(S)-(3-(1-(1h-imidazol-4-yl) ethyl)-2-methylphenyl) methanol for treatment of agonisation

Abstract

The present disclosure relates to methods of treating agonisation. The method comprises administering (S)-(3-(1-(1H-imidazol-4-yl) ethyl)-2-methylphenyl) methanol to a mammal in need thereof.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 477,361, filed on December 27, 2022, the entire disclosure of which is incorporated herein by reference. Summary of the Invention

[0003] The present disclosure relates to methods of treating agitation. The methods include administering (S)-(3-(1-(1H - imidazol - 4 - yl)ethyl)-2 - methylphenyl)methanol to a mammal in need thereof. Detailed Description

[0004] Agitation is a common behavioral symptom in neurodegenerative and neuropsychiatric disorders. Methods of treating agitation are disclosed herein. These methods include administering (S)-(3-(1-(1H - imidazol - 4 - yl)ethyl)-2 - methylphenyl)methanol to a mammal in need thereof.

[0005]

[0006] The term "treating" broadly encompasses any kind of treatment activity, including diagnosing, curing, alleviating, or preventing disease in a human or other animal, or any activity that otherwise affects the structure or any function of the body of a human or other animal. In some embodiments, the mammal 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.

[0007] For the treatment of agitation and other conditions, (S)-(3-(1-(1H - imidazol - 4 - yl)ethyl)-2 - methylphenyl)methanol can be administered orally, including by swallowing or sublingually (including buccal). Other possible routes can include subcutaneous injection, intramuscular, intravenous, etc. In some embodiments, (S)-(3-(1-(1H - imidazol - 4 - yl)ethyl)-2 - methylphenyl)methanol is administered orally.

[0008] 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 rapidly converts under the conditions of using the compound as described herein to the compound described herein.

[0009] Dosage forms for oral administration may also contain one or more of the following: binders such as tragacanth, gum arabic, corn starch or gelatin, and the dosage form for oral administration is such as a solid dosage form, for example, a solid oral dosage form, including capsules, tablets or pills; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch and alginic acid, etc.; sweeteners such as sucrose, lactose or saccharin; lubricants such as magnesium stearate; buffering agents such as phosphate, carbonate and / or citrate buffering agents; or flavoring agents such as peppermint, wintergreen oil or cherry flavoring. When the dosage form is a capsule, in addition to the types of materials described above, it may also contain a liquid carrier. Various other materials may be present as coatings, for example, tablets, pills or capsules may be coated with shellac, sugar or both. It is desirable that the materials in the dosage form or pharmaceutical composition are pharmaceutically pure and non-toxic in the amounts employed.

[0010] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol's effective dose may vary according to 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 mg / kg / day to 50 mg / kg / day.

[0011] (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. Thus, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol can be administered at a lower frequency than dexmedetomidine, such as once or twice a day.

[0012] Agitation may be associated with the following neurodegenerative disorders: such as Alzheimer's disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), Down's dementia, post-traumatic stress disorder (including aggressive behavior and hyperarousal in post-traumatic stress disorder), Parkinson's disease, vascular dementia, vascular cognitive impairment, sundown 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 type (SDAT), concussion and concussion syndrome, etc.

[0013] Agitation may also be associated with the following neuropsychiatric disorders: such as schizophrenia, bipolar disorder, bipolar mania, delirium, autism and depression (including dementia or mood disorders in subjects with major depressive disorder (e.g., stress-related major depressive disorder)).

[0014] Treating hyperarousal associated with acute agitation in patients with schizophrenia, bipolar disorder or dementia is also an intended use of (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol.

[0015] Agitation may also be associated with surgery (before, during, after), traumatic brain injury, substance abuse and / or withdrawal (e.g., associated with opioids or alcohol).

[0016] Agitation can be acute and chronic. In dementia, agitation is often associated with restlessness and confusion and may involve pacing and asking many questions prior to the agitation. It is believed that (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol has the advantage of being useful for acute agitation events and more chronic episodes of severe restlessness.

[0017] 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 mammals such as humans.

[0018] 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 mammals such as humans.

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

[0020] 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 mammals such as humans.

[0021] 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 mammals such as humans.

[0022] 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 mammals such as humans.

[0023] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with aggressive behavior and hyperarousal in post-traumatic stress disorder in mammals such as humans.

[0024] 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 mammals such as humans.

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

[0026] 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 mammals such as humans.

[0027] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with the sundown syndrome in Alzheimer's disease or dementia in mammals such as humans.

[0028] 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 mammals such as humans.

[0029] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with multiple sclerosis in mammals such as humans.

[0030] 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 mammals such as humans.

[0031] 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 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 the following in mammals such as humans: progressive supranuclear palsy; senile dementia of the Alzheimer type (SDAT).

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

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

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

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

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

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

[0039] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with autism in mammals such as humans.

[0040] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with depression, which includes dementia or mood disorders in mammals suffering from major depressive disorder (e.g., stress-related major depressive disorder).

[0041] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat excessive arousal associated with acute agitation in mammals such as humans suffering from schizophrenia.

[0042] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat excessive arousal associated with acute agitation in mammals such as humans suffering from bipolar disorder. [[ID=—27]]

[0043] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat hyperarousal associated with acute agitation in mammals such as humans suffering from dementia.

[0044] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with surgery (before, during, after) in mammals such as humans.

[0045] 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 mammals such as humans.

[0046] In some embodiments, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is used to treat agitation associated with drug abuse and / or withdrawal (e.g., opioids or alcohol) in mammals such as humans.

[0047] Treatment methods include benzodiazepines such as alprazolam and antipsychotics such as Seroquel, but drugs in these classes have highly sedating effects. There is a need for drugs that can be used for both acute and chronic symptoms without causing significant sedation.

[0048] In the following examples, the following is demonstrated.

[0049] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol shows efficacy in a rodent agitation / aggression behavior model.

[0050] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol shows separation of anti-agitation dose from sedative dose in rodents, despite the fact that both anti-agitation and sedative effects require the drug to enter the CNS.

[0051] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol shows good oral bioavailability in rat and mouse models.

[0052] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol shows rapid absorption from the gastrointestinal tract into the bloodstream and into the brains of rats and mice.

[0053] There are differences in the pharmacokinetic properties, especially oral bioavailability, between the two enantiomers of (3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol.

[0054] Animal models have shown 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 as the dosing frequency may be lower, e.g., once or twice a day.

[0055] In animal models, rapid absorption and sustained exposure in plasma and the brain enable its use for acute and chronic agitation.

[0056] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol has a lower sedative effect in animal models, which allows the drug to be used to reduce agitation without causing the patient to fall asleep.

[0057] Example 1

[0058] We have demonstrated for the first time that the dexmedetomidine metabolite ((S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol) has oral bioavailability and is very rapidly absorbed from the gastrointestinal tract. Rodent groups were administered intravenously or orally to determine certain pharmacokinetic properties, including oral bioavailability and half-life. Bioavailability was determined by comparing plasma exposure after IV administration in a [19% hydroxypropyl-β-cyclodextrin / 5% DMSO in saline solution] formulation with plasma exposure after oral gavage in a 0.5% methylcellulose formulation. The oral bioavailability was as high as 51% in mice and 34% in rats. The maximum plasma concentration was reached within 10 minutes in mice and 17 minutes in rats. The drug also rapidly penetrates the blood-brain barrier, thus rapidly reaching pharmacological concentrations in the brain within 30 minutes.

[0059] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol also exhibits sustained levels in plasma and the brain, with a decrease of less than 2-fold on average between 2 and 8 hours. The plasma half-life after oral administration is 4.2 to 7 hours. In contrast, the oral bioavailability of dexmedetomidine is only 8.6%, with a half-life of 2 hours after oral administration in rats. Surprisingly, (R)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol exhibits a much lower oral bioavailability of 7% in rats.

[0060]

[0061] Example 2

[0062] 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 also occur in humans. Dexmedetomidine or (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol at a concentration of 2 μM was incubated with 7 different human CYP enzymes and the NADPH cofactor for up to 60 minutes. The % of the remaining compound was measured. Five CYP enzymes were involved in the metabolism of dexmedetomidine, with 28% (CYP2B6), 84% (CYP2C8), 74% (CYP2C19), 7% (CYP2D6), and 89% (CYP3A4) remaining in the incubation. In contrast, no CYP 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 >90% of the starting concentration were measured in all incubations.

[0063] Example 3

[0064] The activity of (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol was tested in an agonist model and a sedation model.

[0065] The resident-intruder model is an established preclinical model of aggression and agitation and allows for the spontaneous and natural expression of aggressive attack behavior / agitation and defensive behavior in laboratory rodents in a semi-natural laboratory environment. When rodents are exposed to a novel male in their home cage environment, they perceive the novel male animal as an intruder and exhibit a series of defensive behaviors such as anogenital sniffing, chasing, biting, and attacking (Nelson et al., ILAR Journal (2000) 41(3):153-162). The latency to attack and the number of attacks are measures of agitation. (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol was effective (attack inhibition >80%) when orally administered at 2 mg / kg and above in this model, but showed minimal activity at 1 mg / kg.

[0066] The sedative effect was evaluated in the locomotor activity (LMA) model. Mice were placed in a new small room, and their exploratory activity during a 30-minute period was measured as the distance traveled. (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol was partially sedative at 2 mg / kg (approx. 25% inhibition of distance traveled) and 3 mg / kg (<50% inhibition of distance traveled) in the LMA model and minimally sedative at 1 mg / kg.

[0067] Thus, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol at 2 mg / kg was more than 80% effective in the aggressive behavior model (resident-intruder model) at 2 mg / kg, but had only about 25% activity in the sedation model (LMA model). In contrast, dexmedetomidine was more than 80% effective in the resident-intruder model at 0.5 mg / kg, but had minimal effectiveness (20% aggression inhibition) 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. In the LMA model, the maximum activity level achievable with (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol was lower than the maximum activity level achievable with dexmedetomidine.

[0068] These data demonstrate that (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol is superior to dexmedetomidine due to a greater therapeutic window between the anti-agonist and sedative doses. This separation occurs even though both the anti-agonist and sedative effects are effects that require drug activity in the brain.

[0069] If stereochemistry is not specified, the name or structure depiction includes any stereoisomers or any mixture of stereoisomers.

[0070] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (such as amounts, percentages, etc.) used in the specification and claims are to be understood as indicating the exact value in all instances and all instances modified by the term "about". Thus, unless indicated to the contrary, the numerical parameters set forth in the specification and the 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 in light of the number of reported significant digits and by applying ordinary rounding techniques. Rounding of any value to a lesser number of significant digits is specifically contemplated herein. For example, the term "about 1.1" is intended to contemplate a value of "about 1". Similarly, values such as "about 100" are intended to contemplate "about 1×102 The value of “ ” indicates only a single significant digit, and the value should be rounded so that only a single significant digit remains.

[0071] The terms “a”, “the”, and similar referents used in the context of describing embodiments (especially in the context of the following claims) should be construed to cover both the singular and the plural, unless otherwise specified herein or clearly contradicted by the context. Unless otherwise specified herein or clearly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all examples or representative language (e.g., “such as”) provided herein is merely intended to better illustrate the embodiments and does not limit the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the claims.

[0072] Groupings of alternative elements or embodiments disclosed herein should not be construed as limitations. Each member of a group may be cited and claimed individually or in any combination with other members of the group or other elements found herein. For reasons of convenience and / or expediting the application process, one or more members of a group may be included in or deleted from the group. When any such inclusion or deletion occurs, the specification is considered to include the modified group, thus satisfying the written description of all Markush groups (if used in the appended claims).

[0073] Any use of the terms “comprising”, “having”, “including”, etc. is also intended to contemplate the use of “consisting essentially of” and “consisting of”.

[0074] Certain embodiments are described herein, including the best mode known to the inventors for practicing the claimed embodiments. Of course, after reading the foregoing description, variations of these described embodiments will become apparent to those of ordinary skill in the art. The inventors expect those skilled in the art to appropriately employ such variations, and the inventors intend the claimed embodiments to be practiced in a manner different from that specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. In addition, unless otherwise specified herein or clearly contradicted by the context, any combination of the above elements in all possible variations is contemplated.

[0075] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example and not limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to the embodiments precisely shown and described.

Claims

1. A method for treating agitation, the method comprising: Administer (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol to a mammal in need thereof.

2. The method according to claim 1, wherein the agonist is associated with a neurodegenerative disorder.

3. The method according to claim 1, wherein the agonist is associated with a neuropsychiatric disorder.

4. The method according to claim 1, wherein the agonist is associated with surgery.

5. The method according to claim 1, wherein the agonist is associated with traumatic brain injury.

6. The method according to claim 1, wherein the agonist is associated with drug abuse or withdrawal.

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

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

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

10. The method according to 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.

Images