(S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol for the treatment of agitation

Abstract

The present disclosure relates to methods of treating agitation, comprising administering (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol to a mammal in need thereof. Agitation is a common behavioral symptom in neurodegenerative and neuropsychiatric disorders. Disclosed herein are methods of treating agitation. These methods comprise administering (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol to a mammal in need thereof.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 477,361, filed December 27, 2022, which is incorporated herein by reference in its entirety. Summary of the Invention [Means for solving the problem]

[0002] The present disclosure relates to a method of treating agitation, the method comprising administering (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol to a mammal in need thereof. DETAILED DESCRIPTION OF THE INVENTION

[0003] Agitation is a common behavioral symptom in neurodegenerative and neuropsychiatric disorders. Disclosed herein are methods for treating agitation. These methods include administering (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol to a mammal in need thereof.

[0004] [ka]

[0005] The terms "treat" or "treatment" broadly include any type of therapeutic activity, including the diagnosis, cure, mitigation, or prevention of disease in humans or other animals, or any activity that otherwise affects the structure or any function of the body of humans or other animals. In some embodiments, the mammal being treated is a human. In some embodiments, the mammal being treated is a non-human mammal, such as a dog, cat, mouse, rat, rabbit, monkey, horse, pig, etc.

[0006] For the treatment of agitation and other conditions, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol may be administered orally, including by swallowing or sublingually (including buccally). Other possible routes may include subcutaneous injection, intramuscular injection, intravenous injection, and the like. In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is administered orally.

[0007] Unless otherwise specified, any reference herein to a compound, such as (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternative solid forms such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that can be rapidly converted to a compound described herein under the conditions in which the compound is used as described herein.

[0008] Solid dosage forms for oral administration, such as solid oral dosage forms including capsules, tablets, or pills, may also contain one or more of the following: binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, or alginic acid; sweeteners such as sucrose, lactose, or saccharin; lubricants such as magnesium stearate; buffers such as phosphate, carbonate, and / or citrate buffers; or flavorings such as peppermint, wintergreen oil, or cherry flavoring. If the dosage form is a capsule, it may contain a liquid carrier in addition to the above-mentioned types of materials. Various other materials may be present as coatings; for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. It may be desirable for the materials in the dosage form or pharmaceutical composition to be pharmaceutically pure and non-toxic in the amounts used.

[0009] The effective dose of (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol can vary depending on the severity of the disease, the patient's age, the patient's weight, the patient's general health, the route of administration, and similar factors. In some embodiments, the human dose is about 0.01 to 50 mg / kg / day.

[0010] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol has been found to have a half-life that is 2 to 4 times longer than that of dexmedetomidine. Therefore, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol can be administered less frequently than dexmedetomidine, for example, once or twice daily.

[0011] Agitation may be associated with neurodegenerative conditions such as Alzheimer's disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), Down's dementia, post-traumatic stress disorder including aggression and hyperarousal in post-traumatic stress disorder, Parkinson's disease, vascular dementia, vascular cognitive impairment, SanDown syndrome in Alzheimer's disease or dementia, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, and progressive supranuclear palsy, senile dementia of the Alzheimer's type (SDAT), concussion, and concussion syndrome.

[0012] Agitation may also be associated with neuropsychiatric conditions such as schizophrenia, bipolar disorder, bipolar mania, delirium, autism, and depression, including dementia or mood disorders in subjects with major depression (e.g., stress-related major depression).

[0013] Treatment of hyperarousal associated with acute agitation in patients with schizophrenia, bipolar disorder, or dementia is also a contemplated use of (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol.

[0014] Agitation may also be associated with surgery (pre-operative, intra-operative, post-operative), traumatic brain injury, substance abuse and / or withdrawal symptoms (eg, associated with opioids or alcohol).

[0015] Agitation can be both acute and chronic. In dementia, agitation is often associated with restlessness and confusion and may be preceded by pacing and asking lots of questions. (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is believed to have the advantage of being useful for both acute agitation events and more chronic episodes of severe restlessness.

[0016] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with Alzheimer's disease in a mammal, such as a human.

[0017] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with frontotemporal dementia (ETD) in a mammal, such as a human.

[0018] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with dementia in a mammal, such as a human.

[0019] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with dementia with Lewy bodies (DLB) in a mammal, such as a human.

[0020] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with Down's dementia in a mammal, such as a human.

[0021] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with post-traumatic stress disorder in a mammal, such as a human.

[0022] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with, including aggression and hyperarousal in post-traumatic stress disorder in a mammal, such as a human.

[0023] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with Parkinson's disease in a mammal, such as a human.

[0024] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with vascular dementia in a mammal, such as a human.

[0025] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with vascular cognitive impairment in a mammal, such as a human.

[0026] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with Alzheimer's disease or Down's syndrome in dementia in a mammal, such as a human.

[0027] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with Huntington's disease in a mammal, such as a human.

[0028] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with multiple sclerosis in a mammal, such as a human.

[0029] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with Creutzfeldt-Jakob disease in a mammal, such as a human.

[0030] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with multiple system atrophy in a mammal, such as a human.

[0031] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with progressive supranuclear palsy, senile dementia of the Alzheimer's type (SDAT) in mammals, such as humans.

[0032] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with concussion in a mammal, such as a human.

[0033] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with concussion syndrome in a mammal, such as a human.

[0034] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with schizophrenia in a mammal, such as a human.

[0035] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with bipolar disorder in a mammal, such as a human.

[0036] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with bipolar mania in a mammal, such as a human.

[0037] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with delirium in a mammal, such as a human.

[0038] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with autism in a mammal, such as a human.

[0039] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with depression, including dementia or mood disorders, in a mammal with major depression (e.g., stress-induced major depression).

[0040] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat hyperarousal associated with acute excitement in a mammal, such as a human, with schizophrenia.

[0041] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat hyperarousal associated with acute excitement in a mammal, such as a human, with bipolar disorder.

[0042] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat hyperarousal associated with acute excitement in a mammal, such as a human, with dementia.

[0043] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat surgery-related agitation (pre-operative, intra-operative, post-operative) in a mammal, such as a human.

[0044] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with traumatic brain injury in a mammal, such as a human.

[0045] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with substance abuse and / or withdrawal (e.g., opioid or alcohol) in a mammal, such as a human.

[0046] Treatment approaches include benzodiazepines such as Xanax and antipsychotics such as Seroquel, but these classes of drugs are highly sedating. There is a need for drugs that can be used both acutely and chronically without causing significant sedation. [Example]

[0047] In the following examples, the following is demonstrated:

[0048] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol shows efficacy in models of agitation / aggression in rodents.

[0049] Despite the fact that both antiexcitatory and sedative effects require the presence of the drug in the CNS, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol exhibits a dissociation of antiexcitatory from sedative effects in rodents.

[0050] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol exhibits good oral bioavailability in rat and mouse models.

[0051] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol exhibits rapid absorption from the GI tract into the blood and entry into the brain in rats and mice.

[0052] There is a distinction between the two enantiomers of (3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol with respect to pharmacokinetic properties, particularly oral bioavailability.

[0053] Animal models suggest that (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol has a higher oral bioavailability in humans than dexmedetomidine, which may be more convenient for patients because dosing can be less frequent, for example, once or twice daily.

[0054] Rapid absorption and sustained exposure in plasma and brain in animal models may enable use for both acute and chronic stimulation.

[0055] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is less sedating in animal models, which may allow the drug to be used to reduce agitation without putting the patient to sleep.

[0056] Example 1 We demonstrate for the first time that the dexmedetomidine metabolite, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol, is orally bioavailable with very rapid absorption from the GI tract. To determine specific pharmacokinetic properties, including oral bioavailability and half-life, it was administered intravenously or orally to groups of rodents. Bioavailability was determined by comparing plasma exposure after IV dosing in a [19% hydroxypropyl β-cyclodextrin / 5% DMSO in saline] formulation with plasma exposure after oral gavage dosing in a 0.5% methylcellulose formulation. Oral bioavailability ranged from 51% in mice to 34% in rats. Maximum plasma concentrations were achieved within 10 and 17 minutes in mice and rats, respectively. The drug also rapidly penetrates the blood-brain barrier, rapidly reaching pharmacological concentrations in the brain within 30 minutes.

[0057] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol also showed sustained levels in plasma and brain, with an average decrease of less than two-fold between 2 and 8 hours. The plasma half-life after oral administration is 4.2 to 7 hours. In comparison, the oral bioavailability of dexmedetomidine was only 8.6% after oral administration in rats, with a half-life of 2 hours. Surprisingly, (R)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol showed a much lower oral bioavailability of 7% in rats.

[0058] [ka]

[0059] Example 2 We also determined that (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is less susceptible to metabolism by human recombinant cytochrome P450 (CYP) enzymes than dexmedetomidine, suggesting that the longer half-life observed in rodents may occur in humans as well. A 2 μM concentration of dexmedetomidine or (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol was incubated with seven different human CYP enzymes and NADPH cofactors for up to 60 minutes. The % of compound remaining was measured. Five of the CYP enzymes were involved in the metabolism of dexmedetomidine: 28% (CYP2B6), 84% (CYP2C8), 74% (CYP2C19), 7% (CYP2D6), and 89% (CYP3A4) remained during the incubation. Conversely, none of the CYPs metabolized (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol. Concentrations of (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol that were >90% of the starting concentration were measured in all incubations.

[0060] Example 3 The activity of (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol was tested in models of excitement and sedation.

[0061] The resident-intruder model is an established preclinical model of aggression and agitation, allowing the spontaneous and natural expression of both aggressive aggression / agitation and defensive behaviors in laboratory rodents in a semi-natural laboratory setting. When rodents are exposed to a novel male in their home cage environment, they recognize the novel male as an intruder and exhibit a repertoire of defensive behaviors, including anogenital sniffing, chasing, biting, and attacking (Nelson et al., ILAR Journal (2000) 41(3):153-162). Latency to attack and number of attacks are measures of agitation. (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol was effective in this model at 2 mg / kg orally and above (>80% inhibition of seizures), but showed minimal activity at 1 mg / kg.

[0062] Sedation was assessed in the LMA model. Mice were placed in a novel chamber, and their exploratory activity was measured as distance traveled during a 30-minute session. (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol partially sedated the LMA model at 2 mg / kg (approximately 25% inhibition of distance traveled) and 3 mg / kg (<50% inhibition of distance traveled), and minimally sedated it at 1 mg / kg.

[0063] Thus, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol at 2 mg / kg was more than 80% effective in the aggression model (resident-invasion model) but only about 25% active in the sedation model (LMA model). In contrast, dexmedetomidine at 0.5 mg / kg was more than 80% effective in the resident-invasion model but was minimally effective (20% inhibition of seizures) at 0.2 mg / kg, and was highly sedative (>70%) at 0.5 mg / kg and partially sedative at 0.2 mg / kg in the LMA model. The maximal achievable level of activity in the LMA model with (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol was lower than the maximal achievable level of activity with dexmedetomidine.

[0064] These data demonstrate that (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is advantageous over dexmedetomidine by having a larger therapeutic window between antiexcitatory and sedative doses. This separation occurs despite the fact that both antiexcitatory and sedative effects require drug activity in the brain.

[0065] Where stereochemistry is not indicated, the name or structural depiction includes any stereoisomer or any mixture of stereoisomers.

[0066] Unless otherwise specified, all numbers expressing properties such as amounts, quantities, percentages, and the like of ingredients used in the specification and claims should be understood in all instances as referring to both the exact value stated and that which may be modified by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed by, at the very least, taking into account the number of reported significant digits and applying ordinary rounding techniques. Rounding of any value to the nearest significant digit is specifically contemplated herein. For example, the term "about 1.1" is intended to contemplate a value of "about 1." Similarly, a value such as "about 100" should be construed as "about 1 x 10" or ... 2 " values, which show only one significant figure, should be rounded so that only one significant figure is present.

[0067] The terms "a," "an," "the," and similar referents as used in the context of describing embodiments (particularly in the context of the claims that follow) should be construed to encompass both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or representative language (e.g., "etc.") provided herein is intended merely to better describe embodiments and does not impose a limitation on the scope of any claims. No language in the specification should be construed as indicating any non-claimed element essential to the practice of a claim.

[0068] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or to expedite procedural flow. When any such inclusion or deletion occurs, the specification, when used in the appended claims, will be deemed to contain the modified group and thus satisfy the written recitation of all Markush groups.

[0069] Use of the terms "comprising," "comprises," "having," "includes," "including," and the like is intended to also contemplate the use of "consisting essentially of," "consists essentially of," "consisting of," or "consists of."

[0070] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the claimed subject matter as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

[0071] Finally, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be used are within the scope of the claims. Thus, by way of example, and not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Therefore, the scope of the claims is not limited to the embodiments precisely shown and described.

Claims

1. A method of treating agitation comprising administering (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol to a mammal in need thereof.

2. The method of claim 1 , wherein the excitation is associated with a neurodegenerative condition.

3. The method of claim 1 , wherein the arousal is associated with a neuropsychiatric condition.

4. The method of claim 1 , wherein the excitement is associated with surgery.

5. 10. The method of claim 1, wherein the excitation is associated with traumatic brain injury.

6. 10. The method of claim 1, wherein the arousal is associated with substance abuse or withdrawal symptoms.

7. 10. The method of claim 1, wherein the (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is administered orally.

8. 8. The method of claim 1, 2, 3, 4, 5, 6, or 7, wherein the mammal is a human.

9. 2. The method of claim 1, wherein the (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is administered orally to the mammal.

10. 10. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the mammal experiences minimal sedation.

11. An oral dosage form comprising (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol.

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