Compounds for the treatment of hyperkinetic movement disorders

Abstract

This invention relates to compounds of formula (I), methods for preparing the compounds, pharmaceutical compositions containing the compounds, and the use of the compounds as medicaments for treating ADHD.

Description

[0001] Invention Field

[0002] This invention relates to racemic and diastereomeric enriched 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R ,2R [2-(trifluoromethyl)-cyclopropyl]-2H-pyrrole-5-one compounds, methods for preparing them, pharmaceutical compositions containing them, and their use as medicines for treating hyperactivity disorders in mammals. Background of the Invention

[0004] Hyperactivity disorder (HMD), also known as movement disorder, is characterized by abnormal, often repetitive, involuntary movements that overlap with normal motor activities. Its five main types are tremor, chorea, dystonia, myoclonus, and tic. Specific disorders include Huntington's disease chorea, tardive dyskinesia, Tourette syndrome (and potentially related hyperactivity disorders such as generalized chorea, throwing disorders, and dystonia). Tic is the most common hyperactivity disorder in children. Dystonia, stereotyped movements, choreoathetosis, tremor, and myoclonus can also occur, but are less common. Many hyperactivity disorders manifest as multiple types of movements and may include combinations of various forms of ADHD.

[0005] HMD itself can be a disease entity or a symptom of another underlying neurological condition. They can be caused by genetic abnormalities and neurodegenerative diseases; structural lesions; infections; drugs and toxins; or psychological factors. Mental illness and corresponding long-term psychotropic medications are associated with HMD (i.e., tardive dyskinesia). Similarly, anti-Parkinson's disease medication treatment may lead to chorea and dystonia (i.e., levodopa-induced dyskinesia) after several years of treatment. However, in many cases, there is no clear cause, and they are therefore identified as idiopathic.

[0006] Tremor, especially essential tremor (ET), is the most common type of HMD seen in clinical practice. It is estimated that 10 to 20 million individuals in the United States have ET. Huntington's disease is the most common cause of chorea, with a global prevalence of 5–14 per 100,000 people. Early-onset dystonia occurs in 2–50 children per million and late-onset dystonia in 30–7,000 adults per million. Adult-onset focal dystonia is by far the most common form of isolated dystonia. Focal dystonia is approximately ten times more common than generalized dystonia. Neck dystonia is the most documented form of focal dystonia. Tardive dyskinesia represents a group of delayed-onset, persistent iatrogenic dyskinesias secondary to exposure to dopamine receptor blockers (DRBAs, i.e., "tranquilizers"). The overall prevalence of tardive dyskinesia in patients treated with DRBAs is close to 30%. The prevalence in the general population is approximately 180 per 100,000.

[0007] The basal ganglia (BG) is a complex network of nuclei in the forebrain that plays a crucial role in motor control (facilitating smooth voluntary movement). The BG consists of a group of subcortical nuclei: the globus pallidus, caudate nucleus, putamen, substantia nigra, and subthalamic nucleus, and any damage or disruption to these nuclei can lead to motor and cognitive impairment. Motor function is regulated by two distinct pathways that process signals passing through the basal ganglia: the direct pathway and the indirect pathway, in which dopamine promotes the motor circuitry. These pathways have opposing effects on the thalamus. Stimulation of the direct pathway induces excitation of thalamic neurons (which in turn establish excitatory connections with cortical neurons). Stimulation of the indirect pathway induces inhibition of thalamic neurons (preventing them from exciting motor cortical neurons). Normal function of the basal ganglia involves a balance between the activity of these two pathways. One hypothesis is that the "direct pathway" selectively promotes certain motor (or cognitive) programs in the cerebral cortex adapted to the current task, while the "indirect pathway" simultaneously inhibits the execution of competing motor programs.

[0008] Basal ganglion dysfunction can lead to a wide range of neurological disorders, including control and motor impairments as well as cognitive deficits: Tourette syndrome, obsessive-compulsive disorder and behavioral disorders, addiction, Parkinson's disease, Huntington's disease, dystonia, and unilateral throwing disorder.

[0009] More specifically for HMDS, tremor is associated with lesions in the brainstem, cerebellum, or thalamus. Chorea and throwing disorders are associated with lesions in the subthalamic nucleus. Dystonia is primarily associated with dysfunction of the putamen or globus pallidus. In rare cases, convulsions may also involve inflammation or degeneration of the basal ganglia. Tardive dyskinesia has traditionally been attributed to hypersensitivity and upregulation of dopamine D2 receptors in the motor striatum due to chronic dopamine receptor blockade. In all HMDS, the reduced firing rate of the inhibitory output nuclei of the basal ganglia appears to lead to deinhibition of subsequent thalamic cortical activity, resulting in cortical hyperexcitability, which in turn causes uncontrolled / involuntary movements.

[0010] Currently, only a few medications have been shown to provide at most slight, and mostly transient, benefits to patients with HMD. Oral medications (such as antiepileptics, anticholinergics, dopamine depletors, beta-blockers, and GABA agonists) primarily work through inhibitory pathways to suppress abnormal movements, excluding dopa-responsive dystonia, which is improved with dopaminergic drugs such as levodopa. Some focal or multifocal movement disorders can be targeted with botulinum toxin injections to reduce antagonist muscle activity, with some success. More severe or systemic HMD may require neuromodulation with intrathecal baclofen or deep brain stimulation (DBS). For some, relaxation therapies (such as yoga and biofeedback) and avoidance of aggravating stimuli (such as caffeine and stressors) will also reduce the frequency and severity of tremors, tics, and dystonia.

[0011] Reversible vesicular monoamine transporter-2 (VMAT-2) inhibitors, which block transporters that package monoamines (such as dopamine, norepinephrine, serotonin, and histamine) into presynaptic vesicles for release into the synaptic cleft, have been tested for the treatment of tardive dyskinesia. These transporters are widely distributed throughout the brain and exhibit some region specificity corresponding to monoaminergic brain regions.

[0012] Bubenazine was the first approved VMAT-2 inhibitor. Subsequently, deuterated bubenazine and valbenazine were developed, exhibiting improved pharmacokinetic and pharmacodynamic properties compared to bubenazine. These two most recently approved molecules have received FDA approval for both tardive dyskinesia and Huntington's disease / chorea.

[0013] Drugs that block or reduce dopamine are also used to manage the seizures of Tourette syndrome; aripiprazole, haloperidol, and pimozide are the only drug treatments approved by the FDA.

[0014] Benzohexol can be used to treat tremor and dystonia, but its tolerability is poor. Pramipexole, beta-blockers, antiepileptic drugs, and benzodiazepines have also been used to treat tremor and myoclonus, with mixed results. Botulinum toxin injections are useful for focal and multifocal dystonia. Generalized dystonia may benefit from intrathecal baclofen treatment. DBS has shown benefit for various HMDs, especially essential tremor, tremor caused by Parkinson's disease, and essential generalized dystonia.

[0015] Drug addiction is a chronic and relapsing mental disorder characterized by compulsive seeking and use of drugs despite negative consequences, intense cravings for drugs, and feelings of negativeness during drug withdrawal. Addiction exists in several phases: active and excessive consumption of drugs, more controlled use of drugs, withdrawal, and relapse. These different phases in the process are associated with different behavioral and neurobiological mechanisms: (1) binge eating and intoxication, (2) withdrawal / negative effects, and (3) preoccupation / anticipation.

[0016] The dopaminergic system and basal ganglia are highly associated with drug addiction. Dopamine, a neurotransmitter, plays a crucial role in addiction by inducing pleasure, reinforcing behavior, and triggering cravings. The limbic regions of the basal ganglia (i.e., the nucleus accumbens, ventral globus pallidus, and ventral tegmentum) are highly suggested to play a central role in reward learning and addiction. Several highly addictive drugs, including cocaine, amphetamines, nicotine, and opioids, are thought to exert their effects by enhancing the potency of dopamine signaling in the mesocortical pathway. Drug sensitization occurs when repeated exposure to drug use induces hypersensitivity to the drug and its associated stimuli. This hypersensitivity, in turn, leads to increased cravings for the drug, resulting in excessive interest in these substances.

[0017] The “motivation sensitization theory” separates the neural circuits supporting “drug liking” and “drug wanting.” Motivational salience, or “wanting,” is a form of motivation generated by a large and powerful neural system that includes intermediate-limbic dopamine. The theory posits that drug addiction is caused by the over-amplification of psychological “wanting” triggered by specific cues, without any specific amplification of “liking.” This process is caused by long-term alterations in the dopamine-related motivational system of susceptible individuals known as neurosensitization (Berridge & Robinson, Am Psychol. 71(8) (2016)).

[0018] Levetiracetam, or (S)-(-)-α-ethyl-2-oxo-1-pyrrolidineacetamide, is a levorotatory compound disclosed in European Patent No. EP-162036 as a protective agent for the treatment and prevention of hypoxic and ischemic attacks of the central nervous system. Levetiracetam has the following structure:

[0019]

[0020] Levetiracetam has been approved and is marketed as Keppra. ® It is marketed in many countries, including the EU and the US, for the treatment of various forms of epilepsy (therapeutic indication), for which its dextrorotatory enantiomer (R)-(+)-α-ethyl-2-oxo-1-pyrrolidineacetamide has been shown to be completely inactive (Gower et al., Eur. J. Pharmacol. 222, 193-203 (1992)).

[0021] Levetiracetam is also considered a potential alternative therapy for Tourette syndrome (Martinez-Granero et al., Neuropsychiatric Dis and Treat. 6, 309-316 (2010)). A randomized, placebo-controlled, double-blind study (Awaad et al., J Pediatr Neurol. 7, 257-263 (2009)) enrolled 24 children aged 6–18 years diagnosed with TS and associated epilepsy or headache who were randomly assigned to receive either levetiracetam (Lev) (500–1250 mg / day) or placebo over 8 weeks. Of the 12 patients receiving Levetiracetam, 9 showed improvement in seizures, 2 were lost to follow-up, and 1 patient with other comorbidities (ADHD and OCD) discontinued Levetiracetam due to aggressive behavior.

[0022] The efficacy and safety of levetiracetam in tardive dyskinesia were also evaluated in a double-blind, placebo-controlled, randomized study (Woods et al., J Clin Psychiatry 69:4, 546-554 (2008)). In this study, a total of 50 patients treated with antipsychotic medication were randomized to receive levetiracetam 500 to 3000 mg / day or placebo for 12 weeks. A mixed regression model showed that the total score of the Abnormal Involuntary Movement Scale (AIMS) decreased by 43.5% from baseline in the levetiracetam group and by 18.7% compared to the placebo group (p=0.022).

[0023] A double-blind, placebo-controlled trial investigated the effects of a single 1,000 mg dose of levetiracetam on essential tremor in 24 patients. Hand tremor was significantly reduced for at least 2 hours, as measured by acceleration and functional tests. However, levetiracetam has never been developed or approved for the treatment of tremor, tardive dyskinesia, or seizures in Tourette syndrome. Levetiracetam belongs to a class of chemical molecules known as levetiracetams.

[0024] Other piracetam drugs include piracetam, oxiracetam, piracetam, prazanol, and phenylpiracetam, which have been used in humans, and some are available as dietary supplements. As adjunctive therapy, piracetam appears to be beneficial for individuals with myoclonic epilepsy and tardive dyskinesia.

[0025] Imidazolothiadiazole pyrrolidone compounds are disclosed in WO 2011 / 047860.

[0026] WO 2019 / 215062 discloses pyrrole-5-one compounds for the treatment of epilepsy; specifically, compounds 17-A and 17-B, which contain a geminitro group, are illustrated:

[0027] Invention Overview

[0029] This invention relates to compounds, compositions, and methods for treating hyperactivity disorders in mammals.

[0030] Other aspects of the invention will become apparent from the detailed description.

[0031] Detailed description of the invention

[0032] The first aspect of the invention is a compound of formula (I) in racemic form or enriched with diastereomer purity.

[0033]

[0034] And its pharmaceutically acceptable salts and metabolites.

[0035] One specific embodiment is 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoro-methyl)cyclopropyl]-2H-pyrrole-5-one, wherein in one embodiment, the diastereomeric excess is at least 90% (de), preferably at least 94% (de), more preferably at least, and most preferably at least 98% (de).

[0036] Another specific embodiment is 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1S,2S)-2-(trifluoro-methyl)cyclopropyl]-2H-pyrrole-5-one (enantiomer 2), in one embodiment, wherein the diastereomeric excess is at least 90% (de), preferably at least 94% (de), more preferably at least, and most preferably at least 98% (de).

[0037] The intended compound (I) includes a racemic form, or one or more enantiomers, diastereomers, or geometric isomers, or mixtures thereof. Furthermore, any chemical formula given in this application also relates to a hydrate, solvate, or polymorph of the compound, or a mixture thereof.

[0038] The intended compound (I) represents both the unlabeled and isotopically labeled forms of the compound. The isotopically labeled compound has the same structure as the chemical formulas given in this application, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, 36 Cl and 125 I. These isotope-labeled compounds can be used for metabolic studies (preferably using...) 14 C) Reaction kinetic studies (e.g., using...) 2 H or 3 H) Detection or imaging techniques [e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT)], including drug or substrate tissue distribution assays, or those applicable to patients undergoing radiation therapy. In particular, 18 F or 11 C-labeled compounds may be particularly preferred for PET or SPECT studies. PET and SPECT studies can be performed according to, for example, Brooks, DJ, “Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development,” NeuroRx 2005, 2(2), 226-236 and the references cited therein. Furthermore, heavier isotopes such as deuterium (i.e., 2H) Substitution may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. The isotopically labeled compounds and their prodrugs of the present invention can generally be prepared by performing the procedures disclosed in the following schemes or examples and preparation examples, replacing non-isotopically labeled reagents with readily available isotopically labeled reagents.

[0039] The present invention also includes pharmaceutically acceptable salts of compounds represented by formula (I), preferably salts of those compounds described in this application, pharmaceutical compositions comprising such salts, and methods of using such salts.

[0040] The term "pharmaceutically acceptable salt" is intended to refer to a salt of the free acid of a compound represented in this application, which is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. Generally, see SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a subject without producing excessive toxicity, irritation, or anaphylactic reactions. The compounds described in this application may have sufficiently acidic groups, sufficiently basic groups, both types of functional groups, or multiple groups of each type, and therefore can react with many inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts.

[0041] Pharmaceutically acceptable examples of salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptarates, propynylates, oxalates, malonates, succinates, octanoates, sebacic acid, fumarates, maleates, and butynediol. ,4-Diosyl salt, hexyn-1,6-diosyl salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. For a list of other suitable pharmaceutically acceptable salts, see Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985.

[0042] Pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, by treating the free base with the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc., or with organic acids such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, hydroxyethanesulfonic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranoside, etc. Glucuronic acid or galacturonic acid, α-hydroxy acids such as mandelic acid, citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid, 2-acetoxybenzoic acid, naphtholic acid or cinnamic acid, sulfonic acids such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples in this application; and any other acids and mixtures thereof that are considered equivalent or acceptable substitutes according to the ordinary skill level of the art.

[0043] This invention also relates to pharmaceutically acceptable prodrugs of formula (I) and methods of treatment using such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a specified compound that, upon administration to a subject, can be converted into said compound in vivo through chemical or physiological processes such as solvent decomposition or enzymatic cleavage, or under physiological conditions (e.g., upon reaching physiological pH). A "pharmaceutically acceptable prodrug" is a non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. For example, exemplary procedures for selecting and preparing suitable prodrug derivatives are described in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

[0044] This invention also relates to pharmaceutically active metabolites of compounds of formula (I), and the use of such metabolites in the methods of this invention. "Pharmaceutically active metabolite" means the pharmacologically active product of the in vivo metabolism of a compound of formula (I) or its salts. The prodrugs and active metabolites of the compounds can be determined using conventional techniques known or available in the art. See, for example, Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

[0045] 1-[[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]-thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrole-5-one is a metabolite of the compound of formula (I), and in one embodiment, the diastereomer is in excess of at least 90% (de), preferably at least 94% (de), more preferably at least, and most preferably at least 98% (de).

[0046] The compounds of this invention can be used as pharmaceuticals.

[0047] Specifically, the compounds of the present invention can be used as medicines for treating ADHD. Specific ADHDs include: Huntington's disease, Tourette syndrome, or tardive dyskinesia caused by tranquilizers. Other preferred indications include drug addiction (e.g., caused by amphetamines, methamphetamine, cocaine, nicotine, opioids, alcohol, MDMA, etc.) and drug use disorders; encompassing all different stages associated with the aforementioned disorders (i.e., drug consumption, craving, and relapse).

[0048] The method of the present invention comprises administering a compound according to the invention to a mammal (preferably a human) suffering from the disease or symptom mentioned above, in an amount sufficient to alleviate or prevent the disease or symptom.

[0049] Pharmaceutical compositions containing compounds according to the invention can be administered, for example, orally, parenterally, i.e., intravenously, intramuscularly, or subcutaneously, intrathecally, transdermally (patch), by inhalation, or intranasally.

[0050] For oral administration, the compounds of the present invention may be provided in solid form (e.g., tablets or capsules) or in the form of solutions, emulsions, or suspensions. To prepare oral compositions, the compounds of the present invention may be formulated to doses, for example, from about 0.01 to about 50 mg / kg daily, or from about 0.05 to about 20 mg / kg daily, or from about 0.1 to about 10 mg / kg daily. Other doses include from about 0.1 mg to about 1 g daily, from about 1 mg to about 10 mg daily, from about 10 mg to about 50 mg daily, from about 50 mg to about 250 mg daily, or from about 250 mg to about 1 g daily. Oral tablets may comprise the active ingredient mixed with compatible, pharmaceutically acceptable excipients such as diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, and preservatives. Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Typical oral liquid excipients include ethanol, glycerin, water, etc. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginate are typical disintegrants. Binders may include starch and gelatin. Lubricants (if present) may be magnesium stearate, stearic acid, or talc. If desired, tablets may be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0051] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules. To prepare hard gelatin capsules, the active ingredient can be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules can be prepared by mixing the active ingredient with water, oil (e.g., peanut oil or olive oil), liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0052] Liquids intended for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be provided as lyophilized or dry powder products, reconstituted with water or other suitable media before use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous media, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethanol, or water; preservatives (e.g., methylparaben or propylparaben or sorbic acid); wetting agents, such as lecithin; and, if desired, flavoring or coloring agents.

[0053] The terms “treatment of symptoms associated with enhancement or improvement of ADHD” or “anti-ADHD” or “treatment of ADHD” or “improvement of ADHD” are used.

[0054] The compounds according to the invention can be used to prepare pharmaceutical compositions for treating ADHD, as well as substance addiction and substance use disorders. Such compositions typically contain an active pharmaceutical ingredient and pharmaceutically acceptable excipients.

[0055] The present invention also contemplates compositions capable of releasing active substances in a controlled manner. Pharmaceutical compositions that can be used for parenteral administration are in conventional forms, such as aqueous or oily solutions or suspensions, and are generally packaged in ampoules, disposable syringes, glass or plastic vials, or infusion containers.

[0056] In addition to the active ingredient, these solutions or suspensions may optionally contain sterile diluents such as water for injection, physiological saline, oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents, antimicrobial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetate, citrate or phosphate, and substances for adjusting the isotonic molar concentration, such as sodium chloride or glucose.

[0057] The present invention also includes pharmaceutical compositions containing compounds of the present invention in a pharmaceutically acceptable co-crystal form.

[0058] Such pharmaceutical compositions may also contain known or marketed therapeutics for the treatment of ADHD or substance addiction / substance use disorder.

[0059] Examples of such therapeutic agents that may be used in pharmaceutical compositions include, but are not limited to, quetiapine fumarate, aripiprazole, risperidone / paliperidone, olanzapine, cariprazine hydrochloride, lurasidone hydrochloride, ziprasidone hydrochloride, haloperidol / fluperidone, clozapine, extended-release formulations of quetiapine fumarate, and ilopiperidone, flunarizine and cinnarizine, loxapine, asenapine, pimozide, morinone, lithium, chlorpromazine, trifluprozine, thioridazine, mesoridazine, trifluoperazine, prochlorperazine, perphenazine, fluphenazine, peprazole, metoclopramide, thiopride, sulpiride, criprix, ramoxipride, verapride, aminosulpiride, levosulpiride, duloxetine, citalopram, olanzapine, chlorprothixone, thiothixone, amoxapine; and all compounds that may potentially cause tardive dyskinesia.

[0060] Surprisingly, the compounds according to the invention induced a significant reduction in dopamine in the striatum (the main structure of the basal ganglia) without affecting other monoamines (i.e., serotonin and norepinephrine) in other brain regions, such as the cortex and prefrontal cortex. It is believed that this reduction in dopamine is predictive in any assay designed to measure dopamine levels in the striatum and is suitable for identifying potential effects in any treatment of HMD or psychoactive use disorder. Inhibition of hyperdopaminergic function is thought to be associated with anti-hyperkinetic effects and with treatment of psychoactive addiction and psychoactive use disorder (Koch et al., Pharm & Therapeutics, 212 (2020); Alvers et al., Psychopharmacology, 224 (2012)).

[0061] Example

[0062] The following examples illustrate how compounds covered by formula (I) can be synthesized. These examples are provided for illustrative purposes only and are not intended to limit the invention in any way, nor should they be construed as limiting the invention in any way. Those skilled in the art will understand that conventional variations and modifications can be made to the following examples without departing from the spirit or scope of the invention.

[0063] The following examples illustrate the preparation of compounds of formula (I) according to the present invention.

[0064] Example

[0065] Abbreviations / Recurring Reagents

[0066] ACN: Acetonitrile

[0067] DCM: Dichloromethane

[0068] DMSO: Dimethyl sulfoxide

[0069] h: hours

[0070] HPLC: High-performance liquid chromatography

[0071] IPAC: Isopropyl acetate

[0072] LCMS: Liquid Chromatography-Mass Spectrometry

[0073] MeOH: Methanol

[0074] min: minutes

[0075] MTBE: Methyl tert-butyl ether

[0076] NMR: Nuclear Magnetic Resonance

[0077] Rac: racemic

[0078] RuPhos: 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl

[0079] RT: Room temperature

[0080] SFC: Supercritical Fluid Chromatography

[0081] TLC: Thin-layer chromatography

[0082] Use Biovia Draw 20.1 to determine the IUPAC name.

[0083] Analytical methods

[0084] All reactions involving reagents sensitive to air or moisture are carried out under a nitrogen or argon atmosphere, using dry solvents and glassware. Commercially available solvents and reagents are generally used without further purification, including anhydrous solvents (typically Sure-Seal™ products from Aldrich Chemical Company or AcroSeal™ from ACROSorganics) when necessary. Reactions are generally monitored using thin-layer chromatography, HPLC, or mass spectrometry.

[0085] The following different methods and instruments were used for LCMS mode mass spectrometry measurements:

[0086] -Acid LCMS Method 1:

[0087] LCMS analysis was performed using a QDA Waters simple quadrupole mass spectrometer equipped with an ESI source and a UPLC Acquity with a diode array detector (200 to 400 nm). Full MS scans were performed from m / z 70 to 800 in positive / negative mode, with acid elution for data acquisition. Reversed-phase separation was performed at 45 °C using a Waters Acquity UPLC HSS T3 1.8 µm (2.1 × 50 mm) column with acid elution. Gradient elution was performed using H₂O / ACN / TFA (95 / 5 / 0.05%) (solvent A) and acetonitrile (solvent B).

[0088]

[0089] Products are typically vacuum-dried before final analysis and biological testing.

[0090] NMR spectroscopy was performed on a Windows 7 professional workstation equipped with Topspin 3.2 software and a 5mm dual-resonance broadband probe (PABBI). 1 H / 19F-BB Z-GRD Z82021 / 0075) or 1 mm triple resonance probe (PATXI) 1 H / D- 13 C / 15 The chemical shifts were recorded on a BRUKER AVANCEIII 400 MHz Ultrashield NMR spectrometer (N Z-GRD Z868301 / 004). The chemical shifts were measured in deuterated solvent (DMSO-). d 6 、 MeOH- d 4 The signal generated by the residual protons of (or CDCl3) is used as a reference. Chemical shifts are given in parts per million (ppm), and coupling constants (J) are given in Hertz (Hz). Spin multiplicity is given as broad peak (br), singlet (s), doublet (d), triplet (t), quartet (q), and multiplicity (m).

[0091] The absolute configuration of the compound was determined using VCD spectroscopy: IR and VCD spectra were recorded on a BioTools ChiralIR-2X MIR FT-VCD spectrometer equipped with a dual photoelastic modulator (dualPEM). 5 mg of sample was dissolved in 150 µL LCDCl3, transferred to a BaF2 liquid IR cell with a path length of 0.075 mm, and IR / VCD data were acquired for up to 16 hours between 1,000 and 2,000 cm⁻¹. Theoretical IR / VCD spectra were generated at the theoretical level for B3PW91 / cc-pVTZ using Maestro (Schrodinger) and Gaussian09 (Gaussian) software packages. Experimental and theoretical datasets were visually compared using Excel (Microsoft) and CompareVOA (BioTools).

[0092] All final products were analyzed by LCMS in both basic and acidic modes, as detailed below:

[0093] - Alkaline method 1:

[0094] LCMS analysis was performed using a QDAWaters simple quadrupole mass spectrometer equipped with an ESI source and a UPLC Acquity Classic with a diode array detector (210 to 400 nm). Data were acquired using positive / negative modes with alkaline elution and full MS scans from m / z 70 to 800. Reversed-phase separation was performed on a Waters Acquity UPLC BEH C18 1.7 µm (2.1 × 100 mm) column at 45 °C with alkaline elution. Gradient elution was performed using H₂O / ACN / ammonium formate (95 / 5 / 63 mg / L) + 100 µL / L NH₄OH (solvent A) and ACN / H₂O / ammonium formate (95 / 5 / 63 mg / L) + 100 µL / L NH₄OH (solvent B). Injection volume: 1 µL. Full flow rate in MS.

[0095]

[0096] -Acidic LCMS Method 2:

[0097] LCMS analysis was performed using a QDA Waters simple quadrupole mass spectrometer equipped with an ESI source and a UPLC Acquity Hclass with a diode array detector (wavelength range 210 to 400 nm). Data were acquired using positive / negative mode with full MS scans from m / z 70 to 800 and acid elution. Reversed-phase separation was performed on a Waters Acquity UPLC HSS T3 1.8 µm (2.1 × 100 mm) column at 45 °C using acid elution. Gradient elution was performed using H₂O / ACN / TFA (95 / 5 / 0.05%) (solvent A) and acetonitrile (solvent B).

[0098]

[0099] 1. Preparation of Intermediate A – rac-2-hydroxy-3-[(1R ,2R 2-(trifluoromethyl)-cyclopropyl]-2H-furan-5-one

[0100]

[0101] 1.1.rac-2-ethoxy-3-[(1R ,2R Synthesis of 2-(trifluoromethyl)cyclopropyl]-2H-furan-5-one a1

[0102] To 4-bromo-5-ethoxy-2(5H)-furanone (CAS: 32978-38-4, 31.38 g, 147.04 mmol) and rac-6-methyl-2-[(1R ,2R RuPhos (15.48 g, 32.52 mmol) and palladium(II) acetate (3.88 g, 16.43 mmol) were added to a toluene (750 mL) solution of [-2-(trifluoromethyl)cyclopropyl]-1,3,6,2-dioxonitroborane-4,8-dione (CAS: 1309955-07-4, 44.9 g, 161.3 mmol), while maintaining the external temperature of the container at 95 °C. Then, potassium carbonate (81.06 g, 590 mmol) dissolved in water (150 mL) was added in a single batch, and the reaction mixture was stirred while maintaining the internal temperature of the reaction at 85 °C. After 2 hours, the reaction mixture was cooled to 15 °C and quenched with 650 mL of water. The mixture was stirred at room temperature for 0.5 hours, filtered through a diatomaceous earth mat, and the aqueous phase was extracted twice with 300 mL of toluene. The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under vacuum to obtain a dark brown oil, which was then purified by rapid chromatography (Biotage Isolera Four, 330 g Interchim silica gel column, with a heptane / DCM gradient). The purest fraction was collected, and the solvent was evaporated to dryness to give rac-2-ethoxy-3-[(1R ,2R 2-(trifluoromethyl)cyclopropyl]-2H-furan-5-one a1 (27.3 g, 75% yield) is a yellow oil.

[0103]

[0104] LC / MS Acid: [M+H] + = 237

[0105] 1.2.rac-2-hydroxy-3-[(1R ,2R Synthesis of 2-(trifluoromethyl)cyclopropyl]-2H-furan-5-one A

[0106] Tetrafluoroboric acid (48 wt.% aqueous solution, 220 mL) was added to rac-2-ethoxy-3-[(1R] in ACN (110 mL). ,2R [2-(trifluoromethyl)cyclopropyl]-2H-furan-5-one a1 (27.3 g, 109.9 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 72 hours. Tetrafluoroboric acid (48 wt.% aqueous solution, 25 mL) was added again to the reaction mixture, and the reaction mixture was stirred overnight. The reaction mixture was diluted with 500 mL DCM and 500 mL water was added. The mixture was quenched in portions with 150 g sodium carbonate and carefully (at room temperature) for 4 hours. At the end of the addition, the pH of the aqueous phase was 7.5. The organic and aqueous phases were separated, and the aqueous phase was extracted twice with 500 mL DCM. The combined organic phases were dried over MgSO4, filtered, and the solvent was removed under limited vacuum (40 °C bath, maximum pressure 500 mbar). 2-hydroxy-3-[(1R ,2R [-2-(trifluoromethyl)cyclopropyl]-2H-furan-5-one A, as an oil (product in ACN and DCM solutions) (72.8 g, qNMR purity: 30.6%), was directly used in the next reaction.

[0107] 1 ¹H NMR: (400 MHz, CDCl₃) δ 5.99 (mult., 1H), 5.85 (d, J = 17.5 Hz, 1H), 4.97 (dd, J = 14.3, 7.6 Hz, 1H), 2.22 – 2.11 (m, 1H), 1.54 – 1.37 (m, 1H), 1.33 – 1.24 (m, 1H), no hydroxyl protons observed.

[0108] LC / MS Acid: [M+H] + = 209

[0109] 2. Preparation of Compounds 2 and 3 - 1-[[2-(methoxymethyl)-6-(trifluoromethyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrolo-5-one 2 and 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1S,2S)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrolo-5-one 3

[0110]

[0111] rac-2-hydroxy-3-[(1R ,2R A mixture of [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylamine B (72.84 g, 107.2 mmol) (CAS: 1403586-73-1, obtained according to the method described in WO 2019 / 215062) in methanol (200 mL) was stirred overnight at room temperature. The mixture was cooled to 0 °C, and sodium borohydride (12.1 g, 321.4 mmol) was added in portions, and the mixture was stirred at room temperature for 3 hours. Acetic acid (19 mL, 331 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 250 mL of water, and the aqueous layer was extracted twice with 250 mL of DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness to obtain a pale yellow solid, which was purified by rapid chromatography (Biotage Isolera Four, 330 g Interchim silica gel column, in a DCM / MeOH gradient). The purest fraction was collected, and the solvent was evaporated to give rac-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R ,2R 1-2-(trifluoromethyl)cyclopropyl]-2H-pyrrole-5-one (31.6 g, yield 66%).

[0112]

[0113] LC / MS Acid: [M+H] + = 441

[0114] rac-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R ,2R 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrolo-5-one 1 (86.4 g) was separated by a preparative SFC (Pic Solution Prep 600 - ChiralPak IH 76.5x260mm 20 μm - CO2 + IPA 15% - 700mL / min., RT) to obtain 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrolo-5-one 2 (Enantiomer 1 (eluted first, 40.9 g, yield 45.6%) and 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1S,2S)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrole-5-one 3 (enantiomer 2, eluted second, 18.2 g).

[0115] 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrolo-5-one 2 (40.89 g, 87.76 mmol) was dissolved in MTBE (120 mL) at room temperature. Heptane (42 mL) was added dropwise. The mixture was then stirred at 20 °C for 2 hours, cooled to 10 °C during the 2 hours, and stirred overnight at 10 °C. The solid was filtered, washed twice with the mother liquor, and finally washed with 50 mL of fresh heptane. The solid was dried in an oven at 35 °C for 72 hours to give 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrole-5-one 2, a white crystalline solid (32.8 g, yield 85%).

[0116] 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1S,2S)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrolo-5-one 3 (18.2 g, 34.65 mmol) was dissolved at 45 °C in a mixture of IPAC (50 mL) and heptane (120 mL). The mixture was cooled to 10 °C over 10 hours and then stirred overnight at 10 °C. The suspension was cooled to 0 °C and then heptane (200 mL) was added dropwise. The solid was filtered and washed once with heptane (40 mL). The solid was dried in a vacuum oven at 35°C for 16 hours to give 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1S,2S)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrole-5-one 3 (14.7 g, 95% yield).

[0117] Analytical chiral HPLC (Chiralpak IB, 1.5 mL / min, 30°C, 70% heptane - 30% IPA - 0.1% DEA, 215 bar): 2: 4.65 min, 3: 4.17 min

[0118] Preparation of compound 4 - 1-[[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]-thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrolo-5-one

[0119]

[0120] At room temperature, boron tribromide (1 M dichloromethane solution, 22.7 mL) was added to a solution of 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrolo-5-one 2 (2 g, 4.54 mmol) in dichloromethane (22.7 mL). The reaction mixture was stirred at room temperature for 45 minutes. Methanol was added slowly and carefully until the precipitate formed in the reaction mixture disappeared completely. The solvent was evaporated under reduced pressure, water was added to the residue, and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried with MgSO4, filtered, and evaporated under reduced pressure to give pure 1-[[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrole-5-one, a white solid (1.91 g, yield 98.6%).

[0121]

[0122] LC / MS acid: [M+H]+ = 427

[0123] Table (I) shows the IUPAC name of the compound (generated by Biovia Draw 20.1), the ion peaks observed in mass spectrometry, and 1 H NMR explanation.

[0124] Table I: Example compounds.

[0125]

[0126]

[0127] Cytochrome P450 inhibition and time-dependent inhibition

[0128] To assess the inhibitory potential of cytochrome P450 isoforms, test compounds (at six concentrations from 0.1 to 25 µM) or media were pre-incubated with human liver microsomes (HLM) under three different experimental conditions: 0 min pre-incubation (assessing reversible inhibition) and 30 min in the presence or absence of NADPH (assessing time-dependent inhibition), before being incubated with probe substrates: phenacetin (CYP1A2), diclofenac (CYP2C9), S-metphenytoin (2C19), dextromethorphan (CYP2D6), midazolam, and testosterone (CYP3A4).

[0129] Reagents and materials

[0130] 0.1M phosphate buffer, pH 7.4, 37℃.

[0131] Mixed HLM (provided by a reputable commercial supplier and stored at 80°C before use) was prepared using the above buffer solution and incubated at a protein concentration of 400×.

[0132] NADPH – 100 mM solution, prepared immediately with buffer before pre-incubation and stored on ice until use; incubation concentrations of 1 mM or 2 mM, for - NADPH or + NADPH pre-incubation of samples, respectively.

[0133] The Tecan automation system was used for testing at 37°C and an oscillation speed of 700 rpm.

[0134] Compound preparation

[0135] Pre-incubate the test compound (1 µL) and human liver microsomes (395 µL) for 30 minutes with or without NADPH (4 µL buffer or NADPH, respectively), or for 0 minutes (4 µL buffer). Then, add the probe substrate (1 µL) and NADPH (4 µL) to all conditions (total incubation volume 405 µL) and incubate for 5 minutes or 15 minutes (2C19 only), monitoring for metabolite formation. A time-dependent inhibitor is included as a positive control.

[0136]

[0137] Sample Analysis

[0138] For each condition, 50 µL aliquots were transferred to 96-well plates, and the reaction was terminated by adding 100 µL of ice-cold methanol containing a mixture of deuterated internal standards. The terminated plate was centrifuged at 2500 rpm for 30 min at 4 °C, and 40 µL of the supernatant was transferred to a new 96-well plate. Before LC-MS / MS analysis using a universal method, 60 µL of deionized formic acid (final concentration 0.1%) was added.

[0139] Data Analysis

[0140] The reduction in metabolite production compared to the median control was used to calculate the IC50 for each experimental condition using a simple inhibition model (Winnonlin model 103 below). 50 Value (concentration of the test compound that produces 50% inhibition):

[0141]

[0142] Where E represents the effect and C represents the concentration of the test compound.

[0143] EC 50 The value depends only on what we call IC. 50 The inhibitory effect of the test compounds was determined. Three IC50 values ​​were measured. 50 Values: 0-minute pre-incubation (for reversible inhibition), and 30-minute pre-incubation in the presence and absence of NADPH (for assessing time-dependent inhibition). IC 50 The multiple change is calculated using the following formula:

[0144]

[0145] The compounds of this invention exhibit IC values ​​for all CYP P450 isoforms. 50 Values ​​>25 µM (in the absence of NADPH) and >20 µM (in the presence of NADPH) indicate very low CYP inhibitory activity.

[0146] Monoamine quantification in brain tissue

[0147] All experiments were conducted in accordance with EU Directive 2010 / 63 / EU and Belgian law, and were approved by the UCB Biopharma SRL Animal Experimentation Ethics Committee.

[0148] Male Sprague Dawley rats (Janvier, France) were housed in groups of two, acclimatizing to the new environment for at least one week prior to the experiment. Animals were housed in a temperature-controlled environment (20-21°C) and humidity-controlled environment (approximately 40%), using a 12:12 light / dark cycle (lights turned on at 6:00 AM). All animals had free access to standard pelleted food and water. Rats weighed approximately 300 grams at the time of the drug test. Additional enrichment facilities (red cylinders) were provided. Animal health was monitored daily by handlers, and experimental personnel monitored animal health on the day of the experiment.

[0149] Compound 2 was administered to rats via intraperitoneal (ip) injection (5 mL / kg) at doses of 0 (n=12), 0.1 (n=8), 0.3 (n=8), and 1 (n=8) mg / kg, followed by return of the rats to their original cages. The compound was administered as a suspension prepared in a medium containing 1% (w / v) methylcellulose (400 cps), 0.1% (w / v) silicone antifoam 1510 US, and 0.1% (w / v) Tween 80. Rats were sacrificed 45 minutes post-administration; blood was collected from the heart and the brain was rapidly removed. Plasma was obtained by centrifugation at 3000 g for 15 minutes at 4 °C. The striatum, cortex, and anterior frontal cortex (PFC) were carefully dissected (on ice). All samples were stored at -80 °C until analysis.

[0150] To assess the effects of compound 2 on monoamine levels in different brain regions, levels of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) were measured in different brain regions. Plasma exposure to the compound was also measured.

[0151] To measure the levels of DA, NE, and 5-HT, tissue samples were homogenized in 1 / 20 (v / v) EDAT 0.3 nM / HClO4 0.05N and centrifuged at 150,000 rpm for 15 min at 4 °C. 10 µL of the supernatant was injected into the HPLC system. The HPLC system used was a Thermo Scientific Vanquish UHPLC system coupled with a Thermo Scientific Q Exactive Plus high-resolution mass spectrometer. The software used was Thermo Scientific Xcalibur. The autosampler temperature was set to 15 °C. The analytical UPLC column was a Waters Acquity HSS T3, 1.8 µm, 100 × 2.1 mm ID, operated at 40 °C. The flow rate was 0.4 mL / min. Gradient mode was used for analysis, with a cycle time of 12 min.

[0152] Mobile phase A was 10 mM ammonium formate aqueous solution, and mobile phase B was 100% acetonitrile. The volume injected onto the column was 10 µl.

[0153] For statistical analysis, one-way ANOVA was used to assess the effects of different doses of compound 2 (0, 0.1, 0.3, and 1 mg / kg) on ​​monoamine levels in different brain regions, followed by a Tukey post-hoc test to compare differences among the four means. Homogeneity of variance (Lvene's test for isovariance) and normality were checked before each data set analysis. No transformation was required.

[0154] The results showed that compound 2 selectively reduced dopamine levels in the striatum without significantly affecting other monoamines (NE or 5-HT) in this brain region. Surprisingly, compound 2 did not regulate DA, NE, and 5-HT in other brain regions outside the striatum, such as the cortex and prefrontal cortex.

[0155] The following statistical analysis supports this observation:

[0156] - Striatal DA levels: One-way ANOVA showed a significant dose-response effect [F(3,32)=4.97, p<0.01]. Post-hoc analysis showed a significant difference between the 1 mg / kg dose and the mediator group (p<0.01).

[0157] - 5-HT levels in the striatum: One-way ANOVA did not show any significant effect of the dose [F(3,32)=2.65, p>0.05].

[0158] -DA levels in PFC: One-way ANOVA did not show any significant effect of the dose [F(3,32)=0.77,p>0.05].

[0159] - 5-HT levels in PFC: One-way ANOVA did not show any significant effect of the dose [F(3,32)=0.63, p>0.05].

[0160] Figure 1 The results showed that administration of compound 2 resulted in a significant reduction in dopamine specifically in the striatum, rather than in other brain regions such as the anterior frontal cortex. This effect was also specific to dopamine, excluding serotonin and norepinephrine. Therefore, we can conclude that although compound 2 can completely penetrate the brain, it has a specific effect on dopamine regulation in the basal ganglia.

Claims

1. Compounds of formula (I) in racemic form or enriched with diastereomer purity. And its pharmaceutically acceptable salts and its main metabolites.

2. The compound according to claim 1, wherein it is 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrole-5-one.

3. The compound according to claim 1, wherein it is 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1S,2S)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrole-5-one.

4. The compound according to any one of claims 1 to 3, which is the major metabolite of compound (I) 1-[[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-2H-pyrrole-5-one.

5. The compound according to any one of claims 2 to 4, wherein at least 90% of the diastereomer is in excess (de).

6. The compound according to any one of the preceding claims, used as a medicine.

7. The compound according to any one of claims 1 to 5, used as a medicament for treating ADHD.

8. The compound of claim 7, wherein the hyperactivity disorder is selected from Huntington's disease, Tourette syndrome, or tardive dyskinesia or substance use disorder induced by tranquilizers.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, and a suitable pharmaceutically acceptable excipient.

Images