WO2024102802A1 - Zélatriazine pour le traitement de la dépression - Google Patents

Zélatriazine pour le traitement de la dépression Download PDF

Info

Publication number
WO2024102802A1
WO2024102802A1 PCT/US2023/079063 US2023079063W WO2024102802A1 WO 2024102802 A1 WO2024102802 A1 WO 2024102802A1 US 2023079063 W US2023079063 W US 2023079063W WO 2024102802 A1 WO2024102802 A1 WO 2024102802A1
Authority
WO
WIPO (PCT)
Prior art keywords
dose
depression
compound
salt
subject
Prior art date
Application number
PCT/US2023/079063
Other languages
English (en)
Inventor
Wei Yin
Antonio Laurenza
Dimitrios ARKILO
Original Assignee
Takeda Pharmaceutical Company Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Publication of WO2024102802A1 publication Critical patent/WO2024102802A1/fr

Links

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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • GPR139 is an orphan G-protein coupled receptor. GPR139 may be coupled with Gs, Gq and Gi signaling, and appears to be constitutively active when recombinantly expressed in mammalian cells.
  • GPR139 is abundantly expressed in the CNS (central nervous system), expressed to a lesser extent in the pancreas and pituitary, and expressed at low levels in other peripheral tissues.
  • CNS central nervous system
  • GPR139 is highly conserved among different species. For example, human, mouse, and rat GPR139 protein sequences share greater than 94% identity at the amino acid level. The predominant expression in the brain, and the high degree of sequence homology across different species, suggest that GPR139 has an important role in physiology.
  • GPR139 has high levels of expression in the medial habenula, a subdivision of a brain nucleus controlling dopaminergic and serotonergic effector systems, which modulate reward, emotion, and cognition (Boulos L.
  • Anhedonia defined as the loss of interest in the usually pleasurable activities, is a characteristic of depression and several other neuropsychiatric disorders, and is recognized as a core feature of major depressive disorder (MDD) (Hasler G. et al., Neuropsychopharmacology.2004;29(10):1765- 81). Clinically, in addition to being associated with greater depression severity, greater social impairment, worse quality of life, and higher risk of suicide, anhedonia is also predictive of poor clinical outcome, including in adolescents.
  • MDD major depressive disorder
  • Currently available antidepressant drugs have limitations, including a low treatment response rate (e.g., treatment-resistant depression (“TRD”)) and a time lag of several weeks before a therapeutic effect is observed.
  • TRD treatment-resistant depression
  • anhedonia reportedly does not respond well to commonly used serotonergic antidepressants (Shelton R.C. and Tomarken A.J., Psychiatr Serv.2001;52(11):1469-78.).
  • MDD with anhedonia represents an important unmet therapeutic need.
  • a method for treating depression in a subject in need thereof comprising administering to the subject a weekly dose of 2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)-N- ⁇ (1S)-1-[4- (trifluoromethoxy)phenyl]ethyl ⁇ acetamide (Compound 1), or a pharmaceutically acceptable salt thereof.
  • a method for treating anhedonia in major depressive disorder (MDD) in a subject in need thereof comprising administering to the subject a weekly dose of 2-(4-oxo-1,2,3- benzotriazin-3(4H)-yl)-N- ⁇ (1S)-1-[4-(trifluoromethoxy)phenyl]ethyl ⁇ acetamide (Compound 1), or a pharmaceutically acceptable salt thereof.
  • the weekly dosing is oral weekly dosing.
  • an oral weekly dose of Compound 1 for treatment of depression is administered to the subject a weekly dose of 2-(4-oxo-1,2,3- benzotriazin-3(4H)-yl)-N- ⁇ (1S)-1-[4-(trifluoromethoxy)phenyl]ethyl ⁇ acetamide
  • FIG.1A shows that Compound 1 (abbreviated as Compd 1) dose-dependently increases cFOS protein in the mouse medial habenula (MHb) immunohistochemistry (IHC) 1 hour post dosing.
  • FIG. 1B shows the absence of tachyphylaxis of Compound 1-dependent cFOS induction in the mouse medial habenula (MHb) after 10-day sub chronic dosing of Compound 1.
  • FIG.1C shows representative cFOS positive cells in the mouse medial habenula (MHb) immunohistochemistry (IHC) after acute or sub chronic treatment with Compound 1.
  • FIG.2A shows the dosing schedule for the SDT, SCT, or FST tests of Example 2.
  • FIG.2B shows that chronic 21 day dosing of Compound 1 reduces unpredictable chronic mild stress (uCMS)- induced anhedonia-like behavior in rats in the sweet drive test (SDT).
  • FIG.2C shows the results of the Sucrose Consumption Test (SCT) which shows that chronic 21 day dosing of Compound 1 reduces unpredictable chronic mild stress (uCMS)-induced anhedonia-like behavior in rats in the sucrose consumption test (SCT).
  • SCT Sucrose Consumption Test
  • FIG.2D shows the results of the Forced swimming Test (FST) which shows that chronic 21 day dosing of Compound 1 reduces unpredictable chronic mild stress (uCMS)-induced anhedonia-like behavior in.
  • FIG.3 shows that Compound 1 reduces amphetamine induced dopamine release in the rat nucleus accumbens.
  • 2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)-N- ⁇ (1S)-1-[4- (trifluoromethoxy)phenyl]ethyl ⁇ acetamide has the following structure: Compound 1.
  • Compound 1 is alternatively named (S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4- (trifluoromethoxy)phenyl)ethyl)acetamide, and is a GPR139 agonist.
  • systemic exposure (C max and AUC) to Compound 1 generally increased less than dose proportionally.
  • the oral weekly dosing comprises a first dose that may be higher than the subsequent weekly doses.
  • the oral weekly dosing comprises a first dose that may be the same as subsequent weekly doses.
  • “about” can mean a range of up to 20%, e.g., up to 10%, e.g., up to 5%, e.g., up to 1% of a given value.
  • the term can mean within an order of magnitude, e.g., within 5-fold, e.g., within 2-fold, of a value.
  • “about”, indicates that the numeric value or range of values may vary by 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the recited value or range of values while still describing the particular dose or measurement.
  • the term “about” indicates that the numeric value or range of values may vary by 5%. In some embodiments, the term “about” indicates that the numeric value or range of values may vary by 10%.
  • the term “administration” of an agent to a subject includes any route of introducing or delivering the agent to a subject to perform its intended function. Administration can be carried out by any suitable oral or non-oral route, including, but not limited to, intravenously, intramuscularly, intraperitoneally, subcutaneously, and other suitable routes as described herein. Administration includes self-administration and administration by another.
  • the term “agonist” refers to both full agonists and partial agonists and other agonists.
  • Prior therapy for depression refers to any treatment the subject has undergone for depression before undergoing the treatment described herein.
  • Examples of prior therapy include, but are not limited to, other antidepressant medications such as tricyclic (e.g., clomipramine) or tetracyclic (e.g., maprotiline) antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), bupropion, selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, serotonin modulators and stimulators, serotonin antagonists and reuptake inhibitors, norepinephrine reuptake inhibitors, norepinephrine–dopamine reuptake inhibitors, glutamate modulators (e.g., esketamine or ketamine, memantine, riluzole), electro-convulsive therapy (ECT), talk therapy, and/or cognitive behavioral therapy (C
  • a patient who “failed to respond to at least one prior therapy for depression” refers to a subject who either failed to respond at all to at least one prior therapy for depression, or Attorney Reference No.: 15496.0035-00304 responded to at least one prior therapy for depression but then subsequently relapsed.
  • a patient who “failed to respond to at least one prior therapy for depression” refers to a subject who showed, for example, less than about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% improvement in his or her symptoms of depression from baseline (before administration of the therapy) to a point in time during or after the therapy.
  • a patient who “failed to respond to at least one prior therapy for depression” refers to a subject who shows, for example, less than about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% improvement in his or her symptoms of depression during or after one or more administrations of a prior therapy, based on one or more measures of depression, including, but not limited to, Dimensional Anhedonia Rating Scale (DARS), Montgomery ⁇ sberg Depression Rating Scale (MADRS) score, Clinical Global Impression - Severity (CGI-S) score, Clinical Global Impression - Improvement (CGI-I) score, Temporal Experience of Pleasure Scale (TEPS) total, anticipatory and consummatory scores, Patient Global Impression-Severity (PGI-S) score, Patient Global Impression-Improvement (PGI-I) score, subject-rated depression (Patient Health Questionnaire
  • DARS Dimensional Anhedonia Rating Scale
  • MADRS Montgomery ⁇ sberg Depression Rating Scale
  • “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” refers to derivatives of Compound 1 wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present application include the conventional non- toxic salts of Compound 1 formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present application can be synthesized from Compound 1 which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (Me
  • the term “individual,” “patient, “or “subject,” which are used interchangeably, refers to any animal, including mammals, preferably mice, rats, monkeys, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor, or other clinician.
  • the therapeutically effective amount will vary depending on the compound, the disease, disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.
  • treating refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., arresting further development of the pathology and/or symptomatology) or ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., reversing the pathology and/or symptomatology), such as decreasing the severity of disease.
  • weekly dose or “weekly dosing” refers to a dosing schedule wherein if a first dose is administered on Day 1, then subsequent doses are administered with a gap of about 7 days between consecutive doses. For example, a dose on Day 1 is followed by a dose on about Day 8, Day 15, Day 22, Day 29 and so on.
  • Each weekly dose may be administered as a single dose, split dose, or multiple administrations to reach the intended weekly dose.
  • a weekly dose of 160 mg may administered in any combination, e.g., as a single pill comprising 160 mg, two pills comprising 80 mg each, or four pills comprising 40 mg each etc.
  • the disclosure is directed to a method of treating depression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in amounts and dosing schedules as described herein.
  • a method for treating depression in a subject in need thereof comprising administering to the subject a weekly dose of 2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)-N- ⁇ (1S)-1-[4- (trifluoromethoxy)phenyl]ethyl ⁇ acetamide (Compound 1), or a pharmaceutically acceptable salt thereof.
  • the depression is major depressive disorder (MDD). In some embodiments, the depression is treatment resistant depression. Attorney Reference No.: 15496.0035-00304 [0030] In some embodiments, the depression is disruptive mood dysregulation disorder, major depressive disorder, persistent depressive disorder dysthymia, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, moderate depression, severe depression, and/or specifiers for depressive disorders. In some embodiments, the method further treats cognitive impairment associated with the depression. In some embodiments, the method further treats cognitive impairment associated with the depression, as measured by the Brief Assessment of Cognition.
  • the method further treats cognitive impairment involving decline in speed of processing, executive function, attention, or verbal learning and memory associated with the depression. In some embodiments, the method further treats cognitive impairment associated with the depression involving decline in speed of processing. In some embodiments, the method further treats cognitive impairment associated with the depression involving decline in executive function. In some embodiments, the method further treats cognitive impairment associated with the depression involving decline in attention. In some embodiments, the method further treats cognitive impairment associated with the depression involving decline in verbal learning. In some embodiments, the method further treats cognitive impairment associated with the depression involving decline in memory.
  • a method for treating anhedonia in major depressive disorder (MDD) in a subject in need thereof comprising administering to the subject a weekly dose of 2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)-N- ⁇ (1S)-1-[4- (trifluoromethoxy)phenyl]ethyl ⁇ acetamide (Compound 1), or a pharmaceutically acceptable salt thereof.
  • the subject has already received at least one prior therapy for depression.
  • the subject has failed to respond to at least one prior therapy for depression.
  • the subject is a responder to at least one prior therapy for depression.
  • Compound 1 may be administered concomitantly with (i.e., adjunct to) the prior therapy.
  • the prior therapy for depression comprises administration of: ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; (R)-ketamine or a salt thereof; norketamine or a salt thereof; 2 diastereomeric hydroxyketamine or a salt thereof; 6 diastereomeric hydroxynorketamine (HNK) or a salt thereof; (2S,6S)-HNK or a salt thereof; (2R,6R)-HNK or a salt thereof; dehydronorketamine or a salt thereof; methoxetamine or a salt thereof; or combinations thereof.
  • the prior therapy for depression comprises an administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; methoxetamine or a salt thereof; or combinations thereof.
  • the prior therapy for depression comprises an administration of ketamine or a salt thereof; (S)-ketamine (esketamine) or a salt thereof; or Attorney Reference No.: 15496.0035-00304 combinations thereof.
  • the prior therapy for depression comprises an administration of: benzodiazepine (chlordiazepoxide or a salt thereof, diazepam or a salt thereof, potassium clorazepate or a salt thereof, lorazepam or a salt thereof, clonazepam or a salt thereof, alprazolam or a salt thereof, etc.); L-type calcium channel inhibitor (pregabalin or a salt thereof, etc.); tricyclic or tetracyclic antidepressant (imipramine or a salt thereof, amitriptyline or a salt thereof, desipramine or a salt thereof, clomipramine or a salt thereof, etc.); selective serotonin reuptake inhibitor (fluvoxamine or a salt thereof, fluoxetine or a salt thereof, citalopram or a salt thereof, sertraline or a salt thereof, paroxetine or a salt thereof, escitalopram or a salt thereof, etc.); serotonin re
  • Compound 1 is administered in combination with behavior modification therapy (e.g., behavior modification described by M. G. Craske et al., Depression and Anxiety 33:927–938 (2016)).
  • the weekly dosing comprises administering to the subject a first dose of Compound 1, or a pharmaceutically acceptable salt thereof, followed by one or more additional weekly doses, wherein each additional weekly dose is less than or equal to the first dose.
  • “One or more additional weekly doses” refers to at least one additional weekly dose after the first dose of Compound 1.
  • one additional weekly dose may be administered after the first dose on Day 1.
  • one to seven additional weekly doses may be administered Attorney Reference No.: 15496.0035-00304 after the first dose on Day 1.
  • one to ten additional weekly doses may be administered after the first dose on Day 1.
  • one to twenty additional weekly doses may be administered after the first dose on Day 1.
  • additional weekly doses may be continued for longer than twenty additional weekly doses.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered as an oral dose.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered as an oral weekly dose.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered as an oral tablet.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered as an oral suspension.
  • the first dose is between about 20 mg to about 180 mg per day. In some embodiments of the weekly dosing, the first dose is between about 40 mg to about 160 mg per day. In some embodiments of the weekly dosing, the first dose is between about 80 mg to about 160 mg per day. In some embodiments of the weekly dosing, the first dose is about 160 mg per day. In some embodiments of the weekly dosing, the first dose is about 120 mg per day. In some embodiments of the weekly dosing, the first dose is about 100 mg per day. In some embodiments of the weekly dosing, the first dose is about 80 mg per day.
  • the first dose is about 60 mg per day. In some embodiments of the weekly dosing, the first dose is about 40 mg per day. In some embodiments of the weekly dosing, the first dose is about 20 mg per day. [0038] In some embodiments of the weekly dosing, after administration of the first dose, each additional weekly dose is between about 20 mg to about 100 mg per day. In some embodiments of the weekly dosing, after administration of the first dose, each additional weekly dose is between about 40 mg to about 80 mg per day. In some embodiments of the weekly dosing, after administration of the first dose, each additional weekly dose is between about 60 mg to about 80 mg per day.
  • each additional weekly dose is about 160 mg per day. In some embodiments of the weekly dosing, after administration of the first dose, each additional weekly dose is about 120 mg per day. In some embodiments of the weekly dosing, after administration of the first dose, each additional weekly dose is about 100 mg per day. In some embodiments of the weekly dosing, after administration of the first dose, each additional weekly dose is about 80 mg per day. In some embodiments of the weekly dosing, after administration of the first dose, each additional weekly dose is about 60 mg per day. In some embodiments of the weekly dosing, after administration of the first dose, each additional weekly dose is about 40 mg per day.
  • each additional weekly dose is about 20 mg per day.
  • the subject is in a fed state at the time of dosing. In some embodiments of the methods described herein, the subject is in a fasted state at the time of dosing.
  • compositions for use in treating depression comprising 2- (4-oxo-1,2,3-benzotriazin-3(4H)-yl)-N- ⁇ (1S)-1-[4-(trifluoromethoxy)phenyl]ethyl ⁇ acetamide (Compound 1), or a pharmaceutically acceptable salt thereof, administered in a first dose and one or more additional weekly doses, wherein each additional weekly dose is less than or equal to the first dose.
  • compositions for use in the prevention of relapse of depression comprising 2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)-N- ⁇ (1S)-1-[4- (trifluoromethoxy)phenyl]ethyl ⁇ acetamide (Compound 1), or a pharmaceutically acceptable salt thereof, administered in a first dose and one or more additional weekly doses, wherein each additional weekly dose is less than or equal to the first dose.
  • a first dose comprising 2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)-N- ⁇ (1S)-1-[4-(trifluoromethoxy)phenyl]ethyl ⁇ acetamide (Compound 1), or a pharmaceutically acceptable salt thereof
  • additional weekly doses comprising 2-(4-oxo-1,2,3-benzotriazin-3(4H)- yl)-N- ⁇ (1S)-1-[4-(trifluoromethoxy)phenyl]ethyl ⁇ acetamide (Compound 1), or a pharmaceutically acceptable salt thereof, for preventing relapse of depression, wherein each additional weekly dose is less than or equal to the first dose.
  • the first dose and the additional weekly doses are the same. In some embodiments of the weekly dosing described herein, the first dose is higher than the additional weekly doses (or, in other words, each additional weekly dose is less than the first dose).
  • the dosing methods described herein are suitable for treatment of schizophrenia, autism spectrum disorder, sleep disorders, depression, bipolar disorder, cognitive impairment, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive compulsive disorder, anxiety disorders, pain, and fibromyalgia. In some embodiments, the dosing methods described herein are suitable for treatment of anhedonia.
  • the dosing methods described herein are suitable for treatment of anhedonia in MDD, anhedonia in schizophrenia, cognitive impairment associated with schizophrenia (CIAS), Parkinson's disease (disease progression), Parkinson's disease (symptoms), substance use disorder (SUD) associated with use of opiates, or alcohol and alcohol induced hyperalgesia, autism (repetitive behavior, social interaction), bipolar disorder, Tourette syndrome, insomnia, anorexia nervosa, anxiety (e.g., generalized anxiety disorder (GAD)), bulimia nervosa, attention deficit hyperactive disorder (ADHD), post traumatic stress disorder (PTSD), SUD – psychostimulants, SUD – nicotine, type II diabetes, and obesity.
  • CUAC generalized anxiety disorder
  • ADHD attention deficit hyperactive disorder
  • PTSD post traumatic stress disorder
  • SUD – psychostimulants SUD – nicotine, type II diabetes, and obesity.
  • the dosing methods described herein are suitable for treatment of schizophrenia, autism spectrum disorder, depression, bipolar disorder, attention deficit hyperactivity disorder, and drug addiction. In some embodiments, the dosing methods described herein are suitable for treatment of depression, treatment resistant depression, or depression with inadequate response to a prior treatment. In some embodiments, the dosing methods described herein are suitable for treatment of Major Depressive Disorder (MDD). In some embodiments, the dosing methods described herein are suitable for treatment of anhedonia in MDD. In some embodiments, the dosing methods described herein are suitable for treatment of anhedonia in schizophrenia.
  • MDD Major Depressive Disorder
  • the dosing methods described herein are suitable for treatment of anhedonia in MDD. In some embodiments, the dosing methods described herein are suitable for treatment of anhedonia in schizophrenia.
  • the dosing methods described herein are suitable for treatment of a condition mediated by G-Protein Coupled Receptor 139 (GPR139) agonism (e.g., by use of Compound 1 which is a GPR139 agonist).
  • GPR139 G-Protein Coupled Receptor 139
  • the methods described herein may be used for the treatment of anhedonia associated with depression (including and not limited to major depressive disorder (MDD), anhedonia associated with post-partum (peripartum) depression, anhedonia associated with persistent depressive disorder where depression has lasted for two years or longer, anhedonia associated with dysthymia (low grade persistent depression), anhedonia associated with chronic major depression, anhedonia associated with manic depression, anhedonia associated with seasonal affective disorder (SAD), anhedonia associated with psychotic depression, anhedonia associated with premenstrual dysphoric depression (PMDD), anhedonia associated with situational depression, anhedonia associated with atypical depression, anhedonia associated with treatment resistant depression, or anhedonia associated with depression with inadequate response to a prior treatment).
  • MDD major depressive disorder
  • peripartum post-partum
  • persistent depressive disorder where depression has lasted for two years or longer
  • dysthymia low grade persistent depression
  • the methods described herein may be used for the treatment of depression (including and not limited to major depressive disorder (MDD), post-partum (peripartum) depression, persistent depressive disorder where depression has lasted for two years or longer, dysthymia (low grade persistent depression), chronic major depression, manic depression, seasonal affective disorder (SAD), psychotic depression, prementstrual dysphoric depression (PMDD), situational depression, atypical depression, treatment resistant depression, or depression with inadequate response to a prior treatment).
  • the methods described herein may be used for the treatment of cognitive impairment associated with schizophrenia (CIAS), or other symptoms of schizophrenia including positive or negative symptoms of schizophrenia.
  • the methods described herein may be used for the treatment of Parkinson's disease (e.g., delay disease progression), or other symptoms of Parkinson's disease.
  • the methods described herein may be used for the treatment of substance use disorder (SUD) e.g., SUD associated with the use of opiates (i.e., opioid use disorder (OUD), or SUD related to alcohol and alcohol induced hyperalgesia.
  • SUD substance use disorder
  • the methods described herein may be used for the Attorney Reference No.: 15496.0035-00304 treatment of autism (e.g., repetitive behavior, or social interaction deficits).
  • the methods described herein may be used for the treatment of bipolar disorder.
  • the methods described herein may be used for the treatment of Tourette syndrome. In some embodiments, the methods described herein may be used for the treatment of insomnia. In some embodiments, the methods described herein may be used for the treatment of anorexia nervosa. In some embodiments, the methods described herein may be used for the treatment of anxiety (including and not limited to generalized anxiety disorder (GAD)). In some embodiments, the methods described herein may be used for the treatment of bulimia nervosa. In some embodiments, the methods described herein may be used for the treatment of attention deficit hyperactivity disorder (ADHD). In some embodiments, the methods described herein may be used for the treatment of post traumatic stress disorder (PTSD).
  • PTSD post traumatic stress disorder
  • the methods described herein may be used for the treatment of SUD associated with the use of psychostimulants or nicotine. [0051] In some embodiments, the methods described herein may be used for the treatment of type II diabetes. In some embodiments, the methods described herein may be used for the treatment of obesity. [0052] In some embodiments, the methods described herein are useful for the treatment of anhedonia in schizophrenia, or anhedonia in MDD. In some embodiments, the anhedonia associated with any condition described herein is physical anhedonia. In some embodiments, the anhedonia associated with any condition described herein is social anhedonia. In some embodiments, the anhedonia associated with any condition described herein is anticipatory anhedonia.
  • the anhedonia associated with any condition described herein is consummatory anhedonia.
  • any condition described herein is associated with suicidality or suicide ideation.
  • any method described herein may provide improvements in a patient’s anhedonia as measured using the Dimensional Anhedonia Rating Scale (DARS); the Montgomery– ⁇ sberg Depression Rating Scale (MADRS); the Snaith–Hamilton Pleasure Scale (SHAPS); the Temporal Experience of Pleasure scale (TEPS); or any combination thereof.
  • DARS Dimensional Anhedonia Rating Scale
  • MADRS Montgomery– ⁇ sberg Depression Rating Scale
  • SHAPS Snaith–Hamilton Pleasure Scale
  • TEPS Temporal Experience of Pleasure scale
  • Compound 1, or a pharmaceutically acceptable salt thereof may be administered as an oral suspension or as a solid dosage form.
  • the solid dosage form may be an immediate release form or an extended release form.
  • the solid dosage form may be in the form of compressed tablets or granules, or the solid dosage form may be powder-filled capsules.
  • Tablets may comprise pharmaceutically acceptable binders, disintegrants, diluents, and lubricants.
  • the tablets may be coated with a film comprising polymers and plasticizers.
  • binders include but are not limited to, hydroxypropyl methylcellulose (also referred to as hypromellose), polyvinylpyrrolidone, natural gums Attorney Reference No.: 15496.0035-00304 (e.g., acacia gum), microcrystalline cellulose, methylcellulose, ethylcellulose, sucrose, starch, and gelatin.
  • diluents include but are not limited to, lactose, lactose monohydrate, spray-dried monohydrate lactose, lactose-316 FAST FLO®, mannitol, isomalt, sucrose, dextrose, sorbitol, microcrystalline cellulose, silicified microcrystalline cellulose, acidified cellulose, starch 1500, prosolve MCC, colloidal silica, dicalcium phosphate dihydrate, and calcium carbonate.
  • disintegrants include but are not limited to, croscarmellose sodium, crospovidone, starch (e.g., partially pregeletanized maize starch), cellulose, low substituted hydroxypropyl cellulose, alginic acid, sodium starch glycolate, and acid-carbonate effervescent systems.
  • lubricants include but are not limited to magnesium stearate, calcium stearate, stearic acid (stearin), talc, starch, fumed silica, hydrogenated oil, polyethylene glycol, sodium stearyl fumarate, and glyceryl behenate.
  • a kit comprising weekly doses of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the kit comprises a first dose of Compound 1, or a pharmaceutically acceptable salt thereof, and additional doses of Compound 1, or a pharmaceutically acceptable salt thereof.
  • FIG.1A shows cFos positive cells 1, 2 or 4 hours after treatment. cFOS staining was done according to established procedures.
  • FIG.1B shows the absence of tachyphylaxis of Compound 1-dependent cFOS induction in the mouse medial habenula (MHb) immunohistochemistry (IHC) after 10-day sub chronic dosing of Compound 1.
  • FIG.1C shows representative images of cFOS immunoreactivity in the medial habenula (MHb) immunohistochemistry (IHC) after Compound 1 dosing.
  • Compound 1 increased cFOS expression in the habenula in wild type mice, but not in GPR139 knock out mice. No desensitization of cFOS in the habenula was observed.
  • Data are presented as means, and error bars represent the standard error of the mean (SEM).
  • FIG.2A shows the dosing schedule for Compound 1 or comparator antidepressant fluoxetine (FLX) in the SDT, SCT, and FST tests.
  • FIG.2B shows that chronic 21 day dosing of Compound 1 reduces unpredictable chronic mild stress (uCMS)-induced anhedonia-like behavior in rats in the sweet drive test (SDT).
  • FIG.2C shows that chronic 21 day dosing of Compound 1 reduces unpredictable chronic mild stress (uCMS)-induced anhedonia-like behavior in rats in the sucrose consumption test (SCT).
  • FIG.2D shows that chronic 21 day dosing of Compound 1 reduces unpredictable chronic mild stress (uCMS)-induced anhedonia-like behavior in rats in the forced swimming test (FST).
  • NAc nucleus accumbens
  • Example 4 A study to evaluate once-weekly oral Compound 1 in the treatment of anhedonia in major depressive disorder (MDD) in humans [0061] This study will evaluate efficacy of Compound 1, used as adjunctive treatment to oral antidepressant medication(s), compared with placebo on improving symptoms of anhedonia in subjects with major depressive disorder (MDD).
  • MDD major depressive disorder
  • Study Design The study will consist of a screening period of up to 28 days (Day -28 to -1), an 8-week treatment period (Day 1 to 57), and an 8-week safety follow-up period (4 and 8 weeks [Day 78 and 106] after last dose of study treatment).
  • Day 1 refers to the first day of dosing
  • Day -1 refers to the day before start of dosing, and so on.
  • Approximately 88 subjects are planned to be enrolled in the study.
  • Eligible subjects include patients with MDD whose most recent major depressive episode has been treated with a stable dose of antidepressant medication(s), defined as ⁇ 50% change in dose for at least 6 weeks prior to randomization, at or above the therapeutic dose based on the Massachusetts General Hospital - Attorney Reference No.: 15496.0035-00304 Antidepressant Treatment Response Questionnaire (MGH ATRQ) in the current episode of depression and who continue to have anhedonia (Snaith Hamilton Pleasure Scale SHAPS ⁇ 30). Subjects will be randomized in a 1:1 ratio in a double-blinded fashion to receive either adjunctive treatment with Compound 1 or placebo, administered on a once-weekly basis, for a period of 8 weeks.
  • MGH ATRQ Antidepressant Treatment Response Questionnaire
  • HAM-D17 Hamilton Depression Rating Scale-17 Item
  • HAM-D17 score at baseline: remission (HAM-D17 ⁇ 7), mild illness (HAM-D17 from 8 to 18), and moderate to severe illness (HAM-D17 ⁇ 19).
  • Adherence to concomitant antidepressant medication and study treatment will be assessed with a medication adherence application throughout the study.
  • Study population Subjects 18 to 65 years of age (inclusive), with MDD who are taking antidepressant medication(s) but continue to have clinically significant anhedonia.
  • Duration of study treatment and study participation The expected duration of treatment for each subject is approximately 8 weeks.
  • Total study participation is approximately 20 weeks, which includes a 4-week screening period and an 8-week safety follow-up period.
  • Compound 1 will be supplied as 40 mg tablets for oral administration. Subjects will be administered a loading dose of 160 mg on Day 1, followed by a once weekly dose of 80 mg in Weeks 2 to 8. Endpoints [0067] Primary: Change in anhedonia severity, as measured by change in Dimensional Anhedonia Rating Scale (DARS), from baseline to Day 57. [0068] Secondary: Change in total Montgomery ⁇ sberg Depression Rating Scale (MADRS) score from baseline to Day 57 in subjects with moderate or higher severity depression. Change in Clinical Global Impression - Severity (CGI-S) score from baseline to Day 57.
  • DARS Dimensional Anhedonia Rating Scale
  • MADRS Montgomery ⁇ sberg Depression Rating Scale
  • CGI-S Clinical Global Impression - Severity
  • CGI-I Clinical Global Impression - Improvement
  • Other Change in Temporal Experience of Pleasure Scale (TEPS) total, anticipatory and consummatory scores from baseline to Day 57.
  • TEPS Temporal Experience of Pleasure Scale
  • PKI-S Patient Global Impression-Severity
  • PHQ-9 Patient Health Questionnaire
  • PRT Probabilistic Reward Task
  • Safety endpoints include: treatment-emergent adverse events (TEAEs), clinical laboratory tests (hematology, clinical chemistry, and urinalysis), vital sign measurements (including orthostatic blood pressure and pulse rate), 12-lead electrocardiogram, and Columbia-Suicide Severity Rating Scale (C SSRS).
  • TEAEs treatment-emergent adverse events
  • clinical laboratory tests hematology, clinical chemistry, and urinalysis
  • vital sign measurements including orthostatic blood pressure and pulse rate
  • 12-lead electrocardiogram including orthostatic blood pressure and pulse rate
  • C SSRS Columbia-Suicide Severity Rating Scale
  • MINI Mini International Neuropsychiatric Interview
  • Subject is currently on stable pharmacological treatment for depression, defined as ⁇ 50% change in dose during the 6 weeks prior to randomization to ⁇ 1 of the oral antidepressants medications listed in the MGH ATRQ (with the exception of antidepressant medications excluded in Table 1) and as confirmed by medical and pharmacy records.
  • Subjects receiving psychotherapy including cognitive behavioral therapy [CBT]) or behavioral activation (BA) can continue receiving psychotherapy; however, CBT or BA must have been ongoing for the last 3 months prior to the start of the screening. No new therapy of any kind, including transcranial magnetic stimulation (TMS) or electroconvulsive therapy (ECT), is allowed to initiate during this study.
  • CBT cognitive behavioral therapy
  • BA behavioral activation
  • TMS transcranial magnetic stimulation
  • ECT electroconvulsive therapy
  • the subject is judged by the investigator to be in good health or have stable medical conditions, based on clinical evaluations, including laboratory safety tests (Screening only), medical history, physical examination, 12 lead ECG, and vital sign measurements performed at the Screening Visit and Baseline (Day 1).
  • H A body mass index (BMI) of 17 to 35 kg/m2, inclusive (BMI is defined as the subject's weight in kilograms divided by the square of the subject's height in meters).
  • BMI body mass index
  • I. Negative serum ⁇ -human chorionic gonadotropin ( ⁇ -hCG) pregnancy test at screening and urine pregnancy test at Day 1, for females of childbearing potential.
  • ⁇ -hCG Negative serum ⁇ -human chorionic gonadotropin
  • Female subjects of childbearing potential must agree to use an acceptable method of contraception listed below consistently from Screening until 55 days after the last dose of study treatment. Women are considered to not be of childbearing potential if they are either: i. Postmenopausal, defined as no menses for 12 months without an alternative medical cause and confirmed by elevated follicle-stimulating hormone (FSH) consistent with a postmenopausal range, OR ii. Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. Acceptable methods of contraception are required for women of childbearing potential and include the following: iii. Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS). iv.
  • IUD Intrauterine device
  • IUS intrauterine hormone-releasing system
  • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (which may be oral, intravaginal, or transdermal) beginning at least 3 months prior to screening and must be used in combination with a barrier method of contraception (preferably male condom).
  • a barrier method of contraception preferably male condom.
  • Use of combined hormonal contraception alone is not considered an acceptable method as Compound 1 may decrease the efficacy of hormonal contraceptives due to a potential drug interaction.
  • v. Progestogen-only hormonal contraception associated with inhibition of ovulation (which may be oral, injected, or implanted) beginning at least 3 months prior to screening and must be used in combination with a barrier method of contraception (preferably male condom).
  • Subjects will be excluded from the study if they meet any of the following criteria: a. Pregnant or breastfeeding. b. Other than MDD (primary focus of treatment), having a current psychiatric disorder, such as personality disorder, schizophrenia, schizoaffective disorder, other psychotic disorder, bipolar disorder, eating disorder, dementia, fibromyalgia, intellectual disability, or mental disorder due to a general medical condition, as defined by DSM- 5, or has been treated with electroconvulsive therapy (ECT) within 6 months prior to Screening.
  • ECT electroconvulsive therapy
  • Comorbid anxiety disorders are not exclusionary.
  • c. Have a positive urine drug screen at Screening or Day 1 for disallowed substances, including, barbiturates, phencyclidine, cocaine, cannabinoids, amphetamines, or a history of illicit drug or alcohol abuse within 1 year prior to Screening judged by the investigator to be excessive or compulsive, or currently using drugs of abuse or any prescribed or over the-counter medication in a manner that the investigator considers indicative of abuse or dependence.
  • Subjects testing positive for marijuana at screening may be eligible for participation in the study provided that the investigator's clinical assessment indicates that the subject is not a regular user of marijuana, and after counseling they agree to not use marijuana for the duration of the study.
  • a local urine dipstick drug screen must be performed at the Day 1 visit and verified to be negative prior to conducting any other study procedures at this visit.
  • e. Have a significant risk of suicidal or violent behavior. Subjects with any suicidal ideation of type 4 (active suicidal ideation with some intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and intent) in the past 12 months before screening based on the C-SSRS or according to the investigator's clinical judgment should be excluded.
  • f. A history of seizure disorder, stroke, Alzheimer’s disease, Parkinson disease, multiple sclerosis, head injury associated with loss of consciousness for more than 15 minutes, or other neurodegenerative disorder.
  • hepatitis B surface antigen HBV-Ab
  • hepatitis C virus antibody HCV-Ab
  • PCR polymerase chain reaction
  • HAV-Ab human immunodeficiency virus antibody
  • HIV-Ab antigen or a history of human immunodeficiency virus infection or have a known or suspected diagnosis of Acquired Immune Deficiency Syndrome (AIDS).
  • HIV-Ab human immunodeficiency virus antibody
  • Other, clinically significant, laboratory or vital sign abnormalities that are not attributed to a stable, well controlled medical condition.
  • Attorney Reference No.: 15496.0035-00304 j. A clinically significant ECG abnormality confirmed by central rater at screening or prior to randomization confirmed by the site investigator.
  • k An unstable medical condition or chronic disease (including history of neurological [including cognitive impairment, myasthenia gravis], hepatic, renal, cardiovascular, gastrointestinal, pulmonary, autoimmune, or endocrine disease that may affect study participation or results) within 3 months before Day 1, or malignancy within 6 months before Day 1, or any history of gallstones, endoscopic retrograde cholangio pancreatography or cholestasis. l.
  • QT interval corrected for heart rate using Fridericia's correction >450 msec (males) or >470 msec (females) either at screening (per central rater) or Day 1 (per investigator), confirmed with 1 repeat test; or the subject has long QT syndrome or is under the treatment with Class 1A (e.g., quinidine, procainamide) or Class 3 (e.g., amiodarone, sotalol) antiarrhythmic drugs.
  • Class 1A e.g., quinidine, procainamide
  • Class 3 e.g., amiodarone, sotalol
  • m Evidence of chronic renal or liver disease based on any of these screening laboratory test abnormalities: i. Serum creatinine >1.5 ⁇ ULN. ii. AST >2 ⁇ ULN. iii. ALT >2 ⁇ ULN. iv.
  • p. Have ingested grapefruit juice, grapefruit products, Seville oranges, or Seville orange products within 7 days before Day 1.
  • q. Used any active investigational drug in the context of a clinical study within 30 days or 5 half-lives (whichever is longer) before baseline or plans to use such an investigational drug (other than the study treatment) during the study.
  • Table 2 provides a summary of plasma PK parameter estimates of Compound 1 following first dose administration of Compound 1 at 40, 80, 120, or 160 mg to healthy subjects (Day 1)
  • Table 2 Compound 1 t max (h) C max (ng/mL) AUC 96 AUC t 4 8 1 1 %CV: percent coefficient of variation;
  • AUC area under the plasma concentration-time curve;
  • AUC96 area under the plasma concentration-time curve from time 0 to 96 hours;
  • AUCt area under the plasma concentration-time curve from time 0 to time t, the time of last measurable concentration;
  • AUC ⁇ area under the plasma concentration-time curve during the dosing interval;
  • C max maximum observed plasma concentration;
  • PK pharmacokinetic; tmax: time of first occurrence of Cmax.
  • Table 3 provides a summary of plasma PK parameter estimates of Compound 1 following multiple weekly oral administrations of Compound 1 to healthy subjects (Day 22). A first dose of Compound 1 was given on Day 1 followed by weekly doses of Compound 1 on Days 8, 15, and 22. Day 22 dose-normalized parameters used the Day 22 dose. Table 3 C 1 [ 1 2 . . . . . .6 V 7 Attorney Reference No.: 15496.0035-00304 80/40 [6] Mea 2.000 1251. 889.3 621.3 149396 301.
  • AUC area under the plasma concentration-time curve
  • AUC ⁇ area under the plasma concentration-time curve during the dosing interval
  • Cav,ss average plasma concentration at steady state
  • CL/F apparent clearance after extravascular administration
  • Cmax maximum observed plasma concentration
  • C trough observed plasma concentration at the end of a dosing interval
  • PK pharmacokinetic
  • R ac (AUC) accumulation ratio (based on AUC ⁇ ); R ac (C max ): accumulation ratio (based on Cmax); t1/2z: terminal disposition phase half-life; tmax: time of first occurrence of C max ; V z /F: apparent volume of distribution during the terminal disposition phase after extravascular administration.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes de traitement de la dépression avec le composé 1.
PCT/US2023/079063 2022-11-11 2023-11-08 Zélatriazine pour le traitement de la dépression WO2024102802A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202263383428P 2022-11-11 2022-11-11
US63/383,428 2022-11-11
US202363515014P 2023-07-21 2023-07-21
US63/515,014 2023-07-21

Publications (1)

Publication Number Publication Date
WO2024102802A1 true WO2024102802A1 (fr) 2024-05-16

Family

ID=89168312

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/079063 WO2024102802A1 (fr) 2022-11-11 2023-11-08 Zélatriazine pour le traitement de la dépression

Country Status (1)

Country Link
WO (1) WO2024102802A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016081736A1 (fr) * 2014-11-20 2016-05-26 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazines utilisées en tant que modulateurs de gpr139
WO2022058791A1 (fr) * 2020-09-21 2022-03-24 Takeda Pharmaceutical Company Limited Traitement de la schizophrénie

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016081736A1 (fr) * 2014-11-20 2016-05-26 Takeda Pharmaceutical Company Limited 4-oxo-3,4-dihydro-1,2,3-benzotriazines utilisées en tant que modulateurs de gpr139
WO2022058791A1 (fr) * 2020-09-21 2022-03-24 Takeda Pharmaceutical Company Limited Traitement de la schizophrénie

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY, pages: 1418
BERGE ET AL., J. PHARM. SCI., vol. 66, no. 1, 1977, pages 1 - 19
BOULOS L. J. ET AL., BIOL PSYCHIATRY, vol. 81, no. 4, 2017, pages 296 - 305
HASLER G. ET AL., NEUROPSYCHOPHARMACOLOGY, vol. 29, no. 10, 2004, pages 1765 - 81
M. G. CRASKE ET AL., DEPRESSION AND ANXIETY, vol. 33, 2016, pages 927 - 938
SCHIFFER HANS ET AL: "S180. THE SELECTIVE GPR139 AGONIST TAK-041 REVERSES ANHEDONIA AND SOCIAL INTERACTION DEFICITS IN RODENT MODELS RELATED TO NEGATIVE SYMPTOMS IN SCHIZOPHRENIA", SCHIZOPHRENIA BULLETIN, vol. 46, no. Supplement_1, 18 May 2020 (2020-05-18), pages S106 - S107, XP093124899, ISSN: 0586-7614, Retrieved from the Internet <URL:http://academic.oup.com/schizophreniabulletin/article-pdf/46/Supplement_1/S106/33288881/sbaa031.246.pdf> [retrieved on 20240129], DOI: 10.1093/schbul/sbaa031.246 *
SHELTON R.C.TOMARKEN A.J., PSYCHIATR SERV, vol. 52, no. 11, 2001, pages 1469 - 78
STAHL ET AL.: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY

Similar Documents

Publication Publication Date Title
TWI389689B (zh) 氟利本西林（ｆｌｉｂａｎｓｅｒｉｎ）於治療停經前性慾疾病之用途
US20220152057A1 (en) Methods and compositions for treating various disorders
US20060199805A1 (en) Pharmaceutical compositions for the treatment and/or prevention of anxiety disorders
TWI428130B (zh) 治療急性躁狂症之藥學組成物及方法
MXPA02001568A (es) Ciclobenzaprina para tratar trastornos de ansiedad generalizada y composiciones de la misma.
WO2007093624A2 (fr) Nouvelles compositions pharmaceutiques pour le traitement du trouble d&#39;hyperactivité avec déficit de l&#39;attention
CN115154470A (zh) 使用食欲素-2受体拮抗剂治疗抑郁症的方法
TW202313003A (zh) 用於治療憂鬱之組成物及方法
KR20150120479A (ko) 니트라이트의 약제학적 제형 및 이의 용도
CN107949379A (zh) L‑4‑氯代犬尿氨酸的治疗用途
WO2022086858A1 (fr) Méthodes de traitement d&#39;un trouble de stress post-traumatique et états pathologiques associés
KR20240148425A (ko) Cns-관련 장애의 치료를 위한 신경활성 스테로이드
JPH0667842B2 (ja) 基本的うつ病を軽減するためのうつ病治療剤
JP7309824B2 (ja) 不安障害を治療するための（２Ｓ）－１－［４－（３，４－ジクロロフェニル）ピペリジン－１－イル］－３－［２－（５－メチル－１，３，４－オキサジアゾール－２－イル）ベンゾ［ｂ］フラン－４－イルオキシ］プロパン－２－オールまたはその代謝産物
EP2694065B1 (fr) Composition pour le traitement de la baisse du désir sexuel
WO2024102802A1 (fr) Zélatriazine pour le traitement de la dépression
JP7539898B2 (ja) オピオイド鎮痛耐性を治療するためのｍＧｌｕＲ５アンタゴニストの使用
WO2023159035A1 (fr) Stéroïdes neuroactifs pour le traitement de troubles liés au snc
WO2024196957A1 (fr) Procédé de traitement des dyskinésies induites par la l-dopa à l&#39;aide de befiradol
IL298748A (en) Use of a combination of colchicine and a CXCR-2 inhibitor for the treatment or prevention of hereditary Mediterranean fever (FMF) and its outbreaks
KR20100022956A (ko) 급성 조증 치료용 카르바모일-시클로헥산

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23821820

Country of ref document: EP

Kind code of ref document: A1