Treatment of sleep-wake disorders
Inventors
Ahnaou, Abdallah • Drinkenburg, Wilhelmus H. I. M. • Palumbo, Joseph • Sporn, Jonathan
Assignees
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Publication Number
US-11753368-B2
Publication Date
2023-09-12
Expiration Date
Abstract
This invention is directed to a method of treating Excessive daytime Sleepiness (EDS) in a subject, comprising the step of administering a therapeutically effective amount of a compound of Formula (I): Formula (I) or a pharmaceutically acceptable salt or ester thereof wherein Rx is a member selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy containing 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy containing 1 to 3 carbon atoms; x is an integer of 1 to 3, with the proviso that R may be the same or different when x is 2 or 3; R1 and R2 can be the same or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to 7 carbon atoms; R1 and R2 can be joined to form a 5 to 7-membered heterocycle substituted with a member selected from the group consisting of hydrogen, alkyl, and aryl groups, wherein the cyclic compound can comprise 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the nitrogen atoms are not directly connected with each other or with the ox en atom.
Core Innovation
Carbamate phenylalkylamino compounds of Formula (I) are disclosed for treating excessive daytime sleepiness (EDS) and pathological somnolence. The disclosure defines substituent options including Rx, x, R1 and R2, including embodiments involving ring formation to provide a phenylalkylamino carbamate structure. The disclosure also provides stereochemical embodiments, including enantiomeric embodiments of Formula I and enantiomerically enriched Formula I.
The disclosure emphasizes enantiomeric embodiments in which Formula I is enantiomerically enriched or substantially free of other enantiomers, including embodiments described with one enantiomer predominating. Specific (D)- or (R)-enantiomer embodiments and a described test compound are presented (Formula Ib and a test compound described as O-carbamoyl-(D)-phenylalaninol/(R)-(beta-amino-benzenepropyl) carbamate).
A sleep-wake pharmacology rationale is described in which the compounds increase wakefulness in animal models, using EEG-quantified vigilance states and sleep stage architecture. The test compound is described to alter vigilance states with increases in active wakefulness and changes in light slow wave sleep, deep slow wave sleep, and REM sleep early, with a later rebound increase in deep sleep.
The treatment context is described as use for multiple etiologies/causes of sleep-wake disorders, including misalignments of the body's circadian pacemaker with the environment, jet lag, shift work, and sedating drugs. The disclosure further characterizes the treatment as prophylaxis and as a reduction of severity, and identifies that the pharmacology supports treating sleep-wake disorder causes selected from a defined group.
Claims Coverage
The document includes two independent claims covering methods of treating a sleep-wake disorder by administering a therapeutically effective amount of a Formula (I) compound or pharmaceutically acceptable salt or ester, and separately an enantiomer of Formula I substantially free of other enantiomers or an enantiomeric mixture in which one enantiomer predominates; each independent claim ties treatment to a set of causes for the sleep-wake disorder.
Treating a sleep-wake disorder with Formula (I) where R, R1, R2 are hydrogen and x=1
Administration of a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein R, R1, R2 are hydrogen and x=1, for treating a sleep-wake disorder in a subject; the cause of the sleep-wake disorder is selected from stroke, narcolepsy, idiopathic CNS hypersomnia, sleep deficiency, sleep apnea, obstructive sleep apnea, insufficient nocturnal sleep, chronic pain, acute pain, Parkinson's disease, urinary incontinence, multiple sclerosis fatigue, Attention Deficit Hyperactivity Disorder (ADHD), Alzheimer's disorder, cardiac ischemia, misalignments of the body's circadian pacemaker with the environment, jet lag, shift work, and sedating drugs.
Treating a sleep-wake disorder with a stereochemically defined Formula I enantiomer
Administration of a therapeutically effective amount of an enantiomer of Formula I substantially free of other enantiomers or an enantiomeric mixture wherein one enantiomer predominates, or a pharmaceutically acceptable salt or ester thereof, wherein R, R1, R2 are hydrogen and x=1, for treating a sleep-wake disorder in a subject; the cause of the sleep-wake disorder is selected from stroke, narcolepsy, idiopathic CNS hypersomnia, sleep deficiency, sleep apnea, obstructive sleep apnea, insufficient nocturnal sleep, chronic pain, acute pain, Parkinson's disease, urinary incontinence, multiple sclerosis fatigue, Attention Deficit Hyperactivity Disorder (ADHD), Alzheimer's disorder, cardiac ischemia, misalignments of the body's circadian pacemaker with the environment, jet lag, shift work, and sedating drugs.
Across the two independent claims, the inventive coverage is directed to treating sleep-wake disorders by administering Formula (I) carbamate phenylalkylamino compounds, with one claim covering a defined ring/substituent condition and the other adding stereochemical restriction to an enantiomer substantially free of other enantiomers or an enantiomeric mixture where one enantiomer predominates.
Stated Advantages
Compounds increase wakefulness in animal models, as supported by EEG-quantified vigilance state changes.
The described pharmacology includes increased active wakefulness and sleep-stage shifts, including increased transitions from sleep stages to wake.
The described pharmacology includes changes to REM sleep timing, including increased REM sleep onset latency.
The disclosure describes a rebound increase in deep sleep later after early sleep suppression effects.
The treatment is described as usable across multiple EDS etiologies/causes, including circadian/environmental misalignment scenarios.
The disclosure characterizes the treatment as prophylaxis and as reduction of severity.
Documented Applications
Treatment of excessive daytime sleepiness (EDS) and pathological somnolence (sleep-wake disorder treatment context).
Treatment for sleep-wake disorder causes including circadian pacemaker/environment misalignment, jet lag, shift work, and sedating drugs.
Use in a sleep-wake pharmacology setting with EEG-quantified vigilance states in animal models, including comparison to cocaine and amphetamine.
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