WO2020094592A1 - Composés pour le traitement de symptômes négatifs et de déficiences cognitives - Google Patents

Composés pour le traitement de symptômes négatifs et de déficiences cognitives Download PDF

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Publication number
WO2020094592A1
WO2020094592A1 PCT/EP2019/080152 EP2019080152W WO2020094592A1 WO 2020094592 A1 WO2020094592 A1 WO 2020094592A1 EP 2019080152 W EP2019080152 W EP 2019080152W WO 2020094592 A1 WO2020094592 A1 WO 2020094592A1
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Prior art keywords
imidazol
triazolo
dimethyl
phenyl
ethyl
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PCT/EP2019/080152
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English (en)
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Anette Frost Jensen
Lars Ole Lyngsø
Flemming Elmelund Nielsen
Jacob Nielsen
Raimund Buller
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H. Lundbeck A/S
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Priority to BR112020013697-2A priority Critical patent/BR112020013697A2/pt
Publication of WO2020094592A1 publication Critical patent/WO2020094592A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to novel compounds and pharmaceutical compositions comprising said compounds useful for treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions, particularly in schizophrenia.
  • Schizophrenia is a psychiatric disorder characterized by three main symptom domains; positive symptoms (delusions, hallucinations, or disorganized/catatonic behavior etc.), negative symptoms (affective flattening, social withdrawal, asociality, anhedonia, avolition, blunted affect, alogia, psychomotor poverty, or poverty of thought and content of speech etc.), and symptoms of cognitive dysfunctions (impaired executive functioning, working memory, attention deficits, social cognitive impairment, jumping to conclusions, Theory of Mind (TOM) impairments, deficits in emotion recognition or affect discrimination etc.). Further information regarding schizophrenia and related diagnosis as well as the various symptom domains described above are available in e.g. the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), American Psychiatric Publishing, 2013.
  • Negative symptoms and cognitive impairments are also a predominant part of the prodromal phase of schizophrenia, sometimes referred to as psychosis prodrome.
  • the prodromal phase of schizophrenia is characterized by a heterogeneous group of behaviors temporally related to the onset of psychosis. Accordingly, the prodromal phase of schizophrenia can be defined as the time interval from the onset of unusual behavioral symptoms to the onset of psychotic symptoms.
  • An individual who is in the prodromal phase of schizophrenia is at clinical high risk of developing psychosis, which can be assessed by suitable diagnostic tools, such as the Structured Interview for Prodromal Syndromes (SIPS) (Miller TJ, et. al, 2003, Schizophr Bull., 29(4): 703-15).
  • SIPS Structured Interview for Prodromal Syndromes
  • Alzheimer's disease and other dementias such as frontotemporal dementia (FTD), Huntington's disease, autism spectrum disorder (ASD), bipolar disorder (BPD), stress disorders, anxiety disorders, major depressive disorder (MDD), Parkinson's disease, temporal lobe epilepsy, stroke, and traumatic brain injury (TBI) (Boone et al., 2003, J Int Neuropsychol Soc., 9, 698- 709; Bastiaansen, J. et al., 2011, J. Autism Dev.
  • FDD frontotemporal dementia
  • ASD autism spectrum disorder
  • BPD bipolar disorder
  • stress disorders anxiety disorders
  • MDD major depressive disorder
  • Parkinson's disease temporal lobe epilepsy
  • stroke and traumatic brain injury (TBI) (Boone et al., 2003, J Int Neuropsychol Soc., 9, 698- 709; Bastiaansen, J. et al., 2011, J. Autism Dev.
  • apathy In some patient groups, these negative symptoms are generally referred to as apathy. This is true for both Parkinson's and Alzheimer's patients, as well as patients with associated dementias, frontotemporal dementias and stroke (Robert P. et al., 2009, European Psychiatry, 24, 98-104). In these patients, the apathy is characterized by the loss of initiation and motivation to participate in activities, social withdrawal, and emotional indifference. Patients with apathy are at increased risk to progressively suffer from decreased daily function and specific cognitive deficits such as executive cognitive dysfunction. In Alzheimer's disease and Parkinson's disease the apathy symptoms exist alongside the neurodegenerative symptoms classically associated with such diseases. The level of apathy related symptoms in a patient can be assessed by e.g.
  • NPI Neuropsychiatric Inventory
  • SCIA Structured Clinical Interview for Apathy
  • AES Apathy Evaluation Scale
  • AS Apathy Scale
  • AL Apathy Inventory
  • L Geb Apathy Rating Scale
  • PDE10A phosphodiesterase 10A
  • MSNs medium spiny neurons
  • This hydrolyzation transforms cAMP and cGMP into their inactive forms; 5'AMP and 5'GMP, respectively (Fujishige K. et al., 1999, J Biol Chem., 274(26): 18438-18445).
  • PDE10A inhibitors are expected to positively modulate (activate) signalling from dopamine D1 receptors via the direct pathway and negatively modulate (inhibit) signalling from dopamine D2 receptors via the indirect pathway (Polito M. et al., 2015, eNeuro, 31, 2(4)).
  • PDE10A inhibitors could embody a new class of antipsychotics, which could provide efficacy on all three symptom domains of schizophrenia (positive, negative and cognitive symptoms), concurrently (Kehler and Nielsen, 2011, Current Pharmaceutical Design, 17: 137-150; Kehler et al., 2007, Expert Opinion on Therapeutic Patents, 17:2,147-158; Dunlop et al., 2015, Journal of Psychopharmacology, 29(2), 230-238; Arnt J. et al., 2008, Drugs of the Future, 33(9): 777-791; Siuciak J., 2008, CNS Drugs; 22(12): 983-993).
  • PDE10A inhibitors have recently been moved into clinical development as monotherapy of schizophrenia. Two major clinical trials have been conducted by Pfizer and Takeda, exploring the efficacy of PDE10A inhibitor monotherapy, in cohorts of patients with acutely exacerbated schizophrenia. Pfizer tested their PDE10A inhibitor, MP-10, in clinical trial NCT01175135, and Takeda, tested their PDE10A inhibitor, TAK- 063, in clinical trial NCT02477020. Both trials failed to meet their endpoints (Macek et al, 2019, Schizophrenia Research 204, 289-294; DeMartinis N.
  • the PDE10A inhibitor 5,8-Dimethyl- 2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine and pharmaceutically acceptable salts thereof may be capable of treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions, when administered as monotherapy to patients who do not exhibit strong positive (psychotic or exacerbated) symptoms.
  • the present invention provides new compounds, which are pharmaceutically acceptable salts of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]- [l,2,4]triazolo[l,5-a]pyrazine in any crystalline or amorphous form, or the free base of 5,8-Dimethyl-2-[2- (l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine in a non-crystalline form.
  • the inventions provides a pharmaceutically acceptable salt of 5,8-Dimethyl-2-[2-(l- methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine, such pharmaceutically acceptable salts may e.g.
  • the pharmaceutically acceptable salt is in a crystalline form.
  • the compounds of the invention may be formulated as a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable excipient.
  • the invention provides novel compounds for use as a medicament.
  • the compounds of the invention are administered as monotherapy to a patient in need thereof.
  • the patient to be treated suffers from persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptom, persistent predominant negative symptoms and/or cognitive impairments.
  • Such patient may suffer from schizophrenia and be in a clinical stable phase or display prodrome of schizophrenia
  • a is meant to describe one or more, such as "a pharmaceutically acceptable salt of 5,8- Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine" which is meant to describe one or more a pharmaceutically acceptable salt(s) of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl- lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine.
  • negative symptoms as used herein is meant to describe, symptoms such as alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, poverty of speech, dysphoric mood, lack of insight and demoralisation.
  • persistent negative symptoms is meant to describe a clinical state of a patient where the negative symptoms have been persistent for at least about 6 months.
  • prominent negative symptoms is meant to describe a clinical state of a patient where the negative symptoms are a prominent part of the patient's clinical presentation.
  • the patients with "predominant negative symptoms” are meant to describe a subpopulation of patients with "prominent negative symptoms” who display negative symptoms that are at least moderate in severity, as evaluated on an accepted and validated rating scale (e.g. the PANSS negative symptom score, PANSS Marder Negative Symptom Factor score or the Brief Negative Symptom Scale (BNSS)) and display no or only little positive symptoms (e.g. assessed by the PANSS positive symptom score).
  • PANSS negative symptom score PANSS Marder Negative Symptom Factor score or the Brief Negative Symptom Scale (BNSS)
  • BNSS Brief Negative Symptom Scale
  • the term “persistent predominant negative symptoms” are meant to describe “predominant negative symptoms”, as defined above, that have been persistent for at least about 6 months.
  • cognition and “cognitive impairment” are used interchangeably and is meant to describe symptoms affecting cognition such as impaired executive functioning, working memory, attention deficits, social cognitive impairment, jumping to conclusions, Theory of Mind (TOM) impairments, deficits in emotion recognition or affect discrimination.
  • TOM Theory of Mind
  • clinically stable positive symptoms or “clinically stable phase” as used herein is meant to describe a clinical state of a patient suffering from schizophrenia, who has had no exacerbation of their positive symptoms, for a period of about 6 months. Any positive symptoms, which may be present during the clinically stable phase, should not exceed moderate severity, as evaluated on an accepted and valid rating scale, such as the PANSS.
  • the term "monotherapy” in the present context is meant to describe the treatment regimen related directly to the schizophrenic diagnosis.
  • the present invention describes the use of a pharmaceutically acceptable salt of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]- [l,2,4]triazolo[l,5-a]pyrazine or the free base of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)- ethyl]-[l,2,4]triazolo[l,5-a]pyrazin in a non-crystalline form as monotherapy, it means that they should not be administered as adjunctive/add-on treatment to any background antipsychotic treatment regimens, which may be comprised of either typical or atypical antipsychotics (examples of such drugs are given below).
  • a patient being administered a pharmaceutically acceptable salts of 5,8- Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine as monotherapy for treatment of persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptom, persistent predominant negative symptoms and/or cognitive impairments may in parallel with such treatment receive other drugs to treat potential additional pathological conditions, which are unrelated to the schizophrenic diagnosis.
  • antipsychotic drugs may for example be selected from the group comprising haloperidol, pimozide, chlorpromazine, fluphenazine, perazine, perphenazine, trifluoperazine, clopenthixol, thiothixene, loxapine, sultopride, iloperidone, lurasidone, paliperidone, risperidone, ziprasidone, aripiprazole, brexpiprazole, cariprazine, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin and sertindole.
  • [l,2,4]triazolo[l,5-a]pyrazine hemiadipate characterized by the XRPD shown in Figure 7A" is meant to describe the crystalline form of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-
  • the term "pharmaceutically acceptable salts of 5,8-Dimethyl-2-[2-(l-methyl-4- phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine" is meant to describe both pharmaceutically acceptable 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-
  • Fig. 1 Effect of compounds of the invention in the Conditioned Avoidance Response (CAR) assay.
  • CAR Conditioned Avoidance Response
  • Fig. 2A+B Effect of compounds of the invention on synaptic transmission in brain slices.
  • Fig. 3A+B Compounds of the invention modulates cAMP in both dopamine D1 and D2 receptor expressing neurons of the striatum.
  • Fig. 4 Effect of compounds of the invention on social interaction deficit.
  • Fig. 5A+B The chronic mild stress (CMS) model used to assess stress-induced hedonic deficits.
  • CMS chronic mild stress
  • Figures 7A-25B Displays XRPDs of hemiadipate, hydrogen bromide, hydrogen chloride, dihydrogen phosphate, hydrogen sulphate, citrate, fumarate, hemifumarate, D-glucoronate, glutarate, 2-oxo- glutarate, L(-)-malate, maleate, malonate, mesylate, oxalate, hemi-succinate, L(+)-tartrate, and tosylate salt of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine.
  • the invention relates to novel compounds, which are pharmaceutically acceptable salts of 5,8-Dimethyl- 2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine in any polymorphic form, in particular crystalline form, or the free base of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)- ethyl]-[l,2,4]triazolo[l,5-a]pyrazine in a non-crystalline form.
  • the compound of the invention is a pharmaceutically acceptable salt of 5,8-Dimethyl- 2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine.
  • salts include salts formed with inorganic and/or organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, adipic acid, nitrous acid, sulphuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, salicylic acid and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid.
  • inorganic and/or organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, adipic acid, nitrous acid, sulphuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic
  • di- or tri-acids i.e. acids containing two or three acidic hydrogens, such as phosphoric acid, sulphuric acid, fumaric acid and maleic acid.
  • Di- and tri-acids may form 1:1, 1:2 or 1:3 (tri-acids) salts.
  • the compound of the invention is a pharmaceutically acceptable salt of 5,8-Dimethyl- 2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine, wherein said salt is selected from the group comprising: hemiadipate, hydrogen bromide, hydrogen chloride, dihydrogen phosphate, hydrogen sulphate, citrate, fumarate, hemifumarate, D-glucoronate, glutarate, 2-oxo- glutarate, L(-)-malate, maleate, malonate, mesylate, oxalate, hemi-succinate, L(+)-tartrate, and tosylate salt.
  • said salt is selected from the group comprising: hemiadipate, hydrogen bromide, hydrogen chloride, dihydrogen phosphate, hydrogen sulphate, citrate, fumarate, hemifumarate, D-
  • the compounds of the present invention may be crystalline, provided that the compound is not the free base of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]- [l,2,4]triazolo[l,5-a]pyrazine.
  • the crystalline forms of the compounds of the present invention may be solvates, i.e. crystals wherein solvent molecules from part of the crystal structure.
  • the solvate may be formed from water, in which case the solvates are often referred to as hydrates.
  • the solvates may be formed from other solvents, such as e.g. ethanol, acetone, or ethyl acetate.
  • the exact amount of solvate often depends on the conditions. For instance, hydrates will typically loose water as the temperature is increased or as the relative humidity is decreased.
  • the compound of the present invention may be an un-solvated crystal.
  • the crystalline compounds of the present invention may exist in more than one form, i.e. they may exist in more than one polymorphic form.
  • the present invention is intended to encompass all such polymorphic forms, either as pure polymorphic forms or as mixtures of two or more polymorphic forms.
  • the compounds of the present invention may be found in a purified form.
  • purified form is intended to indicate that the compound is essentially free of other compounds or other polymorphic forms.
  • compounds of the present invention are characterized by XRDPs as shown in figures 7A-25B.
  • the inventors of the present invention have surprisingly found that when animals are administered a low dose of amphetamine to mimicking patients with exacerbated positive symptoms and tested in the conditioned avoidance response (CAR) assay, the antipsychotic effect of compounds of the present invention, which is seen in control animals, is abolished (figure 1).
  • CAR conditioned avoidance response
  • PDE10A inhibition is altered in animal models that mimic conditions with increased striatal dopamine tonus. Consequently, the inventors have identified that PDE10A inhibitors display an altered mechanism of action in physiological states with high dopamine, which is illustrated in example 1 and figure 1.
  • the compounds of the present invention have no target overlap with classic antipsychotics, which will likely reduce common peripheral side effects normally observed with such drugs, e.g. weight gain.
  • Such treatment comprises administration of a compound of the present invention as monotherapy to a patient suffering from negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions, wherein the patient has clinically stable positive symptoms.
  • Compounds of the present invention are believed to be useful in treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms and/or persistent predominant negative symptoms in patients which, despite on-going standard of care with e.g. antipsychotic therapy, continue to be socially withdrawn or amotivated/emotionless and limited in their interaction with their surroundings, which may significantly diminishes their quality of life.
  • the present invention discloses that compounds of the invention exhibit their primary efficacy on negative symptoms and/or cognitive dysfunctions, but that this effect is unexpectedly abolished when the striatal level of dopamine is elevated, such as in states of acutely exacerbated schizophrenia.
  • the invention provides new compounds suitable for the treatment of individuals who are in the prodromal phase of schizophrenia.
  • individuals can for example be identified with suitable valid questionnaires, such as the Structured Interview for Prodromal Syndromes (SIPS).
  • SIPS Structured Interview for Prodromal Syndromes
  • the treatment with a compound of the invention may represent a prophylactic treatment strategy, which might ameliorate present symptoms as well as potentially delay or prevent future psychotic incidents.
  • the invention also relates to compounds useful in a method for treating a patient suffering from cognitive dysfunction/impairment, provided that the compounds of the invention is administered as monotherapy - these patients may or may not be schizophrenic.
  • the compounds of the present invention may also be useful for the treatment of non-schizophrenic patients suffering from negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions. This especially include patients who suffers from apathy and/or cognitive impairments associated with Alzheimer's disease or Parkinson's disease.
  • Compounds of the invention may also be used to treat negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a schizophrenic patient who is treatment-naive to antipsychotic drugs, i.e. said patient has not previously been treated with any type of antipsychotic.
  • compounds of the invention are used to treat negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a schizophrenic patient who was previously treated with an antipsychotic drug but discontinued such treatment, e.g. because the drug did not provide adequate improvement of the negative symptoms and/or because the subject could not tolerate the side effects of the drug.
  • the term "therapeutically effective amount" of a compound means an amount sufficient to alleviate, arrest, partially arrest, remove or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of a compound of the invention.
  • An amount adequate to accomplish this is defined as “therapeutically effective amount”.
  • Effective amounts for each purpose will depend on the severity of the symptoms as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, which is all within the ordinary skills of a trained physician.
  • treatment or “treating” is intended to indicate the management and care of a patient for the purpose of alleviating, arresting, partly arresting, removing or delaying progress of the clinical manifestation of the negative symptoms and/or cognitive dysfunctions.
  • the treatment period is at least one week, at least two weeks, at least four weeks, at least six weeks, at least eight weeks, at least 10 weeks or at least twelve weeks.
  • the patient to be treated is a human being.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, buccal, sublingual, transdermal and parenteral (e.g. subcutaneous, intramuscular, and intravenous) route; the oral route being preferred.
  • suitable route such as the oral, rectal, nasal, buccal, sublingual, transdermal and parenteral (e.g. subcutaneous, intramuscular, and intravenous) route; the oral route being preferred.
  • compositions and excipients The present invention also provides new use of pharmaceutical composition comprising one or more compound of the invention.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable excipients in accordance with conventional techniques such as those disclosed in Remington, The Science and Practice of Pharmacy, 22 th edition (2013), Edited by Allen, Loyd V., Jr.
  • excipient or “pharmaceutically acceptable excipient” refers to pharmaceutical excipients including, but not limited to, fillers, antiadherents, binders, coatings, colours, disintegrants, flavours, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, vehicles and adjuvants.
  • compositions for oral administration include solid oral dosage forms such as tablets, capsules, powders and granules; and liquid oral dosage forms such as solutions, emulsions, suspensions and syrups as well as powders and granules to be dissolved or suspended in an appropriate liquid.
  • Solid oral dosage forms may be presented as discrete units (e.g. tablets or hard or soft capsules), each containing a predetermined amount of the active ingredient, and preferably one or more suitable excipients.
  • the solid dosage forms may be prepared with coatings such as enteric coatings or they may be formulated so as to provide modified release of the active ingredient such as delayed or extended release according to methods well known in the art.
  • the solid dosage form may be a dosage form disintegrating in the saliva, such as for example an orodispersible tablet.
  • excipients suitable for solid oral formulation include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talcum, gelatine, pectin, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • the solid formulation may include excipients for delayed or extended release formulations known in the art, such as glyceryl monostearate or hypromellose.
  • the formulation may for example be prepared by mixing the active ingredient with solid excipients and subsequently compressing the mixture in a conventional tableting machine; or the formulation may for example be placed in a hard capsule e.g. in powder, pellet or mini tablet form.
  • the amount of solid excipient will vary widely but will typically range from about 25 mg to about 1 g per dosage unit.
  • Liquid oral dosage forms may be presented as for example elixirs, syrups, oral drops or a liquid filled capsule. Liquid oral dosage forms may also be presented as powders for a solution or suspension in an aqueous or non-aqueous liquid.
  • excipients suitable for liquid oral formulation include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylenglycols, poloxamers, sorbitol, poly-sorbate, mono and di-glycerides, cyclodextrins, coconut oil, palm oil, and water.
  • Liquid oral dosage forms may for example be prepared by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.
  • excipients may be used in solid and liquid oral formulations, such as colourings, flavourings and preservatives etc.
  • compositions for parenteral administration include sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion as well as sterile powders to be reconstituted in sterile solutions or dispersions for injection or infusion prior to use.
  • excipients suitable for parenteral formulation include, but are not limited to water, coconut oil, palm oil and solutions of cyclodextrins.
  • Aqueous formulations should be suitably buffered if necessary and rendered isotonic with sufficient saline or glucose.
  • compositions include suppositories, inhalants, creams, gels, dermal patches, implants and formulations for buccal or sublingual administration.
  • the compounds of the present invention are administered in an amount from about 0.001 mg/kg body weight to about 100 mg/kg body weight per day.
  • daily dosages may be in the range of 0.01 mg/kg body weight to a bout 50 mg/kg body weight per day. The exact dosages will depend upon the frequency and mode of administration, the sex, the age the weight, and the general condition of the subject to be treated, the nature and the severity of the condition to be treated, any concomitant diseases to be treated, the desired effect of the treatment and other factors known to those skilled in the art.
  • a typical oral dosage for adults will be in the range of 0.01-500 mg/day of a compound of the present invention, such as 0.1-100 mg/day, such as 0.5-50 mg/day or 1-25 mg/day or 1-10 mg/day.
  • the compounds of the invention are administered in a unit dosage form containing said compounds in an amount of about 0.01 to 500 mg, such as 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7mg, 8 mg, 9 mg, 10 mg, 50 mg 100 mg, 150 mg, 200 mg or 250 mg of a compound of the present invention .
  • the compounds of the invention is administered orally in a dose of 1-6 mg/day, such as 2-4 mg/day.
  • the first embodiment is denoted El
  • the second embodiment is denoted E2 and so forth.
  • a pharmaceutical composition comprising a compound according to any of embodiments 1-6 and at least one pharmaceutically acceptable excipient.
  • Ell. The compound according to any of embodiments 1-6, for use in treating a patient suffering from persistent negative symptoms, provided that said compound is administered as monotherapy.
  • E14 The compound according to any of embodiments 1-6, for use in treating a patient suffering from predominant negative symptoms, provided that said compound is administered as monotherapy.
  • E15 The compound according to any of embodiments 1-6, for use in treating a patient suffering from persistent predominant negative symptoms, provided that said compound is administered as monotherapy.
  • negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.
  • the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.
  • E20 The compound according to any of embodiments 1-6, for use according to embodiment 19, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.
  • E23 The compound according to any of embodiments 1-6, for use according to any of embodiments 10-20, wherein the patient displays psychosis risk syndrome and/or prodrome of schizophrenia.
  • E24 The compound according to any of embodiments 1-6, for use according to any of embodiments 10-20, wherein the patient is not diagnosed with schizophrenia.
  • E27 A method of treating negative symptoms, comprising the administration of a therapeutically effective amount of a compound according to any of embodiments 1-6 as monotherapy to a patient in need thereof.
  • E28 A method of treating persistent negative symptoms, comprising the administration of a therapeutically effective amount of a compound according to any of embodiments 1-6 as monotherapy to a patient in need thereof.
  • a method of treating prominent negative symptoms comprising the administration of a therapeutically effective amount of a compound according to any of embodiments 1-6 as monotherapy to a patient in need thereof.
  • E30 A method of treating persistent prominent negative symptoms, comprising the administration of a therapeutically effective amount of a compound according to any of embodiments 1-6 as monotherapy to a patient in need thereof.
  • E31 A method of treating predominant negative symptoms, comprising the administration of a therapeutically effective amount of a compound according to any of embodiments 1-6 as monotherapy to a patient in need thereof.
  • a method of treating persistent predominant negative symptoms comprising the administration of a therapeutically effective amount of a compound according to any of embodiments 1-6 as monotherapy to a patient in need thereof.
  • E34 The method according to any of embodiments 27-33, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.
  • E35 The method according to embodiment 34, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.
  • E36 A method of treating a patient suffering from cognitive impairments, comprising the administration of a therapeutically effective amount of a compound according to any of embodiments 1-6 as monotherapy.
  • E40 The method according to any of embodiments 27-37, wherein the patient displays psychosis risk syndrome and/or prodrome of schizophrenia.
  • E41 The method according to any of embodiments 27-37, wherein the patient is not diagnosed with schizophrenic.
  • E42. The method according to any of embodiments 27-38, wherein the patient suffers from deficit schizophrenia.
  • E50 Use according to any of embodiments 44-49, wherein the negative symptoms are primary negative symptoms.
  • E51 Use according to any of embodiments 44-50, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.
  • E52 Use according to embodiment 51, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.
  • E53 Use of a compound according to any of embodiments 1-6 in the manufacture of a medicament for treatment of cognitive impairments, provided that said compound is administered as monotherapy.
  • E54 Use according to embodiment 53, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.
  • E55 Use according to any of embodiments 44-54, wherein the patient to be treated suffers from schizophrenia.
  • E57 Use according to any of embodiments 44-54, wherein the patient displays psychosis risk syndrome and/or prodrome of schizophrenia.
  • E60 Use according embodiment 55, wherein the patient suffers from simple schizophrenia or simple type schizophrenia.
  • E62 The compound according to any of embodiments 1-6, for use according to embodiment 61, wherein the administered dose is between 0.1 - 15 mg/day.
  • E63 The compound according to any of embodiments 1-6, for use according to any of embodiments 44-60, wherein the treatment comprises administration of said compound by any enteral route in a therapeutically effective amount.
  • E66 The compound according to any of embodiments 1-6, for use according to any of embodiments 61-65, wherein the dose is 1-6 mg/day.
  • E67 The compound according to any of embodiments 1-6, for use according to embodiment 56, wherein the schizophrenic patient is in a clinical stable phase with respect to the patient's positive symptoms.
  • clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.
  • E70 The compound according to any of embodiments 1-6, for use according to any of embodiments 44-52, 55-60 or 69, wherein the patient has a PANSS Marder Negative Symptom Factor Score >20.
  • E71 The compound according to any of embodiments 1-6, for use according to any of embodiments 44-52 or 55-60, wherein said treatment is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in BNSS score.
  • E72 The compound according to any of embodiments 1-6, for use according to any of embodiments 44-60, wherein said treatment is effective in treating the negative symptoms and/or the cognitive impairments by improving personal and social function in said patient as quantified by the change in PSP score.
  • E73 The compound according to any of embodiments 1-6, for use according to embodiment 44-60, wherein said treatment is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in PANSS score.
  • E74 The compound according to any of embodiments 1-6, for use according to embodiment 44-60, wherein said treatment is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in Clinical Global Impression - Schizophrenia (CGI-SCH-S) negative symptom score.
  • CGI-SCH-S Clinical Global Impression - Schizophrenia
  • E75 The compound according to any of embodiments 1-6, for use according to embodiment 44-60, wherein said treatment is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in Clinical Global Impression - Schizophrenia (CGI-SCH- DC) negative symptom score.
  • CGI-SCH- DC Clinical Global Impression - Schizophrenia
  • E76 The compound according to any of embodiments 1-6, for use according to embodiment 44-60, wherein said treatment is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in Calgary Depression Scale for Schizophrenia (CDSS) total score.
  • CDSS Calgary Depression Scale for Schizophrenia
  • step b The process of any of embodiments 81-83, wherein the acid added in step b is selected from the group consisting of: adipic acid, hydrobromide, hydrochloride, phosphoric acid, sulfuric acid, citric acid, fumaric acid, D-glucuronic acid, pentanedioic acid, 2-oxo-pentadioic acid, L(-)-malic acid, maleic acid, malonic acid, mesylic acid, oxalic acid, butanedioic acid, L(+)-tartaric acid and p- toluenesulfonic acid.
  • the acid added in step b is selected from the group consisting of: adipic acid, hydrobromide, hydrochloride, phosphoric acid, sulfuric acid, citric acid, fumaric acid, D-glucuronic acid, pentanedioic acid, 2-oxo-pentadioic acid, L(-)-malic acid, male
  • the administered doses are calculated as the amount of base of 5,8- Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine administered.
  • Example 1- Efficacy of Compounds of the Invention in the Conditioned Avoidance Response (CAR) in Rats in High Dopamine State:
  • the dopamine receptors regulate the dopamine signal by controlling cAMP synthesis and PDE10A regulates the gain of this signal by controlling cAMP degradation
  • the effect of PDE10A inhibition might be altered in conditions with increased striatal dopamine tonus, such as found in patients with prominent positive symptoms.
  • Figure 1 shows the effect of compounds of the invention in the Conditioned Avoidance Response (CAR) assay in rats as further described in example 1.
  • the compound of the invention used in this assay was the free base of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine, which was tested alone and in combination with a low dose d-amphetamine to induce a high dopamine state.
  • the efficacy was measured as the mean number of avoidances and results are depicted as mean +/- SEM.
  • the graph displays the effect of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]- [l,2,4]triazolo[l,5-a]pyrazine alone and in combination with low dose d-amphetamine.
  • Bars represent the following dose groups (left to right): 1) Vehicle; 2) d-amphetamine (0.2 mg/kg); 3) 5,8-Dimethyl-2-[2-(l- methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine (0.6 mg/kg); 4) 5,8-Dimethyl-2-[2- (l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine (0.3 mg/kg) + d-amphetamine (0.2 mg/kg); 5) 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine (0.6 mg/kg) + d-
  • Figure 2 shows the effect of compounds of the invention on synaptic transmission in brain slices from rat prefrontal cortex as further described in example 2. Negative symptoms and cognitive dysfunctions are believed to be associated with low dopamine activity in the prefrontal cortex, caused by reduced cortical dopamine D1 receptor signalling. This data show that compounds of the invention increase synaptic transmission in brain slices from rat prefrontal cortex, and hence, has the potential to treat the associated negative and cognitive symptoms.
  • the compound of the invention used in this assay was the free base of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine.
  • the brain slices from rat prefrontal were treated with either vehicle (DMSO) or 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH- imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine and in addition forskolin was applied after 60 minutes of measurements to increase the cAMP tonus in the slices, which was otherwise low due to reduced input from other brain areas.
  • the application of forskolin gave rise to an increase in fEPSP slope in control slices treated with vehicle (DMSO, white circles).
  • Example 3 Compounds of the Invention Modulates cAMP in both Dopamine D1 and D2 Expressing Neurons of the Striatum:
  • c-Fos is known to be regulated by cAMP and thus this peptide functions as an indirect marker for cAMP levels and thereby also PDE10A activity.
  • Figure 3 shows that compounds of the invention modulates cAMP in both dopamine D1 and D2 receptor expressing neurons of the striatum, which are both relevant to schizophrenia; Dopamine D1 receptors in the striatum are relevant for reward processing, which is perturbed in patients with negative symptoms, whereas Dopamine D2 receptor antagonism underlies the effect of current antipsychotics on positive symptoms of schizophrenia.
  • Compounds of the invention increase c-Fos expression in both D1 (fig 3A, black bars) and D2 (fig 36, black bars) receptor expressing neurons compared to vehicle (white bars), **** p ⁇ 0.0001 vs vehicle.
  • C-Fos is an indirect marker of neuronal activity, known to be upregulated by cAMP, hence the data show that Compounds of the invention increase cAMP levels in D1 expressing neurons, similar to a D1 agonist, and in D2 receptor expressing neurons similar to D2 antagonists.
  • This assay is further described in example 3.
  • the compound of the invention used in this assay was the maleate salt of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine.
  • Figure 4 shows the effect of compounds of the invention on social interaction deficit elicited by sub chronic treatment with PCP as further described in example 4.
  • Social withdrawal or asociality is a core domain of negative symptomatology in schizophrenia and in animal models, PCP (administered once daily for 14 days at a dose of 13 mg/kg) can induce significant deficit in social interaction as measured by mean interaction time(s) and results are depicted as mean +/- SEM.
  • These deficits in social interaction were counteracted by compounds of the invention and indicate that compounds of the invention may be useful in the treatment of social withdrawal, which is a core domain of negative symptoms.
  • the compound of the invention used in this assay was the maleate of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2- yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine.
  • the graph displays the effect of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]- [l,2,4]triazolo[l,5-a]pyrazine on social interaction deficit elicited by sub-chronic treatment with PCP.
  • Data showed a significant PCP-induced deficit in social interaction.
  • Dosing groups (left to right): 1) Vehicle treated control animals (no PCP treatment); 2) sub-chronic treatment with PCP + vehicle; 3) sub-chronic treatment with PCP + 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]- [l,2,4]triazolo[l,5-a]pyrazine 0.02 mg/kg; 4) sub-chronic treatment with PCP + 5,8-Dimethyl-2-[2-(l- methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine 0.08 mg/kg. *p ⁇ 0.05 compared to sub-chronic treatment with PCP + vehicle.
  • CMS chronic mild stress
  • FIG. 5 The chronic mild stress (CMS) model is used to assess stress-induced hedonic deficits, measured as intake of a 1% sucrose solution in rats subjected to CMS for 7 weeks. Chronic mild stress led to the expected reduction in sucrose and subsequent administration of a compound of the invention rapidly normalized the sucrose intake in a dose dependent manner. This data suggests that compounds of the invention may be useful in the treatment of anhedonia. This assay is further described in example 4.
  • 5A This graph shows the sucrose consumption in control animals (non-stressed animals) and the effect of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine (0-10 mg/kg, p.o) or vehicle (10% cremophor, 1 mL/kg) on this parameter.
  • Dosing groups Vehicle/cremophor (open circles); 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- ajpyrazine 0.1 mg/kg (open squares); 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]- [l,2,4]triazolo[l,5-a]pyrazine 0.3 mg/kg (open triangles); 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH- imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine 1.0 mg/kg (closed circles); 5,8-Dimethyl-2-[2-(l- methyl-4-phenyl-lH-imidazol-2
  • 5B This graph shows the sucrose consumption in animals exposed to chronic mild stress and the effect of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine (0-10 mg/kg, p.o) or vehicle (10% cremophor, 1 mL/kg) on this parameter. Treatment commenced following 2 weeks of stress.
  • Dosing groups Vehicle/cremophor (open circles); 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl- lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine 0.1 mg/kg (open squares); 5,8-Dimethyl-2-[2-(l- methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine 0.3 mg/kg (open triangles); 5,8- Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine 1.0 mg/kg (closed circles); 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-
  • Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the cognitive domains which are abnormal in schizophrenia.
  • the NOR task is a test paradigm thought to reflect visual learning and recognition processing that has been compared to human cognitive tests, such as the visual paired comparison task (Rajagopal L. et al., 2014, Current Pharmaceutical Design, 20, 5104-5114).
  • Sub-chronic administration of phencyclidine (subPCP) has been shown to induce a behavioural and neurobiological syndrome in rodents upon cessation of treatment that bears a remarkable similarity to symptoms related to schizophrenia, including cognitive dysfunctions.
  • the vehicle-treated rats spent significantly more time exploring a novel object during the 3-minute test period compared to subPCP rats (figure 6). Animals that had received PCP for 7 days prior to testing spent approximately an equal amount of time exploring both a familiar and a novel object.
  • FIG. 6 The novel object recognition (NOR) task in rats is an in vivo assay used to mimic cognitive impairments as further described in example 5.
  • Sub-chronic administration of PCP induces a behavioural and neurobiological syndrome in rodents upon cessation of treatment that bears a remarkable similarity to some of the core symptoms in schizophrenic patients, including cognitive disruption.
  • As expected vehicle-treated rats spent significantly more time exploring a novel object compared to a familiar object, which is the natural behavior of rodents.
  • animals that has received PCP for 7 days prior to testing spent approximately an equal amount of time exploring a familiar and a novel object, which indicate a state of cognitive impairment.
  • the graph displays the effect of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]- [l,2,4]triazolo[l,5-a]pyrazine in the novel object recognition (NOR) task in rats.
  • White bars represent the time spent exploring the novel object and the black bars represent time spent exploring the familiar object within a test period of 3 minutes.
  • V+V Vehicle+Vehicle
  • PCP+V represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were also treated with vehicle prior to performing the NOR task
  • PCP+V represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with vehicle prior to performing the NOR task
  • PCP+0.1 mg/kg represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with 5,8- Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine 0.1 mg/kg prior to performing the NOR task
  • PCP+0.3 mg/kg represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with 5,8-Dimethyl-2-[2-(l)
  • the clinical efficacy of the compound of the invention for treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in patients can be tested by conducting a randomized double blinded placebo-controlled study. Such study may include the evaluation of the efficacy of two fixed-flexible doses (1-2 mg and 3-4 mg per day) of a compound of the invention.
  • the primary outcome measures could be the change in negative symptoms from baseline to week 12 of the study when assessment of said negative symptoms are done on a valid rating scale, such as the PANSS Marder Negative Symptom Factor score or the Brief Negative Symptom Scale (BNSS).
  • a valid rating scale such as the PANSS Marder Negative Symptom Factor score or the Brief Negative Symptom Scale (BNSS).
  • the secondary outcome measures could be the change in Personal and Social Performance (PSP) score, Positive and Negative Syndrome Scale (PANSS) total score, PANSS Marder Negative Symptom Factor score, PANSS Negative subscale score, Clinical Global Impression - Schizophrenia (CG l-SCH-S) negative symptoms score and/or Global Impression - Schizophrenia (CGI-SCH-DC) negative symptoms score between baseline and 12 weeks of treatment.
  • PSP Personal and Social Performance
  • PANSS Positive and Negative Syndrome Scale
  • PANSS Positive and Negative Syndrome Scale
  • PANSS Positive and Negative Syndrome Scale
  • PANSS PANSS Marder Negative Symptom Factor
  • PANSS Negative subscale score PANSS Negative subscale score
  • Patients to be included should correlate with the subpopulations of schizophrenia suitable to be treated with compounds of the invention as described herein above.
  • Such patient may be diagnosed with schizophrenia and suffers from persistent prominent or persistent predominant negative symptoms. Further, the patient is in a clinically stable phase of schizophrenia and has not more than moderate severity on relevant positive symptoms, which may be selected from delusions, hallucinatory behavior, suspiciousness/persecution, uncooperativeness, unusual thought content and conceptual disorganization.
  • relevant positive symptoms which may be selected from delusions, hallucinatory behavior, suspiciousness/persecution, uncooperativeness, unusual thought content and conceptual disorganization.
  • a positive response in treatment could e.g.
  • BNSS total score or any of the other suitable scales, such as those mentioned herein above and in the description of the present invention
  • a detailed clinical protocol may be designed as described below and study protocols NCT03793712 and NCT03929497 (hereby incorporated by reference in their entirety (to the maximum extent permitted by law)).
  • a compound of the invention low dose (1-2 mg/day), tablet, once daily, 12 or 24 weeks
  • a compound of the invention low dose (3-4 mg/day), tablet, once daily, 12 or 24 weeks
  • the patient has schizophrenia, diagnosed according to DSM-5 ® as confirmed by the Mini- International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders Studies (MINI- Schz).
  • the patient is in a clinically stable phase of schizophrenia and has not more than moderate severity on relevant positive symptoms, that is a score of ⁇ 4 (moderate) out of score of 7 on each of the following PANSS items: Delusions (PI), Hallucinatory behaviour (P3), Suspiciousness / opposition (P6), Uncooperativeness (G8), Unusual thought content (G9) at Screening Visit 1, Washout Visit(s), Screening Visit 2, and Baseline Visit and a score ⁇ 5 on Conceptual disorganization (P2).
  • PI Delusions
  • P3 Hallucinatory behaviour
  • P6 Suspiciousness / opposition
  • Uncooperativeness G8
  • Unusual thought content G9
  • the patient currently has no clinically significant acute extrapyramidal side effects (acute EPS) or tardive dyskinesia (TD) based upon the protocol-specified clinical examination.
  • acute EPS acute extrapyramidal side effects
  • TD tardive dyskinesia
  • NSFS PANSS Marder Negative Symptom Factor Score
  • Nl Blunted affect
  • N2 Emotional withdrawal
  • N3 Poor rapport
  • N4 Passive/apathetic social withdrawal
  • N6 Lack of spontaneity & flow of conversation
  • G7 Motor retardation
  • G16 Active social avoidance
  • the patient has a Clinical Global Impression-Schizophrenia Severity of Illness (CGI-SCH-S) overall severity score ⁇ 4 at Screening Visit 1.
  • CGI-SCH-S Clinical Global Impression-Schizophrenia Severity of Illness
  • the patient does not currently have a diagnosis of Major Depressive Disorder or have depressive symptoms rated with a total score >5 on the Calgary Depression Scale for Schizophrenia (CDSS).
  • CDSS Calgary Depression Scale for Schizophrenia
  • the patient has a caregiver or an identified responsible person (for example, partner, family member, social worker, case worker, or nurse) considered reliable by the investigator in providing support to the patient to ensure compliance with study treatment, outpatient visits, and protocol procedures.
  • a caregiver or an identified responsible person for example, partner, family member, social worker, case worker, or nurse
  • the patient has had an acute exacerbation requiring hospitalization within the last 6 months prior to Screening Visit 1.
  • the patient has had an acute exacerbation requiring change in antipsychotic medication (with reference to drug or dose) within the last 6 months prior to Screening Visit 1.
  • the patient has a current diagnosis or a history of substance use disorder according to DSM-5 ® criteria within 6 months prior to Screening Visit 1 with the exception of tobacco, or mild cannabis or mild alcohol use disorder (occasional - but not weekly recreational cannabis use is acceptable).
  • the patient is at significant risk of harming himself/herself or others in the investigator's opinion.
  • the patient has tested positive for hepatitis A virus antibody (anti-HAV IgM), hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (anti-HCV). If the anti-HCV test result is positive, but acute/chronic infection is excluded with a negative FICV RNA test patient can be included in the study.
  • anti-HAV IgM hepatitis A virus antibody
  • HBsAg hepatitis B surface antigen
  • anti-HCV hepatitis C virus antibody
  • HIV human immunodeficiency virus
  • the patient has a present condition that might compromise liver function (for example, alcohol abuse, hepatitis, hepatic insufficiency, cholestasis, haemachromatosis, deficit in alpha 1 antitrypsine, Wilson's Disease, autoimmune diseases, cirrhosis).
  • liver function for example, alcohol abuse, hepatitis, hepatic insufficiency, cholestasis, haemachromatosis, deficit in alpha 1 antitrypsine, Wilson's Disease, autoimmune diseases, cirrhosis).
  • the patient has any other disorder for which the treatment takes priority over treatment of schizophrenia or is likely to interfere with the study treatment or impair treatment compliance.
  • BNSS Negative Symptom Scale
  • the BNSS is a brief clinician rating scale, intended to measure negative symptoms. It consists of 13 items organized into 6 subscales: anhedonia, distress, asociality, avolition, blunted affect and alogia. The items score the impairment. Items 1 to 4 are rated from 0 (Normal) to 6 (Extremely severe) and items 5 to 13 are rated from 0 (No impairment) to 6 (Severe deficit).
  • the BNSS total score is calculated by summing the 13 individual items; subscale scores are calculated by summing the individual items within each subscale. Users of the BNSS should have training in psychiatric interview techniques and have clinical experience working with patients with schizophrenia and related psychotic disorders. The BNSS total scores ranges from 0 to 78.
  • PSP Personal and Social Performance
  • the PSP is a clinician-rated scale designed and validated to measure a patient's current level of social functioning.
  • the PSP consists of 4 items: socially useful activities (including work and study), personal and social relationships, self-care, and disturbing and aggressive behaviours.
  • the 4 items are assessed on a 6- point scale, from absent to very severe. Based on these assessments and their combination, individual scores are converted into a global score ranging from 1 to 100.
  • the PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms.
  • the PANSS includes 3 sub-scales and 30 items. 7 items make up the positive scale (for example: delusions, conceptual disorganization and hallucinatory behaviour), 7 items make up the negative scale (for example: blunted affect, emotional withdrawal and poor rapport) and 16 items make up the general psychopathology scale (for example: somatic concern, anxiety and guilt feelings). Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe).
  • the PANSS total score is the sum of all items, and ranges from 30 to 210. Subscale scores are the sum of items within each subscale.
  • the PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms.
  • the PANSS includes 3 sub-scales and 30 items.
  • the PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms.
  • the PANSS includes 3 sub-scales and 30 items.
  • CGI-SCH-S Clinical Global Impression - Schizophrenia
  • the CG l-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia.
  • the CG l-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder.
  • the CGI-SCFI-S severity of illness category symptoms and overall severity are rated on a 7-point scale ranging from 1 (normal - not ill) to 7 (Among the most severely ill). For the first four ratings (positive, negative, depressive, and cognitive symptoms), the assessment should focus on the severity of symptoms only. Additionally, for 'overall severity' rating, both severity of symptoms and interference with functioning should be considered.
  • CGI-SCFI-DC Clinical Global Impression - Schizophrenia
  • the CG l-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia.
  • the CG l-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder.
  • category symptoms and overall severity are rated on a 7- point scale ranging from 1 (very much improved) to 7 (very much worse).
  • Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived.
  • the CG l-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia.
  • the CG l-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder.
  • category symptoms and overall severity are rated on a 7- point scale ranging from 1 (very much improved) to 7 (very much worse).
  • Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived.
  • Response defined as CGI-SCFI-DC negative symptoms 1 or 2
  • the BNSS is a brief clinician rating scale, intended to measure negative symptoms. It consists of 13 items organized into 6 subscales: anhedonia, distress, asociality, avolition, blunted affect and alogia. The items score the impairment. Items 1 to 4 are rated from 0 (Normal) to 6 (Extremely severe) and items 5 to 13 are rated from 0 (No impairment) to 6 (Severe deficit).
  • the BNSS total score is calculated by summing the 13 individual items; subscale scores are calculated by summing the individual items within each subscale. Users of the BNSS should have training in psychiatric interview techniques and have clinical experience working with patients with schizophrenia and related psychotic disorders.
  • the BNSS total scores ranges from 0 to 78. Response criteria defined as 20, 30 or 40% decrease in BNSS total score.
  • the PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms.
  • the PANSS includes 3 sub-scales and 30 items
  • CGI-SCH-S Clinical Global Impression - Schizophrenia
  • the CGI-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia.
  • the CG l-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder.
  • the CGI-SCH-S severity of illness category symptoms and overall severity are rated on a 7-point scale ranging from 1 (normal - not ill) to 7 (Among the most severely ill). For the first four ratings (positive, negative, depressive, and cognitive symptoms), the assessment should focus on the severity of symptoms only. Additionally, for 'overall severity' rating, both severity of symptoms and interference with functioning should be considered.
  • CGI-SCH-DC Clinical Global Impression - Schizophrenia
  • the CGI-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia.
  • the CGI-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder.
  • category symptoms and overall severity are rated on a 7- point scale ranging from 1 (very much improved) to 7 (very much worse). Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived.
  • CDSS Calgary Depression Scale for Schizophrenia
  • the CDSS is a 9-item clinician rated scale specifically developed for the assessment of depression in patients with schizophrenia.
  • the items on the CDSS are all typical depressive symptoms and do not appear to overlap with the negative symptoms of schizophrenia. All items are rated on a 4-point scale from 0 (absent) to 3 (severe).
  • Example 7 Preparation of Compounds of the Invention Table 1 display an overview of the salt forms of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)- ethyl]-[l,2,4]triazolo[l,5-a]pyrazine
  • Example 1A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Hemiadipate a-form
  • adipic acid (4.82 g) and ethanol (44 mL).
  • the mixture was heated to 65 °C where the resulting solution was passed through a filter.
  • the hot filtrate of adipic acid in ethanol was transferred to the 60 °C hot solution of the base of 5,8-Dimethyl-2-[2-(l-methyl-4- phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine in ethanol.
  • the flask used to dissolve the adipic acid was rinsed with hot ethanol (22 mL) and passed through the filter and transferred to the hot mixture of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine and adipic acid.
  • the mixture was heated to reflux for 1 hour and then cooled to 20 °C over 2 hours.
  • the hemiadipate of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine was isolated by filtration and washed two times with ethanol (2x 44 mL).
  • the 5,8-Dimethyl-2- [2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine hemiadipate was dried overnight in vacuo at 50 °C.
  • Example 2A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine hydrogen bromide Hydrate A+B In one experiment, the base of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-
  • [l,2,4]triazolo[l,5-a]pyrazine (100 mg, 0.301 mmol) was dissolved in acetone (5 mL, 70 mmol). The solution was treated with 8.8 M hydrogen bromide in water (0.102 mL) and the mixture was stirred at room temperature for 12 hours. The hydrobromide of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH- imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and washed with acetone.
  • Example 2B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine hydrogen bromide Hydrate A
  • [l,2,4]triazolo[l,5-a]pyrazine hydrobromide obtained in example 2A was made into a slurry in water. After slurry in water, the isolated solid was found to be a new crystalline form of a hydrate of 5,8- Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine hydrobromide.
  • [l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and washed with acetone.
  • a hydrate of 5,8- Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine hydrobromide was dried at 50°C.
  • [l,2,4]triazolo[l,5-a]pyrazine (100 mg, 0.301 mmol) was dissolved in acetone (5 mL, 70 mmol). The mixture was treated with 12 M hydrogen chloride in water (0.0752 mL) and the mixture was stirred at room temperature for 12 hours. The hydrochloride of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH- imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and washed with acetone.
  • Example 3B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine hydrogen chloride Hydrate A
  • [l,2,4]triazolo[l,5-a]pyrazine hydrochloride obtained in example 3A was made into a slurry in water. After slurry in water, the isolated solid was found to be a new crystalline hydrate form of 5,8-Dimethyl- 2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine hydrochloride.
  • [l,2,4]triazolo[l,5-a]pyrazine (100 mg, 0.301 mmol) was dissolved in acetone (1 mL, 14 mmol). The solution was treated with phosphoric acid (0.017 mL, 0.30 mmol) and the mixture was left at room temperature for 2 hours.
  • the dihydrogen phosphate of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH- imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration.
  • Example 4B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Dihydrogen phosphate Hydrate A
  • Example 5A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Hydrogen sulphate Hydrate A In one experiment, the base of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-
  • [l,2,4]triazolo[l,5-a]pyrazine (100 mg, 0.301 mmol) was dissolved in acetone (1 mL, 14 mmol). The solution was treated at near reflux with sulfuric acid (0.016 mL, 0.301 mmol) and the mixture was left at room temperature for 3 hours.
  • the Hydrogen sulphate of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH- imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration.
  • Example 5B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Hydrogen sulphate Hydrate B
  • Example 6A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Citrate a-form
  • [l,2,4]triazolo[l,5-a]pyrazine (150 mg, 0.451 mmol) was dissolved in acetone (3 mL, 41 mmol). The solution was treated at near reflux with solid citric acid (86.7 mg, 0.451 mmol) and the mixture was stirred at room temperature for 1 hour. The citrate of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH- imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and washed with acetone.
  • Example 7A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine fumarate a-form
  • [l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and washed with acetone.
  • the 5,8-Dimethyl-2-[2- (l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine fumarate was dried at 40°C.
  • Example 7B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine fumarate Hydrate A
  • Example 7C 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine fumarate Hydrate B
  • Example 8A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Hemi-fumarate a-form
  • [l,2,4]triazolo[l,5-a]pyrazine (100 mg, 0.301 mmol) was dissolved in acetone (5 mL, 70 mmol). The solution was treated with fumaric acid (0.105 g, 0.902 mmol) in acetone (2 mL) and the mixture was stirred at room temperature for 12 hours. The solvent was reduced to half and the mixture stirred at room temperature for 2 hours.
  • the hemi-fumarate of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH- imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and washed with acetone.
  • the 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine hemi- fumarate was dried at 50°C.
  • Example 8B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Hemi-fumarate Hydrate A This a-form of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine hemi-fumarate was made into a slurry in water.
  • Example 8C 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Hemi-fumarate b-form
  • Example 8D 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Hemi-fumarate Hydrate B
  • Example 9B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine D-glucoronate Amorphous The a-form of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine D-glucoronate obtained in example 9A was dissolved in water and the water was allowed to evaporate.
  • Example 10A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Glutarate Hydrate A
  • a hydrate of glutarate of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)- ethyl]-[l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and dried.
  • Example 11A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine 2-oxoglutarate Hydrate A
  • Example 11B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine 2-oxoglutarate a-form
  • Example 12A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine L(-)-malate a-form
  • Example 12B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine L(-)-malate Hydrate A
  • Example 13A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Maleate a-form
  • the maleate of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)- ethyl]-[l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and washed with acetone.
  • the 5,8- Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine maleate was dried at 40°C.
  • Example 13B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Maleate Hydrate A The a-form of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine maleate obtained in example 13A was made into a slurry in water.
  • Example 13C 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Maleate a+b-form
  • [l,2,4]triazolo[l,5-a]pyrazine (29.1 g,) was dissolved in tetrahydrofuran (291 mL, 3588 mmol) and treated with maleic acid (11.24 g, 96.88 mmol) near reflux. The mixture was left for 1 hour at room temperature and then transferred to ice. The solid was then isolated by filtration and dried in vacuo at 40°C. The resulting solid was then re-crystallized by dissolving in lOx tetrahydrofuran and heating to reflux.
  • Example 14A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Malonate a-form
  • Example 14B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Malonate Hydrate A
  • Example 15A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Mesylate Hydrate A The a+b+Solvate-form of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-
  • Example 16A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Oxalate a-form
  • [l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and washed with acetone.
  • the 5,8-Dimethyl-2-[2- (l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine oxalate was dried at 40°C.
  • Example 16B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Oxalate Hydrate A
  • Example 17A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Hemi-succinate a+b-form
  • [l,2,4]triazolo[l,5-a]pyrazine (1.0 g, 3.01 mmol) was dissolved in acetone (25 mL, 340 mmol) and treated with butanedioic acid (355 mg, 3.01 mmol) at 70°C. The mixture was left stirring overnight at room temperature.
  • Another crystalline form of hemi-succinate of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl- lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and dried in vacuo at 50°C.
  • Example 17C 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Hemi-succinate b+g-form
  • [l,2,4]triazolo[l,5-a]pyrazine (0.25 g, 0.75 mmol) was dissolved in acetone (2.5 mL, 34 mmol) and butanedioic acid was added (0.044 g, 0.38 mmol) and treated at near reflux. The mixture was left for 1 hour at room temperature and then transferred to an ice bath. Yet another crystalline form of hemi- succinate of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and dried in vacuo at 40°C.
  • Example 17D 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine Hemi-succinate Hydrate A
  • Example 18A 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine L(+)-tartrate a-form
  • [l,2,4]triazolo[l,5-a]pyrazine 150 mg, 0.451 mmol was dissolved in acetone (3.0 mL, 41 mmol) and treated near reflux with solid L(+)-tartaric acid (67.7 mg, 0.451 mmol). The mixture was left stirring for 1 hour at room temperature.
  • the L(+)-tartrate of 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)- ethyl]-[l,2,4]triazolo[l,5-a]pyrazine was isolated by filtration and dried in vacuo at 40°C.
  • Example 18B 5,8-Dimethyl-2-[2-(l-methyl-4-phenyl-lH-imidazol-2-yl)-ethyl]-[l,2,4]triazolo[l,5- a]pyrazine L(+)-tartrate Hydrate A

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Abstract

La présente invention concerne de nouveaux composés et des compositions comprenant lesdits composés utiles pour traiter des symptômes négatifs, des symptômes négatifs persistants, des symptômes négatifs proéminents, des symptômes négatifs apparents persistants, des symptômes négatifs dominants, des symptômes négatifs dominants persistants et/ou des dysfonctionnements cognitifs, en particulier dans la schizophrénie.
PCT/EP2019/080152 2018-11-06 2019-11-05 Composés pour le traitement de symptômes négatifs et de déficiences cognitives WO2020094592A1 (fr)

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