Novel Phenylalkylamines as 5‑HT2A Agonists for Treating Psychiatric Disorders

Abstract

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

Important Compound Classes

Title

Novel Phenylalkylamines and Their Use in the Treatment of Psychiatric Disorders

Patent Publication Number

WO 2025/059373 A1

URL

https://patents.google.com/patent/WO2025059373A1/en

Publication Date

March 20, 2025

Priority Application

US 63/537,925 and US 63/543,940

Priority Date

September 12, 2023 and October 13, 2023

Inventors

Kruegel, A. C.; Cunningham, M. J.

Assignee Company

Gilgamesh Pharmaceuticals Inc., USA

Disease Area

Psychiatric disorders

Biological Target

5-HT2A

Summary

Psychiatric disorders are mental disorders that cause abnormal thinking and perceptions. Psychiatric disorders include depressive disorders, anxiety, panic disorders, schizophrenia, eating disorders, substance use disorders, post-traumatic stress disorders, attention deficit disorder, and obsessive-compulsive disorder.

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 phenylalkylamines as 5-HT2A agonists for the treatment of psychiatric disorders. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = H, methyl, ethyl, −CH₂–OH, −CH₂–O–(methyl), −CH₂F, or −CH₂CH₂F;

R₂ = H, C₁–C₅ alkyl, C₃–C₅ alkenyl, C₃–C₅ alkynyl, or C₃–C₅ cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more F;

R₃ = H, C₁–C₃ alkyl, cyclopropyl or F, wherein alkyl and cyclopropyl are optionally substituted with one or more F;

R₄ = C₂–C₈ alkyl, C₂–C₈ alkenyl, C₂–C₈ alkynyl, C₃–C₁₀ cycloalkyl, −(C₂–C₈ alkyl)–(C₃–C₁₀ cycloalkyl), −S–(C₁–C₈ alkyl), −S–(C₃–C₈ alkenyl), −S–(C₃–C₈ alkynyl)–, −S–(C₃–C₁₀ cycloalkyl), Cl, Br, I, CF₃, NO₂, or SF₅;

R₅ = C₁–C₅ alkyl, C₂–C₅ alkenyl, C₂–C₅ alkynyl, or C₃–C₅ cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one or more F; and

R₆ = H, C₁–C₃ alkyl, cyclopropyl or F, wherein alkyl and cyclopropyl are optionally substituted with one or more F.

Key Structures

Biological Assay

The 5-HT2A receptor FLIPR functional assay was performed. The compounds described in this application were tested for agonist activity at 5-HT2A receptor. The 5-HT2A EC₅₀ values (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.

Claims

Total claims: 81

Compound claims: 64

Pharmaceutical composition claims: 4

Method of treatment claims: 13

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”.