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Publication Number
US-12269825-B2
Publication Date
2025-04-08
Expiration Date
Abstract
This invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HT2A receptor, serotonin transporter (SERT) and/or pathways involving dopamine D1/D2 receptor signaling systems, and/or the treatment of residual symptoms.
Core Innovation
The invention relates to substituted heterocycle-fused gamma-carbolines, including compounds of Formula I with deuterium (D, 2H) at defined positions and optional pharmaceutically acceptable salt forms. The compounds are characterized by deuterium substitution constraints, including specific selection rules for R2 and R3 and fixed hydrogen substitution at R4 and R5.
The invention addresses CNS disorders that involve 5-HT2A, serotonin transporter (SERT), and/or dopaminergic D1/D2 receptor signaling, including residual (negative) symptoms of psychosis and schizophrenia. It also describes treatment contexts extending to other central nervous system disorder categories referenced in the document, and includes method embodiments for treating or preventing such disorders by administering a therapeutically effective amount of a pharmaceutical composition.
The document provides a rationale that deuterium substitution partially limits ketone and N-methyl metabolism, with an intended improvement in the metabolic profile. It describes metabolism and pharmacokinetic considerations involving CYP3A4-driven pathways, ketone reduction/reversal, and differences in hepatic microsome stability for certain deuterations, along with plasma results for compounds identified as Compound Q, Compound S, Compound R, and Compound T across species.
In addition to compound definitions, the invention includes pharmaceutical composition and formulation embodiments, including compositions in free or pharmaceutically acceptable salt form with a diluent or carrier. The document also describes extended formulation options, including immediate and sustained or delayed release embodiments, and depot-like oral systems, along with administration methods for treating or preventing the referenced CNS disorders, including possible adjunct therapy associations.
Claims Coverage
The provided material contains one independent claim covering a pharmaceutical composition defined by a compound of Formula I with specific deuterium labeling constraints (R1–R5), followed by dependent claim refinements. The independent claim includes one main inventive feature centered on the labeled Formula I deuterated compound present in free or salt form with a diluent or carrier.
Deuterated Formula I pharmaceutical composition with constrained H/D labeling
A pharmaceutical composition comprising a compound of formula I wherein R1 is CH3; R2 and R3 are each independently H or D; R4 and R5 are each H; provided that R2 and R3 are not both H; and wherein D is deuterium, in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier.
Across the provided independent claim set, the core claim scope is directed to pharmaceutical compositions containing a constrained deuterated compound of Formula I (R1 fixed as CH3, R4/R5 fixed as H, and H/D constraints on R2/R3) supplied as free or pharmaceutically acceptable salt, together with a diluent or carrier.
Stated Advantages
Improved metabolic profile via deuterium substitution that partially limits ketone and N-methyl metabolism.
Documented Applications
Treating or preventing central nervous system disorders involving 5-HT2A, SERT, and/or dopaminergic D1/D2 receptor signaling, including residual (negative) symptoms of psychosis and schizophrenia.
Treating or preventing agitation in dementia and agitation in autism and related autistic disorders.
Adjunctive therapy contexts are described, including association with other therapeutic agents such as GABA modulators, an NMDA receptor antagonist (memantine), acetylcholinesterase inhibitors, and other enumerated agents referenced in the dependent claims.
The document explicitly enumerates method disorder selections including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with cephalic pain, social phobias, agitation, post-traumatic stress disorder, impulse control disorders, and intermittent explosive disorder.
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