WO2025233259A1 - Compound for use in the treatment of depression, obsessive-compulsive disorder, post-traumatic stress disorder and/or borderline personality disorder - Google Patents

Compound for use in the treatment of depression, obsessive-compulsive disorder, post-traumatic stress disorder and/or borderline personality disorder

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Publication number
WO2025233259A1
WO2025233259A1 PCT/EP2025/062166 EP2025062166W WO2025233259A1 WO 2025233259 A1 WO2025233259 A1 WO 2025233259A1 EP 2025062166 W EP2025062166 W EP 2025062166W WO 2025233259 A1 WO2025233259 A1 WO 2025233259A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
disorder
onal
interna
gmbh
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/EP2025/062166
Other languages
French (fr)
Inventor
Franco DE CRESCENZO
Mayumi Ishida
Dirk Kemmer
Jon Charles Lorenz
Manabu Nakatani
Alexander Samuel NYDELL
Suttipol RADOMKIT
Holger Rosenbrock
Atsushi Sakurai
Takeshi Sawada
Markus SCHRANZ
Sanil SREEKUMAR
Marissa SIMONE
Shuoxun WANG
Dirk Weber
Jada A. H. WHITE
Kazutoshi Yokoyama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
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Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of WO2025233259A1 publication Critical patent/WO2025233259A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays or needleless injectors
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Compound 1 for the use in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma ⁇ c Stress Disorder, and/or Borderline Personality Disorder, chemical synthesis of Compound 1, polymorphs of Compound 1, and pharmaceu ⁇ cal composi ⁇ ons comprising Compound 1 and/or its polymorphs.
  • MDD Major depressive disorder
  • This disorder is a recurrent lifelong illness, and with treatment e.g an ⁇ depressants, episodes last about 3–6 months, and most pa ⁇ ents recover within 12 months. Longer-term (2–6 years), the propor ⁇ on of people who recover is much less, dropping to approximately 60% at 2 years, 40% at 4 years, and 30% at 6 years with comorbid anxiety having a key role in limi ⁇ ng recovery.
  • the pharmacotherapy for major depressive disorder has been founded on enhancement of monoaminergic neurotransmission, e.g.
  • SSRIs serotonin reuptake inhibitors
  • BD N- methyl-D-aspartate
  • NMDA N- methyl-D-aspartate
  • Bipolar disorder is a serious and debilita ⁇ ng psychiatric disorder affec ⁇ ng mul ⁇ ple domains of mood, emo ⁇ ons, and cogni ⁇ on (Jawad et al. Brain Sci.2023 Jun 4;13(6):909).
  • BD has a global prevalence of >1% and cons ⁇ tutes a major healthcare burden.
  • Pa ⁇ ents with BD o ⁇ en have two dis ⁇ nct mood episodes, i.e., mania/hypomania and depression.
  • BD is broadly classified into BD-I, BD-II, and cyclothymia in the Diagnos ⁇ c and Sta ⁇ s ⁇ cal Manual of Mental Disorders (DSM) 5th edi ⁇ on.
  • DSM Diagnos ⁇ c and Sta ⁇ s ⁇ cal Manual of Mental Disorders
  • bipolar II disorder a common bipolar phenotype that is related to chronic depression
  • Obsessive compulsive disorder is a long-las ⁇ ng disorder in which a person experiences uncontrollable and recurring thoughts (obsessions), engages in repe ⁇ ve behaviors (compulsions), or both (Na ⁇ onal Ins ⁇ tute of Mental Health homepage: www.nimh.nih.gov/health/topics/obsessive-compulsive-disorder-ocd).
  • OCD Obsessive compulsive disorder
  • DSM Sta ⁇ s ⁇ cal Manual of Mental Disorders
  • Common obsessions include: Fear of germs or contamina ⁇ on; Fear of forge ⁇ ng, losing, or misplacing something; Fear of losing control over one’s behavior; Aggressive thoughts toward others or Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 3 - 05.05.2025 oneself; Unwanted, forbidden, or taboo thoughts involving sex, religion, or harm; Desire to have things symmetrical or in perfect order. Compulsions are repe ⁇ ve behaviors a person feels the urge to do, o ⁇ en in response to an obsession.
  • Common compulsions include: Excessive cleaning or handwashing; Ordering or arranging items in a par ⁇ cular, precise way; Repeatedly checking things, such as that the door is locked or the oven is off; Compulsive coun ⁇ ng; Praying or repea ⁇ ng words silently.
  • OCD has a life ⁇ me prevalence of 2–3% and is more common in females than in males (Stein et al., Nat Rev Dis Primers, 2019 Aug 1;5(1):52. doi: 10.1038/s41572-019-0102-3). OCD typically starts early in life and has a long dura ⁇ on, and in females, onset o ⁇ en occurs during adolescence.
  • OCD Treatment of OCD comprises several components, star ⁇ ng with building a therapeu ⁇ c alliance with the pa ⁇ ent and psychoeduca ⁇ on, followed by psychological and/or pharmacological approaches.
  • SSRIs are thefirst-line pharmacological treatment for OCD based on their evidence of efficacy, tolerability, safety and absence of abuse poten ⁇ al, but responder rates are poor and side effects might limit their use in OCD, so that ul ⁇ mately, be ⁇ er (and preferably faster) treatments are needed to help more individuals with OCD.
  • Post-Trauma ⁇ c Stress Disorder is a disorder that develops in some people who have experienced a shocking, scary, or dangerous event, and it is characterized by symptoms of re- experiencing, avoidance, nega ⁇ ve altera ⁇ ons in cogni ⁇ on and mood, and marked altera ⁇ ons in arousal and reac ⁇ vity following exposure to a trauma ⁇ c event (Merians et al., Med Clin North Am.2023 Jan;107(1):85-99. doi: 10.1016/j.mcna.2022.04.003). Symptoms of PTSD usually begin within 3 months of the trauma ⁇ c event, but they some ⁇ mes emerge later.
  • DSM Diagnos ⁇ c and Sta ⁇ s ⁇ cal Manual of Mental Disorders
  • PTSD is a long-life effect of the con ⁇ nuous occurrence of trauma ⁇ c condi- ⁇ ons, leading to the produc ⁇ on of feelings of helplessness, intense fear, and horror in the person.
  • Treatment of PTSD includes the removal or reduc ⁇ on of th-ese emo ⁇ onal feelings or symptoms with the aim to improve the daily life func ⁇ oning of a person, and it might include also pharmacotherapy with SSRIs.
  • pharmacotherapies are less effec ⁇ ve than trauma- focused psychotherapeu ⁇ c interven ⁇ ons in reducing PTSD severity, pharmacotherapies are recommended as only as second-line treatment.
  • Boderline Personality Disorder is a serious mental health disorder characterized by pervasive instability in moods, interpersonal rela ⁇ onships, self-image, and behavior. The disorder's pervasive instability in moods, interpersonal rela ⁇ onships, self-image, and behavior o ⁇ en disrupts family dynamics, work life, and the individual's sense of self-iden ⁇ ty.
  • BPD is a mental health condi ⁇ on that places a significant burden not only on the individuals diagnosed with it but also on their families and the broader health-care systems. BPD affects approximately 1.6% of the general popula ⁇ on, but thisfigure may be as high as 5.9%.
  • BPD can occur in anyone, but the onset of a coherent syndrome of BPD typically occurs during adolescence, generally a ⁇ er the age of 12 years (Bohus M, Stoffers-Winterling J, Sharp C, Krause-Utz A, Schmahl C, Lieb K, Lancet October 23, 2021; Volume 398 (Issue 10310), 1528- 1540. doi: 10.1016/S0140-6736(21)00476-1.). This cri ⁇ cal period of development is o ⁇ en marked by significant emo ⁇ onal and psychological changes, which can exacerbate the symptoms of BPD.
  • the disorder appears to be more common in those with a family history of the disorder or a history of child abuse, neglect, or separa ⁇ on from caregivers in early childhood.
  • BPD o ⁇ en co-develops with or is preceded by symptoms of internalizing disorders such as depression and anxiety, and externalizing disorders like conduct problems, hyperac ⁇ vity, and substance use. This comorbidity further complicates the diagnosis and management of BPD.
  • the disorder is associated with various adverse outcomes, including low occupa ⁇ onal and educa ⁇ onal a ⁇ ainment, lack of long-term rela ⁇ onships, increased partner conflict, sexual risk-taking, low levels of social support, and low life sa ⁇ sfac ⁇ on.
  • WO2020/079039 discloses a number of 4-pyrazin-2-ylmethyl-morpholines showing NR2B nega ⁇ ve allosteric modula ⁇ ng proper ⁇ es.
  • WO2020/079039 discloses Compound 1 Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 5 - 05.05.2025 Further, WO2020/079039 generically discloses that the compounds exemplified therein may be used in the treatment of psychiatric disorders, diseases and condi ⁇ ons wherein nega ⁇ ve allosteric modula ⁇ on of NR2B is of therapeu ⁇ c benefit, e.g.
  • mood disorders and mood affec ⁇ ve disorders (1) mood disorders and mood affec ⁇ ve disorders; (2) schizophrenia spectrum disorders; (3) neuro ⁇ c, stress-related and somatoform disorders including anxiety disorders; (4) disorders of psychological development; (5) behavioral syndromes associated with physiological disturbances and physical factors; (6) substance-related and addic ⁇ ve disorders; (7) disease associated with symptoms of nega ⁇ ve and posi ⁇ ve valence; (8) pain; (9) cerebrovascular diseases; (10) episodic and paroxysmal disorders; (11) neurodegenera ⁇ ve diseases.
  • WO2020/079039 discloses that the compounds exemplified therein may be used in the treatment of a disorder, disease or condi ⁇ on selected from the list consis ⁇ ng of (1) treatment of mood disorders and mood affec ⁇ ve disorders including bipolar disorder I depressed, hypomanic, manic and mixed form; bipolar disorder II; depressive disorders, such as single depressive episode or recurrent major depressive disorder, minor depressive disorder, depressive disorder with postpartum onset, depressive disorders with psycho ⁇ c symptoms; major depressive disorder with or without concomitant anxious distress, mixed features, melancholic features, atypical features, mood-congruent psycho ⁇ c features, mood-incongruent psycho ⁇ c features, catatonia.
  • a disorder, disease or condi ⁇ on selected from the list consis ⁇ ng of (1) treatment of mood disorders and mood affec ⁇ ve disorders including bipolar disorder I depressed, hypomanic, manic and mixed form; bipolar disorder II; depressive disorders, such as single depressive episode or recurrent major de
  • disorders belonging to the neuro ⁇ c, stress-related and somatoform disorders including anxiety disorders, general anxiety disorder, panic disorder with or without agoraphobia, specific phobia, social phobia, chronic anxiety disorders; obsessive compulsive Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 6 - 05.05.2025 disorder; reac ⁇ on to sever stress and adjustment disorders, such as post-trauma ⁇ c stress disorder; other neuro ⁇ c disorders such as depersonaliza ⁇ on-derealisa ⁇ on syndrome.
  • the objec ⁇ ve technical problem underlying the present inven ⁇ on is thus to provide a drug substance which may be used in the treatment of Major Depressive Disorder, Treatment- resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma ⁇ c Stress Disorder, and/or Borderline Personality Disorder.
  • administra ⁇ on of Compound 1 – in comparison with placebo – resulted in promising preliminary efficacy signals of a rapid, sustained effect with good tolerability.
  • Compound 1 has surprisingly been found to fulfil the above-men ⁇ oned criteria required for use in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma ⁇ c Stress Disorder, and/or Borderline Personality Disorder.
  • the present inven ⁇ on provides Compound 1: Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 7 - 05.05.2025 for use in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma ⁇ c Stress Disorder, and/or Borderline Personality Disorder.
  • the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that 0.5 - 40 mg of Compound 1 are to be administered.
  • the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that 2.5 - 25 mg, preferably 5 – 20 mg, of Compound 1 are to be administered. According to another aspect, the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that 0.5, 2.5, 5, 10, 20, 25, 30, or 40 mg of Compound 1 are to be administered. According to another aspect, the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that 2.5, 5, 10, 20, or 25 mg of Compound 1 are to be administered. According to another aspect, the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that 5, 10, or 20 mg of Compound 1 are to be administered.
  • the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 is to be administered once daily, twice weekly, every other day or once weekly. According to another aspect, the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 is to be administered once daily. According to another aspect, the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 is to be administered orally. According to another aspect, the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 is to be administered in addi ⁇ on to treatment with another an ⁇ depressant drug.
  • the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 is to be administered as an adjunc ⁇ ve therapy to another an ⁇ depressant drug.
  • the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 to be administered as an adjunc ⁇ ve therapy to another an ⁇ depressant drug for the treatment of Major Depressive Disorder.
  • the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that the an ⁇ depressant drug is selected from the group consis ⁇ ng of selec ⁇ ve serotonin reuptake inhibitors (SSRI) and serotonin and norepinephrine reuptake inhibitors (SNRI).
  • SSRI serotonin reuptake inhibitors
  • SNRI serotonin and norepinephrine reuptake inhibitors
  • the present inven ⁇ on provides Compound 1 according to any one of the preceding aspects, characterized in that the an ⁇ depressant drug is selected from the group consis ⁇ ng of Sertraline, Sertraline Hydrochloride, Escitalopram, Escitalopram Oxalate, Fluoxe ⁇ ne, Duloxe ⁇ ne, Citalopram, Citalopram Hydrobromide, Desvenlafaxine Succinate Monohydrate, Doxepin, Fluoxe ⁇ ne Hydrochloride, Mirtazapine, Trazodone, and Venlafaxine Hydrochloride.
  • WO2020/079039 discloses the synthesis of Compound 1 Form II. Now, it has surprisingly been found that another polymorphic form, Compound 1 Form I, exists.
  • Both Compound 1 Form II and Compound 1 Form I can be synthesized in pure form.
  • Compound 1 Form II was obtained in a purity >99% (ra ⁇ o between Compound 1 Form II and Compound 1 Form I >99:1 based on XRPD).
  • both Compound 1 Form II and Compound 1 Form I are characterized by its corresponding XRPD, Raman, and DSC data.
  • the polymorphic form resul ⁇ ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, shows a X-ray powder diffrac ⁇ on pa ⁇ ern comprising a peak at the following 2-theta value measured using monochroma ⁇ c CuK ⁇ 1 radia ⁇ on of ⁇ 1.54056 ⁇ , 40kV, 40mA: 6.8° ⁇ 0.2°.
  • the polymorphic form resul ⁇ ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, shows a X-ray powder diffrac ⁇ on pa ⁇ ern comprising peaks at any one or all of the following 2-theta values measured using monochroma ⁇ c CuK ⁇ 1 radia ⁇ on of ⁇ 1.54056 ⁇ , 40kV, 40mA: 6.8° ⁇ 0.2°, 10.8° ⁇ 0.2°, 11.6° ⁇ 0.2°, 17.6° ⁇ 0.2°, 22.1° ⁇ 0.2°.
  • the polymorphic form resul ⁇ ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, shows a X-ray powder diffrac ⁇ on pa ⁇ ern comprising a peak at the Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 9 - 05.05.2025 following 2-theta value measured using monochroma ⁇ c CuK ⁇ 1 radia ⁇ on of ⁇ 1.54056 ⁇ , 40kV, 40mA: 6.8° ⁇ 0.2°, and the Raman spectrum comprises a peak at the following Raman shi ⁇ expressed in wavenumbers in cm-1: 89.8 ⁇ 1.5.
  • the polymorphic form resul ⁇ ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, has a purity >75% (ra ⁇ o between Compound 1 Form II and Compound 1 Form I >75:25 based on XRPD).
  • the polymorphic form resul ⁇ ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, has a purity >90% (ra ⁇ o between Compound 1 Form II and Compound 1 Form I >90:10 based on XRPD).
  • the polymorphic form resul ⁇ ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, has a purity >95% (ra ⁇ o between Compound 1 Form II and Compound 1 Form I >95:5 based on XRPD).
  • the polymorphic form resul ⁇ ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, has a purity >99% (ra ⁇ o between Compound 1 Form II and Compound 1 Form I >99:1 based on XRPD).
  • the present inven ⁇ on provides Compound 1 Form I having a purity >10% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >10:90 based on XRPD).
  • the present inven ⁇ on provides Compound 1 Form I having a purity >20% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >20:80 based on XRPD). According to another aspect, the present inven ⁇ on provides Compound 1 Form I having a purity >30% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >30:70 based on XRPD). According to another aspect, the present inven ⁇ on provides Compound 1 Form I having a purity >40% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >40:60 based on XRPD).
  • the present inven ⁇ on provides Compound 1 Form I having a purity >50% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >50:50 based on XRPD). According to another aspect, the present inven ⁇ on provides Compound 1 Form I having a purity >60% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >60:40 based on XRPD). According to another aspect, the present inven ⁇ on provides Compound 1 Form I having a purity >70% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >70:30 based on XRPD).
  • the present inven ⁇ on provides Compound 1 Form I having a purity >75% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >75:25 based on XRPD). According to another aspect, the present inven ⁇ on provides Compound 1 Form I having a purity >80% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >80:20 based on XRPD). According to another aspect, the present inven ⁇ on provides Compound 1 Form I having a purity >90% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >90:10 based on XRPD).
  • the present inven ⁇ on provides Compound 1 Form I having a purity >95% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >95:5 based on XRPD). Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 11 - 05.05.2025 According to another aspect, the present inven ⁇ on provides Compound 1 Form I having a purity >99% (ra ⁇ o between Compound 1 Form I and Compound 1 Form II >99:1 based on XRPD). In another aspect, the present inven ⁇ on relates to Compound 1, Compound 1 Form I, Compound 1 Form II or mixtures thereof for use in the treatment of above men ⁇ oned diseases, condi ⁇ ons and symptoms.
  • the present inven ⁇ on relates to the pharmaceu ⁇ cal composi ⁇ on comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and/or Magnesium stearate.
  • the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on comprising a tablet core consis ⁇ ng of Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and Magnesium stearate.
  • the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on comprising a tablet core consis ⁇ ng of 0.1-10 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 50-90 % (wt/wt) lactose monohydrate, 10-50 % (wt/wt) microcrystalline cellulose, 0.5-15 % (wt/wt) hydroxypropyl cellulose, 0.5-15 % (wt/wt) croscarmellose sodium and 0.1-3 % (wt/wt) Magnesium stearate.
  • the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on comprising a tablet core consis ⁇ ng of 0.3-7 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 55-80 % (wt/wt) lactose monohydrate, 15-45 % (wt/wt) microcrystalline cellulose, 1-7 % (wt/wt) hydroxypropyl cellulose, 1-7 % (wt/wt) croscarmellose sodium and 0.2-1 % (wt/wt) Magnesium stearate.
  • the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on comprising a tablet core consis ⁇ ng of 0.6-1 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 60-70 % (wt/wt) lactose monohydrate, 20-40 % (wt/wt) microcrystalline cellulose, 2-4 % (wt/wt) hydroxypropyl cellulose, 2-4 % (wt/wt) croscarmellose sodium and 0.3-0.8 % (wt/wt) Magnesium stearate.
  • mannitol, maize starch, croscarmellose sodium and/or Magnesium stearate with Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof in a pharmaceu ⁇ cal composi ⁇ on the drug load can be adjusted to the same level for all dose strengths and a fast dissolu ⁇ on of the tablet can be reached.
  • Another aspect of the present inven ⁇ on relates to the pharmaceu ⁇ cal composi ⁇ on comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and mannitol and/or maize starch.
  • the present inven ⁇ on relates to the pharmaceu ⁇ cal composi ⁇ on comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and mannitol, maize starch, croscarmellose sodium and/or Magnesium stearate.
  • the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on comprising a tablet core consis ⁇ ng of Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and mannitol, maize starch, croscarmellose sodium and Magnesium stearate.
  • the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on comprising a tablet core consis ⁇ ng of 0.1-10 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 40-95 % (wt/wt) mannitol, 2-20 % (wt/wt) Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 13 - 05.05.2025 maize starch, 0.5-10 % (wt/wt) croscarmellose sodium and 0.1-3 % (wt/wt) Magnesium stearate.
  • the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on comprising a tablet core consis ⁇ ng of 0.3-7 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 50-90 % (wt/wt) mannitol, 3-15% (wt/wt) maize starch, 1-7 % (wt/wt) croscarmellose sodium and 0.3-2 % (wt/wt) Magnesium stearate.
  • the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on comprising a tablet core consis ⁇ ng of 0.6-5 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 60-88 % (wt/wt) mannitol, 5-10 % (wt/wt) maize starch, 2-5 % (wt/wt) croscarmellose sodium and 0.5-1.5 % (wt/wt) Magnesium stearate.
  • the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on comprising a tablet core consis ⁇ ng of 3-20 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 40-95 % (wt/wt) mannitol, 2-20 % (wt/wt) maize starch, 0.5-10 % (wt/wt) croscarmellose sodium and 0.1-3 % (wt/wt) Magnesium stearate.
  • the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on comprising a tablet core consis ⁇ ng of 4-15 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 50-90 % (wt/wt) mannitol, 3-15 % (wt/wt) maize starch, 1-7 % (wt/wt) croscarmellose sodium and 0.3-2 % (wt/wt) Magnesium stearate.
  • the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on comprising a tablet core consis ⁇ ng of 6-10 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 60-88 % (wt/wt) mannitol, 5-10 % (wt/wt) maize starch, 2-5 % (wt/wt) croscarmellose sodium and 0.5-1.5 % (wt/wt) Magnesium stearate.
  • Another aspect of the present inven ⁇ on relates to a pharmaceu ⁇ cal composi ⁇ on as defined above for use in the above-men ⁇ oned diseases, condi ⁇ ons and symptoms.
  • Another aspect of the present inven ⁇ on relates to a method of treatment of above-men ⁇ oned diseases, condi ⁇ ons and symptoms.
  • Figure 1 shows the X-ray powder diffractogram of Compound 1 Form I
  • Figure 2 shows the X-ray powder diffractogram of Compound 1 Form II
  • Figure 3 shows the RAMAN spectrum of Compound 1 Form I
  • Figure 4 shows the RAMAN spectrum of Compound 1 Form II
  • Figure 5 shows the Differen ⁇ al Scanning Calorimetry profile for Compound 1 Form I
  • Figure 6 shows the Differen ⁇ al Scanning Calorimetry profile for Compound 1 Form II
  • Figure 7 shows Adjusted mean (SE) of absolute change from baseline in MADRS total score over ⁇ me
  • Compound 1 If not otherwise specified, the term Compound 1 relates to the compound of the following structure in any polymorphic form or mixtures or pharmaceu ⁇ cally acceptable salts or hydrates thereof. Subject Human pa ⁇ ent.
  • the standard error range for the 2-theta values is ⁇ 0.2°.
  • RAMAN spectroscopy Raman spectra were collected using an Agilent TRS 1000. Data was acquired over spectral range 38 – 2400 cm-1 using a 830 nm enhanced photo diode excita ⁇ on laser, a spot size of 4 mm and spectral resolu ⁇ on of ⁇ 8 cm -1 . The spectral resolu ⁇ on is 1.5 cm -1 .
  • the compounds are characterised by a mel ⁇ ng point determined by Differen ⁇ al Scanning Calorimetry (DSC), evaluated by the peak maximum or onset temperature.
  • DSC Differen ⁇ al Scanning Calorimetry
  • the hea ⁇ ng rate of the experiment is 10°C/min.
  • the values given were determined using a TA Instruments Discovery DSC 2500 TM .
  • the reac ⁇ on mixture is then heated to 60-65 °C and s ⁇ rred for about 2 hours. A ⁇ er the reac ⁇ on is complete, the batch is cooled to 5-10 °C. Water (204 kg) is added over not less than 30 min at a rate to maintain the internal batch temperature below 25 °C. The slurry is s ⁇ rred for not less than 8 hours. The product is collected byfiltra ⁇ on and rinsed with water (85.0 kg). The product is then dried in an oven at ⁇ 40 °C under reduced pressure for not less than 12 hours. I-3 is obtained as solid (25.2 kg, 97%).
  • I-4 is obtained as solid (15.2 kg). Seed crystals I-4 can be obtained by crystalliza ⁇ on of I-4 in acetonitrile and water.
  • the reac ⁇ on mixture is s ⁇ rred for about 1 hour and addi ⁇ onal thionyl chloride (9.1 kg, 76.1 mol) is added. A ⁇ er the reac ⁇ on is complete, the batch is cooled to 0-5 °C and added 2 M aqueous sodium hydroxide solu ⁇ on (121 kg), at a rate to maintain the internal temperature below 20 °C. The batch is then seeded with I-5 (100 g). Addi ⁇ onal 2 M aqueous sodium hydroxide solu ⁇ on (121 kg) is added to adjust the pH value to be >10.
  • the slurry is heated to 55-60 °C for dissolu ⁇ on,filtered at ⁇ 60 °C, and rinsed with a mixture of isopropanol (7.88 kg) and water (2.62 kg).
  • the batch is then cooled to 35-40 °C, seeded with I-5 (102 g), and aged for ⁇ 1 hour.
  • the batch is cooled to 5-10 °C over 2 hours and aged for not less than 8 h.
  • the slurry of the product isfiltered and washed with water (50.9 kg).
  • the product is dried in an oven at about 40 °C under reduced pressure for not less than 8 hours.
  • I-5 is obtained as solid (22.9 kg, 55% over two steps star ⁇ ng from I-3).
  • Seed crystals I-5 can be obtained by crystalliza ⁇ on of I-5 in isopropanol and water.
  • the reac ⁇ on mixture Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 28 - 05.05.2025 is s ⁇ rred at -10 °C for about 4 hours.
  • a ⁇ er full conversion, methylamine hydrochloride (7.55 kg, 111.8 mol) is added followed by the addi ⁇ on of pyridine (8.75 kg, 110.6 mol).
  • the batch is s ⁇ rred at -10 °C for about 1 hour un ⁇ l comple ⁇ on.
  • the reac ⁇ on mixture is quenched by the addi ⁇ on of water (24 kg) and 3 M aqueous hydrochloric acid solu ⁇ on (60.6 kg).
  • Seed crystals I-7 (85 g) is added and the slurry is aged at 30-40 °C for 1 hour. The slurry is then cooled to 20-25 °C over 1 hour and aged overnight. The slurry of the product isfiltered and washed with heptane (23 kg). The product is dried in an oven at 40-45 °C under reduced pressure for not less than 8 hours. I-7 is obtained as solid (12.1 kg, 67%). Seed crystals I-7 can be obtained by crystalliza ⁇ on of I-7 in isopropyl acetate and heptane.
  • a solu ⁇ on of I-5 (19.1 kg, 75.2 mol) in acetonitrile (45 kg) is then added.
  • the resul ⁇ ng reac ⁇ on mixture is heated to about 60 °C and s ⁇ rred for about 4 hours un ⁇ l comple ⁇ on.
  • the mixture is concentrated under reduced pressure at 40-45 °C to remove about 70 L of solvent.
  • the resul ⁇ ng mixture is cooled to 30-35 °C and isopropyl acetate (66 kg) is added prior to cooling the batch to 20-25 °C. Water (76 kg) is added followed by addi ⁇ on of concentrated hydrochloric acid (11.4 kg) to adjust the pH to not more than 5.
  • a ⁇ er phase separa ⁇ on the organic layer is discarded and the pH of the aqueous layer is adjusted to pH not less than 8 by addi ⁇ on of 2M NaOH (80 kg). Dichloromethane (151 kg) is added for extrac ⁇ on.
  • a ⁇ er phase separa ⁇ on the organic layer is par ⁇ ally removed under reduced pressure at 35-40 °C to reduce the reactor volume to about 47 L.
  • Heptane 104 kg is added over about 1 hour and the slurry is cooled to 20-25 °C and aged for not less than 8 hours. The slurry of the product isfiltered and washed with heptane (65 kg). The product is dried in an oven at 40-45 °C under reduced pressure for not less than 6 hours.
  • the solu ⁇ on is then cooled to 40-45 °C and added seed crystals Compound 1 Form II (44 g).
  • the slurry is aged at 40-45 °C for not less than 1 hour.
  • Water (242 kg) is added over not less than 2 hours.
  • the slurry is cooled to 20-25 °C over about 30 min and aged for not less than 6 hours.
  • the slurry isfiltered and the solid product is washed with water (44 kg).
  • the product is dried in an oven at about 65 °C under reduced pressure for not less than 12 hours.
  • Compound 1 Form II is obtained as solid (21.0 kg, 96%).
  • Seed crystals Compound 1 Form II can be obtained by crystalliza ⁇ on of 1 in isopropanol and water.
  • Prepara ⁇ on of Compound 1 Form I 1 crude (7.5g) is suspended in a mixture of isopropanol (37.5 ml) and water (37.5ml). The batch is heated to 60 o C to ensure complete dissolu ⁇ on and the solu ⁇ on is polishfiltered. Thefiltered solu ⁇ on is then transferred to a 1Lflask and water (375ml) is immediately added to quickly precipitate the solid, as Form I is a metastable form that must be collected quickly before conversion to Form II. The solid is then isolated byfiltra ⁇ on and dried under vacuum at 60oC.
  • the mixture is heated to about 80 °C over 30 min and s ⁇ rred for about 2 hours. A ⁇ er the reac ⁇ on is complete, water (4 kg) is added and the solu ⁇ on is cooled to about 40 °C. The agita ⁇ on is stopped and the aqueous layer is discarded. The organic layer is concentrated under reduced pressure at about 80 °C to remove isopropyl acetate ( ⁇ 4 L).
  • the batch is cooled to about 60 °C and added isopropanol (3 L).
  • the batch is cooled to about 50 °C and added isopropanol (0.5 L).
  • the batch is cooled to about 40 °C and added isopropanol (0.5 L).
  • the batch is cooled to about 30 °C and added a suspension of seed crystals II-2 (2 g) in isopropanol (20 mL).
  • the slurry is aged at about 30 °C for not less than 30 min and cooled to 5- 10 °C over 2 hours.
  • Water (4 kg) is added over 1 hour.
  • the slurry of the product is aged for not less than 1 hour at about 5 °C.
  • the slurry isfiltered and washed with water (4 kg).
  • the product is Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 32 - 05.05.2025 dried in an oven at about 40 °C under reduced pressure for not less than 24 hours.
  • II-2 is obtained as solid (1.09 kg, 90%).
  • Seed crystals II-2 can be obtained by crystalliza ⁇ on of 1 in isopropanol and water.
  • I-2 0.55 kg, 4.36 mol
  • the addi ⁇ on line is rinsed with acetonitrile (0.4 kg).
  • the mixture is heated to about 70 °C over not less than 45 minutes and s ⁇ rred for about 24 hours.
  • the batch is added water (1.5 kg) and cooled to 40-50 °C.
  • the agita ⁇ on is stopped and the lower aqueous layer is discarded.
  • Water (2 kg) is added.
  • Acetonitrile ( ⁇ 3.25 L) is removed under reduced pressure at 60-70 °C.
  • the batch temperature is adjusted to about 60 °C and isopropanol (2.33 kg) is added.
  • the batch is cooled to about 50 °C and added isopropanol (0.4 kg).
  • the batch is cooled to about 40 °C and added isopropanol (0.4 kg).
  • the batch is cooled to 5-10 °C and added water (2.98 kg).
  • the reactor is pressurized to 500 psi with syngas and heated to about 90 °C. A ⁇ er 24 hours, the reactor is cooled to about 25 °C, vented, and purged with nitrogen. The mixture isfiltered through Celite (0.1 kg) and rinsed with toluene (0.9 kg). Thefiltrate is washed with 10 wt% aqueous citric acid solu ⁇ on (1.66 kg). The organic phase is concentrated under reduced pressure at about 45 °C to obtain a solu ⁇ on of II-3 in toluene (668 g, 48.4 wt% by 1H NMR, 79%).
  • the reac ⁇ on mixture is cooled to 0-5 °C and added 50 wt% aqueous sodium hydroxide solu ⁇ on (1.92 kg, 23.9 mol) at a rate to maintain the internal batch temperature at not more than 20 °C.
  • Isopropyl acetate (7 kg) and water (8 kg) are added and the batch temperature is adjusted to 5- 10 °C.
  • a solu ⁇ on of benzyloxy chloroformate (1.58 kg, 8.78 mol) in isopropyl acetate (1 kg) followed by addi ⁇ on of 50 wt% aqueous sodium hydroxide solu ⁇ on (0.51 kg, 6.38 mol) at a rate to maintain the internal batch temperature at 5-10 °C.
  • the expected pH value is 11-12.
  • the reac ⁇ on mixture is then s ⁇ rred at 20-25 °C for about 1.5 hours. A ⁇ er comple ⁇ on, the lower aqueous layer is discarded and the organic layer is washed with water (6 kg). The organic layer is concentrated under reduced pressure at 50-60 °C to reduce the reactor volume to about 4-6 L.
  • Methyl tert-butyl ether (8 L) is added over 15 min at 50-60 °C and the batch temperature is adjusted to 40-45 °C.
  • a slurry of seed crystals II-4 in methyl tert-butyl ether (200 mL) is added and the batch is cooled to about 25 °C over 1 hour.
  • a mixture of methyl tert- butyl ether (8 L) and heptane (8 L) is added and the slurry is aged for about 1 hour.
  • the slurry of the product isfiltered and washed with heptane (16 L).
  • the product is dried in an oven at about 50 °C under reduced pressure for not less than 12 hours.
  • II-4 is obtained as solid (1.6 kg, 71%).
  • the reactor is sealed and purged with nitrogen.
  • the reactor is pressurized to 30 psi with hydrogen and heated to about 35 °C. A ⁇ er 4 hours, the reactor is cooled to about 25 °C, vented, and purged with nitrogen.
  • a solu ⁇ on of II-3 in toluene (1.38 kg, 42.3 wt%, 2.51 mol) is added.
  • the reactor is sealed and purged with nitrogen.
  • the reactor is pressurized to 30 psi with hydrogen and heated to about 50 °C. A ⁇ er 12 hours, the reactor is cooled to about 25 °C, vented, and purged with nitrogen.
  • the mixture is filtered through Celite (0.1 kg) and rinsed with ethanol (0.3 kg).
  • a ⁇ er phase separa ⁇ on the organic layer is collected and the aqueous layer is extracted with isopropyl acetate (2.52 kg).
  • the combined organic phase is concentrated under reduced pressure at about 50 °C to reduce the reactor volume to about 1-1.2 L.
  • the batch is cooled to about 40 °C and added heptane (4.1 kg).
  • the batch is cooled to about 20 °C over 30 min and aged for not less than 2 hours.
  • the slurry isfiltered and washed with heptane (1.7 kg).
  • the product is dried in an oven at 50-60 °C under reduced pressure for not less than 8 hours.1 crude is obtained as solid (0.8 kg, 87%).
  • Recrystalliza ⁇ on of 1 crude to prepare Compound 1 Form II can be performed according to the procedure described in Synthesis route I. Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 36 - 05.05.2025 Milling process Compound 1
  • the milling was performed using the pilot plant impact classifier mill (Hosokowa Alpine MPA 50 ZPS) applying the following process parameters for Compound 1 (unmilled Form II): Beater disc speed Classifier Speed Dosage [kg/h] Process gasflow [rpm] [rpm] [m 3 /h] 1 0000 5000 2 80** **measured a ⁇ er product separa ⁇ onfilter unit A par ⁇ cle size distribu ⁇ on of x50 ⁇ 25mm was achieved.
  • perace ⁇ c acid 103 mL, 491 mmol
  • perace ⁇ c acid 103 mL, 491 mmol
  • the reac ⁇ on mixture is s ⁇ rred at 10 °C for about 20 hours.
  • An aqueous 21 wt% sodium sulfite solu ⁇ on 49 g is added to quench peroxides.
  • Ethyl acetate 200 mL is added followed by the addi ⁇ on of saturated aqueous sodium bicarbonate solu ⁇ on (472 mL) to adjust pH to 6-8.
  • Prepara ⁇ on of Compound M-1 III-1 (4.0 g, 15.5 mmol) is charged to a pressure reactor followed by addi ⁇ on of 2,2,2- trifluoroethanol (20 mL). The reactor is sealed and heated to about 120 °C. The reac ⁇ on mixture is s ⁇ rred for about 2 hours. A ⁇ er full conversion, the batch is concentrated under reduced pressure at 50-55 °C to dryness. Methyl tert-butyl ether (40 mL) is added and the solvent is removed under reduced pressure at 50-55 °C. Methyl tert-butyl ether (40 mL) is added and the slurry is s ⁇ rred for about 0.5 hour.
  • III-2 is obtained as solid (2.3 g, Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 38 - 05.05.2025 92%).
  • III-2 (2.2 g, 14.2 mmol) is added to a round bo ⁇ omflask followed by addi ⁇ on of THF (14 mL).
  • NaH 60 wt%, 1.4 g, 15.6 mmol is added in one por ⁇ on at 20-25 °C.
  • the reac ⁇ on mixture is s ⁇ rred for about 1 hour.
  • Table 1 The X-ray powder reflec ⁇ on and intensi ⁇ es (standardised) are shown in Table 1.
  • Table 1 2 q [°] d-value [ ⁇ ] Intensity I/I0 [%] 5.34 16.54 100 10.67 8.28 22 15.99 5.54 8 20.27 4.38 10 21.22 4.18 6
  • 2-theta [°] denotes the angle of diffrac ⁇ on in degrees
  • the d- value [ ⁇ ] denotes the specified distances in ⁇ between the la ⁇ ce planes.
  • the crystalline Compound 1 Form I is characterised in that in the Raman spectrum has characteris ⁇ c bands at 64.9 cm-1 ⁇ 1.5, 99.6 cm-1 ⁇ 1.5.
  • thermoanalysis of the crystalline Compound 1 Form I shows an onset of mel ⁇ ng at 124.0 ⁇ 1.1 °C (with a mel ⁇ ng peak at 124.8 ⁇ 0.5 °C, DSC: 10 K.min-1 hea ⁇ ng rate; DSC/TG diagram is shown in Figure 5).
  • Compound 1 Form II is highly crystalline as can be seen in the X-ray powder diffrac ⁇ on diagram in Figure 2 and RAMAN spectrum in Figure 4.
  • the X-ray powder reflec ⁇ on and intensi ⁇ es are shown in Table 2.
  • the crystalline Compound 1 Form II is characterised in that in the Raman spectrum has characteris ⁇ c band at 89.8 cm-1 ⁇ 1.5.
  • thermoanalysis of the crystalline Compound 1 Form II shows an onset of mel ⁇ ng at 128.3 ⁇ 1.5 °C (with a mel ⁇ ng peak at 129.4 ⁇ 1.5 °C, DSC: 10 K.min-1 hea ⁇ ng rate; DSC/TG diagram is shown in Figure 6).
  • the pharmaceu ⁇ cal composi ⁇ on according to the inven ⁇ on is a tablet core or a tablet for oral administra ⁇ on.
  • the tablet core is comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and/or Magnesium stearate.
  • the pharmaceu ⁇ cal composi ⁇ on according to the inven ⁇ on is a tablet core or a tablet for oral administra ⁇ on.
  • the tablet core is comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and mannitol, maize starch, croscarmellose sodium and/or Magnesium stearate.
  • the tablet is op ⁇ onally comprising afilm coa ⁇ ng, enveloping said tablet core.
  • thefilm coat consists of different, and commonly used amounts of hypromellose, propylene glycol, talc, calcium carbonate, and iron oxides. 1 Removed during processing, not present in thefinal product Formula ⁇ on 1, Formula ⁇ on 2, and Formula ⁇ on 3 exhibit very fast and complete dissolu ⁇ on characteris ⁇ cs.
  • the results of the drug substance-excipient compatibility study indicate that Formulations 2 and 3 containing mannitol and maize starch exhibit an increased stability. Further, the stress stability results indicate that the film-coating containing propylene glycol as a plasticizer shows superior stability compared to the film-coating containing macrogol.
  • a pharmaceu ⁇ cal composi ⁇ on comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof in Formula ⁇ on 3 leads to adjustment of the drug load to the same level for all dose strengths, and a fast dissolu ⁇ on of the tablet can be reached.
  • a colouredfilm coat may be added that allows differen ⁇ a ⁇ on of the different dosage strengths.
  • Formula ⁇ on 1, Formula ⁇ on 2, and Formula ⁇ on 3 may be obtained by using Compound 1, Compound 1 Form I, Compound 1 Form II, or mixtures thereof, respec ⁇ vely.
  • Formula ⁇ on 1, Formula ⁇ on 2, and Formula ⁇ on 3 are useful pharmaceu ⁇ cal composi ⁇ ons.
  • the Formulation 1 is preferably produced using the following equipment: - High-shear granulator - Screening mill - Tray dryer or fluid-bed dryer - Screening mill - Diffusion mixer Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 46 - 05.05.2025 - Tablet press
  • the Formula ⁇ on 2 is preferably produced using the following equipment: - Diffusion mixer - Screening mill - Roller compactor - Tablet press
  • the Formula ⁇ on 3 is preferably produced using the following equipment: - Diffusion mixer - Screening mill - Roller compactor - Tablet press - Mixing vessel with propeller mixer and/or homogenizer for film-coating suspension - Film coater C) Process descrip ⁇ on: Wet granula ⁇ on process (preferably for produc ⁇ on of Formula ⁇ on 1) Granula ⁇ on For high shear granula ⁇ on the required quan ⁇ ty of Compound 1 (depending on the dose strength), lactose monohydrate, microcrystalline
  • the granula ⁇ on liquid is added either manually or by spray nozzles and the wet mass is granulated for about 1-10 min, again using impeller and chopper blades.
  • a ⁇ er discharging of the high shear mixer/granulator the wet granules are wet-screened through a 1-5 mm mesh size sieve to destroy large agglomerates.
  • the wet-screened material is transferred to a conven ⁇ onal tray drier (orfluid bed drier) and dried at an inlet air temperature of approximately 50 - 100 °C.
  • Granules are dried when the water ac ⁇ vity of the resul ⁇ ng dry granules is below 0.6.
  • the dried granules are then dry screened with the help of a screening mill, e.g. Comil screen machine. Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 47 - 05.05.2025
  • the screened granules arefilled into a suitable diffusion mixer, e.g. a container mixer, croscarmellose sodium (crosslinked carboxymethylcellulose sodium) and magnesium stearate are added subsequently, and blended for in sum 5 - 20 min, preferably 13 minutes at a mixing speed of 10 rpm un ⁇ l homogeneous. Tabletting
  • Thefinal table ⁇ ng blend is compressed on a suitable tablet press (e.g.
  • Dry granula ⁇ on process (preferably for produc ⁇ on of Formula ⁇ on 2 and 3) Granulation
  • mannitol, maize starch and croscarmellose sodium are mixed using a diffusion mixer homogeneously for about 5-30 min.
  • the mixture is screened with the help of a screening mill.
  • the screened mixture isfilled into a suitable diffusion mixer, e.g. a container mixer, and magnesium stearate are added subsequently, and blended for in sum 1 - 10 min, preferably 5 minutes at a mixing speed of 18 rpm un ⁇ l homogeneous.
  • the resul ⁇ ng blend is compressed with a roller compactor into ribbons, which are subsequently milled by an integrated screening mill into granules.
  • the granules are filled into a suitable diffusion mixer, e.g. a container mixer, and magnesium stearate are added subsequently, and blended for in sum 1 - 10 min, preferably 5 minutes at a mixing speed of 18 rpm until homogeneous.
  • a suitable diffusion mixer e.g. a container mixer
  • magnesium stearate are added subsequently, and blended for in sum 1 - 10 min, preferably 5 minutes at a mixing speed of 18 rpm until homogeneous.
  • Thefinal table ⁇ ng blend is compressed on a suitable tablet press (e.g. rotary press) to the respec ⁇ ve target weight of the required dose strength of Compound 1 tablets using the appropriate tools (e.g.
  • Tablets of all dosages are compressed to result in a tensile strength of approximately 1.5 MPa, this tensile strength is translated into individual hardness specifica ⁇ ons for all dosages according to the equa ⁇ ons given in the USP/NF.
  • Film-coating A coloredfilm coa ⁇ ng may be applied to the tablet cores for product differen ⁇ a ⁇ on to prevent from medica ⁇ on errors.
  • a coa ⁇ ng suspension is prepared byfilling purified water into a suitable mixing vessel, and dissolving propylene glycol and then hydroxypropylmethylcellulose with the help of a propeller or high shear s ⁇ rrer.
  • an aqueous slurry of calcium carbonate, talc, iron oxide yellow and/or iron oxide red if needed (in case of coloredfilm tablets) is poured and s ⁇ rred into thefilm-forming polymer solu ⁇ on.
  • the dry ma ⁇ er of this coa ⁇ ng suspension is in the range of 10 -20%, preferably about 10-15 %.
  • the suspension may also be prepared from a ready to use dry mixture that contains the same or chemically comparable components.
  • the above prepared tablet cores arefilled into a suitablefilm coater (i.e.
  • alterna ⁇ vely Accela Cota pan with perforated pan and top spray system is also applicable, less preferred is a pan coater), and preheated up to a temperature of approximately 40 - 50 °C or above at an inlet air temperature of approximately 60 - 70 °C, preferably at 65 °C.
  • a ⁇ er this product temperature is reached the coa ⁇ ng suspension is sprayed onto the cores with the help of one or more spray nozzles.
  • the spraying isfinished thefilm- coated tablets may be dried if needed, then cooled down to 45 °C or below before the Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 49 - 05.05.2025 equipment is discharged.
  • the total process ⁇ me for thefilm-coa ⁇ ng is in the range of 1 - 6 hours (depending on the spray rate as well as the batch size), other process dura ⁇ ons are also feasible.
  • Direct compression process (preferably for produc ⁇ on of Formula ⁇ on 3) Blending Compound 1, mannitol, maize starch and croscarmellose sodium are blended using a diffusion mixer.
  • the powder mixture is sieved with the help of a screening mill.
  • the sieved mixture is blended using a diffusion mixer.
  • Predetermined hardness specifica ⁇ ons for the different tool dimensions have to be followed in order to achieve the intended drug dissolu ⁇ on profile and product characteris ⁇ cs.
  • Tablets of all dosages are compressed to result in a tensile strength of approximately 1.5 MPa, this tensile strength is translated into individual hardness specifica ⁇ ons for all dosages according to the equa ⁇ ons given in the USP/NF.
  • Film-coating A coloredfilm coa ⁇ ng may be applied to the tablet cores for product differen ⁇ a ⁇ on to prevent from medica ⁇ on errors.
  • a coa ⁇ ng suspension is prepared byfilling purified water into a suitable mixing vessel, and dissolving propylene glycol and then hydroxypropylmethylcellulose with the help of a propeller or high shear s ⁇ rrer.
  • an aqueous slurry of calcium carbonate, talc, iron oxide yellow and/or iron oxide red if needed (in case of coloredfilm tablets) is poured and s ⁇ rred into thefilm-forming polymer solu ⁇ on.
  • the dry ma ⁇ er of this coa ⁇ ng suspension is in the range of 10 -20%, preferably about 10-15 %.
  • the suspension may also be prepared from a ready to use dry mixture that contains the same or chemically comparable components.
  • the above prepared tablet cores arefilled into a suitablefilm coater (i.e. with perforated pan and top spray system, alterna ⁇ vely Accela Cota pan with perforated pan and top spray system is also applicable, less preferred is a pan coater), and preheated up to a temperature of approximately 40 - 50 °C or above at an inlet air temperature of approximately 60 - 70 °C, preferably at 65 °C.
  • Clinical trial 1 single oral administra ⁇ on of Compound 1 A randomized, double-blind, placebo-controlled, parallel-group single administra ⁇ on trial assessing the safety, tolerability, PK, and preliminary efficacy of Compound 1 in two different doses (5 mg and 20 mg) versus placebo (1:1:1 randomiza ⁇ on) as an adjunc ⁇ ve therapy to selec ⁇ ve serotonin reuptake inhibitors (SSRI)/serotonin and norepinephrine reuptake inhibitors (SNRI) in pa ⁇ ents with Major Depressive Disorder.
  • SSRI serotonin reuptake inhibitors
  • SNRI norepinephrine reuptake inhibitors
  • STUDY medicine Compound 1 (5 mg and 20 mg) and matching placebo were supplied as un-coated tablets (Formula ⁇ on 1, oral administra ⁇ on).
  • STUDY POPULATION In total, 59 pa ⁇ ents with depression (Major Depressive Disorder, MDD) on stable an ⁇ depressant treatment (Table 8) as described below were randomized into this trial.
  • pa ⁇ ents have shown insufficient treatment response (defined by less than 50 % response to one or more an ⁇ depressant drugs of adequate dose and treatment dura ⁇ on (according to Summary of Product Characteris ⁇ cs) as evaluated by An ⁇ depressant Treatment Response Ques ⁇ onnaire (ATRQ).
  • Pa ⁇ ents who, in addi ⁇ on to their monotherapy with an SSRI/SNRI, are taking addi ⁇ onal low dose an ⁇ depressant medica ⁇ ons for purposes other than trea ⁇ ng depressive symptoms, are not excluded. The dose must be less than the lowest dose indicated for MDD. Use of bupropion is not allowed.
  • SSRI Serotonin Reuptake Inhibitors
  • SNRI Serotonin- Norepinephrine Reuptake Inhibitors
  • MADRS Montgomery- ⁇ sberg Depression Ra ⁇ ng Scale
  • MADRS is a ten-item ques ⁇ onnaire used to measure the severity of Major Depressive Disorder (MDD).
  • MDD Major Depressive Disorder
  • MADRS AUC0-166:30 MADRS is a ten-item ques ⁇ onnaire used to measure the severity of Major Depressive Disorder (MDD).
  • MDD Major Depressive Disorder
  • the possible total score could range from 0 to 60 (from normal with absence of symptoms to severe depression). Up to Day 15 Other Endpoints - Number and percentage of pa ⁇ ents with drug-related AEs from start of treatment to Day 15. - Change from baseline in MADRS total score at individual ⁇ me points throughout the trial - MADRS response (defined as a reduc ⁇ on of at least 50% from baseline, at individual ⁇ me points) - Remission (defined as a value ⁇ 10, at individual ⁇ me points), and change from baseline in Leuven affect and pleasure scale (LAPS) subscales at individual ⁇ me points.
  • LAPS Leuven affect and pleasure scale
  • PK parameters of Compound 1 including maximum plasma concentra ⁇ on (Cmax), ⁇ me from dosing to Cmax (tmax), area under for concentra ⁇ on- ⁇ me curve from 0 to last quan ⁇ fiable data point (AUZ 0–tz ) and t1 to 2 (AUC t1–t2 ), were evaluated.
  • Cmax maximum plasma concentra ⁇ on
  • tmax ⁇ me from dosing to Cmax
  • AUZ 0–tz area under for concentra ⁇ on- ⁇ me curve from 0 to last quan ⁇ fiable data point
  • t1 to 2 AUC t1–t2
  • STATISTICAL METHODS Analysis of covariance has been used for the analysis of the primary and secondary endpoints.
  • These models includefixed effects for baseline MADRS total score and treatment. Further con ⁇ nuous endpoints have been analysed using a mixed model for repeated measures. Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 55 - 05.05.2025
  • This model includesfixed effects for baseline value, treatment, ⁇ me, treatment-by- ⁇ me interac ⁇ on, and baseline-by- ⁇ me interac ⁇ on; random subject effects have been incorporated into an unstructured within-subject covariance matrix. Descrip ⁇ ve sta ⁇ s ⁇ cs have been calculated for all endpoints.
  • the 20 mg dose demonstrated rapid ac ⁇ ng an ⁇ depressant effects, sustained for five days post-administra ⁇ on – a difference of 3.4, 3.6 and 4.9 MADRS points improvement over placebo at Day 2, 4, and 6 a ⁇ er a single oral administra ⁇ on.
  • a clinically meaningful change from baseline was found a ⁇ er 8 days for both 5 mg and 20 mg (see Table 9 and Figure 7). This is a signal not only of a rapid effect but also of an effect that is sustained over ⁇ me.
  • Plasma exposure increases propor ⁇ onally with the dose between 5 mg and 20 mg.
  • PK pharmacokine ⁇ c
  • its pharmacokine ⁇ c (PK) profile is characterized by rapid ac ⁇ on and clearance, a feature o ⁇ en referred to as a 'hit and run' profile.
  • These characteris ⁇ cs support the poten ⁇ al for daily administra ⁇ on of the Compound 1.
  • the long-las ⁇ ng efficacy as seen in Figure 7 may support twice weekly, every other day or once weekly administra ⁇ on.
  • Test solu ⁇ ons Intracellular (pipe ⁇ e) solu ⁇ on: (all concentra ⁇ ons in mM) CsCl 20, CsF 110, HEPES 10, EGTA 5, MgCl 2 1, cAMP 0.4, Mg-ATP 4;
  • Perfusion solu ⁇ on (vehicle) Perfusion solu ⁇ on (baseline) + 100 ⁇ M NMDA and 1 ⁇ M Glycine;
  • Perfusion solu ⁇ on (metabolite M-1) Perfusion solu ⁇ on (vehicle) + M-1 at a concentra ⁇ on of 0.03 - 10 ⁇ M dissolved in DMSO at afinal concentra ⁇ on of 0.1 %.
  • Inhibi ⁇ on of NR1/2B during constant channel opening Patch clamp recordings were performed in whole-cell configura ⁇ on by use of PatchMaster so ⁇ ware. Following seal forma ⁇ on and establishing the whole cell configura ⁇ on by disrup ⁇ ng the cell membrane in the ⁇ p of the patch pipe ⁇ e, cells were typically clamped in whole cell mode at a poten ⁇ al of -60 mV. A ⁇ er reaching a stable baseline recording, the cell was superfused with control solu ⁇ on and subsequently with a concentra ⁇ on of 0.03 - 10 ⁇ M of the metabolite M-1. Solu ⁇ ons were applied by a gravity driven system for 120 sec in presence of the agonists NMDA (100 ⁇ M) and Glycin (1 ⁇ M).
  • M-1 was tested in a cumula ⁇ ve manner at Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 62 - 05.05.2025 concentra ⁇ ons of 0 ⁇ M (control), 0.03, 0.1, 0.3, 1, 3 and 10 ⁇ M with an applica ⁇ on dura ⁇ on of 60s for each compound concentra ⁇ on.
  • Cells were recorded as long as the seal resistance, series resistance and leakage current remained stable. Only cells with stable parameters were included to the analysis.
  • Ketamine (10 ⁇ M) was applied to inhibit NR1/2B dependent currents. Current responses for analysis were taken as a mean amplitude of the last 10 seconds of control or compound applica ⁇ on.
  • concentra ⁇ on a [%] block is calculated by dividing the current induced during compound applica ⁇ on by the mean measured NMDA/Glycine induced current (control).
  • Compound 1 may be used as a medicament, characterized in that Compound 1 is to be administered orally.
  • Compound 1 may be used in the treatment of psychiatric disorders, characterized in that Compound 1 is to be administered orally.
  • Compound 1 may be used in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma ⁇ c Stress Disorder, and/or Borderline Personality Disorder characterized in that Compound 1 is to be administered orally.
  • Compound 1 may be used as a medicament, characterized in that Compound 1 is to be administered once daily, twice weekly, every other day or once weekly.
  • Compound 1 may be used in the treatment of psychiatric disorders, characterized in that Compound 1 is to be administered once daily, twice weekly, every other day or once weekly.
  • Compound 1 may be used in the treatment of psychiatric disorders, characterized in that Compound 1 is to be administered once daily. Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 63 - 05.05.2025 Compound 1 may be used as a medicament, characterized in that 5 to 20 mg of Compound 1 are to be administered. Compound 1 may be used as a medicament, characterized in that 5, 10 or 20 mg of Compound 1 are to be administered. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that 5 to 20 mg of Compound 1 are to be administered. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that 5, 10 or 20 mg of Compound 1 are to be administered.
  • Compound 1 has the poten ⁇ al to address core symptoms of depression, emo ⁇ onal dysregula ⁇ on, anxiety and suicidality, all of which are domains sugges ⁇ ve of its effect in Borderline Personality Disorder (BPD).
  • BPD Borderline Personality Disorder
  • Pa ⁇ ents who, in addi ⁇ on to their monotherapy with an SSRI/SNRI, are taking addi ⁇ onal low dose an ⁇ depressant medica ⁇ ons for purposes other than trea ⁇ ng Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 65 - 05.05.2025 depressive symptoms, are not excluded. The dose must be less than the lowest dose indicated for MDD. 4) In the current episode, pa ⁇ ents have shown insufficient treatment response defined by less than 50% response to a maximum of 4 an ⁇ depressant treatments of adequate dose and treatment dura ⁇ on (according to Summary of Product Characteris ⁇ cs) as evaluated by the an ⁇ depressant treatment response ques ⁇ onnaire (ATRQ).
  • ATRQ an ⁇ depressant treatment response ques ⁇ onnaire
  • EXCLUSION CRITERIA 1 Per MINI, have ever met diagnos ⁇ c criteria for schizophrenia, schizoaffec ⁇ ve disorder, schizophreniform disorder, bipolar disorder, or delusional disorder. 2) Diagnosis with an ⁇ social, paranoid, schizoid or schizotypal personality disorder, or MDD with psycho ⁇ c features as per Diagnos ⁇ c and Sta ⁇ s ⁇ cal Manual of Mental Disorders, Fi ⁇ h Edi ⁇ on (DSM-5) criteria, at the ⁇ me of screening visit. Any other personality disorder at screening visit that significantly affects current psychiatric status and likely to impact trial par ⁇ cipa ⁇ on, as per the judgement of inves ⁇ gator.
  • RANDOMIZATION Pa ⁇ ents eligible for the trial based on the aforemen ⁇ oned criteria will be assigned at random in a 2:1:1:2 ra ⁇ o to one of 4 study arms (placebo qd, 5 mg Compound 1 qd, 10 mg Compound 1 qd, 20 mg Compound 1 qd) and treated for 6 weeks.
  • Boehringer Ingelheim Interna ⁇ onal GmbH 01-3592-WO-1 - 66 - 05.05.2025 VARIABLES ASSESSED The primary and key secondary efficacy endpoints are summarized below. Efficacy Endpoints Change from baseline in Montgomery- ⁇ sberg Depression Ra ⁇ ng Scale (MADRS) total score at Day 8. The MADRS evaluates core symptoms of depression.
  • SMDDS Major Depressive Disorder Scale
  • the SMDDS is a 16-item, pa ⁇ ent-reported outcome (PRO) measure developed to capture the core symptoms of major depressive disorder (MDD).
  • Pa ⁇ ents respond to each ques ⁇ on using a ra ⁇ ng scale between 0 ("Not at all” or “Never") to 4 ("Extremely” or “Always”).
  • the total score ranges from 0 to 60 with a higher score indica ⁇ ng more severe depressive symptomatology. It is calculated by crea ⁇ ngfirst a single score for items 11 and 12 by selec ⁇ ng the highest severity on either item, and then crea ⁇ ng the sum of the 15 responses. Change from baseline in SMDDS total score at Week 4.
  • Placebo approximately 74 pa ⁇ ents Compound 1 (5 mg): approximately 37 pa ⁇ ents Compound 1 (10 mg): approximately 37 pa ⁇ ents Compound 1 (20 mg): approximately 74 pa ⁇ ents VARIABLES ASSESSED
  • the primary and key secondary efficacy endpoints are summarized below. Primary Endpoints Change from baseline in Montgomery- ⁇ sberg Depression Ra ⁇ ng Scale (MADRS) total score at Week 6. Secondary Endpoints None.
  • Compound 1 may be used as a medicament, characterized in that 0.5 - 40 mg of Compound 1 are to be administered.
  • Compound 1 may be used as a medicament, characterized in that 2.5 - 25 mg of Compound 1 are to be administered.
  • Compound 1 may be used as a medicament, characterized in that 0.5, 2.5, 5, 10, 20, 25, 30, or 40 mg of Compound 1 are to be administered.
  • Compound 1 may be used as a medicament, characterized in that 2.5, 5, 10, 20, or 25 mg of Compound 1 are to be administered.
  • Compound 1 may be used as a medicament, characterized in that Compound 1 it to be administered once daily, twice weekly, every other day or once weekly.

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Abstract

The present invention relates to Compound 1 for the use in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Traumatic Stress Disorder, and/or Borderline Personality Disorder, chemical synthesis of Compound 1, polymorphs of Compound 1, and pharmaceutical compositions comprising Compound 1 and/or its polymorphs.

Description

Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 1 - 05.05.2025 New medical use of Compound 1 The present inven^on relates to Compound 1 for the use in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma^c Stress Disorder, and/or Borderline Personality Disorder, chemical synthesis of Compound 1, polymorphs of Compound 1, and pharmaceu^cal composi^ons comprising Compound 1 and/or its polymorphs. Major depressive disorder (MDD) has been ranked as the third cause of the burden of disease worldwide in 2008 by WHO, which has projected that this disease will rankfirst by 2030 (Malhi GS, Mann JJ. Depression. Lancet.2018 Nov 24;392(10161):2299-2312). It is diagnosed when an individual has a persistently low or depressed mood, anhedonia or decreased interest in pleasurable ac^vi^es, feelings of guilt or worthlessness, lack of energy, poor concentra^on, appe^te changes, psychomotor retarda^on or agita^on, sleep disturbances, or suicidal thoughts. Per the Diagnos^c and Sta^s^cal Manual of Mental Disorders, 5th Edi^on (DSM-5), an individual must havefive of the above-men^oned symptoms, of which one must be a depressed mood or anhedonia causing social or occupa^onal impairment, to be diagnosed with MDD. The 12-month prevalence of major depressive disorder varies considerably across countries but is approximately 6%, overall. The life^me risk of depression is three ^mes higher (15–18%), meaning major depressive disorder is common, with almost one infive people experiencing one episode at some point in their life^me. The onset of depression is usually gradual, but it can be abrupt some^mes, and depression’s course throughout life varies considerably. This disorder is a recurrent lifelong illness, and with treatment e.g an^depressants, episodes last about 3–6 months, and most pa^ents recover within 12 months. Longer-term (2–6 years), the propor^on of people who recover is much less, dropping to approximately 60% at 2 years, 40% at 4 years, and 30% at 6 years with comorbid anxiety having a key role in limi^ng recovery. The pharmacotherapy for major depressive disorder has been founded on enhancement of monoaminergic neurotransmission, e.g. by selec^ve serotonin reuptake inhibitors (SSRIs), but treatment response is only around 40-50% (Steinert T, World Psychiatry.2018 Feb;17(1):114-115), so that ul^mately there are about 30% of pa^ent, where treatment failed and meet the criteria treatment-resistant (McIntyre et al. World Psychiatry. 2023 Oct; 22(3): 394–412). Newer genera^ons of poten^al an^depressants try to target other Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 2 - 05.05.2025 brain systems such as the glutamatergic and/or GABAergic system by e.g. inhibi^on of N- methyl-D-aspartate (NMDA) receptors. Bipolar disorder (BD) is a serious and debilita^ng psychiatric disorder affec^ng mul^ple domains of mood, emo^ons, and cogni^on (Jawad et al. Brain Sci.2023 Jun 4;13(6):909). Overall, BD has a global prevalence of >1% and cons^tutes a major healthcare burden. Pa^ents with BD o^en have two dis^nct mood episodes, i.e., mania/hypomania and depression. Using the criteria for mood episodes and their dura^on, severity, and occurrence, BD is broadly classified into BD-I, BD-II, and cyclothymia in the Diagnos^c and Sta^s^cal Manual of Mental Disorders (DSM) 5th edi^on. Bipolar depression accounts for the majority of ^me spent unwell for pa^ents with bipolar disorder; high rates of morbidity and mortality arise from full symptoma^c episodes and interepisode subsyndromal symptoms (McIntyre et al., Curr Med Res Opin.2019 Nov;35(11):1993-2005). Life^me and 12 month prevalence of bipolar II disorder, a common bipolar phenotype that is related to chronic depression, have been es^mated at 1.1% and 0.8%, respec^vely, with briefer and less severe hypomanic episodes thought to be experienced by up to 4–6% of the popula^on. More than 90% of individuals who have a manic episode proceed to develop recurrent mood episodes and about 60% of manic episodes occur immediately before a major depressive episode. Though mania/hypomania are the defining features of BD, pa^ents typically spend rela^vely more ^me experiencing depressive symptoms, and despite the significant burden of bipolar depression, there are only a handful of Food and Drug Administra^on (FDA)-approved treatments for this specific condi^on (i.e., olanzapine andfluoxe^ne combina^on, que^apine, lurasidone, cariprazine, and lumateperone), which have significant long-term adverse effects (Cordner ZA., General Psychiatry, 2022;35:e100760. doi:10.1136/gpsych-2022-100760). Obsessive compulsive disorder (OCD) is a long-las^ng disorder in which a person experiences uncontrollable and recurring thoughts (obsessions), engages in repe^^ve behaviors (compulsions), or both (Na^onal Ins^tute of Mental Health homepage: www.nimh.nih.gov/health/topics/obsessive-compulsive-disorder-ocd). People with OCD, classified by the Diagnos^c and Sta^s^cal Manual of Mental Disorders (DSM) 5th edi^on, have ^me-consuming symptoms that can cause significant distress or interfere with daily life and they may have obsessions, compulsions, or both. Obsessions^are repeated thoughts, urges, or mental images that are intrusive, unwanted, and make most people anxious. Common obsessions include: Fear of germs or contamina^on; Fear of forge^ng, losing, or misplacing something; Fear of losing control over one’s behavior; Aggressive thoughts toward others or Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 3 - 05.05.2025 oneself; Unwanted, forbidden, or taboo thoughts involving sex, religion, or harm; Desire to have things symmetrical or in perfect order. Compulsions are repe^^ve behaviors a person feels the urge to do, o^en in response to an obsession. Common compulsions include: Excessive cleaning or handwashing; Ordering or arranging items in a par^cular, precise way; Repeatedly checking things, such as that the door is locked or the oven is off; Compulsive coun^ng; Praying or repea^ng words silently. OCD has a life^me prevalence of 2–3% and is more common in females than in males (Stein et al., Nat Rev Dis Primers, 2019 Aug 1;5(1):52. doi: 10.1038/s41572-019-0102-3). OCD typically starts early in life and has a long dura^on, and in females, onset o^en occurs during adolescence. Treatment of OCD comprises several components, star^ng with building a therapeu^c alliance with the pa^ent and psychoeduca^on, followed by psychological and/or pharmacological approaches. Regarding pharmacotherapy, SSRIs are thefirst-line pharmacological treatment for OCD based on their evidence of efficacy, tolerability, safety and absence of abuse poten^al, but responder rates are poor and side effects might limit their use in OCD, so that ul^mately, be^er (and preferably faster) treatments are needed to help more individuals with OCD. Post-Trauma^c Stress Disorder (PTSD) is a disorder that develops in some people who have experienced a shocking, scary, or dangerous event, and it is characterized by symptoms of re- experiencing, avoidance, nega^ve altera^ons in cogni^on and mood, and marked altera^ons in arousal and reac^vity following exposure to a trauma^c event (Merians et al., Med Clin North Am.2023 Jan;107(1):85-99. doi: 10.1016/j.mcna.2022.04.003). Symptoms of PTSD usually begin within 3 months of the trauma^c event, but they some^mes emerge later. Based on the Diagnos^c and Sta^s^cal Manual of Mental Disorders (DSM) 5th edi^on, to meet the criteria for PTSD, a person must have symptoms for longer than 1 month, and the symptoms must be severe enough to interfere with aspects of daily life, such as rela^onships or work. The symptoms also must be unrelated to medica^on, substance use, or other illness. In America, around 3.6% of the grown-up popula^on, which is es^mated to be 5.2 million, have PTSD over a year (Thakur et al., Curr Mol Pharmacol.2022;15(3):502-516). PTSD is a long-life effect of the con^nuous occurrence of trauma^c condi-^ons, leading to the produc^on of feelings of helplessness, intense fear, and horror in the person. Treatment of PTSD includes the removal or reduc^on of th-ese emo^onal feelings or symptoms with the aim to improve the daily life func^oning of a person, and it might include also pharmacotherapy with SSRIs. However, based on reviews and meta-analyses showing that pharmacotherapies are less effec^ve than trauma- focused psychotherapeu^c interven^ons in reducing PTSD severity, pharmacotherapies are recommended as only as second-line treatment. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 4 - 05.05.2025 Boderline Personality Disorder (BPD) is a serious mental health disorder characterized by pervasive instability in moods, interpersonal rela^onships, self-image, and behavior. The disorder's pervasive instability in moods, interpersonal rela^onships, self-image, and behavior o^en disrupts family dynamics, work life, and the individual's sense of self-iden^ty. BPD is a mental health condi^on that places a significant burden not only on the individuals diagnosed with it but also on their families and the broader health-care systems. BPD affects approximately 1.6% of the general popula^on, but thisfigure may be as high as 5.9%. It is more commonly diagnosed in females, with 75% of diagnoses made in women. BPD can occur in anyone, but the onset of a coherent syndrome of BPD typically occurs during adolescence, generally a^er the age of 12 years (Bohus M, Stoffers-Winterling J, Sharp C, Krause-Utz A, Schmahl C, Lieb K, Lancet October 23, 2021; Volume 398 (Issue 10310), 1528- 1540. doi: 10.1016/S0140-6736(21)00476-1.). This cri^cal period of development is o^en marked by significant emo^onal and psychological changes, which can exacerbate the symptoms of BPD. The disorder appears to be more common in those with a family history of the disorder or a history of child abuse, neglect, or separa^on from caregivers in early childhood. BPD o^en co-develops with or is preceded by symptoms of internalizing disorders such as depression and anxiety, and externalizing disorders like conduct problems, hyperac^vity, and substance use. This comorbidity further complicates the diagnosis and management of BPD. The disorder is associated with various adverse outcomes, including low occupa^onal and educa^onal a^ainment, lack of long-term rela^onships, increased partner conflict, sexual risk-taking, low levels of social support, and low life sa^sfac^on. These outcomes highlight the pervasive impact of BPD on mul^ple aspects of an individual's life. Increased service use is another significant concern associated with BPD. Individuals with the disorder o^en require extensive mental health services, including psychotherapy and, in some cases, medica^on for comorbid condi^ons or during crises when psychosocial interven^ons are insufficient. WO2020/079039 discloses a number of 4-pyrazin-2-ylmethyl-morpholines showing NR2B nega^ve allosteric modula^ng proper^es. Among others, WO2020/079039 discloses Compound 1 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 5 - 05.05.2025 Further, WO2020/079039 generically discloses that the compounds exemplified therein may be used in the treatment of psychiatric disorders, diseases and condi^ons wherein nega^ve allosteric modula^on of NR2B is of therapeu^c benefit, e.g. (1) mood disorders and mood affec^ve disorders; (2) schizophrenia spectrum disorders; (3) neuro^c, stress-related and somatoform disorders including anxiety disorders; (4) disorders of psychological development; (5) behavioral syndromes associated with physiological disturbances and physical factors; (6) substance-related and addic^ve disorders; (7) disease associated with symptoms of nega^ve and posi^ve valence; (8) pain; (9) cerebrovascular diseases; (10) episodic and paroxysmal disorders; (11) neurodegenera^ve diseases. Specifically, WO2020/079039 discloses that the compounds exemplified therein may be used in the treatment of a disorder, disease or condi^on selected from the list consis^ng of (1) treatment of mood disorders and mood affec^ve disorders including bipolar disorder I depressed, hypomanic, manic and mixed form; bipolar disorder II; depressive disorders, such as single depressive episode or recurrent major depressive disorder, minor depressive disorder, depressive disorder with postpartum onset, depressive disorders with psycho^c symptoms; major depressive disorder with or without concomitant anxious distress, mixed features, melancholic features, atypical features, mood-congruent psycho^c features, mood-incongruent psycho^c features, catatonia. (3) treatment of disorders belonging to the neuro^c, stress-related and somatoform disorders including anxiety disorders, general anxiety disorder, panic disorder with or without agoraphobia, specific phobia, social phobia, chronic anxiety disorders; obsessive compulsive Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 6 - 05.05.2025 disorder; reac^on to sever stress and adjustment disorders, such as post-trauma^c stress disorder; other neuro^c disorders such as depersonaliza^on-derealisa^on syndrome. The objec^ve technical problem underlying the present inven^on is thus to provide a drug substance which may be used in the treatment of Major Depressive Disorder, Treatment- resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma^c Stress Disorder, and/or Borderline Personality Disorder. In a clinical study designed to inves^gate Compound 1 for the treatment of Major Depressive Disorder it was surprisingly found that administra^on of Compound 1 – in comparison with placebo – resulted in promising preliminary efficacy signals of a rapid, sustained effect with good tolerability. According to the present inven^on, Compound 1 has surprisingly been found to fulfil the above-men^oned criteria required for use in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma^c Stress Disorder, and/or Borderline Personality Disorder. According to afirst aspect, the present inven^on provides Compound 1: Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 7 - 05.05.2025 for use in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma^c Stress Disorder, and/or Borderline Personality Disorder. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that 0.5 - 40 mg of Compound 1 are to be administered. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that 2.5 - 25 mg, preferably 5 – 20 mg, of Compound 1 are to be administered. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that 0.5, 2.5, 5, 10, 20, 25, 30, or 40 mg of Compound 1 are to be administered. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that 2.5, 5, 10, 20, or 25 mg of Compound 1 are to be administered. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that 5, 10, or 20 mg of Compound 1 are to be administered. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 is to be administered once daily, twice weekly, every other day or once weekly. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 is to be administered once daily. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 is to be administered orally. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 is to be administered in addi^on to treatment with another an^depressant drug. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 is to be administered as an adjunc^ve therapy to another an^depressant drug. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 8 - 05.05.2025 According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that Compound 1 to be administered as an adjunc^ve therapy to another an^depressant drug for the treatment of Major Depressive Disorder. According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that the an^depressant drug is selected from the group consis^ng of selec^ve serotonin reuptake inhibitors (SSRI) and serotonin and norepinephrine reuptake inhibitors (SNRI). According to another aspect, the present inven^on provides Compound 1 according to any one of the preceding aspects, characterized in that the an^depressant drug is selected from the group consis^ng of Sertraline, Sertraline Hydrochloride, Escitalopram, Escitalopram Oxalate, Fluoxe^ne, Duloxe^ne, Citalopram, Citalopram Hydrobromide, Desvenlafaxine Succinate Monohydrate, Doxepin, Fluoxe^ne Hydrochloride, Mirtazapine, Trazodone, and Venlafaxine Hydrochloride. WO2020/079039 discloses the synthesis of Compound 1 Form II. Now, it has surprisingly been found that another polymorphic form, Compound 1 Form I, exists. Both Compound 1 Form II and Compound 1 Form I, respec^vely, can be synthesized in pure form. Compound 1 Form II was obtained in a purity >99% (ra^o between Compound 1 Form II and Compound 1 Form I >99:1 based on XRPD). Further, both Compound 1 Form II and Compound 1 Form I are characterized by its corresponding XRPD, Raman, and DSC data. The polymorphic form resul^ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, shows a X-ray powder diffrac^on pa^ern comprising a peak at the following 2-theta value measured using monochroma^c CuKα1 radia^on of λ = 1.54056 Å, 40kV, 40mA: 6.8° ±0.2°. The polymorphic form resul^ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, shows a X-ray powder diffrac^on pa^ern comprising peaks at any one or all of the following 2-theta values measured using monochroma^c CuKα1 radia^on of λ = 1.54056 Å, 40kV, 40mA: 6.8° ±0.2°, 10.8° ±0.2°, 11.6° ±0.2°, 17.6° ±0.2°, 22.1° ±0.2°. The polymorphic form resul^ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, shows a X-ray powder diffrac^on pa^ern comprising a peak at the Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 9 - 05.05.2025 following 2-theta value measured using monochroma^c CuKα1 radia^on of λ = 1.54056 Å, 40kV, 40mA: 6.8° ±0.2°, and the Raman spectrum comprises a peak at the following Raman shi^ expressed in wavenumbers in cm-1: 89.8 ±1.5. The polymorphic form resul^ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, has a purity >75% (ra^o between Compound 1 Form II and Compound 1 Form I >75:25 based on XRPD). The polymorphic form resul^ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, has a purity >90% (ra^o between Compound 1 Form II and Compound 1 Form I >90:10 based on XRPD). The polymorphic form resul^ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, has a purity >95% (ra^o between Compound 1 Form II and Compound 1 Form I >95:5 based on XRPD). The polymorphic form resul^ng from the synthesis according to WO2020/079039, namely Compound 1 Form II, has a purity >99% (ra^o between Compound 1 Form II and Compound 1 Form I >99:1 based on XRPD). According to another aspect, the present inven^on provides Compound 1 Form I showing a X- ray powder diffrac^on pa^ern comprising a peak at the following 2-theta value measured using monochroma^c CuKα1 radia^on of λ = 1.54056 Å, 40kV, 40mA: 5.3° ±0.2°. According to another aspect, the present inven^on provides Compound 1 Form I showing a X- ray powder diffrac^on pa^ern comprising peaks at any one or all of the following 2-theta values measured using monochroma^c CuKα1 radia^on of λ = 1.54056 Å, 40kV, 40mA: 5.3° ±0.2°, 10.7° ±0.2°, 16.0° ±0.2°, 20.3° ±0.2°, 21.2° ±0.2°. According to another aspect, the present inven^on provides Compound 1 Form I showing a X- ray powder diffrac^on pa^ern comprising a peak at the following 2-theta value measured using monochroma^c CuKα1 radia^on of λ = 1.54056 Å, 40kV, 40mA: 5.3° ±0.2°, and the Raman spectrum comprises peaks at any one or all of the following Raman shi^s expressed in wavenumbers in cm-1: 64.9 ±1.5, 99.6 ±1.5. According to another aspect, the present inven^on provides Compound 1 Form I having a purity >10% (ra^o between Compound 1 Form I and Compound 1 Form II >10:90 based on XRPD). Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 10 - 05.05.2025 According to another aspect, the present inven^on provides Compound 1 Form I having a purity >20% (ra^o between Compound 1 Form I and Compound 1 Form II >20:80 based on XRPD). According to another aspect, the present inven^on provides Compound 1 Form I having a purity >30% (ra^o between Compound 1 Form I and Compound 1 Form II >30:70 based on XRPD). According to another aspect, the present inven^on provides Compound 1 Form I having a purity >40% (ra^o between Compound 1 Form I and Compound 1 Form II >40:60 based on XRPD). According to another aspect, the present inven^on provides Compound 1 Form I having a purity >50% (ra^o between Compound 1 Form I and Compound 1 Form II >50:50 based on XRPD). According to another aspect, the present inven^on provides Compound 1 Form I having a purity >60% (ra^o between Compound 1 Form I and Compound 1 Form II >60:40 based on XRPD). According to another aspect, the present inven^on provides Compound 1 Form I having a purity >70% (ra^o between Compound 1 Form I and Compound 1 Form II >70:30 based on XRPD). According to another aspect, the present inven^on provides Compound 1 Form I having a purity >75% (ra^o between Compound 1 Form I and Compound 1 Form II >75:25 based on XRPD). According to another aspect, the present inven^on provides Compound 1 Form I having a purity >80% (ra^o between Compound 1 Form I and Compound 1 Form II >80:20 based on XRPD). According to another aspect, the present inven^on provides Compound 1 Form I having a purity >90% (ra^o between Compound 1 Form I and Compound 1 Form II >90:10 based on XRPD). According to another aspect, the present inven^on provides Compound 1 Form I having a purity >95% (ra^o between Compound 1 Form I and Compound 1 Form II >95:5 based on XRPD). Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 11 - 05.05.2025 According to another aspect, the present inven^on provides Compound 1 Form I having a purity >99% (ra^o between Compound 1 Form I and Compound 1 Form II >99:1 based on XRPD). In another aspect, the present inven^on relates to Compound 1, Compound 1 Form I, Compound 1 Form II or mixtures thereof for use in the treatment of above men^oned diseases, condi^ons and symptoms. Further, it has surprisingly been found that by combining lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and/or Magnesium stearate with Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof in a pharmaceu^cal composi^on the drug load can be adjusted to the same level for all dose strengths and a fast dissolu^on of the tablet can be reached. Another aspect of the present inven^on relates to the pharmaceu^cal composi^on comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and/or Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^on comprising a tablet core consis^ng of Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^on comprising a tablet core consis^ng of 0.1-10 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 50-90 % (wt/wt) lactose monohydrate, 10-50 % (wt/wt) microcrystalline cellulose, 0.5-15 % (wt/wt) hydroxypropyl cellulose, 0.5-15 % (wt/wt) croscarmellose sodium and 0.1-3 % (wt/wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^on comprising a tablet core consis^ng of 0.3-7 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 55-80 % (wt/wt) lactose monohydrate, 15-45 % (wt/wt) microcrystalline cellulose, 1-7 % (wt/wt) hydroxypropyl cellulose, 1-7 % (wt/wt) croscarmellose sodium and 0.2-1 % (wt/wt) Magnesium stearate. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 12 - 05.05.2025 According to another aspect, the present inven^on relates to a pharmaceu^cal composi^on comprising a tablet core consis^ng of 0.6-1 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 60-70 % (wt/wt) lactose monohydrate, 20-40 % (wt/wt) microcrystalline cellulose, 2-4 % (wt/wt) hydroxypropyl cellulose, 2-4 % (wt/wt) croscarmellose sodium and 0.3-0.8 % (wt/wt) Magnesium stearate. Further, it has surprisingly been found that by combining mannitol and/or maize starch with Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof in a pharmaceu^cal composi^on the stability can be increased. Further, it has surprisingly been found that by adding afilm coa^ng comprising propylene glycol to the pharmaceu^cal composi^on (tablet core) the stability can be increased. The aforemen^onedfilm coa^ng is enveloping the pharmaceu^cal composi^on (tablet core) which is comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and mannitol and/or maize starch. Further, it has surprisingly been found that by combining mannitol, maize starch, croscarmellose sodium and/or Magnesium stearate with Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof in a pharmaceu^cal composi^on the drug load can be adjusted to the same level for all dose strengths and a fast dissolu^on of the tablet can be reached. Another aspect of the present inven^on relates to the pharmaceu^cal composi^on comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and mannitol and/or maize starch. Another aspect of the present inven^on relates to the pharmaceu^cal composi^on comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and mannitol, maize starch, croscarmellose sodium and/or Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^on comprising a tablet core consis^ng of Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and mannitol, maize starch, croscarmellose sodium and Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^on comprising a tablet core consis^ng of 0.1-10 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 40-95 % (wt/wt) mannitol, 2-20 % (wt/wt) Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 13 - 05.05.2025 maize starch, 0.5-10 % (wt/wt) croscarmellose sodium and 0.1-3 % (wt/wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^on comprising a tablet core consis^ng of 0.3-7 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 50-90 % (wt/wt) mannitol, 3-15% (wt/wt) maize starch, 1-7 % (wt/wt) croscarmellose sodium and 0.3-2 % (wt/wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^on comprising a tablet core consis^ng of 0.6-5 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 60-88 % (wt/wt) mannitol, 5-10 % (wt/wt) maize starch, 2-5 % (wt/wt) croscarmellose sodium and 0.5-1.5 % (wt/wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^on comprising a tablet core consis^ng of 3-20 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 40-95 % (wt/wt) mannitol, 2-20 % (wt/wt) maize starch, 0.5-10 % (wt/wt) croscarmellose sodium and 0.1-3 % (wt/wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^on comprising a tablet core consis^ng of 4-15 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 50-90 % (wt/wt) mannitol, 3-15 % (wt/wt) maize starch, 1-7 % (wt/wt) croscarmellose sodium and 0.3-2 % (wt/wt) Magnesium stearate. According to another aspect, the present inven^on relates to a pharmaceu^cal composi^on comprising a tablet core consis^ng of 6-10 % (wt/wt) Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof, and 60-88 % (wt/wt) mannitol, 5-10 % (wt/wt) maize starch, 2-5 % (wt/wt) croscarmellose sodium and 0.5-1.5 % (wt/wt) Magnesium stearate. Another aspect of the present inven^on relates to a pharmaceu^cal composi^on as defined above for use in the above-men^oned diseases, condi^ons and symptoms. Another aspect of the present inven^on relates to a method of treatment of above-men^oned diseases, condi^ons and symptoms. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 14 - 05.05.2025 Brief Descrip^on of the Figures Figure 1 shows the X-ray powder diffractogram of Compound 1 Form I Figure 2 shows the X-ray powder diffractogram of Compound 1 Form II Figure 3 shows the RAMAN spectrum of Compound 1 Form I Figure 4 shows the RAMAN spectrum of Compound 1 Form II Figure 5 shows the Differen^al Scanning Calorimetry profile for Compound 1 Form I Figure 6 shows the Differen^al Scanning Calorimetry profile for Compound 1 Form II Figure 7 shows Adjusted mean (SE) of absolute change from baseline in MADRS total score over ^me
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 15 - 05.05.2025 General defini^ons Terms not specifically defined herein should be given the meanings that would be given to them by one skilled in the art in light of the disclosure and the context. Compound 1 If not otherwise specified, the term Compound 1 relates to the compound of the following structure in any polymorphic form or mixtures or pharmaceu^cally acceptable salts or hydrates thereof. Subject Human pa^ent.
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 16 - 05.05.2025 EXPERIMENTAL PART List of abbrevia^ons Ac acetate AE Adverse Event a.m.u. atomic mass unit arb arbitrary ATP Adenosine triphosphate Boc tert-butyloxycarbonyl cAMP Cyclic adenosine monophosphate Cbz Benzyloxycarbonyl CDI 1,1’-carbonyldiimidazole conc concentrated Cpd Compound DIEA diisopropylethylamine DMSO Dimethyl sulfoxide DSM-5 Diagnos^c and Sta^s^cal Manual of Mental Disorders, 5th edi^on ECG electrocardiogram EGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N’,N’-tetraace^c acid), also known as egtazic acid ESI electrospray ioniza^on h hour HCl hydrochloric acid HEK293 cell line derived from human embryonic kidney cells HEPES hydroxyethyl-piperazineethane-sulfonic acid buffer HR high-resolu^on HRMS high resolu^on mass spectrometry IC50 half maximal inhibitory concentra^on IPA isopropanol IPAc isopropyl acetate KetoABNO 9-azabicyclo[3,3,1]nonan-3-one-9-oxyl kg kilogram L liter M mole, mol/L MDD Major depressive disorder Me methyl Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 17 - 05.05.2025 MedDRA Medical Dic^onary for Drug Regulatory Ac^vi^es MHz megahertz mL milliliter MMRM mixed model for repeated measure MS mass spectrometry m/z mass-to-charge ra^o N number of pa^ents NMDA N-methyl-D-aspartate receptor NMP 1-methyl-2-pyrrolidone NMR nuclear magne^c resonance NR1 N-methyl D-aspartate receptor subtype 1 NR2B N-methyl D-aspartate receptor subtype 2B pH poten^al of hydrogen psi pounds per square inch qd quaque die (once a day) q.s. quantum sa^s rpm revolu^ons per minute RT room temperature SAE Serious Adverse Event SE Standard Error SNRI Serotonin-Norepinephrine Reuptake Inhibitor SSRI Selec^ve Serotonin Reuptake Inhibitor THF tetrahydrofuran TMEDA tetramethylethylenediamine TS Treated set wt weight XRPD X-ray powder diffrac^on Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 18 - 05.05.2025 Prepara^on and physicochemical characteriza^on of Compound 1 Descrip^on of analy^cal methods used ESI mass spectrometry (ESI+) Instrument Thermo Orbitrap Fusion Lumos Instrument control so^ware XCalibur Version 4.4.16.14 Ion source HESI (Heated Electrospray) Detector Orbitrap Resolving power 120,000 Automa^c Gain Control (AGC) 50 ms (Maximum Injec^on Time) Microscans 1 Polarity Posi^ve Data Type Profile Spray Voltage (Sta^c) 3.5 kV Sheath Gas Flow Rate 40 arb Aux Gas Flow Rate 10 arb Sweep Gas Flow Rate 0 arb Vaporizer Temperature 350 °C Ion Transfer Tube Temperature 300 °C RF Lens 60% Desolva^on gas Nitrogen Sample inlet Thermo Vanquish UPLC Spray solventflow rate 0.3 mL/min Sample concentra^on < 0.05 mg/mL Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 19 - 05.05.2025 Reagents Fisher Op^ma LC/MS Water, Acetonitrile, Formic Acid Scan range (m/z) 100 – 700 a.m.u. 1H NMR spectroscopy Instrument Bruker 400 MHz Frequency 400.13 MHz So^ware Topspin 4.1.3 Pulse program zg10 Solvent CDCl3 Concentra^on 10 mg / 500 µL Temperature 300 K Calibra^on CDCl3; 7.24 ppm Sweep width 14.7 ppm; 5882.4 Hz Size 64 K Pulse width 10 degrees Relaxa^on delay 2.0 s Number of scans 16 Dummy scans 4 Apodiza^on 32768 1H NMR spectroscopy Instrument Bruker 600 MHz Frequency 600.20 MHz So^ware Topspin 4.1.4 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 20 - 05.05.2025 Pulse program zg10 Solvent DMSO Concentra^on 2.8 mg / 250 µL Temperature 300 K Calibra^on DMSO; 2.50 ppm Sweep width 20.83 ppm; 12500 Hz Size 32768 pts Pulse width 10 degrees Relaxa^on delay 2.0 s Number of scans 64 Dummy scans 2 Apodiza^on Exponen^al, 0.05 Hz 13C NMR spectroscopy Instrument Bruker 400 MHz Frequency 100.62 MHz So^ware Topspin 4.1.3 Pulse program Zgpg Solvent CDCl3 Concentra^on 10 mg / 500 µL Temperature 300 K Calibra^on CDCl3; 77.0 ppm Sweep width 236.6 ppm; 23809.5 Hz Size 64 K Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 21 - 05.05.2025 Pulse width 90 degrees Relaxa^on delay 2.0 s Number of scans 2000 Dummy scans 4 Apodiza^on 32768 13C NMR spectroscopy Instrument Bruker 600 MHz Frequency 150.92 MHz So^ware Topspin 4.1.4 Pulse program zgpg30 Solvent DMSO Concentra^on 2.8 mg / 250 µL Temperature 300 K Calibra^on DMSO; 39.50 ppm Sweep width 236.62 ppm; 35714.285 Hz Size 65536 pts Pulse width 30 degrees Relaxa^on delay 0.5 s Number of scans 16384 Dummy scans 8 Apodiza^on Exponen^al, 1.0 Hz Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 22 - 05.05.2025 19F NMR spectroscopy Instrument Bruker 400 MHz Frequency 376.46 MHz So^ware Topspin 4.1.3 Pulse program zgig Solvent CDCl3 Concentra^on 10 mg / 500 uL Temperature 300 K Calibra^on C6F6 in C6D6 at -164.9 ppm Sweep width 198.2 ppm; 74626.8 Hz Pulse width 90 degrees Relaxa^on delay 1.0 s Number of scans 16 Dummy scans 4 Apodiza^on 89552 X-ray powder (XRPD) diagram X-ray powder diagrams were generated using a Bruker D8 Advance Davinci-diffractometer in reflectance modefi^ed with a LynxEye Posi^on Sensi^ve detector and a Cu-anode as X-ray source with monochroma^c CuK^1 radia^on (λ = 1.54056 Å, 40kV, 40mA). The standard error range for the 2-theta values is ±0.2°. RAMAN spectroscopy Raman spectra were collected using an Agilent TRS 1000. Data was acquired over spectral range 38 – 2400 cm-1 using a 830 nm enhanced photo diode excita^on laser, a spot size of 4 mm and spectral resolu^on of < 8 cm-1. The spectral resolu^on is 1.5 cm-1. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 23 - 05.05.2025 Differen^al Scanning Calorimetry diagram The compounds are characterised by a mel^ng point determined by Differen^al Scanning Calorimetry (DSC), evaluated by the peak maximum or onset temperature. The hea^ng rate of the experiment is 10°C/min. The values given were determined using a TA Instruments Discovery DSC 2500TM.
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 24 - 05.05.2025 Prepara^on of Compound 1 General descrip^on of the synthe^c route Two synthesis routes have been developed. Synthesis route I requires a total of seven isola^on steps to obtain Compound 1 from commercially available star^ng materials. Synthesis route II offers a shorter sequence withfive isola^on steps. Synthesis route I impact CH3NH2•HCl CDI, pyridine MeCN (impact-milled) Prepara^on of Compound I-3 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 25 - 05.05.2025 I-1 ([33332-25-1], 17.1 kg, 99.1 mol) and potassium carbonate (16.3 kg, 117.9 mol) are charged to a reactor followed by addi^on of 1-methyl-2-pyrrolidone (70.0 kg). To the resul^ng slurry is added I-2 ([452-81-3], 13.95 kg, 110.6 mol) at a rate to maintain the internal batch temperature at 20-35 °C. The reac^on mixture is then heated to 60-65 °C and s^rred for about 2 hours. A^er the reac^on is complete, the batch is cooled to 5-10 °C. Water (204 kg) is added over not less than 30 min at a rate to maintain the internal batch temperature below 25 °C. The slurry is s^rred for not less than 8 hours. The product is collected byfiltra^on and rinsed with water (85.0 kg). The product is then dried in an oven at ~40 °C under reduced pressure for not less than 12 hours. I-3 is obtained as solid (25.2 kg, 97%). 1H NMR (400 MHz, CDCl3) δ: 8.80 (d, J = 1.3 Hz, 1H), 8.54 (d, J = 1.3 Hz, 1H), 7.14-7.09 (m, 1H), 7.04-6.99 (m, 2H), 4.00 (s, 3H), 2.38 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 164.2, 161.0, 153.9 (d, J = 247.7 Hz), 144.2, 138.1 (d, J = 6.8 Hz), 137.7, 137.1 (d, J = 12.7 Hz), 135.0, 125.5 (d, J = 3.3 Hz), 123.2 (d, J = 1.1 Hz), 117.7 (d, J = 17.8 Hz), 53.0, 21.2 (d, J = 1.3 Hz). 19F{1H} NMR (376 MHz, CDCl3) δ: -128.1. HRMS (ESI): m/z calcd for C13H12N2O3F [M+H]+: 263.0827, found: 263.0826. Prepara^on of Compound I-4 To a solu^on of I-3 (24.1 kg, 91.9 mol) in acetonitrile (113.3 kg) is added methanol (9.65 kg) followed by a slow addi^on of a solu^on of 4.1 M lithium borohydride in tetrahydrofuran (24.6 kg, 110.3 mol) at a rate to maintain the internal batch temperature at 20-25 °C. The reac^on mixture is s^rred at 20-25 °C for about 2 hours un^l comple^on. To the batch is added water (144 kg) over not less than 2 hrs. Vola^les are removed under reduced pressure at 30-35 °C. The batch is cooled to 5-10 °C and added seed crystals I-4 (48.0 g). The resul^ng slurry is aged for not Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 26 - 05.05.2025 less than 1 hour prior to addi^on of water (96.0 kg) over not less than 30 minutes at a rate to maintain the internal batch temperature at 5-10 °C. The batch temperature is adjusted to 20-25 °C and the slurry is aged for not less than 2 hours. The product is collected byfiltra^on and rinsed with water (96.0 kg). The product is dried in an oven at 40-50 °C under reduced pressure for not less than 8 hours. I-4 is obtained as solid (15.2 kg). Seed crystals I-4 can be obtained by crystalliza^on of I-4 in acetonitrile and water. 1H NMR (400 MHz, CDCl3) δ: 8.41 (d, J = 1.4 Hz, 1H), 8.10-8.09 (m, 1H), 7.13-7.08 (m, 1H), 7.03- 6.97 (m, 2H), 4.75 (s, 2H), 3.20 (br s, 1H), 2.37 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 159.0, 154.2 (d, J = 247.3 Hz), 148.7, 139.0, 137.7 (d, J = 12.5 Hz), 137.4 (d, J = 6.8 Hz), 133.9, 125.4 (d, J = 3.3 Hz), 123.4 (d, J = 1.3 Hz), 117.6 (d, J = 17.9 Hz), 62.7, 21.1 (d, J = 1.3 Hz). 19F{1H} NMR (376 MHz, CDCl3) δ: -128.5. HRMS (ESI): m/z calcd for C12H12N2O2F [M+H]+: 235.0877, found: 235.0877. Prepara^on of Compound I-5 A solu^on of I-4 (28.1 kg, 120.0 mol) in acetonitrile (118 kg) isfiltered through a pad of Celite (5.25 kg) and rinsed with acetonitrile (79 kg) to remove insoluble solids. Thefiltrate is concentrated under reduced pressure at 50-55 °C to ~80 L. Thionyl chloride (15.25 kg, 128.2 mol) is added at ~10 °C, while the internal batch temperature is controlled to be below 25 °C. The reac^on mixture is s^rred for about 1 hour and addi^onal thionyl chloride (9.1 kg, 76.1 mol) is added. A^er the reac^on is complete, the batch is cooled to 0-5 °C and added 2 M aqueous sodium hydroxide solu^on (121 kg), at a rate to maintain the internal temperature below 20 °C. The batch is then seeded with I-5 (100 g). Addi^onal 2 M aqueous sodium hydroxide solu^on (121 kg) is added to adjust the pH value to be >10. To the batch is then added water (56 kg) and Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 27 - 05.05.2025 aged at ~10 °C for about 1 hour. The slurry of the product isfiltered and washed with water (112 kg). The product is dried in a vacuum oven at about 40 °C for not less than 8 hours. I-5 is obtained as brown solid (26 kg). Recrystalliza^on I-5 (25.4 kg, mol) is suspended in a mixture of isopropanol (48.0 kg) and water (16.0 kg) at ~20 °C. The slurry is heated to 55-60 °C for dissolu^on,filtered at ~60 °C, and rinsed with a mixture of isopropanol (7.88 kg) and water (2.62 kg). The batch is then cooled to 35-40 °C, seeded with I-5 (102 g), and aged for ~1 hour. The batch is cooled to 5-10 °C over 2 hours and aged for not less than 8 h. The slurry of the product isfiltered and washed with water (50.9 kg). The product is dried in an oven at about 40 °C under reduced pressure for not less than 8 hours. I-5 is obtained as solid (22.9 kg, 55% over two steps star^ng from I-3). Seed crystals I-5 can be obtained by crystalliza^on of I-5 in isopropanol and water. 1H NMR (400 MHz, CDCl3) δ: 8.45 (d, J = 1.4 Hz, 1H), 8.16 (d, J = 1.4 Hz, 1H), 7.13-7.08 (m, 1H), 7.04-6.98 (m, 2H), 4.66 (s, 2H), 2.37 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 159.0, 154.2 (d, J = 247.4 Hz), 145.9, 140.6, 137.6 (d, J = 6.7 Hz), 137.5 (d, J = 12.6 Hz), 134.6, 125.4 (d, J = 3.3 Hz), 123.3 (d, J = 1.3 Hz), 117.6 (d, J = 17.9 Hz), 43.6, 21.1 (d, J = 1.3 Hz). 19F{1H} NMR (376 MHz, CDCl3) δ: -128.4. HRMS (ESI): m/z calcd for C12H11N2OClF [M+H]+: 253.0539, found: 253.0538. Prepara^on of Compound I-7 A solu^on of I-6 ([868689-63-8], 17.2 kg, 74.4 mol) in acetonitrile (54 kg) is cooled to about -10 °C. To the mixture is added 1,1’-carbonyldiimidazole (19.2 kg, 118.4 mol) as solid por^ons wise at a rate to maintain the internal batch temperature at not more than 0 °C. The reac^on mixture Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 28 - 05.05.2025 is s^rred at -10 °C for about 4 hours. A^er full conversion, methylamine hydrochloride (7.55 kg, 111.8 mol) is added followed by the addi^on of pyridine (8.75 kg, 110.6 mol). The batch is s^rred at -10 °C for about 1 hour un^l comple^on. The reac^on mixture is quenched by the addi^on of water (24 kg) and 3 M aqueous hydrochloric acid solu^on (60.6 kg). Organic vola^les are removed under reduced pressure at 40-50 °C to reduce the reactor volume to about 130 L. The remaining aqueous solu^on is extracted twice with isopropyl acetate (89 kg and 60 kg, respec^vely). The combined organic phase is washed sequen^ally with 3 M aqueous hydrochloric acid solu^on (82 kg) and 5 wt% aqueous sodium hydroxide solu^on (54 kg). The solvent is removed under reduced pressure at 45-50 °C to a remaining volume of about 60 L. Heptane (47 kg) is added and the the reactor volume is further reduced to about 60 L. The mixture is cooled to 35-40 °C and heptane (58 kg) is added over 30 min. Seed crystals I-7 (85 g) is added and the slurry is aged at 30-40 °C for 1 hour. The slurry is then cooled to 20-25 °C over 1 hour and aged overnight. The slurry of the product isfiltered and washed with heptane (23 kg). The product is dried in an oven at 40-45 °C under reduced pressure for not less than 8 hours. I-7 is obtained as solid (12.1 kg, 67%). Seed crystals I-7 can be obtained by crystalliza^on of I-7 in isopropyl acetate and heptane. 1H NMR (400 MHz, CDCl3) δ:6.55 (br s, 1H), 4.32 (d, J = 10.8 Hz, 1H), 3.93-3.83 (m, 3H), 3.54 (td, J = 11.7, 2.9 Hz, 1H), 2.87-2.67 (m, 2H), 2.81 (d, J = 5.0 Hz, 3H), 1.44 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ: 169.5, 154.7, 80.5, 75.3, 66.5, 46.3, 42.9, 28.4, 25.6. HRMS (ESI): m/z calcd for C11H21N2O4 [M+H]+: 245.1496, found: 245.1497.
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 29 - 05.05.2025 Prepara^on of Compound 1 crude To a solu^on of I-7 (20.3 kg, 83.1 mol) in acetonitrile (45 kg) is added concentrated hydrochloric acid (24.4 kg, 248.2mol) at 20 °C. The reac^on mixture is s^rred at 20 °C for about 1 hour. A^er full conversion, to the reac^on mixture is added diisopropylethylamine (42.8 kg, 330.8 mol) at a rate to maintain the internal batch temperature not more than 35 °C. A solu^on of I-5 (19.1 kg, 75.2 mol) in acetonitrile (45 kg) is then added. The resul^ng reac^on mixture is heated to about 60 °C and s^rred for about 4 hours un^l comple^on. The mixture is concentrated under reduced pressure at 40-45 °C to remove about 70 L of solvent. The resul^ng mixture is cooled to 30-35 °C and isopropyl acetate (66 kg) is added prior to cooling the batch to 20-25 °C. Water (76 kg) is added followed by addi^on of concentrated hydrochloric acid (11.4 kg) to adjust the pH to not more than 5. A^er phase separa^on, the organic layer is discarded and the pH of the aqueous layer is adjusted to pH not less than 8 by addi^on of 2M NaOH (80 kg). Dichloromethane (151 kg) is added for extrac^on. A^er phase separa^on, the organic layer is par^ally removed under reduced pressure at 35-40 °C to reduce the reactor volume to about 47 L. At 30-35 °C, Heptane (104 kg) is added over about 1 hour and the slurry is cooled to 20-25 °C and aged for not less than 8 hours. The slurry of the product isfiltered and washed with heptane (65 kg). The product is dried in an oven at 40-45 °C under reduced pressure for not less than 6 hours. 1 crude is obtained as solid (23.7 kg, 85%). 8.42 (d, J = 1.4 Hz, 1H), 8.07 (d, J = 1.4 Hz, 1H), 7.10 (t, J = 8.2 Hz, 1H), 7.02-6.96 (m, 2H), 6.55-6.54 (m, 1H), 4.04 (dd, J = 10.5, 2.7 Hz, 1H), 3.90 (ddd, J = 11.3, 3.3, 1.5 Hz, 1H), 3.71 (td, J = 11.4, 2.5 Hz, 1H), 3.65 (s, 2H), 3.21 (dt, J = 14.2, 2.8 Hz, 1H), 2.80 (d, J = 5.0 Hz, 3H), 2.70 (dd, J = 11.5, 1.8 Hz, 1H), 2.36 (s, 3H), 2.25 (td, J = 11.5, 3.3 Hz, 1H), 2.06 (dd, J = 11.2, 10.8 Hz, 1H). Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 30 - 05.05.2025 13C{1H} NMR (100 MHz, CDCl3) δ: 170.3, 158.9, 154.3 (d, J = 247.3 Hz), 146.5, 141.0, 137.7 (d, J = 12.5 Hz), 137.3 (d, J = 6.7 Hz), 134.4, 125.3 (d, J = 3.3 Hz), 123.5 (d, J = 1.2 Hz), 117.6 (d, J = 17.9 Hz), 75.7, 66.6, 61.2, 55.5, 53.8, 25.6, 21.1 (d, J = 1.2 Hz). 19F{1H} NMR (376 MHz, CDCl3) δ: -128.6. HRMS (ESI): m/z calcd for C18H22N4O3F [M+H]+: 361.1671, found: 361.1669. Prepara^on of Compound 1 Form II 1 crude (22.55 kg, 62.6 mol) is suspended in a mixture of isopropanol (26.1 kg) and H2O (33.1 kg). The batch is heated to 60-65 °C to ensure complete dissolu^on of solids. The solu^on is polishfiltered at 60-65 °C and rinsed with a mixture of isopropanol (17.4 kg) and water (22 kg). The solu^on is then cooled to 40-45 °C and added seed crystals Compound 1 Form II (44 g). The slurry is aged at 40-45 °C for not less than 1 hour. Water (242 kg) is added over not less than 2 hours. The slurry is cooled to 20-25 °C over about 30 min and aged for not less than 6 hours. The slurry isfiltered and the solid product is washed with water (44 kg). The product is dried in an oven at about 65 °C under reduced pressure for not less than 12 hours. Compound 1 Form II is obtained as solid (21.0 kg, 96%). Seed crystals Compound 1 Form II can be obtained by crystalliza^on of 1 in isopropanol and water. Prepara^on of Compound 1 Form I 1 crude (7.5g) is suspended in a mixture of isopropanol (37.5 ml) and water (37.5ml). The batch is heated to 60oC to ensure complete dissolu^on and the solu^on is polishfiltered. Thefiltered solu^on is then transferred to a 1Lflask and water (375ml) is immediately added to quickly precipitate the solid, as Form I is a metastable form that must be collected quickly before conversion to Form II. The solid is then isolated byfiltra^on and dried under vacuum at 60oC. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 31 - 05.05.2025 Synthesis route II Prepara^on of Compound II-2 a) Condi^on I (Cs2CO3): II-1 ([23229-26-7], 1.0 kg, 4.2 mol) and cesium carbonate (1.65 kg, 5.1 mol) are charged to a reactor followed by addi^on of isopropyl acetate (3.5 kg). To the resul^ng suspension is added 2-fluoro-4-methylphenol ([452-81-3], 0.58 kg, 4.6 mol) at a rate to maintain the internal batch temperature at no more than 30 °C. The mixture is heated to about 80 °C over 30 min and s^rred for about 2 hours. A^er the reac^on is complete, water (4 kg) is added and the solu^on is cooled to about 40 °C. The agita^on is stopped and the aqueous layer is discarded. The organic layer is concentrated under reduced pressure at about 80 °C to remove isopropyl acetate (~4 L). The batch is cooled to about 60 °C and added isopropanol (3 L). The batch is cooled to about 50 °C and added isopropanol (0.5 L). The batch is cooled to about 40 °C and added isopropanol (0.5 L). The batch is cooled to about 30 °C and added a suspension of seed crystals II-2 (2 g) in isopropanol (20 mL). The slurry is aged at about 30 °C for not less than 30 min and cooled to 5- 10 °C over 2 hours. Water (4 kg) is added over 1 hour. The slurry of the product is aged for not less than 1 hour at about 5 °C. The slurry isfiltered and washed with water (4 kg). The product is Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 32 - 05.05.2025 dried in an oven at about 40 °C under reduced pressure for not less than 24 hours. II-2 is obtained as solid (1.09 kg, 90%). Seed crystals II-2 can be obtained by crystalliza^on of 1 in isopropanol and water. b) Condi^on II (K2CO3): II-1 (1.0 kg, 4.20 mol) and potassium carbonate (0.70 kg, 5.06 mol) are charged to a reactor followed by addi^on of acetonitrile (3.19 kg). To the resul^ng slurry is added I-2 (0.55 kg, 4.36 mol) over not less than 10 min and the addi^on line is rinsed with acetonitrile (0.4 kg). The mixture is heated to about 70 °C over not less than 45 minutes and s^rred for about 24 hours. A^er the reac^on is complete, the batch is added water (1.5 kg) and cooled to 40-50 °C. The agita^on is stopped and the lower aqueous layer is discarded. Water (2 kg) is added. Acetonitrile (~3.25 L) is removed under reduced pressure at 60-70 °C. The batch temperature is adjusted to about 60 °C and isopropanol (2.33 kg) is added. The batch is cooled to about 50 °C and added isopropanol (0.4 kg). The batch is cooled to about 40 °C and added isopropanol (0.4 kg). The batch is cooled to 5-10 °C and added water (2.98 kg). The resul^ng slurry is aged at 5-10 °C for about 1 hour. The slurry isfiltered and washed with water (3 kg). The product is dried in an oven at about 40 °C under reduced pressure for not less than 12 hours. II-2 is obtained as solid (1.0 kg, 83%). 1H NMR (400 MHz, CDCl3) δ: 8.26 (d, J = 1.3 Hz, 1H), 8.15 (d, J = 1.4 Hz, 1H), 7.12-7.07 (m, 1H), 7.04-6.98 (m, 2H), 2.38 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 159.0, 154.1 (d, J = 247.5 Hz), 143.5, 137.8 (d, J = 6.7 Hz), 137.5 (d, J = 12.5 Hz), 134.9, 132.4, 125.5 (d, J = 3.3 Hz), 123.2 (d, J = 1.2 Hz), 117.7 (d, J = 17.8 Hz), 21.2 (d, J = 1.3 Hz). 19F{1H} NMR (376 MHz, CDCl3) δ: -128.4. HRMS (ESI): m/z calcd for C11H9N2OBrF [M+H]+: 282.9877, found: 282.9877. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 33 - 05.05.2025 Prepara^on of Compound II-3 To a clean and dry pressure reactor is added II-2 (504.5 g, 1.78 mol), palladium (II) acetate (3.0 g, 0.013 mol) and cataCXium A ([321921-71-5], 15 g, 0.042 mol). A solu^on of tetramethylethylenediamine (200 mL, 1.33 mol) in toluene (de-gassed, 3.5 kg) is added to the reactor. The reactor is sealed and purged with syngas (1:1 molar ra^o of CO:H2). The reactor is pressurized to 500 psi with syngas and heated to about 90 °C. A^er 24 hours, the reactor is cooled to about 25 °C, vented, and purged with nitrogen. The mixture isfiltered through Celite (0.1 kg) and rinsed with toluene (0.9 kg). Thefiltrate is washed with 10 wt% aqueous citric acid solu^on (1.66 kg). The organic phase is concentrated under reduced pressure at about 45 °C to obtain a solu^on of II-3 in toluene (668 g, 48.4 wt% by 1H NMR, 79%). 1H NMR (400 MHz, CDCl3) δ: 10.1 (s, 1H), 8.69 (d, J = 1.3 Hz, 1H), 8.58 (d, J = 1.3 Hz, 1H), 7.15- 7.10 (m, 1H), 7.06-7.00 (m, 2H), 2.39 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 190.9, 161.5, 153.9 (d, J = 247.7 Hz), 142.8, 142.0, 138.2 (d, J = 6.8 Hz), 137.1 (d, J = 12.8 Hz), 135.4, 125.5 (d, J = 3.3 Hz), 123.1 (d, J = 0.7 Hz), 117.7 (d, J = 17.8 Hz), 21.2 (d, J = 1.3 Hz). 19F{1H} NMR (376 MHz, CDCl3) δ: -128.1. HRMS (ESI): m/z calcd for C12H10N2O2F [M+H]+: 233.0721, found: 233.0720. Prepara^on of Compound II-4 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 34 - 05.05.2025 To a solu^on of I-7 (1.95 kg, 7.98 mol) in acetonitrile (4.7 kg) is added concentrated hydrochloric acid (2.36 kg, 23.9 mol) at a rate to maintain the internal batch temperature at not more than 25 °C. The reac^on mixture is s^rred at 15-20 °C for about 2 hours. A^er full conversion, the reac^on mixture is cooled to 0-5 °C and added 50 wt% aqueous sodium hydroxide solu^on (1.92 kg, 23.9 mol) at a rate to maintain the internal batch temperature at not more than 20 °C. Isopropyl acetate (7 kg) and water (8 kg) are added and the batch temperature is adjusted to 5- 10 °C. To the reac^on mixture is added a solu^on of benzyloxy chloroformate (1.58 kg, 8.78 mol) in isopropyl acetate (1 kg) followed by addi^on of 50 wt% aqueous sodium hydroxide solu^on (0.51 kg, 6.38 mol) at a rate to maintain the internal batch temperature at 5-10 °C. The expected pH value is 11-12. The reac^on mixture is then s^rred at 20-25 °C for about 1.5 hours. A^er comple^on, the lower aqueous layer is discarded and the organic layer is washed with water (6 kg). The organic layer is concentrated under reduced pressure at 50-60 °C to reduce the reactor volume to about 4-6 L. Methyl tert-butyl ether (8 L) is added over 15 min at 50-60 °C and the batch temperature is adjusted to 40-45 °C. A slurry of seed crystals II-4 in methyl tert-butyl ether (200 mL) is added and the batch is cooled to about 25 °C over 1 hour. A mixture of methyl tert- butyl ether (8 L) and heptane (8 L) is added and the slurry is aged for about 1 hour. The slurry of the product isfiltered and washed with heptane (16 L). The product is dried in an oven at about 50 °C under reduced pressure for not less than 12 hours. II-4 is obtained as solid (1.6 kg, 71%). 1H NMR (400 MHz, CDCl3) δ: 7.36-7.29 (m, 5H), 6.54 (br s, 1H), 5.15 (ABq, J = 12.3 Hz, 2H), 4.47 (d, J = 11.2 Hz, 1H), 4.00-3.89 (m, 3H), 3.61-3.55 (m, 1H), 3.01-2.78 (m, 2H), 2.83 (d, J = 5.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 169.2, 155.3, 136.4, 128.7, 128.3, 128.2, 75.2, 67.6, 66.5, 46.2, 43.4, 25.7. HRMS (ESI): m/z calcd for C14H19N2O4 [M+H]+: 279.1339, found: 279.1340. Seed crystals II-4 can be obtained by crystalliza^on of II-4 in isopropyl acetate, methyl tert-butyl ether, and heptane. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 35 - 05.05.2025 Prepara^on of Compound 1 crude To a clean and dry pressure reactor is added 10% palladium on carbon (13.5 g, 0.013 mol) and II-4 (776 g, 2.79 mol). Ethanol (1.91 kg) is added to the reactor. The reactor is sealed and purged with nitrogen. The reactor is pressurized to 30 psi with hydrogen and heated to about 35 °C. A^er 4 hours, the reactor is cooled to about 25 °C, vented, and purged with nitrogen. A solu^on of II-3 in toluene (1.38 kg, 42.3 wt%, 2.51 mol) is added. The reactor is sealed and purged with nitrogen. The reactor is pressurized to 30 psi with hydrogen and heated to about 50 °C. A^er 12 hours, the reactor is cooled to about 25 °C, vented, and purged with nitrogen. The mixture is filtered through Celite (0.1 kg) and rinsed with ethanol (0.3 kg). To thefiltrate is added water (1.77 kg) and 3 M aqueous hydrochloric acid solu^on (1.23 kg). Ethanol and toluene (4-5 L) are removed under reduced pressure at about 45 °C. The batch is added isopropyl acetate (3.85 kg) and cooled to about 25 °C. A^er phase separa^on, the organic layer is discarded and the aqueous layer is washed with isopropyl acetate (1.72 kg). To the aqueous is added isopropyl acetate (4.18 kg) followed by addi^on of 6 M aqueous sodium hydroxide solu^on (1.5 kg) to adjust the pH to about 10-11. A^er phase separa^on, the organic layer is collected and the aqueous layer is extracted with isopropyl acetate (2.52 kg). The combined organic phase is concentrated under reduced pressure at about 50 °C to reduce the reactor volume to about 1-1.2 L. The batch is cooled to about 40 °C and added heptane (4.1 kg). The batch is cooled to about 20 °C over 30 min and aged for not less than 2 hours. The slurry isfiltered and washed with heptane (1.7 kg). The product is dried in an oven at 50-60 °C under reduced pressure for not less than 8 hours.1 crude is obtained as solid (0.8 kg, 87%). Recrystalliza^on of 1 crude to prepare Compound 1 Form II can be performed according to the procedure described in Synthesis route I. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 36 - 05.05.2025 Milling process Compound 1 The milling was performed using the pilot plant impact classifier mill (Hosokowa Alpine MPA 50 ZPS) applying the following process parameters for Compound 1 (unmilled Form II): Beater disc speed Classifier Speed Dosage [kg/h] Process gasflow [rpm] [rpm] [m3/h] 10000 5000 2 80** **measured a^er product separa^onfilter unit A par^cle size distribu^on of x50 < 25mm was achieved. Par^cle size was analyzed using a Sympatec H4055 with ASPIROS dosing unit at 2 bar pressure and an R2 lense. Prepara^on of metabolite M-1 Synthesis route III has been developed to provide synthe^c access to metabolite M-1. Synthesis route III Prepara^on of Compound III-1 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 37 - 05.05.2025 I-7 (40 g, 164 mmol) and KetoABNO (10.6 g, 65.5 mmol) are charged to a reactor followed by addi^on of acetonitrile (200 mL). The batch is cooled to 0-10 °C. To the resul^ng slurry is added perace^c acid (103 mL, 491 mmol) at a rate to maintain the internal batch temperature at 0-15 °C. The reac^on mixture is s^rred at 10 °C for about 20 hours. An aqueous 21 wt% sodium sulfite solu^on (49 g) is added to quench peroxides. Ethyl acetate (200 mL) is added followed by the addi^on of saturated aqueous sodium bicarbonate solu^on (472 mL) to adjust pH to 6-8. A^er phase separa^on, the organic layer is concentrated under reduced pressure at about 50 °C to give a crude reac^on mixture which is purified by silica gel chromatography (gradient 50-100% methyl tert-butyl ether in hexanes). III-1 is obtained as solid (13.9 g, 33%). 1H NMR (600 MHz, CDCl3) δ: 8.02-8.01 (NH, m, 1H), 4.41 (dd, J = 9.3, 3.9 Hz, 1H), 4.26 (ABq, J = 11.0 Hz, 2H), 3.95 (dd, J = 13.1, 3.9 Hz, 1H), 3.62 (dd, J = 15.5, 6.9 Hz, 1H), 2.61 (d, J = 3.1 Hz, 3H), 1.46 (s, 9H). 13C{1H} NMR (150 MHz, CDCl3) δ: 168.0, 166.8, 150.5, 82.7, 72.2, 67.3, 45.9, 27.5, 25.4. Prepara^on of Compound M-1 III-1 (4.0 g, 15.5 mmol) is charged to a pressure reactor followed by addi^on of 2,2,2- trifluoroethanol (20 mL). The reactor is sealed and heated to about 120 °C. The reac^on mixture is s^rred for about 2 hours. A^er full conversion, the batch is concentrated under reduced pressure at 50-55 °C to dryness. Methyl tert-butyl ether (40 mL) is added and the solvent is removed under reduced pressure at 50-55 °C. Methyl tert-butyl ether (40 mL) is added and the slurry is s^rred for about 0.5 hour. The product is collected byfiltra^on and dried in an oven at about 40 °C under reduced pressure for not less than 12 hours. III-2 is obtained as solid (2.3 g, Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 38 - 05.05.2025 92%). III-2 (2.2 g, 14.2 mmol) is added to a round bo^omflask followed by addi^on of THF (14 mL). NaH (60 wt%, 1.4 g, 15.6 mmol) is added in one por^on at 20-25 °C. The reac^on mixture is s^rred for about 1 hour. A solu^on of I-5 (3.9 g, 15.6 mmol) in THF (5 mL) is then added and the resul^ng mixture is s^rred at 50-55 °C for about 12 hours. A^er comple^on, the batch is cooled to about 10 °C. Water (27 mL) and ethyl acetate (14 mL) are added sequen^ally. A^er phase separa^on, the organic layer is collected and the aqueous layer is extracted with isopropyl acetate (14 mL). The combined organic phase is washed with brine (14 mL), dried over MgSO4, filtered, and concentrated under reduced pressure at about 55 °C to give a crude reac^on mixture (6.4 g, 44.2 wt%). The crude reac^on mixture is then purified by supercri^calfluid chromatography following the condi^on below: Column: 30 x 150 mm, 5µ Methane Sulfonamide (MS) Mobile Phase A (MPA): Compressed liquid CO2 Mobile Phase B (MPB): Methanol Opera^ng Parameters 1) Mobile Phase: 15% Isocra^c MPB in MPA, Flowrate: 80 mL/min 2) Back Pressure Regulator (BPR) set at 120 bar, T = 35 °C 3) Column Temperature: Room Temperature 4) Detec^on set @ 2 wavelengths: 220 and 254 nm 5) Loading; 210 mg (per injec^on) every 7 minutes Frac^ons containing product are combined and concentrated to dryness under reduced pressure at 30 °C and then at 20 °C for not less than 12 hours. M-1 is obtained as solid (2.2 g, 41%). 1H NMR (400 MHz, CDCl3) δ: 8.40 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 1.0 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 7.02-6.97 (m, 2H), 6.56-6.54 (m, 1H), 4.69 (ABq, J = 15.0 Hz, 2H), 4.32 (ABq, J = 16.5 Hz, 2H), 4.29 (dd, J = 10.9, 3.5 Hz, 1H), 3.79 (dd, J = 12.4, 3.6 Hz, 1H), 3.54 (dd, J = 12.2, 11.1 Hz, 1H), 2.84 (d, J = 5.0 Hz, 3H), 2.36 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 168.2, 165.9, 159.1, 154.2 (d, J = 247.3 Hz), 145.1, 140.4, 137.6 (d, J = 12.7 Hz), 137.5 (d, J = 6.8 Hz), 134.6, 125.4 (d, J = 3.3 Hz), 123.4 (d, J = 1.1 Hz), 117.6 (d, J = 17.9 Hz), 73.1, 67.6, 49.0, 48.6, 25.8, 21.1 (d, J = 1.2 Hz). 19F{1H} NMR (376 MHz, CDCl3) δ: -128.5. HRMS (ESI): m/z calcd for C18H20N4O4F [M+H]+: 375.1463, found: 375.1463. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 39 - 05.05.2025 Solid state proper^es of Compound 1 unmilled (Form I or Form II) Appearance In the solid state, Compound 1 Form I and Compound 1 Form II are white/off-white powders. Crystallinity and polymorphism Compound 1 Form I is highly crystalline as can be seen in the X-ray powder diffrac^on diagram in Figure 1 and RAMAN spectrum in Figure 3. The X-ray powder reflec^on and intensi^es (standardised) are shown in Table 1. Table 1 2q [°] d-value [Å ] Intensity I/I0 [%] 5.34 16.54 100 10.67 8.28 22 15.99 5.54 8 20.27 4.38 10 21.22 4.18 6 In Table 1 above the value "2-theta [°]" denotes the angle of diffrac^on in degrees and the d- value [Å] denotes the specified distances in Å between the la^ce planes. The crystalline Compound 1 Form I is characterised in that in the x-ray powder diagram has, inter alia, the characteris^c values 2-theta = 5.3° ±0.2° (100% rela^ve intensity), 10.7° ±0.2° (22% rela^ve intensity), 16.0° ±0.2° (8% rela^ve intensity), 20.3° ±0.2° (10% rela^ve intensity), 21.2° ±0.2° (6% rela^ve intensity), (most prominent peaks in the diagram of Figure 1, Table 1). Compound 1 Form I is characterised in that in the x-ray powder diagram has a strong unique reflec^on at the value 2-theta = 5.3 ±0.2° and a further unique reflec^on at the value 2-theta = 16.0 ±0.2°. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 40 - 05.05.2025 Compound 1 Form I is characterised in that in the x-ray powder diagram has a strong unique reflec^on at the value 2-theta = 5.3 ±0.2°. The crystalline Compound 1 Form I is characterised in that in the Raman spectrum has characteris^c bands at 64.9 cm-1 ±1.5, 99.6 cm-1 ±1.5. The thermoanalysis of the crystalline Compound 1 Form I shows an onset of mel^ng at 124.0 ± 1.1 °C (with a mel^ng peak at 124.8 ± 0.5 °C, DSC: 10 K.min-1 hea^ng rate; DSC/TG diagram is shown in Figure 5). Compound 1 Form II is highly crystalline as can be seen in the X-ray powder diffrac^on diagram in Figure 2 and RAMAN spectrum in Figure 4. The X-ray powder reflec^on and intensi^es (standardised) are shown in Table 2. Table 2 2q [°] d-value [Å ] Intensity I/I0 [%] 6.80 12.98 43 10.78 8.20 100 11.57 7.64 22 17.64 5.02 54 22.11 4.02 41 23.98 3.71 7 25.10 3.55 6 In Table 2 above the value "2-theta [°]" denotes the angle of diffrac^on in degrees and the d- value [Å] denotes the specified distances in Å between the la^ce planes. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 41 - 05.05.2025 The crystalline Compound 1 Form II is characterised in that in the x-ray powder diagram has, inter alia, the characteris^c values 2-theta = 6.8° ±0.2° (43% rela^ve intensity), 10.8° ±0.2° (100% rela^ve intensity), 11.6° ±0.2° (22% rela^ve intensity), 17.6° ±0.2° (54% rela^ve intensity), 22.1° ±0.2° (41% rela^ve intensity), (most prominent peaks in the diagram of Figure 2, Table 2). Compound 1 Form II is characterised in that in the x-ray powder diagram has a strong unique reflec^on at the value 2-theta = 6.8° ±0.2° (43% rela^ve intensity), and a further unique reflec^on at the value 2-theta = 22.1° ±0.2° (41% rela^ve intensity). Compound 1 Form II is characterised in that in the x-ray powder diagram has a strong unique reflec^on at the value 2-theta = 6.8° ±0.2°. The crystalline Compound 1 Form II is characterised in that in the Raman spectrum has characteris^c band at 89.8 cm-1 ±1.5. The thermoanalysis of the crystalline Compound 1 Form II shows an onset of mel^ng at 128.3 ± 1.5 °C (with a mel^ng peak at 129.4 ± 1.5 °C, DSC: 10 K.min-1 hea^ng rate; DSC/TG diagram is shown in Figure 6).
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 42 - 05.05.2025 Examples for pharmaceu^cal composi^on The pharmaceu^cal composi^on according to the inven^on is a tablet core or a tablet for oral administra^on. The tablet core is comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and/or Magnesium stearate. According to another aspect, the pharmaceu^cal composi^on according to the inven^on is a tablet core or a tablet for oral administra^on. The tablet core is comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof and mannitol, maize starch, croscarmellose sodium and/or Magnesium stearate. The tablet is op^onally comprising afilm coa^ng, enveloping said tablet core. Examples for Formula^on 1 (shown in Table 3) Table 3 Composi^on of tablet core Formula^on 1 Dose strength 0.5 mg 2.5 mg 5 mg % per tablet Drug load (%, wt/wt) 0.735 0.735 0.735 0.735 Ingredient [mg/tab] [mg/tab] [mg/tab] [%, wt/wt] Compound 1 (milled) 0.500 2.500 5.000 0.735 Lactose monohydrate 42.680 213.400 426.800 62.765 Cellulose, microcrystalline 20.400 102.000 204.000 30.000 Hydroxypropyl cellulose 2.040 10.200 20.400 3.000 Croscarmellose sodium 2.040 10.200 20.400 3.000 Magnesium stearate 0.340 1.700 3.400 0.500 Water, purified 1 q.s. q.s. q.s. q.s. Total Mass 68.000 340.000 680.000 100.000 1 Removed during processing, not present in thefinal product Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 43 - 05.05.2025 Examples for Formula^on 2 (shown in Table 4) Table 4 Composi^on of tablet core Formula^on 2 % per % per tablet Dose strength 0.5 mg 2.5 mg 10 mg tablet Drug load (%, wt/wt) 0.7353 0.7353 0.753 2.9412 2.9412 Ingredient [mg/tab] [mg/tab] [%, wt/wt] [mg/tab] [%, wt/wt] Compound 1 (milled) 0.5000 2.5000 0.7353 10.0000 2.9412 Mannitol 59.3400 296.7000 87.2647 289.2000 85.0588 Maize starch 5.4400 27.2000 8.0000 27.2000 8.0000 Croscarmellose sodium 2.0400 10.2000 3.0000 10.2000 3.0000 Magnesium stearate 0.6800 3.4000 1.0000 3.4000 1.0000 Total Mass 68.000 340.000 100.000 340.0000 100.000 Examples for Formula^on 3 (shown in Table 5 and Table 6) Table 5 Composi^on of tablet core of Formula^on 3 % per Dose strength 5 mg 10 mg 20 mg tablet Drug load (%, wt/wt) 8 8 8 8 Ingredient [mg/tab] [mg/tab] [mg/tab] [%, wt/wt] Compound 1 (milled) 5 10 20 8 Mannitol 50 100 200 80 Maize starch 5 10 20 8 Croscarmellose sodium 1.875 3.75 7.5 3 Magnesium stearate 0.625 1.25 2.5 1 Sub-total Core 62.500 125.000 250.000 100.000 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 44 - 05.05.2025 Table 6 Composi^on offilm coated tablets Formula^on 3 Dose strength 5 mg 10 mg 20 mg [mg/tab] [mg/tab] [mg/tab] tablet core of Formula^on 3 62.5 125 250 Film-coat* 4 6 10 Water, purified 1 q.s. q.s. q.s. Total Film coated tablet 66.5 131 260 * Based on the intended color, thefilm coat consists of different, and commonly used amounts of hypromellose, propylene glycol, talc, calcium carbonate, and iron oxides. 1 Removed during processing, not present in thefinal product Formula^on 1, Formula^on 2, and Formula^on 3 exhibit very fast and complete dissolu^on characteris^cs. The results of the drug substance-excipient compatibility study indicate that Formulations 2 and 3 containing mannitol and maize starch exhibit an increased stability. Further, the stress stability results indicate that the film-coating containing propylene glycol as a plasticizer shows superior stability compared to the film-coating containing macrogol. A pharmaceu^cal composi^on comprising Compound 1, Compound 1 Form I, Compound 1 Form II, or a mixture thereof in Formula^on 3 leads to adjustment of the drug load to the same level for all dose strengths, and a fast dissolu^on of the tablet can be reached. For Formula^on 3, this results in a moreflexible usage of the granules, as they can be compressed to all dose strengths at adequate tablet size and tablet weight. A colouredfilm coat may be added that allows differen^a^on of the different dosage strengths. Formula^on 1, Formula^on 2, and Formula^on 3 may be obtained by using Compound 1, Compound 1 Form I, Compound 1 Form II, or mixtures thereof, respec^vely. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 45 - 05.05.2025 The use of Compound 1 Form II for the manufacture of Formula^on 1, Formula^on 2 and Formula^on 3 is preferred. Formula^on 1, Formula^on 2, and Formula^on 3 are useful pharmaceu^cal composi^ons. Manufacturing offilm-coated tablets A) Material used Table 7 Descrip^on of needed excipient grades Par^cular preferred grade / type [in addi^on to pharmacopoeial USP/NF (United States Ingredient Pharmacopeia and the Na^onal Formulary), Ph.Eur., JP, CN specifica^on] Mannitol No addi^onal specifica^on Maize starch No addi^onal specifica^on Croscarmellose sodium No addi^onal specifica^on Magnesium stearate No addi^onal specifica^on Ready to usefilm-coa^ng mixture No addi^onal specifica^on Purified water No addi^onal specifica^on B) Equipment used The following equipment was used in the process of preparing the pharmaceu^cal composi^on according to the inven^on. The Formulation 1 is preferably produced using the following equipment: - High-shear granulator - Screening mill - Tray dryer or fluid-bed dryer - Screening mill - Diffusion mixer Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 46 - 05.05.2025 - Tablet press The Formula^on 2 is preferably produced using the following equipment: - Diffusion mixer - Screening mill - Roller compactor - Tablet press The Formula^on 3 is preferably produced using the following equipment: - Diffusion mixer - Screening mill - Roller compactor - Tablet press - Mixing vessel with propeller mixer and/or homogenizer for film-coating suspension - Film coater C) Process descrip^on: Wet granula^on process (preferably for produc^on of Formula^on 1) Granula^on For high shear granula^on the required quan^ty of Compound 1 (depending on the dose strength), lactose monohydrate, microcrystalline cellulose and hydroxypropyl cellulose are filled in the product bowl of a high-shear mixer/granulator, then mixed homogeneously for about 1-5 min using impeller and chopper blades. Next, the granula^on liquid is added either manually or by spray nozzles and the wet mass is granulated for about 1-10 min, again using impeller and chopper blades. A^er discharging of the high shear mixer/granulator, the wet granules are wet-screened through a 1-5 mm mesh size sieve to destroy large agglomerates. The wet-screened material is transferred to a conven^onal tray drier (orfluid bed drier) and dried at an inlet air temperature of approximately 50 - 100 °C. Granules are dried when the water ac^vity of the resul^ng dry granules is below 0.6. The dried granules are then dry screened with the help of a screening mill, e.g. Comil screen machine. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 47 - 05.05.2025 The screened granules arefilled into a suitable diffusion mixer, e.g. a container mixer, croscarmellose sodium (crosslinked carboxymethylcellulose sodium) and magnesium stearate are added subsequently, and blended for in sum 5 - 20 min, preferably 13 minutes at a mixing speed of 10 rpm un^l homogeneous. Tabletting Thefinal table^ng blend is compressed on a suitable tablet press (e.g. rotary press or single tablet press) to the respec^ve target weight of the required dose strength of Compound 1 tablets using the appropriate tools (e.g. in case of 0.5 mg tablets: 5.5 mm round biconvex, in case of 2.5 mg tablets: 10 mm round biconvex and in case of 5 mg tablets: 17.8×8.6 mm oval biconvex). Predetermined hardness specifica^ons for the different tool dimensions have to be followed in order to achieve the intended drug dissolu^on profile and product characteris^cs. Tablets of all dosages are compressed to result in a tensile strength of approximately 1.5 MPa, this tensile strength is translated into individual hardness specifica^ons for all dosages according to the equa^ons given in the USP/NF. Dry granula^on process (preferably for produc^on of Formula^on 2 and 3) Granulation For dry granula^on the required quan^ty of Compound 1 (depending on the dose strength), mannitol, maize starch and croscarmellose sodium are mixed using a diffusion mixer homogeneously for about 5-30 min. Then, the mixture is screened with the help of a screening mill. Next, the screened mixture isfilled into a suitable diffusion mixer, e.g. a container mixer, and magnesium stearate are added subsequently, and blended for in sum 1 - 10 min, preferably 5 minutes at a mixing speed of 18 rpm un^l homogeneous. The resul^ng blend is compressed with a roller compactor into ribbons, which are subsequently milled by an integrated screening mill into granules. Next, the granules are filled into a suitable diffusion mixer, e.g. a container mixer, and magnesium stearate are added subsequently, and blended for in sum 1 - 10 min, preferably 5 minutes at a mixing speed of 18 rpm until homogeneous. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 48 - 05.05.2025 Tabletting Thefinal table^ng blend is compressed on a suitable tablet press (e.g. rotary press) to the respec^ve target weight of the required dose strength of Compound 1 tablets using the appropriate tools (e.g. in case of 0.5 mg tablets: 5.5 mm round; biconvex and in case of 2.5 mg and 10 mg tablets: 10 mm round; biconvex) or (e.g. in case of 5 mg tablets: 5.5 mm round biconvex, in case of 10 mg tablets: 7 mm round biconvex and in case of 20 mg tablets: 7 mm round biconvex). Predetermined hardness specifica^ons for the different tool dimensions have to be followed in order to achieve the intended drug dissolu^on profile and product characteris^cs. Tablets of all dosages are compressed to result in a tensile strength of approximately 1.5 MPa, this tensile strength is translated into individual hardness specifica^ons for all dosages according to the equa^ons given in the USP/NF. Film-coating A coloredfilm coa^ng may be applied to the tablet cores for product differen^a^on to prevent from medica^on errors. For this purpose, a coa^ng suspension is prepared byfilling purified water into a suitable mixing vessel, and dissolving propylene glycol and then hydroxypropylmethylcellulose with the help of a propeller or high shear s^rrer. In a next step an aqueous slurry of calcium carbonate, talc, iron oxide yellow and/or iron oxide red if needed (in case of coloredfilm tablets) is poured and s^rred into thefilm-forming polymer solu^on. The dry ma^er of this coa^ng suspension is in the range of 10 -20%, preferably about 10-15 %. The suspension may also be prepared from a ready to use dry mixture that contains the same or chemically comparable components. The above prepared tablet cores arefilled into a suitablefilm coater (i.e. with perforated pan and top spray system, alterna^vely Accela Cota pan with perforated pan and top spray system is also applicable, less preferred is a pan coater), and preheated up to a temperature of approximately 40 - 50 °C or above at an inlet air temperature of approximately 60 - 70 °C, preferably at 65 °C. A^er this product temperature is reached the coa^ng suspension is sprayed onto the cores with the help of one or more spray nozzles. A spray rate of about 10 - 600 g/min (depending on the batch size as well as drum speed and other opera^ng condi^ons) at an inlet air temperature of about 40 - 80 °C, preferably 65 °C. A^er the spraying isfinished thefilm- coated tablets may be dried if needed, then cooled down to 45 °C or below before the Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 49 - 05.05.2025 equipment is discharged. The total process ^me for thefilm-coa^ng is in the range of 1 - 6 hours (depending on the spray rate as well as the batch size), other process dura^ons are also feasible. Direct compression process (preferably for produc^on of Formula^on 3) Blending Compound 1, mannitol, maize starch and croscarmellose sodium are blended using a diffusion mixer. The powder mixture is sieved with the help of a screening mill. The sieved mixture is blended using a diffusion mixer. Then, the mixture is sieved together with magnesium stearate. Thenfinal blending is performed for in sum 5 - 20 min, preferably 13 minutes at a mixing speed of 10 rpm un^l homogeneous. Table^ng Thefinal table^ng blend is compressed on a suitable tablet press (e.g. rotary press) to the respec^ve target weight of the required dose strength of Compound 1 tablets using the appropriate tools (e.g. in case of 5 mg tablets: 5.5 mm round biconvex, in case of 10 mg tablets: 7 mm round biconvex and in case of 20 mg tablets: 9 mm round biconvex). Predetermined hardness specifica^ons for the different tool dimensions have to be followed in order to achieve the intended drug dissolu^on profile and product characteris^cs. Tablets of all dosages are compressed to result in a tensile strength of approximately 1.5 MPa, this tensile strength is translated into individual hardness specifica^ons for all dosages according to the equa^ons given in the USP/NF. Film-coating A coloredfilm coa^ng may be applied to the tablet cores for product differen^a^on to prevent from medica^on errors. For this purpose, a coa^ng suspension is prepared byfilling purified water into a suitable mixing vessel, and dissolving propylene glycol and then hydroxypropylmethylcellulose with the help of a propeller or high shear s^rrer. In a next step an aqueous slurry of calcium carbonate, talc, iron oxide yellow and/or iron oxide red if needed (in case of coloredfilm tablets) is poured and s^rred into thefilm-forming polymer solu^on. The dry ma^er of this coa^ng suspension is in the range of 10 -20%, preferably about 10-15 %. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 50 - 05.05.2025 The suspension may also be prepared from a ready to use dry mixture that contains the same or chemically comparable components. The above prepared tablet cores arefilled into a suitablefilm coater (i.e. with perforated pan and top spray system, alterna^vely Accela Cota pan with perforated pan and top spray system is also applicable, less preferred is a pan coater), and preheated up to a temperature of approximately 40 - 50 °C or above at an inlet air temperature of approximately 60 - 70 °C, preferably at 65 °C. A^er this product temperature is reached the coa^ng suspension is sprayed onto the cores with the help of one or more spray nozzles. A spray rate of about 10 - 600 g/min (depending on the batch size as well as drum speed and other opera^ng condi^ons) at an inlet air temperature of about 40 - 80 °C, preferably 65 °C. A^er the spraying isfinished thefilm- coated tablets may be dried if needed, then cooled down to 45 °C or below before the equipment is discharged. The total process ^me for thefilm-coa^ng is in the range of 1 - 6 hours (depending on the spray rate as well as the batch size), other process dura^ons are also feasible. Based on the quality of the tablets produced by the industrial process, the use of Compound 1 Form II for the manufacture of Formula^on 3 is preferred. Formula^on 1, Formula^on 2, and Formula^on 3 are useful pharmaceu^cal composi^ons.
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 51 - 05.05.2025 CLINICAL TRIALS Clinical trial 1: single oral administra^on of Compound 1 A randomized, double-blind, placebo-controlled, parallel-group single administra^on trial assessing the safety, tolerability, PK, and preliminary efficacy of Compound 1 in two different doses (5 mg and 20 mg) versus placebo (1:1:1 randomiza^on) as an adjunc^ve therapy to selec^ve serotonin reuptake inhibitors (SSRI)/serotonin and norepinephrine reuptake inhibitors (SNRI) in pa^ents with Major Depressive Disorder. STUDY medicine Compound 1 (5 mg and 20 mg) and matching placebo were supplied as un-coated tablets (Formula^on 1, oral administra^on). STUDY POPULATION In total, 59 pa^ents with depression (Major Depressive Disorder, MDD) on stable an^depressant treatment (Table 8) as described below were randomized into this trial. Table 8 selec^ve serotonin reuptake inhibitors/serotonin and norepinephrine reuptake inhibitors for concomitant an^depressant therapy Placebo Cpd 1 Cpd 1 Cpd 1 Total 5 mg 20 mg total Preferred name N % N % N % N % N % Number of pa^ents 19 100.0 20 100.0 20 100.0 40 100.0 59 100.0 Number of pa^ents with at 19 100.0 20 100.0 20 100.0 40 100.0 59 100.0 least one concomitant medica^on ANTIDEPRESSANTS 19 100.0 20 100.0 20 100.0 40 100.0 59 100.0 SERTRALINE 8 42.1 7 35.0 8 40.0 15 37.5 23 39.0 SERTRALINE 2 10.5 4 20.0 3 15.0 7 17.5 9 15.3 HYDROCHLORIDE ESCITALOPRAM 1 5.3 2 10.0 3 15.0 5 12.5 6 10.2 ESCITALOPRAM OXALATE 1 5.3 4 20.0 1 5.0 5 12.5 6 10.2 FLUOXETINE 1 5.3 2 10.0 2 10.0 4 10.0 5 8.5 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 52 - 05.05.2025 Placebo Cpd 1 Cpd 1 Cpd 1 Total 5 mg 20 mg total Preferred name N % N % N % N % N % DULOXETINE 3 15.8 0 0.0 1 5.0 1 2.5 4 6.8 CITALOPRAM 1 5.3 1 5.0 0 0.0 1 2.5 2 3.4 CITALOPRAM 0 0.0 0 0.0 1 5.0 1 2.5 1 1.7 HYDROBROMIDE DESVENLAFAXINE 1 5.3 0 0.0 0 0.0 0 0.0 1 1.7 SUCCINATE MONOHYDRATE DOXEPIN 0 0.0 1 5.0 0 0.0 1 2.5 1 1.7 FLUOXETINE 0 0.0 0 0.0 1 5.0 1 2.5 1 1.7 HYDROCHLORIDE MIRTAZAPINE 1 5.3 0 0.0 0 0.0 0 0.0 1 1.7 TRAZODONE 0 0.0 0 0.0 1 5.0 1 2.5 1 1.7 VENLAFAXINE 1 5.3 0 0.0 0 0.0 0 0.0 1 1.7 HYDROCHLORIDE INCLUSION CRITERIA 1) Established diagnosis of Major Depressive Disorder (MDD) as confirmed at the ^me of screening by the Mini Interna^onal Neuropsychiatric Interview (MINI), with a dura^on of current depressive episode ≥ 8 weeks and ≤ 24 months at the ^me of screening visit. 2) At least moderate severity of MDD confirmed by a trained site-based rater. 3) In the current episode, pa^ents have shown insufficient treatment response (defined by less than 50 % response to one or more an^depressant drugs of adequate dose and treatment dura^on (according to Summary of Product Characteris^cs) as evaluated by An^depressant Treatment Response Ques^onnaire (ATRQ). Pa^ents, who, in addi^on to their monotherapy with an SSRI/SNRI, are taking addi^onal low dose an^depressant medica^ons for purposes other than trea^ng depressive symptoms, are not excluded. The dose must be less than the lowest dose indicated for MDD. Use of bupropion is not allowed. 4) Documented ongoing monotherapy treatment of ≥ 6 weeks at randomisa^on with a protocol specified Selec^ve Serotonin Reuptake Inhibitors (SSRI) or Serotonin- Norepinephrine Reuptake Inhibitors (SNRI) at adequate dose (according to ATRQ assessment). Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 53 - 05.05.2025 EXCLUSION CRITERIA 1) Pa^ent had met diagnos^c criteria per Diagnos^c and Sta^s^cal Manual of Mental Disorders, 5th edi^on (DSM-5) for schizophrenia, schizoaffec^ve disorder, schizophreniform disorder, bipolar disorder, delusional disorder or MDD with psycho^c features at any ^me point in the pa^ent's life. 2) Diagnosis of any other mental disorder that was the primary focus of treatment within 6 months prior to screening, as per clinical discre^on of the inves^gator. 3) Pa^ents with a Body Mass Index (weight [kg]/height [m]²) lower than 18 kg/m² at screening. 4) Diagnosis of a moderate to severe substance-related disorder within the last 6 months before screening visit (with excep^on of caffeine and tobacco). RANDOMIZATION Pa^ents eligible for the trial based on the before men^oned criteria were assigned at random in a 1:1:1 ra^o to one of 3 study arms (placebo, 5 mg Compound 1, 20 mg Compound 1; in a single administra^on, oral) and followed up for 2weeks. VARIABLES ASSESSED The results of the primary and key secondary efficacy endpoints and the primary and secondary endpoints are summarized below. Efficacy Endpoints Maximum decrease from baseline (peak decrease) in Montgomery-Åsberg Depression Ra^ng Scale (MADRS) at any day within a 7 days-interval. MADRS is a ten-item ques^onnaire used to measure the severity of Major Depressive Disorder (MDD). Nine of the items are based upon pa^ent reports and one is on the rater's observa^on (apparent sadness) during the ra^ng interview. MADRS items are rated on a 0 to 6 con^nuum (0=no abnormality, 6=severe). The possible total score could range from 0 to 60 (from normal with absence of symptoms to severe depression). Up to Day 15 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 54 - 05.05.2025 Secondary Endpoints Montgomery-Åsberg Depression Ra^ng Scale Area under the response curve from pre-dose to the last measurement during inpa^ent stay at 166:30 hours (MADRS AUC0-166:30) MADRS is a ten-item ques^onnaire used to measure the severity of Major Depressive Disorder (MDD). Nine of the items are based upon pa^ent reports and one is on the rater's observa^on (apparent sadness) during the ra^ng interview. MADRS items are rated on a 0 to 6 con^nuum (0=no abnormality, 6=severe). The possible total score could range from 0 to 60 (from normal with absence of symptoms to severe depression). Up to Day 15 Other Endpoints - Number and percentage of pa^ents with drug-related AEs from start of treatment to Day 15. - Change from baseline in MADRS total score at individual ^me points throughout the trial - MADRS response (defined as a reduc^on of at least 50% from baseline, at individual ^me points) - Remission (defined as a value ≤10, at individual ^me points), and change from baseline in Leuven affect and pleasure scale (LAPS) subscales at individual ^me points. - PK parameters of Compound 1, including maximum plasma concentra^on (Cmax), ^me from dosing to Cmax (tmax), area under for concentra^on-^me curve from 0 to last quan^fiable data point (AUZ0–tz) and t1 to 2 (AUCt1–t2), were evaluated. - The following criteria to consider this trial successful regarding efficacy were: ^ Observed MADRS change from baseline compared to Placebo ≥ 3 points at one ^me point, AND ^ ≥ 2 points at a neighboring ^me point within a week, AND ^ Adequate safety. STATISTICAL METHODS Analysis of covariance (ANCOVA) has been used for the analysis of the primary and secondary endpoints. These models includefixed effects for baseline MADRS total score and treatment. Further con^nuous endpoints have been analysed using a mixed model for repeated measures. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 55 - 05.05.2025 This model includesfixed effects for baseline value, treatment, ^me, treatment-by-^me interac^on, and baseline-by-^me interac^on; random subject effects have been incorporated into an unstructured within-subject covariance matrix. Descrip^ve sta^s^cs have been calculated for all endpoints. RESULTS Overall, 59 pa^ents were eligible and were randomized and treated (placebo, n=19; Compound 1, 5 mg, n=20; Compound 1, 20 mg, n=20). Of the 40 pa^ents receiving single dose Compound 1, four (5 mg, n=3; 20 mg n=1) prematurely discon^nued the study. Fi^y-five (93%) pa^ents completed the study. Demographic and baseline characteris^cs were generally balanced between groups. The median age (range) was 54.0 (18–65) years, the majority were female (54.2%), 53.5% were Black or African American, and 71.2% were non-Hispanic or La^no. At baseline, the median (range) BMI was 29.4 kg/m2 (21.6–50.1 kg/m2) and the mean (SD) MADRS total score was 34.6 (5.8). Overall, 36% had a history of cannabis use (22% current; 14% former), with most cannabis users (43%) randomized to the Compound 1, 5 mg group. Surprisingly, promising preliminary efficacy signals of a rapid, sustained effect with good tolerability have been observed. Surprisingly, it was found that in comparison with placebo, the difference in adjusted mean change from baseline in MADRS total score (standard error) was as follows (Figure 7): - Compound 1, 5 mg: at Day 1, -1.9 (3.1); Day 2, -1.6 (3.1); Day 4, -0.9 (3.0); Day 6, -0.8 (3.7); Day 8, 3.5 (3.6); - Compound 1, 20 mg: at Day 1, -1.6 (3.1); Day 2, -3.4 (3.0); Day 4, -3.6 (2.9); Day 6, -4.9 (3.7); Day 8, -0.7 (3.5). Surprisingly, the 20 mg dose demonstrated rapid ac^ng an^depressant effects, sustained for five days post-administra^on – a difference of 3.4, 3.6 and 4.9 MADRS points improvement over placebo at Day 2, 4, and 6 a^er a single oral administra^on. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 56 - 05.05.2025 A clinically meaningful change from baseline was found a^er 8 days for both 5 mg and 20 mg (see Table 9 and Figure 7). This is a signal not only of a rapid effect but also of an effect that is sustained over ^me. Table 9: Change from baseline in MADRS total score Time Point/ N Adjusted SE Adjusted SE Standardized Effect Treatment Mean difference Size Day 1 Placebo 18 -9.5 2.2 5 mg Compound 1 18 -11.4 2.2 -1.9 3.1 -0.19 20 mg Compound 1 20 -11.1 2.1 -1.6 3.1 -0.17 Day 2 Placebo 19 -10.3 2.2 5 mg Compound 1 20 -11.9 2.1 -1.6 3.1 -0.16 20 mg Compound 1 20 -13.7 2.1 -3.4 3.0 -0.36 Day 4 Placebo 19 -10.4 2.1 5 mg Compound 1 20 -11.3 2.1 -0.9 3.0 -0.10 20 mg Compound 1 20 -14.0 2.0 -3.6 2.9 -0.39 Day 6 Placebo 19 -11.6 2.6 5 mg Compound 1 20 -12.4 2.6 -0.8 3.7 -0.07 20 mg Compound 1 20 -16.5 2.6 -4.9 3.7 -0.42 Day 8 Placebo 19 -15.4 2.5 5 mg Compound 1 20 -11.8 2.5 3.5 3.6 0.32 20 mg Compound 1 20 -16.0 2.5 -0.7 3.5 -0.06 N: number of pa^ents, SE: Standard Error Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 57 - 05.05.2025 In Clinical trial 1, Compound 1 exhibited an unexpectedly favorable safety and tolerability profile. No severe adverse events, no dissocia^on, no clinically relevant changes on group level for blood pressure and no notablefindings in the electrocardiogram (ECG) were observed. Furthermore, the compound's safety profile is further corroborated by the results obtained from the Clinician-Administered Dissocia^ve States Scale (CADSS, Table 10). This scale revealed very benign outcomes regarding dissocia^ve side effects, since few pa^ents had a CADSS score of clinically relevant severity of >4 at any ^me point measured a^er administra^on of Compound 1 and no pa^ent had dissocia^on as an adverse event. In addi^on to the CADSS, the compound was also evaluated regarding suicidality using the Columbia Suicide Severity Ra^ng Scale (CSSRS, Table 11). The results from these assessments demonstrated no dissocia^on (CADSS), and no signs of increased suicidality (CSSRS). Table 10: Frequency [%] of pa^ents (N: number of pa^ents) categorized by CADSS total score based on clinician's ra^ngs - Treated set N 0 >=1 to 4 >4 Missing Treatment/ Visit - Time point N % N % N % N % Placebo Baseline 19 17 89.5 1 5.3 0 0.0 1 5.3 Day 1, 1:00 19 16 84.2 2 10.5 0 0.0 1 5.3 Day 1, 7:00 19 14 73.7 2 10.5 0 0.0 3 15.8 Day 15 19 16 84.2 1 5.3 0 0.0 2 10.5 5 mg Compound 1 Baseline 20 17 85.0 0 0.0 1 5.0 2 10.0 Day 1, 1:00 20 18 90.0 1 5.0 0 0.0 1 5.0 Day 1, 7:00 20 17 85.0 0 0.0 0 0.0 3 15.0 Day 15 20 13 65.0 0 0.0 0 0.0 7 35.0 Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 58 - 05.05.2025 N 0 >=1 to 4 >4 Missing Treatment/ Visit - Time point N % N % N % N % 20 mg Compound 1 Baseline 20 20 100.0 0 0.0 0 0.0 0 0.0 Day 1, 1:00 20 19 95.0 0 0.0 0 0.0 1 5.0 Day 1, 7:00 20 18 90.0 2 10.0 0 0.0 0 0.0 Day 15 20 18 90.0 0 0.0 0 0.0 2 10.0 Compound 1 total Baseline 40 37 92.5 0 0.0 1 2.5 2 5.0 Day 1, 1:00 40 37 92.5 1 2.5 0 0.0 2 5.0 Day 1, 7:00 40 35 87.5 2 5.0 0 0.0 3 7.5 Day 15 40 31 77.5 0 0.0 0 0.0 9 22.5 Total Baseline 59 54 91.5 1 1.7 1 1.7 3 5.1 Day 1, 1:00 59 53 89.8 3 5.1 0 0.0 3 5.1 Day 1, 7:00 59 49 83.1 4 6.8 0 0.0 6 10.2 Day 15 59 47 79.7 1 1.7 0 0.0 11 18.6 Time points 1:00 or 7:00 refer to a ^me point 1 h or 7 h a^er administra^on of Placebo/Compound 1, respec^vely. Thesefindings, when considered in conjunc^on with the promising results on depressive symptoms determined by the MADRS total score (Table 9), suggest a new therapeu^c applica^on for Compound 1. Specifically, the absence of dissocia^ve effects (Table 10), along with the compound's favorable safety profile, align with the therapeu^c needs of pa^ents with borderline personality disorder.
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 59 - 05.05.2025 Table 11: Changes to worst C−SSRS categories from baseline during treatment – Treated Set Treatment Category_ Treatment Baseline Category No suicidal Suicidal Suicidal idea^on or idea^on behavior behavior n (%) n (%) n (%) Placebo No suicidal idea^on 17 (100.0) 0 (0.0) 0 (0.0) (N = 17) or behavior Suicidal idea^on 0 (0.0) 0 (0.0) 0 (0.0) Suicidal behavior 0 (0.0) 0 (0.0) 0 (0.0) 5 mg Compound 1 No suicidal idea^on 18 (100.0) 0 (0.0) 0 (0.0) (N = 18) or behavior Suicidal idea^on 0 (0.0) 0 (0.0) 0 (0.0) Suicidal behavior 0 (0.0) 0 (0.0) 0 (0.0) 20 mg Compound No suicidal idea^on 19 (95.0) 0 (0.0) 0 (0.0) 1 (N = 20) or behavior Suicidal idea^on 0 (0.0) 1 (5.0) 0 (0.0) Suicidal behavior 0 (0.0) 0 (0.0) 0 (0.0) Compound 1 total No suicidal idea^on 37 (97.4) 0 (0.0) 0 (0.0) (N = 38) or behavior Suicidal idea^on 0 (0.0) 1 (2.6) 0 (0.0) Suicidal behavior 0 (0.0) 0 (0.0) 0 (0.0) Total (N = 55) No suicidal idea^on 54 (98.2) 0 (0.0) 0 (0.0) or behavior Suicidal idea^on 0 (0.0) 1 (1.8) 0 (0.0) Suicidal behavior 0 (0.0) 0 (0.0) 0 (0.0)
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 60 - 05.05.2025 In Clinical trial 1, the pharmacokine^c (PK) profiles and pharmacokine^c parameters were determined (Table 12). Table 12: Non-compartmental PK parameters of Compound 1 a^er single oral administra^on of Compound 1 as tablet in fasted condi^ons. Dose Group 5 mg Compound 1 20 mg Compound 1 N gMean gCV% N gMean gCV% Cmax (nmol/L) 20 185 44.8 18 681 48.6 tmax (h)1 20 0.500 0.250-3.10 18 0.500 0.250-4.00 AUC0-24 (nmol·h/L) 20 601 24.7 18 2270 21.4 AUC0-∞(nmol·h/L) 20 623 26.4 18 2340 20.7 t1/2 (h) 20 4.98 30.1 18 5.21 21.0 Compound 1 was rapidly absorbed a^er oral administra^on as tablet. Therea^er, plasma concentra^ons decreased rapidly in a monophasic manner. Plasma exposure increases propor^onally with the dose between 5 mg and 20 mg. Addi^onally, its pharmacokine^c (PK) profile is characterized by rapid ac^on and clearance, a feature o^en referred to as a 'hit and run' profile. These characteris^cs support the poten^al for daily administra^on of the Compound 1. The long-las^ng efficacy as seen in Figure 7 may support twice weekly, every other day or once weekly administra^on. The human metabolite M-1 has been observed Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 7.02-6.97 (m, 2H), 6.56-6.54 (m, 1H), 4.69 (ABq, J = 15.0 Hz, 2H), 4.32 (ABq, J = 16.5 Hz, 2H), Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 61 - 05.05.2025 4.29 (dd, J = 10.9, 3.5 Hz, 1H), 3.79 (dd, J = 12.4, 3.6 Hz, 1H), 3.54 (dd, J = 12.2, 11.1 Hz, 1H), 2.84 (d, J = 5.0 Hz, 3H), 2.36 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 168.2, 165.9, 159.1, 154.2 (d, J = 247.3 Hz), 145.1, 140.4, 137.6 (d, J = 12.7 Hz), 137.5 (d, J = 6.8 Hz), 134.6, 125.4 (d, J = 3.3 Hz), 123.4 (d, J = 1.1 Hz), 117.6 (d, J = 17.9 Hz), 73.1, 67.6, 49.0, 48.6, 25.8, 21.1 (d, J = 1.2 Hz). 19F{1H} NMR (376 MHz, CDCl3) δ: -128.5. HRMS (ESI): m/z calcd for C18H20N4O4F [M+H]+: 375.1463, found: 375.1463. Determina^on of in vitro Pharmacological Ac^vity The ac^vity of the human metabolite M-1 was demonstrated using the following in-vitro NMDA receptor NR1/2B cell assay via whole-cell patch-clamp electrophysiology: Cell culture: A HEK293 cell line expressing human NR1/2B was used. Expression of receptor was induced by treatment with tetracycline (1μg/ml). Cell viability was improved by applica^on of Ketamine (2.0 mM) to the culture media 14h - 24h before recordings cells. Cells were plated onto glass coverslips for patch clamp experiments. Test solu^ons: Intracellular (pipe^e) solu^on: (all concentra^ons in mM) CsCl 20, CsF 110, HEPES 10, EGTA 5, MgCl21, cAMP 0.4, Mg-ATP 4; Perfusion solu^on (vehicle): Perfusion solu^on (baseline) + 100μM NMDA and 1μM Glycine; Perfusion solu^on (metabolite M-1): Perfusion solu^on (vehicle) + M-1 at a concentra^on of 0.03 - 10μM dissolved in DMSO at afinal concentra^on of 0.1 %. Inhibi^on of NR1/2B during constant channel opening: Patch clamp recordings were performed in whole-cell configura^on by use of PatchMaster so^ware. Following seal forma^on and establishing the whole cell configura^on by disrup^ng the cell membrane in the ^p of the patch pipe^e, cells were typically clamped in whole cell mode at a poten^al of -60 mV. A^er reaching a stable baseline recording, the cell was superfused with control solu^on and subsequently with a concentra^on of 0.03 - 10μM of the metabolite M-1. Solu^ons were applied by a gravity driven system for 120 sec in presence of the agonists NMDA (100μM) and Glycin (1μM). M-1 was tested in a cumula^ve manner at Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 62 - 05.05.2025 concentra^ons of 0 µM (control), 0.03, 0.1, 0.3, 1, 3 and 10µM with an applica^on dura^on of 60s for each compound concentra^on. Cells were recorded as long as the seal resistance, series resistance and leakage current remained stable. Only cells with stable parameters were included to the analysis. At the end of the recordings Ketamine (10μM) was applied to inhibit NR1/2B dependent currents. Current responses for analysis were taken as a mean amplitude of the last 10 seconds of control or compound applica^on. Data evalua^on and IC50 calcula^on: For the M-1 test concentra^on a [%] block is calculated by dividing the current induced during compound applica^on by the mean measured NMDA/Glycine induced current (control). The IC50 was calculated by applying a Bolzman equa^on: Y = Bo^om + (Top-Bo^om)/1+10^((LogEC50-X)*Hillslope)). Using this assay the metabolite M-1 exhibits an IC50 of 599 nM. Compound 1 may be used as a medicament, characterized in that Compound 1 is to be administered orally. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that Compound 1 is to be administered orally. Compound 1 may be used in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma^c Stress Disorder, and/or Borderline Personality Disorder characterized in that Compound 1 is to be administered orally. Compound 1 may be used as a medicament, characterized in that Compound 1 is to be administered once daily, twice weekly, every other day or once weekly. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that Compound 1 is to be administered once daily, twice weekly, every other day or once weekly. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that Compound 1 is to be administered once daily. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 63 - 05.05.2025 Compound 1 may be used as a medicament, characterized in that 5 to 20 mg of Compound 1 are to be administered. Compound 1 may be used as a medicament, characterized in that 5, 10 or 20 mg of Compound 1 are to be administered. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that 5 to 20 mg of Compound 1 are to be administered. Compound 1 may be used in the treatment of psychiatric disorders, characterized in that 5, 10 or 20 mg of Compound 1 are to be administered. The above data suggest Compound 1 has the poten^al to address core symptoms of depression, emo^onal dysregula^on, anxiety and suicidality, all of which are domains sugges^ve of its effect in Borderline Personality Disorder (BPD). These results show that by administra^on of Compound 1 borderline personality disorder may successfully be treated.
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 64 - 05.05.2025 Clinical trial 2: once daily oral administra^on of Compound 1 A 6-week, mul^-centre, randomised, double-blind (pa^ent and inves^gator), placebo-controlled, dose-finding trial to evaluate the efficacy, tolerability, and safety of different doses of oral Compound 1 (5 mg, 10 mg, and 20 mg) as adjunc^ve therapy to SSRI/SNRI in pa^ents with Major Depressive Disorder (MDD). STUDY medicine Compound 1 (2.5 mg, and 10 mg) and matching placebo will be supplied as un-coated tablets (Formula^on 2, oral administra^on, once daily). STUDY POPULATION In total, approximately 204 pa^ents with depression (Major Depressive Disorder, MDD) on stable an^depressant treatment as described below will be randomized into this trial in order to have approximately 180 pa^ents evaluable for the primary analysis. INCLUSION CRITERIA 1) Established diagnosis of major depressive disorder (MDD), single episode or recurrent, as confirmed at the ^me of screening by the mini-interna^onal neuropsychiatric interview (MINI) with a dura^on of current depressive episode ≥8 weeks at the ^me of screening visit. 2) Hamilton Depression Ra^ng Scale-17 (HDRS-17) - Severity scale score >17. 3) A documented ongoing monotherapy treatment of ≥6 weeks at the randomisa^on visit, with an selec^ve serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) specified in the inves^gator sitefile (ISF) at adequate dose (at least minimum effec^ve dose as per prescribing informa^on). - The pa^ent must adhere to the screening visit dose of the background SSRI/SNRI un^l the end of the trial. Pa^ents should be on a stable dose for at least 4 weeks prior to randomisa^on. - Pa^ents, who, in addi^on to their monotherapy with an SSRI/SNRI, are taking addi^onal low dose an^depressant medica^ons for purposes other than trea^ng Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 65 - 05.05.2025 depressive symptoms, are not excluded. The dose must be less than the lowest dose indicated for MDD. 4) In the current episode, pa^ents have shown insufficient treatment response defined by less than 50% response to a maximum of 4 an^depressant treatments of adequate dose and treatment dura^on (according to Summary of Product Characteris^cs) as evaluated by the an^depressant treatment response ques^onnaire (ATRQ). EXCLUSION CRITERIA 1) Per MINI, have ever met diagnos^c criteria for schizophrenia, schizoaffec^ve disorder, schizophreniform disorder, bipolar disorder, or delusional disorder. 2) Diagnosis with an^social, paranoid, schizoid or schizotypal personality disorder, or MDD with psycho^c features as per Diagnos^c and Sta^s^cal Manual of Mental Disorders, Fi^h Edi^on (DSM-5) criteria, at the ^me of screening visit. Any other personality disorder at screening visit that significantly affects current psychiatric status and likely to impact trial par^cipa^on, as per the judgement of inves^gator. 3) Diagnosis of any other mental disorder that was the primary focus of treatment within 6 months prior to screening (as per clinical discre^on of the inves^gator). 4) History or presence (upon clinical examina^on) of seizure disorders or an increased risk of seizures (first degree rela^ve with epilepsy), stroke, brain tumour or any other major neurological illness that could impact par^cipa^on in the trial. 5) A current or recent history of clinically significant suicidal idea^on with intent within the past 3 months, corresponding to a score of 4 or 5 for idea^on on the Columbia-suicide severity ra^ng scale (C-SSRS) or a suicidal a^empt within the past year, as indicated by the C-SSRS at screening visit. 6) Pa^ents with a body mass index (weight [kg]/height [m]²) lower than 18 kg/m² or greater than 40 kg/m² at screening. RANDOMIZATION Pa^ents eligible for the trial based on the aforemen^oned criteria will be assigned at random in a 2:1:1:2 ra^o to one of 4 study arms (placebo qd, 5 mg Compound 1 qd, 10 mg Compound 1 qd, 20 mg Compound 1 qd) and treated for 6 weeks. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 66 - 05.05.2025 VARIABLES ASSESSED The primary and key secondary efficacy endpoints are summarized below. Efficacy Endpoints Change from baseline in Montgomery-Åsberg Depression Ra^ng Scale (MADRS) total score at Day 8. The MADRS evaluates core symptoms of depression. It is a clinician-rated measure of depression severity and consists of 10 items. MADRS items are rated on a 0-6 con^nuum (0 = no abnormality, 6 = severe). The possible total score could range from 0 to 60 - from normal with absence of symptoms to severe depression. Secondary Endpoints Change from baseline in MADRS total score at Week 6. Response defined as ≥50% MADRS reduc^on from baseline at Day 8. Response defined as ≥50% MADRS reduc^on from baseline at Week 6. Remission defined as MADRS total score ≤10 at Week 6. Change from baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) total score at Day 8. The SMDDS is a 16-item, pa^ent-reported outcome (PRO) measure developed to capture the core symptoms of major depressive disorder (MDD). Pa^ents respond to each ques^on using a ra^ng scale between 0 ("Not at all" or "Never") to 4 ("Extremely" or "Always"). The total score ranges from 0 to 60 with a higher score indica^ng more severe depressive symptomatology. It is calculated by crea^ngfirst a single score for items 11 and 12 by selec^ng the highest severity on either item, and then crea^ng the sum of the 15 responses. Change from baseline in SMDDS total score at Week 4. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 67 - 05.05.2025 STATISTICAL METHODS To demonstrate clinical efficacy and to evaluate the dose response rela^onship for Compound 1, a mul^ple comparison procedure with modelling techniques (MCPMod) approach is planned to be used for the primary analysis. As a basis for the MCPMod analysis and to assess quan^ta^ve treatment benefit, a mixed model for repeated measure (MMRM) analysis will be used to generate covariate adjusted es^mates of mean change from baseline in MADRS total score at Day 8 and associated covariance matrices.
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 68 - 05.05.2025 Clinical trial 3: once daily oral administra^on of Compound 1 A 6-week, mul^-centre, randomised, double-blind (pa^ent and inves^gator), placebo- controlled, dose-finding trial to evaluate the efficacy, tolerability, and safety of different doses (5 mg, 10 mg, and 20 mg) of oral Compound 1 in pa^ents with major depressive disorder. STUDY medicine Compound 1 (2.5 mg, and 10 mg) and matching placebo will be supplied as un-coated tablets (Formula^on 2, oral administra^on, once daily). STUDY POPULATION In total, approximately 222 pa^ents with depression (Major Depressive Disorder, MDD) will be randomized into this trial in order to have approximately 180 pa^ents evaluable for the primary analysis. INCLUSION CRITERIA - Established diagnosis of MDD, single episode or recurrent with a dura^on of current depressive episode ≥8 weeks and ≤24 months at the ^me of randomisa^on - Hamilton Depression Ra^ng Scale-17 (HDRS-17) – Severity score ≥20 - Clinical Global Impression Severity Scale (CGI-S) score ≥4 EXCLUSION CRITERIA - Have ever met diagnos^c criteria for schizophrenia, schizoaffec^ve disorder, schizophreniform disorder, bipolar disorder, or delusional disorder - Diagnosis of any other mental disorder that was the primary focus of treatment within 6 months prior to screening, as per clinical discre^on of the inves^gator - Treatment failure to 2 or more an^depressants in the current episode Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 69 - 05.05.2025 - A current or recent history of clinically significant suicidal idea^on with intent within the past 3 months or a suicidal a^empt within the past year - Pa^ents with a body mass index (weight [kg]/height [m]2) lower than 18 kg/m² or greater than 40 kg/m2 at screening - Diagnosis of a moderate to severe substance related disorder within 6 months prior to screening visit (with excep^on of caffeine and tobacco) - Frequent use of benzodiazepines RANDOMIZATION Pa^ents will be randomized to the 6-week double-blind treatment period and will be assigned to placebo or one of 3 doses of Compound 1 (low to high dose) in a 2:1:1:2 ra^o. Placebo: approximately 74 pa^ents Compound 1 (5 mg): approximately 37 pa^ents Compound 1 (10 mg): approximately 37 pa^ents Compound 1 (20 mg): approximately 74 pa^ents VARIABLES ASSESSED The primary and key secondary efficacy endpoints are summarized below. Primary Endpoints Change from baseline in Montgomery-Åsberg Depression Ra^ng Scale (MADRS) total score at Week 6. Secondary Endpoints None. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 70 - 05.05.2025 Other Endpoints MADRS - Change from baseline in MADRS total score at Day 8 - Rela^ve (percent) change from baseline in total MADRS score at individual ^me points - Response defined as ≥50% MADRS reduc^on from baseline at individual ^me points - Remission defined as MADRS total score ≤10 at individual ^me points - Change from baseline in MADRS anhedonia subscale score at individual ^me points SMDDS - Change from baseline in Symptoms of Major Depressive Disorder Scale (SMDDS) at individual ^me points Pharmacokine^cs The following PK assessments will be performed for Compound 1: - pre-dose plasma concentra^ons of Compound 1 and relevant metabolites at different ^me points (if applicable) - three post-dose plasma concentra^ons of Compound 1 and relevant metabolites at one ^me point (if applicable) - At End of Trial Visit: plasma concentra^ons of Compound 1 and relevant metabolites (if applicable) 24 h a^erfinal dose Other - Change from baseline in Clinical Global Impression-Severity (CGI-S) score at individual ^me points - Change from baseline in Pa^ent Global Impression-Severity (PGI-S) score at individual ^me points - Pa^ent Global Impression- Change in Clinical Status (PGI-C) score at End of Trial Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 71 - 05.05.2025 - Change from baseline in EQ-5D-5 L VAS score at individual ^me points - Change from baseline in Generalised Anxiety Disorder-7 assessment (GAD-7) at individual ^me points STATISTICAL METHODS To demonstrate clinical efficacy and to evaluate the dose response rela^onship for Compound 1, a mul^ple comparison procedure with modelling techniques (MCPMod) approach is planned to be used for the primary analysis. As a basis for the MCPMod analysis and to assess quan^ta^ve treatment benefit, a mixed model for repeated measure (MMRM) analysis will be used to generate covariate adjusted es^mates of mean change from baseline in MADRS total score at Week 6 and associated covariance matrices. Use in treatment/method of use: Compound 1 may be used as a medicament, characterized in that 0.5 - 40 mg of Compound 1 are to be administered. Preferably, Compound 1 may be used as a medicament, characterized in that 2.5 - 25 mg of Compound 1 are to be administered. Compound 1 may be used as a medicament, characterized in that 0.5, 2.5, 5, 10, 20, 25, 30, or 40 mg of Compound 1 are to be administered. Preferably, Compound 1 may be used as a medicament, characterized in that 2.5, 5, 10, 20, or 25 mg of Compound 1 are to be administered. Compound 1 may be used as a medicament, characterized in that Compound 1 it to be administered once daily, twice weekly, every other day or once weekly.

Claims

Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 72 - 05.05.20251. Compound 1 1, for use in the treatment of Major Depressive Disorder, Treatment-resistant Depression, Bipolar Depressive Disorder, Depressive Episodes associated with Bipolar disorders, Obsessive Compulsive Disorder, Post-Trauma^c Stress Disorder, and/or Borderline Personality Disorder characterized in that 0.5 - 40 mg of Compound 1 are to be administered once daily, twice weekly, every other day or once weekly. 2. The compound for use according to claim 1 characterized in that Compound 1 is to be administered orally. 3. The compound for use according to any one of the claims 1 to 2 characterized in that Compound 1 is to be administered in addi^on to treatment with another an^depressant drug.
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 73 - 05.05.2025 4. A process for preparing Compound 1 characterized in that a) compound II-1 is reacted with compound I-2 under condi^ons facilita^ng nucleophilic subs^tu^on and elimina^on of HBr to yield compound II-2 , b) compound II-2 is carbonylated to yield compound II-3
Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 74 - 05.05.2025 c) compound II-4 is deprotected by hydrogena^on followed by reduc^ve amina^on of compound I-8 and compound II-3 to yield Compound 1 . 5. An intermediate compound selected from the group consis^ng of . showing a X-ray powder diffrac^on pa^ern comprising a peak at the following 2-theta value measured using monochroma^c CuK^1 radia^on of λ = 1.54056 Å, 40kV, 40mA: 5.3° ±0.2°. Boehringer Ingelheim Interna^onal GmbH 01-3592-WO-1 - 75 - 05.05.2025 7. A pharmaceu^cal composi^on comprising Compound 1 and lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and/or Magnesium stearate. 8. A pharmaceu^cal composi^on comprising Compound 1 and mannitol and/or maize starch.
PCT/EP2025/062166 2024-05-07 2025-05-05 Compound for use in the treatment of depression, obsessive-compulsive disorder, post-traumatic stress disorder and/or borderline personality disorder Pending WO2025233259A1 (en)

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