Use of a purine compound for the treatment of autism spectrum disorder, RETT syndrome, and fragile x syndrome

Abstract

Use of a substituted purine compound or a pharmaceutically acceptable salt thereof for treating one or more of autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS). A method for treating one or more of ASD, RTT, and FXS comprising administration of a substituted purine compound or a pharmaceutically acceptable salt thereof. Use of a substituted purine compound or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical for the treatment of one or more of ASD, RTT, and FXS. A pharmaceutical dose of a substituted purine compound or a pharmaceutically acceptable salt thereof for use in the treatment of one or more of ASD, RTT, and FXS in a subject, wherein the dose comprises 5 to 1000 mg / kg, preferably 10 to 600 mg / kg, more preferably 25 to 100 mg / kg, most preferably about 40 mg / kg of the substituted purine compound or a pharmaceutically acceptable salt thereof.

Description

USE OF A PURINE COMPOUND FOR THE TREATMENT OF AUTISM SPECTRUM DISORDER, RETT SYNDROME, AND FRAGILE X SYNDROMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority from US provisional application no. 63 / 721122 filed November 15, 2024, and Canadian Patent Application No. 3256758 filed November 15, 2024, the contents of which are hereby incorporated by reference.FIELD OF THE INVENTION

[0002] Example embodiments relate generally to the use of a substituted purine compound and salts thereof acting as adenosine A2a receptor (A2aR) antagonists for treating autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS).BACKGROUND

[0003] Adenosine is a key synaptic neuromodulator that acts to enhance and / or sharpen the salience of incoming information.1 2It realizes its biological actions through a class of membrane specific receptors that belong to the super family of receptors coupled with G proteins. At least four subtypes of adenosine receptors have been identified: A1, A2a, A1b, and A3. The two main receptor types, A1 and A2, act to inhibit and stimulate adenylyl cyclase respectively, and also affect transmitter release, nerve activity, and transmitter system interactions.1 3

[0004] A2a receptors specifically have been shown to play a regulatory role in the immune system and are abundant in the basal ganglia and synapses throughout most of the brain, but are mainly located in synapses of the glutamatergic, GABAergic, cholinergic, dopaminergic, serotonergic, and noradrenergic pathways.1 2A2a receptors have been found to enhance glutamate release and the function of glutamate receptors.1 2

[0005] Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with pervasive abnormalities in the central nervous system (CNS). ASD is characterized by stereotypic repetitive behavior, impaired social interaction, and deficits in communication.45Accumulating evidence points to altered social reward and motivation as key underlying mechanisms of these pathologies.6As of 2024, approximately 1 in 36 children have been identified with ASD.7Despite its prevalence, however, ASD remains a relatively underserved neurodevelopmental disorder.

[0006] WO2013058681 A2 discloses using A2aR antagonists for treating diseases of the central nervous system (CNS). Additionally, the A2aR antagonist istradefylline has been shown to represent a promising therapeutic strategy to relieve social deficits associated with neuropsychiatric disorders like ASD. Human ASD commonly involves impairment with dopamine D2 reward circuitry signaling in the Nucleus Accumbens (NAc), which can be restored by inhibiting the A2a receptor. Istradefylline has been utilized as a pharmacological repressor of D2 receptorexpressing striatal projection neuron (D2R-SPN) activity.6A single istradefylline injection has been shown to restore direct social interaction in mice expressing symptoms of autism.6

[0007] Oprml- / - mice show core symptoms of autism. In a direct social interaction test, Oprml- / - animals show decreased time in close social contact, due to lower frequency and duration of nose and paw contacts. Following behavior was decreased, whereas self-grooming, especially after social contact, was increased in mutants (n=8 per genotype). In the three-chamber task, controls but not Oprml- / - mice spend more time interacting with a mouse rather than a toy (interaction phase) or a novel rather than a familiar conspecific. Oprml- / - mice display motor stereotypies, with increased rearing, grooming, circling, and head shakes. Mutant mice show deficient patterns of exploration in a Y-maze. Spontaneous alternations (SPA) are decreased in Oprml- / - animals; alternate arm returns (AAR) and same arm returns (SAR) are increased. The Oprml- / - is a well characterised mouse model of ASD.

[0008] Rett syndrome (RTT) is a progressive genetic neurodevelopmental disorder characterized by cognitive and motor impairments, development of stereotypic hand movements, and epilepsy. RTT affects 1 in 10,000 females, and about 90% of cases are caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene, located on the X chromosome, which encodes the Mecp2 protein.8-11Evidence from mice models exhibiting symptoms of Rett syndrome has indicated impairment in the adenosinergic system.8

[0009] Fragile X syndrome (FXS) is an inherited genetic disorder that is characterized by hyperactivity, intellectual delay, attention disorders, and seizures. FXS is caused by an expansion of CGG-repeats in the fragile X mental retardation 1 gene (FMR1) that encodes the fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that controls synaptic plasticity by regulating mRNA metabolism and repressing protein synthesis in dendrites and synapses.12Thus, when expression of the FMR1 gene is impaired, excessive protein synthesisresults.12

[0010] It has been shown that pharmacological blockade of A2aRs using istradefylline also partially restores some of the phenotypes in animal models of Fragile X syndrome, both by reducing over-activation of the metabotropic glutamate 5 receptor (mGlu5R) and by acting on other A2aR-related downstream targets.12However, it has not been approved for treatment of FXS.

[0011] Trofinetide, sold under the brand name Daybue, is the only medication approved for the treatment of Rett syndrome. The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.

[0012] There are no approved pharmaceutical interventions for autism or FXS.

[0013] Therefore, there is need for a pharmaceutical with high bioavailability that is highly effective, fast-acting, safe and tolerable in higher doses, and suitable for treating such neurological diseases as autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS).SUMMARY

[0014] The inventors have found a fluorinated purine compound that is useful as an A2aR antagonist for the treatment of diseases such as autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS).

[0015] In one aspect, use of a compound of formula:or a pharmaceutically acceptable salt thereof for treating one or more of autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS) is provided.

[0016] In some example embodiments, the compound of formula (I) is administered orally. In some example embodiments, the compound of formula (I) is administered by injection. In some example embodiments, the compound of formula (I) is administered with a pharmaceutically acceptable excipient.

[0017] In some example embodiments, the use further comprises use of an additional therapeutic agent, wherein the additional therapeutic agent is one or more of trofinetide, aripiprazole, risperidone, fluoxetine, and fluvoxamine.

[0018] In one aspect, there is provided a method for treating one or more of autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS), the method comprising administration of a compound of formula (I) (MB204) or a pharmaceutically acceptable salt thereof.

[0019] In one aspect, use of a compound of formula (I) (MB204) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical for the treatment of one or more of autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS) is provided.

[0020] In one aspect, there is provided a pharmaceutical dose of a compound for use in the treatment of one or more of autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS) in a subject, wherein the compound is of formula (I) (MB204) or a pharmaceutically acceptable salt thereof, and wherein the dose comprises 5 to 1000 mg / kg of the compound of formula (I).

[0021] In some example embodiments, the dose comprises 10 to 600 mg / kg of the compound of formula (I). In some example embodiments, the dose comprises 20 to 200 mg / kg of the compound of formula (I). In some example embodiments, the dose comprises 25 to 100 mg / kg of the compound of formula (I). In some example embodiments, the dose comprises about 40 mg / kg of the compound of formula (I).

[0022] In some example embodiments, the dose is administered at least once daily. In some example embodiments, the dose is administered twice daily.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Reference will now be made, by way of example, to the accompanying drawings which show example embodiments, and in which:

[0024] Fig. 1 is a schematic diagram illustrating the experimental design and testing timeline of the behavioral evaluation for the immediate effect autism single dose study, evaluating the immediate effect of the substituted purine A2aR antagonist of the present disclosure on the sociability of 0mpr1+ / ' and Omprt1’ mice.

[0025] Fig. 2 shows the results of the direct social interactions behavioral assay on 0mpr1+ / ' and Omprt1' mice using nose contact as proxy. Fig. 2A is a graph illustrating instances of nose contact. Fig. 2B is a graph illustrating time spent in nose contact. Fig. 2C is a graph illustrating mean duration of nose contact.

[0026] Fig. 3 shows the results of the direct social interactions behavioral assay on 0mpr1+ / ' and Omprt1' mice using paw contact as proxy. Fig. 3A is a graph illustrating instances of paw contact. Fig. 3B is a graph illustrating time in paw contact. Fig. 3C is a graph illustrating mean duration of paw contact.

[0027] Fig. 4 shows the results of the direct social interactions behavioral assay on 0mpr1+ / ' and Omprt1' mice using grooming behavior as proxy. Fig. 4A is a graph illustrating episodes of grooming. Fig. 4B is a graph illustrating time spent in grooming. Fig. 4C is a graph illustrating episodes of grooming immediately after social contact.

[0028] Fig. 5 shows the results of the direct social interactions behavioral assay on 0mpr1+ / ' and Omprt1' mice using following and rearing behavior as proxy. Fig. 5A is a graph illustrating episodes of following. Fig. 5B is a graph illustrating episodes of rearing.

[0029] Fig. 6 shows the results of the Y-maze exploration behavioral assay on 0mpr1+ / ' and Omprt1' mice. Fig. 6A is a graph illustrating alternance. Fig. 6B is a graph illustrating % spontaneous alternations (SPA) (i.e. , successive entries into each arm forming overlapping triplet sets). Fig. 6C is a graph illustrating % alternate arm returns (AAR). Fig. 6D is a graph illustrating % same arm returns (SAR).

[0030] Fig. 7 is a schematic diagram illustrating the experimental design and testing timeline of the behavioral evaluation for the carry over effect autism single dose study, evaluating the carry over effects of chronic trofinetide and the substituted purine A2aR antagonist of the present disclosure on the sociability of Mecp2+ / +and Mecp2+ / ~ mice.

[0031] Figs. 8-11 show the results of the direct social interactions behavioral assay for the carry over effect autism single dose study, evaluating the carry over effects of chronic trofinetide and the substituted purine A2aR antagonist of the present disclosure on the sociability of Mecp2+ / +and Mecp2+ / ' mice that are actively under drug treatment.

[0032] Fig. 8 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice actively under drug treatment using nose contact as proxy. Fig. 8A is a graph illustrating instances of nose contact. Fig. 8B is a graph illustrating time spent in nose contact. Fig. 8C is a graph illustrating mean duration of nose contact.

[0033] Fig. 9 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice actively under drug treatment using paw contact as proxy. Fig. 9A is a graph illustrating instances of paw contact. Fig. 9B is a graph illustrating time spent in paw contact. Fig.9C is a graph illustrating mean duration of paw contact.

[0034] Fig. 10 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice actively under drug treatment using grooming behavior as proxy. Fig. 10A is a graph illustrating episodes of grooming. Fig. 10B is a graph illustrating episodes of grooming immediately after social contact.

[0035] Fig. 11 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice actively under drug treatment using following and rearing behavior as proxy. Fig. 11A is a graph illustrating episodes of following. Fig. 11 B is a graph illustrating episodes of rearing.

[0036] Figs. 12-15 show the results of the direct social interactions behavioral assay for the carry over effect autism single dose study, evaluating the carry over effects of chronic trofinetide and the substituted purine A2aR antagonist of the present disclosure on the sociability of Mecp2+ / +and Mecp2+ / ' mice 7 days off drug treatment.

[0037] Fig. 12 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice 7 days off drug treatment using nose contact as proxy. Fig. 12A is a graph illustrating instances of nose contact. Fig. 12B is a graph illustrating time spent in nose contact. Fig. 12C is a graph illustrating mean duration of nose contact.

[0038] Fig. 13 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice 7 days off drug treatment using paw contact as proxy. Fig. 13A is a graph illustrating instances of paw contact. Fig. 13B is a graph illustrating time spent in paw contact. Fig. 13C is a graph illustrating mean duration of paw contact.

[0039] Fig. 14 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice 7 days off drug treatment using grooming behavior as proxy. Fig. 14A is a graph illustrating episodes of grooming. Fig. 14B is a graph illustrating episodes of grooming immediately after social contact.

[0040] Fig. 15 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice 7 days off drug treatment using following and rearing behavior as proxy. Fig.15A is a graph illustrating episodes of following. Fig. 15B is a graph illustrating episodes of rearing.

[0041] Figs. 16-19 show the results of the direct social interactions behavioral assay for the carry over effect autism single dose study, evaluating the carry over effects of chronic trofinetide and the substituted purine A2aR antagonist of the present disclosure on the sociability of Mecp2+ / +and Mecp2+ / ' mice 14 days off drug treatment.

[0042] Fig. 16 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice 14 days off drug treatment using nose contact as proxy. Fig. 16A is a graph illustrating instances of nose contact. Fig. 16B is a graph illustrating time spent in nose contact. Fig. 16C is a graph illustrating mean duration of nose contact.

[0043] Fig. 17 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice 14 days off drug treatment using paw contact as proxy. Fig. 17A is a graph illustrating instances of paw contact. Fig. 17B is a graph illustrating time spent in paw contact. Fig. 17C is a graph illustrating mean duration of paw contact.

[0044] Fig. 18 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice 14 days off drug treatment using grooming behavior as proxy. Fig. 18A is a graph illustrating episodes of grooming. Fig. 18B is a graph illustrating episodes of grooming immediately after social contact.

[0045] Fig. 19 shows the results of the direct social interactions behavioral assay of Mecp2+ / +and Mecp2+ / ' mice 14 days off drug treatment using following and rearing behavior as proxy. Fig.19A is a graph illustrating episodes of following. Fig. 19B is a graph illustrating episodes of rearing.

[0046] Figs. 20-21 show the results of the three-chambers social preference behavioral assay for the carry over effect autism single dose study, evaluating the carry over effects of chronic trofinetide and the substituted purine A2aR antagonist of the present disclosure on the sociability of Mecp2+ / +and Mecp2+ / ~ mice that are actively under drug treatment.

[0047] Fig. 20A is a graph illustrating time spent in the chamber(s) while actively under drug treatment. Fig. 20B is a graph illustrating % social preference while actively under drug treatment.

[0048] Fig. 21 shows the results of the three-chambers social preference behavioral assay of Mecp2+ / +and Mecp2+ / ~ mice actively under drug treatment using nose contact as proxy. Fig. 21 A is a graph illustrating instances of nose contact. Fig. 21 B is a graph illustrating time spent in nose contact. Fig. 21 C is a graph illustrating mean duration of nose contact.1

[0049] Figs. 22-23 show the results of the three-chambers social preference behavioral assay for the carry over effect autism single dose study, evaluating the carry over effects of chronic trofinetide and the substituted purine A2aR antagonist of the present disclosure on the sociability of Mecp2+ / +and Mecp2+ / ~ mice 10 days off drug treatment.

[0050] Fig. 22A is a graph illustrating time spent in the chamber(s) 10 days off drug treatment. Fig. 22B is a graph illustrating % social preference 10 days of drug treatment.

[0051] Fig. 23 shows the results of the three-chambers social preference behavioral assay of Mecp2+ / +and Mecp2+ / ~ mice 10 days off drug treatment using nose contact as proxy. Fig. 23A is a graph illustrating instances of nose contact. Fig. 23B is a graph illustrating time spent in nosecontact. Fig. 23C is a graph illustrating mean duration of nose contact.

[0052] Figs. 24-25 show the results of the motor stereotypies behavioral assay, evaluating the effects of chronic trofinetide and the substituted purine antagonist of the present disclosure in Mecp2+ / +and Mecp2+ / ~ mice. Fig. 24A is a graph illustrating episodes of rearing. Fig. 24B is a graph illustrating episodes of grooming. Fig. 24C is a graph illustrating time spent burying. Fig.25A is a graph illustrating episodes of circling. Fig. 25B is a graph illustrating number of shakes.

[0053] Fig. 26 shows the results of the Y-maze exploration behavioral assay, evaluating the effects of chronic trofinetide and the substituted purine antagonist of the present disclosure in Mecp2+ / +and Mecp2+ / ~ mice. Fig. 26A is a graph illustrating number of arm entries. Fig. 26B is a graph illustrating % alternation (i.e. , spontaneous alternations, alternate arm returns, and same arm returns).

[0054] Fig. 27 shows the results of the string test behavioral assay, evaluating the effects of chronic trofinetide and the substituted purine antagonist of the present disclosure in Mecp2+ / +and Mecp2+ / ' mice.

[0055] Figure 28 is a graph showing the GPCR screening result of the compound of istradefyline compared to MB204.

[0056] Figure 29 is a graph showing dose at which side effects are induced by istradefylline as compared to MB204.

[0057] Figure 30 is a graph showing the plasma concentrations over time after administration of 3 mg / kg istradefyline p.o. versus 3 mg / / kg p.o of the compound of MB204.DETAILED DESCRIPTION

[0058] Embodiments of the disclosure are discussed in detail below. In describing embodiments, specific terminology is employed for the sake of clarity. However, the disclosure is not intended to be limited to the specific terminology so selected. A person skilled in the relevant art will recognize that other equivalent parts can be employed and other methods developed without parting from the spirit and scope of the disclosure. All references cited herein are incorporated by reference as if each had been individually incorporated.

[0059] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0060] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.

[0061] The term “comprising” as used herein will be understood to mean that the list following is non-exhaustive and may or may not include any other additional suitable items, for example one or more further feature(s), component(s) and / or ingredient(s) as appropriate.

[0062] The terms "pharmaceutically effective amount", "therapeutically effective amount" or "therapeutically effective dose," "effective amount" refer to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The term "therapeutically effective amount" includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.

[0063] The term "pharmaceutically acceptable salts" in this disclosure includes salts of the compounds of this disclosure that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. For example, salts may be derived from pharmaceutically acceptable inorganic bases that include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. For example, salts may be derived from pharmaceutically acceptable organic bases that include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge, S. M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19, 1977). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0064] In some embodiments, the neutral form of the compounds is regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0065] The "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human.

[0066] The terms "treat", "treating", "treatment" and grammatical variations thereof as used in this disclosure, include partially or completely delaying, alleviating, mitigating or reducing the intensity, progression, or worsening of one or more attendant symptoms of a disorder or condition and / or alleviating, mitigating or impeding one or more causes of a disorder or condition. Treatments according to the disclosure may be applied preventively, prophylactically, pallatively or remedially.

[0067] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with isotopes, such as for example deuterium (2H), tritium (3H), iodine-125 (1251) or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0068] The inventors herein developed the compound of formula:for the treatment of one or more of autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS).

[0069] In some embodiments, the compound are administered by intravenous injection, by injection into tissue, intraperitoneally, orally, or nasally. In some embodiments, the composition have a form of a solution, dispersion, suspension, powder, capsule, tablet, pill, time release capsule, time release tablet, or time release pill.

[0070] In some embodiments, the compounds are systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier; or by inhalation or insufflation. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the compounds may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The compounds may be combined with a fine inert powdered carrier and inhaled by the subject or insufflated. The percentage of the compositions and preparations may, of course, be varied and may be a suitablepercentage of the weight of a given unit dosage form. The amount of compounds in such therapeutically useful compositions is such that an effective dosage level may be obtained.

[0071] In some embodiments, the tablets, troches, pills, capsules, or the like also contains the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring may be added. It is appreciated that a capsule may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. It is understood that any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In some embodiments, the compounds are incorporated into sustained-release preparations and devices. For example, the compounds may be incorporated into time release capsules, time release tablets, and time release pills.

[0072] In some embodiments, the compounds are administered intravenously or intraperitoneally by infusion or injection. Solutions of the compounds may be prepared in water, optionally mixed with a nontoxic surfactant. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, triacetin, or mixtures thereof or in oils. In some embodiments, these preparations contain a preservative to prevent the growth of microorganisms under ordinary conditions of storage and use.

[0073] In some embodiments, the pharmaceutical dosage forms for injection or infusion is sterile aqueous solutions or dispersions or sterile powders comprising the compounds which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. In some embodiments, the liquid carrier or vehicle is a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. In some embodiments, the proper fluidity is maintained by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. In some embodiments, various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like is used to prevent of the action of microorganisms. In some embodiments, isotonic agents, for example, sugars, buffers or sodium chloride is included. In some embodiments, agents delaying absorption, for example, aluminum monostearate or gelatin is used to prolong absorption of the injectable compositions.

[0074] In some embodiments, sterile injectable solutions is prepared by incorporating the compounds in the required amount in the appropriate solvent, and optionally with some of the other ingredients enumerated above, as may be required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the composition may be vacuum dried and / or freeze dried, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-fi Itered solutions.

[0075] Methods for synthesizing the compounds for formulae I, MB204 are provided in CA3170917 by the present inventor.Example 1 : Autism Single Dose Studies - Immediate Effect (OprmDAnimals

[0076] The Oprml- / - is a well characterised mouse model of ASD. An Oprm ' (B6.129S2-Oprm1tm1Kff / J) mouse line was acquired from Jackson Laboratories (Farmington, USA) and bred on a hybrid background: 50% 129SVPas - 50% C57BL / 6J. Equivalent numbers of male andfemale mice were generated in-house from homozygous parents (F2), bred from heterozygous animals (F1), to prevent genetic derivation. Mice in the same cage were of the same genotype: this breeding scheme and housing conditions likely favor social deficits in mutant mice by maintaining them together during early post-natal development. For similar reasons, mice in a same cage received the same pharmacological treatment. Mice were aged 8 to 10 weeks at the beginning of experiments. Animals were group-housed and maintained on a 12hr light / dark cycle (lights on at 7:00 AM) at controlled temperature (21±1°C). Food and water were available ad libitum. Cardboard igloos and laying (Dietex®, Argenteuil, France) were provided in each cage as enrichment. All experimental procedures were conducted in accordance with the European Communities Council Directive 2010 / 63 / EU and approved by the Comite d’Ethique en Experimentation animale Vai de Loire (C2EA-19).Pharmacological Preparation and Administration

[0077] A suspension of the presently disclosed substituted purine compound for the treatment of one or more of ASD, RTT, and FXS, was prepared in a 50 mM citrate buffer at pH 4.2. Mice received either vehicle (50 mM citrate buffer) or the pharmacological suspension containing the disclosed compound at a dose of 1 or 2.5 mg / kg in a single per-os administration.Behavioral Evaluation - Direct Social Interaction Test

[0078] The direct social interaction test was conducted one hour following drug administration. The following experimental groups were compared: Normal, VEH mice (first bar in Figs. 2A to 6); Normal, low dose mice (1 mg / kg MB204; second bar); Normal, high dose mice (2.5 mg / kg MB204; third bar); 0prm1 VEH mice (fourth bar), 0prm1 low dose mice (1 mg / kg MB204; fifth bar); and 0prm1 high dose mice (2.5 mg / kg MB204; sixth bar). Dosing of mice using drug containing compound of formula I was performed orally, and testing was performed approximately 1 hour following dosing (Fig. 1).

[0079] On testing day, a pair of unfamiliar mice (not cage mates, age-, sex-, genotype- and treatment-matched) were introduced in one of 4 square arenas (40 x 40 cm, separated by 40 cm-high opaque grey Plexiglas walls) for 10 minutes (15 lx). The total amount of time spent in nose contact (nose-to-nose, nose-to-body or nose-to-anogenital region) (Fig. 2), the number of these contacts (Fig. 2A), the time spent in paw contact (Fig. 3) and the number of these contacts (Fig.3A), grooming episodes (allogrooming) (Fig. 4), notably ones occurring immediately (<5s) after a social contact (Fig. 4C), as well as the number of following episodes (Fig. 5) were scored aposteriori on video recordings (MediaRecorder®, Noldus, Wageningen, the Netherlands) using an ethological keyboard (Labwatcher®, View Point, Lyon, France) by trained experimenters and individually for each animal. The mean duration of nose and paw contacts was calculated as the number of events divided by the total time spent in these events.

[0080] As seen in Figs. 2A to 5, the results demonstrated statistically significant recovery of social interaction in Oprml negative mice on low dose MB204 and even better recovery (to normal) on high dose MB204.Behavioral Evaluation - Y-Maze Exploration

[0081] The Y-maze test was conducted 3 hours following drug administration (Figs. 1 and 6). Spontaneous alternation behavior was used to assess perseverative behavior. Each Y-maze (Imetronic, Pessac, France) consisted of three connected Plexiglas arms (15x15x17 cm) covered with distinct wall patterns (15 lx). Floors were covered with lightly sprayed fresh sawdust to limit anxiety. Each mouse was placed at the center of a maze and allowed to freely explore this environment for 5 minutes. The pattern of entries into each arm was scored on video-recordings (MediaRecorder®, Noldus, Wageningen, the Netherlands). Spontaneous alternations (SPA), i.e. successive entries into each arm forming overlapping triplet sets (Fig. 6B), alternate arm returns (AAR) (Fig. 6C) and same arm returns (SAR) (Fig. 6D) were scored, and the percentage of SPA, AAR and SAR was calculated as following: total I (total arm entries -2) * 100.

[0082] As seen in Fig. 6, the results demonstrated statistically significant improvement in task performance in Oprml negative mice on low dose MB204 and at or above normal performance on high dose MB204.Example 2: Autism and Retts Single Dose Studies (Mecp2) - Drug Effect, Drug Carry Over Effect and Comparison MB204 versus TrofenitideExperimental Protocol

[0083] The Mecp2-null mouse is an accepted mouse model of Rett syndrome and autismspectrum disorder.

[0084] Trofenitide (100 mg / kg, ip) and the presently disclosed substituted purine compound for the treatment of one or more of ASD, RTT, and FXS (1 mg / kg, po) were tested on the autism-like phenotype of Mecp2 in mice. Both compounds were administered chronically and behavioraltesting began 14 days after the treatment began. The lasting effects of the compounds on sociability were also assessed 7, 10, and 14 days after the treatment was stopped with a sample size of n = 4 animals per group (Fig. 7).Behavioral Evaluation - Direct Social Interaction Test

[0085] On testing day, a pair of unfamiliar mice (not cage mates, age, sex-, genotype- and treatment-matched) were introduced in one of 4 square arenas (40 x 40 cm, separated by 40 cm-high opaque grey Plexiglas walls) for 10 minutes (15 lx). The total amount of time spent in nose contact (nose-to-nose, nose-to-body or nose-to-anogenital region) (Figs. 8, 12, & 16), the number of these contacts (Figs. 8A, 12A, & 16A), the time spent in paw contact (Figs. 9, 13, & 17) and the number of these contacts (Figs. 9A, 13A, & 17A), grooming episodes (allogrooming) (Figs.10, 14, & 18), notably ones occurring immediately (<5s) after a social contact (Figs. 10B, 14B, & 18B), as well as the number of following episodes (Figs. 11, 15, & 19) were scored a posteriori on video recordings (MediaRecorder®, Noldus, Wageningen, the Netherlands) using an ethological keyboard (Labwatcher®, View Point, Lyon, France) by trained experimenters and individually for each animal. The mean duration of nose and paw contacts was calculated as the number of events divided by the total time spent in these events.

[0086] Fig. 20B summarizes multiple measurements of sociability: number of nose contacts, time spent in nose contacts, and nose contact mean duration, all during drug treatment. The first bar displays results for normal mice, the second bar normal mice with 100 mg / kg trofinetide, the third bar Mecp deficient mice, the fourth bar Mecp deficient mice with 100 mg / kg trofinetide. The fifth bar displays results for normal mice, the sixth bar normal mice with 1 mg / kg MB204, the seventh bar Mecp deficient mice, the eigth bar Mecp deficient mice with 1 mg / kg MB204. In summary, MB204 was very effective in restoring sociability to the Mecp deficient mice, to a normal level, and comparable to Trofinetide at 1% of the dose of Trofinetide.

[0087] Fig. 21A to C details the multiple measurements of sociability: number of nose contacts, time spent in nose contacts, and nose contact mean duration, all during drug treatment. The first pair of bars displays results for normal mice, the second pair normal mice with 100 mg / kg trofinetide, the third pair Mecp deficient mice, the fourth pair Mecp deficient mice with 100 mg / kg trofinetide. The fifth pair of bars displays results for normal mice, the sixth pair normal mice with 1 mg / kg MB204, the seventh pair Mecp deficient mice, the eigth pair Mecp deficient mice with 1 mg / kg MB204. In summary, MB204 was very effective in restoring sociability to the Mecp deficientmice, to a normal level, and comparable to Trofinetide at 1% of the dose of Trofinetide.

[0088] Fig. 22B summarizes multiple measurements of sociability: number of nose contacts, time spent in nose contacts, and nose contact mean duration, all 10 days after drug treatment. The first bar displays results for normal mice, the second bar normal mice with 100 mg / kg trofinetide, the third bar Mecp deficient mice, the fourth bar Mecp deficient mice with 100 mg / kg trofinetide. The fifth bar displays results for normal mice, the sixth bar normal mice with 1 mg / kg MB204, the seventh bar Mecp deficient mice, the eigth bar Mecp deficient mice with 1 mg / kg MB204. In summary, MB204 was very effective in restoring sociability to the Mecp deficient mice, to above normal levels, and significantly better than Trofinetide at 1% of the dose of Trofinetide, 10 days after cessation of drug treatment.

[0089] Fig. 23A to C details multiple measurements of sociability: number of nose contacts, time spent in nose contacts, and nose contact mean duration, all 10 days after drug treatment. The first pair of bars displays results for normal mice, the second pair normal mice with 100 mg / kg trofinetide, the third pair Mecp deficient mice, the fourth pair Mecp deficient mice with 100 mg / kg trofinetide. The fifth pair of bars displays results for normal mice, the sixth pair normal mice with 1 mg / kg MB204, the seventh pair Mecp deficient mice, the eigth pair Mecp deficient mice with 1 mg / kg MB204. In summary, MB204 was very effective in restoring sociability to the Mecp deficient mice, to above normal levels, and significantly better than Trofinetide at 1% of the dose of Trofinetide, 10 days after cessation of drug treatment.

[0090] Figs. 8-19 compared social interaction in normal vehicle mice (first bar), normal mice treated with 100mg / kg Trofinetide (second bar), Mecp2 deficient mice (third bar), Mecp2 deficient mice with 100mg / kg Trofinetide (fourth bar), normal vehicle mice (fifth bar) normal mice with 1 mg / kg MB204 (sixth bar), Mecp2 deficient mice (seventh bar), Mecp2 deficient mice with 1 mg / kg MB204 (eight bar). In terms of sociability observed using the direct social interaction test (Figs.8-19), no effect from trofenitide at the dose of 100 mg / kg was observed. In contrast, the presently disclosed substituted purine compound significantly improved the sociability of Mecp2 heterozygous mice. A complete restoration of social parameters during the treatment was recorded, and this effect persisted one week after treatment ended. Even two weeks posttreatment, a partial rescue effect from the compound was still observed.

[0091] Results showed 100mg / kg Trofinetide induced a very slight to good recovery or norecovery in sociability while 1mg / kg MB204 induced a significant recovery in sociability to almost normal while under drug treatment. Results showed 100mg / kg Trofinetide maintained a very slight recovery in sociability 7 days after discontinuing drug treatment while 1mg / kg MB204 maintained a significant recovery in sociability to almost normal 7 days after discontinuing drug treatment. Results showed 100mg / kg Trofinetide maintained a very slight or no recovery in sociability 7 days after discontinuing drug treatment while 1mg / kg MB204 maintained significant sociability to almost normal 7 days after discontinuing drug treatment. Results showed 100mg / kg Trofinetide maintained no recovery in sociability 14 days after discontinuing drug treatment while 1mg / kg MB204 maintained significant sociability 14 days after discontinuing drug treatment.Behavioral Evaluation - Three-Chamber Social Preference Test

[0092] The three-chamber social preference test is conducted 15 and 16 days after the beginning of pharmacological treatment, as well as 10 days after the treatment is stopped. The test apparatus consists of a transparent acrylic box (exterior walls blinded with black plastic film). Partitions divide the box into three equal chambers (40 x 20 x 22.5 cm). Two sliding doors (8 x5 cm) allow transitions between chambers. Cylindrical wire cages (18x9 cm, 0.5 cm diameter rods spaced 1 cm apart) are used to contain the mouse interactor and object (soft toy mouse). The test is performed in low-light conditions (15 lx) to minor anxiety. Stimulus wild-type mice are habituated to confinement in wire cages for 2 days before the test (20 minutes / day). On testing day, the experimental animal is introduced to the middle chamber and allowed to explore the whole apparatus fora 10-minute habituation phase (wire cages empty) after the sliding doors are raised. The experimental mouse is then confined back in the middle-chamber while the experimenter introduces an unfamiliar wild type age and sex-matched animal into a wire cage in one of the side chambers and a soft toy mouse (8 x 10 cm) in the second wire cage as a control for novelty. Then the experimental mouse is allowed to explore the apparatus for a 10-minute interaction phase. The time spent in each chamber (Fig. 20A & 22A), the time spent in nose contact with each wire cage (empty: habituation; containing a mouse or a toy: interaction) (Fig.21 B & 23B), as well as the number of these nose contacts (Fig.21 A & 23A) are scored a posteriori on video recordings (MediaRecorder®, Noldus, Wageningen, the Netherlands) using an ethological keyboard (Labwatcher®, View Point, Lyon, France) by trained experimenters. The mean duration of nose contacts (Fig. 21 C & 23C) is calculated from these data. Preference ratio is calculated as follows: Time in nose contact with the mouse I (Time in nose contact with the mouse + Time in nose contact with the object) x 100 (Fig. 20B & 22B). The relative position of stimulus mice (versus toy) is counterbalanced between groups.

[0093] Thus Fig. 20A shows bars indicating the preference for mouse socialization (M) versus the non-social toy (T) based on time in chamber during drug treatment. The first pair of bars displays results for normal mice, the second pair normal mice with 100 mg / kg trofinetide, the third pair Mecp deficient mice, the fourth pair Mecp deficient mice with 100 mg / kg trofinetide. The fifth pair of bars displays results for normal mice, the sixth pair normal mice with 1 mg / kg MB204, the seventh pair Mecp deficient mice, the eigth pair Mecp deficient mice with 1 mg / kg MB204. In summary, MB204 was very effective in restoring sociability to the Mecp deficient mice, to a normal level, and comparable to Trofinetide at 1% of the dose of Trofinetide.

[0094] With respect to the three-chamber test for social preference, it was found that trofenitide helped heterozygous Mecp2 mice better distinguish between a Mouse (M) and a Toy (T), based on the number of nose contacts (Figs. 21A & 23A). However, treatment with trofenitide did not seem to affect the quality of the subject’s interactions, as deduced from mean duration of nose contact (Figs. 21 C & 23C). The heterozygous Mecp2 mice spent about the same amount of time exploring both the mouse and the toy, which is quite different from what is observed in wild-type mice. Notably, trofenitide is no longer active 10 days following the end of treatment. In contrast, administration of the substituted purine A2aR antagonist of the present disclosure restored all social preference parameters in injected heterozygous Mecp2 mice, and this positive effect remained for 10 days following the end of treatment.

[0095] Thus Fig. 22A shows bars indicating the preference for mouse socialization (M) versus the non-social toy (T) based on time in chamber 10 days after drug treatment. The first pair of bars displays results for normal mice, the second pair normal mice with 100 mg / kg trofinetide, the third pair Mecp deficient mice, the fourth pair Mecp deficient mice with 100 mg / kg trofinetide. The fifth pair of bars displays results for normal mice, the sixth pair normal mice with 1 mg / kg MB204, the seventh pair Mecp deficient mice, the eigth pair Mecp deficient mice with 1 mg / kg MB204. In summary, MB204 was very effective in restoring sociability to the Mecp deficient mice, to above normal levels, and significantly better than Trofinetide at 1% of the dose of Trofinetide, 10 days after cessation of drug treatment.Behavioral Evaluation - Motor Stereotypies

[0096] The motor stereotypies test is conducted 17 days after the beginning of pharmacological treatment. The experimental protocol was adapted from (11, 12). To detect spontaneous motorstereotypies in mutant versus wild-type animals, mice are individually placed in clear standard home cages (21x11x17 cm) filled with 3-cm deep fresh sawdust for 10 minutes. Light intensity is set at 30 lux. Trained experimenters score numbers of head shakes (Fig. 25B), as well as rearing (Fig. 24A), burying, grooming (Fig. 24B), circling episodes (Fig. 25A) and total time spent burying (Fig. 24C) by direct observation.

[0097] The motor stereotypies test (Figs. 24-25) demonstrated that heterozygous Mecp2 mice displayed few motor stereotypies. With respect to the Y-maze exploration test (Fig. 26), it was found that chronic treatment is beneficial for the perseverative behaviors measured in heterozygous Mecp2 mice, as it can normalize the same arm return (SAR). In contrast, no effect was observed with trofenitide in this test. With respect to the string test for evaluating motor coordination (Fig. 27), a color effect in the motor responses of the mice was observed.

[0098] Fig. 24A to C details the multiple measurements of repetitive stereotype behaviours: number of rearing episodes, number of grooming episodes, and time spent burying, all during drug treatment. The first bar displays results for normal mice, the second bar normal mice with 100 mg / kg trofinetide, the third bar Mecp deficient mice, the fourth bar Mecp deficient mice with 100 mg / kg trofinetide. The fifth bar displays results for normal mice, the sixth bar normal mice with 1 mg / kg MB204, the seventh bar Mecp deficient mice, the eigth bar Mecp deficient mice with 1 mg / kg MB204. In summary, MB204 was comparable to Trofinetide at 1% of the dose of Trofinetide, during drug treatment.

[0099] Fig. 25A to B details further measurements of repetitive stereotype behaviours: number of circling episodes and number of shakes, all during drug treatment. The first bar displays results for normal mice, the second bar normal mice with 100 mg / kg trofinetide, the third bar Mecp deficient mice, the fourth bar Mecp deficient mice with 100 mg / kg trofinetide. The fifth bar displays results for normal mice, the sixth bar normal mice with 1 mg / kg MB204, the seventh bar Mecp deficient mice, the eigth bar Mecp deficient mice with 1 mg / kg MB204. In summary, MB204 was comparable to Trofinetide at 1% of the dose of Trofinetide for shakes, during drug treatment. MB204 was greatly outperformed Trofinetide at 1% of the dose of Trofinetide for circling episodes, during drug treatment.Behavioral Evaluation - Y-Maze Exploration[000100] The Y-maze exploration test is conducted 14 days after the beginning ofpharmacological treatment (Fig. 26). As previously discussed, spontaneous alternation behavior is used to assess perseverative behavior. Each Y-maze (Imetronic, Pessac, France) consisted of three connected Plexiglas arms (15x15x17 cm) covered with distinct wall patterns (15 lx). Floors are covered with lightly sprayed fresh sawdust to limit anxiety. Each mouse is placed at the center of a maze and allowed to freely explore this environment for 5 minutes. The pattern of entries into each arm is scored on video-recordings (MediaRecorder®, Noldus, Wageningen, the Netherlands). Spontaneous alternations (SPA), i.e. successive entries into each arm forming overlapping triplet sets, alternate arm returns (AAR) and same arm returns (SAR) are scored, and the percentage of SPA, AAR and SAR is calculated as following: total I (total arm entries -2) * 100 (Fig. 26B).[000101] Fig. 26A to B details perseverative stereotype behaviours in the Y maze test: number of arm entries and alternation, all during drug treatment. In Fig. 26A the first bar displays results for normal mice, the second bar normal mice with 100 mg / kg trofinetide, the third bar Mecp deficient mice, the fourth bar Mecp deficient mice with 100 mg / kg trofinetide. The fifth bar displays results for normal mice, the sixth bar normal mice with 1 mg / kg MB204, the seventh bar Mecp deficient mice, the eigth bar Mecp deficient mice with 1 mg / kg MB204. In summary, MB204 was comparable to Trofinetide at 1% of the dose of Trofinetide for shakes, during drug treatment. In Figure 26B the first, ninth and seventeens bars displays results for normal mice, the second, tenth and eighteenth bars normal mice with 100 mg / kg trofinetide, the third, eleventh and nineteens bars Mecp deficient mice, the fourth, twelfth and twentieth bars Mecp deficient mice with 100 mg / kg trofinetide. The fifth, thirteenth, and twenty-first bars displays results for normal mice, the sixth, fourteenth and twenty-second bars normal mice with 1 mg / kg MB204, the seventh, fifteenth and twenty-third bars Mecp deficient mice, the eight, sixteenth and twenty-fourth bars Mecp deficient mice with 1 mg / kg MB204. Alternation measurements included spontaneous alternation rate (SPA), alternate arm returns (AAR) and same arm returns (SAR) In summary, MB204 was comparable to Trofinetide at 1% of the dose of Trofinetide during drug treatment. MB204 was greatly outperformed Trofinetide at 1% of the dose of Trofinetide for SAR during drug treatment.Behavioral Evaluation - String Test[000102] The string test measures the time required for a forelimb-hanging mouse to gain hindlimb traction. Defects in latency time reflect potential alteration in traction force or deficient coordination. (Fig. 27).[000103] Fig. 27 shows number of seconds (1, 2, or 3) of latency to grasp on the string test, a measurement of coordination, the first group (1, 2, or 3) displays results for normal mice, the second group normal mice with 100 mg / kg trofinetide, the third group Mecp deficient mice, the fourth group Mecp deficient mice with 100 mg / kg trofinetide. The fifth group displays results for normal mice, the sixth group normal mice with 1 mg / kg MB204, the seventh group Mecp deficient mice, the eigth group Mecp deficient mice with 1 mg / kg MB204.Example 3: Comparison MB204 versus Istradefylline[000104] Pharmacological blockade of A2aRs using istradefylline partially restores some of the phenotypes in animal models of Fragile X syndrome, both by reducing over-activation of the metabotropic glutamate 5 receptor (mGlu5R) and by acting on other A2aR-related downstream targets.12However, it has not been approved for treatment of FXS.[000105] MB204 acts as an A2aRs antagonist, thus providing a pharmaceutical with high bioavailability that is highly effective, fast-acting, safe and tolerable in higher doses, and suitable for treating such neurological diseases as autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS).[000106] In comparison to the best known A2aRs antagonist, istradefylline, MB204 has been shown to have better binding. Figure 28 is a graph showing the GPCR screening result of the compound of istradefyline compared to MB204. In comparison to the istradefylline, MB204 is better tolerated when measured by induction of involuntary movement dosage (see Figure 29). MB204 has improved absorption and bioavailability, as shown in Figure 30. Figure 30 is a graph showing the plasma concentrations over time after administration of 3 mg / kg istradefyline p.o. versus 3 mg / / kg p.o of the compound of MB204.

[0095] All references, including publications, patent applications and patents cited herein are incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.REFERENCES, et al., “Role of adenosine A2A receptors in hot and cold cognition: Effects of single dose istradefyllinein healthy volunteers” (2022) 71:2023 Eur Neuropsychopharma 55-64. a, R.A., “How does adenosine control neuronal dysfunctional and neurodegeneration?” (2016) 139:6 J. Neurochem 1019-1055.holm, B.B. et al., “Adenosine and brain function:” (2005) 63 Int. Rev. Neurobiol 191-270. ri, M.A. et al., “Activation of adenosine A2A receptor signaling regulates the expression of cytokines associated with immunologic dysfunction in BTBR T+Itpr3tf / J mice” (2017) 82 Mol Cell Neurosci 76-87.allier, C. et al., “The social motivation theory of autism” (2012) 16:4 Trends Cogn Sci 231-239.errer, J. et al., “Balance Between Projecting Neuronal Populations of the Nucleus Accumbens Controls Social Behavior in Mice” (2023) 3223:23 Biol Psychiatry 123-135. Centers for Disease Control and Prevention (CDC), “Data and Statistics on Autism Spectrum Disorder” (16 May 2024), online: <https: / / www.cdc.gov / autism / data-research / index.html>.da-Lourenco, C. et al., “Impairment of adenosinergic system in Rett syndrome: Novel therapeutic target to boost BDNF signalling” (2020) 145 Neurobio Dis 105043. rour, M. and H.Y. Zoghbi, “The story of Rett syndrome: From clinic to neurobiology” (2007) 56 Neuron 422-437.ir, R.E. et al., “Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2” (1999) 23 Nat Genet 185-188.nage, V.R.B and M. Rastegar, “Rett syndrome and MeCP2” (2014) 16 NeuroMol Med 231-264.rante, A. et al., “Adenosine A2A receptor inhibition reduces synaptics and cognitive hippocampal alterations in Fmr1 KO mice” (2021) 11:112 Transl Pscyhiatry.

Claims

WHAT IS CLAIMED IS:

1. Use of a compound of formula:(I) or a pharmaceutically acceptable salt thereof for treatment of one or more of autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS).

2. A method for treating one or more of autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS), the method comprising administration of a compound of formula:

3. Use of a compound of formula:(I) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical for the treatment of one or more of autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS).

4. A pharmaceutical dose of a compound for use in the treatment of one or more of autism spectrum disorder (ASD), Rett syndrome (RTT), and Fragile X syndrome (FXS) in a subject, wherein the compound is of formula:(I) or a pharmaceutically acceptable salt thereof, and wherein the dose comprises 5 to 1000 mg / kg of the compound of formula (I).

5. The pharmaceutical dose of claim 4, wherein the dose comprises 10 to 600 mg / kg of the compound of formula (I).

6. The pharmaceutical dose of claim 4, wherein the dose comprises 20 to 200 mg / kg of the compound of formula (I).

7. The pharmaceutical dose of claim 4, wherein the dose comprises 25 to 100 mg / kg of the compound of formula (I).

8. The pharmaceutical dose of claim 4, wherein the dose comprises about 40 mg / kg of the compound of formula (I).

9. The pharmaceutical dose of claim 4, wherein the dose is for administration about once every two weeks.

9. The pharmaceutical dose of claim 4, wherein the dose is for administration about once weekly.

10. The pharmaceutical dose of claim 4, wherein the dose is for administration about once daily.

11. The pharmaceutical dose of claim 4, wherein the dose is for administration about twicedaily.

12. The use, method, or dose of any preceding claim, wherein the compound of formula (I) is for administration orally.

13. The use, method, or dose of any one of claims 1 to 11 , wherein the compound of formula (I) is for administration by injection.

14. The use, method, or dose of any preceding claim, wherein the compound of formula (I) is for administration with a pharmaceutically acceptable excipient.

15. The use, method, or dose of any preceding claim, further comprising use, method or dose with an additional therapeutic agent, wherein the additional therapeutic agent is one or more of trofinetide, aripiprazole, risperidone, fluoxetine, and fluvoxamine.

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