WO2025109339A1 - 4-(6-oxo-2-(trifluoromethyl)-3,6-dihydrochromeno[7,8-d]imidazol-8-yl)benzonitrile for use in the treatment of positive symptoms in schizophrenia - Google Patents

Abstract

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.

Description

-(6-OXO-2-(TRIFLUOROMETHYL)-3,6-DIHYDROCHROMENO[7,8-D]IMIDAZOL-8-YL)BENZONITRI

FOR USE IN THE TREATMENT OF POSITIVE SYMPTOMS IN SCHIZOPHRENIA

FIELD OF THE INVENTION

[0001] 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.

BACKGROUND TO THE INVENTION

[0002] The compound tropoflavin, also known as 7,8-dihydroxyflavone (7,8-DHF), is a naturally occurring flavone found in Godmania aesculifolio, Tridax procumbent and primula tree leaves. It is known to act as a potent and selective agonist of tropomyosin receptor kinase B (TrkB), which is the main signaling receptor of neurotrophin brain-derived neurotrophic factor (BDNF).

[0003] 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.

[0004] A derivative of tropoflavin, 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, has been shown to be useful in the treatment of schizophrenia.

[0005] The Diagnostic and Statistical Manual of Mental Health (DSM) serves as the universal authority for psychiatric diagnosis. DSM-V, published in 2013, defines the symptoms of schizophrenia into three broad categories: (1) positive symptoms; (2) negative symptoms; and (3) cognitive symptoms.

[0006] In general terms the positive symptoms of schizophrenia include hallucinations, delusions, thought disorders and movement disorders. The negative symptoms of schizophrenia include a “flat affect”, a lack of pleasure in everyday life, lack of ability to begin and sustain planned activities, and speaking little, even when forced to interact. Lastly the cognitive symptoms of schizophrenia include poor “executing function”; trouble focusing or paying attention, and problems with working memory.

[0007] Treatment of schizophrenia is generally with antipsychotic medications (typical and atypical antipsychotics) which include aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, chlorpromazine, fluphenazine, haloperidol, and perphenazine.

[0008] Other interventions including psychosocial interventions such as therapy, social skills training, vocational rehabilitation and supported employment are also often included in the treatment paradigm. [0009] During periods of severe symptoms patients are often hospitalized to ensure safety for the patient and in cases for patients who do not respond to drug therapy electroconvulsive therapy may be used.

[0010] The Positive and Negative Syndrome Scale (PANSS) 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.

[0011] 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.

[0012] 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.

BRIEF SUMMARY OF THE DISCLOSURE

[0013] In accordance with a first aspect of the present invention there is provided a compound of Formula I for use in the treatment of positive symptoms in schizophrenia.

[0014] Preferably the compound of Formula I is administered with one or more pharmaceutically acceptable excipients.

[0015] Preferably 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.

[0016] Preferably the compound of Formula I is administered as a single daily dose.

Alternatively, 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.

[0017] Preferably 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.

[0018] In a further embodiment the compound of Formula I is administered with one or more additional drug products.

[0019] In accordance with a second aspect of the present invention there is provided a method of treating positive symptoms in schizophrenia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of Formula I. [0020] In human therapeutics, 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.

[0021] 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.

[0022] 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).

[0023] It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

[0024] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also encompassed by the above-described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.

[0025] In certain embodiments, 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. BRIEF SUMMARY OF THE DRAWINGS

[0026] The present invention is described with reference to the figure listed below:

[0027] 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.

[0028] 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.

[0029] Figure 3 details the effect of the compound of Formula I at concentrations of 3, 10 and 30 mg/kg.

DEFINITIONS

[0030] Various definitions are made throughout this document. Most words have the meaning that would be attributed to those words by one skilled in the art. Words specifically defined either below or elsewhere in this document have the meaning provided in the context of the present invention as a whole and as typically understood by those skilled in the art.

[0031] “Subject,” “individual” or “patient” is used interchangeably herein and refers to a vertebrate, preferably a mammal. Mammals include, but are not limited to, murines, rodents, simians, humans, farm animals, sport animals and pets.

[0032] “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. In yet other embodiments, “treating” or “treatment” 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.

[0033] “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.

[0034] “Schizophrenia” 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.

[0035] “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.

[0036] “Vehicle” refers to a diluent, excipient or carrier with which a compound is administered to a subject. In some embodiments, the vehicle is pharmaceutically acceptable.

[0037] “Active ingredient” or “Active pharmaceutical ingredient” or “API” refers to the compound of the invention.

[0038] “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” has a SMILES code N#CC1=CC=C(C2=CC(C3=CC=C4C(N=C(C(F)(F)F)N4)=C3O2)=O)C=C1 and the structure defined below:

DETAILED DESCRIPTION OF THE INVENTION

[0039] 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. [0040] 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.

[0041] 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.

[0042] 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.

[0043] Once the schizophrenia-like symptoms have been induced in the rat, certain behavioural endpoints can be tested to determine whether a test substance has an effect on a particular symptom domain in schizophrenia.

[0044] For example, spontaneous locomotor activity, akin to positive symptoms of schizophrenia, can be tested in the horizontal crossing assay. Animals displaying schizophrenia-like behaviour will have an increased number of line crossings compared to those that have not been subjected to the dual-hit treatment (Hamieh et al., 2021).

[0045] The number of rears that each rat performs during the horizontal crossing assay was also recorded but is not a commonly recorded outcome measure in models of schizophrenia as conflicting data suggests it may be a measure of positive or negative symptoms. Therefore, for the purpose of the present invention the outcome of this behavioural endpoint is not relevant to the claimed subject matter.

[0046] Prepulse inhibition (PPI), a marker of sensorimotor gating impairment in schizophrenia was also tested in this study. Clinically, schizophrenic patients report oversensitivity to sensory stimulation that theoretically correlates with stimulus overload and leads to cognitive fragmentation and impairment. Although the outcome of this behavioural endpoint is not relevant to the claimed subject matter of the present application, the data are presented here for completeness.

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

Materials and Methods

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.

[0048] The positive control used was clozapine which was dissolved in a drop of hydrochloric acid 1 N and then diluted in physiological saline.

Test Systems

[0049] 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.

[0050] 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.

[0051] Housing and Environmental conditions: Pregnant female rats were housed individually with its litter on wood litter (SAFE, 89290 Augy, France). When rat pups were weaned, vehicle treated control rats were housed in groups of 4 per cage while PCP-treated rats were placed in individual cages.

[0052] 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%.

[0053] Information related to any clinical signs and mortality was archived with the study materials. Body weights were also recorded every testing day (Day 7, 9 and 11 and from Week 7 to Week 11).

[0054] Food and water: All animals had free access to food (Code A04 - SAFE, 89290 Augy, France) and water.

[0055] 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.

EXPERIMENTAL DESIGN

Treatment

[0056] The dose levels and route of administration were selected based on anticipated human therapeutic dose-level and the results obtained from previous animal studies.

[0057] PCP and its vehicle formulations (physiological saline) were administered by subcutaneous route (s.c.) on postnatal Day 7, Day 9 and Day 11.

[0058] The 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.

[0059] 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.

Treatment schedule

[0060] The test substance was evaluated at 3 doses.

[0061] The positive control substance was evaluated at 1 dose.

[0062] The experiment included 6 groups as detailed in Table 1 below.

Table 1. Dose groups

Experimental procedure

Model Induction:

[0063] 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.

[0064] On PND 24, male rat pups were weaned. Vehicle treated control rats (group 1) were housed in groups of 3 or 4 per cage while PCP-treated groups (groups 2 to 6) were placed in individual cages for social isolation until the end of the study. [0065] Rats were reared for 6 weeks post-weaning before the beginning of behavioral testing (week 10). The postnatal weeks of performing behavioral tests and collections are reported in Table 2 below.

Table 2. Experimental procedure

Behavioral tests:

[0066] Chronic treatment and behavioral testing were performed blinded using formulations vials coded as A, B, C... for all PCP-treated groups.

[0067] To keep blind conditions, the clozapine group received administration of vehicle from Week 7 to 8 and then clozapine from Week 9 to 11.

[0068] Due to the number of animals, each behavioral test was divided into 4 sub-experiments performed over 4 consecutive days with N = 5 animal per group per day (Monday - Thursday for Activity Meter and PPI on Week 10 and 11 respectively, i.e. 1 week apart).

Activity Meter Test in the rat

[0069] The method, which detects stimulant or sedative activity, follows that described by Boissier and Simon (Arch. Int. Pharmacodyn., 158, 212-221 , 1965).

[0070] 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.

[0071] The number of (horizontal) crossings by each animal (one per cage) from one pair of photocells to the other is recorded by computer in 10-minute intervals for 40 minutes. A similar procedure is utilized for recording of rearing except that individual photobeam breaks are recorded. The scores are cumulated over the: 1.) 0 to 20 min period; 2.) 20 to 40 min period; and 3.) entire 40-minute recording period.

[0072] It is known that the animals have increased activity during the first 10 minutes of entering the apparatus due to natural curiosity independent of treatment group and as such the 20-40 minute time period data are thought to be more relevant to study the effects of the test article on the number of crossings and the number of rears the animals undertake.

Prepulse Inhibition (PPI) test in the rat

[0073] 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.

[0074] 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.

[0075] The trial types are:

• No stimulus: No stimulus is presented. This serves to evaluate basal levels of movement.

• 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.

• 115 dB startle: A 40 ms burst of white noise at 115 dB is presented, resulting in a startle response.

• 115 dB with pre-pulse: The 87-, 90- or 93-dB stimulus is followed 80 ms later by the 115 db stimulus.

[0076] 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.

Blood and Brain collection

[0077] The method, which is designed to minimize animal suffering and to ensure good quality of biological samples, is adapted from basic procedures commonly used in studies performed in rodents. Blood collection:

[0078] Within 30 minutes of completion of PPI testing (approximately 160-180 minutes after the last administration), rats (N=3 from the 3 OT-003 groups, 9 rats in total) were placed under isoflurane anaesthesia and approximately 1 mL of blood was collected by cardiac puncture using a sterile disposable syringe. 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.

Fresh Frozen Brain collection:

[0079] Within 30 minutes of completion of the PPI test (approximately 160 to 180 minutes after the last administration), rats (N = 10 rats per group, 60 in total, including 9 rats that underwent blood collection) 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.

Statistical Analyses:

[0080] Raw data was entered into calculation sheets previously verified and protected using a standard commercial spreadsheet product (Microsoft Excel™). All data entered were compared with raw data by two people and thus completely verified before data analysis.

[0081] Results in grouped data tables or figures are presented as means followed by a ± sign and the standard error of the mean (s.e.m.).

[0082] All statistical calculations will be performed using commercial software and verified test by test according to standardized internal procedures. All differences will be considered statistically significant when the null hypothesis can be rejected at a risk of less than 0.05.

[0083] Data with the test substance were analyzed by comparing treated groups with PCP controls using one-way ANOVA followed by post-hoc Dunnett’s tests (Groups 3 to 5 will be compared to Group 2).

[0084] Data with the reagent and comparison substances were analysed separately using unpaired Student's t tests (Group 2 vs Group 1 and Group 6 vs Group 2). Results

[0085] 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).

[0086] 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).

[0087] Figure 2A shows the number of rears over the 40 minute test period and Figure 2B shows the number of rears during the 20-40 minute period. Although not statistically significant at the 20-40 minute time period the compound of Formula I vs. PCP-SI gave a p-value of p=0.17

[0088] 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.

Conclusion

[0089] The data presented in Figure 1 A and 1 B with respect to the reduction in the number of line crossings in animals treated with the compound of Formula I suggest this compound might be suitable for use in the treatment of the positive symptoms of schizophrenia.

Claims

1. A compound of Formula I for use in the treatment of positive symptoms in schizophrenia.

2. A compound of Formula I for use according to claim 1, wherein the compound of Formula I is administered with one or more pharmaceutically acceptable excipients.

3. A compound of Formula I for use according to claim 1, wherein the compound of Formula I is formulated in a dosage form selected from a liquid, a lozenge, a fastdisintegrating 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.

4. A compound of Formula I for use according to claim 1, wherein the compound of Formula I is administered as a single daily dose.

5. A compound of Formula I for use according to claim 1, wherein the compound of Formula I is administered as multiple daily doses.

6. A compound of Formula I for use according to claim 5, wherein the compound of Formula I is administered two, three, four or five times per day.

7. A compound of Formula I for use according to claims 4 to 6, wherein each dose comprises at least 0.001 mg of the compound of Formula I.

8. A compound of Formula I for use according to claim 7, wherein each dose comprises between about 0.001 mg and about 500mg of the compound of Formula I.

9. A compound of Formula I for use according to claim 7, wherein each dose comprises between about 500mg and about 1000mg of the compound of Formula I.

10. The compound of Formula I for use according to claim 1, wherein the compound of Formula I is administered with one or more additional drug products.

11. A method of treating the positive symptoms of schizophrenia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of Formula I.