N,N-dimethyltryptamine and related psychedelics and uses thereof
Inventors
Duncton, Matthew Alexander James • CLARK, Sam
Assignees
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Publication Number
US-11866408-B2
Publication Date
2024-01-09
Expiration Date
Abstract
Described herein are compounds that are derivatives of DMT or 5-MeO-DMT and can be metabolically converted to N,N-dimethyltryptamine or analogs thereof upon administration to a subject. In certain embodiments, the compounds described herein are useful for the treatment of conditions associated with a neurological disease.
Core Innovation
The invention is directed to compounds of Formula (I) and Formula (Iq), or pharmaceutically acceptable salts or solvates thereof, defined by constrained substituent variables including R1 being methoxy or hydrogen and R2 being —C(O)R4 or —C(O)OCH(R5)OC(O)OR6. The scope further constrains R4 as alkyl substituted with —N(R18)R19, R5 as hydrogen, alkyl, or cycloalkyl, and R6 as alkyl, cycloalkyl, or —CH(RA1)NH2, with RA1 as alkyl or an amino acid side chain. Additional labeled groups include R13 as hydrogen, R14 as alkyl, R15 as alkyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl, and each of R18 and R19 independently hydrogen or alkyl.
The disclosed compound families include named structural variants such as Formula (Ik), Formula (Im), Formula (Iq), and Formula (Ir), together with further dependent refinements that narrow substituent choices or select depicted structural alternatives. The content also describes multiple specific chemical embodiments and representative structures, including indole-based, fused heteroaromatic, phosphorus-containing, and substituted bicyclic scaffolds with carbonyl, ester, phosphate/phosphonate, sulfonyl, and tertiary amine motifs. Pharmaceutically acceptable salts, and in some items solvates, are included within the compound scope.
The partial content further states that the compound class is metabolically converted to N,N-dimethyltryptamine (DMT) or analogs, and that oral pharmacokinetic evaluation is provided for multiple DMT and 5-MeO-DMT prodrugs after oral dosing. The invention also ties selected Formula (I) compounds to therapeutic use in major depression by producing blood plasma concentrations of DMT or 5-MeO-DMT effective for treatment. Explicitly mentioned context also includes neurological disease, psychiatric disorder, substance abuse disorder-related indications, and neuronal plasticity.
Claims Coverage
The consolidated claim coverage centers on two independent compound claims, for Formula (I) and Formula (Iq), with additional dependent refinements that narrow substituent options and identify specific structural variants. Across the provided content, the inventive features are primarily the constrained Formula-based substituent definitions and the therapeutic-use claim for major depression tied to blood plasma concentrations of DMT or 5-MeO-DMT.
Compound of Formula (I) with constrained substituent variables
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is methoxy or hydrogen; R2 is —C(O)R4 or —C(O)OCH(R5)OC(O)OR6; R4 is alkyl substituted with —N(R18)R19; R5 is hydrogen, alkyl, or cycloalkyl; R6 is alkyl, cycloalkyl, or —CH(RA1)NH2; RA1 is alkyl or an amino acid side chain; R13 is hydrogen; R14 is alkyl; R15 is alkyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl, unsubstituted or substituted with one or more RB; and each of R18 and R19 is independently hydrogen or alkyl.
Compound of Formula (Iq) with constrained substituent variables
A compound of Formula (Iq), or a pharmaceutically acceptable salt thereof, wherein R1 is methoxy or hydrogen; R5 is hydrogen, alkyl, or cycloalkyl; R6 is alkyl, cycloalkyl, or —CH(RA1)NH2; and RA1 is alkyl or an amino acid side chain.
Major depression treatment by producing DMT or 5-MeO-DMT plasma concentrations
A method for treating major depression in a human by administering an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, such that it produces blood plasma concentrations of N,N-dimethyltryptamine (DMT) or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) effective for the treatment of major depression.
Overall, the claims are directed to structurally defined compound families under Formula (I) and Formula (Iq), with tightly constrained R-group definitions and pharmaceutically acceptable salt and solvate coverage. Dependent scope narrows these families through named variants and enumerated substituent selections, and one claim family additionally recites treatment of major depression using administration that achieves effective DMT or 5-MeO-DMT blood plasma concentrations.
Stated Advantages
Different derivative forms yield unexpectedly wide, several-orders-of-magnitude variations in systemic plasma exposure to DMT/5-MeO-DMT.
Systemic plasma exposure variations are not predictable from structural knowledge alone.
5-HT2A modulation with promotion of neural plasticity.
Effective treatment of major depression in a human by administering an effective amount such that blood plasma concentrations of DMT or 5-MeO-DMT are produced at levels effective for the treatment.
Produces metabolite concentration-time profiles for DMT and 5-MeO-DMT following oral administration of DMT/5-MeO-DMT prodrugs.
Compounds are metabolically converted to N,N-dimethyltryptamine (DMT) or analogs.
Useful for neurological disease, psychiatric disorder, and substance abuse disorder-related indications, including contexts involving neuronal plasticity.
Documented Applications
Treating major depression in a human by administering an effective amount of the compound so that it produces blood plasma concentrations of N,N-dimethyltryptamine (DMT) or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) effective for the treatment of major depression.
Oral dosing of DMT/5-MeO-DMT prodrug derivatives with pharmacokinetic assessment and mean concentration-time profiles.
Oral pharmacokinetic evaluation of multiple DMT and 5-MeO-DMT prodrugs, including concentration-time profiles and pharmacokinetic parameters for prodrug and metabolite.
Psychiatric/neurologic and pain disorders via administration of Formula (I) and related compounds, including adjunct/combination approaches.
Use of the disclosed compounds and compositions for neurological disease, psychiatric disorder, and substance abuse disorder-related indications.
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