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

Abstract

The present invention is directed to the treatment of obsessive-compulsive disorder (OCD) and OCD-related disorders (including body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), skin picking disorder, substance / medication-induced obsessive-compulsive disorder and related disorders, obsessive-compulsive disorder and related disorders due to another medical condition, and other specified and unspecified obsessive-compulsive disorder and related disorders), tic disorders including Tourette's syndrome, autism spectrum disorder (ASD), and amyotrophic lateral sclerosis (ALS), Parkinson's disease, traumatic brain injury, Provided is a method for treating glutamate excitotoxicity-related disorders, including multiple sclerosis, Huntington's disease, and schizophrenia, comprising administering an effective amount of a histamine type 1 receptor agonist and / or a histamine type 3 receptor antagonist, such as betahistine or a pharmaceutically acceptable salt, analog, metabolite, prodrug, derivative, metabolite, cocrystal, modification, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof.

Description

[Technical Field]

[0001] The present invention relates to the use of a histamine H1 receptor agonist and / or a histamine receptor H3 antagonist, such as betahistine, or a pharmaceutically acceptable salt, analog, metabolite, prodrug, derivative, metabolite, co-crystal, modification, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof, for the treatment of obsessive-compulsive related disorders (OCRD), including obsessive-compulsive disorder (OCD), tic disorders, including Tourette's syndrome, autism spectrum disorder (ASD), and glutamate excitotoxicity-related disorders, including amyotrophic lateral sclerosis (ALS). [Background technology]

[0002] Obsessive-compulsive disorder (OCD) is a chronic and highly debilitating neuropsychiatric disorder characterized by compulsions and / or obsessions. Obsessions are intrusive, irrational or clearly excessive, distressing, difficult to control, and stereotyped or repetitive thoughts, sensations, or images. Compulsions (sometimes called rituals) are irrational or clearly excessive, difficult to control, and often repetitive behaviors that individuals typically feel compelled to perform in response to those obsessions.

[0003] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) classifies OCD as an obsessive-compulsive and related disorders (OCRD), alongside hoarding disorder, body dysmorphic disorder, trichotillomania (hair pulling disorder), and skin picking disorder. Although OCD is often represented in popular culture as an amusing personal quirk, in reality it is a source of great distress, profoundly affecting quality of life, reducing sufferers' ability to maintain relationships, and impairing 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% of treatment-seeking individuals with OCD have comorbidities, which also vary by gender. In women, eating disorders, anxiety, and depression are the most common comorbidities, while in men, attention-deficit / hyperactivity disorder, autism, and psychiatric and developmental disorders are most common. Any comorbidity in OCD is associated with higher levels of anxiety and depressive symptoms, including suicidal behavior.

[0005] The physiopathology of OCD is complex and has been linked to genetic, infectious / autoimmune, endocrine, postnatal, and postischemic factors. Abnormalities in the cortico-striato-thalamo-cortical circuit (CSTC), which controls habit formation, reward, and behavioral execution, have been repeatedly demonstrated. The neurotransmitter glutamate is prominent in this circuit, and converging evidence suggests that glutamate abnormalities may contribute to the pathophysiology of OCD, and glutamate-modulating drugs are under investigation as potential therapeutic agents.

[0006] General principles of OCD management include specialized cognitive behavioral therapy (CBT), which has consistently been demonstrated to improve OCD symptomatology, and selective serotonin reuptake inhibitors (SSRIs), which are the pharmacotherapy of choice due to their relative safety and effectiveness. SSRIs are typically used at much higher doses than for major depression, which are associated with increased adverse effects and, therefore, increased withdrawal rates.

[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, while others improve and are classified as treatment responders in studies but continue to experience disabling symptoms. Available medications are limited by side effects (especially when second-line agents such as clomipramine or drug combinations, such as the addition of neuroleptics, are used after SSRI non-response). Specialized CBT is limited by the apparently insufficient availability of healthcare providers skilled in these effective treatment techniques.

[0008] Due to the nature of its symptoms and the lack of effective treatment, OCD remains a significant societal burden, and improved treatment methods remain needed. Compared with healthy individuals, OCD patients experience a decline in quality of life comparable to that of patients with schizophrenia. In the World Health Organization's Global Burden of Disease 2004 Update, OCD accounted for more disability-adjusted life years (years lost due to disability) than multiple sclerosis and Parkinson's disease combined.

[0009] Histamine is an important neurotransmitter and modulator in the central nervous system, but its role has not been studied as intensively as other regulatory neurotransmitters, such as serotonin. Histaminergic neurons are found exclusively in the posterior tuberomammillary nucleus of the hypothalamus, but project widely throughout the brain. The enzyme histidine decarboxylase (Hdc) is essential for producing histamine, which is synthesized from the amino acid L-histidine by decarboxylation. Nonsense mutations in the Hdc gene have been detected as a rare but highly penetrant cause of Tourette syndrome (TS), which is accompanied by comorbid OCD, in approximately half of identified cases. Further genetic and preclinical studies support the causal role of histamine signaling dysfunction in these conditions. Pharmacological testing of histaminergic agents in OCD and TS is limited.

[0010] There are four histamine receptors. The histamine 1 receptor (H1R) couples to phospholipase C signaling via the Gαq / 11 protein. H1R is present in cerebrovascular and on neurons and glial cells in many brain regions. H1R activation in astrocytes increases intracellular Ca2+, thereby helping to maintain synaptic homeostasis, including extracellular Ca2+ uptake, which affects Ca2+-dependent signaling.

[0011] H3 receptors (H3Rs) are thought to be exclusively expressed on neurons within the central nervous system. They are present presynaptically at the axon terminals of neurons. They couple to signaling via Gαi proteins, thus reducing cyclic AMP (cAMP) signaling. Activation of presynaptic H3Rs reduces neurotransmitter release, including histamine itself (thus constituting a negative feedback mechanism), as well as glutamate, dopamine, and other transmitters. More recently, it has been recognized that many of the H3Rs in the striatum, a major input nucleus for the CSTC circuitry involved in OCD, are postsynaptic, interacting in complex ways with dopamine signaling. H3Rs are most strongly expressed in the hypothalamus, basal ganglia, hippocampus, and cerebral cortex, a pattern that overlaps with structures involved in OCD physiopathology.

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

[0013] Glutamate excitotoxicity is observed 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 the resulting disruption of glutamate homeostasis may contribute to this excitotoxicity. Chronic exposure to excess extracellular glutamate increases neuronal susceptibility to excitotoxic cell death.

[0014] Additionally, glutamate plays a critical 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 involved in ASD, such as the prefrontal cortex and limbic system. Dysregulation of glutamate transmission can affect various aspects of neurodevelopment, including synaptic plasticity, neuronal migration, and circuit formation, all of which are crucial for normal brain function. Therefore, increasing glutamate clearance is a viable approach for several conditions.

[0015] Betahistine is used in the therapeutic management of vertigo and Meniere's disease. It works by increasing blood flow in the stapedial artery of the inner ear, thereby reducing vestibular pressure and alleviating symptoms such as vertigo and tinnitus. However, its clinical use is not unlimited. Its relatively short half-life requires multiple daily administration, which may cause gastrointestinal side effects in certain patients. Summary of the Invention [Problem to be solved by the invention]

[0016] Various aspects of the present invention address the above-mentioned challenges. [Means for solving the problem]

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

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

[0019] In another embodiment, there is provided 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 H3R antagonist, or a pharmaceutically acceptable salt, metabolite, or prodrug thereof.

[0020] In another embodiment, there is provided 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 prodrug, derivative, metabolite, cocrystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof.

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

[0022] In another embodiment, there is provided a method of treating autism spectrum disorder (ASD) in a human, the method comprising orally administering to a human in need of such treatment an effective amount of betahistine or a pharmaceutically acceptable prodrug, 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 assist those skilled in the art in practicing the present invention. Exemplary embodiments are described in detail below. However, these embodiments are merely exemplary, and the present disclosure is not limited thereto, but rather is defined by the appended claims. Those skilled 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 those skilled in the art to which this disclosure belongs.The terms used in the description are only for describing specific embodiments and are not intended to be limiting.Terms such as those defined in commonly used dictionaries should be interpreted to have meanings consistent with their meanings in the context of the relevant technical field and this disclosure, and it is further understood that unless explicitly defined in this specification, they should not be interpreted in an ideal or overly formal sense.

[0025] As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning indicated below. Additional definitions are provided throughout this application. If a term is not specifically defined herein, the term will be given its art-recognized meaning by those of ordinary skill in the art applying the term, given the context of its use in describing the present invention.

[0026] The articles "a," "an," and "an" refer to one or to more than one (i.e., to at least one) of its grammatical object 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 described below by reference to structures and schemes solely to illustrate the 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." Phrases such as "at least one of," when preceding a list of elements, modify the entire list of elements and not individual elements of the list.

[0028] The terms "comprise" and / or "comprising" or "include" and / or "including", as used herein, specify the presence of stated substituents, groups, features, regions, integers, steps, operations, elements and / or components, but are understood not to exclude the presence or addition of one or more other substituents, groups, features, regions, integers, steps, operations, elements, components and / or groups thereof.

[0029] The methods, compounds, and systems of the present invention are not limited to the particular methods, compounds, components, or compositions described or exemplified herein, and it is also to be understood that the terminology used herein is for the purpose of description and not intended to be limiting.

[0030] Betahistine is a histamine analogue discovered in the 1970s. It is widely used as an antidizziness 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 was revoked due to concerns about its effectiveness in treating Meniere's disease. The FDA has since concluded that while there is no evidence that betahistine is unsafe, there is insufficient evidence to conclude that it has a therapeutic effect on Meniere's disease. Therefore, it has remained unavailable in the United States for decades.

[0031] Betahistine is a weak histamine H1R agonist and a strong H3R antagonist. Therefore, it can affect processes related to OCD, OCRD, and TS in multiple ways: by disinhibiting histamine release (thus alleviating the histamine reduction seen in individuals with mutations in the Hdc gene); by direct action on neurons in the CSTC circuit, including in the striatum; by modulating glial cell activity and function; and by regulating cerebral blood flow. It has been proposed that betahistine's action on blood vessels within the cochlea mediates its effects in Meniere's disease, but again, evidence of benefit in controlled trials is equivocal, and it has not been approved by the US FDA for this or any other indication.

[0032] 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 astroglial glutamate transporters, particularly GLT-1 (also known as excitatory amino acid transporter 2 or EAAT2). Once transported into astrocytes, glutamate is converted to glutamine by the enzyme glutamine synthetase (GS). GLT-1 is responsible for the majority of glutamate reuptake (up to 90% in mechanistic studies in mice). H1R activation upregulates both GLT-1 and GS, which enhances glutamate uptake and metabolism, reducing the amount of glutamate in the synaptic cleft. Without limiting the present invention, it is hypothesized that enhanced glutamate reuptake may be an additional mechanism by which betahistine and similar drugs may reduce symptoms in OCD patients.

[0033] Of note, other drugs that enhance glutamate reuptake, such as riluzole, are under investigation for the treatment of OCD. Riluzole is currently the only FDA-approved drug for the treatment of ALS. H1 agonism upregulates both GLT-1 (as riluzole does) and GS (as riluzole does not), producing a synergistic effect that may result in enhanced effects on glutamate reuptake compared to riluzole.

[0034] H3R antagonists have recently been seen as promising drug targets for cognitive disorders due to their several cognitive-promoting effects, including increased alertness, attention, and learning and memory. They have been shown to increase wakefulness and slow-wave sleep (SWS) while reducing rapid eye movement (REM). In addition to increasing histamine release, H3R antagonists also increase the release of norepinephrine, dopamine, and acetylcholine.

[0035] Betahistine or its pharmaceutically acceptable salts, analogs, metabolites, prodrugs, derivatives, metabolites, cocrystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs or stereoisomers can be administered according to various dosage regimens.For example, betahistine or its pharmaceutically acceptable salts, metabolites and prodrugs can be administered once a day, twice a day, three times a day, or more than three times a day.In some cases, betahistine or its pharmaceutically acceptable salts, metabolites and prodrugs can be administered less than once a day, for example, once every 2 days, once every 3 days, once every 5 days, once every 7 days, once every 10 days, once every 14 days, once every 28 days, or once every month.

[0036] Betahistine, or a pharmaceutically acceptable salt, analog, metabolite, prodrug, derivative, metabolite, cocrystal, modification, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof, can be administered to provide a total weekly dose of 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 cases, the total weekly dose may be 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.

[0037] Dosage regimens include adult doses of 24-48 mg administered over several doses per day, such as, but not limited to, 16 mg betahistine every 8 hours (e.g., via tablet), preferably taken after meals for the first two weeks. Thereafter, an acceptable maintenance dose is 8 mg betahistine every 8 hours. Other dosing regimens within the scope of the present invention include protocols of 32 mg betahistine (e.g., orally) every 8 hours as monotherapy. Another dosing regimen within the scope of the present invention is 32 mg betahistine (e.g., orally) every 8 hours in combination with 50 mg riluzole (e.g., orally) every 12 hours.

[0038] For treating OCD according to the present invention, betahistine, or a pharmaceutically acceptable salt, analog, metabolite, prodrug, derivative, metabolite, co-crystal, modification, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof, may be used in combination with one or more serotonin reuptake inhibitors, including, but not limited to, fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram, citalopram, clomipramine, venlafaxine, mirtazapine, among others. The drug may be administered in combination with one or more other medications, including, but not limited to, one or more monoamine oxidase inhibitors (SRIs), one or more monoamine oxidase inhibitors (MAOIs) including, but not limited to, d-amphetamine, glutamate modulators (such as memantine, N-acetylcysteine, and ketamine, among others), pregabalin, topiramate, lamotrigine, clonazepam and other benzodiazepines, lithium, buspirone, psilocybin, or carbamazepine.

[0039] Riluzole is being investigated as an add-on treatment for refractory OCD. The mechanism thought to cause the therapeutic effect is GLT-1 upregulation, which is shared by H1 agonism in rat models, which also increases GS upregulation. Without being bound to any specific mechanism of action, betahistine in combination with riluzole may cause an increase in glutamate clearance, which in turn reduces OCD symptoms.

[0040] The combination of MAO-I and betahistine in rat models has shown an enhancement of H1 agonism at the lowest betahistine dose, as evidenced by increased cochlear blood flow, a manifestation of H1 agonism. H1 agonism then leads to increased GS and GLT-1 upregulation, as previously mentioned, and a reduction in OCD symptoms and / or glutamate excitotoxicity.

[0041] Betahistine, or a pharmaceutically acceptable salt, analog, metabolite, prodrug, derivative, metabolite, co-crystal, modification, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof, may also be used to treat OCD according to the present invention in combination with neuromodulation techniques such as tDCS, TMS, VNS, DBS, among others.

[0042] To treat ALS according to the present invention, betahistine, or a pharmaceutically acceptable salt, analog, metabolite, prodrug, derivative, metabolite, co-crystal, modification, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof, may be administered in combination with one or more other pharmaceutical agents, including, but not limited to, riluzole, baclofen, diazepam, gabapentin, trihexyphenidyl, and amitriptyline.

[0043] Riluzole is approved by the US FDA for the treatment of ALS and is thought to reduce excitotoxicity. The mechanism underlying its therapeutic effect is thought to be its increased glutamate clearance, which is mediated by GLT-1 upregulation. This is shared by betahistine and other H1R agonists, except that they also upregulate GS, which is predicted to further increase glutamate clearance through a collective effect.

[0044] To treat Parkinson's disease according to the present invention, betahistine, or a pharmaceutically acceptable salt, analog, metabolite, prodrug, derivative, metabolite, co-crystal, modification, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof, may be administered in combination with one or more other pharmaceutical agents, including, but not limited to, dopamine agonists such as levodopa, carbidopa, and especially cabergoline, MAO-B inhibitors, COMT inhibitors, amantadine, especially trihexyphenidyl, benztropine, orphenadrine, procyclidine, and anticholinergics such as biperiden.

[0045] To treat a tic disorder according to the present invention, betahistine, or a pharmaceutically acceptable salt, analog, metabolite, prodrug, derivative, metabolite, co-crystal, modification, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof, may be administered in combination with one or more other pharmaceutical agents, including, but not limited to, first-, second-, or third-generation antipsychotics, tetrabenazine, and topiramate.

[0046] For the treatment of autism spectrum disorder (ASD) according to the present invention, an effective amount of an H1R agonist and / or H3R antagonist, such as betahistine, or a pharmaceutically acceptable salt, analog, metabolite, prodrug, derivative, metabolite, co-crystal, modification, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof, may be administered in combination with one or more other pharmaceutical agents.

[0047] The combination for use in the method of the present invention comprises: Monoamine oxidase inhibitors (MAO-Is), such as selegiline; b. Benzothiazoles or derivatives such as riluzole, pramipexole, troliluzole or combinations thereof; c. Skeletal muscle relaxants such as baclofen, dantrolene, or a combination thereof; d. Benzodiazepines such as diazepam, clonazepam or a combination thereof; e. Anticonvulsants 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 thereof; f. Anticholinergic drugs such as trihexyphenidyl, benztropine, orphenadrine, procyclidine, biperiden, or a combination thereof; g. Tricyclic, tetracyclic, or other antidepressants, such as amitriptyline and mirtazapine, h. First-generation antipsychotics, second-generation antipsychotics, third-generation antipsychotics, such as risperidone, aripiprazole, or a combination thereof; i. Tetrabenazine or topiramate, j. glutamate modulators such as memantine, N-acetylcysteine, ketamine, D-cycloserine, or combinations thereof; k. Serotonin reuptake inhibitors (SRIs) such as clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, or combinations thereof; l. Psychostimulants such as clonidine, guanfacine, methylphenidate, or a combination thereof, atomoxetine, or alpha-2 receptor blockers, m. histamine analogs, histamine derivatives, L-histidine, HTMT (histamine N-methyltransferase), or histamine precursors or prodrugs; n. H1 agonists such as methylhistaprodifen, dimethylhistaprodifen, 2-thiazolylethylamine, 2-pyridylethylamine, suprahistaprodifen, 2-(2-aminoethyl)pyridine (2-PyEA), 2-[3-(trifluoromethyl)phenyl]histamine, 2-(3-chlorophenyl)histamine, 2-phenylhistamine such as 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 H1 agonists synthesized from new orientations or changes to the imidazole ring, or combinations thereof; oA-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, Ildavisant (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, Samerisant (SUVN H3 antagonists or inverse agonists such as G3031), SAR-110894, SAR-152954, SCH-497079, SLS-010, ST-1283, thioperamide, ZPL-868087, or combinations thereof or a pharmaceutically acceptable salt, analog, metabolite, prodrug, derivative, metabolite, co-crystal, modification, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof.

[0048] The present invention further relates to betahistine prodrugs that are intended to overcome the limitations associated with the parent drug while maintaining or enhancing its therapeutic efficacy. Prodrugs obtained by conjugating 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.

[0049] One aspect of the present invention is 11 are each hydrogen, and the amine-substituent R 12is other than hydrogen. The synthesis and use of prodrugs of amine-containing therapeutically active compounds have been discussed in the literature, see Simplicio et al., "Prodrugs for amines," Molecules, 13(3):519-47 (2008), which is incorporated herein by reference in its entirety.

[0050] Aspects of the present invention further relate to betahistine metabolites, prodrugs, and deuterated analogs to overcome limitations associated with the parent drug. As used herein, the term "prodrug" refers to a derivative of betahistine that requires conversion within the body to release betahistine. In some embodiments, the conversion is an enzymatic conversion. In other embodiments, the conversion is a cyclization conversion. In some other embodiments, the conversion is a combination of an enzymatic conversion and a cyclization reaction. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to betahistine. Betahistine prodrugs are designed as conjugates of betahistine with various functional groups or molecular structures, including, but not limited to, amino acids, esters, carbamates, carbonates, phosphate esters, sulfates, glucuronides, peptides, lipids, cyclic structures, self-immolative linkers, polymers, and nanoparticles. In addition, the present invention also includes codrugs and complex prodrugs, which represent more complex prodrug strategies. Therefore, the present invention further relates to the design, synthesis, and application of prodrugs and analogues of betahistine.

[0051] Incorporation of deuterium atoms into the betahistine structure, replacing one or more hydrogen atoms with deuterium atoms, results in the production of deuterated betahistine analogs within the scope of the present invention.

[0052] As used herein, codrugs (or co-prodrugs) refer to a subclass of prodrugs. Codrugs consist of two pharmacologically active agents linked together, one of which is betahistidine, with each active agent acting as a promoiety for the other. Upon administration, codrugs are metabolized, typically by enzymatic or hydrolytic cleavage, to release the two active agents. The primary benefit of codrugs is the effect of the two drugs: improving their pharmacokinetic profiles, reducing side effects, or enhancing their solubility and / or stability. Codrugs can be designed for simultaneous delivery of two active agents to the same biological site of action or to different sites, depending on the desired therapeutic outcome.

[0053] As used herein, a multiple prodrug refers to a drug that is metabolically converted into more than one pharmacologically active molecule. Essentially, one prodrug molecule can yield multiple active drug molecules upon metabolism.

[0054] As used herein, nanoparticle prodrug refers to a drug molecule that is incorporated or encapsulated within a nanoparticle to achieve controlled drug release, enhanced solubility, improved bioavailability, targeted drug delivery, and / or a combination thereof. These nanoparticles may be composed of various materials, such as lipids (liposomes), proteins, metals, or polymers, as known in the art. Prodrugs are typically converted to their active form upon reaching their target site or in response to a specific trigger, such as pH, enzymes, or other stimuli.

[0055] Betahistine prodrugs are intended to modify the pharmacokinetics of the parent betahistine drug, enhancing its stability, absorption, and half-life, thus reducing dosing frequency and improving patient compliance with treatment regimens. Furthermore, by utilizing a different prodrug strategy, these novel compounds reduce the gastrointestinal side effects observed with betahistine and improve the overall safety and tolerability profile of the drug.

[0056] Optional substituents may be selected from, but are not limited to, alkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, halogen, etc., as well as conjugate and functional groups, solubilizing groups, lipid groups, etc., to optimize pharmacokinetics and other properties.

[0057] As used herein, unless otherwise specified, "alkyl" and / or "aliphatic," whether used alone or as part of a substituent group, refers to straight or branched carbon chains having 1 to 20 carbon atoms, or any number within this range, e.g., 1 to 6 carbon atoms or 1 to 4 carbon atoms. 1~6 ) shall independently refer to the number of carbon atoms in the alkyl moiety or in 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.

[0058] As used herein, "cycloalkyl," whether used alone or as part of another group, refers to non-aromatic carbon-containing rings, including cyclized alkyl, alkenyl, and alkynyl groups, having, for example, 3 to 14 ring carbon atoms, preferably 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 bonds. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and / or spiro ring systems), with the carbon atoms located inside or outside the ring system. Any suitable ring position of a 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 that 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.

[0059] The term "aryl," used alone or as part of another group, is defined herein as an unsaturated aromatic monocyclic ring of 6 carbon members or an unsaturated aromatic polycyclic ring of 10 to 14 carbon members. The aryl ring may be, for example, a 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, naphthylene-1-yl, naphthylene-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-hydroxynaphthylene-2-yl, 4,5-dimethoxynaphthylene-1-yl, and 6-cyano-naphthylene-1-yl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbocyclic rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl), which may be substituted at one or more carbon atoms of the aromatic and / or saturated or partially saturated ring.

[0060] The term "heteroaryl," whether used alone or as part of another group, is defined herein as one or more rings having 5 to 20 atoms, wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and at least one additional heteroatom-containing ring is aromatic. In heteroaryl groups containing two or more fused rings, the non-heteroatom-containing ring may be carbocyclic (e.g., 6,7-dihydro-5H-cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have 5 to 14 ring atoms and contain 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 may be oxidized. Heteroaryl groups may be substituted. Non-limiting examples 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, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two 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.

[0061] As used herein, unless a specific definition is provided otherwise, the term "substituted" refers to a group in which at least one hydrogen of a substituent or compound is substituted with deuterium, a halogen (-F, -Cl, -Br, -I), a hydroxy group (-OH), an amino group (-NH), a carboxyl group (-COH), a substituted or unsubstituted C1-C10 amine group, a nitro group (-NO), a C1-C10 alkyl group, a C3-C10 cycloalkyl group, a C6-C12 aryl group, a C1-C10 alkoxy group, a C1-C10 trifluoroalkyl group such as a trifluoromethyl group (-CF3), or a cyano group (-CN). Exemplary substituents include alkyl, alkylidenyl, alkylcarboxy, alkoxy, alkenyl, alkenylcarboxy, alkenyloxy, aryl, aryloxy, alkylaryl, alkylaryloxy, -OH, amido, carboxamido, carboxy, sulfonyl, =0, =S, -NO2, halogen, haloalkyl, fused saturated or unsaturated optionally substituted rings, -S(O)R, -SOR, -SR, -NRR', -OH, -CN, -C(O)R, -OC(O)R, -NHC(O)R, -(CH2) n CO2R or -(CH2) n CONRR', where n is 0-4, and R and R' are independently H, alkyl, aryl, or alkylaryl. Substituents also include replacement of a carbon atom and one or more attached hydrogen atoms.

[0062] In some embodiments, the betahistine prodrug of the present invention has Formula I: [ka] [During the ceremony, R1~R 12 is other than hydrogen or deuterium, R1 to R4 are each independently selected from hydrogen or deuterium; R5 to R7 are each independently selected from hydrogen or deuterium; R9~R 11 are each independently selected from hydrogen or deuterium; R12 is hydrogen, deuterium, optionally substituted alkyl, optionally substituted aryl, -C(O)R 13 , -S(O)R 13 , -S(O)2R 13 , -C(O)OR 13 , -P(O)2OR 13 , -N(R 13 )(R 14 ) and R 13 and R 14 are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted aryl. and pharmaceutically acceptable salts thereof.

[0063] In one aspect of the present invention, R 12 Betahistine is conjugated to an amino acid such that: comprises at least one amino acid in the betahistine prodrug compound of Formula I.

[0064] In the betahistine prodrug compounds of Formula I, R 12 wherein the at least one amino acid is 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.

[0065] In the betahistine prodrug compounds of Formula I, R 12may include non-amino acids 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.

[0066] In the betahistine prodrug compounds of Formula I, R 12 may comprise an amino acid conjugated to an acetyl group, an ester group, an amino acid ester group, a carbamate group, a carbonate group, a phosphate ester group, a glucuronide group, a peptide group, a lipid group, a cyclic group, a self-immolative linker group, a polymeric group, or the like.

[0067] In the betahistine prodrug compounds of Formula I, R 12 When contains an ester group, the ester group is preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl esters.

[0068] In the betahistine prodrug compounds of Formula I, R 12 comprises 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.

[0069] In the betahistine prodrug compounds of Formula I, R 12When comprises a carbamate group, the carbamate 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.

[0070] In the betahistine prodrug compounds of Formula I, R 12 When contains 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.

[0071] In the betahistine prodrug compounds of Formula I, R 12 When contains a phosphate ester group, the phosphate ester 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.

[0072] In the betahistine prodrug compounds of Formula I, R 12contains 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.

[0073] In the betahistine prodrug compounds of Formula I, R 12 When comprises 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 possible di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca-peptides, or combinations of any of the foregoing amino acids.

[0074] In the betahistine prodrug compounds of Formula I, R 12comprises a lipid group, the lipid group is preferably selected from lauric acid, myristic acid, palmitic acid, stearic acid, arachidonic 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.

[0075] In the betahistine prodrug compounds of Formula I, R 12 When contains 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.

[0076] In the betahistine prodrug compounds of Formula I, R 12 comprises a self-immolative linker group, the self-immolative linker group is preferably selected from a para-nitrobenzyl linker, an ortho-nitrobenzyl linker, an aromatic linker, an aliphatic linker, a heterocyclic linker, a carbamate linker, a carbonate linker, an amide linker, a urea linker, a thiourea linker, an ester linker, a thioester linker, a disulfide linker, a sulfonamide linker, 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.

[0077] In the betahistine prodrug compounds of Formula I, R 12 comprises a polymeric group, the polymeric group is preferably selected from polyethylene glycol (PEG), polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), chitosan, hyaluronic acid, dextran, and all possible mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca-polymer combinations of said polymeric groups.

[0078] 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 nanoparticles are 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.

[0079] The present invention includes betahistine and its salts, analogs, metabolites, prodrugs, derivatives, metabolites, cocrystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs, or stereoisomers, wherein betahistine is conjugated or associated with a targeting moiety that facilitates 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-, and pentadeca- combinations of the targeting moieties.

[0080] The present 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, which is 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.

[0081] The present invention comprises betahistine, its salts, analogs, metabolites, prodrugs, derivatives, metabolites, co-crystals, modifications, solvates, hydrates, isotopes, tautomers, esters, polymorphs, or stereoisomers, wherein the betahistine is conjugated to a caging group, the caging group being cleavable under certain conditions to release the active betahistine, the caging group preferably being selected from a nitrobenzyl group, a coumarinylmethyl group, a dimethoxybenzoinyl group, a bromohydroxyquinoline group, a 7-nitroindolinyl group, and all possible combinations of mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, trideca-, tetradeca-, pentadeca-caging group.

[0082] The present invention includes a betahistine prodrug, wherein betahistine is formulated as a peptide prodrug comprising a phosphate ester linked to an 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-, and pentadeca- combinations of said amino acid esters.

[0083] The present 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 being selected from, inter alia, a monoamine oxidase inhibitor (MAO-I) such as selegiline, a combination of MAO-Is, histamine, a histamine analog, a histamine derivative, L-histidine, HTMT (histamine N-methyltransferase) or a histamine precursor or prodrug, a glutamate modulator such as memantine, N-acetylcysteine, ketamine, D-cycloserine, or a combination thereof.

[0084] The present 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 to one or more other betahistine prodrugs, each of said other prodrugs being selected from the group consisting of ester prodrugs, amino acid esters, carbamate prodrugs, carbonate prodrugs, phosphate ester 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.

[0085] The range of prodrug classes contemplated in this invention includes ester prodrugs and amino acid esters, which are expected to improve drug bioavailability and stability. Carbamate and carbonate prodrugs are included due to their potential to provide controlled-release properties and extend the duration of therapeutic effect.

[0086] Phosphate ester prodrugs and sulfate conjugates are used given their potential to enhance solubility and bioavailability, while glucuronide conjugates, commonly used in drug detoxification, are expected to help improve the safety profile of betahistine.

[0087] Peptide and lipid conjugates are expected to enhance cellular uptake and targeted delivery, while cyclic prodrugs may potentially provide enhanced stability and controlled release. Self-immolative linker prodrugs have the added benefit of releasing the active drug and a biologically active leaving group, potentially providing synergistic effects. The present invention also explores the development of polymer conjugates and prodrug nanoparticles that can enhance solubility, control drug release, and improve targeted drug delivery. The scope of the present invention also extends to the design of codrugs and complex prodrugs that enable the simultaneous delivery of two or more drugs, potentially resulting in synergistic therapeutic effects or reduced side effects.

[0088] Each class of prodrug under the present invention is designed to offer distinct advantages over the parent betahistine drug, including improved stability, solubility, absorption, and half-life, along with reduced side effects.

[0089] Additionally, the present invention includes methods for synthesizing these prodrugs and details pharmaceutical compositions containing these prodrugs together with a pharmaceutically acceptable carrier.

[0090] The present invention is useful for treating OCD and / or reducing its symptoms, as indicated by a reduction in Y-BOCS scores, and for treating other OCRDs, as indicated by a reduction in corresponding symptom severity measures.

[0091] The present invention is useful for treating tic disorders and / or reducing the symptoms thereof, for example, by reducing tics as indicated by the Yale Global Tic Severity Scale.

[0092] The present invention is useful for treating ALS and / or reducing the symptoms thereof, as evidenced, for example, by prolonged survival.

[0093] The present invention is useful for treating and / or reducing the symptoms of glutamate excitotoxicity-related disorders, as evidenced, for example, by prolonged survival.

[0094] The present invention is useful for treating autism spectrum disorder and / or reducing the symptoms thereof, as indicated by a reduction in the Aberrant Behavior Scale (ABC) score or a reduction in one or more subscales within the ABC, including the irritability, hyperactivity, lethargy / withdrawal, stereotypies, and inappropriate language subscales.

[0095] The present invention is useful for treating autism spectrum disorders and / or reducing the symptoms thereof, as indicated by a reduction in the Repetitive Behavior Scale (RBS) score or a reduction in one or more subscales within the RBS, including the subscales of stereotypies, self-injurious behaviors, compulsions, rituals, persistence in sameness, and restricted behaviors.

[0096] The following examples are provided below to illustrate methods and results according to the disclosed subject matter. These examples are not intended to be comprehensive 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 that would be apparent to one skilled in the art.

[0097] Background relating basal ganglia histamine regulation to the pathophysiology of OCD and Tourette syndrome. Previous research into the pathophysiology of obsessive-compulsive disorder (OCD) has focused on dysregulation of the basal ganglia system and the neurotransmitters serotonin, dopamine, and glutamate, as well as pharmacological treatment approaches to modulate them (Pittenger 2021). More recent research has begun to examine the role of the histaminergic system in both OCD and Tourette's syndrome (Rapanelli and Pittenger 2016, Pittenger 2020). Notably, OCD and Tourette's syndrome often co-occur, are genetically linked, and both affect the same circuits in the brain; therefore, both clinicians and scientists studying their pathophysiology often consider them together. This line of research began with the discovery of a rare mutation in the gene histidine decarboxylase (HDC), required for histamine biosynthesis, in families with high rates of both OCD and Tourette's syndrome (Ercan-Sencicek, Stillman et al. 2010). Mouse models that recapitulate this genetic disorder exhibit obsessive-compulsive, repetitive behaviors (see below for further discussion of mouse models of OCD and Tourette's syndrome) (Baldan, Williams et al. 2014). Ongoing research in mouse models is further elucidating the critical role of histamine in regulating the basal ganglia system, which is involved in both OCD and Tourette's syndrome (Rapanelli, Frick et al. 2016; Rapanelli, Frick et al. 2017; Xu and Pittenger 2023), as well as the ability to manipulate histamine signaling to control compulsive 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).

[0098] Preclinical evidence showing that betahistine reduces obsessive-compulsive and tic-like stereotypic behaviors in a mouse model. Increased grooming and other repetitive stereotyped behaviors have been used in several genetic and other model systems to capture compulsive behaviors (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's syndrome are exacerbated by amphetamine in patients (Shakeri, Farnia et al. 2016), and compulsive grooming and stereotypy are similarly enhanced in mice by amphetamine challenge, a fact that has been used in the analysis of several mouse models of OCD and Tourette's syndrome (Baldan, Williams et al. 2014; Zike, Chohan et al. 2017; Escobar, Martinez-Pinto et al. 2021). In HDC mutant models of OCD and Tourette's syndrome, compulsive-like repetitive grooming is observed after amphetamine challenge and is attenuated by experimental histamine repletion, demonstrating the utility of the amphetamine challenge model for capturing neural and behavioral events related to OCD in mouse systems (Baldan, Williams et al. 2014).

[0099] This model system was used to test the ability of betahistine to reduce compulsive and tic-like behavior in two experiments in mice. [Example]

[0100] [Example 1] In the 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 injection of either saline or amphetamine (8.5 mg / kg). Activity and stereotypy were measured in an open-field apparatus, distinguishing between these two behavioral categories by identifying associated patterns of infrared beam interruption, as in previous studies using similar techniques (Xu, Kobets et al. 2015; Xu, Li, and Pittenger 2016; Rapanelli, Frick et al. 2017). Amphetamine injection is predicted to produce more locomotor activity in the first 30 minutes after injection and more obsessive-compulsive-like stereotypy in the following 30 minutes. Anti-OCD medication is predicted to reduce stereotypy.

[0101] As shown in Figure 1A, amphetamine caused an increase in locomotor activity counts (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: one-way ANOVA, F[3,20] = 6.14, p = 0.004; the amphetamine-treated group differed from saline by **p < 0.01 or *p < 0.05; pairwise post-hoc comparisons; the betahistine-pretreated group did not differ from the saline / amphetamine group.)

[0102] As shown in Figure 1B, this effect was limited to the first 30 min after injection and was not seen in the second 30 min, as expected. (Statistical analysis: 4 × 2 between / within mixed ANOVA, time × treatment group interaction, F[3,20] = 26.3, p < 0.0001; pairwise post-hoc comparisons, all amphetamine-treated groups were significantly different from saline-treated controls (green) in the first 30 min, **p < 0.01 or ****p < 0.0001.) Thus, amphetamine produces an increase in locomotor activity 30 min after injection that is unaltered by betahistine pretreatment—betahistine does not simply block the effect of amphetamine. This observation is important for interpreting measures of stereotypy.

[0103] As shown in Figure 1C, amphetamine challenge with saline pretreatment caused a marked and statistically significant increase in stereotypy, which was completely blocked by betahistine pretreatment. (Statistical analysis: One-way ANOVA: F[3,20] = 10.4, p = 0.0002; post-hoc pairwise comparisons, saline / amphetamine differed from saline / saline, p < 0.001; betahistine pretreatment group differed from saline / amphetamine, p < 0.01.)

[0104] As shown in Figure 1D and as expected, stereotypy was primarily observed 30–60 min after amphetamine challenge. The same effect was observed in analyses across both time periods, with significant stereotypy in the saline / amphetamine group, which was completely blocked by betahistine pretreatment. (Statistical analysis: 4 × 2 between / within mixed ANOVA, time × treatment group interaction, F[3,20] = 2.47, p = 0.091; pairwise post-hoc comparisons: saline / amphetamine significantly more than saline / salt, p < 0.001; betahistine pretreatment significantly less than saline / amphetamine, p < 0.001). Thus, betahistine blocks the development of obsessive-compulsive behavior-like stereotypy after amphetamine challenge without causing general sedation. This supports the utility of betahistine as a potential treatment for OCD (and Tourette's syndrome). [Example 2]

[0105] In a second experiment, amphetamine challenge was repeated with or without betahistine dihydrochloride pretreatment, and mice were subsequently videotaped for 1 hour. Videos were analyzed using an automated motion capture system (Cleversys HomeCageScan) to quantify locomotor activity and grooming. Previous studies have shown that grooming measurements in this system correlate with manual scoring of grooming from video by trained observers, validating this measure of mouse grooming (Xu, Kobets et al. 2015). Increased mouse grooming has been documented as a model of OCD in multiple previous 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).

[0106] As shown in Figure 2A, locomotor activation after amphetamine was limited in the HomeCageScan environment, which is less accurate in its measurement of locomotor activity than the open field apparatus used in Example 1. (Statistics: One-way ANOVA, F[3,20] = 1.24, p = 0.32) Figure 2B shows that, as in Example 1, the increase in locomotor activity was more clearly evident in the first 30 minutes after amphetamine challenge, and 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 were significantly different from the sal / sal group in the first 30 minutes after amphetamine, **p < 0.01 or ***p < 0.001; there was no effect of betahistine pretreatment.) Thus, as in Example 1, amphetamine induces increased locomotor activity, and betahistine does not nonspecifically block the effects of amphetamine or cause general sedation.

[0107] As shown in Figure 2C, amphetamine challenge caused increased grooming, which was attenuated by pretreatment with 10 mg / kg betahistine but not 1 mg / kg, indicating a dose-response relationship. (Statistical analysis: one-way ANOVA, F[3,20] = 6.53, p = 0.0003; pairwise post-hoc comparisons, the sal / amphetamine and BH1 / amphetamine groups showed more grooming than sal / sal, p < 0.05; BH10 / amphetamine showed reduced grooming compared to both sal / amphetamine and BH1 / amphetamine, p < 0.05.)

[0108] Grooming, as in the stereotypy experiment shown in Figure 1, increased particularly in the next 30 min after injection; this effect was blocked by betahistine pretreatment at a dose of 10 mg / kg. Again, the effect of 1 mg / kg betahistine pretreatment was limited and not statistically significant (statistical analysis: 4 × 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 next 30 min, p < 0.01; BH10 / amphetamine group vs. sal / amphetamine group in the next 30 min, p < 0.05). Thus, betahistine pretreatment at 10 mg / kg blocked the induction of compulsive grooming induced by amphetamine challenge without causing nonspecific sedation. [Example 3]

[0109] Clinical response to betahistine in individuals with treatment-refractory OCD. We describe the case of an individual with treatment-refractory OCD who showed significant improvement after treatment with betahistine dihydrochloride. Below is a clinical description of the case and clinical course by the treating psychotherapist.

[0110] The patient was a man in his late 20s who was diagnosed with OCD in his early teens. During his initial consultation, he demonstrated significant impairment in daily activities, characterized by recurrent intrusive thoughts and recurrent compulsive behaviors. Previous treatments included pharmacotherapy with SSRIs and second-generation neuroleptics, but little improvement was seen, and medication was discontinued due to lack of benefit and problematic side effects, including blunted affect, mental clouding, hyperprolactinemia, and weight gain. Symptom severity was not assessed using standardized clinical scales but was considered to be in the severe range.

[0111] The patient was administered betahistine dihydrochloride (16 mg 2x / day for 2 weeks) by a neurologist for the treatment of trauma-induced dizziness. A significant improvement in OCD symptoms was noted, but they returned within a few days of discontinuing betahistine. Betahistine treatment was resumed at a lower dose (8 mg daily, then 8 mg twice daily), and symptoms again significantly decreased. This treatment has now been continued for several years, with sustained benefits, including a reduction in the frequency and intensity of obsessive-compulsive behaviors and thoughts. On several occasions, symptoms recurred when betahistine was discontinued; when betahistine was resumed, symptoms again improved. This improvement in symptoms was paralleled by improved functioning in occupational and social domains, as evidenced by an approximately 20% improvement in college grades, and an improvement in the ability to maintain social and romantic relationships.

[0112] This sustained improvement in function is demonstrated in Figure 3, which shows medical school grades before and after treatment with betahistine. The subjects' medical school grades over this period are expressed numerically on a scale of 1 to 20. For the eight semesters before taking betahistine, grades ranged from 12.31 to 14.81 (mean 13.5, standard deviation 0.73). For the four semesters after the start of betahistine treatment, grades ranged from 16.04 to 17.49 (mean 16.9, standard deviation 0.65). This difference was highly statistically significant (two-tailed independent-samples t-test: p<0.0001).

[0113] Throughout this application, various publications are referenced by author name and date, or by patent or patent publication number. The disclosures of these publications are hereby incorporated by reference in their entireties into this application in order to more fully describe the state of the art known to those skilled in the art as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an admission that such reference is prior art to the present invention.

[0114] 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 the present invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and examples herein may be used. Furthermore, it is contemplated that specific items in a list of items, or subsets of items within a larger group of items, may be combined with other specific items, subsets of items, or larger groups of items, regardless of whether there is a specific disclosure herein identifying such combinations. [Prior art documents] [Non-patent literature]

[0115] [Non-Patent Document 1] Ahmari, et al., “Repeated cortico-striatal stimulation generates persistent OCD-like behavior.” Science, 340(6137):1234-1239 (2013). [Non-patent document 2] Ahmed, et al., “Pharmacological antagonism of histamine H2R ameliorated L-DOPA-induced dyskinesia via normalization of GRK3 and by suppressing FosB and ERK in PD.” Neurobiol Aging, 81:177-189 (2019). [Non-patent document 3] Baldan, et al., “Histidine decarboxylase deficiency causes Tourette syndrome: parallel findings in humans and mice,” Neuron, 81(1):77-90 (2014). [Non-patent document 4] Chen, et al., “Hematopoietic origin of pathological grooming in Hoxb8 mutant mice,” Cell, 141(5):775-785 (2010). [Non-patent document 5] Ercan-Sencicek, er al., “L-histidine decarboxylase and Tourette's syndrome,” N. Engl. J. Med., 362(20):1901-1908 (2010). [Non-patent document 6] Escobar, et al., “Altered Grooming Syntax and Amphetamine-Induced Dopamine Release in EAAT3 Overexpressing Mice,” Front Cell Neurosci., 15:661478 (2021). [Non-Patent Document 7] Greer, JM et al., “Hoxb8 is required for normal grooming behavior in mice,” Neuron, 33(1):23-34 (2002). [Non-licensed document 8] Nagarajan, et al., “Corticostriatal circuit defects in Hoxb8 mutant mice,” Mol. Psychiatry, 23(9):1868-1877 (2018).

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

[0116] [Figure 1] Not stated in the original text. [Figure 2] Not stated in the original text. [Figure 3] Not stated in the original text.

Claims

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

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

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

4. 1. A method for treating Tourette's syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of betahistine or a pharmaceutically acceptable prodrug, derivative, metabolite, cocrystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof.

5. A method for treating 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 for 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 for 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 in combination with an H1R agonist or an H3R antagonist, or a pharmaceutically acceptable salt, metabolite, or prodrug thereof.

8. 1. A method for treating glutamate excitotoxicity-related disorders, comprising administering to a subject in need thereof a therapeutically effective amount of betahistine or a pharmaceutically acceptable prodrug, derivative, metabolite, cocrystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof.

9. 9. The method of 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, seizures, epilepsy, epilepsy syndromes, status epilepticus, refractory focal epilepsy, autoimmune encephalitis, infectious encephalitis, viral encephalitis, acute disseminated encephalomyelitis, or mitochondrial encephalitis.

10. 1. A method for treating a tic disorder, comprising administering to a subject in need thereof a therapeutically effective amount of betahistine or a pharmaceutically acceptable prodrug, derivative, metabolite, cocrystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof.

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

12. 1. A method for 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 prodrug, derivative, metabolite, cocrystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof.

13. 13. The method of any of claims 1 to 12, wherein betahistine or a pharmaceutically acceptable prodrug, derivative, metabolite, cocrystal, 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. 14. The method of 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 modulator, a benzothiazole or benzothiazole derivative, a serotonin reuptake inhibitor (SRI), a skeletal muscle relaxant, an antipsychotic, an antidepressant, an anticholinergic, an anticonvulsant, and a benzodiazepine or benzodiazepine derivative, or a combination thereof.

15. 15. The method of any of claims 1 to 14, wherein the betahistine or a pharmaceutically acceptable prodrug, derivative, metabolite, cocrystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof is administered orally, intravenously, sublingually, bucally, transdermally, or intranasally.

16. 16. The method of claim 15, wherein the betahistine or a pharmaceutically acceptable prodrug, derivative, metabolite, cocrystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof is administered orally.

17. 17. The method of any of claims 1 to 16, wherein the betahistine or a pharmaceutically acceptable prodrug, derivative, metabolite, cocrystal, 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. 18. The method of any one of claims 1 to 17, wherein the betahistine or a pharmaceutically acceptable prodrug, derivative, metabolite, cocrystal, 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, deuterated betahistine, and a betahistine prodrug.

19. 19. The method of any of claims 1 to 18, wherein the betahistine or a pharmaceutically acceptable prodrug, derivative, metabolite, cocrystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph or stereoisomer thereof is administered once a day, twice a day, three times a day, or more than three times a day.

20. 20. The method of any of claims 1 to 19, wherein the betahistine or a pharmaceutically acceptable prodrug, derivative, metabolite, cocrystal, modification, salt, free acid or base, solvate, hydrate, isotope, tautomer, ester, polymorph, or stereoisomer thereof is administered less than once per day.

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

22. Formula I: 【Chemistry 1】 [During the ceremony, R １ ~R １２ is other than hydrogen or deuterium, R １ ~R ４ are each independently selected from hydrogen or deuterium; R ５ ~R ７ are each independently selected from hydrogen or deuterium; R ９ ~R １１ are each independently selected from hydrogen or deuterium; R １２ is hydrogen, deuterium, optionally substituted alkyl, optionally substituted aryl, —C(O)R １３ , -S(O)R １３ , -S(O) ２ R １３ , -C(O)OR １３ , -P(O) ２ OR １３ , -N(R １３ ) (R １４ ) where R １３ and R １４ are independently selected from hydrogen, optionally substituted alkyl, or optionally substituted aryl.

22. The method of any of claims 1 to 21, comprising administering a compound of the formula: and pharmaceutically acceptable salts thereof.

23. The H1R agonist may be methylhistaprodifen, dimethylhistaprodifen, 2-thiazolylethylamine, 2-pyridylethylamine, suprahistaprodifen, 2-(2-aminoethyl)pyridine (2-PyEA), 2-[3-(trifluoromethyl)phenyl]histamine, 2-(3-chlorophenyl)histamine, 2-phenylhistamine such as 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), H1 agonists synthesized from novel orientations or changes to the imidazole ring, wherein said H3R antagonist is selected from the group consisting of A-960656, ABT-239, ABT-288, ABT-300, ABT-301, ABT-302, ABT-303, ABT-304, ABT-305, ABT-306, ABT-307, ABT-308, ABT-309 ... -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, Enelisant, GR175737, GSK-1004723, GSK-189254, GSK207040, GSK -239512, GSK-334429, GSK-835726, GT-2016, HPP-404, Ildavisant (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 23. The method of any of claims 5 to 7, 9 or 22, wherein the compound is selected from the group consisting of: 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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