WO2020027344A1 - Ch24h inhibitors for mdd use - Google Patents

Ch24h inhibitors for mdd use Download PDF

Info

Publication number
WO2020027344A1
WO2020027344A1 PCT/JP2019/031284 JP2019031284W WO2020027344A1 WO 2020027344 A1 WO2020027344 A1 WO 2020027344A1 JP 2019031284 W JP2019031284 W JP 2019031284W WO 2020027344 A1 WO2020027344 A1 WO 2020027344A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
benzyl
bipyridin
hydroxypiperidin
Prior art date
Application number
PCT/JP2019/031284
Other languages
French (fr)
Inventor
Emiliangelo Ratti
Mahnaz ASGHARNEJAD
Gabriel BELFORT
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 WO2020027344A1 publication Critical patent/WO2020027344A1/en

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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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

  • the present invention relates to (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R)-l-((l-(4-(4- - methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof for use in treatment of major
  • MDD depressive disorder
  • Depression is the leading cause of ill health and disability worldwide. According to the latest estimates from the WHO, more than 300 million people are now living with depression (approximately 16 million adults in the USA) , an increase of more than 18% between 2005 and 2015. Major
  • MDD Depressive Disorder
  • NIMH National Institute of Mental Health
  • STAR*D Sequenced Treatment Alternatives to Relieve Depression
  • Ketamine is used in the treatment of MDD and is suspected to act principally as an NMDA receptor open channel blocker. Ketamine infusion is a transformative treatment for patients with treatment-resistant depression (TRD) .
  • TRD treatment-resistant depression
  • Several studies have demonstrated the acute robust and rapidly acting anti- depressant effects of low sub-anesthetic doses of ketamine infusion within hours, 3-6.
  • APA American Psychiatric Association
  • APA issued a "Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders.” Because of the rapid anti-depressant effect of ketamine, there has been a paradigm shift in drug development for depression; with the focus shifting to identifying treatments that significantly improve depressive symptoms in hours instead of weeks.
  • aspects of this disclosure relate to a method of treating major depressive disorder (MDD) , which optionally includes treatment resistant depression (TRD) , anxiety disorders including generalized anxiety disorder, panic disorder,
  • MDD major depressive disorder
  • TRD treatment resistant depression
  • anxiety disorders including generalized anxiety disorder, panic disorder,
  • Obsessive Compulsive Disorder OCD
  • social anxiety disorder Post Traumatic Stress Disorder (PTSD)
  • PTSD Post Traumatic Stress Disorder
  • nocturnal enuresis bedwetting
  • eating disorders personality disorders and sleep disorder (insomnia)
  • a composition comprising (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof to the mammal in need thereof.
  • a composition comprising (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1
  • administering the effective amount of the composition comprising ( 4-benzyl-4-hydroxypiperidin-l- yl) (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- ( 4-methyl-lH-pyrazol- 1-yl) pyridin-3-yl).piperidin-4-yl) carbonyl) pyrrolidine-2- carbonitrile or a pharmaceutically acceptable salt thereof results in (i) a reduction in 24 (S) -hydroxycholesterol (24HC) levels and/or (ii) a reduction in NMDA receptor function.
  • the effective amount of the compound in some embodiments, the effective amount of the compound
  • composition comprising ( 4-benzyl-4-hydroxypiperidin-l-yl ) (2, 4 ' - bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( ( 1- ( 4- ( 4-methyl-lH-pyrazol-l-yl ) pyridin-3- yl) piperidin-4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof is administered orally or parenterally (e. g. , topically, rectally, intravenously, etc. ) .
  • the effective amount of the compound in some embodiments, the effective amount of the compound
  • composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2,4'— bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3- yl) piperidin-4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof is administered as a single unit dose.
  • the single unit dose is preferably about 0.01 ⁇ mg/kg to 100 mg/kg, more preferably about 0.05 mg/kg to 100 mg/kg, still more preferably about 0.1 to 10 mg/kg.
  • the effective amount of the compound in some embodiments, the effective amount of the compound
  • composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2, 4 ' - bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3- yl) piperidin-4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof is administered according to a dose regimen.
  • the mammal is a human. In further embodiments, the human is an adolescent or an adult.
  • the composition comprising (4- benzyl-4-hydroxypiperidin—1-yl) (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- ( 4-methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof further comprises a pharmaceutically acceptable carrier.
  • the composition comprising (4- benzyl-4-hydroxypiperidin-l-yl) (2,4' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- ( 4-methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof further comprises an additional active agent.
  • additional active agents include: imipramine, clomipramine, desipramine hydrochloride, noxiptiline, phenelzine, amitriptyline hydrochloride,
  • hydrochloride paroxetine hydrochloride, escitalopram oxalate etc.
  • serotonin-noradrenalin reuptake inhibitor venlafaxine hydrochloride, duloxetine hydrochloride, venlafaxine hydrochloride, milnacipran hydrochoride etc.
  • noradrenalin reuptake inhibitor reboxetine mesylate etc.
  • noradrenalin- dopamine reuptake inhibitor bupropion hydrochloride etc.
  • composition comprising (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, which is for treating major depressive disorder (MDD) .
  • MDD major depressive disorder
  • aspects of this disclosure also relate to (4-benzyl-4- hydroxypiperidin-l-yl ) (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof for use in treatment of major
  • MDD depressive disorder
  • aspects of the disclosure relate to a method of treating major depressive disorder (MDD) , optionally, treatment
  • TRD resistant depression
  • anxiety disorders including generalized anxiety disorder, panic disorder, Obsessive
  • OCD Compulsive Disorder
  • a mammal e.g., human, bovine, horse, dog, cat, monkey, mouse, rat; preferably human
  • administering an effective amount of a composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2,4 ' -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin-
  • (4-benzyl- 4-hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl ) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl ) pyridin-3-yl ) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof can reduce NMDA receptor function by blocking the production of 24 (S) -hydroxycholesterol (24HC or cerebrosterol) , which is the product of CH24H enzymatic activity and a potent (EC50 1.2 mM) and specific positive allosteric modulator of NDMA receptors.
  • CH24H inhibitors disclosed herein are hypothesized to have the same or similar mechanism as ketamine, an NMDA receptor open channel blocker, and, accordingly, confer antidepressant effects, specifically in a mammal suffering from any one of Depression, MDD and TRD, anxiety disorders including generalized anxiety disorder, panic disorder, Obsessive Compulsive Disorder (OCD) , social anxiety disorder, Post Traumatic Stress Disorder (PTSD) , nocturnal enuresis (bedwetting) , eating disorders, personality disorders and sleep disorder (insomnia) . These effects are believed to be dose dependent.
  • administering the effective amount of the composition comprising (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl)methanone or a pharmaceutically acceptable salt thereof or.
  • (2R)-l-((l-(4-(4- methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin- ⁇ - yl ) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof results in (i) a reduction in 24 (S)- hydroxycholesterol (24HC) levels and/or (ii) a reduction in NMDA receptor function.
  • a reduction in 24 (S) -hydroxycholesterol (24HC) levels may be measured by an
  • NMDA receptor function recited in (ii) above, may be measured electrophysiologically ex-vivo after administration. It could likely also be measured in dissociated neuronal cultures.
  • active agent means a substance that has a reactive oxygen species.
  • a biologically active component of a pharmaceutical composition e.g. an agent that has a pharmacological effect on the subject or patient to which it is administered.
  • a pharmaceutical composition e.g. an agent that has a pharmacological effect on the subject or patient to which it is administered.
  • Contemplated herein are (4-benzyl-4-hydroxypiperidin-l-yl) (2 , 4 ' -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin- 4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof and additional active agents for use in combination with (4-benzyl-4-hydroxypiperidin-l-yl) (2,4’- bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1-
  • Suitable additional active agents for use in combination with the CH24H inhibitors include those mentioned above .
  • the compounds of Formula (I) and Formula (II) are CH24H inhibitors .
  • the term "effective amount” means an amount effective to successfully achieve a particular
  • the effective amount is an amount to effective to treat Depression, MDD or,
  • TRD anxiety disorders including generalized anxiety disorder, panic disorder, Obsessive Compulsive Disorder (OCD) , social anxiety disorder, Post Traumatic Stress Disorder (PTSD) , nocturnal enuresis (bedwetting) , eating disorders, personality disorders and sleep disorder (insomnia) .
  • OCD Obsessive Compulsive Disorder
  • PTSD Post Traumatic Stress Disorder
  • nocturnal enuresis bedwetting
  • eating disorders eating disorders
  • personality disorders and sleep disorder insomnia
  • Suitable effective amounts may be determined according to methods well known in the art to determine single unit dosage and/or dose regimens .
  • single unit dose in this context refers to an effective amount provided in a single administration.
  • suitable single unit doses for use in the claimed methods include about 0.01 to 100 mg/kg body weight, preferably 0.05 to 30 mg/kg body weight, more preferably 0.1 to 10 mg/kg body weight for oral administration to an adult patient (body weight 60 kg) .
  • dose regimen in this context refers to an effective amount provided over a fixed number of administrations over a specified duration of time.
  • Non-limiting examples of routes of administration relevant to the claimed methods include oral and parenteral (e.g., topical, rectal, or intravenous) routes.
  • routes of administration relevant to the claimed methods include oral and parenteral (e.g., topical, rectal, or intravenous) routes.
  • the dosage form suited for a particular route of administration include oral preparations such as tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet) , capsules (including soft capsule, microcapsule) , granule, powder, troche, syrup, emulsion, suspension, films (e.g., orally disintegrable films) and the like; and parenteral agents such as injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparations (e.g., dermal
  • these preparations may be a release control preparation (e.g., sustained-release microcapsule) such as an immediate-release preparation or a sustained-release preparation.
  • a release control preparation e.g., sustained-release microcapsule
  • major depressive disorder As used herein, the term "major depressive disorder" or
  • MDD refers to a disorder characterized by the Diagnostic and Statistical Manual of Mental Disorders (DSM) , specifically DSM- 5 incorporated by reference herein in its entirety. MDD requires the occurrence or one or more major depressive episodes, which are characterized by depressed mood and/or anhedonia (diminished loss of interest or pleasure in almost all activities), and optionally one or more of the following symptoms :
  • psychomotor agitation or retardation (a speeding or slowing of muscle movement) ;
  • Major depressive episodes must be at least two weeks long; cause significant distress or severely impact social, occupational or other life areas; not be precipitated by drug use; not meet the criteria for another mental disorder (e.g., schizophrenia or bipolar disorder) ; and not be better explained by bereavement (such as loss experienced after a death) .
  • another mental disorder e.g., schizophrenia or bipolar disorder
  • bereavement such as loss experienced after a death
  • treatment resistant depression refers to MDD that does not respond adequately to appropriate courses of at least two antidepressants.
  • an adequate response is usually defined as at least 50% decreased in the severity of depression symptoms.
  • pharmaceutically acceptable salt represents salts or zwitterionic forms of the compounds of the present technology which are water or oil-soluble or dispersible; which are suitable for treatment of diseases without undue toxicity, irritation, and allergic-response;
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L- ascorbate, aspartate, benzoate, benzenesulfonate (besylate) , bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate,
  • basic groups in the compounds of the present technology can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and
  • salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion.
  • the present technology contemplates sodium, potassium,
  • magnesium, and calcium salts of the compounds of the compounds of the present technology and the like are examples of magnesium, and calcium salts of the compounds of the compounds of the present technology and the like.
  • pharmaceutically acceptable carrier means one or more organic or inorganic carrier substances conventionally used in the formulation of chemical compositions. Suitable pharmaceutically acceptable carriers can be determined by methods well known in the art e.g.
  • excipients such as, lubricants, binders and disintegrants for solid preparations; solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, and soothing agents for liquid preparations; and/or preparation additives such as
  • suitable pharmaceutically acceptable carriers include:
  • lactose sucrose, D-mannitol, D- sorbitol, starch, gelatinated starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthesis aluminum silicate and magnesium alumino metasilicate;
  • magnesium stearate, calcium stearate, talc and colloidal silica magnesium stearate, calcium stearate, talc and colloidal silica
  • gelatinated starch sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D- mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone;
  • a disintegrant lactose, sucrose, starch,
  • carboxymethylcellulose calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low-substituted
  • a solvent water, physiological brine, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil;
  • solubilizing agent polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium
  • sodium chloride sodium chloride, glycerol, D- mannitol, D-sorbitol and glucose;
  • phosphate phosphate, acetate, carbonate, and
  • benzyl alcohol for a soothing agent: benzyl alcohol
  • p-oxybenzoates for a preservative: p-oxybenzoates , chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid;
  • aqueous water-soluble food tar colors e.g., food colors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like
  • water insoluble lake dyes e.g., aluminum salt of the above-mentioned water-soluble food tar color
  • natural dyes e.g., b-carotene, chlorophyll, ferric oxide red
  • saccharin sodium dipotassium glycyrrhizinate, aspartame, and stevia.
  • Example provides data from a rat model of depression, the reduction of submissive behaviour model (RSBM) .
  • (2R) -1- (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin- 4-yl ) carbonyl ) pyrrolidine-2-carbonitrile was tested in the rat RSBM for its potential effects on submissive behavior.
  • Adult male Wistar rats (7-9 weeks) were used for the experiment.
  • Potable water passed through a water filtration system was provided ad libitum in polycarbonate bottles with stainless steel sipper tubes.
  • the testing apparatus was constructed from transparent plastic and consisted of two identical chambers (24 x 17 x 14 cm) connected by a tunnel (6 x 6 x 52 cm) .
  • a total of 220 male Wistar rats (110 pairs) were selected.
  • the animals were randomized on the basis of body weight and matched for body weight, pairwise.
  • the pairs were habituated to the testing apparatus and milk for a period of 5 min per day for 5 days (first week) .
  • the animals were housed such that these pairs met only during the trial time.
  • the dominant animal's score is greater by 25% than the submissive animal's score. 40 pairs, which met the above criteria, were selected and randomized based on the dominance levels (the difference in the average drinking score per week between the dominant and the submissive partners) . The experiment was carried out by an experimenter who was blinded to treatment. Dosing was commenced from the day after the animals were randomized for the study (day 14) . Both the dominant and submissive animals of the control group were orally treated with vehicle (0.5%

Landscapes

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

Abstract

The present disclosure relates to methods of treating certain depressive disorders by administration of (4-benzyl-4-hydroxypiperidin-1-yl)(2,4'-bipyridin-3-yl)methanone or a pharmaceutically acceptable salt thereof or (2R)-1-((1-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)piperidin-4-yl)carbonyl)pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof.

Description

DESCRIPTION
Title of the Invnetion: CH24H Inhibitors for MDD use
Technical Field
[0001]
The present invention relates to (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R)-l-((l-(4-(4- - methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof for use in treatment of major
depressive disorder (MDD) .
[0002]
(Background of the Invention)
Depression is the leading cause of ill health and disability worldwide. According to the latest estimates from the WHO, more than 300 million people are now living with depression (approximately 16 million adults in the USA) , an increase of more than 18% between 2005 and 2015. Major
Depressive Disorder (MDD) is characterized by depressed mood, loss of interest or pleasure in daily activities and impaired functioning. It is well known that despite the availability of 30 to 40 antidepressants, approximately 50% of individuals diagnosed with MDD do not respond adequately to first-line treatment with available antidepressants and up to 1/3 of patients do not achieve remission after multiple trials of antidepressant treatment. In the National Institute of Mental Health (NIMH) -sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only 27.5% of patients with depression responded with up to 14 weeks of treatment.
Furthermore, up to one-third of the patients did not achieve remission by the end of the study. In those who respond, the full therapeutic effect usually takes 8-10 weeks, a time lag that is particularly concerning in patients with severe symptoms, including risk of suicide. As per a report issued by WHO in May of 2017, suicide is the second leading cause of death among the 15 to 29 years old individuals.
[0003]
Ketamine is used in the treatment of MDD and is suspected to act principally as an NMDA receptor open channel blocker. Ketamine infusion is a transformative treatment for patients with treatment-resistant depression (TRD) . Several studies have demonstrated the acute robust and rapidly acting anti- depressant effects of low sub-anesthetic doses of ketamine infusion within hours, 3-6. Recently, the American Psychiatric Association (APA) issued a "Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders." Because of the rapid anti-depressant effect of ketamine, there has been a paradigm shift in drug development for depression; with the focus shifting to identifying treatments that significantly improve depressive symptoms in hours instead of weeks.
Compounds like ketamine, with fast onset of action, can be used in the treatment of TRD and have the potential to lower the incidence of suicide.
Summary of the Invention
[0004]
Aspects of this disclosure relate to a method of treating major depressive disorder (MDD) , which optionally includes treatment resistant depression (TRD) , anxiety disorders including generalized anxiety disorder, panic disorder,
Obsessive Compulsive Disorder (OCD) , social anxiety disorder, Post Traumatic Stress Disorder (PTSD) , nocturnal enuresis (bedwetting) , eating disorders, personality disorders and sleep disorder (insomnia) , in a mammal comprising administering an effective amount of a composition comprising (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof to the mammal in need thereof.
[0005]
In some embodiments, administering the effective amount of the composition comprising ( 4-benzyl-4-hydroxypiperidin-l- yl) (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- ( 4-methyl-lH-pyrazol- 1-yl) pyridin-3-yl).piperidin-4-yl) carbonyl) pyrrolidine-2- carbonitrile or a pharmaceutically acceptable salt thereof results in (i) a reduction in 24 (S) -hydroxycholesterol (24HC) levels and/or (ii) a reduction in NMDA receptor function.
[0006]
In some embodiments, the effective amount of the
composition comprising ( 4-benzyl-4-hydroxypiperidin-l-yl ) (2, 4 ' - bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( ( 1- ( 4- ( 4-methyl-lH-pyrazol-l-yl ) pyridin-3- yl) piperidin-4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof is administered orally or parenterally (e. g. , topically, rectally, intravenously, etc. ) .
[0007]
In some embodiments, the effective amount of the
composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2,4'— bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3- yl) piperidin-4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof is administered as a single unit dose. The single unit dose is preferably about 0.01· mg/kg to 100 mg/kg, more preferably about 0.05 mg/kg to 100 mg/kg, still more preferably about 0.1 to 10 mg/kg.
[0008]
In some embodiments, the effective amount of the
composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2, 4 ' - bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3- yl) piperidin-4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof is administered according to a dose regimen.
[0009]
In some embodiments, the mammal is a human. In further embodiments, the human is an adolescent or an adult.
[0010]
In some embodiments, the composition comprising (4- benzyl-4-hydroxypiperidin—1-yl) (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- ( 4-methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof further comprises a pharmaceutically acceptable carrier.
[0011]
In some embodiments, the composition comprising (4- benzyl-4-hydroxypiperidin-l-yl) (2,4' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- ( 4-methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof further comprises an additional active agent. Non-limiting examples of additional active agents include: imipramine, clomipramine, desipramine hydrochloride, noxiptiline, phenelzine, amitriptyline hydrochloride,
nortriptyline hydrochloride, amoxapine, mianserin
hydrochloride, maprotiline hydrochloride, setiptiline,
sulpiride, fluvoxamine maleate, trazodone hydrochloride, paroxetine hydrochloride hydrate, lithium carbonate, selective serotonin reuptake inhibitor (fluvoxamine maleate, fluoxetinehydrochloride, citalopram hydrobromide, sertraline
hydrochloride, paroxetine hydrochloride, escitalopram oxalate etc.), serotonin-noradrenalin reuptake inhibitor (venlafaxine hydrochloride, duloxetine hydrochloride, venlafaxine hydrochloride, milnacipran hydrochoride etc.), noradrenalin reuptake inhibitor (reboxetine mesylate etc.), noradrenalin- dopamine reuptake inhibitor (bupropion hydrochloride etc. ) , mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT1A agonist (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride etc.).
[0012]
Aspects of this disclosure also relate to a
pharmaceutical composition comprising (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, which is for treating major depressive disorder (MDD) .
[0013]
Aspects of this disclosure also relate to (4-benzyl-4- hydroxypiperidin-l-yl ) (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof for use in treatment of major
depressive disorder (MDD).
[0014]
(Detailed Description of the Invention)
Aspects of the disclosure relate to a method of treating major depressive disorder (MDD) , optionally, treatment
resistant depression (TRD) , anxiety disorders including generalized anxiety disorder, panic disorder, Obsessive
Compulsive Disorder (OCD) , social anxiety disorder, Post
Traumatic Stress Disorder (PTSD), nocturnal enuresis
(bedwetting) , eating disorders, personality disorders and sleep disorder (insomnia), in a mammal (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat; preferably human) comprising administering an effective amount of a composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2,4 ' -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin-
4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof to the mammal in need thereof.
[0015]
Not to be bound by theory, it is believed that (4-benzyl- 4-hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl ) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl ) pyridin-3-yl ) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof can reduce NMDA receptor function by blocking the production of 24 (S) -hydroxycholesterol (24HC or cerebrosterol) , which is the product of CH24H enzymatic activity and a potent (EC50 = 1.2 mM) and specific positive allosteric modulator of NDMA receptors. By blocking the production of 24 (S) -hydroxycholesterol, specific inhibitors of CH24H have the potential to reduce excitatory neurotransmission through NMDA receptors. Accordingly, the CH24H inhibitors disclosed herein are hypothesized to have the same or similar mechanism as ketamine, an NMDA receptor open channel blocker, and, accordingly, confer antidepressant effects, specifically in a mammal suffering from any one of Depression, MDD and TRD, anxiety disorders including generalized anxiety disorder, panic disorder, Obsessive Compulsive Disorder (OCD) , social anxiety disorder, Post Traumatic Stress Disorder (PTSD) , nocturnal enuresis (bedwetting) , eating disorders, personality disorders and sleep disorder (insomnia) . These effects are believed to be dose dependent.
[0016]
Accordingly, in some embodiments, administering the effective amount of the composition comprising (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl)methanone or a pharmaceutically acceptable salt thereof or. (2R)-l-((l-(4-(4- methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin-^- yl ) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof results in (i) a reduction in 24 (S)- hydroxycholesterol (24HC) levels and/or (ii) a reduction in NMDA receptor function.
[0017]
For instance, a reduction in 24 (S) -hydroxycholesterol (24HC) levels, recited in (i) above, may be measured by an
LC/MS assay. Similarly, a reduction in NMDA receptor function, recited in (ii) above, may be measured electrophysiologically ex-vivo after administration. It could likely also be measured in dissociated neuronal cultures.
[0018]
Definitions
Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies known to those of ordinary skill in the art. Publications and other materials setting forth such known methodologies to which reference is made are incorporated herein by reference in their entireties as though set forth in full. Any suitable materials and/or methods known to those of ordinary skill in the art can be utilized in carrying out the present invention. However, specific materials and methods are described. Materials, reagents, and the like to which reference is made in the following description and examples are obtainable from
commercial sources, unless otherwise noted.
[0019]
The following terms are used throughout as defined below.
[0020]
As used herein, singular articles such as "a" and "an" and "the" and similar referents denote both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Disclosure of ranges of values should be understood as a shorthand reference to each separate value falling within the range and at the endpoints, again unless otherwise clearly indicated, and each separate value is to be understood as being described herein as if it were individually set forth.
[0021]
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.
[0022]
The use of any and all examples, or exemplary language ("e.g." or "such as") herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non- claimed feature as essential.
[0023]
As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent
depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used,
"about" will mean up to plus or minus 10% of the particular term.
[0024]
As used herein, the term "active agent" means a
biologically active component of a pharmaceutical composition, e.g. an agent that has a pharmacological effect on the subject or patient to which it is administered. Contemplated herein are (4-benzyl-4-hydroxypiperidin-l-yl) (2 , 4 ' -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin- 4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof and additional active agents for use in combination with (4-benzyl-4-hydroxypiperidin-l-yl) (2,4’- bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3- yl) piperidin-4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof. Non-limiting
examples of suitable additional active agents for use in combination with the CH24H inhibitors include those mentioned above .
[0025]
The compound (4-benzyl-4-hydroxypiperidin-l-yl) (2, 4 ' - bipyridin-3-yl ) methanone, shown below as Formula (I) is described in US Patent No. 8,648,079
[0026]
Formula (I)
Figure imgf000010_0001
[0027]
The compound ( (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l- yl) pyridin-3-yl ) piperidin-4-yl) carbonyl) pyrrolidine-2- carbonitrile, shown below as Formula (II) is described in US Patent No. 9,643,957: [0028]
Formula (II)
Figure imgf000011_0001
[0029]
The compounds of Formula (I) and Formula (II) are CH24H inhibitors .
[0030]
As used herein, the term "effective amount" means an amount effective to successfully achieve a particular
biological effect. In the present case, the effective amount is an amount to effective to treat Depression, MDD or,
optionally, TRD, anxiety disorders including generalized anxiety disorder, panic disorder, Obsessive Compulsive Disorder (OCD) , social anxiety disorder, Post Traumatic Stress Disorder (PTSD) , nocturnal enuresis (bedwetting) , eating disorders, personality disorders and sleep disorder (insomnia) . Suitable effective amounts may be determined according to methods well known in the art to determine single unit dosage and/or dose regimens .
[0031]
The term "single unit dose" in this context refers to an effective amount provided in a single administration. Nonlimiting examples of suitable single unit doses for use in the claimed methods include about 0.01 to 100 mg/kg body weight, preferably 0.05 to 30 mg/kg body weight, more preferably 0.1 to 10 mg/kg body weight for oral administration to an adult patient (body weight 60 kg) .
[0032]
The term "dose regimen" in this context refers to an effective amount provided over a fixed number of administrations over a specified duration of time.
[0033]
Suitable routes of administration and doses and
formulations suited thereto are known in the art. Non-limiting examples of routes of administration relevant to the claimed methods include oral and parenteral (e.g., topical, rectal, or intravenous) routes. Examples of the dosage form suited for a particular route of administration include oral preparations such as tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet) , capsules (including soft capsule, microcapsule) , granule, powder, troche, syrup, emulsion, suspension, films (e.g., orally disintegrable films) and the like; and parenteral agents such as injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparations (e.g., dermal
preparation, ointment), suppository (e.g., rectal suppository, vaginal suppository) , pellet, nasal preparation, pulmonary preparation (inhalant), eye drop and the like. Optionally, these preparations may be a release control preparation (e.g., sustained-release microcapsule) such as an immediate-release preparation or a sustained-release preparation.
[0034]
As used herein, the term "major depressive disorder" or
"MDD" refers to a disorder characterized by the Diagnostic and Statistical Manual of Mental Disorders (DSM) , specifically DSM- 5 incorporated by reference herein in its entirety. MDD requires the occurrence or one or more major depressive episodes, which are characterized by depressed mood and/or anhedonia (diminished loss of interest or pleasure in almost all activities), and optionally one or more of the following symptoms :
significant weight or appetite disturbance; sleep disturbance;
psychomotor agitation or retardation (a speeding or slowing of muscle movement) ;
loss of energy or fatigue;
feelings of worthlessness (low self-esteem) ;
diminished ability to think, concentrate and make decisions;
recurrent thoughts of death, dying or suicide; and longstanding interpersonal rejection ideation (i.e., others would be better off without me) ,
specific suicide plan(s), or suicide attempt (s).
[0035]
Major depressive episodes must be at least two weeks long; cause significant distress or severely impact social, occupational or other life areas; not be precipitated by drug use; not meet the criteria for another mental disorder (e.g., schizophrenia or bipolar disorder) ; and not be better explained by bereavement (such as loss experienced after a death) .
[0036]
As used herein, the term "treatment resistant depression" or "TRD" refers to MDD that does not respond adequately to appropriate courses of at least two antidepressants. Here, an adequate response is usually defined as at least 50% decreased in the severity of depression symptoms.
[0037]
The term "pharmaceutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds of the present technology which are water or oil-soluble or dispersible; which are suitable for treatment of diseases without undue toxicity, irritation, and allergic-response;
which are commensurate with a reasonable benefit/risk ratio; and which are effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L- ascorbate, aspartate, benzoate, benzenesulfonate (besylate) , bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate,
glycerophosphate, glycolate, hemisulfate, heptanoate,
hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate) , lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- toluenesulfonate (p-tosylate) , and undecanoate. Also, basic groups in the compounds of the present technology can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
Examples of acids which can be employed to form
pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and
phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present technology contemplates sodium, potassium,
magnesium, and calcium salts of the compounds of the compounds of the present technology and the like.
[0038]
As used herein, the term "pharmaceutically acceptable carrier" means one or more organic or inorganic carrier substances conventionally used in the formulation of chemical compositions. Suitable pharmaceutically acceptable carriers can be determined by methods well known in the art e.g.
excipients, lubricants, binders and disintegrants for solid preparations; solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, and soothing agents for liquid preparations; and/or preparation additives such as
preservatives, antioxidants, colorants, and sweetening agents. Non-limiting examples of such suitable pharmaceutically acceptable carriers include:
for an excipient: lactose, sucrose, D-mannitol, D- sorbitol, starch, gelatinated starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthesis aluminum silicate and magnesium alumino metasilicate;
for a lubricant: magnesium stearate, calcium stearate, talc and colloidal silica;
for a binder: gelatinated starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D- mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone;
for a disintegrant : lactose, sucrose, starch,
carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low-substituted
hydroxypropylcellulose;
for a solvent: water, physiological brine, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil;
for a solubilizing agent: polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium
carbonate, sodium citrate, sodium salicylate and sodium
acetate; for a suspending agent: surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl
aminopropionate, lecithin, benzalkoniu chloride, benzethonium chloride, and glycerol monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium
carboxymethylcellulose, methylcellulose,
hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose and the like; polysorbates, and
polyoxyethylene hydrogenated castor oil;
for an isotonicity agent: sodium chloride, glycerol, D- mannitol, D-sorbitol and glucose;
for a buffer: phosphate, acetate, carbonate, and
citrate;
for a soothing agent: benzyl alcohol;
for a preservative: p-oxybenzoates , chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid;
for an antioxidant: sulfite and ascorbate;
for a colorant: aqueous water-soluble food tar colors (e.g., food colors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like), water insoluble lake dyes (e.g., aluminum salt of the above-mentioned water-soluble food tar color) , and natural dyes (e.g., b-carotene, chlorophyll, ferric oxide red); and
for a sweetening agent: saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
[0039]
As used herein, the term "treating" includes the
prevention, reduction, and/or complete resolution of the symptoms associated with or the cause of the target indication and/or a lessening of severity of the condition.
[0040]
The following references are incorporated by reference herein to the same extent as if individually incorporated. 1. Trivedi, M. H. et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163, 28-40, doi: 10.1176/appi.ajp.163.1.28 (2006).
2. Warden, D. , Rush, A. J. , Trivedi, M. H., Fava, M. & Wisniewski, S. R. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep 9, 449-459 (2007).
3. aan het Rot, M. et al. Safety and efficacy of repeated- dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 67, 139-145, doi : 10.1016/j .biopsych.2009.08.038 (2010) .
4. Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47, 351-354 (2000).
5. Valentine, G. W. et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [ (1) H] -MRS. Psychiatry Res 191, 122-127, doi : 10.1016/j .pscychresns .2010.10.009 (2011).
6. Zarate, C. A., Jr. et al. A randomized trial of an N- methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63, 856-864,
doi : 10.1001/archpsyc .63.8.856 (2006) .
7. Sanacora, G. et al. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry 74, 399-405, doi : 10.1001/j amapsychiatry.2017.0080 (2017).
8. Machado-Vieira, R. , Salvadore, G., Luckenbaugh, D. A.,
Manji, H. K. & Zarate, C·. A., Jr. Rapid onset of antidepressant action: a new paradigm in the research and treatment of major depressive disorder. J Clin Psychiatry 69, 946-958 (2008) .
9. Davies, S. N., Alford, S. T., Coan, E. J. , Lester, R. A. & Collingridge, G. L. Ketamine blocks an NMDA receptor-mediated component of synaptic transmission in rat hippocampus in a voltage-dependent manner. Neurosci Lett 92, 213-217 (1988).
10. Paul, S. M. et al. The major brain cholesterol metabolite 24 (S) -hydroxycholesterol is a potent allosteric modulator of N- methyl-D-aspartate receptors. J Neurosci 33, 17290-17300, doi: 10.15237JNEUROSCI.2619-13..2013 (2013).
11. Shorvon, S. & Ferlisi, M. The treatment of super
refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 134, 2802- 2818, doi : 10.1093/brain/awr215 (2011).
Examples
[0:041]
The invention is further illustrated by, though in no way limited to, the following examples.
[0042]
Examples
Efficacy data in Preclinical Depression model
The following Example provides data from a rat model of depression, the reduction of submissive behaviour model (RSBM) . (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin- 4-yl ) carbonyl ) pyrrolidine-2-carbonitrile was tested in the rat RSBM for its potential effects on submissive behavior. Adult male Wistar rats (7-9 weeks) were used for the experiment.
Animals were housed in group of 3 - 4 per cage at a standard temperature (22 ± 3°C), relative humidity between 30-70%, and in a light-controlled environment (lights on from 7 am to 7 pm) . Pelleted rodent SAFETM Laboratory diet manufactured by SAFE, was provided for 1 hour per day (Monday to Thursday) and ad libitum access from Friday afternoon to Sunday evening.
Potable water passed through a water filtration system was provided ad libitum in polycarbonate bottles with stainless steel sipper tubes. The testing apparatus was constructed from transparent plastic and consisted of two identical chambers (24 x 17 x 14 cm) connected by a tunnel (6 x 6 x 52 cm) . A total of 220 male Wistar rats (110 pairs) were selected. The animals were randomized on the basis of body weight and matched for body weight, pairwise. The pairs were habituated to the testing apparatus and milk for a period of 5 min per day for 5 days (first week) . The animals were housed such that these pairs met only during the trial time. Each pair was given equal access to milk containing 9% sucrose in a beaker (10 mL) , which was placed in an opening on the floor at the midpoint of the tunnel. During the second week, time spent in drinking the milk by a pair of rats was recorded and scored for a period of 5 min. Once the 5 min period was over, the rat pair was returned to their respective home cages. Pairs of rats that met the following criteria were selected -in , the study: 1) The
difference in the average drinking score of a pair was
significant (two-tailed-t-test , p<0.05). 2) The dominant animal's score is greater by 25% than the submissive animal's score. 40 pairs, which met the above criteria, were selected and randomized based on the dominance levels (the difference in the average drinking score per week between the dominant and the submissive partners) . The experiment was carried out by an experimenter who was blinded to treatment. Dosing was commenced from the day after the animals were randomized for the study (day 14) . Both the dominant and submissive animals of the control group were orally treated with vehicle (0.5%
methylcellulose in water, 2 mL/kg) . For the (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl) pyridin-3-yl)piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile treatment groups, submissive animals were orally treated with (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile (0.3 or 3 mg/kg, 2 mL/kg) and their dominant partners were orally treated with vehicle (0.5% methylcellulose, 2 mL/kg). During the test period (three weeks: i.e. from week 3 - 5, Monday to Friday), time spent in drinking the milk was recorded for each animal of a pair for a period of 5 min. Once the trial was over for all the animals in the group, they were given free access to food for 1 h and the treatments were administered. Animals were given free access to food from Friday afternoon to Sunday evening. The dominance level of the vehicle group was compared with the dominance level of the drug treatment group during the drug treatment period using repeated measures ANOVA followed by Dunnett's test. Values of p < 0.05 were considered
statistically significant. A 3-week treatment with (2R)-1-((1- (4- ( 4-methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile at 3 mg/kg p.o.
significantly reduced the dominance level during week 5, though (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin- 4-yl) carbonyl) pyrrolidine-2-carbonitrile at 0.3 mg/kg failed to have a significant effect. These results support the use of (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin- 4-yl) carbonyl) pyrrolidine-2-carbonitrile to treat depression including MDD.
In the similar manner to the above Example, the use of
(4-benzyl-4-hydroxypiperidin-l-yl) (2,4' -bipyridin-3- yl)methanone to treat depression including MDD may be
confirmed.
[0043]
Formulation Example
For (4-benzyl-4-hydroxypiperidin-l-yl) (2 , 4 ' -bipyridin-3- yl)methanone, the formulation (film coating tablet) was produced in line with the following specification (Table 2) .
[0044]
[Table 2]
Figure imgf000021_0001
1) These ingredients are components of OPADRY® Red 03F45081 and OPADRY (registered trademark) Yellow 03F42240 (premixed coating materials) .
[0045]
This application is based on patent applications Nos. US 62/714,175 and US 62/714,176, both filed on August 3, 2018 in USA, the contents of which are encompassed in full herein.

Claims

1. A method of treating major depressive disorder (MDD) in a mammal comprising administering an effective amount of a composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2, 4 ' - bipyridin-3-yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( ( 1- ( 4- ( 4-methyl-lH-pyrazol-l-yl ) pyridin-3- yl) piperidin-4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof to the mammal in need thereof.
2. The method of claim 1, wherein the MDD is treatment
resistant depression (TRD) .
3. The method of claim 1, wherein administering the effective amount of the composition comprising (4-benzyl-4- hydroxypiperidin-l-ylj (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof results in (i) -a reduction in 24 (S)- hydroxycholesterol (24HC) levels and/or (ii) a reduction in NMDA receptor function. 4. The method of claim 1, wherein the effective amount of the composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2,
4'- bipyridin-3-yl ) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- ( 4-methyl-lH-pyrazol-l-yl ) pyridin-3- yl) piperidin-4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof is administered orally or parenterally .
5. The method of claim 1, wherein the effective amount of the composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2, 4 ' - bipyridin-3-yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- ( 4-methyl-lH-pyrazol-l-yl ) pyridin-3- yl) piperidin-4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof is administered as a single unit dose.
6. The method of claim 5, wherein the single unit dose is about 0.01 mg/kg to 100 mg/kg.
7. The method of claim 5, wherein the single unit dose is about 0.05 mg/kg to 100 mg/kg.
8. The method of claim 5, wherein the single unit dose is about 0.1 to 10 mg/kg.
9. The method of claim 1, wherein the effective amount of the composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2, 4 ' - bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3- yl) piperidin-4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof is administered according to a dose regimen.
10. The method of claim 1, wherein the mammal is a human.
11. The method of claim 1, wherein the composition comprising ( 4-benzyl-4-hydroxypiperidin-l-yl) (2,4' -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( ( 1— ( 4— ( 4 -methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin- 4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof further comprises a pharmaceutically acceptable carrier.
12. The method of claim 1, wherein the composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2,4' -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3-yl ) piperidin- 4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof further comprises an additional active agent.
13. A pharmaceutical composition comprising (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4- methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin-4- yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, which is for treating major depressive disorder (MDD) .
14. (4-Benzyl-4-hydroxypiperidin-l-yl) (2 , 4 ' -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof or (2R) -1- ( (1- (4- (4-methyl-lH-pyrazol-l-yl) pyridin-3-yl) piperidin- 4-yl) carbonyl) pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof for use in treatment of major
depressive disorder (MDD) .
15. A method of treating major depressive disorder (MDD) in a mammal comprising administering an effective amount of a composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2, 4 ' - bipyridin-3-yl)methanone or a pharmaceutically acceptable salt thereof to the mammal in need thereof.
16. The method of claim 15, wherein the MDD is treatment resistant depression (TRD) .
17. The method of claim 15, wherein administering the effective amount of the composition comprising (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof results in (i) a reduction in 24 ( S.) -hydroxycholesterol (24HC) levels and/or (ii) a reduction in NMDA receptor function.
18. The method of claim 15, wherein the effective amount of the composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2,4'- bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof is administered orally or parenterally .
19. The method of claim 15, wherein the effective amount of the composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2,4'- bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof is administered as a single unit dose.
20. The method of claim 19, wherein the single unit dose is about 0.01 mg/kg to 100 mg/kg.
21. The method of claim 19, wherein the single unit dose is about 0.05 mg/kg to 100 mg/kg.
22. The method of claim 19, wherein the single unit dose is about 0.1 to 10 mg/kg.
23. The method of claim 15, wherein the effective amount of the composition comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2 , 4 ' - bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof is administered according to a dose regimen.
24. The method of claim 15, wherein the mammal is a human.
25. The method of claim 15, wherein the composition comprising ( 4-benzyl-4-hydroxypiperidin-l-yl) (2,4' -bipyridin-3- yl) methanone or a pharmaceutically acceptable salt thereof further comprises a pharmaceutically acceptable carrier.
26. The method of claim 15, wherein the composition . comprising (4-benzyl-4-hydroxypiperidin-l-yl) (2 , 4 ' -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof further comprises an additional active agent.
27. A pharmaceutical composition comprising (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ' -bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier, which is for treating major depressive disorder (MDD) -.
28. (4-Benzyl-4-hydroxypiperidin-l-yl) (2, 41 -bipyridin-3- yl )methanone or a pharmaceutically acceptable salt thereof for use in treatment of major depressive disorder (MDD) .
PCT/JP2019/031284 2018-08-03 2019-08-01 Ch24h inhibitors for mdd use WO2020027344A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201862714175P 2018-08-03 2018-08-03
US201862714176P 2018-08-03 2018-08-03
US62/714,175 2018-08-03
US62/714,176 2018-08-03

Publications (1)

Publication Number Publication Date
WO2020027344A1 true WO2020027344A1 (en) 2020-02-06

Family

ID=67841124

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2019/031284 WO2020027344A1 (en) 2018-08-03 2019-08-01 Ch24h inhibitors for mdd use

Country Status (1)

Country Link
WO (1) WO2020027344A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130090341A1 (en) * 2011-10-07 2013-04-11 Takeda Pharmaceutical Company Limited Heterocyclic compounds
US20130236573A1 (en) * 2012-03-12 2013-09-12 Janssen Pharmaceutica Nv Esketamine for the treatment of treatment-refractory or treatment-resistant depression
US20160022701A1 (en) * 2013-03-13 2016-01-28 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
US20160024049A1 (en) * 2013-04-04 2016-01-28 Takeda Pharmaceutical Company Limited Heterocyclic compound
US20170114042A1 (en) * 2014-06-09 2017-04-27 Takeda Pharmaceutical Company Limited Radiolabeled compounds
US9643957B2 (en) 2012-12-11 2017-05-09 Takeda Pharmaceutical Company Limited Heterocyclic compounds having cholesterol 24-hydroxylase activity

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130090341A1 (en) * 2011-10-07 2013-04-11 Takeda Pharmaceutical Company Limited Heterocyclic compounds
US8648079B2 (en) 2011-10-07 2014-02-11 Takeda Pharmaceutical Company Limited Heterocyclic compounds
US20130236573A1 (en) * 2012-03-12 2013-09-12 Janssen Pharmaceutica Nv Esketamine for the treatment of treatment-refractory or treatment-resistant depression
US9643957B2 (en) 2012-12-11 2017-05-09 Takeda Pharmaceutical Company Limited Heterocyclic compounds having cholesterol 24-hydroxylase activity
US20160022701A1 (en) * 2013-03-13 2016-01-28 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
US20160024049A1 (en) * 2013-04-04 2016-01-28 Takeda Pharmaceutical Company Limited Heterocyclic compound
US20170114042A1 (en) * 2014-06-09 2017-04-27 Takeda Pharmaceutical Company Limited Radiolabeled compounds

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
AAN HET ROT, M. ET AL.: "Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression", BIOL PSYCHIATRY, vol. 67, 2010, pages 139 - 145, XP026804712
BERMAN, R. M. ET AL.: "Antidepressant effects of ketamine in depressed patients", BIOL PSYCHIATRY, vol. 47, 2000, pages 351 - 354, XP002565719, doi:10.1016/S0006-3223(99)00230-9
DAVIES, S. N.ALFORD, S. T.COAN, E. J.LESTER, R. A.COLLINGRIDGE, G. L.: "Ketamine blocks an NMDA receptor-mediated component of synaptic transmission in rat hippocampus in a` voltage-dependent manner", NEUROSCI LETT, vol. 92, 1988, pages 213 - 217, XP025439245, doi:10.1016/0304-3940(88)90063-8
MACHADO-VIEIRA, R.SALVADORE, G.LUCKENBAUGH, D. A.MANJI, H. K.ZARATE, C-. A., JR.: "Rapid onset of antidepressant action: a new paradigm in the research and treatment of major depressive disorder", J CLIN PSYCHIATRY, vol. 69, 2008, pages 946 - 958
PAUL, S. M. ET AL.: "The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N- methyl-D-aspartate receptors", J NEUROSCI, vol. 33, 2013, pages 17290 - 17300, XP055543316, doi:10.1523/JNEUROSCI.2619-13.2013
S. M. PAUL ET AL: "The Major Brain Cholesterol Metabolite 24(S)-Hydroxycholesterol Is a Potent Allosteric Modulator of N-Methyl-D-Aspartate Receptors", THE JOURNAL OF NEUROSCIENCE, vol. 33, no. 44, 30 October 2013 (2013-10-30), US, pages 17290 - 17300, XP055543316, ISSN: 0270-6474, DOI: 10.1523/JNEUROSCI.2619-13.2013 *
SANACORA, G. ET AL.: "A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders", JAMA PSYCHIATRY, vol. 74, 2017, pages 399 - 405
SHORVON, S. & FERLISI, M.: "The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol", BRAIN, vol. 134, 2011, pages 2802 - 2818
TRIVEDI, M. H. ET AL.: "Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice", AM J PSYCHIATRY, vol. 163, 2006, pages 28 - 40
VALENTINE, G. W. ET AL.: "The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS", PSYCHIATRY RES, vol. 191, 2011, pages 122 - 127, XP028127503, doi:10.1016/j.pscychresns.2010.10.009
WARDEN, D.RUSH, A. J.TRIVEDI, M. H.FAVA, M.WISNIEWSKI, S. R.: "The STAR*D Project results: a comprehensive review of findings", CURR PSYCHIATRY REP, vol. 9, 2007, pages 449 - 459
ZARATE, C. A., JR. ET AL.: "A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression", ARCH GEN PSYCHIATRY, vol. 63, 2006, pages 856 - 864, XP002565718, doi:10.1001/archpsyc.63.8.856

Similar Documents

Publication Publication Date Title
CN108042808B (en) Combination comprising brexpiprazole or salt thereof and a second drug for the treatment of central system diseases
US20060199805A1 (en) Pharmaceutical compositions for the treatment and/or prevention of anxiety disorders
EP1988898A2 (en) Pharmaceutical compositions for the treatment of attention deficit hyperactivity disorder comprising flibanserin
HRP20000798A2 (en) Combination therapy for treatment of bipolar disorders
CZ20004279A3 (en) Medicament for treating stubborn depression and pharmaceutical composition
KR20230096003A (en) Use of Benzodiazepines to Increase Sensitivity to Psilocybin After Chronic SSRI Regimen
US20230181572A1 (en) Carbamoyl cyclohexane derivatives for treating autism spectrum disorder
US11173147B2 (en) Prophylactic or therapeutic agent for delirium
EP3952872B1 (en) Carbamoyl cyclohexane derivatives for treating autism spectrum disorder
EA015483B1 (en) Use of a p38 kinase inhibitor for treating psychiatric disorders
WO2020027344A1 (en) Ch24h inhibitors for mdd use
TW201242597A (en) A synergistic pharmaceutical combination for the treatment of pancreatic cancer
US20220265641A1 (en) Serotonergic agent and 5-ht1a-receptor antagonist
US20220235034A1 (en) Selective histamine h3 receptor antagonists for treating autism spectrum disorder
WO2020059894A1 (en) CH24H Inhibitors For Pain Use
JP2017513895A (en) Blexpiprazole and nalmefene combination and its use to treat substance-related disorders
CA3162938A1 (en) Methods for treating behavioral and psychological symptoms in patients with dementia
EA047219B1 (en) METHODS FOR TREATING BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS IN PATIENTS WITH DEMENTIA

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: 19762487

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19762487

Country of ref document: EP

Kind code of ref document: A1