3-Pyrrolidine-indole Derivatives as 5-HT2-Selective Receptor Modulators for the Potential Treatment of Mental Disorders

Important Compound Classes

Titles

3-Pyrrolidine-indole Derivatives as Serotonergic Psychedelic Agents for the Treatment of CNS Disorders; Psilocin Derivatives as Serotonergic Psychedelic Agents for the Treatment of CNS Disorders; and Compounds for Use in a Method of Treating, Preventing and/or Reducing the Symptoms of Pain

Patent Publication Numbers

WO 2021/155467 A1 (URL: https://patents.google.com/patent/WO2021155467A1/en?oq=WO+2021%2f155467+A1); WO 2021/155468 A1 (URL:https://patents.google.com/patent/WO2021155468A1/en?oq=WO+2021%2f155468+A1); and WO 2021/175816 A1 (URL:https://patents.google.com/patent/WO2021175816A1/en?oq=WO+2021%2f175816+A1).

Publication Dates

August 12, 2021 (WO 2021/155467 A1 and WO 2021/155468 A1); and September 10, 2021 (WO 2021/175816 A1)

Priority Applications

62/969,894 US; 62/969,934 US; and 2003059.9 GB

Priority Dates

February 4, 2020 (WO 2021/155467 A1 and WO 2021/155468 A1); and March 3, 2020 (WO 2021/175816 A1)

Inventors

Slassi, A.; Araujo, J. (WO 2021/155467 A1 and WO 2021/155468 A1); Kuypers, K.; Ramaekers, J.; Feilding, A. (WO 2021/175816 A1)

Assignee Companies

Mindset Pharma Inc. [CA/CA], 217 Queen Street West, Suite 401, Toronto, Ontario M5 V 0R2, Canada (WO 2021/155467 A1 and WO 2021/155468 A1); and The Beckley Foundation [GB/GB], Beckley Park, Oxford OX3 9SY, U.K. (WO 2021/175816 A1)

Disease Area

Mental disorders and pain

Biological Target

Serotonin receptor (SR)

Summary

The National Alliance on Mental Health in the United States estimates that untreated mental illness costs the country up to $300 billion every year due to losses in productivity (https://www.nami.org/getattachment/Get-Involved/NAMI-National-Convention/Convention-Program-Schedule/Hill-Day-2017/FINAL-Hill-Day-17-Leave-Behind-all-(1).pdf, accessed 03/15/2022). Mental health disorders (mental illnesses) encompass a wide range of disorders that include eating disorders, post-traumatic stress disorder, depressive disorders, attention deficit/hyperactivity disorder, obsessive-compulsive disorder, anxiety and panic disorders, schizophrenia, substance misuse disorders, and so forth. The severity of symptoms varies such that some individuals experience debilitating disease symptoms that preclude normal social function while others suffer with intermittent repeated episodes across their lifespan.

Although the severity of symptoms and diagnostic criteria among mental illness conditions are distinct in part, there exist phenotypic endophenotypes associated with alterations in cognition, mood, and behavior, which may extend to neurological conditions such as traumatic brain injury, Fragile X, Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. Many therapeutic drugs that modulate serotonergic function are commercially available to treat psychological disorders, including selective serotonin reuptake inhibitors, serotonin reuptake inhibitors, monoamine oxidase inhibitors, and antidepressants.

The field of psychedelic neuroscience has witnessed a recent renaissance, and psychedelics are one of the oldest classes of known psychopharmacological agents. Psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A (5-HT_2A) receptors, with particular importance to those expressed on apical dendrites of neocortical pyramidal cells in layer V, but also may bind to sigma-1 receptors with lower affinity. They are powerful psychoactive substances that alter not only perception but also mood and numerous cognitive processes. Psychedelic are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-HT_2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics.

Psychedelics may have persisting effects long after their acute effects, which includes changes in mood and brain function, possibly leading to neuroplasticity, and they promote cell survival, have a neuroprotective effect, and modulate brain neuroimmune systems. Although there is a general perception that psychedelic drugs are dangerous, from a physiologic safety standpoint they are known to be safe classes of central nervous system (CNS) drugs.

The present application includes a method for activating a serotonin receptor in a cell, either in a biological sample or in a patient, comprised of administering an effective amount of one or more compounds of the application to the cell. In addition, the therapy provides a method of treating psychosis or psychotic symptoms, comprised of administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. Clinical studies have investigated the use of psychedelics for treating psychiatric disorders including depression, existential anxiety, and substance addiction.

Patent application WO 2021175816 A1 provides a method of treating, relieving, preventing, and/or reducing the symptoms of pain, comprising the administration of a lysergamide or a pharmaceutically acceptable salt. Lysergamides such as LSD, at sub-hallucinogenic doses, can significantly relieve the symptoms of pain over a prolonged period of time. Treatments to relieve pain typically include the administration of one or more analgesic drugs, which are classified into primarily non-opioid drugs, opioid drugs, and co-analgesic drugs. These can be effective in treating some types of pain; however, they may exhibit significant toxicity and/or side effects. A report in 2017 showed that more than 70 000 people died from opioid overdose in the United States, in addition to addictions and other undesired effects such as respiratory depression.

The study with LSD involved 24 healthy participants (12 male, 12 female), who participated in a randomized, double-blind, placebo-controlled study in which they received single oral doses of 20 μg of LSD (hydrate) and placebo on four separate test days. A minimum washout of 5 days proceeded in between to avoid carry-over effects. Data analysis revealed that the administration of a low dose of LSD significantly increased pain tolerance (p = 0.006) and decreased painfulness (p = 0.012) as well as unpleasantness (p = 0.008).

Definitions

R¹ = H, C₁–C₃ alkyl, C1–C₆ alkylene P(O)(OR⁹)₂, S(O)R⁹, C(O)N(R⁹)₂

R², R³, and R⁴ are independently selected from H and C₁–C₆ alkyl

R⁵ is selected from H and C₁–C₆ alkyl

R⁶, R⁷, and R⁸ are independently selected from hydrogen, halogen, CN, OR⁹, N(R⁹), C₁–C₆ alkyl, C₁–C₆ haloalkyl, and so forth

Y is selected from O, NR¹⁰, S(O), and SO₂

R⁹ and R¹⁰ are independently selected from hydrogen, substituted or unsubstituted C₁–C₆ alkyl, and C₂–C₆ alkenyl

A is selected from hydrogen, C₁–C₆ alkyl, and C₂–C₆ alkenyl

Key Structures

Biological Assay

A fluorometric imaging plate reader (FLIPR) assay and a radioligand binding assay were used to evaluate effective inhibitors of the target human 5-HT_2A receptors.

Biological Data

The table below shows exemplary compounds targeting the human 5-HT_2A receptor under agonist mode, where A = EC₅₀ < 1000 nM; B = EC₅₀ > 1000 nM but < 10 000 nM, and C = EC₅₀ < 10 000 nM. Metabolic stability of exemplary compounds was evaluated in human, rat, and mouse using NADPH. In vivo assessment of the pharmacokinetics was carried out in mice and rats.

The author declares no competing financial interest.