Novel Mixed Serotonin Receptor Binder Compounds as 5‑HT2C Agonists for Treating Psychotic Disorders

Abstract

Provided herein are novel mixed serotonin receptor binder compounds as 5-HT2C agonists, pharmaceutical compositions, use of such compounds in treating psychotic disorders, and processes for preparing such compounds.

Important Compound Classes

Title

Mixed Serotonin Receptor Binders for Treatment of Psychotic Disorders

Patent Publication Number

WO 2025/137639 A1

URL: https://patents.google.com/patent/WO2025137639A1/en

Publication Date

June 26, 2025

Priority Application

US 63/614,457 and US 63/735,148

Priority Date

December 22, 2023 and December 17, 2024

Inventors

Prince, R.; Ghosh, M.; Chytil, M.; Powell, N. A.; Leach, P.; McTighe, S.

Assignee Company

Delix Therapeutics Inc., USA

Disease Area

Psychotic disorders

Biological Target

5-HT2C

Summary

Over the last decades, predominant interest in serotonergic targets with respect to schizophrenia has centered around 5-HT2A antagonism/inverse agonism. 5-HT2C receptor agonists have emerged as an additional serotonergic target of interest. 5-HT2C agonists have been suggested as treatments for multiple symptom domains of schizophrenia including positive, negative, cognitive, and depressive symptoms without the adverse events or tolerability issues associated with existing agents. The 5-HT2C receptor is a highly complex, highly regulated receptor that is widely distributed throughout the brain. There are multiple allelic variants of the 5-HT2C receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the utility of either agonists or antagonists in the treatment of schizophrenia. The preclinical profile of 5-HT2C agonists from a neurochemical, electrophysiological and behavioral prospective is indicative of antipsychotic-like efficacy. Selective 5-HT2C agonist, vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients. These data suggest that 5-HT2C agonists are potential therapeutics for the treatment of psychotic disorders.

The present application describes a series of novel mixed serotonin receptor binder compounds as 5-HT2C agonists for the treatment of psychotic disorders. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁, R₂, R₃, R₄ and R₅ = H, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ hydroxyalkyl, C₁–C₆ aminoalkyl, C₁–C₆ heteroalkyl, halogen, -CN, -NO₂, -OR_a, -SR_a, -NR_aR_b, -S­(=O)­R_b, -S­(=O)₂R_b, -S­(O)₂NR_cR_d, -NR_bS­(=O)₂R_b, -NR_bS­(=O)₂NR_cR_d, -C­(=O)­R_b, -C­(=O)­OR_b, -OC­(=O)­R_b, -OC­(=O)­OR_b, -OC­(=O)­NR_cR_d, -NR_bC­(=O)­R_b, -NR_bC­(O)­OR_b, -NR_bC­(=O)­NR_cR_d, -C­(=O)­NR_cR_d, -P­(=O)­(OR_c)­(OR_d), -P­(=O)­R_cR_d, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

R_6a, R_6b, R_7a, and R_7b = H, C₁–C₆ alkyl, halogen, -CN, -NO₂, -OR_b, -SR_b, -NR_cR_d, cycloalkyl, or C₁–C₃ alkyl­(cycloalkyl);

R₈ = H, C₁–C₆ alkyl, or -L-R_8a; R₉ = H or C₁–C₆ alkyl; and

R₁₀ = H or C₁–C₆ alkyl.

Key Structures

Biological Assay

Serotonin 5-HT2C receptor in vitro cellular IPOne agonism activity assay was performed. The compounds described in this application were tested for agonist activity at 5-HT2C receptor. The 5-HT2C EC₅₀ (μM) values are shown in the following Table.

Biological Data

Table below shows representative compounds that were tested for agonist activity at 5-HT2C. The biological data obtained from testing representative examples are listed in the following Table.

For EC₅₀: A means <0.010 μM

Claims

Total claims: 102

Compound claims: 89

Pharmaceutical composition claims: 2

Method of treatment claims: 11

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The author declares no competing financial interest.

Published as part of ACS Medicinal Chemistry Letters special issue “Psychedelics and Entactogens”.