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WO2025109339A1 - 4-(6-oxo-2-(trifluorométhyl)-3,6-dihydrochroméno[7,8-d]imidazol-8-yl)benzonitrile destiné à être utilisé pour le traitement de symptômes positifs dans la schizophrénie - Google Patents

4-(6-oxo-2-(trifluorométhyl)-3,6-dihydrochroméno[7,8-d]imidazol-8-yl)benzonitrile destiné à être utilisé pour le traitement de symptômes positifs dans la schizophrénie Download PDF

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Publication number
WO2025109339A1
WO2025109339A1 PCT/GB2024/052961 GB2024052961W WO2025109339A1 WO 2025109339 A1 WO2025109339 A1 WO 2025109339A1 GB 2024052961 W GB2024052961 W GB 2024052961W WO 2025109339 A1 WO2025109339 A1 WO 2025109339A1
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Prior art keywords
compound
formula
schizophrenia
use according
administered
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PCT/GB2024/052961
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English (en)
Inventor
Thomas Pfeiffer
Man-Ling HO
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Ontrack Therapeutics Ltd
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Ontrack Therapeutics Ltd
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Priority claimed from GBGB2317991.4A external-priority patent/GB202317991D0/en
Application filed by Ontrack Therapeutics Ltd filed Critical Ontrack Therapeutics Ltd
Publication of WO2025109339A1 publication Critical patent/WO2025109339A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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

Definitions

  • the present invention relates to the compound 4-(6-oxo-2-(trifluoromethyl)-3,6- dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile, also known as CF3CN, referred to herein as the compound of Formula I, for use in the treatment of positive symptoms in schizophrenia.
  • tropoflavin also known as 7,8-dihydroxyflavone (7,8-DHF)
  • 7,8-DHF 7,8-dihydroxyflavone
  • TrkB tropomyosin receptor kinase B
  • BDNF neurotrophin brain-derived neurotrophic factor
  • Tropoflavin has been shown to have therapeutic efficacy in several animal models including depression, Alzheimer’s disease, cognitive deficits in schizophrenia, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral ischemia, fragile X syndrome and Rett syndrome.
  • DSM Diagnostic and Statistical Manual of Mental Health
  • antipsychotic medications typically and atypical antipsychotics
  • antipsychotic medications typically include aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, chlorpromazine, fluphenazine, haloperidol, and perphenazine.
  • the Positive and Negative Syndrome Scale is an assessment tool used to determine the symptomatology of schizophrenia. Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology.
  • the antipsychotic medications which are approved to treat schizophrenia do not treat specific aspects of the disease. As such there is a need for more suitable treatments in particular for patients suffering mainly from the positive symptoms of schizophrenia.
  • the present application provides data from animal models to demonstrate that the compound of Formula I may be useful in the treatment of positive symptoms in schizophrenia.
  • the compound of Formula I is administered with one or more pharmaceutically acceptable excipients.
  • the compound of Formula I is formulated in a dosage form selected from a liquid, a lozenge, a fast-disintegrating tablet, a lyophilized preparation, a film, a spray, an aerosol, a sustained-release tablet or capsule, a modified release, a sustained relief, a tablet, a capsule a cream, an ointment, or a mucoadhesive.
  • a dosage form selected from a liquid, a lozenge, a fast-disintegrating tablet, a lyophilized preparation, a film, a spray, an aerosol, a sustained-release tablet or capsule, a modified release, a sustained relief, a tablet, a capsule a cream, an ointment, or a mucoadhesive.
  • the compound of Formula I is administered as a single daily dose.
  • the compound of Formula I is administered as multiple daily doses. Further still the compound of Formula I is administered two, three, four or five times per day.
  • each dose comprises at least 0.001 mg of the compound of Formula I. More preferably each dose comprises between about 0.001 mg and about 500mg of the compound of Formula I. Alternatively each dose comprises between about 500mg and about 1000mg of the compound of Formula I.
  • the compound of Formula I is administered with one or more additional drug products.
  • a method of treating positive symptoms in schizophrenia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I.
  • the physician will determine the dosage regimen that is most appropriate according to a preventive or curative treatment and according to the age, weight, stage of the disease and other factors specific to the subject to be treated.
  • the compositions in other embodiments, should provide a dosage of from about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day.
  • Dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, or about 1000 mg, and in some embodiments from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form.
  • the amount of active ingredient in the formulations provided herein, which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof, will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered.
  • the frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject.
  • Exemplary doses of a formulation include milligram or microgram amounts of the active compound per kilogram of subject (e.g., from about 1 microgram per kilogram to about 50 milligrams per kilogram, from about 10 micrograms per kilogram to about 30 milligrams per kilogram, from about 100 micrograms per kilogram to about 10 milligrams per kilogram, or from about 100 microgram per kilogram to about 5 milligrams per kilogram).
  • milligram or microgram amounts of the active compound per kilogram of subject e.g., from about 1 microgram per kilogram to about 50 milligrams per kilogram, from about 10 micrograms per kilogram to about 30 milligrams per kilogram, from about 100 micrograms per kilogram to about 10 milligrams per kilogram, or from about 100 microgram per kilogram to about 5 milligrams per kilogram.
  • administration of the same formulation provided herein may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • Figure 1 details the effect of the compound of Formula I on the number of crossings made (A) from 0-40 minutes and (B) from 20-40 minutes.
  • Figure 2 details the effect of the compound of Formula I at concentrations of 3, 10 and 30 mg/kg on the number of rears made (A) from 0-40 minutes and (B) from 20-40 minutes.
  • Figure 3 details the effect of the compound of Formula I at concentrations of 3, 10 and 30 mg/kg.
  • Subject refers to a vertebrate, preferably a mammal. Mammals include, but are not limited to, murines, rodents, simians, humans, farm animals, sport animals and pets.
  • Treating” or “treatment” of any disease or disorder refers, in some embodiments, to ameliorating the disease or disorder (i.e. , arresting or reducing the development of the disease or at least one of the clinical symptoms thereof,). Treatment may also be considered to include preemptive or prophylactic administration to ameliorate, arrest or prevent the development of the disease or at least one of the clinical symptoms. Treatment can also refer to the lessening of the severity and/or the duration of one or more symptoms of a disease or disorder. In a further feature, the treatment rendered has lower potential for long term side effects over multiple years. In other embodiments “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the patient.
  • treating refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter) or both. In yet other embodiments, “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • “Therapeutically effective amount” means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, adsorption, distribution, metabolism and excretion etc., of the patient to be treated.
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
  • delusions as defined by DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) as abnormalities in one or more of the following five domains: delusions, hallucinations, disorganized thinking (speech), grossly disorganized or abnormal motor behavior (including catatonia), and negative symptoms.
  • “Positive symptoms in schizophrenia” refers to one or more of the following symptoms of schizophrenia: Hallucinations, which includes seeing, feeling and hearing things that aren’t there which includes hearing voices; Delusions, which involves believing things that others don’t; and Disorganised thinking, which refers to when the things that a person with schizophrenia says that don’t make sense to other people, for example, switching topics without any obvious link.
  • Vehicle refers to a diluent, excipient or carrier with which a compound is administered to a subject.
  • the vehicle is pharmaceutically acceptable.
  • active ingredient or “Active pharmaceutical ingredient” or “API” refers to the compound of the invention.
  • the Example below describes the effect of the compound of Formula I in an animal model which demonstrates the compound’s ability to treat the positive symptoms of schizophrenia.
  • the aim of the study was to evaluate the potential effects of chronic treatment with the compound of Formula I to reverse deficits observed in the neonatal phencyclidine (PCP) administration and post-weaning social isolation dual-hit model of schizophrenia in the rat.
  • the dual-hit model has high construct validity in mimicking the risk factors and stressors experienced early in development by schizophrenia patients.
  • the first hit occurs in the neonatal stage of the rat’s life where administration of PCP causes glutaminergic dysfunction and in consequence increases the rat’s brain to be susceptible to schizophrenia type behaviour.
  • the second hit occurs in the adolescent stage of the rat’s life whereby social isolation causes severe stress in the rat and further disrupts the rat’s brain development meaning that by adulthood the rat has developed schizophrenia-like symptoms.
  • PPI Prepulse inhibition
  • EXAMPLE 1 EFFECT OF TEST COMPOUND ON REVERSING DEFICITS OBSERVED IN THE NEONATAL PHENCYCLIDINE ADMINISTRATION AND POST-WEANING SOCIAL ISOLATION DUAL-HIT MODEL OF SCHIZOPHRENIA IN THE RAT
  • Drug preparation and administration [0047] Compound of Formula I (5% DMSO in 0.5 Methylcellulose 400cp in water) was given at 3, 10 & 30 mg/kg. This was made fresh daily and constantly stirred prior to dosing.
  • the positive control used was clozapine which was dissolved in a drop of hydrochloric acid 1 N and then diluted in physiological saline.
  • Species used Wistar rats. Number: 30 pregnant Wistar female rats to obtain at least 120 male pups. Breeder: Janvier Labs, 53940 Le Genest-Saint-lsle, France.
  • Receipt and acclimation period Pregnant female rats were delivered to the laboratory at least 3 days before birth during which time they will be acclimatized to laboratory conditions.
  • Environmental enrichment such as tunnels, gnawing and nesting material were provided.
  • the animal house was maintained under artificial lighting (12 hours) between 7:00 and 19:00 in a controlled ambient temperature of 22 ⁇ 2°C, and relative humidity between 30-70%.
  • Contaminant analyses The batches of diet and wood litter are analyzed by the suppliers for composition and contaminant levels. Bacterial and chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrates by-products). It is expected that no contaminants that could interfere with, or prejudice, the outcome of the study will be found in the diet, drinking water or wood litter.
  • PCP and its vehicle formulations were administered by subcutaneous route (s.c.) on postnatal Day 7, Day 9 and Day 11.
  • test substance and vehicle formulations were administered orally by gavage once daily for 21 days before the beginning of the behavioral evaluation (i.e. starting on post-natal Week 7). Administration continued up to the end of the study (i.e. a total of 29 days, including the last testing day). On testing days, test substance was administered 120 minutes before the session.
  • Clozapine was administered by intraperitoneal route (i.p.) daily starting on post-natal Week 9 (one week before the activity meter test) and up to the end of the study. On testing days, Clozapine was administered 30 minutes before the session.
  • test substance was evaluated at 3 doses.
  • the positive control substance was evaluated at 1 dose.
  • Conscious male rat pups belonging to the same litter were treated with neonatal PCP or vehicle (physiological saline) (1 ml/kg) on postnatal days (PNDs) 7, 9 and 11 by subcutaneous administration at the neck area.
  • the clozapine group received administration of vehicle from Week 7 to 8 and then clozapine from Week 9 to 11.
  • the activity meter consists of 16 covered Plexiglas cages (40 x 25 x 25 cm) contained within a darkened cabinet and connected to silent electronic counters. Each cage is equipped with four photocell assemblies (two at each end of the cage) 3 cm above the floor, in order to measure the number of movements by each animal (one per cage) in the horizontal plane. Ten additional photocell assemblies are placed at even intervals 20 cm above the floor along the long wall to record rearing.
  • PPI Prepulse Inhibition
  • the apparatus consists of a commercially available soundproofed startle chamber (San Diego Instruments, San Diego, U.S.A.). All experimental events and data recording are controlled by computer program (SDI SR Lab). Rats are placed within the startle chamber in a small Perspex cylinder, slightly larger than the rat, which is attached to a base plate containing a strain gauge. Vertical movements of the rat such as those that occur during a startle response result in deformation of the base plate which generates a current in the strain gauge that is proportional to the size of the movement, i.e. the size of the startle response. A loudspeaker is placed directly above the rat to provide background sound and stimuli.
  • SDI SR Lab computer program
  • the PPI experiment consists of a 33-minute session of which the first 10 minutes are for habituation, during which background noise of 70 dB intensity is provided within the chamber with additional exposure to ten 115 dB startle stimuli during the last 2 minutes. The outputs from the startle platform during the habituation period are not analysed. At the end of the habituation period eight trial types are presented in pseudo random order, 8 times each. Trials are separated by 15-25 seconds.
  • Pre-pulse A 20 ms burst of white noise at 87, 90 or 93 dB is presented. This stimulus does not produce a clear startle response.
  • the output from the startle platform is recorded for 100 ms starting from the onset of the startle stimulus.
  • Three variables are recorded for each trial: the average response over the whole recording period, the peak response and the time to peak response.
  • PPI is calculated for each rat by averaging the 8 trials of each type and calculating the percentage reduction in startle amplitude (average and peak values) caused by the 87-, 90- or 93-dB pre-pulse.
  • the time to peak response is a measure of reaction time.
  • the blood samples were immediately transferred into prelabelled tube containing lithium heparin. After sealing each tube, the blood samples were manually agitated and stored on ice until centrifugation (within 30 minutes of sampling). The samples were centrifuged at +4°C, at 1500 g, for 10 minutes.
  • the entire resultant plasma obtained were immediately transferred to 2 suitably labelled polypropylene tubes (2 aliquots of approximately 150 pl). The tubes were stored upright at approximately -20°C.
  • rats 10 rats per group, 60 in total, including 9 rats that underwent blood collection
  • rats were placed under isoflurane anesthesia and were decapitated.
  • Their brain was quickly removed from the skull and hemispheres dissected, rinsed in physiological saline, weighed, placed in separate pre-labelled vials. Then, brain hemispheres were snap frozen on liquid nitrogen (or equivalent). The vials were stored upright and protected from light at approximately -70°C.
  • Raw data was entered into calculation sheets previously verified and protected using a standard commercial spreadsheet product (Microsoft ExcelTM). All data entered were compared with raw data by two people and thus completely verified before data analysis.
  • Figure 1 details the number of crossings made by the rats during the test period.
  • Figure 1A shows the number of crossings made over the entire 40 minute test period, here it is shown that the compound of Formula I at a concentration of 30mg/kg was able to statistically significantly reduce the number of crossings compared to the vehicle treated animals that had been subjected to the dual hit protocol (p ⁇ 0.05).
  • the positive control clozapine was also able to reduce the number of crossings to a similar level (p ⁇ 0.05).
  • Figure 1 B shows the number of crossings for the period 20-40 minutes, this data shows that the compound of Formula I at a concentration of 30mg/kg was able to statistically significantly reduce the number of crossings compared to the vehicle treated animals that had been subjected to the dual hit protocol (p ⁇ 0.01). The positive control clozapine was also able to reduce the number of crossings to a lesser extent (p ⁇ 0.05).
  • Figure 3 shows the % difference in startle response with and without prepulse.
  • the compound of Formula I had no effect on PPI, however it can be seen that this model of schizophrenia did not induce a robust PPI deficit in the PCP + social isolation treated rats.

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Abstract

La présente invention concerne le composé 4-(6-oxo-2-(trifluorométhyl)-3,6-dihydrochroméno[7,8-d]imidazol-8-yl) benzonitrile, également connu sous le nom de CF3CN, appelé ici composé de formule I, destiné à être utilisé pour le traitement de symptômes positifs dans la schizophrénie.
PCT/GB2024/052961 2023-11-24 2024-11-22 4-(6-oxo-2-(trifluorométhyl)-3,6-dihydrochroméno[7,8-d]imidazol-8-yl)benzonitrile destiné à être utilisé pour le traitement de symptômes positifs dans la schizophrénie Pending WO2025109339A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB2317991.4 2023-11-24
GBGB2317991.4A GB202317991D0 (en) 2023-11-24 2023-11-24 Compounds for use in the treatment of positive symptoms in schizophrenia
GB2404115.4A GB2635787A (en) 2023-11-24 2024-03-22 Compounds for use in the treatment of positive symptoms in schizophrenia
GB2404115.4 2024-03-22

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WO2025109339A1 true WO2025109339A1 (fr) 2025-05-30

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080070984A1 (en) * 2006-09-15 2008-03-20 Tran Pierre V Compositions and Methods of Treating Schizophrenia
WO2020033604A1 (fr) * 2018-08-07 2020-02-13 Emory University Dérivés hétérocycliques de flavone, compositions et procédés associés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080070984A1 (en) * 2006-09-15 2008-03-20 Tran Pierre V Compositions and Methods of Treating Schizophrenia
WO2020033604A1 (fr) * 2018-08-07 2020-02-13 Emory University Dérivés hétérocycliques de flavone, compositions et procédés associés

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"The Diagnostic and Statistical Manual of Mental Health (DSM", 2013
BOISSIERSIMON, ARCH. INT. PHARMACODYN, vol. 158, 1965, pages 212 - 221
CHEN CHUN ET AL: "Optimized TrkB Agonist Ameliorates Alzheimer's Disease Pathologies and Improves Cognitive Functions via Inhibiting Delta-Secretase", ACS CHEMICAL NEUROSCIENCE, vol. 12, no. 13, 9 June 2021 (2021-06-09), US, pages 2448 - 2461, XP055896565, ISSN: 1948-7193, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.1c00181> [retrieved on 20250209], DOI: 10.1021/acschemneuro.1c00181 *
JOSE MARÍA CID ET AL: "Discovery of 3-Cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3- a ]pyridine (JNJ-42153605): A Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 20, 25 October 2012 (2012-10-25), pages 8770 - 8789, XP055182412, ISSN: 0022-2623, DOI: 10.1021/jm3010724 *

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