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WO2025184576A1 - Méthodes de prévention et de traitement de la dépression - Google Patents

Méthodes de prévention et de traitement de la dépression

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Publication number
WO2025184576A1
WO2025184576A1 PCT/US2025/017952 US2025017952W WO2025184576A1 WO 2025184576 A1 WO2025184576 A1 WO 2025184576A1 US 2025017952 W US2025017952 W US 2025017952W WO 2025184576 A1 WO2025184576 A1 WO 2025184576A1
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WIPO (PCT)
Prior art keywords
substituted
group
depression
compound
alkyl
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PCT/US2025/017952
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English (en)
Inventor
Stella T. Sarraf
Peter W. Vanderklish
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Spinogenix Inc
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Spinogenix Inc
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Publication of WO2025184576A1 publication Critical patent/WO2025184576A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings

Definitions

  • a mood disorder may be described as a psychiatric disorder in which a subject’s general emotional state or mood is distorted or inconsistent with the circumstances, and interferes with the subject’s ability to carry out functions of daily life. Common mental states include sadness, emptiness or irritability. A common mood disorder is depression. [0003] Depression, otherwise known as major depressive disorder or clinical depression, is a serious mood disorder. Depression is more than just sadness.
  • Sadness is a normal emotion that may arise from a specific event or situation, for example, loss of a job, the end of a relationship, or the death of a loved one. Depression is evident in a combination of factors relating to the duration of negative feelings, impact on a person’s health, and the effect upon the person’s ability to function in daily life. The person may have every reason in the world to be happy and yet lose the ability to experience joy or pleasure, and is likely to suffer in conduct of their affairs, interpersonal relationships, and daily life. [0004] Those who suffer from depression experience persistent feelings of sadness and hopelessness and lose interest in activities they once enjoyed. Depression may be diagnosed, for example according to the guidelines of the Diagnostic and Statistical Manual of Mental Disorders (“DSM”).
  • DSM Diagnostic and Statistical Manual of Mental Disorders
  • Symptoms identified in the DSM include: persistent depressed mood, diminished interest or pleasure in almost all activities, significant decrease or increase in appetite, a slowing down of thought and a reduction of physical movement, fatigue, feelings of worthlessness or excessive guilt, diminished ability to think or concentrate, and recurrent thoughts of death or suicidal ideation. Generally, the individual will suffer significant distress or impairment in social or occupational functioning.
  • Current treatments for depression include talk therapy, and pharmaceutical intervention. However, current pharmaceutical treatments generally target the uptake of neurotransmitters, and suffer from serious, sometimes severe side effects.
  • the side effects SMRH:4908-5304-8610.1 1 Attorney Docket No. 62WD-385403-WO may be difficult to diagnose in individuals that already suffer from psychological disturbance.
  • FIG. 1 is a chart showing number of total, mushroom, stubby and thin spines per 100 ⁇ m for WT and 3xTg-AD mice treated with vehicle and treated with Compound 1 at 3, 10, and 30 mg/kg.
  • the compounds and methods described herein provide for the administration of compounds that provide benefit in the treatment and prevention of mood disorders and symptoms thereof.
  • the compositions and methods are useful for treating a mood disorder, which may be depression.
  • the active ingredient or principal ingredient will include an agent, such as a compound, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers of a compound as described herein.
  • the active ingredient or principal ingredient may also include one or more additional pharmaceutically active materials.
  • SMRH:4908-5304-8610.1 2 Attorney Docket No. 62WD-385403-WO I.
  • the compounds provided herein promote spinogenesis without affecting spine morphology.
  • the promotion is relative to the absence of administration of the compound.
  • the term “dendrite” refers to the branched extension of a neuron cell. Dendrites are typically responsible for receiving electrochemical signals transmitted from the axon of an adjacent neuron.
  • the terms “dendritic spines” or “dendrite spines” refer to protoplasmic protuberances on a neuron cell (e.g., on a dendrite). In some embodiments, dendritic spines may be described as having a membranous neck which may be terminated with a capitulum (e.g., head).
  • Dendritic spines are classified according to their shape: headless, thin, stubby, mushroom, or branched.
  • Dendritic spine density refers to the total number of dendritic spines per unit length of a neuron cell. For example, the dendritic spine density may be given as the number of dendritic spines per micron.
  • the term “dendritic spine formation” and the like refer, in the usual and customary sense to processes which lead to an increased number of dendritic spines or increased development of dendritic spines.
  • dendritic spine morphology and the like refer, in the usual and customary sense, to physical characterization of a dendritic spine (e.g., shape and structure).
  • Improvement of dendritic spine morphology is a change in morphology (e.g., increase in length or increase in width) that results in increased functionality (e.g., increased number of contacts between neurons or decreased space between neighboring neurons (e.g., SMRH:4908-5304-8610.1 3 Attorney Docket No. 62WD-385403-WO synaptic cleft)).
  • increased functionality e.g., increased number of contacts between neurons or decreased space between neighboring neurons (e.g., SMRH:4908-5304-8610.1 3 Attorney Docket No. 62WD-385403-WO synaptic cleft).
  • exemplary methods for such characterization include measurement of the dimensions (i.e., length and width) of dendritic spines. Accordingly, the term “improving dendritic spine morphology” generally refers to an increase in length, width, or both length and width of a dendritic spine.
  • Binding refers to at least two distinct species (e.g. chemical compounds including biomolecules, or cells) to becoming sufficiently proximal to react or interact thereby resulting in the formation of a complex.
  • the binding of two distinct species may result in the formation of a complex wherein the species are interacting via non-covalent or covalent bonds.
  • the resulting complex is formed when two distinct species (e.g., a protein and a compound described herein) interact via non-covalent bonds (e.g., electrostatic, van der Waals, or hydrophobic).
  • the term “activation,” “activate,” “activating” and the like in reference to a protein-activator (e.g. agonist) interaction means positively affecting (e.g. increasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the activator (e.g. compound described herein).
  • the terms “inhibition,” “inhibit,” “inhibiting” and the like are to be given their customary meanings to those of skill in the art.
  • the terms “inhibition,” “inhibit,” “inhibiting” mean negatively affecting (e.g.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -C(O)NH2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms.
  • This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), t-butyl ((CH 3 ) 3 C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
  • linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl (
  • Substituted alkyl refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, guanidino, halo, hydroxy, heteroaryl
  • Alkenyl refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond.
  • Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C6.
  • Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more.
  • alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, SMRH:4908-5304-8610.1 5 Attorney Docket No.
  • Alkenyl groups can be substituted or unsubstituted.
  • Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyl, substituted
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-.
  • Acyl includes the “acetyl” group CH3C(O)-.
  • “Acylamino” refers to the groups -NR 47 C(O)alkyl, -NR 47 C(O)substituted alkyl, -NR 47 C(O)cycloalkyl, -NR 47 C(O)substituted cycloalkyl, -NR 47 C(O)cycloalkenyl, -NR 47 C(O)substituted cycloalkenyl, -NR 47 C(O)alkenyl, -NR 47 C(O)alkenyl, -NR 47 C(O)substituted alkenyl, -NR 47 C(O)aryl, -NR 47 C(O)substituted aryl, -NR 47 C(O)heteroaryl, -NR 47 C(O)substituted heteroaryl, -NR 47 C(O)heterocyclic, and -
  • Acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O-.
  • Alkynyl refers to an unbranched or branched hydrocarbon group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl).
  • alkynyl also includes those groups having at least one carbon-carbon triple bond and a carbon-carbon double bond.
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy. “Substituted alkoxy” refers to the group -O-(substituted alkyl) wherein substituted alkyl is defined herein. [0031] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • Alkylthio refers to the group “alkyl-S-”.
  • Acyl refers to a group -C(O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • “Amido” refers to both a “C-amido” group which refers to the group -C(O)NR y R z and an “N-amido” group which refers to the group -NR y C(O)R z , wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.
  • “Amino” refers to the group -NH 2 .
  • “Substituted amino” refers to the group -NR 48 R 49 , wherein R 48 and R 49 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cylcoalkyl, -SO 2 -cycloalkenyl, -SO 2 -substituted cylcoalkenyl, -SO 2 -aryl, -SO 2 -substituted aryl
  • Aminocarbonyl refers to the group -C(O)NR 50 R 51 , wherein R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
  • Aminocarbonylamino refers to the group -NR 47 C(O)NR 50 R 51 , wherein R 47 is hydrogen or alkyl; R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and, wherein R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
  • Aminocarbonyloxy refers to the group -O-C(O)NR 50 R 51 , wherein R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
  • Aminosulfonyl refers to the group -SO2NR 50 R 51 , wherein R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
  • Aminosulfonyloxy refers to the group -O-SO2NR 50 R 51 wherein R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and SMRH:4908-5304-8610.1 8 Attorney Docket No.
  • Aminosulfonylamino refers to the group -NR 47 SO2NR 50 R 51 , wherein R 47 is hydrogen or alkyl; R 50 and R 51 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and, wherein R 50 and R 51 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.
  • Aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl).
  • the condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like), provided that the point of attachment is at an aromatic carbon atom.
  • Preferred aryl groups include phenyl and naphthyl.
  • Substituted aryl refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloal
  • Arylene refers to a divalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings.
  • Substituted arylene refers to an arylene having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents as defined for aryl groups.
  • Aryloxy refers to the group -O-aryl, wherein aryl is as defined herein. Exemplary aryloxy groups include phenoxy and naphthoxy.
  • Substituted aryloxy refers to the group -O-(substituted aryl).
  • Aralkyl refers to an aryl group pendant to an alkyl group. Examples of aralkyl groups include benzyl, phenethyl, and 3-naphthylpropyl.
  • Carbamoyl refers to both an “O-carbamoyl” group which refers to the group –O- C(O)NR y R z and an “N-carbamoyl” group which refers to the group -NR y C(O)OR z , wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.
  • Carboxyl or “carboxy” refers to –COOH, or salts thereof.
  • Carboxyl ester refers to the group -C(O)(O)-alkyl, -C(O)(O)-substituted alkyl, -C(O)O-alkenyl, -C(O)(O)-substituted alkenyl, -C(O)(O)-aryl, -C(O)(O)-substituted aryl, -C(O)(O)-cycloalkyl, -C(O)(O)-substituted cycloalkyl, -C(O)(O)-cycloalkenyl, -C(O)(O)-substituted cycloalkenyl, -C(O)(O)-heteroaryl, -C(O)(O)-substituted heteroaryl, -C(O)(O)-heterocyclic, and -
  • (Carboxyl ester)amino refers to the group -NR 47 C(O)(O)-alkyl, -NR 47 C(O)(O)-substituted alkyl, -NR 47 C(O)O-alkenyl, -NR 47 C(O)(O)-substituted alkenyl, -NR 47 C(O)(O)-aryl, -NR 47 C(O)(O)-substituted-aryl, -NR 47 C(O)(O)-cycloalkyl, -NR 47 C(O)(O)-substituted cycloalkyl, -NR 47 C(O)(O)-cycloalkenyl, -NR 47 C(O)(O)-substituted cycloalkenyl, -NR 47 C(O)(O)-heteroaryl, -NR 47 C(O)(O)-substituted heteroaryl, -
  • (Carboxyl ester)oxy refers to the group -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, - SMRH:4908-5304-8610.1 10 Attorney Docket No.
  • Cycloalkyl refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C 3-6 , C4-6, C5-6, C3-8, C4-8, C5-8, C6-8, C3-9, C3-10, C3-11, and C3-12. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane.
  • Cycloalkenyl refers to cycloalkyl groups which are partially unsaturated, having one or more double or triple bonds in the ring.
  • Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl and cycloalkenyl groups can be substituted or unsubstituted.
  • Substituted cycloalkyl and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,
  • “Hydroxy” or “hydroxyl” refers to the group -OH.
  • “Imino” refers to a group -C(NR)R, wherein each R is independently alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.
  • “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
  • Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen.
  • Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).
  • Heteroalkyl refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group.
  • heteroalkyl includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O) 2 -, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted.
  • heteroalkyl groups include -OCH3, -CH2OCH3, - SCH 3 , -CH 2 SCH 3 , -NRCH 3 , and -CH 2 NRCH 3 , where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted.
  • heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • Heteroaryl refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms can also be useful, including, but not limited to, SMRH:4908-5304-8610.1 12 Attorney Docket No. 62WD-385403-WO B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-.
  • Heteroaryl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.
  • the heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroaryl groups can also be fused to aromatic ring systems, which may or may not contain a heteroatom, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, benzofuran, indolizine or benzothiene.
  • benzopyrroles such as indole and isoindole
  • benzopyridines such as quinoline and isoquinoline
  • benzopyrazine quinoxaline
  • benzopyrimidine quinazoline
  • benzopyridazines such as phthalazine and cinnoline
  • benzothiophene benzofuran
  • the heteroaryl groups can be fused to non-aromatic ring systems, which may or may not contain a heteroatom, provided that the point of attachment is through an atom of the aromatic heteroaryl group.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
  • Certain non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, thizolyl, and furanyl.
  • Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine.
  • Heteroaryl groups can be substituted or unsubstituted. “Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl. [0059] “Heteroaryloxy” refers to -O-heteroaryl. “Substituted heteroaryloxy” refers to the group -O-(substituted heteroaryl).
  • Heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated, or partially saturated, ring system having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited SMRH:4908-5304-8610.1 13 Attorney Docket No. 62WD-385403-WO to, -S(O)- and -S(O) 2 -.
  • Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4.
  • the heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane.
  • groups such as aziridine, azetidine, pyrrolidine, piperidine, a
  • heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline.
  • fused ring systems one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through a non-aromatic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, or sulfonyl moieties.
  • Heterocycloalkyl groups can be unsubstituted or substituted.
  • “Substituted heterocyclic” or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
  • Heterocyclyloxy refers to the group -O-heterocyclyl.
  • “Substituted heterocyclyloxy” refers to the group -O-(substituted heterocyclyl).
  • “Spirocycloalkyl” and “spiro ring systems” refers to divalent cyclic groups from 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro union (the union formed by a single atom which is the only common member of the rings) as exemplified by the following structure: . SMRH:4908-5304-8610.1 14 Attorney Docket No.
  • “Sulfonyl” refers to the group -S(O) 2 R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
  • “Substituted sulfonyl” refers to the group -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cylcoalkyl, -SO2-cycloalkenyl, -SO2-substituted cylcoalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO 2 -heterocyclic, -SO 2 -substituted heterocyclic.
  • Substituted sulfonyl includes groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.
  • “Substituted sulfonyloxy” refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO 2 -alkenyl, -OSO 2 -substituted alkenyl, -OSO 2 -cycloalkyl, -OSO 2 -substituted cylcoalkyl, -OSO 2 -cycloalkenyl, -OSO 2 -substituted cylcoalkenyl, -OSO 2 -aryl, -OSO 2 -substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, and -OSO2-substi
  • Alkylsulfonyl refers to the group -S(O) 2 R, where R is alkyl.
  • Alkylsulfinyl refers to the group -S(O)R, where R is alkyl.
  • saccharide refers to a sugar, such as a monosaccharide, a disaccharide, an oligosaccharide or a polysaccharide.
  • Monosaccharides include, but are not limited to, glucose, ribose and fructose.
  • Disaccharides include, but are not limited to, sucrose and lactose.
  • Oligosaccharides refers to 2 to 10 sugars linked together preferably through an alpha linkage. Examples of oligosaccharides include maltose, lactose, sucrose, and the like. Polysaccharides include, but are not limited to, cellulose, hemicellulose and lignocellulose or starch. Saccharides or sugars useful in the present invention include any and all naturally occurring sugars, such as, but not limited to, glucose, glucuronic acid, iduronic acid, galactose, fucose, glucosamine, N-acetylglucosamine, fructose, sialic acid, including aldol and pyranose forms thereof, as well as D and L isomers thereof.
  • “Thiocyanate” refers to the group –SCN.
  • a substituted ring can be substituted with one or more fused and/or spiro cycles. Such fused cycles include a fused cycloalkyl, a fused heterocyclyl, a fused aryl, a fused heteroaryl ring, each of which rings can be unsubstituted or substituted. Such spiro cycles SMRH:4908-5304-8610.1 15 Attorney Docket No.
  • 62WD-385403-WO include a fused cycloalkyl and a fused heterocyclyl, each of which rings can be unsubstituted or substituted. [0071]
  • the groups defined above can optionally be substituted by any suitable number and type of substituents.
  • R’, R” and R”’ each independently refer to hydrogen, unsubstituted alkyl, such as unsubstituted C 1-6 alkyl.
  • R’ and R”, or R” and R”’ when attached to the same nitrogen, are combined with the nitrogen to which they are attached to form a heterocycloalkyl or heteroaryl ring, as defined above.
  • polymers arrived at by defining substituents with further substituents to themselves e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc. are not intended for inclusion herein.
  • each of the above definitions is constrained by a limitation that, for example, substituted aryl groups are limited to -substituted aryl- (substituted aryl)-substituted aryl.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively.
  • a protecting group may be any known in the art, for example, as described in Peter G. M. Wuts and Theodora W. Greene, Greene's protective groups in organic synthesis (Wiley-Interscience, 2007).
  • any formula or structure given herein is also intended to represent isotopically labeled forms of the compounds as well as unlabeled forms.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an isotope having the indicated atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure, or counter-ions thereto, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • isotopically labeled compounds are possible under the present disclosure, for example those into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the disclosure also includes “deuterated analogs” of compounds, and counter-ions thereto, in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Such compounds may exhibit increased resistance to metabolism and thus may be useful for increasing the half-life of a compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984).
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. SMRH:4908-5304-8610.1 17 Attorney Docket No.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F labeled compound may be useful for PET or SPECT studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound. [0080] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • any atom specifically designated as a deuterium (D) is meant to represent enrichment of deuterium above a naturally occurring level at the indicated position.
  • Compounds described herein may be present as a salt, such as a pharmaceutically acceptable salt.
  • Compounds are capable of forming salts such as acid and/or base salts.
  • Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. Salts of compounds described herein can be prepared according to procedures described herein and as known in the art. [0082] The term “pharmaceutically acceptable salt” of a given compound, refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids.
  • Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluene-sulfonic acid, salicylic acid, isobutyric acid, suberic acid, lactic acid, and the like.
  • salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl) 2 ), tri(substituted alkyl) amines (i.e., N(substituted alkyl) 3 ), alkenyl amines (i.e., NH2(alkyl)), dialkyl amine
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n- propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • Methods of preparing a salt also include mixing a compound by redox reaction with an active metal, or by exchange of ions, for example, due to differing solubility of salts.
  • substituted means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, SMRH:4908-5304-8610.1 19 Attorney Docket No. 62WD-385403-WO provided that the designated atom’s normal valence is not exceeded.
  • the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, aryl, -N3, carbamoyl, carboxyl, carboxyl ester, -CN, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, -OH, imino, oxo, -NO 2 , alkylsulfinyl, -SO3H, alkylsulfonyl, thiocyanate, -SH, thione, or combinations thereof.
  • the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorine atoms). Such impermissible substitution patterns are well known to the skilled artisan.
  • the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
  • the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.
  • the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
  • a “solvate” is a solid form of a compound in which solvent molecules are incorporated. A solvate is formed by the interaction of a solvent and a compound.
  • a hydrate is a solvate in which the solvent is water.
  • Solvates of salts of compounds described herein are also provided.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except SMRH:4908-5304-8610.1 20 Attorney Docket No. 62WD-385403-WO insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Treatment provides a beneficial or desired result, e.g., an improvement in one or more clinical indicia of a disorder.
  • Beneficial or desired results may include one or more of the following: decreasing or ameliorating one or more symptoms of the disorder, and/or diminishing the extent of the disorder; (e.g., stabilizing the disorder, preventing or delaying the worsening or progression of the disorder); providing partial or total remission of the disorder; enhancing effect of another medication; increasing the quality of life; and/or prolonging survival in a population of patients.
  • prevention or “preventing” means blocking development of a disorder, or symptoms thereof.
  • Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk of or has a family history of the disorder. Prevention may comprise delay in reaching predefined disease milestones or reduction in appearance or progression of a marker.
  • Subject refers to an animal, such as a mammal, e.g. a human that may benefit from administration of a compound described herein. The methods described herein may be useful in human therapy and/or veterinary applications.
  • the subject is a mammal.
  • the subject is a human.
  • a therapeutically effective amount or “effective amount” of a compound described herein means an amount sufficient to effect treatment when administered to a subject, to provide a benefit as described herein.
  • a therapeutically effective amount may be an amount sufficient to decrease a symptom of a mood disorder.
  • the therapeutically effective amount may vary depending on the subject, the disorder being treated, the weight and age of the subject, the severity of the disorder, and the manner of administering, which can readily be determined by a medical practitioner.
  • the term “refractory” means that a subject having a mood disorder has previously been resistant to treatment of the disorder. For example, one or more symptoms of the mood disorder persisted following treatment.
  • the subject is refractory to treatment with an antidepressant as described herein.
  • SMRH:4908-5304-8610.1 21 Attorney Docket No. 62WD-385403-WO [0091]
  • the term “marker” means a characteristic of a subject that indicates a risk for developing a disorder.
  • a marker may be a genetic indicator associated with a disorder; a marker may be a personal history of the disorder; a marker may be a family history, e.g., a genetic relative or relatives having had the disorder or a related disorder; or a marker may be a physiological indicator such as a test result.
  • hallucinogen and “hallucinogenic” refer to substances that, when administered to a subject, causes perceptual anomalies.
  • hallucinogenic substances include ketamine, 3,4-methylenedioxy-methamphetamine (MDMA), bufotenin, phencyclidine (PCP), lysergic acid diethylamide (LSD), mescaline, psilocybin, salvia divinorum, dimethyltryptamine (DMT), and gamma-hydroxybutyric acid.
  • Compounds that are hallucinogens may also be referred to as “psychedelic.”
  • the hallucinogen is selected from ketamine, LSD, psilocybin, and MDMA.
  • the hallucinogen is ketamine.
  • Treatment Methods and Uses Described herein are methods for the prevention and treatment of mood disorders by administering to a patient an effective amount of a compound that induces spinogenesis. Contrary to expectation, the present disclosure demonstrates that an increase in dendritic spine density may provide benefit in the treatment of mood disorders such as depression. The methods described herein may also provide for treatment with reduced side effects, and/or for treatment of subjects who are refractory to treatment with one or more antidepressants. [0094] Although administration of ketamine has been linked to anti-depressant activity, the mechanism of action is not well understood. Ketamine is believed to have a number of activities in the brain.
  • ketamine may have varying physiological effects over the long term. For example, it is believed that ketamine’s activity in the short term may arise from promotion of activity in dormant spines. Importantly, ketamine is classified as a hallucinogen and is known to cause perceptual anomalies, including dissociative effects. Such effects make ketamine a poor choice for many patients, including, for example, juvenile or pediatric patients, or patients with histories of psychosis. [0095] In some embodiments, a compound described herein is useful in the treatment of a mood disorder.
  • a mood disorder is a principally psychiatric disorder in which a patient’s SMRH:4908-5304-8610.1 22 Attorney Docket No. 62WD-385403-WO general emotional state or mood is distorted or inconsistent with the circumstances, and interferes with the patient’s ability to carry out functions of daily life.
  • the subject may be sad, empty or irritable, or may have periods of negative feeling alternating with feelings of excessive happiness (mania).
  • the mood disorder may be depression. Depression, sometimes referred to as major depressive disorder or clinical depression, is a common but serious mood disorder. Those who suffer from depression may experience persistent feelings of sadness and hopelessness and lose interest in activities they once enjoyed.
  • DSM Diagnostic and Statistical Manual of Mental Disorders
  • the DSM also provides for specifiers of diagnosed depression: (1) With SMRH:4908-5304-8610.1 23 Attorney Docket No. 62WD-385403-WO Mixed Features – This specifier allows for the presence of manic symptoms as part of the depression diagnosis in patients who do not meet the full criteria for a manic episode; and (2) With Anxious Distress – The presence of anxiety in patients may affect prognosis, treatment options, and the patient’s response to them. [0098] Depression is more than just sadness.
  • sadness and depression does not lie in the extent to which a person feels down, but rather in a combination of factors relating to the duration of these negative feelings, other symptoms, bodily impact, and the effect upon the individual’s ability to function in daily life.
  • Sadness is a normal emotion that may arise from a specific event or situation, for example, loss of a job, the end of a relationship, or the death of a loved one.
  • One marker of depression is that a person suffering from depression generally feels sad or hopeless about all aspects of life. The individual may have every reason in the world to be happy and yet lose the ability to experience joy or pleasure, and is likely to suffer in conduct of their affairs, interpersonal relationships, and daily life.
  • Depression has many causative factors.
  • Contributing factors to depression may include stressors such as physical abuse, psychological abuse, traumatic event(s), personal conflicts, loss of relationship with a loved one, social isolation, illness, substance abuse, or use of certain medication.
  • a subject may have a genetic predisposition to depression.
  • a subject may have suffered physical trauma affecting the brain such as a traumatic brain injury (TBI) or chronic traumatic encephalopathy (CTE).
  • TBI traumatic brain injury
  • CTE chronic traumatic encephalopathy
  • depression is idiopathic.
  • Classes of depression include major depressive disorder — prolonged and persistent periods of extreme sadness; bipolar disorder — also called manic depression or bipolar affective disorder, depression that includes alternating times of depression and mania; seasonal affective disorder (SAD) — a form of depression most often associated with fewer hours of daylight in the far northern and southern latitudes from late fall to early spring; cyclothymic disorder — a disorder that causes emotional ups and downs that are less extreme than bipolar disorder; premenstrual dysphoric disorder — mood changes and irritability that occur during the premenstrual phase of a woman's cycle and go away with the onset of menses; persistent depressive disorder (dysthymia) — long-term (chronic) but low-grade depression; disruptive mood dysregulation disorder — a disorder of chronic, severe and persistent irritability in children that often includes frequent temper outbursts that are inconsistent with the child's developmental age; depression related to medical illness — a SMRH:4908-5304-8610.1 24 Attorney
  • 62WD-385403-WO persistent depressed mood and a significant loss of pleasure in most or all activities that's directly related to the physical effects of another medical condition; and depression induced by substance use or medication ⁇ depression symptoms that develop during or soon after substance use or withdrawal or after exposure to a medication.
  • a method of treating a mood disorder in a patient in need thereof comprising administering a therapeutically effective amount of a compound described herein to the patient.
  • the mood disorder is depression.
  • the patient may be refractory to treatment with an antidepressant.
  • the antidepressant may be an antidepressant described herein.
  • compositions and methods are provided for alleviating, reducing, or reversing a symptom of a mood disorder.
  • the symptom may be any symptom described herein, or known to practitioners, for example, as described in the DSM.
  • Symptoms of depression may include anxiety, loss of interest in daily activities; pessimism, persistent negativity; sadness, emptiness or feeling down, feelings of worthlessness, feelings of helplessness, feelings of hopelessness; fatigue, tiredness or lack of energy; low self-esteem, self-criticism and/or feeling incapable; difficulty concentrating, difficulty remembering details, and/or difficulty making decisions; persistent irritability, hostility and/or excessive anger; decreased activity, effectiveness and/or productivity; avoidance of social activities; feelings of guilt and/or worry over the past; poor appetite or overeating; suicidal ideation; low sex drive and/or loss of interest in sex; sleep disturbances, insomnia, early-morning wakefulness, or sleeping too much; restlessness, loss of interest in pleasurable activities; overeating or appetite loss; unexplained aches, unexplained pains, unexplained headache, persistent cramps, persistent digestive problems; suicidal ideation, and a suicidal act.
  • glutamatergic synapses The loss of synapses that utilize the amino acid glutamate as a neurotransmitter (“glutamatergic” synapses) has been appreciated as an important characteristic of certain neurodegenerative diseases. Importantly, about 90% of glutamatergic synapses involve a post-synaptic dendritic spine. The majority of synapses lost in neurodegenerative conditions are those in which the axon makes contact with a dendritic spine, so-called “axospinous synapses.” Under normal conditions, changes in the density, shape, and protein composition of dendritic spines impact the strength of synaptic communication, and are the basis of SMRH:4908-5304-8610.1 25 Attorney Docket No.
  • 62WD-385403-WO several forms of synaptic change (i.e. “plasticity”) involved in learning and memory, cognitive flexibility, adaptation to injury and disease, and other processes.
  • plasticity The role of spine density in the progress of mood disorders is not well understood. However, it has been observed that stress may reduce synapse density. Since many cognitive disorders exhibits abnormalities in the form and function of dendritic spines, it would be desirable to target them directly using a small molecule to alter or alleviate these spine changes. Such treatments may have benefit in reducing side effects associated with many psychoactive drugs such as typical antidepressants, including sensory anomalies. Thus, the development of novel methods to increase spine density could have important implications for treatment of mood disorders including depression.
  • Spinogenesis may be observed as an increase in the average number of spines per neuron, or a unit length of a neuron, which may be referred to as an increase in dendritic spine density.
  • Spinogenesis may be observed as an improvement in dendritic spine morphology.
  • an improvement in dendritic spine morphology may be observed as an increase in average size of spine heads.
  • Spinogenesis may be observed as an improvement in dendritic spine size, spine plasticity, spine motility, spine density and/or synaptic function.
  • Spinogenesis may be observed as an increase in local spatial average of membrane potential.
  • Spinogenesis may be observed as an increase in postsynaptic concentration (e.g., volume-averaged) of Ca 2+ . Spinogenesis may be observed as an increase in the average ratio of matured to immature spines.
  • a compound described herein increases the dendritic spine density relative to a control. In some embodiments, a compound described herein increases the dendritic spine density relative to that observed at the time that treatment is initiated. In some embodiments, the increase in dendritic spine density results in a reduction in symptoms of a mood disorder in a subject or patient. In some embodiments, the increase in dendritic spine density is accounted for by anatomical observation.
  • the increase in dendritic spine density is observed in the prefrontal cortex, e.g., the medial prefrontal cortex.
  • the average dendritic spine density, relative to the time that treatment with a compound described herein is initiated increases by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000%, or any range between any two of the numbers, end points inclusive.
  • the dendritic spine density, relative SMRH:4908-5304-8610.1 26 Attorney Docket No.
  • the dendritic spine density, relative to the time that treatment with a compound described herein is initiated increases by about 100% to about 300%. In some embodiments, the dendritic spine density, relative to the time that treatment with a compound described herein is initiated, increases by about 200% to about 300%. In some embodiments, the duration of treatment with a compound described herein is 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, four weeks, twelve weeks, four months, or one year.
  • the method increases spine density through promoting the formation of new spines.
  • the method increases the average spine density by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000%, or any range between any two of the numbers, end points inclusive, relative to a control (e.g., the spine density in the absence of the compound).
  • the method increases the average spine density about 50% to about 500% relative to a control (e.g., the spine density in the absence of the compound).
  • the method increases the spine density about 100% to about 300% relative to a control (e.g., the spine density in the absence of the compound). In some embodiments, the method increases the spine density about 200% to about 300% relative to a control (e.g., the spine density in the absence of the compound). [0108] In some embodiments, the method increases spine density through increasing a neuron length.
  • the method increases the average neuron length, relative to the time that treatment with a compound described herein is initiated, by about 100 nm, 300 nm, 500 nm, 700 nm, 1 micron, 2 microns, 3 microns, 4 microns, 5 microns, 7 microns, 10 microns, 15 microns, 20 microns, 25 microns, or any range between any two of the numbers, end points inclusive.
  • the method increases the average neuron length about 500 nm to about 25 microns relative to a control (e.g., the neuron length in the absence of the compound).
  • the method increases the neuron length about 10% to about 300% relative to a control (e.g., the neuron length in the absence of the compound). In some embodiments, the method increases the neuron length about 200% to about 300% relative to a control (e.g., the neuron length in the absence of the compound). SMRH:4908-5304-8610.1 27 Attorney Docket No. 62WD-385403-WO [0109] In some embodiments, the method increases the average number of spines per neuron, relative to the time that treatment with a compound described herein is initiated.
  • average number spines per unit length of a neuron increases by at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or about 1000 more, or any range between any two of the numbers, end points inclusive.
  • the time to realize a change in spine density or spine morphology described herein, for example, average dendritic spine density, average spine density, average neuron length, or average number of spines per neuron is 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days.
  • the subject has been found to suffer abnormal dendritic spine morphology, spine size, spine plasticity, spine motility, spine density and/or abnormal synaptic function.
  • a subject may experience reduced dendritic spine density following anesthesia (e.g., anesthesia during a surgery) or surgery.
  • the mood disorder is associated with an abnormal (e.g., reduced) level of dendritic spine density.
  • the method comprises administering to the subject an effective amount of a compound that inhibits the N-methyl-D-aspartate (NMDA) receptor.
  • NMDA N-methyl-D-aspartate
  • the NMDA receptor is so named because the agonist molecule N-methyl-D-aspartate (NMDA) binds selectively to it, and not to other glutamate receptors.
  • the NMDA receptor is a glutamate receptor and ion channel protein found in nerve cells. It is activated when glutamate and glycine or D-serine bind to it, and when activated it allows positively charged ions to flow through the cell membrane.
  • the NMDA receptor is believed to be important for controlling synaptic plasticity and memory function. Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations.
  • a compound described herein may promote dendritic spine formation by inhibiting the NMDA receptor.
  • a compound described herein blocks NMDA receptor activity, optionally at the 2A subunit thereof.
  • a compound described herein may promote NMDA receptor activity, optionally at the 2A subunit thereof.
  • the mood disorder is related to (e.g. characterized by) an accumulation of amyloid plaques.
  • the mood disorder results from a traumatic brain injury or from chronic traumatic encephalopathy.
  • the subject has not suffered a traumatic brain injury or chronic traumatic encephalopathy.
  • the depression is not a result of substance abuse or another medical condition.
  • administration of a hallucinogen, for example ketamine, to the patient is not advised.
  • the agent may be a compound provided herein.
  • the compound may be a compound described in International Patent Publication No. WO 2019/028164.
  • the compound is a compound of formula I or formula Ia: or a pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof, wherein subscripts n and p are independently selected from 0, 1 or 2; each R 1 is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, thiol, and nitro; A is an arylene or heteroarylene, having 1 to 4 heteroatoms; SMRH
  • 62WD-385403-WO W is selected from the group consisting of -O-, -S-, -SO-, -S(O) 2 -, and -NR 2 -, wherein R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; X is selected from the group consisting of -O-, -S-, -SO-, -S(O) 2 -, and -NR 2 -, wherein R 2 is as defined above, provided that when A is arylene, and Y is -S- or -NR 2 -, then X is not -S-; Y is selected from the group consisting of -O-, -S-, -SO-, S(O)2-, and -NR 2 -, wherein R 2 is as defined above; and Z is selected from the group
  • a compound according to Formula Ib, Formula Ic, Formula Id, Formula Ie, and/or Formula Ig: SMRH:4908-5304-8610.1 30 Attorney Docket No. 62WD-385403-WO or a pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof, wherein R 1 , R 2 , A, Y, Z, n and p are as defined above with respect to formula I and formula Ia; and subscript m is selected from 0, 1 or 2.
  • a compound, or a pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof selected from: SMRH:4908-5304-8610.1 31 Attorney Docket No. 62WD-385403-WO
  • a compound according to Formula Ih or a pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof, wherein: subscripts n and p are independently selected from 0, 1 or 2; subscript q is an integer selected from 2 to 8; and each R 1 and R 2 are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substitute
  • a compound according to Formula Ij or a pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof, wherein: subscript q is an integer selected from 4 or 6; R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen halo, – CH3, and –OCH3; and SMRH:4908-5304-8610.1 35 Attorney Docket No.
  • R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halo, – CH3, –CF3, –OCH3, –OCF3, phenyl, –NO2; wherein at least six of said R groups are hydrogen.
  • a compound, or a pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof selected from: [0123]
  • the compound is (Compound 1), or pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof.
  • the compound may be a compound described in International Patent Publication No. WO2017120198.
  • the compound is a compound of formula II: or a pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof, wherein Y is – NR 33 -, O, or –S-; R 31 is independently halogen, -CX 31 , -CHX 31 , -CH2X 31 , -OCX 31 S, - OCHX 31 , -OCH 2 X 31 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, - SO 2 NH 2 , -NHNH 2 , -ONH 2 , - C(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, - NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted
  • 62WD-385403-WO ONH 2 -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each of X 31 and X 32 are independently halogen; each of z1 and z2 is independently an integer from 0 to 4; and z3 is an integer from 1 to 12.
  • the compound is a compound of formula IIa: or a pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof, wherein R 1 is independently halogen, —CX 1 1 3, —CHX 2, —CH2X 1 , —OCX 1 3, —OCHX 1 2, -OCH2X 1 , —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, — SO 4 H, -SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , — NHSO2H, -NHC(O)H, —NHC(O)OH, —NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
  • the compound is , or pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof.
  • the compound is , or pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof.
  • the compound is a compound of formula III: or a pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof, wherein R1-R8 are selected from the group consisting of hydrogen, deuterium, tritium, fluoride, chloride, bromide, iodide, hydroxide, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, wherein at least one of R 5 -R 8 and one of R1-R4 is H; and P is selected from the group consisting of SMRH:4908-5304-8610.1 38 Attorney Docket No.
  • R 9 -R 16 are selected from the group consisting of hydrogen, deuterium, tritium, fluoride, chloride, bromide, iodide, hydroxide, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, wherein at least one of R 9 -R 12 and one of R 13 -R 16 is H; and X is hydrogen, methyl, or ethyl.
  • the compound of formula III is a compound of formula IIIa: wherein R1-R8 are selected from the group consisting of hydrogen, deuterium, tritium, fluoride, chloride, bromide, iodide, hydroxide, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, wherein at least one of R5-R8 and one of R1-R4 is H; and P is wherein m is an integer between 1 and 20; q is an integer between 1 and 20; R 9 -R 16 are selected from the group consisting of hydrogen, deuterium, tritium, fluoride, chloride, SMRH:4908-5304-8610.1 39 Attorney Docket No.
  • the compound is selected from or pharmaceutically acceptable salt, solvate, and/or an N-oxide thereof.
  • the compound is not ketamine. In some embodiments, the compound does not cause perceptual anomalies in the subject.
  • the compound is not a psychedelic. In some embodiments, the compound is not hallucinogenic.
  • Combination Therapies [0133] When used for the treatment or prevention of the diseases and disorders described above, a compound described herein may be administered together with one or more additional therapies, for example additional therapeutic agents approved for use in the treatment or prevention of the particular disease or disorder, and more particularly therapies and/or therapeutic agents considered to form the current standard of care. [0134] In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents that are being used and/or developed to treat a mood disorder. Where combination therapy is envisaged, the active agents may be administered simultaneously, separately or sequentially in one or more pharmaceutical SMRH:4908-5304-8610.1 40 Attorney Docket No.
  • the one or more additional therapeutic agents is an antidepressant.
  • the antidepressant is selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor, a serotonin noradrenaline dopamine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, a monoamine oxidase inhibitor, a tricyclic antidepressant, or a tetracyclic antidepressant.
  • SSRI selective serotonin reuptake inhibitor
  • serotonin norepinephrine reuptake inhibitor a serotonin noradrenaline dopamine reuptake inhibitor
  • a norepinephrine dopamine reuptake inhibitor a monoamine oxidase inhibitor
  • a tricyclic antidepressant a tetracyclic antidepressant.
  • the antidepressant is a serotonin and norepinephrine reuptake inhibitor selected from the group consisting of levomilnacipran, venlafaxine, desvenlafaxine, sibutramine, nefazodone, milnacipran, duloxetine, and bicifadine, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.
  • a serotonin and norepinephrine reuptake inhibitor selected from the group consisting of levomilnacipran, venlafaxine, desvenlafaxine, sibutramine, nefazodone, milnacipran, duloxetine, and bicifadine, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.
  • the antidepressant is a serotonin noradrenaline dopamine reuptake inhibitor selected from the group consisting of tesofensine and brasofensine, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.
  • the antidepressant is a monoamine oxidase inhibitor selected from the group consisting of isocarboxazid, moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, nialamide, iproniazid, iproclozide, and toloxatone, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.
  • a monoamine oxidase inhibitor selected from the group consisting of isocarboxazid, moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, nialamide, iproniazid, iproclozide, and toloxatone, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.
  • the antidepressant is a tricyclic antidepressant selected from the group consisting of butriptyline, amoxapine, amitriptyline, nortriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, dibenzepin, iprindole, lofepramine, opipramol, protriptyline, and trimipramine, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.
  • the antidepressant is a tetracyclic antidepressant selected from the group consisting of maprotiline, mianserin, mirtazapine, setiptilinem, amoxapine, quetiapine, benzoctamine, loxapine, mazindol, aptazapine, esmirtazapine, oxaprotiline, SMRH:4908-5304-8610.1 41 Attorney Docket No. 62WD-385403-WO ciclazindol, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.
  • the antidepressant is a selective serotonin reuptake inhibitor selected from the group consisting of fluoxetine, norfluoxetine, citalopram, dapoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.
  • the antidepressant is ketamine, esketamine, bupropion, mirtazapine, vilazodone, vortioxetine, aripiprazole, or St.
  • the one or more additional therapeutic agents may be a sedative-hypnotic such as chloral hydrate, estazolam, flurazepam hydrochloride, pentobarbital, pentobarbital sodium, phenobarbital sodium, secobarbital sodium, temazepam, triazolam, zaleplon, or zolpidem tartrate; an anticonvulsant such as acetazolamide sodium, carbamazepine, clonazepam, clorazepate dipotassium, diazepam, divalproex sodium, ethosuximde, fosphenytoin sodium, gabapentin, lamotrigine, magnesium sulfate, phenobarbital, phenobar
  • entacapone levodopa, pergolide mesylate, pramipexole dihydrochloride, ropinirole hydrochloride, selegiline hydrochloride, tolcapone, or trihexyphenidyl hydrochloride; a central nervous system agent such as bupropion hydrochloride, donepezil hydrochloride, droperidol, fluvoxamine maleate, lithium carbonate, lithium citrate, naratriptan hydrochloride, nicotine polacrilex, nicotine transdermal system, propofol, rizatriptan benzoate, sibutramine hydrochloride monohydrate, sumatriptan succinate, tacrine hydrochloride, or zolmitriptan; a cholinergic (e.g., parasymathomimetic) such as bethanechol chloride, edrophonium chloride, neostigmine bromide, neostigmine
  • the one or more additional therapeutic agent may be tacrine, donepezil, galantamine, rivastigmine, memantine, levodopa, carbidopa, lisuride, rasagiline, tolcapone, entacapone, clozapine, desipramine, citalopram, nortriptyline, paroxetine, atomoxetine, venlafaxine, amantadine, donepezil, rivastigmine, bromocriptine, cabergoline, pergolide, pramipexole, ropinirole, rotigotine, apomorphine, benserazide, selegiline, omigapil, CEP- SMRH:4908-5304-8610.1 43 Attorney Docket No.
  • 62WD-385403-WO 1347 isradipine, DOPA, lithium, riluzole, levetiracetam, ezogabine, pregabalin, rufmamide, felbamate, carbamazepine, valproate, sodium valproate, lamotrigine, phenytoin, oxcarbazepine, ethosuximide, gabapentin, tiagabine, topiramate, vigabatrin, phenobarbital, primidone, clonazepam, interferon beta-la, interferon beta-lb, mitoxantrone, natalizumab, fmgolimod, natalizumab, teriflunomide, dimethyl fumarate, glatiramer, ATOH1 gene therapy, ozanezumab, arimoclomol, tirasemtiv, dexpramipexole, pridopidine, or galantamine; or
  • the one or more additional therapeutic agent may be an acetyl-cholinesterase inhibitor (AChEI), for example, acotiamide, alpha-pinene, ambenonium, demecarium, DFP (diisopropylfluorophosphate), donepezil, edrophonium, galantamine, huperzine A, lactucopicrin, ladostigil, neostigmine, physostigmine, pyridostigmine, dyflos, echothiophate, rivastigmine, rosmarinic acid, tacrine, ungeremine, zanapezil, ganstigmine, phenserine, phenethylnorcymserine (PENC), cymserine, thiacymserine, SPH 1371 (galantamine plus), ER 127528, RS 1259, or F3796.
  • AChEI acetyl-cho
  • the one or more additional therapeutic agent may be an amyloid-clearing antibody, for example, bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, BAN2401, or aducanumab.
  • the one or more additional therapies is acceptance and commitment therapy, Adlerian Therapy, animal-assisted therapy, applied behavior analysis, art therapy, attachment-based therapy, biofeedback, brain stimulation therapy, coaching, cognitive behavioral therapy, cognitive processing therapy, cognitive stimulation therapy, culturally sensitive therapy, dialectical behavior therapy, eclectic therapy, emotionally focused therapy, existential therapy, experiential therapy, expressive arts therapy, eye movement desensitization and reprocessing therapy, family systems therapy, civil therapy, forensic therapy, gestalt therapy, hypnotherapy, Imago relationship therapy, integrative therapy, internal family systems therapy, interpersonal psychotherapy, Jungian therapy, marriage and family therapy, mentalization-based therapy, mindfulness-based cognitive therapy, motivational interviewing, multicultural therapy, narrative therapy, neuro- linguistic programming therapy, neurofeedback, parent-child interaction therapy (PCIT), person-centered therapy, play therapy, positive psychology, prolonged exposure therapy, psychoanalytic therapy, psychodynamic therapy, psychological testing and evaluation, rational emotive behavior therapy, reality therapy, relational therapy, sandplay therapy, social recovery therapy, solution
  • PCIT parent-child interaction
  • kits that include compounds described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, optionally a second active ingredient, and suitable packaging.
  • kits further includes instructions for use.
  • a kit includes a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, as a component of a pharmaceutical composition and a label and/or instructions for use of the pharmaceutical composition in the treatment of the indications, including the diseases or conditions, described herein.
  • articles of manufacture that include a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof in a suitable container.
  • the container may be a vial, jar, ampoule, preloaded syringe, nebulizer, aerosol dispensing device, dropper, or intravenous bag.
  • Pharmaceutical Compositions and Modes of Administration [0149] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein, including generally a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.
  • Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and SMRH:4908-5304-8610.1 45 Attorney Docket No. 62WD-385403-WO fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • diluents including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).
  • the pharmaceutical compositions may be administered in either single or multiple doses.
  • the pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes.
  • the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • One mode for administration is parenteral, for example, by injection.
  • Oral administration may be another route for administration of the compositions described herein. Administration may be via, for example, capsule or enteric coated tablets.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium SMRH:4908-5304-8610.1 46 Attorney Docket No. 62WD-385403-WO silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents preserving agents such as methyl and propylhydroxy-benzoates
  • sweetening agents and flavoring agents.
  • the pharmaceutical composition and any container in which it is distributed may be sterilized.
  • the pharmaceutical composition may also contain adjuvants such as preservatives, stabilizers, emulsifiers or suspending agents, wetting agents, salts for varying the osmotic pressure, viscosity alerting agents, or buffers.
  • compositions that include at least one compound described herein, such as a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer- coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.
  • Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”).
  • transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139.
  • Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.
  • the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • SMRH:4908-5304-8610.1 47 Attorney Docket No. 62WD-385403-WO [0157]
  • the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • the pharmaceutical composition may be formulated for nasal administration.
  • Such pharmaceutical compositions may include one or more active ingredients, such as a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, in varying physical states.
  • the active ingredients may be dissolved or suspended in a liquid carrier.
  • the active ingredients may be in a dry form.
  • the dry form may be a powder.
  • Active ingredients in a powder may be amorphous or crystalline.
  • a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof may be amorphous or crystalline.
  • the crystalline active material may be a hydrate or a solvate.
  • Solid compounds, or a salt or crystal thereof may be present in a formulation in a selected average particle size.
  • the particles may have an average particle size (in longest dimension) of 10 nm, 100 nm, 300 nm, 500 nm, 1 ⁇ m, 10 ⁇ m, 50 ⁇ m, 100 ⁇ m, 300 ⁇ m, or 500 ⁇ m, or a range between any two values.
  • Administration may be by inhalation or insufflation.
  • Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein.
  • the compositions are administered by the oral or nasal respiratory route. Effects may be local or systemic.
  • compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent SMRH:4908-5304-8610.1 48 Attorney Docket No. 62WD-385403-WO positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • a pharmaceutical composition for inhalation or insufflation may be an aerosol.
  • the pharmaceutical composition may comprise a liquid suspension or solution comprising about 0.05%, about 0.1%, about 0.3%, about 0.5%, about 0.7%, about 1%, about 2%, about 3%, about 4%, or about 5% w/w of active ingredients.
  • the liquid may comprise water and/or an alcohol.
  • the liquid may include a pH adjusting agent such that the pH is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, or a range of values therebetween.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable preservative.
  • Preservatives suitable for use herein include, but are not limited to, those that protect the solution from contamination with pathogenic particles, including phenylethyl alcohol, benzalkonium chloride, benzoic acid, or benzoates such as sodium benzoate.
  • the pharmaceutical composition comprises from about 0.01% to about 1.0% w/w of benzalkonium chloride, or from about 0.01% and about 1% v/w phenylethyl alcohol.
  • Preserving agents may also be present in an amount from about 0.01% to about 1%, preferably about 0.002% to about 0.02% by total weight or volume of the composition.
  • the pharmaceutical composition may also comprise from about 0.01% to about 90%, or about 0.01% to about 50%, or about 0.01% to about 25%, or about 0.01% to about 10%, or about 0.01% to about 1% w/w of one or more of an emulsifing agent, a wetting agent or a suspending agent.
  • Such agents for use herein include, but are not limited to, polyoxyethylene sorbitan fatty esters or polysorbates, including, but not limited to, polyethylene sorbitan monooleate (Polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate; lecithins; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propane-1,2-diol alginate; agar; carrageenan; locust bean gum; guar gum; tragacanth; acacia; xanthan gum; karaya gum; pectin; amidated pectin; ammonium phosphatides; microcrystalline cellulose; methyl cellulose;
  • the pharmaceutical composition for nasal administration may be provided in the form of a powder.
  • a powdery nasal composition can be directly used as a powder for a unit dosage form.
  • the powder can be filled in capsules such as hard gelatine capsules.
  • the contents of the capsule or single dose device may be administered using e.g. an insufflator.
  • a method for treating a mood disorder may include the step of administering nasally a pharmaceutical composition comprising a compound described herein, or a salt thereof, to a subject in need thereof.
  • a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate.
  • the daily dosage may also be described as a total amount of a compound described herein administered per dose or per day.
  • Daily dosage of a compound described herein, or a salt thereof may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
  • the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.
  • the daily dosage is about 10 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg, or a range of values therebetween.
  • the active ingredients of the present application or the pharmaceutical compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles.
  • the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.
  • the method comprises administering to the subject a dose in an amount provided herein once a month, twice a month, once a week, twice a week, or thrice SMRH:4908-5304-8610.1 51 Attorney Docket No.
  • dosing may be continued for one month, two months, three months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 12 months, 14 months, 18 months, one year, two years, three years, five years, or indefinitely.
  • a method comprising administering a compound described herein at a frequency of between thrice a week and once a month.
  • the chronobiologic facility is equipped with equispaced, soundproof, temperature-controlled (21.0 ⁇ 1.0 °C) compartments provided with filtered air. Each compartment has its own light– dark cycle control.
  • Long Evans (LE) rats weighing 700–800 g, serve as resident rats in confrontation encounters. At their arrival in the laboratory, they are housed in appropriate cages (l: 45 cm; w: 45 cm; h: 17 cm) together with a ligatured female for 1 month. Then, the residents are chosen for their reliable aggressive behavior as assessed during confrontations with intruders. During the social-defeat procedure, the females are removed from the cages. The same 10 LE rats are used for all the successive series of experiments.
  • the behavioral procedure consists of conditioning sessions with the same pairs of residents and intruders.
  • the 45-min conditioning sessions are started at 1000. They are divided into two consecutive periods. During period I (30-min), intruders are placed alone in a protective cage without cover (l: 25 cm; w: 25 cm; h: 30 cm) inside the resident home cage.
  • the resident home cage has no cover and was surrounded by a 100 cm high wire-mesh SMRH:4908-5304-8610.1 52 Attorney Docket No.
  • the protective cage allows unrestricted visual, auditory and olfactory interactions with the resident but precluded close physical contact.
  • period II 15-min
  • the protective cage is removed (defeated intruders) allowing physical confrontation.
  • intruders are attacked within 30 s, and three to four confrontations of ⁇ 10 s each occurred, during which the intruding animal is always dominated by the resident rat and adopted submissive posture, that is, when the defeated rat is on its back under the resident rat for approximately 5 s.
  • the total duration of encounters was ⁇ 1 min for the whole 15 min period II.
  • intruders are exceptionally wounded and only at skin-deep level in such cases (in less than 5% of confrontation sessions).
  • Nondefeated intruders are subjected to the same procedure, but without the resident rat for the whole 15 min period II. Therefore, they are never physically attacked and defeated by the resident.
  • the 45-min conditioning session is repeated once daily for 4 days on week 1.
  • weeks 2 and 3 intruders are subjected to the social-defeat procedure once daily for 2 days, and on week 4, the procedure is repeated again once daily for 4 days.
  • One group of animals is intended for behavioral and physiological analyses and another group for microdialysis experiments.
  • Adrenal gland weight 5 days after the last conditioning session, defeated and nondefeated intruders, treated or not with a compound described herein are decapitated and adrenals are removed, dissected free of adhering fat and weighed.
  • Sweet water consumption SMRH:4908-5304-8610.1 53 Attorney Docket No. 62WD-385403-WO [0177] From 1 week before the beginning of the conditioning sessions (D7 to D1) until 5 days after the last conditioning session, two bottles (one filled with water and the other one containing 1.5% sucrose) are continuously available to rats. Sucrose and water intakes are measured daily at 0900. Bottles are switched every day from left to right side of the cage throughout the experiment in order to avoid any place preference.
  • Sweet water consumption is calculated as a percentage of control values.
  • Food consumption is measured daily at 0900, before (7 days), during (25 days) and after (5 days) the social-defeat procedure. Data are expressed as the sum of daily food intakes measured in each animal group during each week.
  • Forced swimming test [0179] An adapted version of the forced swimming test (FST) originally described by Porsolt et al. is used. Experiments are performed between 0930 and 1300. Five days after the last conditioning session, SD rats are individually placed into glass cylinders (40 cm height; 20 cm diameter) containing 29 cm of water at 30 ⁇ 1°C. After 8 min, they are transferred to a 30°C drying environment for 15 min.
  • FST forced swimming test
  • mice After 24 h (proliferation) or 28 days (differentiation) of the first BrdU injection (day 30, day 58), animals are anesthetized with 375 mg kg ⁇ 1 i.p. of chloral hydrate. Transcardiac perfusion with saline is carried out to clear the blood, followed by 4% cold paraformaldehyde (PFA) in phosphate-buffered saline (PBS). After perfusion, brains are postfixed overnight in 4% SMRH:4908-5304-8610.1 54 Attorney Docket No. 62WD-385403-WO PFA/PBS at 4°C.
  • PFA cold paraformaldehyde
  • PBS phosphate-buffered saline
  • mice After blocking with 5% horse serum in 0.1% Triton X-100, sections are incubated with mouse anti-BrdU antibodies (1:500; Dakocytomation, Trappes, France) overnight at 4°C, then for 2 h with a secondary antibody (1:400; biotinylated horse anti-mouse). After amplification with an avidin–biotin complex, sections are exposed to diaminobenzidine, washed with PBS and mounted onto microscope slides. Slices are processed for counterstaining with cresyl violet and coverslipped. All slides were coded prior to analysis.
  • the total number of BrdU-labeled cells per section is determined and multiplied by 6 to obtain the total number of cells per dentate gyrus (see).
  • Phenotypic analysis of fluorescently labeled SMRH:4908-5304-8610.1 55 Attorney Docket No. 62WD-385403-WO BrdU cells is performed using a confocal microscope. Cells are scanned and optically sectioned in the Z plane. [0184]
  • the layer is carefully demarcated on both right and left sides in each section and its area is calculated using Lucia GF version 4.71.
  • microdialysis After 24 h of the last conditioning session, intruders are anesthetized with chloral hydrate (375 mg kg ⁇ 1 , i.p.). A stainless-steel guide cannula is placed at coordinates allowing the tip to be just above the frontal cortex: anteroposterior, +2.7 mm from bregma; lateral, ⁇ 1.7 mm from bregma; horizontal, ⁇ 0.8 mm from the skull. The cannula is then secured to the skull with dental cement, and the skin was sutured.
  • mice are kept in individual cages for 4 days before the microdialysis experiment.
  • the day before the experiment the rats are placed in a Plexiglas microdialysis bowl (35 cm in diameter) with free access to food and water.
  • a microdialysis probe (cutoff: 20 000 Da; outer diameter 0.5 mm; 2 mm in length) is introduced into the guide cannula so as to protrude by 2 mm into the Fr2 area of frontal cortex.
  • the Fr2 region is considered as an area of the prefrontal cortex.
  • the probe was continuously perfused at a flow rate of 3.0 ⁇ l min ⁇ 1 with an artificial CSF (aCSF).
  • CCKLM CCK-like material
  • mice are deeply anesthetized with chloral hydrate (375 mg kg ⁇ 1 , i.p.), and killed by decapitation. Brains are removed, rapidly frozen in isopentane and stored at ⁇ 20 °C. They are sectioned in a cryostat and stained with cresyl violet for verification of probe location. When a probe is incorrectly placed, corresponding results were discarded.
  • Drugs and treatments [0190] Treatment with a compound described herein is started the day after the last conditioning session of week 1 (day 5) and maintained until the day of microdialysis experiment or killing for HPA axis activity determination, cell proliferation quantification or volumetric analysis of the hippocampus (day 30).
  • Models of depression include chronic intermittent stress (e.g., alone and followed by forced swim), as described in, for example, Willner P., The chronic mild stress (CMS) model of depression: History, evaluation and usage, Neurobiology of Stress (2017) 6, 78-93; social defeat model as described in, for example, Golden, S.A. et al., A standardized protocol for repeated social defeat stress in mice, Nat Protoc.
  • chronic intermittent stress e.g., alone and followed by forced swim
  • CMS chronic mild stress
  • social defeat model as described in, for example, Golden, S.A. et al., A standardized protocol for repeated social defeat stress in mice, Nat Protoc.
  • Spinogenesis for example, in the prefrontal cortex, may be conducted by any suitable method including, for example, by Golgi staining, biolistic labeling with fluorescent dyes, DiI labeling, Molecular Probes Cell TrackerTM CM-DiI, and structured illumination SMRH:4908-5304-8610.1 57 Attorney Docket No. 62WD-385403-WO microscopy.
  • biolistic labeling may be conducted, for example, according to Arsenault, J., et al., Regioselective Biolistic Targeting in Organotypic Brain Slices Using a Modified Gene Gun. J. Vis. Exp. (2014), 92, e52148.
  • DiI may be conducted according to, for example, Gan, W. B., et al., Multicolor “DiOlistic” labeling of the nervous system using lipophilic dye combinations.
  • Example 2 Methods described herein can be useful for treating or preventing a mood disorder such as depression.
  • the present example illustrates a method of treating or preventing depression by administering Compound 1 to a subject in need thereof.
  • SMRH:4908-5304-8610.1 58 Attorney Docket No. 62WD-385403-WO
  • a randomized, placebo-controlled study is conducted in adult participants diagnosed with schizophrenia, a prevalent psychotic disorder with frequent co-morbid depression and anxiety.
  • the initial dose of the compound e.g., Compound 1
  • Patients can receive a dose (e.g., a daily dose) of the compound (e.g., Compound 1) for up to about 6 weeks.
  • participant will be given sufficient amount of placebo or the compound for daily (AM) dosing to last until the next scheduled clinical site visit on Day 22 ⁇ 2 days (21 days ⁇ 2 days). Participants will be contacted by telephone on Days 8, 15, 29, 36 to assess for adverse events, concomitant medication use, and a verbal compliance check and a week after dosing is complete on Day 50. All visits and telephone calls after Day 1 will have a window of ⁇ 2 days. Participants will return to the clinic on Day 71 ⁇ 7 for final efficacy and safety assessments.
  • AM daily
  • One or more symptoms of depression can be alleviated, reduced, or reversed following commencement of the treatment.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
  • the disclosures illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation.

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Abstract

Dans certains modes de réalisation, l'invention concerne une méthode de traitement ou de prévention d'un trouble de l'humeur, consistant à administrer à un patient dont l'état le nécessite une quantité thérapeutiquement efficace d'un composé divulgué.
PCT/US2025/017952 2024-02-29 2025-02-28 Méthodes de prévention et de traitement de la dépression Pending WO2025184576A1 (fr)

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