Atypical inhibitors of monoamine transporters; method of making; and use thereof
Inventors
Newman, Amy Hauck • GIANCOLA, JoLynn Barbara • Slack, Rachel D.
Assignees
US Department of Health and Human Services
Publication Number
US-11365195-B2
Publication Date
2022-06-21
Expiration Date
2038-11-12
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Abstract
Disclosed herein are a series of modafinil analogue compounds that bind with moderate to high affinity to the dopamine (DA) transporter (DAT) and several analogues also having affinity for the serotonin (5-HT) transporter (SERT) and/or sigma-1 receptor. Employing aminopiperidine, piperidineamino, spirobicyclodiaza, or substituted piperazine functional groups, desired dopamine transporter affinity has been retained along with improved metabolic stability over unsubstituted piperazine ring analogues. Importantly, these compounds have no predicted addictive liability. Also disclosed are methods for treating substance use disorders as well as other neuropsychiatric disorders such as ADHD, depression, narcolepsy, and cognitive impairment.
Core Innovation
The invention discloses a series of modafinil analogue compounds that bind with moderate to high affinity to the dopamine transporter (DAT), with several analogues also having affinity for the serotonin transporter (SERT) and/or sigma-1 receptor. These compounds employ aminopiperidine, piperidineamino, spirobicyclodiaza, or substituted piperazine functional groups, retaining desired dopamine transporter affinity along with improved metabolic stability compared to unsubstituted piperazine ring analogues. Importantly, these compounds are designed to have no predicted addictive liability.
The problem addressed by the invention is the lack of FDA-approved pharmacological treatments for cocaine- or methamphetamine-use disorders, despite the addictive nature of these psychostimulants. Existing modafinil analogues with high binding affinity to DAT showed low efficacy in models of methamphetamine intake, possibly due to poor pharmacokinetics, and some exhibited psychostimulant-like behavioral profiles, indicating addictive liability. There is a need for high affinity DAT inhibitors that have enhanced metabolic stability without addictive liability to allow development toward pharmacotherapeutic treatments for psychostimulant use disorders.
The invention also provides pharmaceutical compositions comprising a compound of Formula I and methods for eliciting wake-promoting, cognition-enhancing or mood-enhancing effects. Furthermore, methods for treating substance use disorders, attention deficit (hyperactivity) disorder, depressive disorders, sleep disorders, and cognitive impairment are included, utilizing therapeutically effective amounts of the disclosed compounds or pharmaceutical compositions thereof.
Claims Coverage
The patent contains one independent claim with multiple dependent claims detailing various embodiments of the compounds and compositions. The following are the main inventive features extracted from the independent claim and key dependent claims.
Compound of Formula I with defined substituents
The invention claims compounds of Formula I, or pharmaceutically acceptable salts thereof, where R1 and R2 independently are C6-C12 aryl, monocyclic heteroaryl, or bicyclic heteroaryl optionally substituted with specific groups; Y is S, S(O), or S(O)2; n is 1, 2, or 3; Z is O, S, or 2H; m is 0 or 1; A is one of A1 to A4; R3-R8 have defined substituents with specified provisos ensuring structural variations for stable compounds.
Substituted phenyl groups with fluoro substitution
Compounds or salts in which each of R1 and R2 independently is an optionally substituted phenyl, specifically where substitution is fluoro.
Sulfoxide fragment stereochemistry
Compounds in which the sulfoxide fragment (Y = S(O)) can be racemic or have a specific (R) or (S) configuration.
Pharmaceutical compositions including compounds of Formula I
Pharmaceutical compositions comprising a compound or salt of Formula I and at least one pharmaceutically acceptable carrier, formulated for various administration routes such as injectable fluids, aerosols, creams, gels, tablets, capsules, syrups, ophthalmic solutions, or transdermal patches.
Methods of treatment using compounds of Formula I
Methods for treating substance use disorders, attention deficit (hyperactivity) disorder, depressive disorders, sleep disorders, cognitive impairment or eliciting wake-promoting, cognition-enhancing or mood-enhancing effects by providing therapeutically effective amounts of compounds or salts of Formula I, optionally as pharmaceutical compositions.
The claims comprehensively cover the novel compounds of Formula I with detailed structural variations, their pharmaceutical compositions, and their therapeutic uses for treating neuropsychiatric and substance use disorders as well as cognitive enhancement, with specific stereochemical and substitution embodiments enhancing the scope and potential utility of the invention.
Stated Advantages
The compounds retain desired dopamine transporter affinity with improved metabolic stability over unsubstituted piperazine ring analogues.
They have no predicted addictive liability, which improves their therapeutic potential for treating substance use disorders.
Increased sigma-1 receptor and serotonin transporter affinities may improve efficacy in attenuating substance use disorders and preventing relapse.
These compounds do not produce cocaine-like behavioral effects, limiting addictive liability.
Potential to treat other neuropsychiatric disorders such as ADHD, depression, narcolepsy, cognitive impairment, and sleep disorders.
They may be useful for patients with depressive disorders who do not respond to typical SSRIs or TCAs by elevating both serotonin and dopamine levels.
Documented Applications
Treatment of substance use disorders including cocaine and methamphetamine use disorders.
Treatment of attention deficit (hyperactivity) disorder (ADHD).
Treatment of depressive disorders.
Treatment of sleep disorders such as narcolepsy.
Treatment of cognitive impairment including cognitive impairment related to psychostimulant abuse, schizophrenia, NeuroAIDS, Alzheimer's disease, and age-related memory decline.
Use for eliciting wake-promoting, cognition-enhancing or mood-enhancing effects in patients.
Potential applications in smoking cessation, cancer-associated fatigue, multiple sclerosis-associated fatigue, jet-lag, post-operative grogginess, obesity as an anorectic agent, bipolar disorder, anxiety, and obsessive-compulsive disorders.
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