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US-12617814-B2 - Neuroactive steroids and methods of use thereof

US12617814B2US 12617814 B2US12617814 B2US 12617814B2US-12617814-B2

Abstract

3beta, 17beta disubstituted steroidal compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are provided for the prevention and treatment of a variety of CNS-related conditions.

Inventors

  • Gabriel MARTINEZ BOTELLA
  • Boyd L. Harrison
  • Albert Jean Robichaud
  • Francesco G. Salituro

Assignees

  • Sage Therapeutics, LLC

Dates

Publication Date
20260505
Application Date
20240105

Claims (12)

  1. 1 . A method for treating a CNS-related condition in a subject, comprising administering to the subject an effective amount of a compound selected from the group consisting of: wherein the CNS-related condition is an adjustment disorder, an anxiety disorder, an obsessive-compulsive disorder, a posttraumatic stress disorder, social phobia, a cognitive disorder, a dissociative disorder, an eating disorder, a mood disorder, schizophrenia, a schizoaffective disorder, a sleep disorder, a substance abuse-related disorder, a personality disorder, autism spectrum disorder, a neurodevelopmental disorder, pain, a seizure disorder, stroke, traumatic brain injury, a movement disorder or tinnitus.
  2. 2 . The method of claim 1 , wherein the compound is selected from the group consisting of:
  3. 3 . The method of claim 1 , wherein the compound is selected from the group consisting of:
  4. 4 . The method of claim 1 , wherein the compound is selected from the group consisting of
  5. 5 . The method of claim 1 , wherein the compound is selected from the group consisting of:
  6. 6 . The method of claim 1 , wherein the compound is selected from the group consisting of:
  7. 7 . The method of claim 1 , wherein the compound is selected from the group, consisting of:
  8. 8 . The method of claim 1 , wherein the compound is selected from the group consisting of:
  9. 9 . The method of claim 1 , wherein the compound is selected from the group consisting of:
  10. 10 . The method of claim 1 , wherein the compound is selected from the group consisting of:
  11. 11 . The method of claim 1 , wherein the compound is selected from the group consisting of:
  12. 12 . The method of claim 1 , wherein the compound is selected from the group consisting of:

Description

RELATED APPLICATIONS The present application is a continuation of U.S. patent application Ser. No. 17/381,829, filed Jul. 21, 2021, which is a continuation of U.S. patent application Ser. No. 16/227,013, filed Dec. 20, 2018, now U.S. Pat. No. 11,104,701, which is a continuation of U.S. patent application Ser. No. 15/917,263, filed Mar. 9, 2018, now U.S. Pat. No. 10,227,375, which is a continuation of Ser. No. 15/588,305, filed May 5, 2017 (now abandoned), which is a continuation of Ser. No. 14/775,678, filed Sep. 12, 2015 (now abandoned), which is a U.S. National Stage Application under 35 U.S.C. § 371 of International Application PCT/US2014/026784, filed Mar. 13, 2014 and published as International Publication No. WO2014/160480 on Oct. 2, 2014, which claims claim priority and the benefit under 35 U.S.C. § 119(e) to U.S. provisional patent application U.S.S.N. Provisional Patent Application No. 61/779,735, filed Mar. 13, 2013, which is the disclosures of each of which are incorporated herein by reference in their entireties. BACKGROUND OF THE INVENTION Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K+, Na+, Cl−, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released as a result of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from −70 mV to −50 mV). This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase the membrane permeability of Na+ ions. The reduced membrane potential increases the probability of generating a postsynaptic action potential, which amounts to an increase in neuronal excitability. NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission. Activating these receptors contributes to synaptic plasticity in some circumstances and excitotoxicity in others. These receptors are ligand-gated ion channels that admit Ca2+ after binding of the neurotransmitters glutamate and glycine, and are fundamental to excitatory neurotransmission and normal CNS function. NMDA receptors are heteromeric complexes comprised of NR1, NR2, and/or NR3 subunits and possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine, and glutamate agonists and modulators. Positive modulators may be useful as therapeutic agents with potential clinical uses as cognitive enhancers and in the treatment of psychiatric disorders in which glutamatergic transmission is reduced or defective (see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325). In contrast, negative modulators may be useful as therapeutic agents with potential clinical uses in the treatment of psychiatric disorders in which glutamatergic transmission is pathologically increased (e.g., treatment resistant depression). Neuroactive steroids such as pregnenolone sulfate (PS) have been shown to exert direct modulatory effects on several types of neurotransmitter receptors, such as GABAA, glycine, AMPA, kainate, and NMDA receptors. NMDA receptors are positively modulated by PS; however, the degree of modulation varies considerably, e.g., depending upon the subunit composition of the receptor. In addition to PS, several other 3β-hydroxy steroids have been shown to potentiate NMDA receptors (see, e.g., Paul et al., J. Pharm. and Exp. Ther. 1994, 271, 677-682). Recently, a 3β-hydroxy-ergost-5-ene steroid derivative, referred to as Org-1, was reported as positive modulator of NMDA (NR1a/NR2A). Org-1 was found to selectively modulate NMDA over GABAA (see, e.g., Madau et al., Program No. 613.2/B87. 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009; Connick et al., Program No. 613.1/B86. 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009; Paul el al., J. Neurosci. 2013, 33, 17290-17300). New and improved neuroactive steroids are needed that modulate brain excitability for the prevention and treatment of CNS-related conditions. The compounds, compositions, and methods described herein are directed toward this end. SUMMARY OF THE INVENTION The inventors of the present invention, during an on-going exploration of Org-1 analogs for NMDA modulation, a portion of which is described in PCT/US2012/054261, incorporated herein by reference, discovered several specific combination of elements which provides N