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Publication Number
US-12331052-B2
Publication Date
2025-06-17
Expiration Date
Abstract
The invention relates to particular substituted heterocycle fused gamma-carbolines, 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 the 5-HT2A receptor, the serotonin transporter (SERT), pathways involving the dopamine D1 and D2 receptor signaling system, and/or the μ-opioid receptor.
Core Innovation
The invention relates to a compound of Formula I with a defined structural scaffold and multiple substitution variables, including R1, R2, R3, L, Z, R4, R6, R7, R8, and Ra/Rb/Rc. The Formula I compounds are claimed in free form or in pharmaceutically acceptable salt form, and the disclosure includes explicit constraints on the allowed L-Z moiety construction, including exclusions for certain L-Z moieties and an explicit exclusion that the L-Z moiety is not 1-(4-fluoro-1-phenoxy) propyl.
For the Formula I compounds, Z is selected from aryl and heteroaryl, with the heteroaryl restricted to monocyclic 5-membered or 6-membered heteroaryl or bicyclic 9-membered or 10-membered heteroaryl selected from a listed group. Optional substitution of the aryl or heteroaryl Z group is described via R4 moieties, and the substituent patterns for R1, R2, and R3 are also constrained.
The disclosure further defines pharmaceutical compositions and depot-type systems, including injectable depot particles or microparticles, polymeric matrix depots, and osmotic controlled release oral delivery system constructs. Therapeutic use is directed to central nervous system disorders, including depression, psychosis, schizophrenia, sleep disorders, obsessive-compulsive disorder, pain, and opioid use, dependency, and withdrawal contexts, including combinations and patient populations such as intolerance or nonresponse to certain therapies.
Claims Coverage
The independent claims identified across the provided items cover 2 inventive features. The main inventive features are a Formula I compound with structural constraints and exclusions, and a selected group of such compounds in free or pharmaceutically acceptable salt form for central nervous system treatment.
Formula I substituted heterocycle-fused gamma-carboline compound
A compound of a Formula I with substituent definitions for R1, R2, R3, L, Z, R4, R6, R7, and R8, where Z is selected from aryl and heteroaryl and the heteroaryl is restricted to monocyclic 5- or 6-membered or bicyclic 9- or 10-membered heteroaryl selected from a listed group; the L-Z moiety is constrained by provided exclusions, including not being 1-(4-fluoro-1-phenoxy)propyl, and additional exclusion conditions depending on whether R1 is H or CH3; the compound is provided in free or pharmaceutically acceptable salt form.
Selected group of compounds in free or pharmaceutically acceptable salt form
A compound selected from a defined group of compounds, where each compound is independently in free or pharmaceutically acceptable salt or form.
Overall, the claims center on a substituted heterocycle-fused gamma-carboline scaffold as Formula I with constrained aryl and heteroaryl Z options and L-Z exclusions, and on a selected group of such compounds provided as free or pharmaceutically acceptable salt form.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment or prophylaxis of central nervous system disorders by administering Formula I compounds or defined pharmaceutical compositions to a patient in need.
Combination therapy for central nervous system disorders using Formula I compounds with additional therapeutic agents selected from described classes.
Use of depot formulations providing sustained or delayed release, including polymeric matrix depots and osmotic controlled release oral delivery systems with gelatin capsule multi-layer structures.
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