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WO2024059608A1 - Stéroïdes neuroactifs deutérés - Google Patents

Stéroïdes neuroactifs deutérés Download PDF

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Publication number
WO2024059608A1
WO2024059608A1 PCT/US2023/074030 US2023074030W WO2024059608A1 WO 2024059608 A1 WO2024059608 A1 WO 2024059608A1 US 2023074030 W US2023074030 W US 2023074030W WO 2024059608 A1 WO2024059608 A1 WO 2024059608A1
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compound
pharmaceutically acceptable
acceptable salt
disorder
compounds
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Matthew Hill
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Sage Therapeutics Inc
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Sage Therapeutics Inc
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/007—Steroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to deuterated neuroactive steroids that are useful for modulating (e.g., selectively modulating) the activity of certain GABA receptors and treating or reducing the severity of CNS-related disorders in patients, and prophylactically preventing or reducing the incidence of symptoms of CNS-related disorders in patients.
  • 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.
  • neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes.
  • the neuronal membrane 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 under the influence of neuronal action potentials.
  • an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from -70 mV to -50 mV).
  • 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 membrane permeability to Na + ions.
  • the reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.
  • GABA ⁇ -aminobutyric acid receptor complex
  • GABA ⁇ -aminobutyric acid
  • GABA has a profound influence on overall brain excitability because up to 40% of the neurons in the brain utilize GABA as a neurotransmitter.
  • GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to facilitate the flow of chloride ions down an electrochemical gradient of the GRC into the cell.
  • the present invention provides a compound of Formula (I):
  • R 12a , R 12b , R 15a , R 15b , R 16a , R 16b , R 17 , R 18a , R 18b , R 18c , R 19 , R 21a , R 21b , R m , R n and R o is independently H or -D; provided that at least one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b ,R 15a , R 15b ,R 16a ,R 16b R 17 , R 18a , R 18b , R 18c , R 19 , R 21a , R 21b , R m , R n , R o is
  • one of R 1a and R 1b is -D, and the other of R 1a and R 1b is -H. In other embodiments, each of R 1a and R 1b is -D. And, in some embodiments, each of R 1a and R 1b is -H.
  • one of R 2a and R 2b is -D, and the other of R 2a and R 2b is -H. In other embodiments, each of R 2a and R 2b is -D. And, in some embodiments, each of R 2a and R 2b is -H. [0008] In some embodiments, one of R 3a and R 3b is -D, and the other of R 3a and R 3b is -H. In other embodiments, each of R 3a and R 3b is -D. And, in some embodiments, each of R 3a and R 3b is -H.
  • one of R 3c , R 3d , and R 3e is -D, and the other two of R 3c , R 3d , and R 3e are -H.
  • two of R 3c , R 3d , and R 3e are -D, and the other one of R 3c , R 3d , and R 3e is -H.
  • each of R 3c , R 3d , and R 3e is -D.
  • each of R 3c , R 3d , and R 3e is -H.
  • one of R 4a and R 4b is -D, and the other of R 4a and R 4b is -H. In other embodiments, each of R 4a and R 4b is -D. And, in some embodiments, each of R 4a and R 4b is -H.
  • R 5 is -D. In other embodiments, R 5 is -H.
  • one of R 6a and R 6b is -D, and the other of R 6a and R 6b is -H. Tn other embodiments, each of R 6a and R 6b is -D. And, in some embodiments, each of R 6a and R 6b is -H.
  • one of R 7a and R 7b is -D, and the other of R 7a and R 7b is -H. In other embodiments, each of R 7a and R 7b is -D. And, in some embodiments, each of R 7a and R 7b is -H.
  • R 19 is -D. In other embodiments, R 19 is -H.
  • one of R 11a and R 11b is -D, and the other of R 11a and R 11b is -H. In other embodiments, each of R 11a and R 11b is -D. And, in some embodiments, each of R 11a and
  • R 11b is H.
  • one of R 12a and R 12b is -D, and the other of R 12a and R 12b is -H. In other embodiments, each of R 12a and R 12b is -D. And, in some embodiments, each of R 12a and R 12b is -H.
  • one of R 15a and R 15b is -D, and the other of R 15a and R 15b is -H. In other embodiments, each of R 15a and R 15b is -D. And, in some embodiments, each of R 15a and R 15b is -H.
  • one of R 16a and R 16b is -D, and the other of R 16a and R 16b is -H. In other embodiments, each of R 16a and R 16b is -D. And, in some embodiments, each of R 16a and R 16b is -H.
  • R 17 is -D. Tn other embodiments, R 17 is -H.
  • one of R 18a , R 18b , and R 18c is -D, and the other two of R 18a , R 18b , and R 18c are -H.
  • two of R 18a , R 18b , and R 18c are -D, and the other one of R 18a , R 18b , and R 18c is -H.
  • each of R 18a , R 18b , and R 18c is -D.
  • each of R 18a , R 18b , and R 18c is -H.
  • one of R 21a and R 21b is -D, and the other of R 21a and R 21b is -H. In other embodiments, each of R 21a and R 21b is -D. And, in some embodiments, each of R 21a and R 21b is -H.
  • one of R m , R n , and R o is -D, and the other two of R m , R n , and R o are -H.
  • two of R m , R n , and R o are -D, and the other one of R m , R n , and R o is -H.
  • each of R m , R n , and R o is -D.
  • each of R m , R n , and R o is -H.
  • Another aspect of the present invention provides a compound of Formula (la):
  • R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 5 , R 18 , R 21a , R 21b , R m , R n , and R o is as defined in the compound of Formula (I) or any embodiment thereof
  • Another aspect of the present invention provides a compound of Formula (lb):
  • R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 5 , R 21a , R 21b , R m , R n , and R o is as defined in the compounds of Formulae (I) or (la), or any embodiment of either of these compounds.
  • Another aspect of the present invention provides a compound of Formula (Ic): or a pharmaceutically acceptable salt thereof, wherein each of R 2a , R 2b , R 3c , R 3d , R 3e , R 4a , R 4b , R 5 , R m , R n , and R o is as defined in the compounds of Formulae (I), (la), or (lb), or any embodiment of any of these compounds.
  • Another aspect of the present invention provides a compound of Formula (Id): or a pharmaceutically acceptable salt thereof, wherein each of R 3c , R 3d , R 3e , R 5 , R m , R n , and R o is as defined in the compounds of Formulae (I), (la), (lb), or (Ic), or any embodiment of any of these compounds.
  • Another aspect of the present invention provides a compound of Formula (le): or a pharmaceutically acceptable salt thereof, wherein each of R 3c , R 3d , R 3e , R m , R n , and R o is as defined in the compounds of Formulae (I), (la), (lb), (Ic), or (Id), or any embodiment of any of these compounds.
  • Another aspect of the present invention provides a compound of Formula (If): or a pharmaceutically acceptable salt thereof, wherein each of R 3c , R 3d , and R 3e is as defined in the compounds of Formulae (I), (la), (lb), (Ic), (Id), or (le), or any embodiment of any of these compounds.
  • Another aspect of the present invention provides a compound of Formula (Ig): or a pharmaceutically acceptable salt thereof, wherein each of R m , R n , and R o is as defined in the compounds of Formulae (I), (la), (lb), (Ic), (Id), or (le), or any embodiment of any of these compounds.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, and a pharmaceutically acceptable excipient.
  • Another aspect of the present invention provides a method of modulating a GABA A receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein or a pharmaceutical composition described herein.
  • Another aspect of the present invention provides a method of modulating a GABA A receptor mediated CNS-related disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein or a pharmaceutical composition described herein.
  • Another aspect of the present invention provides a method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein or a pharmaceutical composition described herein.
  • the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus.
  • the CNS-related disorder is a mood disorder.
  • the mood disorder is depression.
  • the depression is postpartum depression.
  • the depression is a major depressive disorder.
  • the major depressive disorder is a moderate major depressive disorder.
  • the major depressive disorder is a severe major depressive disorder.
  • the CNS-related disorder is tremor (e.g., essential tremor).
  • the CNS-related disorder is seizure.
  • the CNS-related disorder is epilepsy.
  • the CNS-related disorder is status epilepticus.
  • the status epilepticus is convulsive status epilepticus or non-convulsive status epilepticus.
  • the status epilepticus is convulsive status epilepticus selected from early status epilepticus, established status epilepticus, refractor status epilepticus, and super-refractory status epilepticus.
  • the status epilepticus is non-convulsive status epilepticus selected from generalized status epilepticus and partial complex status epilepticus.
  • Another aspect of the present invention provides a method for inducing sedation and/or anesthesia in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt described herein or a pharmaceutical composition described herein.
  • Figure 1 is a representative 1 H NMR spectra of Compound No. 1 according to Example 1.
  • Figure 2 is a representative 1 H NMR spectra of Compound No. 2 according to Example
  • Figure 3 is a representative 1 H NMR spectra of Compound No. 3 according to Example
  • Figure 4 is a representative 1 H NMR spectra of Compound No. 4 according to Example
  • Figure 5 is a representative 1 H NMR spectra of Compound No. 5 according to Example
  • the present invention generally relates to deuterated neuroactive steroids, pharmaceutically acceptable formulations thereof, methods of preparing such deuterated neuroactive steroids, and uses of such deuterated neuroactive steroids for modulating GABA receptor activity (e.g., positive allosteric modulation) and/or treating CNS-related disorders.
  • GABA receptor activity e.g., positive allosteric modulation
  • isomers refers to compounds that contain exactly the same number of atoms, i.e., they have exactly the same empirical formula, but differ from each other by the way in which the atoms are arranged. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)- isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • Isomers e.g., stereoisomers
  • HPLC high performance liquid chromatography
  • preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et ctl.. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).
  • the invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • an enantiomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R-position/center/ carbon compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R- compound.
  • the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound.
  • the enantiomerically pure S- compound in such compositions can, for example, comprise, at least about 95% by weight S- compound and at most about 5% by weight R-compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • diastereomerically pure denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of a single diastereomer.
  • Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomers, such as high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Compounds disclosed herein may be “isomerically pure” compounds.
  • the term “isomerically pure” refers to an isomeric form of a compound that is substantially free from other isomeric forms of the compound (e.g., substantially free from other stereoisomers (e.g., enantiomers, diastereomers, geometric (or conformational) isomers, etc.), constitutional isomers, isotopomers, etc.).
  • an “isomerically pure” compound having at least one asymmetric center of a particular configuration i.e., R or S configuration
  • is substantially free from other isomeric forms of the compound having a different configuration at the at least one asymmetric center i.e., R or S configuration
  • An “isomerically pure” compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight, of a single isomer of the compound based on the total weight of all isomers of the compound that are present.
  • analogue means one analogue or more than one analogue.
  • protecting group refers to a moiety or functionality that is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction.
  • Standard protecting groups are provided in Wuts and Greene: “Greene's Protective Groups in Organic Synthesis,” 4th Ed, Wuts, P.G.M. and Greene, T.W., Wiley-Interscience, New York:2006.
  • Compounds and pharmaceutically acceptable salts described herein are deuterium-enriched.
  • Deuterium (D or 2 H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes 1 H (hydrogen or protium), D ( 2 H or deuterium), and T ( 3 H or tritium). The natural abundance of deuterium is 0.015%.
  • the H atom actually represents a mixture of H and D, with about 0.015% being D.
  • compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015% should be considered unnatural and, as a result, novel over their non- enriched counterparts.
  • H hydrogen
  • D deuterium
  • isotopic enrichment factor means the ratio between the isotopic abundance of D at the specified position in a compound of this invention and the naturally occurring abundance of that isotope.
  • a compound e.g., a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig)
  • deuterium-enrichment a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig)
  • deuterium-enriched compounds are referred to as “deuterium-enriched” compounds. If not specifically noted, the percentage of enrichment refers to the percentage of deuterium present in the compound.
  • a compound of this invention has an isotopic enrichment factor for each deuterium present at a site designated at a potential site of deuteration on the compound of at least 3500 (52.5.% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent of other deuterated sites.
  • the resulting compound would be considered to be a compound wherein the isotopic enrichment factor is at least 3500 (52.5%).
  • deuterium present Because the natural abundance of deuterium is about 0.015%, approximately one in every 6,667 naturally occurring sites of hydrogen in a compound described herein, e.g., a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), would be expected to have a deuterium present. [0067] All percentages given for the amount of deuterium present are mole percentages.
  • Deuterium-enriched can be achieved by either exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials.
  • deuterium-enriched compounds of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig).
  • structures depicted herein also are meant to include all isomeric (e g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative that upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • modulation refers to the inhibition or potentiation of GABA A receptor function.
  • a “modulator” e.g., a modulator compound
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic, and may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-di sulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluene
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.
  • prodrug is intended to encompass therapeutically inactive compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention.
  • One method for making a prodrug is to design selected moieties that are hydrolyzed or cleaved at a targeted in vivo site of action under physiological conditions to reveal the desired molecule which then produces its therapeutic effect.
  • the prodrug is converted by an enzymatic activity of the subject.
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • a “subject” to which administration is contemplated includes humans, i.e., a male or female of any age group.
  • exemplary human subjects include, e.g., “a pediatric subject” (e.g., infant, child, adolescent) or “adult subject” (e.g., young adult, middle-aged adult or senior adult).
  • a pediatric subject e.g., infant, child, adolescent
  • adult subject e.g., young adult, middle-aged adult or senior adult.
  • the terms, “disease”, “disorder”, and “condition” are used interchangeably herein.
  • the terms “treat”, “treating”, and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition.
  • the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, or is sufficient to induce anesthesia or sedation.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • the present invention contemplates administration of the compounds of the present invention or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof, as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • the present invention provides compounds that modulate (e.g., inhibit) GABA (e.g., GABA A ) activity.
  • GABA e.g., GABA A
  • the present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein each of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 11a , R 11b ,
  • R 12a R 12b R 15a R 15b R 16a R 16b R 17 R 18a , R 18b , R 18c , R 19 , R 21a , R 21b , R m , R n a n d R o is independently -H or -D; provided that at least one of R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a R 7b , R 11a R 11b R 12a R 12b R 15a R 15b R 16a R 16b R 17 R 18a , R 18b , R 18c , R 19 , R 21a , R 21b , R m , Ra n R o is -D.
  • one of R 1a and R 1b is -D, and the other of R 1a and R 1b is -H.
  • R 1a is -D and R 1b is -H.
  • R 1b is -D and R 1a is -H.
  • each of R 1a and R 1b is -D.
  • each of R 1a and R 1b is -H.
  • R 2a and R 2b is -D.
  • one of R 2a and R 2b is -D, and the other of R 2a and R 2b is -H.
  • R 2a is -D and R 2b is -H.
  • R 2b is -D and R 2a is -H.
  • each of R 2a and R 2b is -D.
  • each of R 2a and R 2b is -H.
  • one of R 3a and R 3b is -D, and the other of R 3a and R 3b is -H.
  • R 3a is -D and R 3b is -H.
  • R 3b is -D and R 3a is -H.
  • each of R 3a and R 3b is -D.
  • each of R 3a and R 3b is -H.
  • one of R 3c , R 3d , and R 3e is -D, and the other two of R 3c , R 3d , and R 3e are -H.
  • R 3c is -D and each of R 3d and R 3e is -H.
  • R 3d is -D and each of R 3c and R 3e is -H.
  • R 3e is -D and each of R 3c and R 3d is -H.
  • two of R 3c , R 3d , and R 3e are -D, and the other one of R 3c , R 3d , and R 3e is -H.
  • each of R 3c and R 3d is -D and R 3e is -H.
  • each of R 3d and R 3e is -D and R 3c is -H.
  • each of R 3c and R 3e is -D and R 3d is -H.
  • each of R 3c , R 3d , and R 3e is D. And, in some embodiments, each of R 3c , R 3d , and R 3e is -H. [0099] 4. R 4a and R 4b .
  • one of R 4a and R 4b is -D, and the other of R 4a and R 4b is -H.
  • R 4a is -D and R 4b is -H.
  • R 4b is -D and R 4a is -H.
  • each of R 4a and R 4b is -D.
  • each of R 4a and R 4b is -H.
  • R 5 is -D. In other embodiments, R 5 is -H.
  • one of R 6a and R 6b is -D, and the other of R 6a and R 6b is -H.
  • R 6a is -D and R 6b is -H.
  • R 6b is -D and R 6a is -H.
  • each of R 6a and R 6b is -D.
  • each of R 6a and R 6b is -H.
  • one of R 7a and R 7b is -D, and the other of R 7a and R 7b is -H.
  • R 7a is -D and R 7b is -H.
  • R 7b is -D and R 7a is -H.
  • each of R 7a and R 7b is -D.
  • each of R 7a and R 7b is -H.
  • R 19 is -D. In other embodiments, R 19 is -H.
  • one of R 11a and R 11b is -D, and the other of R 11a and R 11b is -H.
  • R 11a is -D and R 11b is -H.
  • R 11b is -D and R 11a is -H.
  • each of R 11a and R 11b is -D.
  • each of R 11a and R 11b is -D.
  • one of R 12a and R 12b is -D, and the other of R 12a and R 12b is -H.
  • R 12a is -D and R 12b is -H.
  • R 12b is -D and R 12a is -H.
  • each of R 12a and R 12b is -D.
  • each of R 12a and R 12b is -H.
  • one of R 15a and R 15b is -D, and the other of R 15a and R 15b is -H.
  • R 15a is -D and R 15b is -H.
  • R 15b is -D and R 15a is -H.
  • each of R 15a and R 15b is -D.
  • each of R 15a and R 15b is -D.
  • one of R 16a and R 16b is -D, and the other of R 16a and R 16b is -H. In other embodiments, each of R 16a and R 16b is -D. And, in some embodiments, each of R 16a and R 16b is -H.
  • R 17 is -D. In other embodiments, R 17 is -H.
  • one of R 18a , R 18b , and R 18c is -D, and the other two of R 18a , R 18b , and R 18c are -H.
  • R 18a is -D and each of R 18b and R 18c is -H.
  • R 18b is -D and each of R 18a and R 18c is -H.
  • R 18c is -D and each of R 18b and R 18a is -H.
  • R 18a , R 18b , and R 18c are -D, and the other one of R 18a , R 18b , and R 18c is -H.
  • each of R 18a and R 18b is -D and R 18c is -H.
  • each of R 18b and R 18c is -D and R 18a is -H.
  • each of R 18a and R 18c is -D and R 18b is -H.
  • each of R 18a , R 18b , and R 18c is -D. And, in some embodiments, each of R 18a , R 18b , and R 18c is -H.
  • one of R 21a and R 21b is -D, and the other of R 21a and R 21b is -H.
  • R 21a is -D and R 21b is -H.
  • R 21b is -D and R 21a is -H.
  • each of R 21a and R 21b is D.
  • each of R 21a and R 21b is -H.
  • one of R m , R n , and R o is -D, and the other two of R m , R n , and R o are -H.
  • R m is -D and each of R n and R o is -H.
  • R n is -D and each of R m and R o is -H.
  • R o is -D and each of R m and R n is -H.
  • R m , R n , and R o are -D, and the other one of R m , R n , and R o is -H.
  • each of R m and R n is -D and R o is -H.
  • each of R n and R o is -D and R m is -H.
  • each of R m and R o is -D and R n is -H.
  • each of R m , R n , and R o is -D. And, in some embodiments, each of R m , R n , and R o is -H [0129]
  • Another aspect of the present invention provides a compound of Formula (la): or a pharmaceutically acceptable salt thereof, wherein each of R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 5 , R 18 , R 21a , R 21b , R m , R n , and R o is as defined in the compound of Formula (I) or any embodiment thereof.
  • one of R 2a and R 2b is -D, and the other of R 2a and R 2b is -H.
  • R 2a is -D and R 2b is -H.
  • R 2b is -D and R 2a is -H.
  • each of R 2a and R 2b is -D.
  • each of R 2a and R 2b is -H.
  • one of R 3c , R 3d , and R 3e is -D, and the other two of R 3c , R 3d , and R 3e are -H.
  • R 3c is -D and each of R 3d and R 3e is -H.
  • R 3d is -D and each of R 3c and R 3e is -H.
  • R 3e is -D and each of R 3c and R 3d is -H.
  • two of R 3c , R 3d , and R 3e are -D, and the other one of R 3c , R 3d , and R 3e is -H.
  • each of R 3c and R 3d is -D and R 3e is -H.
  • each of R 3d and R 3e is -D and R 3c is -H.
  • each of R 3c and R 3e is -D and R 3d is -H.
  • each of R 3c , R 3d , and R 3e is -D. And, in some embodiments, each of R 3c , R 3d , and R 3e is -H.
  • one of R 4a and R 4b is -D, and the other of R 4a and R 4b is -H.
  • R 4a is D and R 4b is H.
  • R 4b is D and R 4a is H.
  • each of R 4a and R 4b is -D.
  • each of R 4a and R 4b is -H.
  • R 5 is -D. In other embodiments, R 5 is -H.
  • one of R 18a , R 18b , and R 18c is -D, and the other two of R 18a , R 18b , and R 18c are -H.
  • R 18a is -D and each of R 18b and R 18c is -H.
  • R 18b is -D and each of R 18a and R 18c is -H.
  • R 18c is -D and each of R 18b and R 18a is -H.
  • R 18a , R 18b , and R 18c are -D, and the other one of R 18a , R 18b , and R 18c is -H.
  • each of R 18a and R 18b is -D and R 18c is -H.
  • each of R 18b and R 18c is -D and R 18a is -H.
  • each of R 18a and R 18c is -D and R 18b is -H.
  • each of R 18a , R 18b , and R 18c is -D. And, in some embodiments, each of R 18a , R 18b , and R 18c is -H.
  • one of R 21a and R 21b is -D, and the other of R 21a and R 21b is -H.
  • R 21a is -D and R 21b is -H.
  • R 21b is -D and R 21a is -H.
  • each of R 21a and R 21b is -D.
  • each of R 21a and R 21b is -H.
  • one of R m , R n , and R o is -D, and the other two of R m , R n , and R o are -H.
  • R m is -D and each of R n and R o is -H.
  • R n is -D and each of R m and R o is -H.
  • R m is -D and each of R m and R n is -H.
  • R m , R n , and R o are -D, and the other one of R m , R n , and R o is -H.
  • each of R m and R n is -D and R o is -H.
  • each of R n and R o is -D and R m is -H.
  • each of R m and R o is -D and R n is -H.
  • each of R m , R n , and R o is -D. And, in some embodiments, each of R m , R n , and R o is -H.
  • Another aspect of the present invention provides a compound of Formula (lb): or a pharmaceutically acceptable salt thereof, wherein each of R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 4b , R 5 , R 21a , R 21b , R m , R n , and R o is as defined in the compounds of Formulae (I) or (la), or any embodiment of either of these compounds.
  • one of R 2a and R 2b is -D, and the other of R 2a and R 2b is -H.
  • R 2a is -D and R 2b is -H.
  • R 2b is -D and R 2a is -H.
  • each of R 2a and R 2b is -D.
  • each of R 2a and R 2b is -H.
  • one of R 3c , R 3d , and R 3e is -D, and the other two of R 3c , R 3d , and R 3e are -H.
  • R 3c is -D and each of R 3d and R 3e is -H.
  • R 3d is -D and each of R 3c and R 3e is -H.
  • R 3e is -D and each of R 3c and R 3d is -H.
  • two of R 3c , R 3d , and R 3e are -D, and the other one of R 3c , R 3d , and R 3e is -H.
  • each of R 3c and R 3d is -D and R 3e is -H.
  • each of R 3d and R 3e is -D and R 3c is -H.
  • each of R 3c and R 3e is -D and R 3d is -H. [0147] In some embodiments, each of R 3c , R 3d , and R 3e is -D. And, in some embodiments, each of R 3c , R 3d , and R 3e is -H.
  • one of R 4a and R 4b is -D, and the other of R 4a and R 4b is -H.
  • R 4a is -D and R 4b is -H.
  • R 4b is -D and R 4a is -H.
  • each of R 4a and R 4b is -D.
  • each of R 4a and R 4b is -H.
  • R 5 is -D. Tn other embodiments, R 5 is -H.
  • one of R 21a and R 21b is -D, and the other of R 21a and R 21b is -H.
  • R 21a is -D and R 21b is -H.
  • R 21b is -D and R 21a is -H.
  • each of R 21a and R 21b is -D.
  • each of R 21a and R 21b is -H.
  • one of R m , R n , and R o is -D, and the other two of R m , R n , and R o are -H.
  • R m is -D and each of R n and R o is -H.
  • R n is -D and each of R m and R o is -H.
  • R m is -D and each of R m and R n is -H.
  • R m , R n , and R o are -D, and the other one of R m , R n , and R o is H.
  • each of R m and R n is D and R o is H.
  • each of R n and R o is -D and R m is -H.
  • each of R m and R o is -D and R n is -H.
  • each of R m , R n , and R o is -D. And, in some embodiments, each of R m , R n , and R o is -H.
  • Another aspect of the present invention provides a compound of Formula (Ic): or a pharmaceutically acceptable salt thereof, wherein each of R 2a , R 2b , R 3c , R 3d , R 3e , R 4a , R 4b , R 5 , R m , R n , and R o is as defined in the compounds of Formulae (I), (la), or (lb), or any embodiment of any of these compounds.
  • one of R 2a and R 2b is -D, and the other of R 2a and R 2b is -H.
  • R 2a is -D and R 2b is -H.
  • R 2b is -D and R 2a is -H.
  • each of R 2a and R 2b is -D.
  • each of R 2a and R 2b is -H.
  • one of R 3c , R 3d , and R 3e is -D, and the other two of R 3c , R 3d , and R 3e are -H.
  • R 3c is -D and each of R 3d and R 3e is -H.
  • R 3d is -D and each of R 3c and R 3e is -H.
  • R 3e is -D and each of R 3c and R 3d is -H.
  • two of R 3c , R 3d , and R 3e are -D, and the other one of R 3c , R 3d , and R 3e is -H.
  • each of R 3c and R 3d is -D and R 3e is -H.
  • each of R 3d and R 3e is -D and R 3c is -H.
  • each of R 3c and R 3e is -D and R 3d is -H. [0158] In some embodiments, each of R 3c , R 3d , and R 3e is -D. And, in some embodiments, each of R 3c , R 3d , and R 3c is -H.
  • one of R 4a and R 4b is -D, and the other of R 4a and R 4b is -H.
  • R 4a is -D and R 4b is -H.
  • R 4b is -D and R 4a is -H.
  • each of R 4a and R 4b is -D.
  • each of R 4a and R 4b is -H.
  • R 5 is -D. In other embodiments, R 5 is -H.
  • one of R m , R n , and R o is -D, and the other two of R m , R n , and R o are -H.
  • R m is -D and each of R n and R o is -H.
  • R n is -D and each of R m and R o is H.
  • R m is D and each of R m and R n is H.
  • R m , R n , and R o are -D, and the other one of R m , R n , and R o is -H.
  • each of R m and R n is -D and R o is -H.
  • each of R n and R o is -D and R m is -H.
  • each of R m and R o is -D and R n is -H.
  • each of R m , R n , and R o is -D. And, in some embodiments, each of R m , R n , and R o is -H.
  • Another aspect of the present invention provides a compound of Formula (Id): or a pharmaceutically acceptable salt thereof, wherein each of R 3c , R 3d , R 3e , R 5 , R m , R n , and R o is as defined in the compounds of Formulae (I), (la), (lb), or (Ic), or any embodiment of any of these compounds.
  • one of R 3c , R 3d , and R 3e is -D, and the other two of R 3c , R 3d , and R 3e are H.
  • R 3c is D and each of R 3d and R 3e is H.
  • R 3d is -D and each of R 3c and R 3e is -H.
  • R 3e is -D and each of R 3c and R 3d is -H.
  • two of R 3c , R 3d , and R 3e are -D, and the other one of R 3c , R 3d , and R 3e is -H.
  • each of R 3c and R 3d is -D and R 3e is -H.
  • each of R 3d and R 3e is -D and R 3c is -H.
  • each of R 3c and R 3e is -D and R 3d is -H.
  • each of R 3c , R 3d , and R 3e is -D.
  • each of R 3c , R 3d , and R 3e is -H.
  • R 5 is -D. In other embodiments, R 5 is -H.
  • one of R m , R n , and R o is -D, and the other two of R m , R n , and R o are -H.
  • R m is -D and each of R n and R o is -H.
  • R n is -D and each of R m and R o is -H.
  • R m is -D and each of R m and R n is -H.
  • R m , R n , and R o are -D, and the other one of R m , R n , and R o is -H.
  • each of R m and R n is -D and R o is -H.
  • each of R n and R o is -D and R m is -H.
  • each of R m and R o is -D and R n is -H.
  • each of R m , R n , and R o is -D. And, in some embodiments, each of R m , R n , and R o is -H.
  • Another aspect of the present invention provides a compound of Formula (le): or a pharmaceutically acceptable salt thereof, wherein each of R 3c , R 3d , R 3e , R m , R n , and R o is as defined in the compounds of Formulae (I), (la), (lb), (Ic), or (Id), or any embodiment of any of these compounds.
  • one of R 3c , R 3d , and R 3e is -D, and the other two of R 3c , R 3d , and R 3e are -H.
  • R 3c is -D and each of R 3d and R 3e is -H.
  • R 3d is -D and each of R 3c and R 3e is -H.
  • R 3e is -D and each of R 3c and R 3d is -H.
  • two of R 3c , R 3d , and R 3e are -D, and the other one of R 3c , R 3d , and R 3e is -H.
  • each of R 3c and R 3d is -D and R 3e is -H.
  • each of R 3d and R 3e is -D and R 3c is -H.
  • each of R 3c and R 3e is -D and R 3d is -H.
  • each of R 3c , R 3d , and R 3e is -D.
  • each of R 3c , R 3d , and R 3e is -H.
  • one of R m , R n , and R o is -D, and the other two of R m , R n , and R o are -H.
  • R m is -D and each of R n and R o is -H.
  • R n is -D and each of R m and R o is -H.
  • R m is -D and each of R m and R n is -H.
  • R m , R n , and R o are -D, and the other one of R m , R n , and R o is -H.
  • each of R m and R n is -D and R o is -H.
  • each of R n and R o is -D and R m is -H.
  • each of R m and R o is -D and R n is -H.
  • each of R m , R n , and R o is -D. And, in some embodiments, each of R m , R n , and R o is -H.
  • Another aspect of the present invention provides a compound of Formula (If): or a pharmaceutically acceptable salt thereof, wherein each of R 3c , R 3d , and R 3e is as defined in the compounds of Formulae (I), (la), (lb), (Ic), (Id), or (le), or any embodiment of any of these compounds.
  • one of R 3c , R 3d , and R 3e is -D, and the other two of R 3c , R 3d , and R 3e are -H.
  • R 3c is -D and each of R 3d and R 3e is -H.
  • R 3d is -D and each of R 3c and R 3e is -H.
  • R 3e is -D and each of R 3c and R 3d is -H.
  • two of R 3c , R 3d , and R 3e are -D, and the other one of R 3c , R 3d , and R 3e is -H.
  • each of R 3c and R 3d is -D and R 3e is -H.
  • each of R 3d and R 3e is -D and R 3c is -H.
  • each of R 3c and R 3e is -D and R 3d is -H.
  • each of R 3c , R 3d , and R 3e is -D. And, in some embodiments, each of R 3c , R 3d , and R 3e is -H.
  • Another aspect of the present invention provides a compound of Formula (Ig):
  • each of R m , R n , and R o is as defined in the compounds of Formulae (I), (la), (lb), (Ic), (Id), or (le), or any embodiment of any of these compounds.
  • one of R m , R n , and R o is -D, and the other two of R m , R n , and R o are -H.
  • R m is -D and each of R n and R o is -H.
  • R n is -D and each of R m and R o is -H.
  • R m is -D and each of R m and R n is -H.
  • R m , R n , and R o are -D, and the other one of R m , R n , and R o is -H.
  • each of R m and R n is -D and R o is -H.
  • each of R n and R o is -D and R m is -H.
  • each of R m and R o is -D and R n is -H.
  • each of R m , R n , and R o is -D. And, in some embodiments, each of R m , R n , and R o is -H.
  • Table 1 Representative compounds of Formula (I).
  • the invention provides a pharmaceutical composition
  • a compound or pharmaceutically acceptable salt of the present invention i.e., a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, also referred to as the “active ingredient”, “active pharmaceutical ingredient”, or “API”), and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.
  • compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, topical administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intramuscular (IM) administration, sublingual / buccal, ocular, otic, vaginal, and intranasal or inhalation administration.
  • the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions provided herein are administered in an effective amount.
  • the amount of the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions provided herein actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
  • the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”).
  • Chronic administration refers to administration of a compound, pharmaceutically acceptable salt, or pharmaceutical composition provided herein over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, or the like, or may be continued indefinitely, for example, for the rest of the subject’s life.
  • the chronic administration is intended to provide a consistent level of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig) in the blood or brain, e.g., within the therapeutic window over the extended period of time.
  • compositions of the present invention may be further delivered using a variety of dosing methods.
  • the pharmaceutical composition may be given as an injection, e.g., in order to raise the concentration of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig) in the blood to an effective level.
  • the placement of the injection dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous injection dose allows a slow release of the active ingredient.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefdled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
  • each dose provides from about 0.01 to about 20 mg/kg (e.g., from about 0.1 to about 10 mg/kg, from about 0.2 to about 5 mg/kg, from about 0.1 to about 1 mg/kg, from about 0.2 to about 0.8 mg/kg, from about 0.2 to about 0.7 mg/kg, or from about 0.2 to about 0.5 mg/kg) of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds.
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds is administered at a dosage amount of about 10 mg to about 70 mg (e.g., about 15 mg to about 60 mg, about 25 mg to about 55 mg, or about 30 mg to about 50 mg) per oral dose per day.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight of, e.g., the drug reservoir or drug-adhesive reservoir for the transdermal patch, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0. 1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 5 g/day for a 40 to 80 kg human patient.
  • Liquid forms suitable for oral administration may include a suitable aqueous or non- aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable excipients known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s).
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration or stability of the active ingredients or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
  • Solid compositions may include, for example, any of the following ingredients, or a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, of a similar nature: binders, surfactants, diluents or fillers, buffering agents, anti-adherents, glidants, hydrophilic or hydrophobic polymers, retardants (e.g., delayed release agents), stabilizing agents or stabilizers, disintegrants or superdisintegrants, dispersants, antioxidants, antifoaming agents, fillers, flavors, colorants, lubricants, sorbents, preservatives, plasticizers, coatings, or sweeteners, or mixtures thereof
  • the excipient or excipients could be a binder such as microcrystalline cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, low viscosity hydroxy
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s).
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration and stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
  • Topical delivery compositions of interest include liquid formulations, such as lotions (liquids containing insoluble material in the form of a suspension or emulsion, intended for external application, including spray lotions) and aqueous solutions, semi-solid formulations, such as gels (colloids in which the disperse phase has combined with the dispersion medium to produce a semisolid material, such as a jelly), creams (soft solids or thick liquids) and ointments (soft, unctuous preparations), and solid formulations, such as topical patches
  • delivery vehicle components of interest include, but are not limited to: emulsions of the oil-in-water (O/W) and the water in-oil (W/O) type, milk preparations, lotions, creams, ointments, gels, serum, powders, masks, packs, sprays, aerosols, sticks, and patches.
  • transdermal administration can be accomplished using a patch either of the reservoir or membrane type, or of an adhesive matrix or other matrix variety.
  • Delivery compositions of interest include liquid formulations, such as lotions (liquids containing insoluble material in the form of a suspension or emulsion, intended for external application, including spray lotions) and aqueous solutions, semi- solid formulations, such as gels (colloids in which the disperse phase has combined with the dispersion medium to produce a semisolid material, such as a jelly), creams (soft solids or thick liquids) and ointments (soft, unctuous preparations), and solid formulations, such as topical patches.
  • liquid formulations such as lotions (liquids containing insoluble material in the form of a suspension or emulsion, intended for external application, including spray lotions) and aqueous solutions
  • semi- solid formulations such as gels (colloids in which the disperse phase has combined with the dispersion medium to produce a semisolid material, such as a jelly)
  • creams soft solids or thick liquids
  • ointments soft, unctuous preparations
  • solid formulations
  • delivery vehicle components of interest include, but are not limited to: emulsions of the oil-in-water (O/W) and the water in-oil (W/O) type, milk preparations, lotions, creams, ointments, gels, serum, powders, masks, packs, sprays, aerosols, sticks, and patches.
  • the active agent layer includes one or more active agents, one of which is a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (1g), or a pharmaceutically acceptable salt of any of these compounds.
  • the matrix is an adhesive matrix.
  • the matrix may include polymeric materials.
  • Suitable polymers for the adhesive matrix include, but are not limited to: polyurethanes, acrylates, styrenic block copolymers, silicones, and the like.
  • the adhesive matrix may include, but is not limited to, an acrylate polymer, polysil oxanes, polyisobutylene (PIB), polyisoprene, polybutadiene, styrenic block polymers, combinations of thereof, and the like. Additional examples of adhesives are described in Satas, “Acrylic Adhesives,” Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989), the disclosure of which is herein incorporated by reference.
  • the active agent layer includes a permeation enhancer.
  • the permeation enhancer may include, but is not limited to the following: aliphatic alcohols, such as but not limited to saturated or unsaturated higher alcohols having 12 to 22 carbon atoms, such as oleyl alcohol and lauryl alcohol; fatty acids, such as but not limited to linolic acid, oleic acid, linolenic acid, stearic acid, isostearic acid and palmitic acid; fatty acid esters, such as but not limited to isopropyl myristate, diisopropyl adipate, and isopropyl palmitate; alcohol amines, such as but not limited to triethanolamine, triethanolamine hydrochloride, and diisopropanolamine; polyhydric alcohol alkyl ethers, such as but not limited to alkyl ethers of polyhydric alcohols such as glycerol, ethylene glycol, propylene glycol, 1,
  • the polymer matrix includes a polyvinylpyrrolidone.
  • the composition may further include one or more fdlers or one or more antioxidants.
  • the transdermal formulations described may have a multi- layer structure.
  • the transdermal formulation may have an adhesive matrix and a backing.
  • compositions of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington’s Pharmaceutical Sciences.
  • a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt described herein (e g., a compound of any of Formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), org (Ig), or a pharmaceutically acceptable salt of any of these compounds), and a pharmaceutically acceptable excipient.
  • the compound or pharmaceutically acceptable salt is provided in an effective amount in the pharmaceutical composition.
  • the compound or pharmaceutically acceptable salt is provided in a therapeutically effective amount.
  • the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.
  • compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, vaginal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.
  • the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions provided herein are administered in an effective amount.
  • the amount of the compounds, pharmaceutically acceptable salts, or pharmaceutical compositions provided herein actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
  • the compounds provided herein When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”).
  • Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, or the like, or may be continued indefinitely, for example, for the rest of the subject’s life.
  • the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
  • the pharmaceutical compositions of the present invention may be further delivered using a variety of dosing methods.
  • the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level.
  • the placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level.
  • the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject’s body.
  • the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 5 g/day for a 40 to 80 kg human patient.
  • Liquid forms suitable for oral administration may include a suitable aqueous or non- aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable excipients known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s).
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration or stability of the active ingredients or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington’s Pharmaceutical Sciences.
  • the present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of the present invention.
  • the acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.
  • a non-toxic acid addition salt i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluen
  • the invention provides a pharmaceutical composition
  • a pharmaceutically acceptable excipient e.g., a composition suitable for injection, such as for intravenous (IV) administration.
  • Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection.
  • General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).
  • injectable preparations such as sterile injectable aqueous suspensions
  • suitable dispersing or wetting agents and suspending agents include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.
  • the pharmaceutical composition further comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ - cyclodextrins consisting of 6, 7 and 8 oc-1 ,4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, substituted or unsubstituted methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, e g., for example, sulfobutyl ether ⁇ -cyclodextrin, also known as CAPTISOL®. See, e.g., U.S. 5,376,645.
  • the composition comprises hexapropyl- ⁇ -cyclodextrin. In a more particular embodiment, the composition comprises hexapropyl- ⁇ -cyclodextrin (10-50% in water).
  • the injectable composition can be sterilized, for example, by fdtration through a bacterial-retaining fdter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the compounds provided herein are administered in an effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient’s symptoms, and the like.
  • the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include pre-filled, pre-measured ampules or syringes of the liquid compositions.
  • the compound is usually a minor component (from about 0.1% to about 50% by weight or preferably from about 1% to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • the compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents.
  • the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.
  • compositions suitable for administration to humans are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.
  • kits comprising a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds.
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds may be administered in combination with an additional agent or therapy.
  • a subject to be administered a compound disclosed herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy.
  • Combination therapy may be achieved by administering two or more agents, each of which is formulated and administered separately, or by administering two or more agents in a single formulation.
  • the two or more agents in the combination therapy can be administered simultaneously.
  • the two or more agents in the combination therapy are administered separately.
  • administering can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks.
  • the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.
  • Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents.
  • agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y- Y-X, X-X-Y-Y, etc.
  • exemplary additional agents are described below.
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, is administered in combination with an SSRI(s).
  • SSRIs include antidepressants that increase the level of serotonin in the brain.
  • Exemplary SSRIs include, but are not limited to, Citalopram (Celexa), Escital opram (Lexapro), Fluoxetine (Prozac), Fluvoxamine (Luvox), Paroxetine (Paxil), and Sertraline (Zoloft). [0246] 2.
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, is administered in combination with an MAOI(s).
  • MAOIs include antidepressants that inhibit monoamine oxidase activity in the brain.
  • Exemplary MAOIs include, but are not limited to, Isocarboxazid (Marplan), Phenelzine (Nardil), Selegiline (Emsam), and Tranylcypromine (parnate).
  • NERIs include, but are not limited to, Atomoxetine (Strattera), Reboxetine (Edronax, Vestra), Bupropion (Wellbutrin, Zyban), Duloxetine, Desipramine (Norpramin), Amedalin (UK-3540-1), Daledalin (UK-3557-15), Edivoxetine (LY-2216684), Esreboxetine, Eortalamine (LM-1404), Nisoxetine (LY-94,939), Talopram (tasulopram) (Lu 3- 010), Talsupram (Lu 5-005), Tandamine (AY-23,946), and Viloxazine (Vivalan).
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, is administered in combination with an antipsychotic agent(s).
  • Antipsychotics include D2 antagonists, lowering dopaminergic neurotransmission in the dopamine pathways.
  • antipsychotics include, but are not limited to, Asenapine (Saphris), Aripiprazole (Abilify), Cariprazine (Vrayar), Clozapine (Clozaril), Droperidol, Fluperlapine, Mesoridazine, Quetiapine Hemifumarate, Raclopride, Spiperone, Sulpiride, Trimethobenzamide hydrochloride, Trifluoperazine Dihydrochloride, lurasidone (Latuda), Olanzapine (Zyprexa), Quetiapine (Seroquel), Zotepine, Risperidone (Risperdal), Ziprasidone (Geodon), Mesotidazine, Chlorpromazine hydrochloride, and Haloperidol (Haldol). [0252] 5. Cannabinoids
  • cannabinoids include, but are not limited to, Cannabidiol (Epidiolex), Tetrahydrocannabinolic Acid, Tetrahydrocannabinol, Cannabidolic Acid, Cannabinol, Cannabigerol, Cannabichromene, Tetrahydrocannabivarin, and Cannabidivarin.
  • Cannabidiol Epidiolex
  • Tetrahydrocannabinolic Acid Tetrahydrocannabinol
  • Cannabidolic Acid Cannabinol
  • Cannabigerol Cannabichromene
  • Tetrahydrocannabivarin Tetrahydrocannabivarin
  • Cannabidivarin Cannabidivarin.
  • NMDA receptor antagonists are a class of drugs that inhibit the action of the N-methyl-d-aspartate receptor.
  • NMDA antagonists include, but are not limited to, Ketamine, Esketamine, Ketobemidone, Ifendopril, 5,7-Dichlorokynurenic Acid, Licostinel, Memantine, Gavestinel, Phencyclidine, Dextromethorphan, Remacemide, Selfotel, Tiletamine, Dextropropoxyphene, Aptiganel, Dexanabinol, and Amantadine.
  • NMDA receptor antagonists also include opioids such as Methadone, Dextropropoxyphene, Pethidine, Levorphanol, Tramadol, Neramexane, and Ketobemidone.
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, is administered in combination with GABA receptor agonist(s) (e.g., GABA A receptor agonists).
  • GABA receptor agonist is a class of drugs or compounds that are agonists for one or more of the GABA receptors.
  • GABA receptor agonists include, but are not limited to, Clobazam, Topiramate, Muscimol, Progabide, Riluzole, Baclofen, Gabapentin, Vigabatrin, Valproic Acid, Tiagabine, Lamotrigine, Pregabalin, Phenyloin, Carbamazepine, Thiopental, Thiamylal, Pentobarbital, Secobarbital, Hexobarbital, Butobarbital, Amobarbital, Barbital, Mephobarbital, Phenobarbital, Primidone, Midazolam, Triazolam, Lometazepam, Flutazolam, Nitrazepam, Fluritrazepam, Nimetazepam, Diazepam, Medazepam, Oxazolam, Prazeam, Tofisopam, Rilmazafonoe, Lorazepam, Temazepam, Oxazepam, Fluidazepam,
  • a compound of any of Formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, is administered in combination with a cholinesterase inhibitor(s).
  • cholinergics are compounds which mimic the action of acetylcholine and/or butyrylcholine.
  • Cholinesterase inhibitors are a class of drugs that prevent the breakdown of acetylcholine.
  • Exemplary cholinesterase inhibitors include, but are not limited to, Donepizil (Aricept), Tacrine (Cognex), Rivastigmine (Exelon, Exelon Patch), Galantamine (Razadyne, Reminyl), Memantine/Donepezil (Namzaric), Ambenonium (Mytelase), Neostigmine (Bloxiverz), Pyridostigmine (Mestinon Timespan, Regonol), and Galantamine (Razadyne).
  • the present disclosure also contemplates, among other things, administration of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, to a subject that has been previously administered an agent selected from the group consisting of a bronchial muscle/airway relaxant, an antiviral, oxygen, an antibody, and an antibacterial.
  • an agent selected from the group consisting of a bronchial muscle/airway relaxant, an antiviral, oxygen, an antibody, and an antibacterial.
  • an additional agent is administered to a subject prior to administration of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (Ia), (lb), (Ic), (Id)e (Ie), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, and an additional agent is selected from the group consisting of a bronchial muscle/airway relaxant, an antiviral, oxygen, an antibody, and an antibacterial.
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, is co-administered with an agent selected from a bronchial muscle/airway relaxant, an antiviral, oxygen, and an antibacterial to a subject.
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, is envisioned to be useful as one or more therapeutic agents for treating a CNS-related disorder (e.g., a sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a convulsive disorder, epileptogenesis, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus) in a subject in need thereof (e.g., a subject with Rett syndrome, Fra
  • Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and/or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), treatment resistant depression (TRD), stress, post- traumatic stress disorder (PTSD), compulsive disorders (e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], disorders of memory and/or cognition [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer’ s type dementia, Lewis body type dementia, vascular type dementia],
  • CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus.
  • the CNS-related disorder is depression.
  • the CNS-related disorder is postpartum depression.
  • the CNS-related disorder is major depressive disorder.
  • the major depressive disorder is moderate major depressive disorder. Tn certain embodiments, the major depressive disorder is severe major depressive disorder.
  • a method of alleviating or preventing seizure activity in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds.
  • the method alleviates or prevents epileptogenesis.
  • a pharmaceutically acceptable salt of any of these compounds and another pharmacologically active agent.
  • the compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
  • a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability comprising administering to the subject an effective amount of a compound of any of Formulae (I), (la),
  • a method of treating or preventing stress or anxiety in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds.
  • a method of alleviating or preventing insomnia in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds.
  • a method of inducing sleep and maintaining substantially the level of REM sleep that is found in normal sleep, wherein substantial rebound insomnia is not induced comprising administering an effective amount of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb),
  • a method of alleviating or preventing premenstrual syndrome (PMS) or postnatal depression (PND) in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic),
  • a method of treating or preventing mood disorders in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds.
  • the mood disorder is depression.
  • a method of cognition enhancement or treating memory disorder by administering to the subject a therapeutically effective amount of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds.
  • the disorder is Alzheimer’s disease.
  • the disorder is Rett syndrome.
  • a method of treating attention disorders by administering to the subject a therapeutically effective amount of a compound of any of Formulae (I), (la), (Ib), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds.
  • the attention disorder is ADHD.
  • Inflammation of the central nervous system is recognized to be a feature of all neurological disorders.
  • Major inflammatory neurological disorders include multiple sclerosis (characterized by an immune-mediated response against myelin proteins), and meningoencephalitis (where infectious agents triggered the inflammatory response). Additional scientific evidence suggests a potential role of inflammatory mechanisms in other neurological conditions such as Alzheimer's disease, Parkinson's disease, Huntington' disease, amyotrophic lateral sclerosis, stroke and traumatic brain injuries.
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds is useful in treating neuroinflammation.
  • the compounds or pharmaceutically acceptable salts of the present invention are useful in treating inflammation in neurological conditions, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injuries.
  • the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, is administered to the subject chronically.
  • the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.
  • neuroendocrine disorder or “neuroendocrine dysfunction” refers to a variety of conditions caused by imbalances in the body’s hormone production directly related to the brain.
  • Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. Because the hypothalamus and the pituitary gland are two areas of the brain that regulate the production of hormones, damage to the hypothalamus or pituitary gland, e.g., by traumatic brain injury, may impact the production of hormones and other neuroendocrine functions of the brain.
  • the neuroendocrine disorder or dysfunction is associated with a women’s health disorder or condition (e g., a women’s health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women’s health disorder or condition is polycystic ovary syndrome.
  • Symptoms of neuroendocrine disorder include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, and somatic symptoms; including but not limited to fatigue, poor memory, anxiety, depression, weight gain or loss, emotional lability, lack of concentration, attention difficulties, loss of lipido, infertility, amenorrhea, loss of muscle mass, increased belly body fat, low blood pressure, reduced heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.
  • neurodegenerative disease includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons.
  • Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer’s disease (including the associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug-induced or medication-induced Parkinsonism (such as neuroleptic-induced acute akathisia, acute dys
  • Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest.
  • Methods of treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder.
  • a mood disorder for example clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cataonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior.
  • the method described herein provides therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression).
  • the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremor (e g., Parkinson’s Disease), women’s health disorders or conditions).
  • a disease or disorder described herein e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremor (e g., Parkinson’s Disease), women’s health disorders or conditions).
  • Clinical depression is also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental disorder characterized by pervasive and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression have trouble sleeping, lose weight, and generally feel agitated and irritable. Clinical depression affects how an individual feels, thinks, and behaves and may lead to a variety of emotional and physical problems. Individuals with clinical depression may have trouble doing day-to-day activities and make an individual feel as if life is not worth living.
  • MDD major depressive disorder
  • severe depression unipolar depression
  • unipolar disorder unipolar disorder
  • recurrent depression refers to a mental disorder characterized by pervasive and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities.
  • Peripartum depression refers to depression in pregnancy. Symptoms include irritability, crying, feeling restless, trouble sleeping, extreme exhaustion (emotional and/or physical), changes in appetite, difficulty focusing, increased anxiety and/or worry, disconnected feeling from baby and/or fetus, and losing interest in formerly pleasurable activities.
  • Postnatal depression is also referred to as postpartum depression (PPD), and refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleeping and eating habits, reduced sexual desire, crying episodes, anxiety, and irritability.
  • the PND is a treatment-resistant depression (e.g., a treatment-resistant depression as described herein).
  • the PND is refractory depression (e.g., a refractory depression as described herein).
  • a subject having PND also experienced depression, or a symptom of depression during pregnancy. This depression is referred to herein as) perinatal depression.
  • a subject experiencing perinatal depression is at increased risk of experiencing PND.
  • AD Atypical depression
  • mood reactivity e.g., paradoxical anhedonia
  • positivity significant weight gain or increased appetite.
  • Patients suffering from AD also may have excessive sleep or somnolence (hypersomnia), a sensation of limb heaviness, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.
  • Psychitic major depression or psychotic depression refers to a major depressive episode, in particular of melancholic nature, where the individual experiences psychotic symptoms such as delusions and hallucinations.
  • Catatonic depression refers to major depression involving disturbances of motor behavior and other symptoms. An individual may become mute and stuporose, and either is immobile or exhibits purposeless or playful movements.
  • Seasonal affective disorder refers to a type of seasonal depression wherein an individual has seasonal patterns of depressive episodes coming on in the fall or winter.
  • Dysthymia refers to a condition related to unipolar depression, where the same physical and cognitive problems are evident. They are not as severe and tend to last longer (e.g., at least 2 years).
  • Double depression refers to fairly depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major depression.
  • DPD Depressive Personality Disorder
  • RBD Recurrent Brief Depression
  • Minor depressive disorder or minor depression refers to a depression in which at least 2 symptoms are present for 2 weeks.
  • Bipolar disorder or manic depressive disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During periods of mania the individual may feel or act abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the consequences. The need for sleep is usually reduced. During periods of depression there may be crying, poor eye contact with others, and a negative outlook on life. The risk of suicide among those with the disorder is high at greater than 6% over 20 years, while self-harm occurs in 30-40%. Other mental health issues such as anxiety disorder and substance use disorder are commonly associated with bipolar disorder.
  • Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress.
  • Treatment-resistant depression refers to a condition where the individuals have been treated for depression, but the symptoms do not improve.
  • antidepressants or physchological counseling do not ease depression symptoms for individuals with treatment-resistant depression.
  • individuals with treatment-resistant depression improve symptoms, but come back.
  • Refractory depression occurs in patients suffering from depression who are resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOls, SSRls, and double and triple uptake inhibitors and/or anxiolytic drugs, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation and/or transcranial magnetic stimulation).
  • Post-surgical depression refers to feelings of depression that follow a surgical procedure (e.g., as a result of having to confront one’s mortality). For example, individuals may feel sadness or empty mood persistently, a loss of pleasure or interest in hobbies and activities normally enjoyed, or a persistent felling of worthlessness or hopelessness.
  • Mood disorder associated with conditions or disorders of women’s health refers to mood disorders (e.g., depression) associated with (e.g., resulting from) a condition or disorder of women’s health (e g., as described herein).
  • mood disorders e.g., depression
  • a condition or disorder of women’s health e.g., as described herein.
  • Suicidality suicidal ideation
  • suicidal behavior refers to the tendency of an individual to commit suicide.
  • Suicidal ideation concerns thoughts about or an unusual preoccupation with suicide.
  • the range of suicidal ideation varies greatly, from e.g., fleeting thoughts to extensive thoughts, detailed planning, role playing, incomplete attempts.
  • Symptoms include talking about suicide, getting the means to commit suicide, withdrawing from social contact, being preoccupied with death, feeling trapped or hopeless about a situation, increasing use of alcohol or drugs, doing risky or self-destructive things, saying goodbye to people as if they won’t be seen again.
  • Symptoms of depression include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, sleeplessness, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, absence of positive thoughts or plans, excessive sleeping, overeating, appetite loss, insomnia, self-harm, thoughts of suicide, and suicide attempts.
  • the presence, severity, frequency, and duration of symptoms may vary on a case to case basis. Symptoms of depression, and relief of the same, may be ascertained by a physician or psychologist (e g., by a mental state examination).
  • the method comprises monitoring a subject with a known depression scale, e.g., the Hamilton Depression (HAM-D) scale, the Clinical Global Impression- Improvement Scale (CGI), and the Montgomery- ⁇ sberg Depression Rating Scale (MADRS).
  • a therapeutic effect can be determined by reduction in Hamilton Depression (HAM-D) total score exhibited by the subject. Reduction in the HAM-D total score can happen within 4, 3, 2, or 1 days; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The therapeutic effect can be assessed across a specified treatment period.
  • the therapeutic effect can be determined by a decrease from baseline in HAM-D total score after administering a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or for life).
  • a pharmaceutically acceptable salt of any of these compounds e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or for life).
  • the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder.
  • the baseline HAM-D total score of the subject is at least 24.
  • the baseline HAM-D total score of the subject is at least 18.
  • the baseline HAM-D total score of the subject is between and including 14 and 18.
  • the baseline HAM-D total score of the subject is between and including 19 and 22.
  • the HAM-D total score of the subject before treatment with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds is greater than or equal to 23.
  • the baseline score is at least 10, 15, or 20.
  • the HAM-D total score of the subject after treatment with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D total score after treatment with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, is less than 10, 7, 5, or 3.
  • the decrease in HAM-D total score is from a baseline score of about 20 to 30 (e g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a HAM-D total score at about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds.
  • the decrease in the baseline HAM-D total score to HAM-D total score after treatment with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 fold.
  • the percentage decrease in the baseline HAM-D total score to HAM-D total score after treatment with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds is at least 50% (e g., 60%, 70%, 80%, or 90%).
  • the therapeutic effect is measured as a decrease in the HAM-D total score after treatment with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, relative to the baseline HAM-D total score (e.g., 12, 24, 48 hours after administration; or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days, or more) is at least 10, 15, or 20 points.
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds relative to the baseline HAM-D total score (e.g., 12, 24, 48 hours after administration; or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days, or more) is at least 10, 15, or 20 points.
  • the method of treating a depressive disorder provides a therapeutic effect (e.g., as measured by reduction in Hamilton Depression Score (HAM-D)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8 hours or less.
  • the method of treating the depressive disorder e.g., major depressive disorder
  • provides a therapeutic effect e.g., as determined by a statistically significant reduction in HAM-D total score
  • the method of treating the depressive disorder e.g., major depressive disorder
  • provides a therapeutic effect e.g., as determined by a statistically significant reduction in HAM-D total score
  • a therapeutic effect e.g., as determined by a statistically significant reduction in HAM-D total score
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig) a pharmaceutically acceptable salt of any of these compounds.
  • the method of treating the depressive disorder e.g., major depressive disorder
  • provides a therapeutic effect e.g., as determined by a statistically significant reduction in HAM- D total score
  • a therapeutic effect e.g., as determined by a statistically significant reduction in HAM- D total score
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig) a pharmaceutically acceptable salt of any of these compounds.
  • the method of treating the depressive disorder e.g., major depressive disorder
  • provides a therapeutic effect e.g., as determined by a statistically significant reduction in HAM-D total score
  • a therapeutic effect e.g., as determined by a statistically significant reduction in HAM-D total score
  • a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig) a pharmaceutically acceptable salt of any of these compounds.
  • the therapeutic effect is a decrease from baseline in HAM-D total score after treatment with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, once a day for 14 days.
  • the HAM-D total score of the subject before treatment with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds is at least 24.
  • the HAM-D total score of the subject before treatment with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds is at least 18. In some embodiments, the HAM-D total score of the subject before treatment with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, is between and including 14 and 18.
  • the decrease in HAM-D total score after treating the subject with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, relative to the baseline HAM-D total score is at least 10. In some embodiments, the decrease in HAM-D total score after treating the subject with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, relative to the baseline HAM-D total score is at least 15 (e.g., at least 17).
  • the HAM-D total score associated with treating the subject with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds is no more than a number ranging from 6 to 8. In some embodiments, the HAM-D total score associated with treating the subject with a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, is no more than 7.
  • the method provides therapeutic effect (e g., as measured by reduction in Clinical Global Impression-Improvement Scale (CGI)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8 hours or less.
  • CGI Clinical Global Impression-Improvement Scale
  • the CNS-disorder is a depressive disorder, e.g., a major depressive disorder.
  • the method of treating the depressive disorder, e.g., the major depressive disorder provides a therapeutic effect within the second day of the treatment period.
  • the therapeutic effect is a decrease from baseline in CGI score at the end of a treatment period (e.g., 14 days after administration).
  • the method provides therapeutic effect (e.g., as measured by reduction in Montgomery- ⁇ sberg Depression Rating Scale (MADRS)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8 hours or less.
  • the CNS-disorder is a depressive disorder, e.g., a major depressive disorder.
  • the method of treating the depressive disorder, e.g., the major depressive disorder provides a therapeutic effect within the second day of the treatment period.
  • the therapeutic effect is a decrease from baseline in MADRS score at the end of a treatment period (e.g., 14 days after administration).
  • a therapeutic effect for major depressive disorder can be determined by a reduction in Montgomery- ⁇ sberg Depression Rating Scale (MADRS) score exhibited by the subject.
  • the MADRS score can be reduced within 4, 3, 2, or 1 days; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less.
  • the Montgomery- ⁇ sberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire (regarding apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts) which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders.
  • the method provides therapeutic effect (e.g., as measured by reduction in Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, I days; 24, 20, 16, 12, 10, 8 hours or less.
  • the therapeutic effect is an improvement measured by the EPDS.
  • the method provides therapeutic effect (e.g., as measured by reduction in Generalized Anxiety Disorder 7-Item Scale (GAD-7)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less.
  • GID-7 Generalized Anxiety Disorder 7-Item Scale
  • anxiety disorders e.g., generalized anxiety disorder, panic disorder, obsessive compulsive disorder, phobia, post-traumatic stress disorder.
  • Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety.
  • Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.
  • Generalized anxiety disorder is a common chronic disorder characterized by long- lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.
  • panic disorder a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing.
  • panic attacks defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent.
  • a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes.
  • Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals).
  • the OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist.
  • the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm.
  • the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness.
  • sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.
  • the single largest category of anxiety disorders is that of phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate cosmic consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.
  • Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience.
  • Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.
  • Conditions or disorders related to women’s health include, but are not limited to, gynecological health and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy issues (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and issues related to women’s overall health and wellness (e g., menopause).
  • PMS premenstrual syndrome
  • PMDD premenstrual dysphoric disorder
  • PCOS polycystic ovary syndrome
  • Gynecological health and disorders affecting women include menstruation and menstrual irregularities; urinary tract health, including urinary incontinence and pelvic floor disorders; and such disorders as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.
  • PMS Premenstrual syndrome
  • PMDD Premenstrual dysphoric disorder
  • PMDD symptoms include mood swings, depressed mood or feelings of hopelessness, marked anger, increased interpersonal conflicts, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, change in appetite, feeling out of control or overwhelmed, sleep problems, physical problems (e g., bloating, breast tenderness, swelling, headaches, joint or muscle pain).
  • Pregnancy issues include preconception care and prenatal care, pregnancy loss (miscarriage and stillbirth), preterm labor and premature birth, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.
  • SIDS sudden infant death syndrome
  • Miscarriage refers to a pregnancy that ends on its own, within the first 20 weeks of gestation.
  • Abortion refers to the deliberate termination of a pregnancy, which can be performed during the first 28 weeks of pregnancy.
  • Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency.
  • PCOS Polycystic ovary syndrome
  • PCOS Polycystic ovary syndrome
  • Symptoms of PCOS include irregular or no menstrual periods, heavy periods, excess body and facial hair, acne, pelvic pain, difficulty getting pregnant, and patches of thick, darker, velvety skin.
  • PCOS may be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.
  • Menopause refers to the 12 months after a woman’s last menstrual period and marks the end of menstrual cycles. Menopause typically occurs in a woman’s 40s or 50s. Physical symptoms such as hot flashes and emotional symptoms of menopause may disrupt sleep, lower energy, or trigger anxiety or feelings of sadness or loss. Menopause includes natural menopause and surgical menopause, which is a type of induced menopause due to an event such as surgery (e.g., hysterectomy, oophorectomy; cancer). It is induced when the ovaries are gravely damaged by, e.g., radiation, chemotherapy, or other medications.
  • surgery e.g., hysterectomy, oophorectomy; cancer
  • the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, can be used in a method described herein, for example in the treatment of a disorder described herein such as epilepsy, status epilepticus, or seizure.
  • Epilepsy is a brain disorder characterized by repeated seizures over time.
  • Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.
  • the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, and methods described herein can be used to treat or prevent epileptogenesis.
  • Epileptogenesis is a gradual process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptogenesis results from neuronal damage precipitated by the initial insult (e.g., status epilepticus).
  • SE Status epilepticus
  • Status epilepticus can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges.
  • convulsive status epilepticus e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus
  • non-convulsive status epilepticus e.g., generalized status epilepticus, complex partial status epilepticus
  • generalized periodic epileptiform discharges e.g., periodic epileptiform discharges.
  • Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus.
  • Early status epilepticus is treated with a first line therapy.
  • Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered.
  • Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered.
  • Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.
  • Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non- convulsive status epilepticus, or typical absence non-convulsive status epilepticus.
  • focal non-convulsive status epilepticus e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus
  • generalized non-convulsive status epilepticus e.g., late onset absence non-convulsive status epilepticus, atypical absence non- convulsive
  • the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, can also be administered as a prophylactic to a subject having a CNS disorder e.g., a traumatic brain injury, status epilepticus, e g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epi
  • a seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain.
  • the term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person’s body shakes rapidly and uncontrollably. During convulsions, the person’s muscles contract and relax repeatedly.
  • seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.
  • Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms.
  • the patient most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of “losing time.”
  • Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.
  • Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.
  • Tonic seizures are characterized by stiffening of the muscles.
  • Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.
  • Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures;
  • movement disorders refers to a variety of diseases and disorders that are associated with hyperkinetic movement disorders and related abnormalities in muscle control.
  • exemplary movement disorders include, but are not limited to, Parkinson’s disease and parkinsonism (defined particularly by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.
  • the methods described herein can be used to treat tremor, for example a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, can be used to treat cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, or rubral tremor.
  • Tremor includes hereditary, degenerative, and idiopathic disorders such as Wilson’s disease, Parkinson’s disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid-, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese, arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders.
  • metabolic diseases e.g., thyroid-parathyroid-, liver disease and hypoglycemia
  • peripheral neuropathies associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regional pain syndrome
  • toxins
  • Clinical tremor can be classified into physiologic tremor, enhanced physiologic tremor, essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes’ tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.
  • essential tremor syndromes including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor
  • dystonic tremor including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor
  • dystonic tremor including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor
  • dystonic tremor including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor
  • Tremor is an involuntary, at times rhythmic, muscle contraction and relaxation that can involve oscillations or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk, legs).
  • body parts e.g., hands, arms, eyes, face, head, vocal folds, trunk, legs.
  • Cerebellar tremor or intention tremor is a slow, broad tremor of the extremities that occurs after a purposeful movement. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from, e.g., tumor, stroke, or disease (e.g., multiple sclerosis, an inherited degenerative disorder).
  • Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and/or painful and abnormal postures or positions. Dystonic tremor may affect any muscle in the body. Dystonic tremors occur irregularly and often can be relieved by complete rest.
  • Essential tremor or benign essential tremor is the most common type of tremor.
  • Essential tremor may be mild and nonprogressive in some, and may be slowly progressive, starting on one side of the body but affect both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved.
  • Tremor frequency may decrease as the person ages, but severity may increase. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and/or increase their severity. Symptoms generally evolve over time and can be both visible and persistent following onset.
  • Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz) rhythmic muscle contractions that occurs in the legs and trunk immediately after standing.
  • Parkinsonian tremor is caused by damage to structures within the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson’s disease and is typically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk. Onset of parkinsonian tremor typically begins after age 60. Movement starts in one limb or on one side of the body and can progress to include the other side.
  • Physiological tremor can occur in normal individuals and have no clinical significance. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. The tremor classically has a frequency of about 10 Hz.
  • Psychogenic tremor or hysterical tremor can occur at rest or during postural or kinetic movement.
  • Patient with psychogenic tremor may have a conversion disorder or another psychiatric disease.
  • Rubral tremor is characterized by coarse slow tremor which can be present at rest, at posture, and with intention.
  • the tremor is associated with conditions that affect the red nucleus in the midbrain, classical unusual strokes.
  • Parkinson’s Disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms found in Parkinson’s Disease, but is a symptom complex rather than a progressive neurodegenerative disease.
  • Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures. Dystonic movements can be patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.
  • Chorea is a neurological disorder characterized by jerky involuntary movements typically affecting the shoulders, hips, and face. Huntington’s Disease is an inherited disease that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington’s disease can hinder walk, talk, and swallowing. [0367] Ataxia refers to the loss of full control of bodily movements, and may affect the fingers, hands, arms, legs, body, speech, and eye movements. [0368] Myloclonus and Startle is a response to a sudden and unexpected stimulus, which can be acoustic, tactile, visual, or vestibular.
  • Tics are an involuntary movement usually onset suddenly, brief, repetitive, but non- rhythmical, typically imitating normal behavior and often occurring out of a background of normal activity. Tics can be classified as motor or vocal, motor tics associated with movements while vocal tics associated with sound. Tics can be characterized as simple or complex. For example simple motor tics involve only a few muscles restricted to a specific body part.
  • Tourette Syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic.
  • Restless Legs Syndrome is a neurologic sensorimotor disorder characterized by an overwhelming urge to move the legs when at rest.
  • Stiff Person Syndrome is a progressive movement disorder characterized by involuntary painful spasms and rigidity of muscles, usually involving the lower back and legs. Stiff-legged gait with exaggerated lumbar hyperlordosis typically results. Characteristic abnormality on EMG recordings with continuous motor unit activity of the paraspinal axial muscles is typically observed. Variants include “stiff-limb syndrome” producing focal stiffness typically affecting distal legs and feet.
  • Gait disorders refer to an abnormality in the manner or style of walking, which results from neuromuscular, arthritic, or other body changes. Gait is classified according to the system responsible for abnormal locomotion, and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.
  • Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug which alone provides the correct combination of effects, or occasionally with a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achieve very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the distress and pain they would otherwise experience.
  • drugs e.g., hypnotics, sedatives, paralytics, analgesics
  • Sedation is the reduction of irritability or agitation by administration of a pharmacological agent, generally to facilitate a medical procedure or diagnostic procedure.
  • Sedation and analgesia include a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.
  • Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are typically unaffected.
  • Moderate sedation/analgesia is a drug-induced depression of consciousness during which the patient responds purposefully to verbal command, either alone or accompanied by light tactile stimulation. No interventions are usually necessary to maintain a patent airway. Spontaneous ventilation is typically adequate. Cardiovascular function is usually maintained.
  • Deep sedation/analgesia is a drug-induced depression of consciousness during which the patient cannot be easily aroused, but responds purposefully (not a reflex withdrawal from a painful stimulus) following repeated or painful stimulation.
  • Independent ventilatory function may be impaired and the patient may require assistance to maintain a patent airway.
  • Spontaneous ventilation may be inadequate.
  • Cardiovascular function is usually maintained.
  • General anesthesia is a drug-induced loss of consciousness during which the patient is not arousable, even to painful stimuli. The ability to maintain independent ventilatory function is often impaired and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.
  • Sedation in the intensive care unit allows the depression of patients' awareness of the environment and reduction of their response to external stimulation. It can play a role in the care of the critically ill patient, and encompasses a wide spectrum of symptom control that will vary between patients, and among individuals throughout the course of their illnesses. Heavy sedation in critical care has been used to facilitate endotracheal tube tolerance and ventilator synchronization, often with neuromuscular blocking agents.
  • sedation e.g., long-term sedation, continuous sedation
  • a prolonged period of time e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1 month, 2 months.
  • Long-term sedation agents may have long duration of action.
  • Sedation agents in the ICU may have short elimination half-life.
  • Procedural sedation and analgesia also referred to as conscious sedation, is a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows a subject to tolerate unpleasant procedures while maintaining cardiorespiratory function.
  • Also described herein are methods of ameliorating one or more symptoms of a respiratory condition in a subject comprising administering to the subject an effective amount of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds.
  • a method of treating a subject wherein the subject exhibits one or more symptoms of a respiratory condition and/or has been diagnosed with a respiratory condition comprising administering to said subject an effective amount of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds.
  • the present disclosure contemplates a method of treating a subject comprising administering to said subject a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, wherein the subject has a respiratory condition.
  • administration of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, to a subject exhibiting symptoms of a respiratory condition may result in the reduction of the severity of one or more symptoms of a respiratory condition or retard or slow the progression of one or more symptoms of a respiratory condition.
  • a subject with a respiratory condition has been or is being treated with mechanical ventilation or oxygen. In some embodiments, a subject with a respiratory condition has been or is being treated with mechanical ventilation.
  • a sedative is propofol or a benzodiazepine.
  • the present disclosure includes administering to a subject in need thereof a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds in an amount sufficient to increase oxygen saturation in blood. In some embodiments, oxygen saturation in blood is measured using pulse oximetry. [0392] In some embodiments, the present disclosure contemplates a method of treating a cytokine storm in a patient. Tn some embodiments a method of treating a cytokine storm comprising the step of administering to the patient a compound of any of Formulae (I), (la), (lb),
  • a symptom of a cytokine storm is lung inflammation.
  • a patient undergoing a cytokine storm has acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • a subject with a respiratory condition suffers from respiratory distress.
  • respiratory distress includes acute respiratory distress.
  • a subject with a respiratory condition may exhibit one or more symptoms selected from the group consisting of airway hyper-responsiveness, inflammation of lung tissue, lung hypersensitivity, and inflammation-related pulmonary pain.
  • a subject with a respiratory condition may exhibit inflammation of lung tissue.
  • inflammation of lung tissue is bronchitis or bronchiectasis.
  • inflammation of lung tissue is pneumonia.
  • pneumonia is ventilator-associated pneumonia or hospital-acquired pneumonia.
  • pneumonia is ventilator-associated pneumonia.
  • administration of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, to a subject exhibiting symptoms of a respiratory condition results in reduction of the severity of inflammation of lung tissue in a subject with a respiratory condition or retard or slow the progression of inflammation of lung tissue in a subject with a respiratory condition.
  • administration of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, to a subject exhibiting symptoms of a respiratory condition results in reduction of the severity of pneumonia in a subject with a respiratory condition or retard or slow the progression of pneumonia in a subject with a respiratory condition.
  • administration of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, to a subject exhibiting symptoms of a respiratory condition results in reduction of the severity of lung hypersensitivity in a subject with a respiratory condition or retard or slow the progression of lung hypersensitivity in a subject with a respiratory condition.
  • administration of a compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, or a composition comprising the compound of any of Formulae (I), (la), (lb), (Ic), (Id), (le), (If), or (Ig), or a pharmaceutically acceptable salt of any of these compounds, to a subject exhibiting symptoms of a respiratory condition results in reduction of the severity of inflammation-related pulmonary pain in a subject with a respiratory condition or retard or slow the progression of inflammation-related pulmonary pain in a subject with a respiratory condition.
  • a subject with a respiratory condition is undergoing or has undergone treatment for an infection, fibrosis, a fibrotic episode, chronic obstructive pulmonary disease, Sarcoidosis (or pulmonary sarcoidosis) or asthma/asthma-related inflammation.
  • a subject exhibits symptoms of and/or has been diagnosed with asthma.
  • a subject is or has undergone an asthmatic attack.
  • a subject is undergoing or has undergone treatment for fibrosis or a fibrotic episode.
  • the fibrosis is cystic fibrosis.
  • a respiratory condition is the result of and/or related to a disease or condition selected from the group consisting of cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, pulmonary sarcoidosis, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation- fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseud
  • an infection is a viral infection or a bacterial infection.
  • an infection is a viral infection.
  • an infection is a bacterial infection.
  • a viral infection is an infection of a virus selected from the group consisting of a coronavirus, an influenza virus, human rhinovirus, a human parainfluenza virus, human metapneumovirus and a hantavirus.
  • a virus is a coronavirus.
  • a coronavirus is selected from the group consisting of SARS-CoV, SARS- CoV-2, and MERS-CoV.
  • a disease associated with a coronavirus is selected from the group consisting of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).
  • a disease associated with a coronavirus is selected from the group consisting of COVID-19.
  • a coronavirus is selected from a group consisting of SARS-CoV-1, SARS-CoV-2, and 2012-nCoV. Tn some embodiments, a coronavirus is SARS- CoV-2.
  • a bacterial infection is an infection of a bacteria selected from the group consisting of Streptococcus pneumoniae, Chlamydia pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Haemophilus influenzae.
  • Staphylococcus aureus is methicillin-resistant Staphylococcus aureus.
  • the compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) trituration, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the preparation of representative neuroactive steroids that have been listed herein.
  • the compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD- 10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
  • LC-ELSD/MS Mobile Phase: 1.5ML/4L TFA in water (solvent A) and 0.75ML/4L TFA in acetonitrile (solvent B), using the elution gradient 30%-90% (solvent B) over 0.9 minutes and holding at 90% for 0.6 minutes at a flow rate of 1.2 ml/min;
  • PE petroleum ether
  • EtOAc ethyl acetate
  • THF tetrahydrofuran
  • PCC pyridinium chlorochromate
  • TLC thin layer chromatography
  • PCC pyridinium chlorochromate
  • t-BuOK potassium tert-butoxide
  • 9-BBN 9-borabicyclo[3.3.1]nonane
  • Pd(t-Bu 3 P) 2 bis(tri-tert- butylphosphine)palladium(O)
  • AcCl acetyl chloride
  • i-PrMgCl Isopropylmagnesium chloride
  • TBSC1 tert-Butyl(chloro)dimethylsilane
  • BHT 2,6-di-t- butyl-4-methylphenoxide
  • Me methyl
  • i-Pr iso-propyl
  • Example 1 Synthesis of l-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-((methoxy- d 3 )methyl)-13-methylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H- tetrazol-2-yl)ethan-l-one (Compound No. 1).
  • Example 2 Synthesis of l-((3R,5S,8R,9R,10S13S,14S17S)-3-hvdroxy-3- (methoxymethyl)-13-methylhexadecahvdro-lH-cvclopenta[a]phenanthren-17-yl)-2-(5- (methyl-d 3 )-2H-tetrazol-2-yl)ethan-l-one (Compound No. 2).
  • Example 3 Synthesis of l-((3R,5S,8R,9Ra0Sa3Sa4Sa7S)-3-hydroxy-3- (methoxymethyl)-13-methylhexadecahydro-lH-cyclopenta[a]phenanthren-17-yl-2.,2.,4a-d4)- 2-(5-methyl-2H-tetrazol-2-yl)ethan-l-one (Compound No. 3).
  • reaction mixture was neutralized with aqueous HC1 (2.5 M, 1000 mL) and fdtered.
  • the filtrate was extracted with EtOAc (2 x 1 L), washed with brine (1 L), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to afford 3.2 (43 g).
  • NADPH Cofactor Preparation' NADPH powder ( ⁇ -Nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt; NADPH 4Na (Vendor: BONTAC, Cat. No. BT04) was weighed and diluted into a 2mM MgCI 2 solution (working solution concentration: 2 mM; final concentration in reaction system: 1 mM).
  • Stop Solution Preparation [0526] Cold acetonitrile (ACN) including 200 ng/mL tolbutamide and 200 ng/mL labetalol as internal standard (IS) were used.
  • ACN acetonitrile
  • IS internal standard
  • Reaction plate NCF60 was incubated at 37°C. After pre-incubation, an Apricot automation workstation was used to add 98 ⁇ L/well of NADPH cofactor to every reaction plate except NCF60 (Blank, TO, T5, T15, T30, T45 and T60) to start the reaction. The final concentration of each component in the incubation medium was as shown in the table below.
  • microsome metabolic stability with human, dog, rat, and mouse microsomes were consistent across species
  • Example 7 Steroid Inhibition of TBPS Binding.
  • the cerebellum was removed.
  • the cortex was deposited on aluminum foil. Cortex was stored in the refrigerator by 10.
  • the cortex was centrifuged in a buffer. The pellet was passed to the Polytron, recentrifuged, and resuspended in a buffer. Proteins were determined according to the Bradford method.
  • Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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Abstract

La présente invention concerne un composé deutéré de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, dans la formule, R1a, R1b, R2a, R2b, R3, R4a, R4b, R5, R6a, R6b, R7a, R7b, R11a, R11b, R12a, R12b, R15a, R15b, R16a, R16b, R17, R18, R19, R21a, R21b, Rm, Rn et R° sont définis dans la description. L'invention concerne également des compositions pharmaceutiques comprenant un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci et des procédés d'utilisation du composé de formule (I) dans le traitement de troubles liés au SNC.
PCT/US2023/074030 2022-09-15 2023-09-13 Stéroïdes neuroactifs deutérés Ceased WO2024059608A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5376645A (en) 1990-01-23 1994-12-27 University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
WO2013056181A1 (fr) 2011-10-14 2013-04-18 Sage Therapeutics, Inc. Composés 19-nor-prégnane 3,3-disubstitués, compositions et utilisations associées
WO2015180679A1 (fr) 2014-05-29 2015-12-03 Sage Therapeutics, Inc. Stéroïdes neuroactifs, leurs compositions et utilisations
WO2017156103A1 (fr) * 2016-03-08 2017-09-14 Sage Therapeutics, Inc. Stéroïdes neuroactifs, compositions, et leurs utilisations
WO2022040545A1 (fr) * 2020-08-20 2022-02-24 Intra-Cellular Therapies, Inc. Composés organiques

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US5376645A (en) 1990-01-23 1994-12-27 University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
WO2013056181A1 (fr) 2011-10-14 2013-04-18 Sage Therapeutics, Inc. Composés 19-nor-prégnane 3,3-disubstitués, compositions et utilisations associées
WO2015180679A1 (fr) 2014-05-29 2015-12-03 Sage Therapeutics, Inc. Stéroïdes neuroactifs, leurs compositions et utilisations
WO2017156103A1 (fr) * 2016-03-08 2017-09-14 Sage Therapeutics, Inc. Stéroïdes neuroactifs, compositions, et leurs utilisations
WO2022040545A1 (fr) * 2020-08-20 2022-02-24 Intra-Cellular Therapies, Inc. Composés organiques

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