Novel Compounds as 5‑HT2A Agonists for Treating Mental Illness or CNS Disorders

Abstract

Provided herein are novel compounds as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating mental illness or CNS disorders and processes for preparing such compounds.

Important Compound Classes

Title

Compounds Active at the Serotonergic 5-HT2A Receptor

Patent Publication Number

WO 2025/118034 A1

URL

https://patents.google.com/patent/WO2025118034A1/en

Publication Date

June 12, 2025

Priority Application

AU 2023903954

Priority Date

December 6, 2023

Inventors

Jorgensen, W.; Tan, J.; Whish, L.; Banister, S.

Assignee Company

Psylo Pty Ltd., Australia

Disease Area

Mental Illness and CNS disorders

Biological Target

5-HT2A

Summary

Mental illness covers many neuropsychiatric disorders which cause enormous burden to the lives of their sufferers. Diagnoses such as treatment resistant depression, major depressive disorders, eating disorders, substance abuse disorders, post-traumatic stress disorder, obsessive compulsive disorder, attention deficit disorder, schizophrenia, and others can cause such devastating symptoms that many sufferers lose the capability of leading a normal life.

Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. After the discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and the identification of serotonin in the brain, early research focused intensively on LSD. Today, there is consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A (5-HT2A) receptors. Psychedelics have both rapid onset and persisting effects, which includes changes in mood and brain function. The classical psychotic agents include LSD, psilocybin or mescaline.

The 5-HT2A receptor plays an important role in emotional responses and is an important target to be considered in the action of 5-HT2A agonist psychedelics. In fact, a majority of known 5-HT2A agonists produce hallucinogenic effects in humans. Psilocybin activates 5HT1A receptors, which may contribute to antidepressant/antianxiety effects.

Psychosis is often referred to as an abnormal state of mind that is characterized by hallucinatory experiences, delusional thinking and disordered thoughts. Anecdotal evidence suggests that low, nonhallucinogenic doses of psychedelics can reduce symptoms of schizophrenia and psychosis.

The present application describes a series of novel compounds as 5-HT2A agonists for the treatment of mental illness or central nervous system (CNS) disorders. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

L = C₁–C₄ alkylene, C₂–C₄ alkenylene, and C₂–C₄ alkynylene;

R₁ = H, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₂–C₆ alkenyl, C₂–C₆ haloalkenyl, C₂–C₆ alkynyl, C₂–C₆ haloalkynyl, C₃–C₈ cycloalkyl, C₄–C₁₄ alkylenecycloalkyl, C₃–C₈ heterocycloalkyl, C₄–C₁₄ alkyleneheterocycloalkyl, C₆–C₁₂ aryl, C₇–C₁₈ alkylenearyl, C₅–C₁₀ heteroaryl, and C₆–C₁₆ alkyleneheteroaryl;

R₂ = H, C₁–C₆ haloalkyl, C₃–C₈ cycloalkyl, C₄–C₁₄ alkylenecycloalkyl, C₃–C₈ heterocycloalkyl, C₄–C₁₄ alkyleneheterocycloalkyl, C₆–C₁₂ aryl, C₇–C₁₈ alkylenearyl, C₅–C₁₀ heteroaryl, and C₆–C₁₆ alkyleneheteroaryl;

R₃ = H, C₁–C₆ alkyl, C₃–C₈ cycloalkyl, or C₄–C₁₄ alkylenecycloalkyl; and

R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ = H, halogen, CN, OR₁₃, N­(R₁₃)₂, SR₁₃, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₂–C₆ alkenyl, C₂–C₆ haloalkenyl, C₂–C₆ alkynyl, C₂–C₆ haloalkynyl, C₁–C₆ alkylamine, C₁–C₆ alkoxy, C₁–C₆ haloalkoxy and CO₂R₁₃.

Key Structures

Biological Assay

The 5-HT2A receptor FLIPR Ca²⁺ flux functional assay was performed. The compounds described in this application were tested for agonist activity at 5-HT2A receptor. The 5-HT2A EC₅₀ (nM) are shown in the following Table.

Biological Data

Table below shows representative compounds that were tested for agonist activity at 5-HT2A. The biological data obtained from testing representative examples are listed in the following table.

Compd. No.	5-HT2A EC50 (nM)
I-2	188
I-44	91
I-69	22
I-70	30
I-71	30
I-75	72

Claims

Total claims: 22

Compound claims: 15

Pharmaceutical composition claims: 2

Method of treatment claims: 3

Method of increasing neuronal plasticity claims: 2

Recent Review Articles

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The author declares no competing financial interest.

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