HRMS (ES+) calcd for C24H31O8 [M+H+]: 447.2019,found: 447.2023.
Synthesis of 2-epi-salvinorin B butyrate (204b). Compound 204b (7.3 mg, 73%) was prepared as a white solid from 202b (8.5 mg, 22 μmol), Et3N (6.1 μL, 44 μmol), and butyryl chloride (4.5 μL, 44 μmol) utilizing method A: Rf 0.60 (19:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 0.95 (t, J=7.4 Hz, 3H), 1.10 (s, 3H), 1.39-1.43 (m, 1H), 1.47 (s, 3H), 1.57-1.70 (m, 5H), 1.79-1.83 (m, 1H), 2.07-2.24 (m, 3H), 2.29-2.48 (m, 4H), 2.53 (s, 1H), 2.89 (dd, J=3.4 Hz, J=13.1 Hz, 1H), 3.71 (s, 3H), 4.84-4.86 (m, 1H), 5.54 (dd, J=5.1, 11.4 Hz, 1H), 6.37 (br s, 1H), 7.40-7.41 (m, 2H); 13C NMR (CDCl3) 13.6, 15.2, 16.0, 18.1, 18.4, 30.9, 34.9, 35.9, 38.6, 43.1, 43.5, 51.0, 51.4, 51.8, 61.6, 72.0, 76.2, 108.2, 125.5, 139.2, 143.7, 171.2, 172.1, 172.2, 204.5 ppm; HRMS (ES+) calcd for C25H33O8 [M+H+]: 461.2175, found: 461.2166.
Synthesis of 2-epi-(O-methyl)-salvinorin B (205b). Compound 205b (7.0 mg, 68%) was prepared as a white solid from 202b (10.0 mg, 26 μmol), CH3CN (1.5 mL), Ag2O (59.0 mg, 0.26 mmol), and iodomethane (32 μL, 0.51 mmol) utilizing method B: Rf 0.58 (1:1, EtOAc:hexanes); 1H NMR (CDCl3) δ 1.08 (s, 3H), 1.45 (s, 3H), 1.53-1.67 (m, 3H), 1.73-1.77 (m, 1H), 2.05-2.28 (m, 4H), 2.50 (dd, J=5.1, 13.2 Hz, 1H), 2.72 (s, 1H), 2.98 (dd, J=4.1, 12.8 Hz, 1H), 3.26 (s, 3H), 3.45-3.47 (m, 1H), 3.70 (s, 3H), 5.56 (dd, J=5.1, 11.7 Hz, 1H), 6.39 (d, J=1.2 Hz, 1H), 7.40-7.42 (m, 2H); 13C NMR (CDCl3) 15.1, 16.1, 18.1, 31.4, 34.9, 38.4, 42.7, 43.5, 50.5, 51.4, 51.6, 57.1, 60.6, 71.9, 83.0, 108.3, 125.5, 139.3, 143.7, 171.4, 172.9, 209.4 ppm; HRMS (ES+) calcd for C22H29O7 [M+H+]: 405.1913, found: 405.1899.
Synthesis of 2-epi-(O-ethyl)-salvinorin B (206b). Compound 206b (7.2 mg, 52%) was prepared as a white solid from 202b (13.0 mg, 33,mol), CH3CN (2 mL), Ag2O (77.0 mg, 0.33 mmol), and iodoethane (53 μL, 0.66 mmol) utilizing method B: Rf 0.58 (1:1, EtOAc:hexanes); 1H NMR (CDCl3) δ 1.08 (s, 3H), 1.19 (t, J=6.9 Hz, 3H), 1.45 (s, 3H), 1.53-1.77 (m, 4H), 2.07-2.28 (m, 4H), 2.49 (dd, J=5.1, 13.2 Hz, 1H), 2.75 (s, 1H), 3.01 (dd, J=3.7, 13.1 Hz, 1H), 3.33-3.46 (m, 2H), 3.57 (t, J=3.0 Hz, 1H), 3.70 (s, 3H), 5.55 (dd, J=5.1, 11.7 Hz, 1H), 6.38-6.39 (m, 1H), 7.41-7.42 (m, 2H); 13C NMR (CDCl3) 15.1, 15.4, 16.2, 18.1, 31.7, 34.9, 38.4, 42.7, 43.4, 50.6, 51.4, 51.6, 60.6, 65.1, 71.9, 83.1, 108.3, 125.5, 139.3, 143.7, 171.4, 173.0, 209.7 ppm; HRMS (ES+) calcd for C23H31O7 [M+H+]: 419.2070, found: 419.2061.
Synthesis of 2-aminosalvinorin (207a). To a suspension of 202a (51.0 mg, 0.13 mmol) in ClCH2CH2Cl (6 mL) was added Et3N (36 μL, 0.26 mmol) and SOCl2 (2.0 N solution in CH2Cl2, 330 μL, 0.66 mmol), and the reaction solution was stirred at 80° C. (2.5 h). The reaction was concentrated and the residue was purified by column chromatography (SiO2; 2:1, hexanes:EtOAc). To a DMSO (300 μL) solution of 230 (15.3 mg, 37 μmol) was added sodium azide (4.9 mg, 75 μmol), and the reaction was stirred at 45° C. (1.5 h) followed by room temperature (18 h). The reaction crude was purified by column chromatography (SiO2; 2:1, hexanes:EtOAc). To a CH3CN (300 μL) solution of azide 228a (15.1 mg, 36 μmol) and NaI (9.8 mg, 65 μmol) was added TMSCl (8.4 μL, 65 μmol) and the reaction was stirred at room temperature (8 min). An aqueous 10% Na2S2O3 solution (500 μL) and CH2Cl2 (500 μL) were added to the reaction and the organic layer washed with brine, dried (MgSO4), concentrated, and purified by column chromatography (SiO2; 19:1, CH2Cl2:CH3OH) to obtain the desired product 207a as a white solid (2.3 mg, 5% yield, over three steps). Rf 0.18 (19:1, CH2Cl2:CH3OH); 1H NMR (CDCl3) δ 1.08 (s, 3H), 1.47 (s, 3H), 1.53-1.60 (m, 2H), 1.64-1.68 (m, 1H), 1.74-1.79 (m, 3H), 1.87-2.00 (m, 1H), 2.05-2.09 (m, 1H), 2.15-2.18 (m, 2H), 2.36 (ddd, J=3.3, 6.9, 13.7 Hz, 1H), 2.57 (dd, J=5.3, 13.4 Hz, 1H), 2.75 (dd, J=3.3, 13.2 Hz, 1H), 3.41 (dd, J=6.9, 12.6 Hz, 1H), 3.72 (s, 3H), 5.56 (dd, J=5.3, 11.5 Hz, 1H), 6.37-6.38 (m, 1H), 7.40-7.42 (m, 2H).
Synthesis of 2-epi-aminosalvinorin (207b). To a cold (0° C.) suspension of 202a (118.0 mg, 0.30 mmol) in CH2Cl2 (10 mL) was added pyridine (50 μL, 0.62 mmol) and trifluoromethanesulfonic anhydride (55 μL, 0.33 mmol), and the reaction solution was stirred at 0° C. (1 h). The reaction solution washed with aqueous 1 N HCl (10 mL), brine (10 mL), dried (MgSO4) and evaporated. To a cold (0° C.) DMF (2 mL) solution of the crude triflate 227a was added sodium azide (21.9 mg, 0.34 mmol), and the reaction was stirred at 0° C. (1 h). EtOAc (20 mL) and H2O (20 mL) were added to the reaction, and the organic layer was washed with saturated aqueous NaHCO3 (20 mL), brine (20 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography (SiO2; 2:1, hexanes:EtOAc). A CH2Cl2 (1 mL) solution of triphenylphosphine (20.9 mg, 80 μmol) was added to a CH2Cl2 (1 mL) solution of azide 228b (30.0 mg, 72 μmol), and the reaction was stirred at room temperature (1.5 h). The reaction solvent was evaporated and the residue was dissolved in THF (1 mL). H2O was added and the reaction was stirred at 60° C. (18 h). EtOAc (1 mL) and H2O (1 mL) were added to the reaction, and the aqueous layer was extracted with EtOAc (1 mL). Combined organic layers were dried (MgSO4), concentrated, and purified by column chromatography (SiO2; 49:1, CH2Cl2:CH3OH) to obtain the desired product 207b as a white solid (19.8 mg, 35% yield, over three steps). Rf 0.20 (19:1, CH2Cl2:CH3OH); 1H NMR (CDCl3) δ 1.08 (s, 3H), 1.47 (s, 3H), 1.52-1.60 (m, 2H), 1.63-1.68 (m, 1H), 1.74-1.79 (m, 3H), 1.87-2.00 (m, 1H), 2.06 (dd, J=2.9, 11.6 Hz, 1H), 2.14-2.18 (m, 2H), 2.36 (ddd, J=3.3, 7.1, 13.7 Hz, 1H), 2.57 (dd, J=5.4, 13.5 Hz, 1H), 2.74 (dd, J=3.3, 13.2 Hz, 1H), 3.39 (dd, J=6.9, 12.6 Hz, 1H), 3.71 (s, 3H), 5.56 (dd, J=5.3, 11.5 Hz, 1H), 6.37-6.38 (m, 1H), 7.40-7.41 (m, 2H); 13C NMR (CDCl3) 15.3, 16.5, 18.2, 35.2, 35.4, 38.2, 42.3, 43.7, 51.5, 51.8, 54.5, 59.5, 64.6, 72.0, 108.3, 125.4, 139.3, 143.7, 171.3, 172.2, 209.3 ppm; HRMS (ES+) calcd for C21H28NO6 [M+H+]: 390.1916, found: 390.1923.
Synthesis of 2-(N-methyl)-salvinorin (208a). Compound 208a (59.1 mg, 58%) was prepared as a pale pink solid from 202b (99.3 mg, 0.25 mmol), CH2Cl2 (10 mL), trifluoromethanesulfonic anhydride (90 μL, 0.53 mmol), pyridine (90 μL, 1.1 mmol), and methylamine (2.0 N in THF, 5 mL) utilizing method C: Rf 0.32 (19:1, CH2Cl2:CH3OH); 1H NMR (CDCl3) δ 1.09 (s, 3H), 1.46 (s, 3H), 1.50-1.79 (m, 4H), 1.87-2.00 (m, 1H), 2.06 (dd, J=2.9, 11.9 Hz, 1H), 2.12-2.18 (m, 2H), 2.36-2.43 (m, 1H), 2.43 (s, 3H), 2.58 (dd, J=5.0, 13.4 Hz, 1H), 2.72 (dd, J=3.3, 13.5 Hz, 1H), 3.10-3.16 (m, 1H), 3.71 (s, 3H), 4.30 (t, J=6.3 Hz, 1H), 5.56 (dd, J=5.1, 11.7 Hz, 1H), 6.38-6.39 (m, 1H), 7.40-7.42 (m, 2H); 13C NMR (CDCl3) 15.1, 16.4, 18.1, 32.6, 34.2, 35.4, 38.1, 42.1, 43.5, 51.4, 51.7, 54.2, 64.7, 67.0, 71.9, 108.3, 125.3, 139.3, 143.6, 171.3, 172.3, 207.6 ppm; HRMS (ES+) calcd for C22H30NO6 [M+H+]: 404.2073, found: 404.2068.
Synthesis of 2-(N-ethyl)-salvinorin (209a). Compound 209a (25.2 mg, 47%) was prepared as a white solid from 202b (49.7 mg, 0.13 mmol), CH2Cl2 (5 mL), trifluoromethanesulfonic anhydride (40 μL, 0.24 mmol), pyridine (40 μL, 0.49 mmol), and ethylamine (2.0 N in THF, 2 mL) utilizing method C: Rf 0.40 (19:1, CH2Cl2:CH3OH); 1H NMR (CDCl3) δ 1.09 (s, 3H), 1.12 (t, J=6.9 Hz, 3H), 1.46 (s, 3H), 1.49-1.79 (m, 4H), 1.88-2.01 (m, 1H), 2.03-2.08 (m, 1H), 2.12-2.17 (m, 2H), 2.38 (ddd, J=3.3, 7.1, 13.7 Hz, 1H), 2.54-2.66 (m, 3H), 2.71 (dd, J=3.3, 13.5 Hz, 1H), 3.23 (dd, J=7.0, 12.1 Hz, 1H), 3.70 (s, 3H), 5.55 (dd, J=5.1, 11.7 Hz, 1H), 6.37-0.38 (m, 1H), 7.39-7.41 (m, 2H); 13C NMR (CDCl3) 15.5, 15.6, 16.7, 18.4, 33.6, 35.8, 38.5, 42.2, 42.5, 43.9, 51.8, 52.0, 54.7, 65.2, 65.8, 72.2, 108.6, 125.7, 139.5, 143.9, 171.5, 172.5, 208.0 ppm; HRMS (ES+) calcd for C23H32NO6 [M+H+]: 418.2229, found: 418.2211.
Synthesis of 2-(N-isopropyl)-salvinorin (210a). Compound 210a (5.3 mg, 42%) was prepared as a white solid from 202b (11.4 mg, 29 μmol), CH2Cl2 (1 mL), trifluoromethanesulfonic anhydride (25 μL, 0.15 mmol), pyridine (25 μL, 0.31 mmol), and isopropylamine (20 μL, 0.23 mmol) utilizing method C: Rf 0.40 (19:1, CH2Cl2:CH3OH); 1H NMR (CDCl3) δ 1.04 (d, J=6.0 Hz, 6H), 1.08 (s, 3H), 1.47 (s, 3H), 1.50-1.81 (m, 4H), 1.86-1.99 (m, 1H), 2.06 (dd, J=2.7, 11.7 Hz, 1H), 2.12-2.18 (m, 2H), 2.34 (ddd, J=3.3, 6.9, 13.5 Hz, 1H), 2.56 (dd, J=4.9, 13.3 Hz, 1H), 2.72 (dd, J=3.3, 13.2 Hz, 1H), 2.79 (q, J=6.2 Hz, 1H), 3.29 (dd, J=6.9, 12.6 Hz, 1H), 3.71 (s, 3H), 5.56 (dd, J=5.1, 11.7 Hz, 1H), 6.38-6.39 (m, 1H), 7.40-7.42 (m, 2H); 13C NMR (CDCl3) 15.3, 16.5, 18.2, 22.8, 23.6, 34.7, 35.5, 38.3, 42.4, 43.7, 46.8, 51.6, 51.7, 54.6, 63.6, 65.2, 72.0, 108.3, 125.5, 139.3, 143.7, 171.3, 172.3, 208.4 ppm; HRMS (ES+) calcd for C24H34NO6 [M+H+]: 432.2386, found: 432.2374.
Synthesis of 2-epi-(N-isopropyl)-salvinorin (210b). Compound 210b (6.5 mg, 24%) was prepared as a white solid from 2a (25.0 mg, 64 μmol), CH2Cl2 (1.5 mL), trifluoromethanesulfonic anhydride (25 μL, 0.15 mmol), pyridine (25 μL, 0.31 mmol), and isopropylamine (50 μL, 0.59 mmol) utilizing method C: Rf 0.45 (4:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 0.98 (d, J=6.2 Hz, 3H), 1.05 (d, J=6.2 Hz, 3H), 1.08 (s, 3H), 1.45 (s, 3H), 1.47-1.76 (m, 5H), 1.80 (ddd, J=2.3, 3.2, 14.8 Hz, 1H), 2.07-2.17 (m, 2H), 2.37 (ddd, J=2.8, 12.1, 16.3 Hz, 1H), 2.47 (dd, J=4.9, 13.3 Hz, 1H), 2.57-2.65 (m, 1H), 3.09 (dd, J=3.5, 13.3 Hz, 1H), 3.28 (dd, J=2.1, 4.2 Hz, 1H), 3.69 (s, 3H), 5.53 (dd, J=4.8, 11.4 Hz, 1H), 6.37-6.38 (m, 1H), 7.39-7.41 (m, 2H); 13C NMR (CDCl3) 15.2, 16.2, 18.1, 22.6, 24.0, 32.9, 35.0, 38.4, 43.0, 43.2, 47.7, 50.5, 51.4, 51.6, 59.1, 63.0, 71.9, 108.3, 125.6, 139.3, 143.7, 171.6, 173.1, 212.2 ppm; HRMS (ES+) calcd for C24H34NO6 [M+H+]: 432.2386, found: 432.2379.
Synthesis of 2-(N,N-dimethyl)-salvinorin (211a). Compound 211a (3.4 mg, 45%) was prepared as a red solid from 202b (7.0 mg, 18 μmol), CH2Cl2 (1 mL), trifluoromethanesulfonic anhydride (25 μL, 0.15 mmol), pyridine (25 μL, 0.31 mmol), and (CH3)2NH (2.0 N in THF, 1 mL) utilizing method C: Rf 0.36 (19:1, CH2Cl2:CH3OH); 1H NMR(CDCl3) δ 1.11 (s, 3H), 1.46 (s, 3H), 1.52-1.76 (m, 4H), 2.00-2.26 (m, 2H), 2.11-2.33 (m, 3H), 2.40 (s, 6H), 2.62 (dd, J=12.9, 5.1 Hz, 1H), 2.68 (dd, J=9.6, 7.5 Hz, 1H), 3.27 (t, J=9.8 Hz, 1H), 3.73 (s, 3H), 5.55 (dd, J=11.7, 5.4 Hz, 1H), 6.37-6.38 (m, 1H), 7.39-7.40 (m, 2H); 13C NMR (CDCl3) 15.3, 16.4, 18.1, 25.7, 35.5, 38.2, 41.3, 41.9, 43.4, 51.4, 51.9, 54.6, 65.1, 70.8, 72.1, 108.3, 125.5, 139.2, 143.7, 171.4, 172.5, 206.5 ppm; HRMS (ES+) calcd for C23H32NO6 [M+H+]: 418.2229, found: 418.2247.
Synthesis of 2-(acetamide)-salvinorin (212a). Compound 212a (2.1 mg, 82%) was prepared as a white solid from 207a (2.3 mg, 5.9 μmol), Et3N (1.6 μL, 12 μmol), and Ac2O (1.1 μL, 12 μmol) utilizing method A: Rf 0.30 (2:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.10 (s, 3H), 1.47 (s, 3H), 1.52-1.68 (m, 3H), 1.77-1.82 (m, 1H), 1.82-1.95 (m, 1H), 2.03 (s, 3H), 2.06-2.10 (m, 1H), 2.14-2.18 (m, 1H), 2.22 (s, 1H), 2.46 (dd, J=5.6, 13.4 Hz, 1H), 2.66 (ddd, J=3.5, 7.1, 13.4 Hz, 1H), 2.78 (dd, J=3.3, 13.2 Hz, 1H), 3.70 (s, 3H), 4.45-4.53 (m, 1H), 5.55 (dd, J=5.0, 11.6 Hz, 1H), 6.32 (d, J=6.3 Hz, 1H), 6.37-6.38 (m, 1H), 7.39-7.41 (m, 2H); 13C NMR (CDCl3) 15.3, 16.4, 18.1, 23.1, 33.1, 35.5, 38.3, 43.0, 43.5, 51.3, 51.9, 54.0, 57.4, 65.3, 71.9, 108.4, 125.3, 139.4, 143.8, 169.8, 171.0, 171.8, 205.3 ppm; HRMS (ES+) calcd for C23H30NO7 [M+H+]: 449.2288, found: 449.2303.
Synthesis of 2-epi-(acetamide)-salvinorin (212b). Compound 212b (5.2 mg, 94%) was prepared as a white solid from 207b (5.0 mg, 13 μmol), Et3N (3.6 μL, 26 μmol), and Ac2O (2.5 μL, 26 μmol) utilizing method A: Rf 0.32 (19:1, CH2Cl2:CH3OH); 1H NMR (CDCl3) δ 1.09 (s, 3H), 1.47 (s, 3H), 1.51-1.67 (m, 3H), 1.76-1.81 (m, 1H), 1.81-1.95 (m, 1H), 2.03 (s, 3H), 2.06-2.10 (m, 1H), 2.14-2.18 (m, 1H), 2.22 (s, 1H), 2.45 (dd, J=5.8, 12.8 Hz, 1H), 2.65 (ddd, J=3.3, 7.1, 13.7 Hz, 1H), 2.78 (dd, J=3.3, 13.2 Hz, 1H), 3.69 (s, 3H), 4.44-4.53 (m, 1H), 5.54 (dd, J=5.1, 11.7 Hz, 1H), 6.32 (d, J=6.3 Hz, 1H), 6.37-6.38 (m, 1H), 7.39-7.41 (m, 2H); 13C NMR (CDCl3) 15.3, 16.4, 18.1, 23.1, 32.0, 35.4, 38.2, 42.9, 43.4, 51.3, 51.9, 53.9, 57.4, 65.2, 71.9, 108.3, 125.2, 139.4, 143.8, 169.8, 171.1, 171.8, 205.3 ppm; HRMS (ES+) calcd for C23H30NO7 [M+H+]: 432.2022, found: 432.2025.
Synthesis of 2-(propionamide)-salvinorin (213a). Compound 213a (2.1 mg, 46%) was prepared as a white solid from 207a (4.0 mg, 10 μmol), Et3N (2.9 μL, 21 μmol), and propionyl chloride (1.8 μL, 21 μmol) utilizing method A: Rf 0.18 (4:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.10 (s, 3H), 1.17 (t, J=7.5 Hz, 3H), 1.47 (s, 3H), 1.52-1.68 (m, 3H), 1.77-1.82 (m, 1H), 1.82-1.95 (m, 1H), 2.06-2.11 (m, 1H), 2.14-2.19 (m, 1H), 2.23 (s, 1H), 2.27 (q, J=7.5 Hz), 2.46 (dd, J=5.1, 13.2 Hz, 1H), 2.66 (ddd, J=3.2, 6.8, 13.3 Hz, 1H), 2.79 (dd, J=3.3, 13.2 Hz, 1H), 3.70 (s, 3H), 4.46-4.55 (m, 1H), 5.55 (dd, J=4.8, 11.4 Hz, 1H), 6.31 (d, J=6.6 Hz, 1H), 6.38-6.39 (m, 1H), 7.40-7.42 (m, 2H); 13C NMR (CDCl3) 9.7, 15.3, 16.4, 18.1, 29.5, 33.1, 35.4, 38.2, 42.9, 43.4, 51.3, 51.9, 53.9, 57.2, 65.2, 71.9, 108.4, 125.2, 139.4, 143.8, 171.1, 171.8, 173.5, 205.4 ppm; HRMS (ES+) calcd for C24H32NO7 [M+H+]: 446.2179, found: 446.2173.
Synthesis of 2-epi-(propionamide)-salvinorin (213b). Compound 213b (6.4 mg, 84%) was prepared as a white solid from 207b (7.0 mg, 18 μmol), Et3N (5.0 μL, 36 μmol), and propionyl chloride (3.1 μL, 36 μmol) utilizing method A: Rf 0.52 (19:1, CH2Cl2:CH3OH); 1H NMR (CDCl3) δ 1.10 (s, 3H), 1.16 (t, J=6.9 Hz, 3H), 1.47 (s, 3H), 1.52-1.68 (m, 3H), 1.77-1.82 (m, 1H), 1.82-1.95 (m, 1H), 2.04-2.10 (m, 1H), 2.14-2.20 (m, 1H), 2.23 (s, 1H), 2.23-2.30 (m, 2H), 2.46 (dd, J=5.3, 13.7 Hz, 1H), 2.66 (ddd, J=3.2, 6.8, 13.3 Hz, 1H), 2.79 (dd, J=3.3, 13.2 Hz, 1H), 3.70 (s, 3H), 4.46-4.55 (m, 1H), 5.54 (dd, J=5.6, 11.6 Hz, 1H), 6.31 (d, J=6.3 Hz, 1H), 6.37-6.38 (m, 1H), 7.40-7.41 (m, 2H); 13C NMR (CDCl3) 9.9, 15.6, 16.7, 18.3, 29.8, 33.4, 35.7, 38.5, 43.2, 43.7, 51.5, 52.1, 54.2, 57.5, 65.4, 72.1, 108.6, 125.5, 139.6, 144.0, 171.3, 172.1, 173.7, 205.7 ppm; HRMS (ES+) calcd for C24H32NO7 [M+H+]: 446.2179, found: 446.2180.
Synthesis of 2-(N-methylacetamide)-salvinorin (214a). Compound 214a (9.5 mg, 85%) was prepared as a colorless oil from 208a (10.5 mg, 26,mol), Et3N (7.2 μL, 52 μmol), and Ac2O (5.0 μL, 52 μmol) utilizing method A: Rf 0.22 (1:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.14 (s, 3H), 1.42 (s, 3H), 1.53-1.74 (m, 5H), 2.03-2.15 (m, 2H), 2.15 (s, 3H), 2.18 (s, 1H), 2.32-2.44 (m, 1H), 2.59 (dd, J=5.1, 13.5 Hz, 1H), 2.82 (dd, J=3.4, 13.1 Hz, 1H), 2.96 (s, 3H), 3.72 (s, 3H), 5.32 (dd, J=7.4, 13.1 Hz, 1H), 5.52 (dd, J=5.2, 11.2 Hz, 1H), 6.37-6.38 (m, 1H), 7.39-7.41 (m, 2H); 13C NMR (CDCl3) 15.2, 16.6, 18.1, 21.7, 28.8, 32.7, 35.5, 37.9, 41.5, 43.4, 51.3, 51.9, 54.2, 60.4, 64.9, 72.0, 108.4, 125.3, 139.3, 143.7, 171.3, 171.6, 172.2, 204.5 ppm; HRMS (ES+) calcd for C24H32NO7 [M+H+]: 446.2179, found: 446.2165.
Synthesis of 2-epi-(N-methylacetamide)-salvinorin (214b). Compound 214b (7.2 mg, quantitative) was prepared as a white solid from 208b (6.4 mg, 16 μmol), Et3N (4.8 μL, 32 μmol), and Ac2O (3.0 μL, 32 μmol) utilizing method A: Rf 0.14 (4:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.02 (s, 3H), 1.39 (s, 3H), 1.53-1.67 (m, 2H), 1.82 (dd, J=12.6, 12.6 Hz, 1H), 2.04 (s, 3H), 2.08-2.38 (m, 5H), 2.84 (s, 1H), 2.87 (dd, J=5.3, 14.9 Hz, 1H), 2.92 (dd, J=8.1, 13.2 Hz, 1H), 3.15 (s, 3H), 3.56-3.61 (m, 1H), 3.72 (s, 3H), 5.54 (dd, J=5.4, 11.1 Hz, 1H), 6.43 (s, 1H), 7.38-7.45 (m, 2H); 13C NMR (CDCl3) 15.6, 18.4, 20.2, 21.7, 26.0, 35.8, 37.6, 38.3, 41.2, 43.6, 51.4, 51.6, 51.9, 60.8, 63.1, 72.3, 108.8, 125.7, 139.5, 143.5, 170.2, 171.9, 174.5, 205.4 ppm; HRMS (ES+) calcd for C24H32NO7 [M+H+]: 446.2179, found: 446.2177.
Synthesis of 2-(N-methylpropionamide)-salvinorin (215a). Compound 215a (9.7 mg, 80%) was prepared as a colorless oil from 208a (10.6 mg, 26 μmol), Et3N (7.3 μL, 53 μmol), and propionyl chloride (4.6 μL, 53 μmol) utilizing method A: Rf 0.60 (1:1, CH2Cl2:EtOAc); 1H NMR(CDCl3) δ 1.12-1.17 (m, 6H), 1.42 (s, 3H), 1.53-1.74 (m, 5H), 2.02-2.19 (m, 2H), 2.19 (s, 1H), 2.32-2.49 (m, 3H), 2.59 (dd, J=5.1, 13.5 Hz, 1H), 2.83 (dd, J=3.6, 13.2 Hz, 1H), 2.94 (s, 3H), 3.72 (s, 3H), 5.35 (dd, J=7.5, 12.6 Hz, 1H), 5.52 (dd, J=5.3, 11.6 Hz, 1H), 6.37-6.38 (m, 1H), 7.39-7.41 (m, 2H); 13C NMR (CDCl3) 9.1, 15.2, 16.6, 18.0, 26.7, 28.8, 31.9, 35.5, 37.9, 41.4, 43.4, 51.3, 51.8, 54.1, 60.5, 64.9, 72.0, 108.4, 125.3, 139.3, 143.7, 171.3, 172.3, 174.7, 204.7 ppm; HRMS (ES+) calcd for C25H34NO7 [M+H+]: 460.2335, found: 460.2343.
Synthesis of 2-epi-(N-methylpropionamide)-salvinorin (215b)Compound 215b (5.7 mg, 71-%) was prepared as a colorless oil from 208b (7.0 mg, 17 μmol), Et3N (5.0 μL, 35 μmol), and propionyl chloride (3.0 μL, 35 μmol) utilizing method A: Rf 0.25 (4:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.03 (s, 3H), 1.08 (t, J=7.7 Hz, 3H), 1.40 (s, 3H), 1.52-1.63 (m, 2H), 1.83 (dd, J=12.8, 12.8 Hz, 1H), 2.05-2.37 (m, 5H), 2.84-2.93 (m, 2H), 2.94 (s, 1H), 3.13 (s, 3H), 3.56-3.61 (m, 2H), 3.72 (s, 3H), 5.54 (dd, J=5.4, 11.4 Hz, 1H), 6.43 (br s, 1H), 7.39-7.45 (m, 2H); 13C NMR (CDCl3) 8.8, 15.6, 18.4, 19.9, 26.3, 26.7, 35.8, 37.2, 37.9, 41.0, 43.5, 51.5, 51.7, 51.9, 60.8, 63.4, 72.3, 108.8, 125.6, 139.5, 143.5, 172.0, 173.5, 174.5, 205.7 ppm; HRMS (ES+) calcd for C25H34NO7 [M+H+]: 460.2335, found: 460.2335.
Synthesis of 2-(N-ethylacetamide)-salvinorin (216a). Compound 216a (8.4 mg, 50%) was prepared as a colorless oil from 209a (15.4 mg, 37 μmol), Et3N (10.0 μL, 74 μmol), and Ac2O (7.0 μL, 74 μmol) utilizing method A: Rf 0.35 (2:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.18 (s, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.42 (s, 3H), 1.53-1.74 (m, 5H), 2.06-2.17 (m, 2H), 2.17 (s, 3H), 2.19 (s, 1H), 2.43-2.45 (m, 1H), 2.59 (dd, J=5.1, 13.5 Hz, 1H), 2.80 (dd, J=3.3, 12.9 Hz, 1H), 3.06-3.19 (m, 1H), 3.43-3.55 (m, 1H), 3.73 (s, 3H), 5.01 (br s, 1H), 5.52 (dd, J=5.1, 11.7 Hz, 1H), 6.37-6.38 (m, 1H), 7.39-7.40 (m, 2H); 13C NMR (CDCl3) 15.4, 16.3, 16.8, 18.3, 21.6, 29.8, 35.8, 38.2, 41.8, 43.8, 51.7, 52.1, 54.9, 62.4, 65.1, 72.3, 108.7, 125.6, 139.6, 143.9, 171.5, 172.4, 204.5 ppm, the two remaining peaks may be overlapping with other signals; HRMS (ES+) calcd for C25H34NO7 [M+H+]: 460.2335, found: 460.2349.
Synthesis of 2-epi-(N-ethylacetamide)-salvinorin (216b). Compound 216b (4.4 mg, 56%) was prepared as a colorless oil from 209b (7.1 mg, 17 μmol), Et3N (4.7 μL, 34 μmol), and Ac2O (3.2 μL, 34 μmol) utilizing method A: Rf 0.15 (1:1, EtOAc:hexanes); 1H NMR (CDCl3) δ 1.01 (s, 3H), 1.28 (t, J=7.2 Hz, 3H), 1.39 (s, 3H), 1.53-1.57 (m, 4H), 1.83 (dd, J=12.6, 12.6 Hz, 1H), 2.03 (s, 3H), 2.08-2.24 (m, 2H), 2.40-2.51 (m, 1H), 2.86 (dd, J=5.91, 14.6 Hz, 1H), 2.91 (s, 1H), 2.93 (dd, J=4.0, 8.5 Hz, 1H), 2.34-2.54 (m, 3H), 3.72 (s, 3H), 5.53 (dd, J=5.1, 11.1 Hz, 1H), 6.41-6.42 (m, 1H), 7.37-7.44 (m, 2H); 13C NMR (CDCl3) 14.3, 15.7, 18.5, 20.6, 21.1, 26.9, 35.8, 37.3, 41.4, 43.6, 46.0, 51.4, 51.6, 52.1, 60.5, 60.8, 72.3, 108.8, 125.7, 139.5, 143.5, 169.3, 172.0, 174.8, 205.6 ppm; HRMS (ES+) calcd for C25H34NO7 [M+H+]: 460.2335, found: 460.2336.
Synthesis of 2-(N-ethylpropionamide)-salvinorin (217a). Compound 217a (8.8 mg, 79%) was prepared as a colorless oil from 209a (9.8 mg, 23 μmol), Et3N (6.6 μL, 47,mol), and propionyl chloride (4.0 μL, 47 μmol) utilizing method A: Rf 0.59 (2:1, CH2Cl2:EtOAc); 1H NMR (CDCl3) δ 1.14-1.22 (m, 9H), 1.42 (s, 3H), 1.52-1.74 (m, 5H), 2.06-2.18 (m, 2H), 2.18 (s, 1H), 2.32-2.54 (m, 3H), 2.60 (dd, J=5.1, 13.5 Hz, 1H), 2.80 (dd, J=3.3, 12.6 Hz, 1H), 3.05-3.17 (m, 1H), 3.43-3.55 (m, 1H), 3.72 (s, 3H), 4.98 (br s, 1H), 5.51 (dd, J=5.1, 11.7 Hz, 1H), 6.37-6.38 (m, 1H), 7.39-7.41 (m, 2H); 13C NMR (CDCl3) 9.5, 15.1, 16.2, 16.6, 18.1, 26.3, 29.6, 35.5, 37.9, 41.4, 43.5, 51.4, 51.8, 54.6, 62.5, 64.8, 72.0, 108.5, 125.3, 139.4, 143.6, 171.4, 172.3, 174.6, 212.1 ppm, the remaining peak may be overlapping with other signals; HRMS (ES+) calcd for C26H36NO7 [M+H+]: 474.2492, found: 474.2513.
Synthesis of 2-epi-(N-ethylpropionamide)-salvinorin (217b). Compound 217b (6.1 mg, 76%) was prepared as a colorless oil from 209b (7.1 mg, 17 μmol), Et3N (4.7 μL, 34 μmol), and propionyl chloride (3.0 μL, 34,mol) utilizing method A: Rf 0.30 (1:1, EtOAc:hexanes); 1H NMR (CDCl3) δ 1.02 (s, 3H), 1.07 (t, J=7.4 Hz, 3H), 1.27 (t, J=7.2 Hz, 3H), 1.39 (s, 3H), 1.52-1.62 (m, 3H), 1.86 (dd, J=11.4, 14.1 Hz, 1H), 2.09-2.34 (m, 5H), 2.37-2.49 (m, 1H), 2.87 (dd, J=5.4, 14.1 Hz, 1H), 2.94 (dd, J=4.2, 8.1 Hz, 1H), 2.94 (s, 1H), 3.37-3.54 (m, 3H), 3.72 (s, 3H), 5.54 (dd, J=5.4, 11.1 Hz, 1H), 6.42-6.43 (m, 1H), 7.38-7.45 (m, 2H); 13C NMR (CDCl3) 9.1, 14.4, 15.6, 18.5, 20.4, 26.1, 27.0, 35.8, 37.4, 41.3, 43.4, 44.8, 51.5, 51.7, 52.2, 60.6, 60.9, 72.4, 108.7, 125.7, 139.5, 143.5, 172.0, 172.6, 174.8, 205.9 ppm; HRMS (ES+) calcd for C26H36NO7 [M+H+]: 474.2492, found: 474.2508.
Synthesis of O-demethylsalvinorin A (218). Following the procedure of Lee et al.,2 salvinorin A (452 mg, 1.05 mmol) and LiI (577 mg, 4.31 mmol) were protected from light and dried in vacuo for 1.5 h. Pyridine (5 mL) was added, and the reaction stirred at 110° C. for 42 h. At this point, the solvent was removed, and the resulting orange solid was suspended in H2O (2 mL), acidified with aqueous 10% HCl to pH 2, extracted into EtOAc (3×25 mL), dried (MgSO4), and concentrated in vacuo. The brown solid was further purified by column chromatography (SiO2; 19:1, CH2Cl2:CH3OH with 0.05% AcOH) to afford 309 mg (70%) of 218 as an amber solid and approximately a 1:1 mixture of natural:unnatural C(8)-epimers based on the integration of the H(12) peaks in the 1H NMR spectrum: Rf 0.33 (19:1, CH2Cl2:CH3OH with 0.05% AcOH); 1H NMR (CDCl3) δ 1.11 (s, 3H), 1.15 (s, 3H), 1.40-1.53 (m, 2H), 1.47 (s, 3H), 1.53-1.68 (m, 3H), 1.64 (s, 3H), 1.70-1.80 (m, 1H), 1.88 (dt, J=15.0, 3.0 Hz, 1H), 1.94-2.10 (m, 2H), 2.12-2.20 (m, 2H), 2.16 (s, 3H), 2.18 (s, 3H), 2.20 (s, 1H), 2.24-2.41 (m, 5H), 2.27 (s 1H), 2.44-2.55 (m, 2H), 2.79 (dt, J=13.5, 3.0 Hz, 2H), 5.11 (dd, J=12.6, 7.8 Hz, 1H), 5.17 (dd, J=12.2, 7.6 Hz, 1H), 5.27 (br d, J=10.5 Hz, 1H), 5.54 (dd, J=11.9, 5.3 Hz, 1H), 6.37-6.38 (m, 2H), 7.38-7.44 (m, 4H); 13C NMR (CDCl3) 15.2, 15.3, 16.4, 17.6, 18.1, 20.5, 24.6, 30.6, 33.9, 34.8, 35.4, 38.1, 42.0, 42.2, 43.3, 45.2, 48.0, 51.3, 52.7, 53.4, 64.0, 70.1, 72.0, 75.0, 75.1, 108.3, 108.5, 123.3, 125.2, 139.4, 139.7, 143.6, 143.7, 169.8, 170.0, 171.2, 173.6, 176.4, 202.0, 202.3 ppm, the remaining signals were not detected and are believed to overlap between epimers; HRMS (ES+) calcd for C22H27O8 [M+H+]: 419.1706, found: 419.1725.
Synthesis of C(4)-N-methylamide salvinorin A (219a). Compound 219a (5.1 mg, 33%) was prepared as a white semisolid from 218 (14.9 mg, 35.6 μmol, a mixture of C(8)-epimers), EDCI (13.7 mg, 71.5 μmol), DMAP (0.8 mg, 7 μmol), CH2Cl2 (1 mL), and CH3NH2 (33% in EtOH, 6 μL, 48 μmol) using method D: Rf 0.19 (2:1, EtOAc:hexanes); 1H NMR (CDCl3) 1.20 (s, 3H), 1.36-1.43 (m, 1H), 1.46 (s, 3H), 1.53-1.74 (m, 2H), 1.88 (dt, J=12.6, 3.0 Hz, 1H), 2.03 (dd, J=12.0, 3.0 Hz, 1H), 2.09 (s, 1H), 2.13-2.20 (m, 1H), 2.17 (s, 3H), 2.21-2.26 (m, 1H), 2.29-2.44 (m, 2H), 2.52 (dd, J=13.5, 5.1 Hz, 1H), 2.83 (d, J=4.8 Hz, 3H), 5.14 (dd, J=11.4, 7.5 Hz, 1H), 5.53 (dd, J=11.5, 5.3 Hz, 1H), 5.54 (s, 1H), 6.37-6.38 (m, 1H), 7.38-7.40 (m, 2H); 13C NMR (CDCl3) 15.2, 16.0, 18.2, 20.6, 26.4, 31.3, 35.4, 38.9, 42.1, 43.5, 51.6, 55.5, 64.5, 72.1, 75.2, 108.4, 125.2, 139.4, 143.7, 170.1, 170.7, 171.1, 202.0 ppm; HRMS (ES+) calcd for C23H30NO7 [M+H+]: 432.2022, found: 432.2031.
Synthesis of 8-epi-C(4)-N-methylamide salvinorin A (219c). Compound 219c (3.0 mg, 20%) was prepared as a white semisolid from 218 (14.9 mg, 35.6 μmol, a mixture of C(8)-epimers), EDCI (13.7 mg, 71.5 μmol), DMAP (0.8 mg, 7 μmol), CH2Cl2 (1 mL), and CH3NH2 (33% in EtOH, 6 μL, 48 μmol) using method D: Rf 0.30 (2:1, EtOAc:hexanes); 1H NMR(CDCl3) 1.15 (s, 3H), 1.54 (dd, J=15.3, 12.3 Hz, 1H), 1.57-1.65 (m, 1H), 1.63 (s, 3H), 1.83-1.86 (m, 2H), 2.10-2.20 (m, 3H), 2.16 (s, 3H), 2.30-2.36 (m, 1H), 2.35 (s, 1H), 2.39 (dd, J=12.7, 2.3 Hz, 1H), 2.47-2.48 (m, 1H), 2.81 (d, J=4.8 Hz, 3H), 5.04-5.10 (m, 1H), 5.27 (d, J=10.5 Hz, 1H), 5.73 (br d, J=4.2 Hz, 1H), 6.37-6.38 (m, 1H), 7.38-7.39 (m, 1H), 7.44 (br s, 1H); 13C NMR (CDCl3) 15.0, 17.7, 20.6, 24.6, 26.3, 31.0, 34.6, 34.8, 42.0, 45.3, 47.9, 54.9, 64.6, 70.3, 75.5, 108.5, 123.2, 139.8, 143.6, 170.0, 170.9, 173.9, 202.3 ppm; HRMS (ES+) calcd for C23H33N2O7 [M+NH4+]: 449.2288, found: 449.2278.
Synthesis of C(4)-N-ethylamide salvinorin A (220a). Compound 220a (8.1 mg, 29%) was prepared as a yellow semisolid from 218 (26.7 mg, 63.8 μmol, a mixture of C(8)-epimers), EDCI (20.1 mg, 104 μmol), DMAP (1.0 mg, 8.2 μmol), CH2Cl2 (1 mL), and EtNH2 (2.0 M in THF, 40 μL) using method D: Rf 0.23 (3:1, EtOAc:hexanes); 1H NMR (CDCl3) 1.17 (t, J=7.4 Hz, 3H), 1.21 (s, 3H), 1.35-1.44 (m, 1H), 1.46 (s, 3H), 1.54-1.75 (m, 2H), 1.90 (dt, J=13.2, 3.0 Hz, 1H), 2.00-2.05 (m, 1H), 2.08 (s, 1H), 2.13-2.28 (m, 2H), 2.17 (s, 3H), 2.26-2.46 (m, 2H), 2.52 (dd, J=13.5, 5.1 Hz, 1H), 3.31 (dq, J=6.5, 6.5 Hz, 2H), 5.15 (dd, J=11.8, 7.0 Hz, 1H), 5.53 (dd, J=11.6, 5.0 Hz, 1H), 5.54 (s, 1H), 6.37-6.38 (m, 1H), 7.39-7.41 (m, 2H); 13C NMR (CDCl3) 14.9, 15.3, 16.1, 18.3, 20.6, 31.3, 34.6, 35.4, 38.8, 42.1, 43.5, 51.6, 55.5, 64.5, 72.1, 75.2, 108.3, 125.3, 139.4, 143.7, 169.9, 170.1, 171.1, 202.0 ppm; HRMS (ES+) calcd for C24H32NO7 [M+H+]: 446.2179, found: 446.2157.
Synthesis of 8-epi-C(4)-N-ethylamide salvinorin A (220c). Compound 220c (4.6 mg, 16%) was prepared as a yellow semisolid from 218 (26.7 mg, 63.8 μmol, a mixture of C(8)-epimers), EDCI (20.1 mg, 104 μmol), DMAP (1.0 mg, 8.2 μmol), CH2Cl2 (1 mL), and EtNH2 (2.0 M in THF, 40 μL) using method D: Rf 0.47 (3:1, EtOAc:hexanes); 1H NMR (CDCl3) 1.16 (t, J=7.2 Hz, 3H), 1.16 (s, 3H), 1.52 (dd, J=15.0, 12.0 Hz, 1H), 1.57-1.68 (m, 1H), 1.64 (s, 3H), 1.79-1.90 (m, 2H), 2.11-2.22 (m, 3H), 2.16 (s, 3H), 2.27-2.43 (m, 3H), 2.46-2.49 (m, 1H), 3.22-3.35 (m, 2H), 5.09 (dd, J=12.0, 7.2 Hz, 1H), 5.28 (d, J=10.5 Hz, 1H), 5.65 (br t, J=5.3 Hz, 1H), 6.38-6.39 (m, 1H), 7.39-7.40 (m, 1H), 7.43-7.44 (m, 1H); 13C NMR (CDCl3) 14.8, 15.0, 17.7, 20.6, 24.7, 31.1, 34.5, 34.6, 34.7, 42.1, 45.3, 47.9, 54.9, 64.6, 70.3, 75.5, 108.5, 123.2, 139.8, 143.6, 170.0, 170.1, 174.0, 202.4 ppm; HRMS (ES+) calcd for C24H32NO7 [M+H+]: 446.2179, found: 446.2196.
Synthesis of C(4)-N,N-dimethylamide salvinorin A (221a). Compound 221a (3.7 mg, 16%) was prepared as a white semisolid from 218 (22.4 mg, 53.5 μmol, a mixture of C(8)-epimers), EDCI (12.5 mg, 65.2 μmol), DMAP (1.3 mg, 11 μmol), CH2Cl2 (1 mL), and (CH3)2NH (2.0 M in THF, 65 μL) using method D: Rf 0.13 (2:1, EtOAc:hexanes); 1H NMR (CDCl3) 1.30 (s, 3H), 1.34-1.42 (m, 1H), 1.47 (s, 3H), 1.51-1.74 (m, 3H), 1.84-1.89 (m, 1H), 2.05-2.16 (m, 2H), 2.15 (s, 1H), 2.17 (s, 3H), 2.39 (q, J=12.9 Hz, 1H), 2.54 (dd, J=13.2, 5.1 Hz, 1H), 2.98 (s, 3H), 3.03 (dd, J=12.9, 3.0 Hz, 1H), 3.17 (s, 3H), 5.19 (dd, J=12.6, 7.5 Hz, 1H), 5.53 (dd, J=11.7, 5.1 Hz, 1H), 6.36-6.37 (m, 1H), 7.39-7.40 (m, 2H); 13C NMR (CDCl3) 15.3, 16.2, 18.1, 20.6, 31.5, 35.5, 36.1, 37.5, 38.5, 43.2, 43.6, 47.8, 51.7, 65.1, 72.1, 75.3, 108.4, 125.3, 139.4, 143.7, 170.2, 170.9, 171.1, 202.0 ppm; HRMS (ES+) calcd for C24H32NO7 [M+H+]: 446.2179, found: 446.2168.
Synthesis of 8-epi-C(4)-N,N-dimethylamide salvinorin A (221c). Compound 221c (3.8 mg, 16%) was prepared as a white semisolid from 218 (22.4 mg, 53.5 μmol, a mixture of C(8)-epimers), EDCI (12.5 mg, 65.2,mol), DMAP (1.3 mg, 11 μmol), CH2Cl2 (1 mL), and (CH3)2NH (2.0 M in THF, 65 μL) using method D: Rf 0.29 (2:1, EtOAc:hexanes); 1H NMR (CDCl3) 1.25 (s, 3H), 1.51 (dd, J=15.2, 12.5 Hz, 1H), 1.56-1.60 (m, 2H), 1.65 (s, 3H), 1.82-1.94 (m, 2H), 2.07-2.14 (m, 1H), 2.16 (s, 3H), 2.25 (s, 1H), 2.38 (q, J=13.0 Hz, 1H), 2.40 (dd, J=15.0, 2.1 Hz, 1H), 2.46-2.47 (m, 1H), 2.97 (s, 3H), 3.03 (dd, J=12.9, 3.0 Hz, 1H), 3.17 (s, 3H), 5.14 (dd, J=12.7, 7.4 Hz, 1H), 5.27 (dd, J=12.0, 2.1 Hz, 1H), 6.37-6.38 (m, 1H), 7.38-7.40 (m, 1H), 7.44-7.45 (m, 1H); 13C NMR (CDCl3) 15.2, 17.6, 20.6, 24.8, 31.4, 33.1, 34.7, 36.0, 38.5, 43.3, 45.4, 47.4, 48.3, 65.3, 70.2, 75.5, 108.4, 123.4, 139.7, 143.6, 170.0, 171.1, 173.8, 202.3 ppm; HRMS (ES+) calcd for C24H32NO7 [M+H+]: 446.2179, found: 446.2173.
Synthesis of O-demethyl-18-deoxysalvinorin A (222a) and 8-epi-O-demethyl-18-deoxysalvinorin A (222c). Following the procedure of Munro et al., J. Med. Chem. 2005, 48:345 (2005). 218 (15.8 mg, 37.9 μmol), as a mixture of C(8)-epimers, and BH3·THF (1.0 M, 50 μL, 50 μmol) were dissolved in THF (500 μL). The reaction was heated at 55° C. for 2.5 h, quenched with water (500 μL) and concentrated in vacuo. The resulting white film was taken up in saturated NaHCO3 (750 μL), extracted into CH2Cl2 (4×1.5 mL), dried (MgSO4), and concentrated in vacuo. The white solid was further purified by column chromatography (SiO2; 1:1, EtOAc:hexanes) to afford 4.2 mg (27%) of 222a as a colorless oil and 5.6 mg (37%) of 222c as a white solid.
222a: Rf 0.10 (1:1, EtOAc:hexanes); 1H NMR (CDCl3) and 13C NMR (CDCl3) were consistent with the published data3; HRMS (ES+) calcd for C22H29O7 [M+H+]: 405.1913, found: 405.1927.
222c: Rf 0.20 (1:1, EtOAc:hexanes); 1H NMR (CDCl3) δ 0.91 (s, 3H), 1.38-1.46 (m, 1H), 1.52 (dd, J=15, 12 Hz, 1H), 1.64 (s, 3H), 1.70-1.79 (m, 2H), 1.83-1.87 (m, 2H), 2.15-2.20 (m, 2H), 2.16 (s, 3H), 2.24 (s, 1H), 2.36 (dd, J=14.9, 2.2 Hz, 1H), 2.44 (d, J=2.1 Hz, 1H), 2.53 (ddd, J=12.3, 7.4, 2.7 Hz, 1H), 3.42 (t, J=9.0, 1H), 3.92 (dd, J=10.5, 3.6 Hz, 1H), 5.10 (dd, J=12.0, 7.2 Hz, 1H), 5.26 (d, J=10.5 Hz, 1H), 6.39 (t, J=0.9 Hz, 1H), 7.38-7.39 (m, 1H), 7.44-7.45 (m, 1H); 13C NMR (CDCl3) 15.4, 17.6, 20.6, 24.7, 31.6, 33.8, 34.6, 42.0, 45.3, 48.0, 50.2, 61.5, 64.4, 70.1, 76.2, 108.5, 123.4, 139.7, 143.5, 169.9, 173.7, 204.1 ppm; HRMS (ES+) calcd for C22H32NO7 [M+NH4+]: 422.2179, found: 422.2159.
Synthesis of 8-epi-18-deoxysalvinorin A (223c). 222c (8.3 mg, 21 μmol), Ag2O (48.7 mg, 210 μmol), and CH3I (60 μL, 970 μmol) were stirred in CH3CN (0.75 mL) at room temperature for 26.5 h. The solvent was removed, and the residue purified via column chromatography (SiO2; 1:2, EtOAc:hexanes) to afford 2.5 mg (29%) of 223c as a white solid: Rf 0.28 (1:2, EtOAc:hexanes); 1H NMR (CDCl3) δ 0.92 (s, 3H), 1.38-1.56 (m, 2H), 1.64 (s, 3H), 1.70-1.74 (m, 1H), 1.77-1.87 (m, 2H), 1.90-2.00 (m, 1H), 2.14 (s, 3H), 2.17-2.24 (m, 1H), 2.23 (s, 1H), 2.36 (dd, J=14.7, 2.1 Hz, 1H), 2.40-2.48 (m, 2H), 3.22 (dd, J=9.3, 7.8 Hz, 1H), 3.31 (s, 3H), 3.54 (dd, J=9.0, 3.9 Hz, 1H), 5.08 (dd, J=12.0, 6.9 Hz, 1H), 5.26 (d, J=11.7 Hz, 1H), 6.38-6.39 (m, 1H), 7.37-7.40 (m, 1H), 7.44 (br s, 1H); 13C NMR (CDCl3) 15.5, 17.7, 20.6, 24.7, 32.0, 33.9, 34.6, 42.0, 45.4, 47.7, 48.1, 58.8, 64.5, 70.1, 71.6, 76.2, 108.5, 123.4, 139.7, 143.5, 169.8, 173.6, 204.1 ppm; HRMS (ES+) calcd for C23H31O7 [M+H+]: 419.2070, found: 419.2081.
Synthesis of 4-(N-methylamino)methyl salvinorin A (224a). Compound 224a (8.5 mg, quantitative yield) was prepared as an off-white solid from 222a (8.2 mg, 20 μmol), CH2Cl2 (1 mL), trifluoromethanesulfonic anhydride (25 μL, 150 μmol), pyridine (25 μL, 310 μmol), and CH3NH2 (2.0 N in THF, 500 μL) using method E: Rf 0.13 (19:1, CH2Cl2:CH3OH); 1H NMR (CD3OD) δ 0.92 (s, 3H), 1.34-1.42 (m, 1H), 1.43 (s, 3H), 1.47-1.53 (m, 1H), 1.58-1.68 (m, 1H), 1.73-1.88 (m, 2H), 1.98 (dt, J=12.6, 3.0 Hz, 1H), 2.06-2.12 (m, 1H), 2.11 (s, 3H), 2.32-2.44 (m, 3H), 2.57 (s, 1H), 2.70 (s, 3H), 2.82 (dd, J=12.6, 10.2 Hz, 1H), 3.17 (dd, J=12.6, 2.4 Hz, 1H), 5.21 (dd, J=12.5, 7.7 Hz, 1H), 5.60 (dd, J=11.7, 5.1 Hz, 1H), 6.50-4.51 (m, 1H), 7.48-7.49 (m, 1H), 7.55-7.56 (m, 1H); 13C NMR (CD3OD) 15.7, 16.3, 19.3, 20.4, 33.3, 34.8, 36.4, 38.3, 43.2, 43.7, 46.7, 50.5, 51.6, 64.0, 73.7, 76.8, 109.6, 127.0, 141.3, 145.1, 171.6, 174.1, 204.6 ppm; HRMS (ES+) calcd for C23H32NO6 [M+H+]: 418.2229, found: 418.2224.
Synthesis of 8-epi-4-(N-methylamino)methyl salvinorin A (224c). Compound 224c (3.1 mg, 38%) was prepared as a yellow oil from 222c (8.0 mg, 20 μmol), CH2Cl2 (1 mL), trifluoromethanesulfonic anhydride (25 μL, 150 μmol), pyridine (25 μL, 310 μmol), and CH3NH2 (2.0 N in THF, 500 μL) using method E: Rf 0.16 (19:1, CH2Cl2:CH3OH); 1H NMR (CDCl3) δ 0.89 (s, 3H), 1.38-1.45 (m, 1H), 1.51 (dd, J=15.0, 12.3 Hz, 1H), 1.64 (s, 3H), 1.68-1.84 (m, 6H), 2.13 (s, 3H), 2.17-2.23 (m, 1H), 2.24 (s, 1H), 2.30-2.38 (m, 2H), 2.44 (s, 3H), 2.50-2.56 (m, 1H), 2.84 (dd, J=11.7, 2.1 Hz, 1H), 5.08 (dd, J=12.0, 7.2 Hz, 1H), 5.25 (d, J=11.4 Hz, 1H), 6.37-6.38 (m, 1H), 7.37-7.38 (m, 1H), 7.43-7.44 (m, 1H); 13C NMR (CDCl3) 15.0, 17.7, 20.5, 24.8, 32.9, 33.7, 34.7, 36.5, 42.4, 45.4, 47.8, 48.1, 50.8, 64.6, 70.1, 76.2, 108.5, 123.4, 139.7, 143.6, 169.9, 173.7, 204.2 ppm; HRMS (ES+) calcd for C23H32NO6 [M+H+]: 418.2229, found: 418.2219.
Synthesis of 4-(N-ethylamino)methyl salvinorin A (225a). Compound 225a (2.0 mg, 22%) was prepared as an off-white solid from 222a (8.4 mg, 21 μmol), CH2Cl2 (1 mL), trifluoromethanesulfonic anhydride (25 μL, 150 μmol), pyridine (25 μL, 310 μmol), and EtNH2 (2.0 N in THF, 200 μL) using method E: Rf 0.17 (19:1, CH2Cl2:CH3OH); 1H NMR (CD3OD) δ 0.85 (s, 3H), 1.19-1.25 (m, 1H), 1.25 (t, J=7.2 Hz, 3H), 1.35 (s, 3H), 1.40-1.44 (m, 1H), 1.51-1.60 (m, 1H), 1.64-1.82 (m, 2H), 1.91 (dt, J=12.6, 3.0 Hz, 1H), 1.99-2.05 (m, 1H), 2.03 (s, 3H), 2.22-2.39 (m, 3H), 2.47 (s, 1H), 2.80 (dd, J=12.6, 10.2 Hz, 1H), 3.00 (dq, J=12.3, 7.2 Hz, 1H), 3.05 (dq, J=12.3, 7.2 Hz, 1H), 3.12 (dd, J=15.0, 7.2 Hz, 1H), 5.13 (dd, J=12.6, 7.2 Hz, 1H), 5.52 (dd, J=11.7, 5.4 Hz, 1H), 6.41-6.42 (m, 1H), 7.41 (t, J=1.7 Hz, 1H), 7.48-7.49 (m, 1H); 13C NMR (CD3OD) 11.6, 15.7, 16.3, 19.3, 20.5, 33.2, 36.5, 38.3, 43.3, 43.9, 45.1, 46.5, 51.6, 64.0, 73.7, 76.7, 109.6, 127.0, 141.3, 145.1, 171.6, 174.0, 204.4 ppm, the remaining signal was not detected and is believed to coincide with the solvent; HRMS (ES+) calcd for C24H34NO6 [M+H+]: 432.2386, found: 432.2402.
Synthesis of 8-epi-4-(N-ethylamino)methyl salvinorin A (225c). Compound 225c (7.9 mg, 94%) was prepared as a yellow solid from 222c (8.0 mg, 20 μmol), CH2Cl2 (1 mL), trifluoromethanesulfonic anhydride (25 μL, 150 μmol), pyridine (25 μL, 310 μmol), and EtNH2 (2.0 N in THF, 500 μL) using method E: Rf 0.24 (19:1, CH2Cl2:CH3OH); 1H NMR (CDCl3) δ 0.88 (s, 3H), 1.24-1.29 (m, 1H), 1.33 (t, J=7.2 Hz, 3H), 1.54 (dd, J=14.4, 12.0 Hz, 1H), 1.58-1.69 (m, 1H), 1.62 (s, 3H), 1.72-1.84 (m, 3H), 2.11 (s, 3H), 2.12-2.20 (m, 1H), 2.27-2.35 (m, 1H), 2.31 (s, 1H), 2.45 (br s, 1H), 2.54-2.61 (m, 1H), 2.70 (dd, J=12.3, 10.5 Hz, 1H), 2.98-3.11 (m, 2H), 3.13 (d, J=12.6 Hz, 1H), 4.53 (br s, 1H), 5.17 (dd, J=12.5, 6.9 Hz, 1H), 5.26 (d, J=10.8 Hz, 1H), 6.38-6.39 (m, 1H), 7.38 (t, J=1.7 Hz, 1H), 7.43 (br s, 1H); 13C NMR (CDCl3) 11.6, 14.9, 17.6, 20.5, 24.7, 32.1, 33.4, 34.6, 42.2, 44.2, 44.9, 45.2, 47.5, 47.6, 63.6, 70.2, 75.2, 108.6, 123.2, 139.9, 143.7, 170.0, 174.1, 203.2 ppm; HRMS (ES+) calcd for C24H34NO6 [M+H+]: 432.2386, found: 432.2377.
Synthesis of 4-(N,N-dimethylamino)methyl salvinorin A (226a). Compound 226a (9.2 mg, 48%) was prepared as a pale yellow solid from 222a (18.0 mg, 44.4 μmol), CH2Cl2 (2 mL), trifluoromethanesulfonic anhydride (50 μL, 300 μmol), pyridine (50 μL, 620 μmol), and (CH3)2NH (2.0 N in THF, 1 mL) using method E: Rf 0.27 (19:1, CH2Cl2:CH3OH); 1H NMR (CDCl3) δ 0.92 (s, 3H), 1.33 (td, J=13.2, 3.6 Hz, 1H), 1.46 (s, 3H), 1.53-1.85 (m, 4H), 1.99-2.22(m, 4H), 2.15 (s, 3H), 2.20 (s, 1H), 2.24 (s, 6H), 2.31 (dd, J=12.0, 3.0 Hz, 1H), 2.49 (dd, J=13.5, 5.4 Hz, 1H), 2.56 (ddd, J=12.9, 6.9, 2.4 Hz, 1H), 5.14 (dd, J=12.0, 7.2 Hz, 1H), 5.53 (dd, J=12.0, 5.4 Hz, 1H), 6.37-6.38 (m, 1H), 7.39-7.41 (m, 2H); 13C NMR (CDCl3) 15.3, 16.1, 18.2, 20.6, 33.5, 35.3, 37.8, 42.1, 43.3, 46.2, 46.6, 51.5, 59.0, 64.7, 72.1, 76.1, 108.4, 125.2, 139.4, 143.7, 170.0, 171.5, 204.0 ppm; HRMS (ES+) calcd for C24H34NO6 [M+H+]: 432.2386, found: 432.2396.
Synthesis of 8-epi-4-(N,N-dimethylamino)methyl salvinorin A (226c). Compound 226c (6.2 mg, 49%) was prepared as a yellow oil from 222c (11.8 mg, 29.2 μmol), CH2Cl2 (1 mL), trifluoromethanesulfonic anhydride (25 μL, 150 μmol), pyridine (25 μL, 310 μmol), and (CH3)2NH (2.0 N in THF, 500 μL) using method E: Rf 0.16 (49:1, CH2Cl2:CH3OH); 1H NMR (CDCl3) δ 0.88 (s, 3H), 1.50 (dd, J=15.0, 12.0 Hz, 1H), 1.60-1.73 (m, 1H), 1.65 (s, 3H), 1.75-1.93 (m, 4H), 2.12-2.19 (m, 2H), 2.13 (s, 3H), 2.21-2.30 (m, 1H), 2.23 (s, 6H), 2.26 (s, 1H), 2.36 (dd, J=15.0, 2.1 Hz, 1H), 2.43-2.47 (m, 1H), 2.55 (ddd, J=12.9, 7.2, 3.0 Hz, 1H), 5.09 (dd, J=12.3, 7.2 Hz, 1H), 5.26 (d, J=10.8 Hz, 1H), 6.38-6.39 (m, 1H), 7.38-7.39 (m, 1H), 7.43-7.44 (m, 1H); 13C NMR (CDCl3) 14.9, 17.7, 20.6, 24.8, 33.1, 33.7, 34.6, 42.2, 45.4, 45.7, 46.1, 48.1, 58.9, 64.7, 70.1, 76.3 108.5, 123.4, 139.7, 143.5, 169.9, 173.7, 204.3 ppm; HRMS (ES+) calcd for C24H34NO6 [M+H+]: 432.2386, found: 432.2389.
EXAMPLE 35 In Vitro Data The affinities of compounds 1-26 for the human KOR were determined by competitive inhibition of [3H]diprenorphine binding to membranes prepared from Chinese hamster ovary cells (CHO-hKOR) stably transfected with the human κ-opioid receptor (hKOR). The potencies and efficacies of compounds 1-26 on hKOR were determined by their abilities to regulate [35S]GTPγS binding to membranes of CHO-hKOR cells.22 The selective κ-full agonist, U50,488H, was used as a reference compound with its efficacy designated as 100%. The in vitro pharmacological data for C(2)-modified salvinorins 1-17 and C(18)-modified salvinorins 18-26 are listed in Table 2.
aKi values in inhibiting [3H]diprenorphine binding to hKOR.
bEach value represents the mean of at least three independent experiments performed in duplicate.
cEC50 values in activating the hKOR to enhance [35S]GTPγS binding.
dEfficacy determined as the % of maximal response produced by U50,488H run in parallel experiments.
All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.
Other embodiments are within the claims.
Claims
1. 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 CH3, 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 C, reduced salvinorin.
2. The compound of claim 1, wherein said compound is further described by formulas IVa or IVb: wherein
- A, X2, X6, and Y1 are as defined in claim 1.
3. The compound of claim 1, wherein said compound is further described by formulas VIa or VIb: wherein
- W3 is selected from O—R3, O-acyl, S—R3, S-acyl, NH-acyl, NHC(O)NH-acyl, NHC(O)Z5, and NR29R30; and A, X2, and X6 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
- J3 is selected from NH-acyl, NHC(O)NH-acyl, NR31R32, NHC(O)Z5; and A, X2, X6, Z5, R31, and R32 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, X2, X6, and Y1 are as defined in claim 1.
6. The compound of claim 1, wherein said compound is further described by formulas XIa or XIb: wherein
- W3 is selected from O—R3, O-acyl, S—R3, S-acyl, NH-acyl, NHC(O)NH-acyl, NHC(O)Z5, and NR29R30; and A, X2, X6, Z5, R3, R29, and R30 are as defined in claim 1.
7. The compound of claim 1, wherein said compound is further described by formulas XXIIIa or XXIIIb: wherein
- J3 is selected from NH-acyl, NHC(O)NH-acyl, NR31R32, NHC(O)Z5; and A, X2, X6, Z5, R31, and R32 are as defined in claim 1.
8. The compound of claim 1, wherein said compound is further described by formula XX: wherein
- X2, X3, X6, and A are as defined in claim 1.
9. The compound of claim 8, wherein said compound is further described by formula XXIa: wherein
- X2 and X3 are as defined in claim 1.
10. The compound of claim 8, wherein said compound is further described by formula XXIb: wherein
- X2 and X3 are as defined in claim 1.
11. The compound of claim 8, wherein said compound is further described by formula XXIc: wherein
- X2 and X3 are as defined in claim 1.
12. The compound of claim 8, wherein said compound is further described by formula XXId: wherein
- X2 and X3 are as defined in claim 1.
13. The compound of claims 9-12, wherein X2 is selected from 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, and NHC(O)Z5; and R3, R16, R17, R29, R30, R31, R32, Z2, and Z5 are as defined in claim 1.
14. 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 0, 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 CH3, 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.
15. The compound of claim 14, wherein said compound is further described by formula XIXa: wherein
- X2 and X3 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 C2 ester of salvinorin A, a tetrahydrofuranylethyl salvinorin, a salvinorin benzoate, or a C1 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 C2 ester of salvinorin A, a salvinorin benzoate, or a C1 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 C2 ester of salvinorin A, a tetrahydrofuranylethyl salvinorin, a salvinorin benzoate, or a C1 reduced salvinorin.
28. The method of claim 27, wherein said selective kappa receptor partial agonist is 2-(O—(N-methyl)formamide)-salvinorin B.
Type: Application
Filed: Sep 29, 2006
Publication Date: Sep 13, 2007
Inventors: Cecile Beguin (Lexington, MA), William Carlezon (Lincoln, MA), Bruce Cohen (Lexington, MA), Minsheng He (Allston, MA), David Lee (Cambridge, MA), Michele Richards (Edmonton), Lee-Yuan Liu-Chen (Media, PA)
Application Number: 11/540,921
International Classification: A61K 31/366 (20060101); C07D 407/04 (20060101);
