Abstract
Provided herein are novel 3-(2-(aminoethyl)-indol-4-ol derivatives as 5-HT2C agonists, pharmaceutical compositions, use of such compounds in treating depression, alcoholism, drug addiction, post-traumatic stress disorder (PTSD), and seizure disorders, and processes for preparing such compounds.
Important Compound Classes
Title
3-(2-(Aminoethyl)-indol-4-ol Derivatives, Methods of Preparation Thereof and the Use as 2-HT Receptor Modulators
Patent Publication Number
US 2023/0140635 A1
Publication Date
May 4, 2023
Priority Application
US 62/988,826
Priority Date
March 12, 2020
Inventors
Kozikowski, A.; Shapiro, G.; Tueckmantel, W.; McCorvy, J.
Assignee Company
Bright Minds Biosciences Inc., Canada and The Medical College of Wisconsin Inc., USA
Disease Area
Depression, alcoholism, drug addiction, post-traumatic stress disorder (PTSD) and seizure disorders
Biological Target
5-HT2C
Summary
Psilocybin is a naturally occurring psychedelic compound produced by more than 200 species of mushrooms collectively known as “psilocybin mushrooms.” As a prodrug, psilocybin is quickly metabolized by the body to generate the bioactive psilocin, which has mind altering effects not unlike those produced by other psychedelics such as lysergic acid diethylamide (LSD), mescaline, and N,N-dimethyltryptamine (DMT). These effects include, inter alia, euphoria, visual and mental hallucinations, changes in perception, and distortions in one’s sense of time.
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 a 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.
The present application describes a series of novel 3-(2-(aminoethyl)-indol-4-ol derivatives as 5-HT2C agonists for the treatment of depression, alcoholism, drug addiction, post-traumatic stress disorder (PTSD) and seizure disorders. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.
Definitions
R1 = C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3–C6 cycloalkyl, CH2(C3–C6 cycloalkyl), substituted benzyl, halobenzyl, C1–C6 alkylbenzyl, C1–C6 alkoxybenzyl, or C1–C6 alkylaryl;
R2 = H, C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3–C6 cycloalkyl, CH2(C3–C6 cycloalkyl), substituted benzyl, halobenzyl, C1–C6 alkylbenzyl, C1–C6 alkoxybenzyl, or C1–C6 alkylaryl;
R3 = C1–C6 alkyl, C3–C6 cycloalkyl, CH2(C3–C6 cycloalkyl), C3–C6 heterocycloalkyl, CH2(C3–C6 heterocyclyl), 3-oxetanyl, 4–7 membered heterocyclyl or CH2(4–7 membered heterocyclyl); and
Z = H, (R4)(R5)N–C(O)-, C1–C6 alkyl–C(O)-, or C3–C6 cycloalkyl–C(O)-.
Key Structures
Biological Assay
The 5-HT2C receptor Gq-dissociation BRET assay was performed. The compounds described in this application were tested for agonist activity at 5-HT2C receptor. The 5-HT2C IC50 (nM) values are shown in the following Table.
Biological Data
The 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.
Claims
Total claims: 35
Compound claims: 19
Method of treatment claims: 1
Canceled claims: 15
Recent Review Articles
See References − .
The author declares no competing financial interest.
Published as part of ACS Medicinal Chemistry Letters special issue “Psychedelics and Entactogens”.
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