NZ787958A - Methods of treating circadian rhythm sleep disorders - Google Patents

Abstract

Methods of treating irregular sleep-wake rhythm disorder in subjects and compositions for use in the same are disclosed.

Description

s of Treating Circadian Rhythm Sleep Disorders The present application claims the benefit of priority to U.S.

Provisional Application No. 62/335,599 filed May 12, 2016, U.S. Provisional ation No. 62/335,611 filed May 12, 2016, U.S. Provisional Application No. ,976 filed October 27, 2016, U.S. Provisional Application No. 62/414,599 filed October 28, 2016, and U.S. Provisional Application No. 62/414,606 filed October 28, 2016; the entire contents of each are incorporated herein by reference. The present application is a divisional of New Zealand patent application 748555, which is the national phase entry of PCT international ation (published as of each of which is incorporated by reference herein.

Novel methods for and compositions for use in treating at least one circadian rhythm sleep disorder using a compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, are sed.

Irregular Sleep-Wake Rhythm Disorder (“ISWRD”) is an internationally recognized and accepted disorder. The sleep-wake pattern exhibited by subjects with ISWRD is diagnostically distinct from insomnia.

Unlike insomnia er, subjects with ISWRD are ng intermittently and irregularly during the day in addition to not sleeping continuously at night. In contrast, subjects with insomnia may have reduced sleep maintenance, but are not sleeping intermittently and irregularly during the day. ISWRD bances are therefore sometimes referred to as fragmentation of the normal circadian, or 24-hour, diurnal pattern of sleep and wake.

ISWRD is fied and coded as a distinct disorder in several International fication systems including Circadian Rhythm Sleep Disorder, Irregular Sleep-Wake Type G47.23 (ICD-10); Circadian Rhythm Sleep Disorder, Irregular Sleep-Wake Type 307.45-3 (DSM-5); and ian Rhythm Sleep- Wake Disorder, Irregular Wake Rhythm Disorder 307.45-3 (ICSD-3).

There exists an unmet medical need for a safe and effective y that is conveniently administered to address the irregular sleep and wake pattern, which in turn could help with problematic behaviors (e.g., sundowning, restlessness, agitation, and/or wandering) and cognitive difficulties (e.g., with memory and/or attention) associated with ISWRD.

The orexin neurotransmitter pathway is directly ed in modulation of the circadian sleep-wake rhythm, with orexins promoting wakefulness. Orexin receptors are G-protein coupled receptors found predominately in the brain. Their endogenous ligands, orexin-A and orexin-B, are sed by neurons localized in the alamus. Orexin-A is a 33 amino acid peptide and orexin-B is a 28 amino acid peptide. Sakurai, T., et a/., Cell, 1998, 92, 573-85. There are two subtypes of orexin receptors: orexin receptor 1 and orexin receptor 2. Orexin receptor 1 binds orexin-A preferentially, while orexin receptor 2 binds both orexin-A and orexin-B. It has been observed that orexins control wake-sleep conditions. Chemelli, R.M., et a/., Cell, 1999, 98, . Lemborexant is being studied for the treatment of ia er and for the treatment of at least one circadian rhythm sleep disorder in subjects suffering from dementia due to Alzheimer’s disease (“AD”) and/or related disorders and/or mild cognitive impairment due to Alzheimer’s disease. See, e.g., US. Patent Application Publication No. 2012/0095031 and US. Provisional Patent Application Nos. 62/335,599 and 62/335,611, the ts of which are herein incorporated by reference.

In some embodiments, a method of ng at least one circadian rhythm sleep disorder comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), or ceutically acceptable salts and es thereof, is provided. In some embodiments, the at least one circadian rhythm sleep er may be chosen from sleep disruption, sleep- wake fragmentation, circadian rhythm sleep disorder, and ISWRD. In some embodiments, the at least one ian rhythm sleep disorder is ISWRD. In some embodiments, the ISWRD is due to traumatic brain injury. In some embodiments, the ISWRD is due to neurodevelopmental disorders.

In some embodiments, ISWRD is due to dementia. In some embodiments, ISWRD is due to dementia due to Alzheimer’s disease and/or related disorders. In some embodiments, ISWRD is due to mild cognitive ment due to Alzheimer’s disease. In some embodiments, ISWRD is due to mild cognitive impairment due to related disorders. In some embodiments, the ISWRD is due to dementia due to related disorders. In some embodiments, the dementia due to related ers is chosen from vascular dementia, fronto- al dementia, Parkinson’s Disease, and dementias due to other causes.

In some embodiments, the dementia due to related disorders is Parkinson’s Disease. In some embodiments, the subject suffers from at least one other circadian rhythm sleep disorder in addition to ISWRD.

AD and related disorders are a large and increasing public health concern, as the population of older adults increases globally. Among the many symptoms that are associated with dementia, sleep and wake disturbances are both common and are risk factors themselves that contribute to the development and worsening of the neuropathology and symptomatology, including cognitive function and behavioral disturbances ly referred to in the aggregate as Behavioral and Psychological ms of Dementia (BPSD), based on animal models and human studies.

Sleep and wake disturbances appear early in the course of e, e.g., Alzheimer’s Disease, ia, etc, and are associated generally with a loss of circadian rhythmicity. Dementia subjects have a marked decrease in sleep maintenance when they attempt to sleep during the night and spend a large portion of the day asleep. This pattern is referred to as sleep- wake fragmentation and is characterized by decreased amplitudes of the sleep- wake and ess rhythms, with less predictability of the sleep-wake pattern from day to day.

As dementia progresses, subjects often exhibit behavioral disturbances such as agitation and night wandering. They often st disturbed behaviors that are often described as “sundowning” because of their occurrence in the late oon and early evening. ted sleep can also increase the risk for falling, based in part on disorientation after awakening from sleep. It has been shown that subjects with the most disturbed sleep at night have more problematic behaviors during the day, for example, restlessness, agitation, and wandering. These behaviors, which also disrupt the sleep of caregivers, are reasons underlying some decisions to institutionalize dementia subjects.

Animal and human studies support the view that poor sleep is associated with amyloid burden in AD. Recent studies have shown that levels of amyloid beta (“AB”, a type of peptide that can aggregate into toxic forms) in the brain correlate with time spent awake, subsequently sing during sleep. Sleep deprivation increases the concentration of soluble AB and s in c accumulation of AB, whereas sleep extension has the opposite effect.

Kang, J.-E., eta/., Science, 2009, 326, 1005-7. Roh, J.H., eta/., J. Exp. Med, 2014, 211, 2487-96. ted sleep has been associated with higher AB levels and impaired learning. , B.A., eta/., Nat. Neurosci., 2015, 18, 1051-7.

Once AB accumulates and toxic aggregates and ble fibrils that lead to amyloid plaque develop, these may impair brain function and/or lead to neuronal degeneration that leads to increased wakefulness and altered sleep patterns.

Taken together, these studies highlight the bi-directionality of the problem. The neuropathological changes associated with dementia worsen sleep, and poor sleep worsens cognitive function and may contribute directly to the progression of the pathological disease process and the clinical course of s. If sleep has a normalizing/reducing function on AB levels, helping AD subjects to restore normal sleep patterns might result in reduced AB depositions.

Thus, there exists an unmet medical need for a safe and effective therapy that is conveniently administered to address wake fragmentation in ts with ISWRD, which in turn would help with the problematic behaviors (e.g., sundowning, restlessness, agitation, and/or wandering) and cognitive difficulties (e.g., with memory and/or attention) associated with dementia due to Alzheimer’s disease and/or related disorders, and/or mild cognitive impairment due to Alzheimer’s disease, and may also help to slow the brain degeneration that occurs in AD by reducing the accumulation of AB. Increased sleep duration, especially with particular sleep stages such as slow-wave sleep and REM sleep, may improve cognition. These stages are associated with performance on working memory tasks and memory consolidation, respectively. ing sleep may also e behavioral disturbances in AD.

In animal models of Alzheimer’s e, orexin was found to increase soluble ABaccumulation in the brain; conversely, chronic treatment with a dual orexin receptor antagonist or knocking out the orexin gene decreased soluble AB and AB plaque accumulation. Kang, J.-E., et a/., Science, 2009, 326, 1005-7; Roh, J.H., eta/., Journal of Experimental Medicine, 2014, 211, 2487-96. Accumulation of AB plaque is associated with ias such as AD. In some embodiments, there is a ion in the accumulation of AB plaque in the brain. In some embodiments, there is a reduction of soluble toxic AB ates.

In some embodiments, a method of improving continuity of nocturnal sleep in a subject with ISWRD comprising administering an effective amount of a nd of Formula (I), or pharmaceutically acceptable salts and solvates thereof, to a subject in need thereof is provided.

In some embodiments, a method of improving behaviors and cognitive difficulties ated with ISWRD in a subject comprising administering an effective amount of a nd of Formula (I), or pharmaceutically acceptable salts and solvates f, to a subject in need thereof is provided.

In some embodiments, a method of treating or alleviating ISWRD in a subject comprising administering an effective amount of a compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, to a subject in need thereof is provided. In some embodiments, the ISWRD may be ated with dementias such as AD.

In some embodiments, a method for treating excessive daytime sleepiness and/or voluntary or involuntary napping in a subject with ISWRD sing administering an effective amount of a compound of Formula (I), or ceutically acceptable salts and solvates thereof, to a subject in need thereof is provided.

In some embodiments, the at least one circadian rhythm sleep disorder is chosen from sleep tion, sleep fragmentation, circadian rhythm sleep disorder, and irregular sleep-wake rhythm disorder.

In some embodiments, a method of stabilizing one or more circadian rhythms in a subject sing administering an effective amount of a compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, to a subject in need f is provided. In some embodiments, a method of improving one or more circadian rhythms in a t comprising administering an effective amount of a compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, to a subject in need thereof is provided.

In some embodiments, a method of improving continuity of nocturnal sleep in a subject with dementia comprising administering an ive amount of a compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, to a subject in need thereof is provided. In some embodiments, the dementia is due to Alzheimer’s disease and/or related disorders. In some embodiments, a method of improving continuity of nocturnal sleep in a subject with mild ive impairment due to Alzheimer’s disease comprising administering an effective amount of a compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, to a subject in need f is provided.

In some embodiments, a method of improving ors and cognitive ulties associated with dementia in a subject with dementia comprising administering an effective amount of a compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, to a subject in need thereof is provided. In some embodiments, the dementia is due to Alzheimer’s disease and/or related disorders.

In some ments, a method for treating excessive daytime sleepiness and/or napping in a subject with dementia comprising administering an ive amount of a compound of Formula (I), or pharmaceutically acceptable salts and es thereof, to a subject in need thereof is provided.

In some embodiments, the dementia is due to Alzheimer’s disease and/or related disorders. In some embodiments, a method for treating excessive daytime sleepiness and/or napping in a subject with mild cognitive impairment due to Alzheimer’s disease comprising administering an effective amount of a compound of Formula (I), or ceutically acceptable salts and solvates thereof, to a subject in need thereof is provided.

In some embodiments, the s bed herein may consolidate sleep during the nighttime hours. In some embodiments, the methods bed herein may consolidate wakefulness during the daytime hours. In some embodiments, there may be an increase in wake efficiency. In some embodiments, there may be an increase in sleep efficiency. In some embodiments, the methods described herein may decrease daytime ness.

In some embodiments, there may be a decrease in daytime sleepiness and/or daytime napping. In some embodiments, daytime alertness may be improved.

In some embodiments, a stabilization of one or more circadian rhythms may result. In some embodiments, an improvement of one or more ian rhythms may result.

In some embodiments, there is a clinical stabilization in cognitive impairment due to Alzheimer’s disease in the subject. In some embodiments, there is a clinical improvement in cognitive ment due to Alzheimer’s disease in the subject. In some embodiments, there is a clinical reduction in rate of decline in ive impairment due to Alzheimer’s disease in the subject. In some embodiments, there is a clinical stabilization in the subject with ia due to mer’s disease and/or related disorders. In some embodiments, there is a clinical improvement in the subject with ia due to Alzheimer’s disease and/or related disorders. In some embodiments, there is a clinical reduction in rate of decline in the subject with dementia due to Alzheimer’s disease and/or related disorders. In some embodiments, the methods described herein se oral disturbances in the subject. [26A] Particular features of the present sure are set out in the following numbered paragraphs: 1. A method of treating irregular sleep-wake rhythm disorder in a subject comprising administering to a subject in need thereof an effective amount of at least one nd chosen from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing. 2. The method according to paragraph 1, wherein the irregular sleepwake rhythm disorder is due to traumatic brain injury. 3. The method according to paragraph 1, n the irregular sleepwake rhythm disorder is due to at least one neurodevelopmental disorder. 4. The method according to paragraph 1, wherein the irregular sleepwake rhythm disorder is due to dementia due to Alzheimer’s disease and/or [FOLLOWED BY PAGE 9a] related disorders.

. The method according to paragraph 1, wherein the irregular sleepwake rhythm disorder is due to dementia due to Alzheimer’s disease. 6. The method according to any one of paragraphs 1 to 3, n the subject suffers from at least one other circadian rhythm sleep disorder in addition to irregular sleep-wake rhythm disorder. 7. A method of improving continuity of nocturnal sleep in a subject with irregular sleep-wake rhythm disorder comprising administering to a t in need thereof an effective amount of at least one compound chosen from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing. 8. A method of ing behaviors and cognitive difficulties associated with irregular sleep-wake rhythm disorder comprising administering to a subject in need thereof an effective amount of at least one compound chosen from compounds of a (I), ceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing. 9. A method of treating ive daytime sleepiness and/or napping in a subject with irregular sleep-wake rhythm disorder comprising administering to a subject in need thereof an effective amount of a compound chosen from compounds of Formula (I), ceutically acceptable salts of compounds of a (I), and solvates of any of the foregoing.

. The method according to any one of paragraphs 1 to 9, n administration of the at least one compound chosen from compounds of Formula (I), pharmaceutically acceptable salts of nds of Formula (I), and solvates of any of the foregoing, consolidates sleep during the nighttime hours. 11. The method according to any one of paragraphs 1 to 10, wherein administration of the at least one nd chosen from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), and es of any of the foregoing, consolidates wakefulness during the daytime hours. 12. The method according to any one of paragraphs 1 to 11, wherein [FOLLOWED BY PAGE 9b] the subject experiences an increase in sleep efficiency. 13. The method according to any one of paragraphs 1 to 12, wherein the subject experiences a decrease in daytime sleepiness and/or daytime napping. 14. The method according to any one of paragraphs 1 to 13, wherein the subject experiences an increase in daytime alertness.

. The method according to any one of paragraphs 1 to 14, wherein the administration of the at least one compound chosen from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing, results in a ization of one or more ian rhythms. 16. The method according to any one of paragraphs 1 to 14, wherein the administration of the at least one compound chosen from compounds of Formula (I), pharmaceutically able salts of compounds of Formula (I), and solvates of any of the ing, results in an improvement of one or more ian rhythms. 17. A method of treating at one least circadian rhythm sleep disorder in a subject with dementia due to Alzheimer’s e and/or related disorders comprising administering to a subject in need thereof an effective amount of at least one compound chosen from compounds of a (I), ceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing. 18. A method of treating at least one circadian rhythm sleep disorder in a subject with mild cognitive impairment due to Alzheimer’s disease sing administering to a subject in need thereof an effective amount of at least one compound chosen from nds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing. 19. The method according to any one of paragraphs 17 to 18, n the at least one circadian rhythm sleep disorder is chosen from sleep disruption, sleep-wake fragmentation, circadian rhythm sleep disorder, and irregular sleepwake rhythm disorder.

[FOLLOWED BY PAGE 9c] . A method of ing continuity of nocturnal sleep in a subject with dementia due to Alzheimer’s disease and/or related disorders comprising administering to a subject in need thereof an effective amount of at least one compound chosen from compounds of Formula (I), pharmaceutically acceptable salts of nds of Formula (I), and solvates of any of the foregoing. 21. A method of improving continuity of nocturnal sleep in a subject with mild cognitive impairment due to Alzheimer’s disease comprising administering to a subject in need thereof an effective amount of at least one compound chosen from nds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing. 22. A method of improving at least one behavior and/or cognitive difficulty ated with dementia in a subject with dementia due to Alzheimer’s disease and/or related disorders comprising administering to a subject in need f an effective amount of at least one compound chosen from compounds of Formula (I), pharmaceutically acceptable salts of compounds of a (I), and solvates of any of the foregoing. 23. A method of improving at least one behavior and/or cognitive difficulty associated with dementia in a subject with mild cognitive impairment due to Alzheimer’s disease comprising stering to a subject in need thereof an effective amount of at least one compound chosen from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing. 24. A method for treating ive daytime sleepiness and/or napping in a subject with dementia due to Alzheimer’s disease and/or related disorders comprising administering to a t in need thereof an effective amount of at least one compound chosen from compounds of Formula (I), pharmaceutically acceptable salts of nds of Formula (I), and solvates of any of the foregoing.

. A method for treating ive e sleepiness and/or napping in a subject with mild cognitive impairment due to Alzheimer’s e comprising administering to a subject in need thereof an effective amount of at least one compound chosen from compounds of Formula (I), pharmaceutically [FOLLOWED BY PAGE 9d] acceptable salts of compounds of Formula (I), and solvates of any of the 26. The method according to any one of paragraphs 17 to 25, wherein administration of the at least one compound chosen from compounds of Formula (I), ceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing, consolidates sleep during the nighttime hours. 27. The method according to any one of paragraphs 17 to 26, wherein stration of the at least one compound chosen from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing, consolidates wakefulness during the e hours. 28. The method according to any one of paragraphs 17 to 27, wherein the subject experiences an increase in sleep efficiency. 29. The method according to any one of paragraphs 17 to 28, wherein the subject experiences a decrease in daytime sleepiness and/or daytime napping.

. The method according to any one of paragraphs 17 to 29, wherein the subject experiences an increase in wake efficiency. 31. The method according to any one of aphs 17 to 30, wherein the subject experiences an increase in daytime alertness. 32. The method according to any one of paragraphs 17 to 31, wherein the subject experiences a clinical stabilization in cognitive impairment due to Alzheimer’s disease and/or related ers. 33. The method according to any one of paragraphs 17 to 32, wherein the subject experiences a clinical improvement in the cognitive ment due to Alzheimer’s disease and/or related disorders. 34. The method according to any one of paragraphs 17 to 33, wherein the subject experiences a clinical reduction in rate of decline in the cognitive impairment due to Alzheimer’s disease and/or related disorders.

. The method ing to any one of paragraphs 17 to 34, wherein the subject ences a al stabilization of the dementia due to [FOLLOWED BY PAGE 9e] mer’s disease and/or related disorders. 36. The method according to any one of paragraphs 17 to 35, wherein the subject experiences a clinical improvement of the dementia due to Alzheimer’s disease and/or related disorders. 37. The method according to any one of paragraphs 17 to 36, wherein the subject experiences a clinical reduction in rate of decline in dementia due to Alzheimer’s disease and/or related disorders. 38. The method according to any one of paragraphs 17 to 37, wherein the subject experiences a decrease in behavioral bances. 39. The method according to any one of paragraphs 1 to 38, wherein the subject experiences a reduction in the accumulation of Aβ plaque in the brain. 40. The method according to any one of paragraphs 1 to 39, wherein the subject experiences a reduction of soluble toxic Aβ aggregates. 41. A method of stabilizing one or more circadian rhythms in a subject comprising administering to a subject in need thereof an effective amount of at least one compound chosen from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing. 42. A method of ing one or more circadian s in a subject comprising administering to a subject in need thereof an effective amount of at least one compound chosen from compounds of Formula (I), pharmaceutically able salts of compounds of Formula (I), and es of any of the foregoing. 43. The method according to aph 41 or 42, n administration of the at least one compound chosen from compounds of a (I), pharmaceutically acceptable salts of compounds of Formula (I), and solvates of any of the foregoing, consolidates sleep during the nighttime hours. 44. The method according to any one of aph 41 to 43, wherein administration of the at least one compound chosen from compounds of Formula (I), pharmaceutically acceptable salts of compounds of Formula (I), [FOLLOWED BY PAGE 9f] and solvates of any of the foregoing, consolidates wakefulness during the daytime hours. 45. The method according to any one of paragraphs 41 to 44, wherein the subject experiences an increase in sleep efficiency. 46. The method according to any one of paragraphs 41 to 45, wherein the subject experiences a decrease in daytime sleepiness and/or daytime napping. 47. The method ing to any one of paragraphs 41 to 46, n the subject experiences an increase in daytime alertness.

Brief Description of the Drawings FIGS. 1A-1C show the distribution for each of the three nce states: wakefulness (), non-REM sleep (), and REM sleep () among the light (Zeitgeber (ZT) 0.5-12) and the dark (ZT 12-24) times of the circadian day, and the influence of administration of a compound of Formula shows sleep and REM sleep latency after administration of vehicle or a compound of Formula (I).

As used , the following tions shall apply unless otherwise indicated.

[FOLLOWED BY PAGE 10] As used herein, the term “compound of Formula (l)” refers to exant, a compound having the structure: HNQFN_ F(3 E0 also known as (1 2—(((2,4-dimethylpyrimidiny|)oxy)methy|)(3- f|uorophenyl)-N-(5-f|uoropyridinyl)cyclopropanecarboxamide or (1 R,2$)-2— (((2,4-dimethy|pyrimidiny|)oxy)methy|)(3-f|uorophenyl)-N-(5-f|uoropyridin y|)cyc|opropanecarboxamide, or pharmaceutically acceptable salts and solvates thereof. In some ments, the compound of Formula (I) may be a free base, a pharmaceutically acceptable salt, a hydrate or other solvate, a polymorph, or a combination of any two or more of the foregoing. In some embodiments, the compound of Formula (I) may be a free base. In some embodiments, the nd of Formula (I) may be a pharmaceutically acceptable salt of a compound of Formula (I). In some embodiments, the compound of Formula (I) may be a solvate of a compound of a compound of Formula (I). In some embodiments, the compound of Formula (I) may be a hydrate of a compound of Formula (I). In some embodiments, the compound of Formula (I) may be a polymorph of a compound of Formula (I).

As used herein, the term “effective ” means an amount ient to effect an intended result including, but not limited to, treatment of at least one symptom associated with a disorder or condition, such as, for example, ISWRD and/or Alzheimer’s disease, as illustrated below.

As used herein, the term “subject” means an animal subject, such as a mammalian subject, and for example, a human being. As used herein, the subject may be of any age. In some embodiments, the age of the subject may range from less than one year to more than 95 years of age. In some embodiments, the age of the subject may range from less than one year to 15 years of age. In some embodiments, the age of the t may range from 10 years of age to 30 years of age. In some embodiments, the age of the subject may range from 25 years of age to 45 years of age. In some embodiments, the age of the subject may range from 40 years of age to 60 years of age. In some embodiments, the age of the subject may range from 55 years of age to 75 years of age. In some embodiments, the age of the subject may range from 70 years of age to 95 years of age. In some embodiments, the age of the subject may range from 60 years of age to 95 years of age.

As used herein, the terms “treatment” and “treating” refer to an approach for obtaining beneficial or d results including, but not limited to, therapeutic benefit and/or prophylactic benefit.

As used , the term “ISWRD”, also known as “irregular sleep-wake pattern disorder” and “irregular sleep-wake rhythm disorder”, means a sleep cycle that is characterized in potentially having a wake pattern, however it may be accompanied by a rhythm wherein the amplitude of this rhythm may be reduced, or the phase of the pattern may be delayed or advanced, or the period of the pattern may be ned or lengthened, or fragmentation of the n may occur.

With ISWRD, a major sleep period is less well articulated, and in some ments, sleep is fragmented into, for example, at least three or four s during a 24-hour day. In some embodiments, the sleep is fragmented into, for example, at least three periods during a r day. In some embodiments, the sleep is fragmented into, for example, at least four periods during a 24-hour day. The number of sleep fragmentations may vary from day to day. See, e.g., Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 2013, 394-95. This er is one of the circadian rhythm sleep disorders, and is different from general insomnia disorder. In some embodiments, ISWRD may be due to traumatic brain injury. See, e.g., Viola- Saltzman, M. and Watson, N. F., . Clin., 2012, 30, 1299-1312 (describing a potential link between traumatic brain injury and irregular sleep-wake rhythm disorder). In some embodiments, ISWRD may be due to at least one neurodevelopmental disorder. See, e.g., Abbott, SM. and Zee, P.C., Sleep Med. Clin., 2015, 10, 517-22. In some embodiments, the at least one neurodevelopmental disorder may be selected from an Syndrome, autism, mental retardation, and Down Syndrome. See id. In some embodiments, the at least one neurodevelopmental disorder may be Angelman Syndrome. In some embodiments, the at least one neurodevelopmental disorder may be autism. In some embodiments, the at least one neurodevelopmental disorder may be mental retardation. In some embodiments, the at least one neurodevelopmental disorder may be Down Syndrome. In some embodiments, ISWRD may be due to ia. In some embodiments, ISWRD may be due to son’s Disease. In some embodiments, ISWRD may be due to dementia due to Alzheimer’s e.

See, e.g., Vitiello, M.V. and Zee, P.C., Sleep Med. Clin., 2009, 4, 213-18. In some embodiments, ISWRD may be due to dementia due to related disorders.

See, e.g., id. In some embodiments, ISWRD may be due to dementia due to mild cognitive impairment, e.g., traumatic brain injury. See, e.g., id.

According to the DSM-V, Circadian Rhythm Sleep-Wake Disorders of the Irregular Sleep-Wake Type, are described as “[a] temporally disorganized sleep-wake pattern, such that the timing of sleep and wake periods is available through the 24-hour period.” See, e.g., Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 2013, 390.

As used herein, the term “at least one circadian rhythm sleep disorder” means at least one condition chosen from sleep disruption, sleep- wake fragmentation, circadian rhythm sleep disorder, and ISWRD.

As used herein, the term “at least one other circadian rhythm sleep er” means that a subject suffers from ISWRD and at least one other condition chosen from sleep disruption and circadian rhythm sleep disorder.

As used herein, the term “sleep disruption,” also known as “interrupted sleep,” “divided sleep,” ented sleep,” and nted ” among other terms, means a sleep pattern where nighttime sleep is punctuated by one or more periods of wakefulness and daytime is punctuated by one or more periods of sleep. Sleep disruption may be ed by, for example, wake time after sleep onset (WASO), sleep efficiency, duration of ings, and/or number of awakenings (NAW) and sleep fragmentation index (SFI).

As used herein, the term “wake tion” means a wake pattern where daytime wakefulness is punctuated by two or more periods of sleep.

As used herein, the term “wake efficiency” refers to the amount of time awake / time out of bed, and es the number and duration or planned and spontaneous sleep bouts.

As used herein, the term “sleep-wake fragmentation”, also known as “fragmented sleep and wake”, is a disorder characterized by a nal sleep period punctuated by one or more periods of wakefulness and which may be shorter in duration than the subject slept prior to the onset of any of the causes of the sleep disorders. The time spent sleeping during the nighttime sleep period, at any sleep stage, is less uous than normal.

As used herein, the term “circadian rhythm sleep ers” is a family of disorders that affect, among other bodily processes, the timing of sleep. A circadian rhythm sleep disorder may be characterized by at least one disruption or disturbance chosen from the following: A. A persistent or ent pattern of sleep disruption that is primarily due to an alteration of the circadian system or to a misalignment between the endogenous circadian rhythm and the sleep-wake schedule required by an individual's physical environment or social or professional schedule; B. The sleep disruption leads to an ive sleepiness or insomnia, or both; and C. The sleep disturbance causes clinically significant distress or impairment in social, occupational, and other important areas of functioning.

See e.g., id. at 390-98.

As used herein, the terms “stabilization of one or more circadian rhythms, ” ll stabilizing one or more circadian rhythms,” and “stabilizing a circadian rhythm” mean no increase in one or more disturbances and/or disruptions associated with a circadian rhythm sleep disorder.

As used herein, the terms “improving one or more ian rhythms,” “improvement of one or more circadian rhythms,” and “improvement of a circadian rhythm” means a reduction in one or more disturbances and/or disruptions ated with a circadian rhythm sleep As used herein, the term “dementia” refers to a neurocognitive disorder. See, e.g., stic and tical Manual of Mental Disorders, Fifth Edition, 2013, 602-14; Albert, M. S. et a/., Alzheimer’s & Dementia, 2011, 7, 271-72; McKhann, G. M., eta/., Alzheimer’s & Dementia, 2011, 7, 265; Dubois, B., eta/., Lancet Neurol., 2014, 13, 614-29.

As used herein, the term “dementia due to Alzheimer's Disease” includes an insidious onset and gradual progression of behavioral symptoms including, but not limited to, ive difficulties, including memory loss and diminished thinking skills. See, e.g., Diagnostic and Statistical Manual of Mental ers, Fifth Edition, 2013, 602-14; Albert, M. S. eta/., mer’s & Dementia, 2011, 7, 271-72; McKhann, G. M., eta/., mer’s & Dementia, 2011, 7, 265; Dubois, B., eta/., Lancet Neurol. 2014, 13, 614-29.

As used herein, the term “dementia due to related disorders” includes an insidious onset and gradual progression of behavioral symptoms ing, but not limited to, cognitive difficulties, including memory loss and shed thinking skills. The related disorders include, for example, vascular ia, fronto-temporal dementia, Parkinson’s Disease, and dementias due to other causes (e.g., traumatic brain injury, infection with human immunodeficiency virus (HIV), etc.).

As used herein, the term “mild cognitive impairment due to related disorders” means a slight but noticeable and measurable decline in cognitive abilities, e.g., memory and thinking skills, due to disorders such as, for example, vascular dementia, fronto-temporal dementia, Parkinson’s Disease, and ias due to other causes (e.g., infection with human immunodeficiency virus (HIV)).

As used herein, the term “mild cognitive impairment due to Alzheimer’s disease” means a slight but noticeable and measurable decline in cognitive abilities, e.g., memory and thinking skills, due to Alzheimer’s disease, and is discussed in, e.g., stic and Statistical Manual of Mental Disorders, Fifth Edition, 2013, 602-14; Albert, M. S. et a/., Alzheimer’s & Dementia, 2011, 7, 271-72; McKhann, G. M, et a/., Alzheimer’s & Dementia, 2011, 7, 265; , B., eta/., Lancet Neurol., 2014, 13, .

As used herein, the terms “clinical ization in mild cognitive ment due to mer’s disease” and “clinical stabilization in dementia due to Alzheimer’s disease and/or related disorders” mean ization or no or insignificant decline in at least one domain chosen from cognitive, functional, and behavioral, including but not limited to mood, activities of daily living, agitation, restlessness, etc.

As used herein, the terms “clinical improvement in mild cognitive impairment due to Alzheimer’s disease” and “clinical improvement in dementia due to Alzheimer’s disease and/or d disorders” mean improvement in at least one domain chosen from cognitive, functional, and behavioral, ing but not limited to mood, activities of daily living, agitation, restlessness, etc.

As used herein, the terms “clinical reduction in rate of decline in mild cognitive impairment due to Alzheimer’s disease” and cal reduction in rate of decline in dementia due to Alzheimer’s disease and/or related disorders” mean a se in the rate of decline in at least one domain chosen from cognitive, functional, and behavioral, including but not limited to mood, activities of daily living, agitation, restlessness, etc.

As used herein, the term cal ization in ISWRD” means stabilization or no or insignificant decline in at least one domain chosen from sleep-wake fragmentation, amplitudes of the sleep-wake and alertness rhythms, the wake pattern from day to day, sleep efficiency, wake efficiency, etc.

As used herein, the term “clinical improvement in ISWRD” means improvement in at least one domain chosen from sleep-wake fragmentation, amplitudes of the sleep-wake and alertness rhythms, the sleep- wake pattern from day to day, sleep efficiency, wake efficiency, etc.

As used herein, the term “clinical reduction in rate of decline in ISWRD” means a decrease in the rate of decline in at least one domain chosen from at least one domain of sleep-wake fragmentation, amplitudes of the sleep- wake and alertness rhythms, the sleep-wake pattern from day to day, sleep efficiency, wake efficiency, etc.

As used herein, the term “continuity of nocturnal sleep” means sleep that is continuous (i.e., few awakenings, with each lasting only a short time) and during the nighttime hours.

As used herein, the term “sleep time” refers to the time that a subject spends asleep. Sleep time may be continuous or discontinuous.

As used herein, the term “sleep efficiency” refers to the total sleep time a subject obtains during his or her time in bed. Sleep ency is measured by the equation: sleep efficiency = 100%*(tota| sleep time/total time in bed) As used herein, the term “behavioral and psychological symptoms of dementia”, also known as, “BPSD”, ents a heterogeneous group of non-cognitive symptoms and behaviors occurring in subjects with dementia. These symptoms are as clinically nt as cognitive symptoms as they strongly correlate with the degree of functional and cognitive impairment.

Symptoms include, for e, agitation, aberrant motor behavior, anxiety, n, irritability, depression, , disinhibition, delusions, hallucinations, and sleep or appetite changes. See, e.g., Mukaetova-Ladinska, E.B., et a/., Front. Neurol., 2012, 3, Art. 73.

As used herein, a ase in daytime sleepiness” means an increase and/or stabilization in the percentage of time spent awake during the dayfime.

As used herein, a “decrease in daytime napping” means a decrease in the number and duration of daytime napping (planned and unplanned).

As used herein, an “improvement in daytime alertness” means stabilization, ement, and/or slower rate of decline in assessments of alertness.

As used herein, a “decrease in behavioral disturbances” means stabilization, improvement, and/or slower rate of decline in ments of agitation and/or behavioral disturbance.

Subjective and objective determinations, for example, actigraphy, of the aforementioned circadian rhythm sleep disorders and quality are known in the art. In some embodiments, the at least one circadian rhythm sleep disorder is determined by subjective measurements, such as, for example, asking the subject, maintaining a sleep diary, or assessment via a standardized questionnaire regarding how ative and undisturbed sleep has been (e.g., Pittsburgh Sleep Quality Index (Buysse et a/., Psychiatry Research, 1989, 28, 193-213)). In some embodiments, the at least one ian rhythm sleep disorder is determined by observing the subject, such as, for example, observing how long it takes the subject to fall asleep, how many times the subject wakes up during the night, how agitated the subject is (e.g., physical or verbal agitation), how aggressive the subject’s behavior is, how disoriented the subject is upon awakening, etc. In some embodiments, the at least one circadian rhythm sleep disorder is determined using polysomnography. mnography is the monitoring of le electrophysiological ters during sleep and generally includes measurement of EEG activity, electro- ocu|ographic activity and electromyographic activity, as well as other measurements. These results, along with observations, can e not only sleep latency (the amount of time required to fall asleep), but also sleep continuity (overall balance of sleep and wakefulness, or the tage of time spent asleep or the amount of time spent awake after sleep onset) which may be an indication of the quality of sleep. Actigraphic ement techniques may be used as well. Actigraphy is the objective measurement of motor activity in a subject using a device that is worn on the body, generally the non-dominant wrist.

As used herein, the term ient” shall mean an inactive ingredient used as a vehicle (e.g., water, capsule shell, etc.), a t, or a component to tute a dosage form or pharmaceutical composition comprising a drug such as a therapeutic agent. The term also encompasses an inactive ingredient that imparts cohesive function (e.g., binder), disintegrating function (e.g., egrator), lubricant on (e.g., ating agent), and/or the other function (e.g., solvent, surfactant, etc.) to the composition.

As used herein, the term “pharmaceutically acceptable carrier” refers to a nontoxic carrier, adjuvant, and/or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.

Pharmaceutically acceptable carriers, nts and/or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium icate, polyvinyl pyrrolidone, cellulose-based nces, polyethylene glycol, cyclodextrins, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

As used herein, the term “pharmaceutically acceptable salt” is a salt that retains the desired biological activity of the parent compound and does not impart undesired toxicological effects. Examples of such salts include, but are not limited to: (a) acid on salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, c acid, gluconic acid, citric acid, malic acid, ascorbic acid, c acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (b) salts formed from elemental anions such as chlorine, bromine, and iodine. See, e.g., Haynes, eta/., J. Pharm. Sci, 2005, 94, 10; and Berge, eta/., J. Pharm. Sci, 1977, 66, 1, which are incorporated herein by reference.

Dosage forms of the present sure contain compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, in a therapeutically effective amount for treatment of, e.g., ISWRD when administered in ance with the ngs of the present disclosure. Unit dose of the effective amount in a dosage form is from 0.5 mg to 100 mg, from 2 mg to 75 mg, from 2 mg to 70 mg, from 2 mg to 65 mg, from 2 mg to 60 mg, from 2 mg to 55 mg, from 2 mg to 50 mg, from 2 mg to 45 mg, from 2 mg to 40 mg, from 2 mg to 35 mg, from 2 mg to 30 mg, from 2 mg to 25 mg, from 2 mg to mg, from 1 mg to 15 mg, from 2 mg to 15 mg, or chosen from 2 mg, 2.5 mg, 4 mg, 5 mg, 8 mg, 10 mg, or 15 mg. Unit dose is not limited by the type of the dosage form or the number of dosage forms for single dose. In some embodiments, the unit dose may be 2.5 mg. In some embodiments, the unit dose may be 5 mg. In some embodiments, the unit dose may be 10 mg. In some embodiments, the unit dose may be 15 mg.

In some embodiments, a dosage form of the t disclosure may constitute one or more pharmaceutical compositions comprising the compound of Formula (I), or pharmaceutically acceptable salts and solvates f, together with pharmaceutically able ents.

As used herein, the term “composition” used herein includes a product comprising a particular ingredient in a particular amount and any t directly or indirectly brought about by the combination of particular ingredients in particular amounts. Such a term related to the pharmaceutical composition is intended to include a product comprising an active ingredient and an inert ingredient constituting a carrier and include every product directly or indirectly t about by the combination, complexation or aggregation of any two or more ingredients or the dissociation, other kinds of reactions or interaction of one or more ingredients. Thus, the pharmaceutical ition of the present disclosure includes every ition prepared by mixing the compound of the present disclosure with a pharmaceutically acceptable carrier.

As used herein, the term “pharmaceutically acceptable" means that a carrier, diluent, excipient, or vehicle is compatible with other components of a formulation and is nontoxic to a subject.

Solid dosage forms of the t disclosure include capsules, granules, lozenges, pellets, pills, powders, suspensions, and tablets.

The pharmaceutical compositions of the present disclosure may be prepared using standard techniques and manufacturing processes generally known in the art. See, e.g., the monograph of Japanese Pharmacopoeia, 16th Edition; and Pharmaceutical Dosage Forms of US. Pharmacopoeia-NF, Chapter 1151.

In some embodiments, pharmaceutical itions comprise a compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof. In some embodiments, pharmaceutical compositions further se at least one additional component chosen from pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, and pharmaceutically acceptable excipients.

In some embodiments, the at least one additional component in the pharmaceutical compositions is chosen ing upon the route of administration for which the pharmaceutical composition is intended. Non- limiting examples of suitable routes of administration for which the pharmaceutical composition may be used include parenteral, oral, inhalation spray, topical, rectal, nasal, buccal, vaginal and ted reservoir administration. The term “parenteral” as used herein includes subcutaneous, intravenous, uscular, intra-articular, intra-synovial, intrasternal, intracisternal, intrathecal, epatic, intralesional and intracranial ion or infusion techniques. In some embodiments, the mode of administration is chosen from intravenous, oral, subcutaneous, and intramuscular administration.

Sterile injectable forms of the itions of this sure may be, for example, aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents known in the art. The e injectable ation may also be a sterile injectable on or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol. Non-limiting examples of vehicles and ts that may be employed include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils may be employed as a solvent and/or suspending .

For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their yethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or r dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, and/or other dosage forms, may also be used for the purposes of formulation.

For oral administration, the compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, may be provided in an acceptable oral dosage form, including, but not limited to, capsules, tablets, oral disintegrating tablet, sprinkles, and other oral formulations that would be easy to swallow. In some embodiments, the compound of Formula (I), or ceutically able salts and es thereof, is provided in the form of tablet or es. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, is provided in the form of crushable tablets. In the case of s for oral use, carriers commonly used include lactose and cornstarch. ating agents, such as magnesium stearate, may also be added. For oral administration in a capsule form, useful diluents include e and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with an emulsifying and/or suspending agent. If desired, certain sweetening, flavoring or coloring agents may also be added.

In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative es only and are not to be construed as limiting this disclosure in any manner.

EXAMPLES Example 1 Table 1.

Component Tablet Strength (all quantities stated in mg) Compound of Formula (I )a —0 Lactose monohydrate 96.38 93.88 88.88 Low-substituted h drox ooro l cellulose 10.8 10.8 10.8 H drox ooro Icellulose 3.6 3.6 3.6 Purified water :a as...

Low-substituted hydroxypropyl cellulose - m— Total Wei-ht mo 127.2 127.2 127.2 a: Quantity of compound of Formula (I) is ed based on its purity ities, residual solvents, etc.). b: Quantity of lactose monohydrate for compounding is adjusted depending on the quantity of compound of Formula (I) in order to maintain constant weight of core s. 0: Removed during drying process. d: ed proportionally to the yield of sized granules.

Example 2. Effect of administration of a compound of Formula (I) on sleep cycles of mice A compound of Formula (I) was finely crushed and suspended in vehicle, a mixture of 0.5% w/v methylcellulose 400 cP in distilled water.

Experimental data were collected on male senescence accelerated mouse prone-8 (“SAMP8” or “P8”) strain animals and male senescence accelerated mouse resistant-1 (“SAMR1” or “R1”) strain animals at the age of 21 weeks. P8 mice are known to show accelerated symptoms of aging and also ogical and behavioral symptoms of Alzheimer's disease, while R1 mice are used to represent a normal aging process and are also used as a control strain for P8 mice. See, e.g., Miyamoto, eta/., Exp. Geron., 1997, 32, 139—48; Morley eta/., Curr. Pharm. Des., 2012, 18, 1123—30.

Electroencephalogram (“EEG”) and electromyogram (“EMG”) electrodes were implanted on each mouse at 17—18 weeks of age, and the mice were then allowed to recover for at least 18 days in individual recording cages, where they could freely move, under a 12-hour light/12-hour dark cycle.

Amplified EEG and EMG signals were lly recorded for 3 days, separated into individual 24-hour recordings, which were initiated at each -on event.

During the first 30 minutes of the light cycle (ZT 0—0.5), each mouse received an oral administration of either vehicle or 3 mg/kg of the compound of Formula (|) in vehicle or 30 mg/kg of the compound of Formula (|) in e, after which the sleep/wake behavior of mice was recorded until the next lights on event.

Each mouse received every treatment in a cross-over fashion with one treatment per day in the following order: vehicle (10 mL/kg bodyweight), 3 mg/kg, and then 30 mg/kg. Some mice started with vehicle on day 1, some mice started with 3 mg/kg compound of Formula (|) on day 1, and some mice started with 30 mg/kg compound of Formula (|) on day 1.

EEG frequency and EMG activity signal data were ed using software from Kissei Comtec Co., Ltd. to characterize every 10 second epoch as either rapid eye movement (REM) sleep, non-REM sleep, or wakefulness.

Then, lated lness, M sleep, and REM sleep times over the light cycle (11.5 hours) and the dark cycle (12 hours) were calculated.

Additionally, latencies to sleep and REM sleep were calculated as the first appearance of 6 or more epochs of uninterrupted sleep or one or more epochs of REM sleep after the dosing event, respectively. The circadian rhythm parameter phase was determined as the inflection point of a cosine curve fit to the lness bution in 30 minute bins across the day for every individual mouse using JTK_CYCLE software. Hughes, eta/., J. Biol. Rhythms, 2010, 25, 372—80.

The differences between P8 mice and R1 mice (control mice) were statistically analyzed by comparing wake behavior and circadian rhythm of the e-treated animals of each strain, while the effect of administration of a compound of Formula (I) on sleep/wake behavior and circadian rhythm was statistically analyzed for each strain as the difference between sleep/wake behavior and circadian rhythm on the vehicle- administration day and sleep/wake behavior and circadian rhythm on a drug- administration day. Statistical is of wakefulness time, non-REM sleep time, REM sleep time and latency, and sleep latency was performed with a linear mixed model which specified animal as random , and day, strain, treatment and the interaction between strain and ent as fixed effects with Kenward-Roger as denominator degrees of freedom using SAS software. For estimation of wakefulness phase and its covariance, a linear mixed model was used which assumed heterogeneous ce of strain and treatment combination with Kenward-Roger as denominator and s of freedom using SAS software.

As shown in FIGS. 1A-1C, vehicle-treated P8 mice show more wakefulness, less non-REM sleep, and less REM sleep than vehicle-treated R1 mice during light time, a feature which resembles nighttime sleep disturbances in patients with Alzheimer’s disease and/or related disorders. When administered at the beginning of light time, a compound of Formula (I) reduces, in a dose-dependent manner, wakefulness and ses non-REM sleep in both strains of mice, with the amounts of wake and M sleep in treated P8 mice normalized to the level of vehicle-treated R1 mice. Similarly, a dose- dependent increase in the amount of REM sleep in both strains in the light time is observed.

During the dark time (ZT12-24) of the circadian day, previous light time administration of a compound of Formula (I) at the 30 mg/kg dose to R1 mice led to a decrease of wakefulness and increase of non-REM sleep as shown in FIGS. 1A and 1B, respectively, while treatment with the 3 mg/kg appears to have no effect on each of the vigilance . In contrast, administration of a compound of Formula (I) led to a dose-dependent increase in wakefulness, and decreases in non-REM sleep and REM sleep in P8 mice, as shown in FIGS. 1A, 1B, and 1C, respectively. As shown in administration of a compound of Formula (I) leads to a dose-dependent reduction of sleep and REM sleep latencies in both s of mice.

As shown in Table 2, the wake circadian phase of vehicle-treated P8 mice is significantly advanced compared to vehicle-treated R1 mice.

Administration of a nd of a (I) during ZT 0-0.5 resulted in a dose- dependent and significant delay (right-shift) of the wake phase in P8 mice, resulting in a correction to the level of vehicle-treated R1 mice.

Table 2. Wake circadian phase. m-—C:::::2:e Data represent least square means and standard errors ZT: Zeitgeber time in hours (lights on is ZT 0.0, lights off is ZT 12.0) a: significant difference ed to R1 vehicle cohort (P<0.05, linear mixed model with Kenward-Roger) b: significant difference compared to P8 vehicle cohort (P<0.05, linear mixed model with Kenward-Roger) As indicated by the covariance, the phase variability in P8 mice is also higher than in R1 mice. When the compound of Formula (I) was administered during ZTO-O.5, a dose-dependent significant delay (right-shift) of the wake phase in P8 and R1 mice was observed, in addition to a reduction in phase covariance and phase variability.

Example 3. Treatment of subjects with ISWRD Subjects, both male and female with ages ranging from 60 to 90 years old, having mild or moderate Alzheimer’s Disease-Dementia, and who complain of disrupted sleep or le ings at night along with frequent periods of falling asleep during the day may be screened to be eligible for treatment. The study enrollment is approximately 125 ts and is divided into two major phases: domization and Randomization phases, where the Prerandomization phase is further divided into a Screening and a Baseline Period, and the Randomization phase is r divided into a Treatment Period and a Follow-up Period.

Prerandomization Phase Screening Period During an initial visit, a clinician will verify that a subject has been diagnosed with Alzheimer’s Disease-Dementia and will ensure that the subject has Irregular Sleep-Wake Rhythm Disorder. This is accomplished by the subject’s participation in a medical, atric, and sleep history assessment, and mini-mental state examination (“MMSE”) in addition to assessment of the subject’s electrocardiogram, clinical tory tests, vital signs, height and weight.

If a t is determined to be eligible for the study, the subject is provided with an actigraph to wear for the duration of the study. Additionally, a nocturnal sleep period will be ined, which is defined as the desired eight- hour period of time for the subject to spend in bed. The subject’s caregiver is provided with a sleep log which tracks the subject’s sleep time (start and end times) as well as the approximate times when the actigraph was removed from and uently replaced on the subject’s wrist.

The subject wears the actigraph, and the subject’s caregiver ues to maintain the sleep log during the Screening . The Screening Period consists of a period of at least 14 days (but less than 42 days) and concludes when the t and caregiver return to the clinic to provide the clinician with the actigraph and sleep log data, in addition to adverse events and concomitant medication use.

Baseline Period At the start of the Baseline Period, assuming that the actigraphy data confirm the diagnosis of ISWRD, the caregiver meets with the clinician and completes the Sleep Disorders Inventory (“SDI”), Neuropsychiatric Inventory — item version (“NPI-10”), and the Euro-QOL version 5 dimensions, 5 levels (“EQ-5D-5L”), in addition to the baseline assessment for the Clinician’s Global Impression of —Irregular Sleep-Wake Rhythm Disorder Clinical Assessment Scale (“CGIC-ISWRD Scale”) on behalf of the t and completes the EQ-5D-5L, Zarit Burden Inventory (“ZBI-short”), and the Pittsburgh Sleep Quality Index (“PSQI”) on behalf of mself. The subject will also complete the Alzheimer’s Disease Assessment Scale — Cognitive Subscale (“ADAS-cog”) and the EQ-5D-5L.

Randomization Phase Treatment Period Once the Baseline Period concludes, the subject begins the Treatment Period which lasts for four weeks. The subject is ized and receives study drug of either a composition of Example 1, sing a compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, in a dose amount of2.5 mg, 5 mg, 10 mg, or 15 mg, or the subject is administered placebo. The study drug is provided to the caregiver and the ver sters the study drug to the subject within five minutes of when the subject intends to fall asleep. Subjects are requested to try to remain in bed for at least seven hours each night and to in the subject’s sleep time as determined during the Screening Period.

At the two-week mark of the Treatment Period, the subject and caregiver return to meet with the clinician to provide actigraphic and sleep log data. The subject’s vital signs are also assessed, along with reporting adverse events, concomitant medication use, and treatment compliance.

At the four-week mark of the Treatment Period, stration of study drug ceases and the subject and caregiver meet with the clinician to provide actigraphic and sleep log data. Additionally, the subject undergoes clinical laboratory tests, a blood sample for PK analysis is obtained, electrocardiogram analysis, measurement of vital signs and weight, and ing of adverse events, concomitant medications, and treatment compliance. The caregiver completes the SDI, NPl-10, and the EQ-5D-5L on behalf of the subject and the 5L, ZBl-short, and PSQI on behalf of her/himself. The caregiver also provides information on the CGlC-ISWRD scale on behalf of the subject. The subject is administered the ADAS-cog, MMSE, EQ-5D-5L, eC-SSRS, and the CGlC-ISWRD Scale.

Follow-Up Period At the ion of study drug administration, the subject continues to wear the actigraph and the caregiver continues to maintain the sleep log for between 14 and 18 days. During that time, the subject and caregiver meet with the clinician to provide aphic and sleep log data.

Additionally, the subject undergoes clinical laboratory tests, electrocardiogram analysis, measurement of vital signs and weight, analysis of the site of actigraph application, and reporting of adverse events and concomitant medications. This meeting concludes the subject’s and caregiver’s participation in the study.

Study Endpoints Endpoints in this study are to ine the dose response of the change from baseline of sleep efficiency and wake efficiency during the last four weeks of treatment, compared with placebo, as ed using actigraphy.

Prophetic Example 1. Treatment of subjects with ISWRD Subjects experiencing irregular sleep-wake cycles and/or decreased alertness for more than three months may be screened to be eligible for treatment. Prior to treatment, subjects may be monitored for two weeks using actigraphy ques.

The study may comprise approximately 125 subjects, both male and female, with ages ranging from about 65 to about 90 years old, having ISWRD. Subjects may be administered a formulation, as described below, or a placebo.

A formulation as described herein, for e, such as the ition of Example 1, comprising a compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof, in a dose such as, for example, 2.5 mg, 5 mg, 10 mg, or 15 mg may be stered to subjects, for example, at night, just before bedtime. The formulation may be administered according to a closing regimen, such as, for example, once per day each day for four weeks, or for further example, or every second day, for one week, two weeks, three weeks, four weeks, or nitely.

During treatment, subjects could be monitored regularly using techniques commonly known in the art, for example, actigraphy. Other subject features may be monitored before, during and/or after treatment such as al stability and cognitive and memory performance, for example, at wake time. Subjects may also or alternatively be monitored using polysomnography, actigraphy, caregiverjournals and questionnaires, and/or erized cognitive test batteries.

An nt of the study may be to observe the dose response of the change from baseline of sleep efficiency and wake efficiency during the last seven nights of treatment, compared with placebo, as measured using actigraphy.

Prophetic Example 2. Treatment of subjects with Alzheimer’s disease suffering from Sleep-wake Fragmentation Subjects encing irregular sleep-wake cycles and/or decreased alertness for more than three months may be ed on the basis of disease state (e.g., mild to moderate Alzheimer’s disease) to be eligible for treatment. Prior to treatment, subjects may be monitored for two weeks using actigraphy techniques.

The study may se approximately 125 subjects, both male and female, with ages ranging from about 65 to about 90 years old, having irregular sleep-wake rhythm disorder and mild to moderate Alzheimer’s Disease. Subjects may be administered a formulation, as described below, or a placebo.

A formulation as described herein, for example, such as the composition of e 1, comprising a compound of Formula (I), or pharmaceutically acceptable salts and es thereof, in a dose such as, for example, 2.5 mg, 5 mg, 10 mg, or 15 mg may be administered to subjects, for example, at night, just before bedtime. The formulation may be stered according to a closing regimen, such as, for example, once per day each day for four weeks, or for r example, or every second day, for one week, two weeks, three weeks, four weeks, or indefinitely.

WO 97160 During treatment, subjects could be monitored regularly using techniques commonly known in the art, for example, actigraphy. Other subject es may be monitored before, during and/or after treatment. Subjects may also or alternatively be monitored using polysomnography, actigraphy, caregiver journals and questionnaires, and/or computerized cognitive test batteries.

An endpoint of the study may be to observe the dose response of the change from baseline of sleep ency and wake efficiency during the last seven nights of treatment, compared with placebo, as measured using actigraphy.

Claims (1)

WHAT IS CLAIMED:

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