EP-4734971-A2 - DRUG TO TREAT STIMULANT ADDICTION

Abstract

Disclosed are pharmaceutical preparations comprising bromantane or an analogue of bromantane, and methods of using said preparations for pharmacotherapy to alleviate withdrawal syndrome and prevent relapse in the treatment of stimulant use disorder, to transition patients off medications that have abuse or addiction liabilities, or to facilitate extinction learning in the treatment of mental disorders.

Inventors

• RAUTIOLA, Davin

Assignees

• Single Dose Therapeutics, Inc.

Dates

Publication Date

20260506

Application Date

20240810

Claims (8)

1. 1. A method of treating a disorder of maladaptive learning, the method comprising: a. assessing a subject suffering from symptoms of a mental disorder or syndrome to determine the presence of one or more features of maladaptive learning that cause, arise from, or exacerbate the symptoms; and b. facilitating extinction learning in the subject in need thereof by administering a therapeutically effective amount of a pharmaceutical preparation of bromantane to the subject.
2. 2. The method of Claim 1, wherein the disorder of maladaptive learning is a substance use disorder.
3. 3. The method of Claim 2, wherein the substance use disorder is stimulant use disorder.
4. 4. A method of treating a disorder of maladaptive learning, the method comprising: a. assessing a subject suffering from symptoms of a mental disorder or syndrome to determine the presence of one or more features of maladaptive learning that cause, arise from, or exacerbate the symptoms; and b. facilitating extinction learning in the subject in need thereof by administering to the subject an effective amount of a pharmaceutical preparation of an analogue of bromantane having a chemical structure according to Formula I, wherein the molecular scaffold consists of an adamantane ring system (A) covalently linked to a benzene ring (B) by a linker (L); Ri, Ri, and Rs are substituents on A that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, or ethyl; R4, Rs, and Re are substituents on B that are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxide, methoxide, methyl, ethyl, or fused 5 -member ring (pyrrole, furan, thiophene, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyrazole, triazole, tetrazole, oxadiazole, thiadiazole, dioxole, dioxane, oxathiolane, or dithiolane); L is independently selected from amine, amide, or imine.
5. 5. Tire method of Claim 4, wherein L is amine.
6. 6. Tire method of Claim 4, wherein L is amide.
7. 7. The method of Claim 4, wherein L is imine.
8. 8. A pharmaceutical preparation comprising: a. a therapeutically effective amount of bromantane as a drug substance in the form of salt, cocrystal, solvate, complex, or conjugate; and b. one or more pharmaceutically acceptable excipients that function to inhibit crystallization, wherein, the morphology of the drug substance is amorphous.

Description

INVENTION TITLE Drug to treat stimulant addiction ABSTRACT Disclosed are pharmaceutical preparations comprising bromantane [FIG. 1] or an analogue of bromantane, and methods of using said preparations for pharmacotherapy to alleviate withdrawal syndrome and prevent relapse in the treatment of stimulant use disorder, to transition patients off medications that have abuse or addiction liabilities, or to facilitate extinction learning in the treatment of mental disorders. FILED OF INVENTION [0001] The present invention relates to the field of medicine. Specifically, the invention involves the use of bromantane or its analogues to treat disorders of maladaptive learning. BACKGROUND [0002] Central nervous system stimulants are known to be addictive. Tolerance to the effects of stimulants develops quickly and can lead to debilitating chronic dependance or overdose. Morbidity and mortality rates due to abuse of illicit stimulants (e.g., methamphetamine, cocaine) as well as misuse of licit stimulants (e.g., prescription amphetamine) have been increasing over the years, constituting a public health crisis. [0003] Patients who are prescribed stimulant medications to treat certain neurological conditions under the supervision of a physician are also at risk of developing dependencies that can result in adverse effects which outweigh the benefits of treatment. For example, tire current standard of care and first-line treatment for attention deficit disorders entails medication with either the benzylpiperazine-derived stimulant methylphenidate or phenethylamine-derived stimulant amphetamine. Patients taking these medications over a prolonged period of time tend to experience reduced efficacy, and discontinuing such prescriptions has been shown to worsen the original symptoms. [0004] To date, no medication has been approved by the US Food and Drug Administration (FDA) for use in the treatment of Stimulant Use Disorder (StUD), commonly referred to as stimulant addiction or dependence (e.g., amphetamine dependence, cocaine dependence). In the prior art, behavioral and social interventions (e.g., cognitive behavioral therapy, contingency management) are the primary methods utilized to treat StUD; however, the success rate of those psychological approaches is moderate.1 Pharmacological approaches to treatment have aimed to develop drugs that target specific neurotransmitter systems such as dopaminergic, serotonergic, GABAergic, glutamatergic, adrenergic, opioidergic, or muscarinic receptors; hormonal systems such as cholecystokinin or ghrelin receptors; or metabolic pathways such as phosphodiesterases or hydroxysteroid dehydrogenase.2 Likewise, drugs with neuroprotective. anxiolytic, antidepressant, mood stabilizing, psychostimulant, antipsychotic, or immunotherapeutic properties have been investigated. However, a viable pharmacotherapy that significantly impacts the pathology of stimulant dependance without adverse side effects has remained elusive.3 4 [0005] StUD and other forms of addiction are perpetuated, in part, by positive reinforcement, negative reinforcement, incentive salience, stimulus-response associations, and inhibitory control dysfunction? For example, the euphoric effects of a drug provide positive reinforcement, which increase the likelihood of repeated drug use and often drives drug-seeking behavior. Symptoms such as dysphoria or physical discomfort experienced during withdrawal from a drug are examples of negative reinforcement. In turn, psychophysiological associations are learned through these reinforcement mechanisms. Learned associations are not intrinsically adverse, but those that manifest as cravings, habits, or impulsivity can be detrimental. In the context of mental disorders such as StUD, incentive salience (‘cravings’), stimulus-response associations (‘habits’), and inhibitory control dysfunction (‘impulsivity') are indicative of maladaptive learned associations that result in subconscious motivational states which shift attention toward counterproductive thoughts or activities, such as drug use. [0006] Mental disorders characterized by the formation of inappropriate or dysfunctional associations between stimuli and responses can be classified as disorders of maladaptive learning. These disorders arise when normal learning processes become distorted, leading to behaviors that are harmful, excessive, or persist despite negative consequences. StUD is one such example. Maladaptive learning is challenging to rectify because learned responses tend to persist even after external reinforcement and triggers are eliminated. In other words, relapse potential remains high until the imprinted response is sufficiently unlearned. Extinction of maladaptive responses is the basis for extinction learning in the treatment of mental disorders that arise from maladaptive learning. While pharmacotherapies such as cycloserine, selective serotonin reuptake inhibitors (e.g., paroxetine, sertraline), and propranolol