Methods for treating obsessive compulsive related disorders, tic disorders and glutamate excitotoxicity related disorders

Abstract

The present invention provides for methods of treating obsessive-compulsive disorder (OCD) and OCD-related disorders (body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), excoriation (skin-picking) disorder, substance / medication-induced obsessive-compulsive and related disorder, obsessive- compulsive and related disorder due to another medical condition, and other specified and unspecified obsessive-compulsive and related disorders), Tic disorders including Tourette syndrome, autism spectrum disorder (ASD) and glutamate excitotoxicity related disorders including amyotrophic lateral sclerosis (ALS), Parkinson's disease, traumatic brain injury, multiple sclerosis, Huntington's disease, and schizophrenia, comprising the step of administering an effective amount of a histamine type 1 receptor agonist and / or histamine type 3 receptor antagonist, such as betahistine or its pharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs or stereoisomers.

Description

METHODS FOR TREATING OBSESSIVE COMPULSIVE RELATED DISORDERS, TIC DISORDERS AND GLUTAMATE EXCITOTOXICITY RELATED DISORDERS TECHNICAL FIELD

[0001] The present invention relates to the use of histamine H1 receptor agonists and / or histamine receptor H3 antagonists, such as betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs or stereoisomers, for the treatment of obsessive-compulsive related disorders (OCRDs), including obsessive-compulsive disorder (OCD), tic disorders, including Tourette syndrome, autism spectrum disorder (ASD), and glutamate excitotoxicity-related disorders, including amyotrophic lateral sclerosis (ALS). BACKGROUND OF THE INVENTION

[0002] Obsessive-compulsive disorder (OCD) is a chronic and highly debilitating neuropsychiatric disorder characterized by compulsions and / or obsessions. An obsession is a thought, feeling, or image that is of an intrusive, irrational, or clearly excessive, distressing, difficult to control, and stereotyped or repetitive nature. Compulsions (also sometimes called rituals) are repetitive behaviors that are irrational or clearly excessive, difficult to control, and often stereotyped in nature; an individually typically feels compelled to perform compulsions in response to their obsessions.

[0003] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) classifies OCD under obsessive-compulsive and related disorders (OCRDs), alongside hoarding disorder, body dysmorphic disorder, trichotillomania (hair-pulling disorder), and excoriation (skin-picking disorder). OCD is often represented as an amusing personality quirk in popular culture, but in fact it is a source of great suffering and profoundly affects quality of life, reducing sufferers’ ability to maintain relationships and weakening other aspects of social and occupational functioning.

[0004] OCD has a lifetime prevalence of 2-3%. Women are 1.6 times more likely than men to be diagnosed with OCD at some point in their lives, and 92.3% oftreatment seeking individuals with OCD have comorbidity, which also varies depending on sex. In women, eating disorders, anxiety, and depression are the most common comorbidities, whereas in men attention-deficit / hyperactivity disorder, autism, and psychotic and developmental disorders are most common. Any comorbidity in OCD is associated with higher anxiety and depressive symptoms, including suicidal behaviors.

[0005] The physiopathology of OCD is complex and has been linked to genetic, infectious / autoimmune, endocrine, post-partum and post-ischemic factors. Abnormalities of the cortico-striato-thalamo-cortical circuit (CSTC), which controls habit formation, reward, and movement execution, have been shown repeatedly. The neurotransmitter glutamate is prominent in this circuitry; convergent evidence suggests that glutamate abnormalities may contribute to the pathophysiology of OCD, and glutamate modulators are under investigation as potential therapeutics.

[0006] General principles of management of OCD include specialized cognitive- behavioral therapy (CBT), which has been consistently demonstrated to improve OCD symptomatology, and selective serotonin reuptake inhibitors (SSRIs), which are the first line of pharmacotherapy due to their relative safety and efficacy. SSRIs are typically used at much higher doses than in major depression, which is associated with increased adverse effects and thus an increased dropout rate.

[0007] Despite these different treatment methods, 40-60% of OCD patients do not respond adequately to available evidence-based treatments. Approximately 30% do not respond at all; others improve and are categorized in studies as treatment responders but continue to experience impairing symptoms. Available medications are limited by side effects (especially when second line agents such as clomipramine or drug combinations such as the addition of a neuroleptic are used after SSRI nonresponse). Specialty CBT is limited by a markedly inadequate availability of providers skilled in these effective therapeutic techniques.

[0008] Due to the nature of its symptoms and the lack of an efficacious treatment, OCD remains a significant societal burden and there remains a need for improved treatment methods. The diminution in quality of life of OCD patients, as compared to their healthy counterparts, is comparable to that of patients with schizophrenia. In the World Health Organization’s Global Burden of Disease 2004 Update, OCD was the cause of more disability adjusted life-years (number of years lost to disability) than Multiple Sclerosis and Parkinson’s Disease combined.

[0009] Histamine is an important neurotransmitter and modulator of the central nervous system, though its roles has been less intensively investigated than those of other modulatory neurotransmitters such as serotonin. Histaminergic neurons are found exclusively in the posterior tuberomammillary nucleus of the hypothalamus but project broadly throughout the brain. The enzyme histidine decarboxylase (Hdc) is essential to produce histamine, which is synthesized from the amino acid L-histidine by decarboxylation. A nonsense mutation in the Hdc gene has been detected as a rare but high penetrance cause of Tourette’s Syndrome (TS), with comorbid OCD in about half of the identified cases. Additional genetic studies and preclinical work support a causal role of histamine signaling dysfunction in these conditions. Pharmacological tests of histaminergic agents in OCD and TS have been limited.

[0010] There are four histamine receptors. The histamine 1 receptor (H1R) is coupled through the Gαq / 11 protein to phospholipase C signaling. H1R is present in cerebral blood vessels, as well as on neurons and glial cells in many brain regions. H1R activation of astrocytes helps maintain synaptic homeostasis, including extracellular Ca2+ uptake, which increases intracellular Ca2+ and therefore affects Ca2+ dependent signaling .

[0011] The H3 receptor (H3R) is believed to be expressed exclusively on neurons in the central nervous system. It exists primarily presynaptically, on neuronal axon terminals. It is coupled to signaling through the Gαi protein and thus reduces signaling through cyclic AMP (cAMP). The activation of presynaptic H3R reduces neurotransmitter release, including that of histamine itself (thus constituting a negative feedback mechanism) as well as of glutamate, dopamine, and other transmitters. More recently it has been recognized that much of the H3R in the striatum, the large input nucleus of the CSTC circuitry implicated in OCD, is postsynaptic; it interacts with dopamine signaling in complex ways. The H3R is most strongly expressed in the hypothalamus, basal ganglia, hippocampus, and cerebral cortex; this pattern overlaps with structures implicated in by OCD physiopathology.

[0012] Glutamate is the most abundant excitatory neurotransmitter in the Central Nervous System (CNS). Virtually all circuits and networks in the CNS use glutamate, including those implicated in OCD, such as the CSTC. Glutamate is released from vesicles into the synaptic cleft, where it can bind to presynaptic or postsynaptic receptors. Glutamate concentration is tightly regulated, as excess glutamate can cause excitotoxicity, which leads to neuronal death. A key mechanism of glutamatehomeostasis is uptake by specific transporters on glial cells, chiefly GLT-1 and GLT- 2, which mediate the rapid uptake of extracellular glutamate after synaptic release.

[0013] Glutamate excitotoxicity is seen in numerous diseases, including ALS, Parkinson’s disease, traumatic brain injury, stroke, Huntington's disease, and schizophrenia. Impaired glutamate uptake by transporters such as GLT-1 and GLT-2 and consequent disruption of glutamate homeostasis may contribute to this excitotoxicity. Prolonged exposure to excessive extracellular glutamate increases neuronal susceptibility to excitotoxic cell death.

[0014] Additionally, glutamate plays a crucial role in Autism Spectrum Disorder (ASD). Research has shown that the balance of glutamate signaling is disrupted in individuals with ASD, leading to altered synaptic function and connectivity. Abnormalities in glutamate receptors and transporters, as well as imbalances in glutamate levels, have been observed in various brain regions implicated in ASD, such as the prefrontal cortex and limbic system. The dysregulation of glutamate transmission can affect various aspects of neurodevelopment, including synaptic plasticity, neuronal migration, and circuit formation, all of which are critical for normal brain function. Therefore, increasing glutamate clearance is a viable approach for several conditions.

[0015] Betahistine is employed in the therapeutic management of vertigo and Meniere's disease. It functions by enhancing the blood flow within the stapedial artery in the inner ear, consequently reducing vestibular pressure and mitigating symptoms such as vertigo and tinnitus. However, the clinical use of betahistine is not without limitations. Its relatively short half-life necessitates multiple daily doses, and it may cause gastrointestinal side effects in certain patients.SUMMARY OF THE INVENTION

[0016] Various aspects of the present invention address the above challenges.

[0017] In an embodiment, provided is a method of treating an obsessive-compulsive related disorder (OCRD), comprising administering to a subject in need thereof, a therapeutically effective amount of betahistine or a pharmaceutically acceptable pro- drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof.

[0018] In another embodiment, provided is a method of treating an obsessive- compulsive related disorder OCRD in a human, comprising orally administering to a human in need of such treatment an effective amount of a H1R agonist, and / or a H3R antagonist or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0019] In another embodiment, provided is a method of treating glutamate excitotoxicity related disorders in a human, comprising orally administering to a human in need of such treatment an effective amount of a H1R agonist, and / or a H3R antagonist or a pharmaceutically acceptable salt, metabolite, or prodrug thereof.

[0020] In another embodiment, provided is a method of treating glutamate excitotoxicity related disorders, comprising administering to a subject in need thereof, a therapeutically effective amount of betahistine or a pharmaceutically acceptable pro- drug, derivative, metabolite, co crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof.

[0021] In another embodiment, provided is a method of treating tic disorders, comprising administering to a subject in need thereof, a therapeutically effective amount of betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof.

[0022] In another embodiment, provided is a method of treating autism spectrum disorder (ASD) in a human, comprising orally administering to a human in need of such treatment an effective amount of betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof.DETAILED DESCRIPTION OF THE INVENTION

[0023] The following detailed description is provided to aid those skilled in the art in practicing the present invention. Exemplary embodiments will hereinafter be described in detail. However, these embodiments are only exemplary, and the present disclosure is not limited thereto but rather is defined by the scope of the appended claims. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure.

[0024] Unless otherwise defined, 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. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting. It will be further understood that the terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0025] As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present invention.

[0026] The articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element.

[0027] Accordingly, the embodiments are merely described below, by referring to structures and schemes, to explain aspects of the present description. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items. The term “or” means “and / or.” Expressions such as “at least one of,” when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

[0028] It is understood that the terms “comprises” and / or “comprising,” or “includes” and / or “including” when used in this specification, specify the presence of stated substituents, groups, features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other substituents, groups, features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0001] The present methods, compounds, and systems are not limited to specific methods, compounds, components, or compositions described or exemplified herein. It is also to be understood that the terminology used herein is for the purpose of describing and is not intended to be limiting.

[0002] Betahistine is a histamine analogue discovered in the 1970s. It is widely used as an anti-vertigo medication, although controlled studies supporting this use are equivocal. Betahistine is currently approved for the treatment of Meniere's disease in over 80 countries. It was approved by the United States Food and Drug Administration (US FDA), but due to concerns about its efficacy in treating Meniere’s disease, approval was revoked. The FDA has since concluded that although there is no evidence that betahistine is unsafe, there is not sufficient evidence to conclude that it has a therapeutic effect against Meniere’s Disease. It has therefore remained unavailable in the United States for decades.

[0003] Betahistine is a weak histamine H1R agonist and a strong H3R antagonist. It thus can act on processes of relevance to OCD, OCRDs, and TS in multiple ways: through disinhibition of histamine release (and thus mitigation of the histamine reduction seen in individuals with a mutation in the Hdc gene); through direct action on neurons in the CSTC circuitry, including in the striatum; through modulation of glial cell activity and function; and through modulation of cerebral blood flow. Betahistine’s actions on blood vessels in the cochlea have been proposed to mediate its effects in Meniere’s disease – though again, evidence for benefit in controlled trials is equivocal, and it is not approved for this or any other indication by the US FDA.

[0004] An important consequence of H1 receptor activation is neuroprotection by preventing glutamate excitotoxicity through increased glutamate clearance. Glutamate is removed from the synaptic cleft by astrocytic glutamate transporters, especially GLT-1 (also known as excitatory amino acid transporter 2 or EAAT2). Once transported into astrocytes, glutamate is converted into glutamine by the enzyme glutamine synthase (GS). GLT-1 is responsible for the large majority of glutamatereuptake (up to 90% in mechanistic studies in mice). H1R activation upregulates both GLT-1 and GS; this will enhance the mechanisms of glutamate uptake and metabolism, decreasing the amount of glutamate in the synaptic cleft. Without limiting the invention, it is hypothesized that enhanced glutamate reuptake may be an additional mechanism whereby betahistine and similar drugs may reduce symptoms in OCD patients.

[0005] Of note, other drugs that enhance glutamate reuptake, such as riluzole, are under investigation in the treatment of OCD. Riluzole is currently the only FDA- approved medication for the treatment of ALS. H1 agonism may produce enhanced effects on glutamate reuptake relative to riluzole because it upregulates both GLT-1 (as does riluzole) and GS (which riluzole does not), producing a synergistic effect.

[0006] H3R antagonists have recently been seen as a promising drug target for cognitive disorders due to their several pro-cognitive effects, including increased arousal, attention, and learning and memory. They have been shown to increase wakefulness and slow wave sleep (SWS), while reducing rapid eye movement (REM). H3R antagonists, apart from increasing the release of histamine, also increase the release of norepinephrine, dopamine, and acetylcholine.

[0007] Betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs or stereoisomers, can be administered according to various dosing regimens. For instance, betahistine, or its pharmaceutically acceptable salts, metabolites, and prodrugs, can be administered once a day, twice a day, three times per day, or more than three times a day. In some instance, betahistine, or its pharmaceutically acceptable salts, metabolites, and prodrugs, can be administered less than once daily, for instance, once every two days, once every three days, once every five days, once every seven days, once every ten days, once every fourteen days, once every twenty-eight days or once every month.

[0008] Betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs, or stereoisomers, can be administered such that the total weekly dose is at least 50 mg, at least 100 mg, at least 250 mg, at least 500 mg, at least 750 mg, at least 1,000 mg, at least 1,250 mg, at least 1,500 mg, at least 1,750 mg, or at least 2,000 mg. In some instances, the total weekly dose can befrom 5-5,000 mg, 10-5,000 mg, 10-2,500 mg, 50-2,500 mg, 100-2,500 mg, 100-2,000 mg, 250-2,000 mg, or 500-2,000 mg.

[0009] Dosing regimens include dosages for adults of 24–48 mg administered across several doses during the day, such as but not limited to 16 mg of betahistine every 8 hours (e.g., by tablet), to be taken preferably after meals for the first two weeks. After that, an acceptable maintenance dose is 8 mg of betahistine every 8 hours. Other dosing regimens within the scope of the present invention include a protocol of 32 mg of betahistine (e.g., orally) every 8 hours as monotherapy. Another dosing regimen within the scope of the present invention is 32 mg of betahistine (e.g., orally) every 8 hours, in combination with 50 mg of riluzole (e.g., orally) every 12 hours.

[0010] For treating of OCD according to the invention, betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs or stereoisomers, can be administered in combination with one or more other medications, including but not limited to, one or more serotonin reuptake inhibitors (SRIs), including but not limited to fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram, citalopram, clomipramine, venlafaxine, mirtazapine, among others, one or more monoamine oxidase inhibitors (MAOIs), including but not limited to d-amphetamine, glutamate modulating agents (such as memantine, N-acetyl cysteine, and ketamine, among others), pregabalin, topiramate, lamotrigine, clonazepam and other benzodiazepines, lithium, buspirone, psilocybin, or carbamazepine.

[0011] Riluzole has been studied as an add-on treatment for refractory OCD. The mechanism which is thought to cause therapeutic effects is GLT-1 upregulation, is shared by H1 agonism in rat models, which also increases GS upregulation. Without being bound by any specific mechanism of action, betahistine in combination with riluzole could cause an amplified glutamate clearance which in turn would decrease OCD symptoms.

[0012] The combination of MAO-I and betahistine in rat models has shown an amplified agonism of H1 with minimal betahistine doses, demonstrated by increased cochlear blood flow, which is a sign of H1 agonism. H1 agonism then leads to increased GS and GLT-1 upregulation as mentioned before, and to reduced OCD symptoms and / or reduced glutamate excitotoxicity.

[0013] Betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs or stereoisomers, may also be used for treating OCD according to the invention in combination neuromodulation techniques such as tDCS, TMS, VNS, DBS, among others.

[0014] For treating ALS according to the invention, betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs or stereoisomers, can be administered in combination with one or more other medications, including but not limited to riluzole, baclofen, diazepam, gabapentin, trihexyphenidyl, and amitriptyline.

[0015] Riluzole has been approved by the US FDA for the treatment of ALS; it is believed to mitigate excitotoxicity. The mechanism which causes the therapeutic effects is thought to be its increased glutamate clearance, done by GLT-1 upregulation. This is shared by betahistine and other H1R agonists, except that they also lead to upregulation of GS, which is predicted to further increase glutamate clearance through mass action.

[0016] For treating of Parkinson’s according to the invention, betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs or stereoisomers, can be administered in combination with one or more other medications, including but not limited to levodopa, carbidopa, dopamine agonists like cabergoline among others, MAO-B inhibitors, COMT inhibitors, amantadine, anticholinergic drugs such as trihexyphenidyl, benztropine, orphenadrine, procyclidine, and biperiden, among others.

[0017] For treating of tic disorders according to the invention, betahistine, or its pharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs or stereoisomers, can be administered in combination with one or more other medications, including but not limited to, first, second, or third generation antipsychotics, tetrabenazine, and topiramate.

[0018] For treating autism spectrum disorder (ASD) according to the invention, an effective amount of a H1R agonist, and / or a H3R antagonist such as betahistine, or itspharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs or stereoisomers, can be administered optionally in combination with one or more other medications.

[0019] Combinations for use in the methods of the invention include, but are not limited to, betahistine or its pharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs, or stereoisomers, in combination with a. a monoamine oxidase inhibitor (MAO-I) such as selegiline; b. a benzothiazole or derivative, such as riluzole, pramipexole, troriluzole or a combination of these; c. a skeletal muscle relaxant such as baclofen, dantrolene, or a combination of these; d. a benzodiazepine such as diazepam, clonazepam or a combination of these; e. an anticonvulsant such as gabapentin, topiramate, lamotrigine, carbamazepine, BHV-7000, BHV-7010, BHV-80000, any Kv7.2 / 7.3 activator, any Kv7.4 activator, any Kv7 activator, or a combination of these; f. an anticholinergic drug such as trihexyphenidyl, benztropine, orphenadrine, procyclidine, biperiden, or a combination of these; g. a tricyclic, tetracyclic, or other antidepressant drug, such as amitriptyline and mirtazapine; h. a first-generation antipsychotic, a second-generation antipsychotic, a third- generation antipsychotic, such as such as risperidone, aripiprazole, or a combination of these; i. tetrabenazine or topiramate. j. a glutamate-modulating agent such as memantine, N-acetyl cysteine, ketamine, D-cycloserine, or a combination of these; k. a serotonin reuptake inhibitor (SRI) such as clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, or a combination of these, l. a psychostimulant, atomoxetine, or alpha-2 receptor blocker, such as clonidine, guanfacine, methylphenidate, or a combination of these; m. a histamine analogue, a histamine derivative, L-Histidine, HTMT (histamine N-methyltransferase), or a histamine precursor or pro-drug;n. an H1 agonist, such as methylhistaprodifen, dimethylhistaprodifen, 2- thiazolylethylamine, 2-pyridylethylamine, suprahistaprodifen.2-(2- aminoethyl)pyridine (2-PyEA), a 2-phenylhistamine, such as 2-[3- (trifluoromethyl)phenyl]histamine, 2-(3-chlorophenyl)histamine, N-methyl-2- [3-(trifluoromethyl)phenyl]histamine, histaprodifen (2-[2-(3,3- diphenylpropyl)-1H-imidazol-4-yl]ethanamine), suprahistaprodifen (N-2- [(1H-imidazol-4-yl)ethyl]histaprodifen-(2-aminoethyl)imidazole (2-ImEA), or an H1 agonist synthesized from a new orientation or change to the imidazole ring, or combinations of these; o. an H3 antagonist or inverse agonist, such as A-960656, ABT-239, ABT-288, ABT-652, ABT-834, APD-916, AZD-5213, bavisant (BEN2001, JNJ1074, JNJ31001074), betahistine (AM125, AM201), BP1.3656, CEP-32215, cipralisant, ciproxifan, clobenpropit, DL-76, DL-77, E-100, E-162, enerisant, GR175737, GSK- 1004723, GSK-189254, GSK207040, GSK-239512, GSK- 334429, GSK-835726, GT-2016, HPP-404, irdabisant (CEP-26401), JNJ- 17216498, JNJ-39220675, JNJ5207852, LC-1405, LGD-3437, LML-134, MK-0249, MK-3134, MK-7288, PF-03654746, pitolisant (BF2649), S013- 1593, S-38093, samelisant (SUVN G3031), SAR-110894, SAR-152954, SCH- 497079, SLS-010, ST-1283, thioperamide, ZPL-868087, or combinations thereof

[0020] The invention further pertains to betahistine prodrugs intended to overcome the limitations associated with the parent drug, while maintaining or enhancing its therapeutic efficacy. The prodrugs, resulting from conjugation of betahistine with various functional groups or molecular structures, are designed to modify the pharmacokinetic profile of betahistine, providing significant improvements in terms of stability, absorption, and half-life.

[0021] One aspect of the invention relates to betahistine prodrugs of Formula I in which R1-R11are each hydrogen and the amine-substituent R12is other than hydrogen. The synthesis and use of prodrugs for amine-containing therapeutically-active compounds has been reviewed in the literature, see Simplício et al., “Prodrugs for amines,” Molecules, 13(3):519-47 (2008), incorporated by reference herein in its entirety.

[0022] Aspects of the present invention further relate to betahistine metabolites, prodrugs, and deuterated analogs to overcome the limitations associated with the parent drug. As used herein, the term “prodrug” refers to a derivative of betahistine that requires a transformation within the body to release betahistine. In some embodiments, the transformation is an enzymatic transformation. In other embodiments, the transformation is a cyclization transformation. In some other embodiments, the transformation is a combination of an enzymatic transformation and a cyclization reaction. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to betahistine. Betahistine prodrugs are designed as conjugates of betahistine and various functional groups or molecular structures, including, but not limited to, amino acids, esters, carbamates, carbonates, phosphoesters, sulfates, glucuronides, peptides, lipids, cyclic structures, self- immolative linkers, polymers, and nanoparticles. Additionally, the invention also includes co-drugs and multiple prodrugs, which represent more complex prodrug strategies. Thus, the present invention further relates to the design, synthesis, and application of prodrugs and analogs of betahistine.

[0023] The incorporation of deuterium atoms into the betahistine structure, replacing one or more hydrogen atoms with deuterium atoms, leads to the production of deuterated betahistine analogs within the scope of the invention.

[0024] Codrugs (or co-prodrugs) as used herein refers to a subclass of prodrugs. Codrugs consist of two pharmacologically active agents linked together, one of which is betahistidine, where each active agent acts as a promoiety for the other. When administered, the codrug is metabolized, typically through enzymatic or hydrolytic cleavage, to release the two active agents. The main advantage of codrugs is to the effects of two drugs, improve their pharmacokinetic profiles, reduce side effects, or enhance their solubility and / or stability. Codrugs can be designed for simultaneous delivery of the two active agents to the same biological site of action or to different sites, depending on the desired therapeutic outcome.

[0025] Multiple prodrug as used herein refers to a drug that is metabolically transformed into more than one pharmacologically active molecule. Essentially, one prodrug molecule can give rise to multiple active drug molecules upon metabolism.

[0026] Nanoparticle prodrugs as used herein refer to drug molecules that have been incorporated or encapsulated into nanoparticles to achieve controlled drug release, enhanced solubility, improved bioavailability, targeted drug delivery, and / or a combination of these. These nanoparticles can be composed of various materials such as lipids (liposomes), proteins, metals, or polymers, as is known in the art. The prodrug is usually transformed into its active form once it reaches its target site or in response to specific triggers like pH, enzymes, or other stimuli.

[0027] Prodrugs of betahistine are intended to modify the pharmacokinetics of the parent betahistine drug, enhance its stability, absorption, and half-life, thus reducing dosing frequency and improving patient adherence to treatment regimens. Further, by leveraging different prodrug strategies, these novel compounds mitigate the gastrointestinal side effects observed with betahistine, improving the overall safety and tolerability profile of the medication.

[0028] Optional substituents may be selected from alkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, halogen, and the like without limitation, as well as conjugates and functional groups, solubilizing groups, lipid groups, and the like for optimizing pharmacokinetic and other properties.

[0029] As used herein, unless otherwise noted, “alkyl” and / or “aliphatic” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g., C1-6) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like.

[0030] As used herein, “cycloalkyl,” whether used alone or as part of another group, refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and / or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionally substituted. Non-limiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4- hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro- 1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl. The term “cycloalkyl” also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0031] The term “aryl,” wherein used alone or as part of another group, is defined herein as an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Aryl rings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms. Non-limiting examples of aryl groups include: phenyl, naphthylen-1-yl, naphthylen-2-yl, 4- fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N- diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8- hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl, and 6-cyano-naphthylen-1- yl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5- trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and / or saturated or partially saturated rings.

[0032] The term “heteroaryl,” whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused rings, the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted. Non-limitingexamples of heteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4- dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3- d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl.

[0033] As used herein, when specific definition is not otherwise provided, the term "substituted" refers to a group substituted with deuterium, a halogen (-F, -Cl, -Br, -I), a hydroxy group (-OH), an amino group (-NH2), a carboxyl group (-CO2H), a substituted or unsubstituted C1-C10 amine group, a nitro group (-NO2), a C1-C10 alkyl group, a C3-C10 cycloalkyl group, a C6-C12 aryl group, a C1-C10 alkoxy group, a C1 to C10 trifluoroalkyl group such as a trifluoromethyl group (-CF3) and the like, or a cyano group (-CN) instead of at least one hydrogen of a substituting group or compound. Exemplary substituents include alkyl, alkylidenyl, alkylcarboxy, alkoxy, alkenyl, alkenylcarboxy, alkenyloxy, aryl, aryloxy, alkylaryl, alkylaryloxy, - OH, amide, carboxamide, carboxy, sulfonyl, =O, =S, -NO2, halogen, haloalkyl, fused saturated or unsaturated optionally substituted rings, -S(O)R, -SO3R, -SR, -NRR', - OH, -CN, -C(O)R, -OC(O)R, -NHC(O)R, -(CH2)nCO2R or -(CH2)nCONRR’ where n is 0-4, and wherein R and R’ are independently H, alkyl, aryl or alkylaryl. Substituents also include replacement of a carbon atom and one or more associated hydrogen atoms.

[0034] In an aspect, betahistine prodrugs of the invention are compounds of Formula I:wherein, R1-R4re each independently selected from hydrogen or deuterium; R5-R7are each independently selected from hydrogen or deuterium; R9-R11are each independently selected from hydrogen or deuterium; and R12is selected from hydrogen, deuterium, optionally-substituted alkyl, optionally- substituted aryl, -C(O)R13, -S(O)R13, -S(O)2R13, -C(O)OR13, -P(O)2OR13, - N(R13)(R14), wherein R13and R14are independently selected from hydrogen, optionally-substituted alkyl, or optionally-substituted aryl, provided that at least one of R1-R12is other than hydrogen or deuterium; and pharmaceutically acceptable salts thereof.

[0035] In one aspect of the invention, betahistine is conjugated to an amino acid, such that R12comprises at least one amino acid in the betahistine prodrug compound of Formula I.

[0036] In the betahistine prodrug compounds of Formula I, the at least one amino acid of R12is selected from glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, proline, serine, threonine, cysteine, asparagine, glutamine, arginine, histidine, lysine, aspartate (also known as aspartic acid), glutamate (also known as glutamic acid), selenocysteine, and pyrrolysine.

[0037] In the betahistine prodrug compounds of Formula I, R12may comprise a non- amino acid such as ornithine, taurine, citrulline, carnitine, creatine, gamma- aminobutyric acid (GABA), beta-alanine, hydroxyproline, 5-hydroxytryptophan, betaine, choline, inositol, anserine, carnosine, agmatine, sarcosine, polyamines (such as spermine and spermidine), alpha-ketoglutarate, NADH, and coenzyme Q10.

[0038] In the betahistine prodrug compounds of Formula I, R12may comprise an amino acid conjugated to an acetyl group, an ester group, an amino acid ester group, a carbamate group, a carbonate group, a phosphoester group, a glucuronide group, a peptide group, a lipid group, a cyclic group, a self-immolative linker group, a polymer group, and the like.

[0039] In the betahistine prodrug compounds of Formula I, when R12comprises an ester group, the ester group is preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl esters.

[0040] In the betahistine prodrug compounds of Formula I, when R12comprises an amino acid ester group, the amino acid ester group is preferably selected from alanine methyl ester, valine methyl ester, leucine methyl ester, isoleucine methyl ester, methionine methyl ester, phenylalanine methyl ester, tryptophan methyl ester, proline methyl ester, glycine methyl ester, serine methyl ester, threonine methyl ester, cysteine methyl ester, tyrosine methyl ester, asparagine methyl ester, glutamine methyl ester, aspartic acid methyl ester, glutamic acid methyl ester, lysine methyl ester, arginine methyl ester, or histidine methyl ester.

[0041] In the betahistine prodrug compounds of Formula I, when R12 comprises a carbamate ester group, the carbamate ester group is preferably selected from methyl carbamate, ethyl carbamate, propyl carbamate, isopropyl carbamate, butyl carbamate, sec-butyl carbamate, isobutyl carbamate, tert-butyl carbamate, pentyl carbamate, hexyl carbamate, cyclopentyl carbamate, cyclohexyl carbamate, benzyl carbamate, phenethyl carbamate, or phenyl carbamate.

[0042] In the betahistine prodrug compounds of Formula I, when R12comprises a carbonate ester group, the carbonate ester group is preferably selected from dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, diisobutyl carbonate, dipentyl carbonate, dihexyl carbonate, dicyclopentyl carbonate, dicyclohexyl carbonate, dibenzyl carbonate, diphenethyl carbonate, or diphenyl carbonate.

[0043] In the betahistine prodrug compounds of Formula I, when R12comprises a phosphoester group, the phosphoester group is preferably selected from dimethyl phosphite, diethyl phosphite, dipropyl phosphite, diisopropyl phosphite, dibutyl phosphite, diisobutyl phosphite, dipentyl phosphite, dihexyl phosphite, dicyclopentyl phosphite, dicyclohexyl phosphite, dibenzyl phosphite, diphenethyl phosphite, or diphenyl phosphite.

[0044] In the betahistine prodrug compounds of Formula I, when R12comprises a glucuronide group, the glucuronide group is preferably selected from β-D-glucuronic acid methyl ester, β-D-glucuronic acid ethyl ester, β-D-glucuronic acid propyl ester, β-D-glucuronic acid butyl ester, β-D-glucuronic acid pentyl ester, β-D-glucuronic acid hexyl ester, β-D-glucuronic acid heptyl ester, β-D-glucuronic acid octyl ester, β-D- glucuronic acid nonyl ester, β-D-glucuronic acid decyl ester, β-D-glucuronic acid undecyl ester, β-D-glucuronic acid dodecyl ester, β-D-glucuronic acid tridecyl ester, β-D-glucuronic acid tetradecyl ester, or β-D-glucuronic acid pentadecyl ester.

[0045] In the betahistine prodrug compounds of Formula I, when R12comprises a peptide group, the peptide group is preferably selected from glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and any possible di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca- peptide, or a combination of said amino acids.

[0046] In the betahistine prodrug compounds of Formula I, when R12comprises a lipid group, the lipid group is preferably selected from lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, montanic acid, melissic acid, palmitoleic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and all possible mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca-, and lipid combinations of said lipid groups.

[0047] In the betahistine prodrug compounds of Formula I, when R12comprises a cyclic group, the cyclic group is preferably selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, and all possible mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca- cyclic combinations of said cyclic groups.

[0048] In the betahistine prodrug compounds of Formula I, when R12comprises self- immolative linker group, the self-immolative linker group preferably selected from para-nitrobenzyl linkers, ortho-nitrobenzyl linkers, aromatic linkers, aliphatic linkers, heterocyclic linkers, carbamate linkers, carbonate linkers, amide linkers, urea linkers, thiourea linkers, ester linkers, thioester linkers, disulfide linkers, sulfonamide linkers, and all possible mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca- self-immolative linker combinations of said self-immolative linker groups.

[0049] In the betahistine prodrug compounds of Formula I, when R12comprises a polymer group, the polymer group preferably is selected from polyethylene glycol (PEG), polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), chitosan, hyaluronicacid, dextran, and all possible mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca- polymer combinations of said polymer groups.

[0050] Betahistine and its salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs, or stereoisomers may be incorporated into lipid nanoparticles, wherein the nanoparticle is selected from liposomes, micelles, dendrimers, nanotubes, nanoemulsions, nanospheres, nanoporous materials, quantum dots, nanoshells, nanocapsules, and all possible mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca- nanoparticle combinations of said nanoparticles.

[0051] The invention includes betahistine, and its salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs, or stereoisomers, in which betahistine is conjugated to or associated with a targeting moiety, the targeting moiety facilitating the delivery of the prodrug compound to the central nervous system (CNS). The targeting moiety is preferably selected from transferrin, lactoferrin, melanotransferrin, receptor-specific antibodies, receptor-specific peptides, receptor-specific proteins, receptor-specific aptamers, and all possible mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca- combinations of said targeting moieties.

[0052] The invention includes betahistine, its salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs, or stereoisomers, wherein betahistine is activated or released from the prodrug by enzymatic cleavage, the enzymatic cleavage facilitated by an enzyme selected from esterases, amidases, proteases, kinases, phosphatases, glycosidases, lipases, nucleases, and all possible mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca- combinations of said enzymes.

[0053] The invention includes betahistine, its salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs, or stereoisomers, wherein betahistine is conjugated with a caging group, the caging group being cleavable under certain conditions to release the active betahistine, the caging group preferably selected from nitrobenzylgroups, coumarinylmethyl groups, dimethoxybenzoinyl groups, bromohydroxyquinoline groups, 7-nitroindolinyl groups, and all possible mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca- caging group combinations.

[0054] The invention includes betahistine prodrugs, wherein betahistine is formulated as a peptide prodrug that includes a phosphate ester linked with an amino acid ester, said amino acid ester selected from alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, glycine, proline, histidine, arginine, lysine, aspartic acid, glutamic acid, and all possible mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca- combinations of said amino acid esters.

[0055] The invention includes betahistine, its salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs, or stereoisomers, wherein betahistine is formulated as a codrug in combination with another therapeutically active agent, said therapeutically active agent selected from monoamine oxidase inhibitor (MAO-I) such as selegiline, a combination of MAO-Is, histamine, a histamine analogue, a histamine derivative, L- Histidine, HTMT (histamine N-methyltransferase), or a histamine precursor or prodrug, glutamate-modulating agent such as memantine, N-acetyl cysteine, ketamine, D-cycloserine or a combination of these, among others.

[0056] The invention includes betahistine, its salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs, or stereoisomers, wherein betahistine is conjugated with one or more other betahistine prodrugs, each of said other prodrugs is selected from the group consisting of: ester prodrugs, amino acid esters, carbamate prodrugs, carbonate prodrugs, phosphoester prodrugs, sulfate conjugates, glucuronide conjugates, peptide conjugates, lipid conjugates, cyclic prodrugs, self-immolative linker prodrugs, polymer conjugates, nanoparticle prodrugs, codrugs, and all possible mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca- combinations of said additional prodrugs.

[0057] The range of prodrug classes considered in this invention includes ester prodrugs and amino acid esters, which are expected to improve the drug's bioavailability and stability. Carbamate prodrugs and carbonate prodrugs areincluded for their potential to offer controlled release properties, enhancing the duration of therapeutic effect.

[0058] Phosphoester prodrugs and sulfate conjugates are employed considering their potential to increase solubility and bioavailability, while glucuronide conjugates, which are commonly used in drug detoxification, are anticipated to assist in improving the safety profile of betahistine.

[0059] Peptide and lipid conjugates are envisaged to enhance cellular uptake and targeted delivery, while cyclic prodrugs could potentially offer enhanced stability and controlled release. Self-immolative linker prodrugs have the added benefit of releasing the active drug as well as a biologically active leaving group, which could provide synergistic effects. The invention also explores the development of polymer conjugates and prodrug nanoparticles, which can enhance solubility, control drug release, and improve targeted drug delivery. The scope of the invention also extends to the design of codrugs and multiple prodrugs, which enable the simultaneous delivery of two or more drugs, potentially offering synergistic therapeutic effects or mitigating side effects.

[0060] Each class of prodrugs under this invention has been designed to provide distinct advantages over the parent betahistine drug, including improvements in stability, solubility, absorption, and half-life, alongside reductions in side effects.

[0061] Moreover, the invention involves methods of synthesizing these prodrugs, and details pharmaceutical compositions comprising these prodrugs along with pharmaceutically acceptable carriers.

[0062] The present invention is useful for treating and / or reducing symptoms of OCD, as shown by a reduced Y-BOCS score, and for treating other OCRDs, as shown by reduction in corresponding symptom severity measurements.

[0063] The present invention is useful for treating and / or reducing symptoms of tic disorders by the reduction of tics, as shown by, e.g., the Yale Global Tic Severity scale.

[0064] The present invention is useful for treating and / or reducing symptoms of ALS as shown by, e.g., prolonged survival.

[0065] The present invention is useful for treating and / or reducing symptoms of glutamate excitotoxicity related diseases as shown by, e.g., prolonged survival.

[0066] The present invention is useful for treating and / or reducing symptoms of autism spectrum disorders as shown by a decrease in the Aberrant Behavior Scale(ABC) score or a decrease within one or more subscales within the ABC, including the Irritability, Hyperactivity, Lethargy / Withdrawal, Stereotypy, and Inappropriate Speech subscales.

[0067] The present invention is useful for treating and / or reducing symptoms of autism spectrum disorders as shown by a decrease in the Repetitive Behavior Scale(RBS) score or a decrease within one or more subscales within the RBS, including stereotypies, self-injurious behaviors, compulsions, rituals, insistence on sameness, and restricted behaviors subscales.

[0068] The following examples are set forth below to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions, and results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art. Background implicating histamine modulation of the basal ganglia in the pathophysiology of OCD and Tourette syndrome.

[0069] The past work on the pathophysiology of obsessive-compulsive disorder (OCD) has focused on the dysregulation of the basal ganglia system and on the neurotransmitters serotonin, dopamine, and glutamate, and on pharmacotherapeutic approaches that modulate them (Pittenger 2021). More recent studies have begun to examine the role of the histaminergic system in both OCD and Tourette syndrome (Rapanelli and Pittenger 2016, Pittenger 2020). Of note, OCD and Tourette syndrome often occur together, are genetically related, and both affect the same circuitry in the brain; thus, both clinicians and scientists studying pathophysiology often consider them together. This line of work stems from the finding of a rare mutation in the gene histidine decarboxylase (HDC), which is required for the biosynthesis of histamine, in a family with a high rate of both OCD and Tourette syndrome (Ercan-Sencicek, Stillman et al.2010). A mouse model recapitulating this genetic abnormality exhibits compulsion-like repetitive behaviors (see below for further discussion of mouse models of OCD and Tourette syndrome) (Baldan, Williams et al.2014). Ongoing work in mouse models has further elucidated the important role of histamine in themodulation of the basal ganglia system (Rapanelli, Frick et al.2016, Rapanelli, Frick et al.2017, Xu and Pittenger 2023), which is implicated in both OCD and Tourette syndrome, and the ability of manipulations of the histamine signaling to regulate compulsion and tic-like repetitive behaviors (Rapanelli, Frick et al.2017, Rapanelli, Frick et al.2017, Verma, Agrawal and Jain 2018, Zhang, Peng et al.2020). Preclinical evidence showing betahistine mitigates compulsion and tic-like stereotypic behavior in a mouse model.

[0070] Elevated grooming and other repetitive stereotypic behaviors have been used in a number of genetic and other model systems to capture compulsive behavior (Greer and Capecchi 2002, Welch, Lu et al.2007, Chen, Tvrdik et al.2010, Shmelkov, Hormigo et al.2010, Ahmari, Spellman et al.2013, Baldan, Williams et al. 2014, Xu, Li et al.2015, Zike, Chohan et al.2017, Nagarajan, Jones et al.2018, Ahmed, Jayakumar et al.2019, Escobar, Martinez-Pinto et al.2021, Parolari, Schneeberger et al.2021). OCD and Tourette syndrome are worsened in patients by amphetamine (Shakeri, Farnia et al.2016); similarly, compulsive grooming and stereotypy are enhanced in mice by amphetamine challenge, a fact that has been used in analysis of several mouse models of OCD and Tourette syndrome (Baldan, Williams et al.2014, Zike, Chohan et al.2017, Escobar, Martinez-Pinto et al.2021). In the HDC mutant model of OCD and Tourette syndrome, compulsion-like repetitive grooming is seen after amphetamine challenge and is mitigated by experimental repletion of histamine, demonstrating the utility of the amphetamine challenge model for capturing neural and behavioral events of relevance to OCD in a mouse system (Baldan, Williams et al.2014).

[0071] This model system was used to test the ability of betahistine to mitigate compulsion and tic-like behaviors in two experiments in mice. EXAMPLE 1

[0072] In a first experiment, male and female C57Bl / 6 mice were injected with either saline or betahistine dihydrochloride (1 mg / kg or 10 mg / kg) 30 minutes before being injected with either saline or amphetamine (8.5 mg / kg). Activity and stereotypy were measured in an open field apparatus that distinguishes between these two categories of movement by discriminating the associated patterns of infrared beam-breaks, as inprevious studies using a similar approach (Xu, Kobets et al.2015, Xu, Li and Pittenger 2016, Rapanelli, Frick et al.2017). Amphetamine injection is predicted to produce more locomotor behavior in the first 30 minutes after injection and more compulsion-like stereotypy in the second 30 minutes. Anti-OCD pharmacotherapies are predicted to reduce stereotypy.

[0073] As shown in FIG.1A, amphetamine led to increased ambulatory activity accounts (i.e. locomotor activation), which was not significantly reduced by betahistine pretreatment. (Experimental groups: Sal / Sal = saline pretreatment, saline challenge; Sal / Amp = saline pretreatment, amphetamine challenge; BH1 / Amp = betahistine pretreatment 1 mg / kg, amphetamine challenge; BH10 / Amp = betahistine pretreatment 10 mg / kg, amphetamine challenge. (Statistical analysis: 1-way ANOVA, F[3,20] = 6.14, p = 0.004; post-amphetamine treatment groups different from saline at ** p < 0.01 or * p < 0.05; pairwise post-hoc comparisons; betahistine pretreatment groups did not differ from saline / amphetamine group.)

[0074] As shown in FIG.1B, this effect was, as predicted, limited to the first 30 minutes after injection and was not seen in the second 30 minutes. (Statistical analysis: 4 x 2 between / within mixed ANOVA, time x treatment group interaction, F[3,20] = 26.3, p < 0.0001; pairwise post-hoc comparisons, all amphetamine-treated groups significantly different from saline-treated control (green) in the first 30 minutes at ** p < 0.01 or **** p < 0.0001.) Thus, amphetamine produces increased locomotion in the 30 minutes following injection, and this is not altered by betahistine pretreatment – betahistine does not simply block amphetamine’s effects. This observation is key to the interpretation of the stereotypy measure.

[0075] As shown in Figure 1C, amphetamine challenge with saline pretreatment led to a marked and statistically significant increase in stereotypy; this was completely blocked by betahistine pretreatment. (Statistical analysis: 1-way ANOVA: F[3,20] = 10.4, p = 0.0002; post-hoc pairwise comparisons, saline / amphetamine different from saline / saline, p < 0.001; betahistine pretreatment groups different from saline / amphetamine, p < 0.01.)

[0076] As shown in figure 1D, and as predicted, stereotypy was seen primarily 30-60 minutes following amphetamine challenge; the same effects were seen in analysis across both time periods, with marked stereotypy in the saline / amphetamine group that was completely blocked by betahistine pretreatment. (Statistical analysis: 4 x 2 between / within mixed ANOVA, time x treatment group interaction, F[3,20] = 2.47, p= 0.091; pairwise post-hoc comparisons, sal / amphetamine significantly greater than sal / sal, p < 0.001; betahistine pretreatment groups significantly less than sal / amphetamine, p < 0.001). Thus, betahistine blocks the development of compulsion-like stereotypy after amphetamine challenge, without producing generalized sedation. This supports the utility of betahistine as a potential treatment for OCD (and for Tourette syndrome). EXAMPLE 2

[0077] In a second experiment, the amphetamine challenge was repeated, with or without betahistine dihydrochloride pretreatment, and the mice videotaped during the subsequent hour. Videos were analyzed using an automated motion capture system (Cleversys HomeCageScan) to quantify locomotor activity and grooming. Previous work shows the grooming measure in this system to correlate with manual scoring of grooming from video by a skilled observer, validating this measure of mouse grooming (Xu, Kobets et al.2015); elevated mouse grooming has been validated as a model of OCD in multiple past studies (Greer and Capecchi 2002, Welch, Lu et al. 2007, Chen, Tvrdik et al.2010, Shmelkov, Hormigo et al.2010, Xu, Li et al.2015).

[0078] As shown in Figure 2A, locomotor activation after amphetamine was limited in the HomeCageScan environment, which is less precise in its measurement of locomotion than the open field apparatus used in Example 1. (Statistics: 1-way ANOVA, F[3,20] = 1.24, p = 0.32). Figure 2B shows that, as in Example 1, increased locomotion was more clearly apparent in the first 30 minutes following amphetamine challenge; this was not altered by betahistine pretreatment at either 1 mg / kg or 10 mg / kg. (Statistical analysis: 4 x 2 mixed between-within ANOVA, time x treatment group interaction, F[3,20] = 10.1, p = 0.0003; pairwise post-hoc comparisons, all amphetamine- treated groups significantly different from sal / sal group at ** p < 0.01 or *** p < 0.001 in the first 30 minutes following amphetamine, with no effect of betahistine pretreatment.) Thus, as in Example 1, amphetamine induces increased locomotion, and betahistine does not nonspecifically block amphetamine’s effects or cause general sedation.

[0079] As shown in Figure 2C, amphetamine challenge led to increased grooming; this was mitigated by pretreatment with betahistine 10 mg / kg, but not 1 mg / kg, indicating a dose-response relationship. (Statistical analysis: 1-way ANOVA, F[3,20]= 6.53, p = 0.0003; pairwise post-hoc comparisons, sal / amphetamine and BH1 / amphetamine groups showed more grooming than sal / sal, p < 0.05; BH10 / amphetamine showed reduced grooming relative to both sal / amphetamine and BH1 / amphetamine, p < 0.05.)

[0080] Grooming was elevated specifically in the second 30 minutes following injection, like stereotypy in the experiment shown in Figure 1, and this effect was blocked by betahistine pretreatment at the 10 mg / kg dose; again, the effect of 1 mg / kg betahistine pretreatment was limited and not statistically significant. (Statistical analysis: 4 x 2 mixed between-within ANOVA, main effect of group, F[3,20] = 7.3, p = 0.003; pairwise post-hoc comparisons, sal / amphetamine group vs sal / sal group in the second 30 minutes, p < 0.01; BH10 / amphetamine group vs sal / amphetamine group in the second 30 minutes, p < 0.05). Thus, betahistine pretreatment at 10 mg / kg blocks the induction of compulsive grooming produced by amphetamine challenge, without producing nonspecific sedation. Clinical response to betahistine in an individual with treatment-refractory OCD. EXAMPLE 3

[0081] We describe the case of an individual with treatment-refractory OCD who showed marked improvement following treatment with betahistine dihydrochloride. What follows is a clinical description of his case and clinical course by a treating psychotherapist.

[0082] The patient is a male in his late twenties, diagnosed with OCD in his early teen years. During initial consultation he exhibited significant functional impairment in daily activities, characterized by recurrent, intrusive thoughts and repetitive compulsive behaviors. Past treatments had included pharmacotherapy using SSRIs and second-generation neuroleptics, with little improvement; pharmacotherapy had been discontinued due to lack of benefit and problematic side effects including emotional blunting, mental fog, hyperprolactinemia, and weight gain. Symptom severity was not assessed using standardized clinical measures but was judged to be in the severe range.

[0083] The patient was administered betahistine dihydrochloride (16 mg 2x / day for 2 weeks) by a neurologist for treatment of trauma-induced vertigo. OCD symptoms were noted to be markedly improved, but they returned within days of discontinuationof betahistine. Betahistine treatment was reinstituted at a lower dose (8 mg daily, then 8 mg twice daily) and symptoms were again markedly reduced. This treatment has now been continued for several years, with ongoing benefit, including reduced frequency and intensity of compulsive behaviors and obsessive thoughts. On several occasions when betahistine has been discontinued, symptoms have recurred; when betahistine has been reinstituted, symptoms again improved. This improvement in symptoms has been paralleled by improved function in occupational and social domains, as evidenced by a ~20% improvement in university grades and improved ability to maintain social and romantic relationships.

[0084] This sustained improvement in function is shown in FIG.3, which illustrates medical school grades before and after treatment with betahistine. Medical school grades where this subject was in school over this period are numerical on a scale from 1-20. For the 8 semesters prior to taking betahistine, grades ranged from 12.31 to 14.81 (mean 13.5, standard deviation 0.73). For the 4 semesters following initiation of betahistine treatment, grades ranged from 16.04 through 17.49 (mean 16.9, standard deviation 0.65). This difference was highly statistically significant (2-tailed independent sample t-test: p < 0.0001).

[0085] Throughout this application, various publications are referenced by author name and date, or by patent number or patent publication number. The disclosures of these publications are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an acknowledgement that such reference is prior art to the present invention.

[0086] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and Examples herein can be employed. Furthermore, it is intended that specific items within lists of items, or subset groups of items within larger groups of items, can be combined with other specific items, subset groups of items or larger groups of items whether or not there is a specific disclosure herein identifying such a combination.REFERENCES

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Claims

CLAIMS 1. A method of treating an obsessive-compulsive related disorder (OCRD), comprising administering to a subject in need thereof, a therapeutically effective amount of betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof.

2. The method according to claim 1, wherein the OCRD is selected from the group consisting of obsessive-compulsive disorder (OCD), hoarding disorder, trichotillomania (hair-pulling disorder), excoriation (skin-picking) disorder, body dysmorphic disorder, substance / medication-induced obsessive-compulsive and related disorder, obsessive-compulsive disorder due to another medical condition.

3. The method according to claim 2, wherein the OCRD is obsessive compulsive disorder (OCD).

4. A method of treating Tourette’s Syndrome, comprising administering to a subject in need thereof, a therapeutically effective amount of betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof.

5. A method of treating an obsessive-compulsive related disorder OCRD in a human, comprising orally administering to a human in need of such treatment an effective amount of an H1R agonist and / or an H3R antagonist, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

6. A method of treating glutamate excitotoxicity related disorders in a human, comprising orally administering to a human in need of such treatment an effective amount of an H1R agonist and / or an H3R antagonist, or a pharmaceutically acceptable salt, metabolite, or prodrug thereof.

7. A method of treating autism spectrum disorder in a human, comprising orally administering to a human in need of such treatment an effective amount of an H1R agonist, or an H1R agonist in combination with an H3R antagonist, or a pharmaceutically acceptable salt, metabolite, or prodrug thereof 8. A method of treating glutamate excitotoxicity related disorders, comprising administering to a subject in need thereof, a therapeutically effective amount of betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal,modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof.

9. The method according to claim 8, wherein the glutamate excitotoxicity related disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), Parkinson’s disease, traumatic brain injury, concussion, or post-concussion syndrome, cerebral infarction or stroke, multiple sclerosis, Huntington’s disease, schizophrenia, seizure, epilepsy, epileptic syndrome, status epilepticus, refractory focal epilepsy, autoimmune encephalitis, infectious encephalitis, viral encephalitis, acute disseminated encephalomyelitis, or mitochondrial encephalitis.

10. A method of treating tic disorders, comprising administering to a subject in need thereof, a therapeutically effective amount of betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof.

11. The method according to claim 10, wherein the tic disorder is selected from the group consisting of Tourette’s Syndrome or Tourette’s Disorder, chronic motor tic disorder, chronic vocal tic disorder, transient tic disorder, and substance-induced tic disorder.

12. A method of treating autism spectrum disorder (ASD) in a human, comprising orally administering to a human in need of such treatment an effective amount of betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof.

13. The method according to any of claims 1-12, wherein betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof is administered in combination with one or more other therapeutically active compounds.

14. The method according to claim 13, wherein the other therapeutically active compound is selected from the group consisting of a monoamine oxidase inhibitor (MAO-I), a serotonin / norepinephrine dual reuptake inhibitor (SNRI), an antidepressant, a glutamate-modulating agent, a benzothiazole or benzothiazole derivative, a serotonin reuptake inhibitor (SRI), a skeletal muscle relaxant, an antipsychotic agent, an antidepressant, an anticholinergic, an anticonvulsant, and a benzodiazepine or benzodiazepine derivative, or a combination thereof.

15. The method according to any of claims 1-14, wherein said betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof is administered orally, intravenously, sublingually, buccally, transdermally, or intranasally.

16. The method according to claim 15, wherein said betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof is administered orally.

17. The method according to any of claims 1-16, wherein said betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof is administered in combination with a neuromodulation technique selected from the group consisting of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation(TMS), deep brain stimulation (DBS) or a combination thereof.

18. The method according to any of claims 1-17, wherein said betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof is selected from the group consisting of betahistine dihydrochloride, betahistine mesylate, a deuterated betahistine, and a betahistine prodrug.

19. The method according to any of claims 1-18, wherein said betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof is administered once per day, twice per day, three times per day, or more than three times per day.

20. The method according to any of claims 1-19, wherein said betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof is administered less than once daily.

21. The method according to any of claims 1-20, wherein said betahistine or a pharmaceutically acceptable pro-drug, derivative, metabolite, co-crystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph orstereoisomer thereof is administered such that the total weekly dose is at from 50-2,000 mg.

22. The method according to any of claims 1-21, comprising administering a compound of Formula I: wherein,R1-R4re each independently selected from hydrogen or deuterium; R5-R7are each independently selected from hydrogen or deuterium; R9-R11are each independently selected from hydrogen or deuterium; and R12is selected from hydrogen, deuterium, optionally-substituted alkyl, optionally- substituted aryl, -C(O)R13, -S(O)R13, -S(O)2R13, -C(O)OR13, -P(O)2OR13, - N(R13)(R14), wherein R13and R14are independently selected from hydrogen, optionally-substituted alkyl, or optionally-substituted aryl, provided that at least one of R1-R12 is other than hydrogen or deuterium; and pharmaceutically acceptable salts thereof.

23. The method according to any of claims 5-7, 9 or 22, wherein said H1R agonist is selected from the group consisting of methylhistaprodifen, dimethylhistaprodifen, 2- thiazolylethylamine, 2-pyridylethylamine, suprahistaprodifen.2-(2-aminoethyl)pyridine (2-PyEA), a 2-phenylhistamine, such as 2-[3-(trifluoromethyl)phenyl]histamine, 2-(3- chlorophenyl)histamine, N-methyl-2-[3-(trifluoromethyl)phenyl]histamine, histaprodifen (2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine), suprahistaprodifen (N-2-[(1H- imidazol-4-yl)ethyl]histaprodifen-(2-aminoethyl)imidazole (2-ImEA), an H1 agonist synthesized from a new orientation or change to the imidazole ring, and said H3R antagonist is selected from the group consisting of A-960656, ABT-239, ABT-288, ABT- 652, ABT-834, APD-916, AZD-5213, bavisant (BEN2001, JNJ1074, JNJ31001074),betahistine (AM125, AM201), BP1.3656, CEP-32215, cipralisant, ciproxifan, clobenpropit, DL-76, DL-77, E-100, E-162, enerisant, GR175737, GSK- 1004723, GSK- 189254, GSK207040, GSK-239512, GSK-334429, GSK-835726, GT-2016, HPP-404, irdabisant (CEP-26401), JNJ-17216498, JNJ-39220675, JNJ5207852, LC-1405, LGD- 3437, LML-134, MK-0249, MK-3134, MK-7288, PF-03654746, pitolisant (BF2649), S013-1593, S-38093, samelisant (SUVN G3031), SAR-110894, SAR-152954, SCH- 497079, SLS-010, ST-1283, thioperamide, ZPL-868087, and pharmaceutically acceptable salts, metabolites, and prodrugs thereof.

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