阅读说明：本技术 H3r反向激动剂用于治疗与帕金森病(pd)相关的日间过度嗜睡的用途 (Use of H3R inverse agonists for the treatment of excessive daytime sleepiness associated with Parkinson's Disease (PD) ) 是由 D·约翰斯 J·索瓦戈 于 2019-10-10 设计创作，主要内容包括：本发明涉及如本文所定义的化合物(I)或其药学上可接受的盐在治疗与帕金森病相关的日间过度嗜睡中的用途。(The present invention relates to the use of compound (I) or a pharmaceutically acceptable salt thereof as defined herein for the treatment of excessive daytime sleepiness associated with parkinson's disease.)

Use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of promoting wakefulness in a parkinson's disease patient.

Use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of impaired cognitive function associated with parkinson's disease; such as impaired learning, psychomotor function, attention, sustained attention, working memory, episodic memory, and executive function, each of which is associated with parkinson's disease; particularly attention associated with parkinson's disease.

Use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of excessive daytime sleepiness associated with parkinson's disease.

Use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease.

5. The use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

6. Use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional pharmaceutical active ingredients such as levodopa, a combination of levodopa and pergolide, a combination of levodopa and cabergoline, a combination of levodopa and ropinirole, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, A combination of levodopa and carbidopa, a combination of levodopa and entacapone, a combination of levodopa and benserazide, a combination of levodopa and pramipexole, amantadine, selegiline, rasagiline, entacapone, ramelteone, melatonin, zolpidem, eszopiclone, zopiclone, brotizolam, trazodone, doxepin, darifenacin, solifenacin, tolterodine, pregabalin, gabapentin ester, paroxetine, donepezil, rivastigmine, desipramine, carbamazepine, clonazepam, lorazepam, triazolam, temazepam, fluazepam, cabergoline, rotigotine, suvorine, pergolide, pramipexole, cabergoline, ropinirole, carbidopa, benserzapine, olanzapine, quinacrine, clozapine, quinacrine, doxepin, doxine, nezapine, zolamide, doxepin, doxazone, and a, Venlafaxine, modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, alprazolam, sorafenib, and sodium oxybate; or a pharmaceutically acceptable salt thereof.

7. The use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof according to claim 6, wherein the additional pharmaceutical active ingredient is a wakefulness-promoting agent such as modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, sorafenib and sodium hydroxybutyrate or a pharmaceutically acceptable salt thereof; in particular sorafenib, modafinil or armodafinil or pharmaceutically acceptable salts thereof.

8. The use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof according to claim 6, wherein 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof, wherein the additional pharmaceutically active ingredient is selected from the group consisting of: levodopa; a combination of levodopa and pergolide; a combination of levodopa and cabergoline; a combination of levodopa and ropinirole; a combination of levodopa and carbidopa; a combination of levodopa and entacapone; a combination of levodopa and benserazide; a combination of levodopa and pramipexole; or a pharmaceutically acceptable salt thereof.

9. Use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the use is in combination with psychotherapy or behavioral therapy, in particular behavioral therapy, such as cognitive behavioral therapy focused on sleep hygiene regulations (e.g., wherein behavioral therapy is computer-assisted therapy).

10. Use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 9, wherein excessive daytime sleepiness is associated with one or more sleep disorders associated with parkinson's disease, such as rapid eye movement (e.g. rapid eye movement sleep behavior disorder).

11. The use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof is administered orally.

12. Use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein parkinson's disease is co-morbid with psychiatric disorders such as depression, anxiety or psychosis.

13. Use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein parkinson's disease is early, intermediate or advanced parkinson's disease, in particular advanced parkinson's disease.

14. A combination comprising 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof and at least one active ingredient selected from the group consisting of: levodopa, a combination of levodopa and pergolide, a combination of levodopa and cabergoline, a combination of levodopa and ropinirole, a combination of levodopa and carbidopa, a combination of levodopa and entacapone, a combination of levodopa and benserazide, a combination of levodopa and pramipexole, amantadine, selegiline, rasagiline, entacapone, ramelteone, melatonin, zolpidem, eszopiclone, zopiclone, brotizolam, trazodone, doxepin, darifenacin, solifenadine, tolterodine, pregabalin, gabapentin ester, paroxetine, donepezil, rivastigmine, desipramine, clonazepam, lorazepam, triazolam, temazepam, flumazepam, cabergoline, levuline, triptorelin, tipepilin, pergoline, pramipexole, cabergoline, pramipexole, clethole, lorazepam, and levamitriptonile, Ropinirole, carbidopa, benserazide, clozapine, quetiapine, pimavanserin, duloxetine, mirtazapine, nortriptyline, venlafaxine, modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, sodium oxybate; or a pharmaceutically acceptable salt thereof; in particular modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, alprazolam, sorafenib and sodium oxybate or pharmaceutically acceptable salts thereof.

Technical Field

The present invention relates to the use of compound (I) or a pharmaceutically acceptable salt thereof as defined herein for the treatment of excessive daytime sleepiness associated with parkinson's disease.

Background

Parkinson's Disease (PD) is a slowly progressive neurodegenerative disease caused by degeneration of dopaminergic neurons in the substantia nigra of the brain, affecting about 1% of the population over the age of 60 (Rodrigues, t.m. et al, Parkinson and related disorders [ Parkinson's disease and related disorders ], 2016, 27: 25-34). Motor symptoms associated with PD include muscle stiffness, akinesia and dystonia. In addition, parkinson's disease patients also typically have non-motor symptoms such as sleep disorders [ e.g., Excessive Daytime Sleepiness (EDS) ], impaired cognitive function [ e.g., defects in, e.g., attention, executive function, learning, and visual space ], fatigue, olfactory dysfunction, and autonomic dysfunction (e.g., nocturia). In addition, parkinson's disease patients are often associated with psychiatric disorders such as depression, anxiety and psychosis.

Sleep disorders associated with PD include: a) nocturnal manifestations [ e.g. insomnia, abnormal sleep, such as abnormal sleep related or not to Rapid Eye Movement (REM), sleep-related respiratory disorders and sleep-related movement disorders, such as Restless Leg Syndrome (RLS) and Periodic Limb Movement Disorders (PLMD) ] and b) daytime manifestations [ e.g. Excessive Daytime Sleepiness (EDS) and sudden sleep onset ]. They affect up to 90% of PD patients, have an adverse effect on their quality of life (Aarsland, d. et al, adv. neurol. [ neurological progression ]2005, 96, 56-64), and, in addition, carry a significant safety risk (e.g., an increased risk of lethargy-related accidents). The etiology is multifactorial and mainly involves degeneration of sleep regulatory structures (int. rev. neurobiol. [ international review in neurobiology ], 2017; 133: 719-.

Excessive Daytime Sleepiness (EDS) is a common symptom in PD patients with prevalence ranging from 15% to 50% (Suzuki, k. et al, Parkinson's disease, 2011, article ID 219056). Importantly, EDS can occur early in PD, with increasing incidence as the disease progresses. Due to the multifactorial nature of EDS, the causal mechanisms are far from established. However, different factors have been suggested that may lead to EDS in PD patients: it may be the main cause of disease progression itself (i.e. dysregulation of the circadian sleep-wake rhythm due to the neurodegenerative process of PD itself) and secondary to nocturnal sleep disruption caused by concomitant sleep disorders (e.g. PLM), or due to the use of drug therapy such as antidepressants (e.g. serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors or β -blockers), antihistamines, antipsychotics or sedatives, in particular dopamine agonists (Dhawan, v. et al, Age and Aging, 2006, 35: 220-. Furthermore, dopamine replacement therapy, which is the most common treatment for parkinson's disease, is known to be associated with excessive daytime sleepiness (e.g. in the early stages of the disease). Thus, such disabling conditions may be caused by a combination of neurodegenerative processes affecting the majority of the ascending wake system of the brain and the action of dopaminergic drugs (O' suilearbain and Dewey, Arch Neurol [ neurological archives ], 2002, 59(6), 986-. In contrast, other factors (such as mood disorders or cognitive decline) do not show consistency with EDS and are therefore less likely to contribute to the pathogenesis of EDS in PD patients.

Subjective lethargy was present in about 33.5% -54% of parkinson patients, while 16% -19% of controls (charine et al, Sleep Med Rev [ sleeping medical review ], 2017, 33-50). EDS has an adverse effect on quality of life because it affects activities of daily living (Visser et al, J Neurol [ J neurological ], 2008, 255, 1580-. EDS in PD also adversely affects the burden on caregivers (Ozdilek and Gunai, j. neuropsychiatry Clin Neurosci, 2012, 24(4), 478-483).

Despite the high prevalence of sleep disorders in PD patients and the adverse impact on quality of life, clinical trials are rarely performed. The H3R inverse agonist known as Bavisant (bavisant) is currently undergoing clinical trials for the treatment of PD-EDS (clinical trials. gov identifier: NCT03194217), the H3R inverse agonist known as Pitolissant (pitolisant) (also known as Lorison) has completed clinical trials for the treatment of PD-EDS (clinical trials. gov identifier: NCT00642928, NCT01066442, NCT 01036139; Amulf I., European neuropsychopharmacology.22nd ECNP Congress [ 22 th European Congress institute of psychopharmacology (ECNP) ], Istanal Turkey _ Conference Publication 19SUPPL [ Turkey Italian Bull Conference Publication: 19, journal 3, p.204, 2009). Currently, there are no approved drugs available for the treatment of PD-EDS.

Currently available drugs for modulating wakefulness and sleep, such as drugs that promote wakefulness, have a number of disadvantages, for example modafinil, methylphenidate, sodium oxybate and corticosterone, have shown different benefits in clinical studies. Modafinil (modafinil) { i.e., 2- (benzhydrylsulphinyl) acetamide or 2- [ (diphenylmethyl) sulphinyl ] acetamide } is a wakeproof agent, the structure of which is disclosed in U.S. Pat. No. 4,177,290 and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of narcolepsy and shift work disorders. However, in europe, the European Medicines Agency (EMA) recommends restrictions on all modafinil indications for reasons of poor risk/benefit characteristics, except narcolepsy; for example, it is associated with an increased risk of development of cutaneous or hypersensitivity reactions and neuropsychiatric disorders. In addition, the risk of particular cardiovascular diseases is also associated with modafinil (EMA News: EMA/459173/2010, 6.2010, 22). The use of modafinil in the treatment of excessive sleepiness associated with PD has been disclosed in the following references: (1) sleep [ Sleep ], 2002, 25: 905-9 and (2) j. neuron. neurosurg. psychiatry [ journal of neurology, neurosurgery and psychiatry ], 2005, 76: 1636-9. One clinical trial showed that after two weeks of treatment with 100-200mg modafinil per day, the Epworth somnolence scale score could be improved, but not the sleep latency in the wakefulness maintenance trial [ i.e. reference (1) above ], while another trial with 200-400mg modafinil per day for 4 consecutive weeks showed no improvement in the Epworth somnolence scale score [ i.e. reference (2) above ]. Accordingly, there is a need to identify new therapeutic agents useful in the treatment of EDS associated with PD, in particular drugs that are effective and have favorable (e.g., more favorable) risk/benefit profiles.

Disclosure of Invention

In one aspect, the present invention relates to the use of an H3R inverse agonist named 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate, which is hereinafter also referred to as compound (I):

-use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of promoting wakefulness in a parkinson's disease patient;

-use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of excessive daytime sleepiness associated with parkinson's disease;

-use of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease;

use of (E) -1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of impaired cognitive function associated with parkinson's disease

In another aspect, the invention also relates to the use of an inverse agonist of H3R, named 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate:

-a combination comprising 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof and at least one active ingredient selected from the group consisting of: levodopa, a combination of levodopa and pergolide, a combination of levodopa and cabergoline, a combination of levodopa and ropinirole, a combination of levodopa and carbidopa, a combination of levodopa and entacapone, a combination of levodopa and benserazide, a combination of levodopa and pramipexole, amantadine, selegiline, rasagiline, entacapone, ramelteone, melatonin, zolpidem, eszopiclone, zopiclone, brotizolam, trazodone, doxepin, darifenacin, solifenadine, tolterodine, pregabalin, gabapentin ester, paroxetine, donepezil, rivastigmine, desipramine, clonazepam, lorazepam, triazolam, temazepam, flumazepam, cabergoline, levuline, triptorelin, tipepilin, pergoline, pramipexole, cabergoline, pramipexole, clethole, lorazepam, and levamitriptonile, Ropinirole, carbidopa, benserazide, clozapine, quetiapine, pimavanserin, duloxetine, mirtazapine, nortriptyline, venlafaxine, modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, sodium oxybate; or a pharmaceutically acceptable salt thereof; in particular modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, alprazolam, sorafenib and sodium oxybate or pharmaceutically acceptable salts thereof.

In another aspect, the present invention relates to the use of the above combination:

-use of the above combination in the manufacture of a medicament for the treatment of promoting wakefulness in parkinson's disease patients:

-the use of the above combination for the manufacture of a medicament for the treatment of excessive daytime sleepiness associated with parkinson's disease;

-the use of the above combination for the manufacture of a medicament for the treatment of excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease;

-use of the above combination for the manufacture of a medicament for the treatment of cognitive function impairment associated with parkinson's disease

Drawings

FIG. 1: receptor occupancy (%) plotted against the plasma concentration (ng/ml) of compound (I). The vertical lines show the corresponding estimated EC₅₀。

FIG. 2: brain and plasma PK of compound (I) (upper panel), peliostat (middle panel) and baffiryn (lower panel) after oral administration of 10mg/kg in rats.

FIG. 3: time course receptor occupancy studies of compound (I) (upper panel), peliostat (middle panel) and baffiryn (lower panel) following oral administration of 10mg/kg [ compound (I) and baffiryn ] or 300mg/kg (peliostat) in rats.

FIG. 4: time course study of tMeHA after oral administration of 10mg/kg of Compound (I) (upper panel), Pirisperidone (middle panel) and bafferson (lower panel) in rats. Statistical significance of drug and vehicle groups was analyzed using two-way ANOVA analysis of repeated measures (. p < 0.05,. p < 0.01).

Detailed Description

It has been found that compound (I) may be an ideal candidate for the treatment of PD-associated Excessive Daytime Sleepiness (EDS) with therapeutic advantages such as one or more of the following:

i) it reduces excessive daytime sleepiness (i.e. improves wakefulness), e.g. it reduces excessive daytime sleepiness compared to placebo;

ii) it improves (e.g. reduces) subjective sleepiness compared to placebo, e.g. improves Epworth sleepiness scale score (ESS; johns, M.W., Sleep, 1991, 14, 540-545) (e.g., a reduction of > 3 points from baseline);

iii) it improves objective somnolence (e.g. improvement in frequency, duration or intensity) compared to placebo, e.g. it increases Sleep latency, e.g. as measured by the "maintenance of consciousness test (MWT)" or "Multiple Sleep Latency Test (MSLT) [ e.g. in Littner et al Sleep, Sleep 2005, 28(1), 113-;

iv) it improves (e.g. reduces) the Clinical Impression of sleepiness compared to placebo, e.g. as measured by the Clinical Global Impression scale for Global sleepiness (CGI; for example, Guy 1976) score;

v) it reduces excessive daytime sleepiness (i.e., improves wakefulness) without affecting nighttime sleep [ e.g., does not cause insomnia, e.g., as measured by sleep diary data or Polysomnography (PSG) (see, e.g., Berry et al, 2016) ], e.g., as compared to placebo;

vi) it reduces excessive daytime sleepiness without affecting nighttime sleep (e.g., without causing insomnia) as compared to other therapeutic agent(s) [ e.g., pirimott, baffirol, modafinil, armodafinil, or JZP-110 (sorafenib) ];

vii) it improves cognitive function compared to placebo, e.g. it improves one or more cognitive domains selected from the group consisting of learning, psychomotor function, attention, sustained attention, working memory, situational memory and executive function [ e.g. as measured by symbolic digital modal testing (SDMT; see Smith, 1968) and computerized testing (see, e.g., Cho et al, 2011; grove et al, 2014));

viii) it reduces fatigue [ e.g., as measured by the Fatigue Severity Scale (FSS) score, e.g., in Archives of Neurology [ neurological Archives ], 1989; 46: 1121, 1123 or https: pdf// www.healthywomen.org/sites/default/files/fatiguesetracetyscale. pdf ], e.g., as compared to placebo; or

ix) it has advantageous safety features such as advantageous features related to skin reactions, psychiatric adverse events (e.g. does not increase the incidence of depression) or cardiovascular adverse events (e.g. blood pressure, heart rate, electrocardiogram parameters); for example, it has a better safety profile than other therapeutic agents [ e.g., pionst, baffirol, modafinil, armodafinil, or JZP-110 (sorafenib) ].

The embodiment of the invention is as follows:

example (a):

example 1 a: compound (I) or a pharmaceutically acceptable salt thereof, for use in promoting wakefulness in parkinson's disease patients.

Example 2 a: compound (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of impaired cognitive function associated with parkinson's disease; such as impaired learning, psychomotor function, attention, sustained attention, working memory, episodic memory, and executive function, each of which is associated with parkinson's disease; particularly attention associated with parkinson's disease.

Example 3 a: compound (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of excessive daytime sleepiness associated with parkinson's disease.

Example 4 a: compound (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease.

Example 5 a: compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1a to 4a, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

Example 6 a: compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1a to 4a, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional pharmaceutically active ingredients.

Example 7 a: compound (I) or a pharmaceutically acceptable salt thereof, for use according to example 6a, wherein the further pharmaceutically active ingredient is a pro-wakefulness agent.

Example 8 a: compound (I) or a pharmaceutically acceptable salt thereof, for use according to example 6a, wherein the additional pharmaceutically active ingredient is selected from the group consisting of: levodopa; a combination of levodopa and pergolide; a combination of levodopa and cabergoline; a combination of levodopa and ropinirole; a combination of levodopa and carbidopa; a combination of levodopa and entacapone; a combination of levodopa and benserazide; a combination of levodopa and pramipexole; or a pharmaceutically acceptable salt thereof.

Example 9 a: compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of examples 1a to 8a, wherein the use is in combination with psychotherapy or behavioral therapy, in particular behavioral therapy, such as cognitive behavioral therapy focused on sleep hygiene regulations (e.g. wherein the behavioral therapy is computer-assisted therapy).

Example 10 a: compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of examples 3a to 9a, wherein excessive daytime sleepiness is concomitant with one or more sleep disorders associated with parkinson's disease, such as fast eye movement, e.g. fast eye movement sleep behaviour disorder.

Example 11 a: compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1a to 10a, wherein compound (I) is administered in an amount of 0.1 mg/day to 50 mg/day, in particular 1 mg/day to 20 mg/day, such as 5 mg/day, 10 mg/day or 20 mg/day, in particular 10 mg/day.

Example 12 a: compound (I), or a pharmaceutically acceptable salt thereof, for use according to any one of examples 1a to 11a, wherein compound (I), or a pharmaceutically acceptable salt thereof, is administered orally.

Example 13 a: compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of examples 1a to 12a, wherein parkinson's disease is co-morbid with a psychotic disorder such as depression, anxiety or psychosis.

Example 14 a: compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1a to 13a, wherein parkinson's disease is early, intermediate or advanced parkinson's disease, in particular advanced parkinson's disease.

Example 15 a: a combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one active ingredient selected from the group consisting of: levodopa, a combination of levodopa and pergolide, a combination of levodopa and cabergoline, a combination of levodopa and ropinirole, a combination of levodopa and carbidopa, a combination of levodopa and entacapone, a combination of levodopa and benserazide, a combination of levodopa and pramipexole, amantadine, selegiline, rasagiline, entacapone, ramelteone, melatonin, zolpidem, eszopiclone, zopiclone, brotizolam, trazodone, doxepin, darifenacin, solifenadine, tolterodine, pregabalin, gabapentin ester, paroxetine, donepezil, rivastigmine, desipramine, clonazepam, lorazepam, triazolam, temazepam, flumazepam, cabergoline, levuline, triptorelin, tipepilin, pergoline, pramipexole, cabergoline, pramipexole, clethole, lorazepam, and levamitriptonile, Ropinirole, carbidopa, benserazide, clozapine, quetiapine, pimavanserin, duloxetine, mirtazapine, nortriptyline, venlafaxine, modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, sodium oxybate; or a pharmaceutically acceptable salt thereof; in particular modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, alprazolam, sorafenib and sodium oxybate; or a pharmaceutically acceptable salt thereof.

Example 16 a: a combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one active ingredient selected from the group consisting of: modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, sorafenib, and sodium oxybate, or a pharmaceutically acceptable salt thereof; in particular sorafenib, modafinil or armodafinil or pharmaceutically acceptable salts thereof.

Example (b):

example 1 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in promoting wakefulness in parkinson's disease patients.

Example 2 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of impaired cognitive function associated with parkinson's disease; such as impaired learning, psychomotor function, attention, sustained attention, working memory, episodic memory, and executive function, each of which is associated with parkinson's disease; particularly attention associated with parkinson's disease.

Example 3 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of excessive daytime sleepiness associated with parkinson's disease.

Example 4 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease.

Example 5 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 4b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional pharmaceutically active ingredients.

Example 6 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use according to example 5b, wherein the further pharmaceutically active ingredient is a wakefulness-promoting agent.

Example 7 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for use according to example 5b, wherein the additional pharmaceutically active ingredient is selected from the group consisting of: levodopa; a combination of levodopa and pergolide; a combination of levodopa and cabergoline; a combination of levodopa and ropinirole; a combination of levodopa and carbidopa; a combination of levodopa and entacapone; a combination of levodopa and benserazide; a combination of levodopa and pramipexole; or a pharmaceutically acceptable salt thereof.

Example 8 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for use according to any one of examples 1b to 7b, wherein the use is in combination with psychotherapy or behavioral therapy, in particular behavioral therapy, such as cognitive behavioral therapy focused on sleep hygiene regulations (e.g., wherein the behavioral therapy is computer-assisted therapy).

Example 9 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 3b to 8b, wherein excessive daytime sleepiness is concomitant with one or more sleep disorders associated with parkinson's disease, such as fast eye movement, e.g. fast eye movement sleep behaviour disorder.

Example 10 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 9b, wherein compound (I) is administered in an amount of 0.1 mg/day to 50 mg/day, in particular 1 mg/day to 20 mg/day, such as 5 mg/day, 10 mg/day or 20 mg/day, in particular 10 mg/day.

Example 11 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 10b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered orally.

Example 12 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use according to any one of examples 1b to 11b, wherein parkinson's disease is co-morbid with a psychotic disorder such as depression, anxiety or psychosis.

Example 13 b: a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 12b, wherein parkinson's disease is early, intermediate or advanced parkinson's disease, in particular advanced parkinson's disease.

Example (c):

example 1 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for use in promoting wakefulness in parkinson's disease patients.

Example 2 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the treatment of impaired cognitive function associated with parkinson's disease; such as impaired learning, psychomotor function, attention, sustained attention, working memory, episodic memory, and executive function, each of which is associated with parkinson's disease; particularly attention associated with parkinson's disease.

Example 3 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the treatment of excessive daytime sleepiness associated with parkinson's disease.

Example 4 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the treatment of excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease.

Example 5 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for use according to any one of embodiments 1c to 4c, wherein the further pharmaceutically active ingredient is a wakefulness-promoting agent.

Example 6 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient, for use according to any one of embodiments 1c to 4c, wherein the further pharmaceutically active ingredient is selected from the group consisting of: levodopa; a combination of levodopa and pergolide; a combination of levodopa and cabergoline; a combination of levodopa and ropinirole; a combination of levodopa and carbidopa; a combination of levodopa and entacapone; a combination of levodopa and benserazide; a combination of levodopa and pramipexole; or a pharmaceutically acceptable salt thereof.

Example 7 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient, for use according to any one of examples 1c to 6c, wherein the use is in combination with psychotherapy or behavioral therapy, in particular behavioral therapy, such as cognitive behavioral therapy focused on sleep hygiene regulations (e.g. wherein the behavioral therapy is computer-assisted therapy).

Example 8 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient, for use according to any one of embodiments 3c to 7c, wherein excessive daytime sleepiness is concomitant with one or more sleep disorders associated with parkinson's disease, such as fast eye movement, e.g. fast eye movement sleep behaviour disorder.

Example 9 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient, for use according to any one of embodiments 1c to 8c, wherein compound (I) is administered in an amount of 0.1 mg/day to 50 mg/day, in particular 1 mg/day to 20 mg/day, such as 5 mg/day, 10 mg/day or 20 mg/day, in particular 10 mg/day.

Example 10 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient, for use according to any one of embodiments 1c to 9c, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered orally.

Example 11 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient, for use according to any one of embodiments 1c to 10c, wherein parkinson's disease is co-morbid with a psychotic disorder such as depression, anxiety or psychosis.

Example 12 c: a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient, for use according to any one of embodiments 1c to 11c, wherein parkinson's disease is early, intermediate or advanced parkinson's disease, in particular advanced parkinson's disease.

Example (d):

example 1 d: a therapeutic method for promoting wakefulness in a parkinson's disease subject in need thereof, which comprises administering to the subject an effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

Example 2 d: a method of treating impaired cognitive function associated with parkinson's disease in a subject in need thereof, said method comprising administering to said subject an effective amount of compound (I) or a pharmaceutically acceptable salt thereof, in particular wherein cognitive function comprises a cognitive domain selected from the group consisting of: impaired learning, impaired psychomotor function, impaired attention, impaired sustained attention, impaired working memory, impaired situational memory, and impaired executive function, each of which is associated with parkinson's disease; particularly attention associated with parkinson's disease.

Example 3 d: a method for treating excessive daytime sleepiness associated with parkinson's disease in a subject in need thereof, the method comprising administering to the subject an effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

Example 4 d: a method for treating excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease in a subject in need thereof, which comprises administering to the subject an effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

Example 5 d: the method according to any one of embodiments 1d to 4d, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

Example 6 d: the method according to any one of embodiments 1d to 4d, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional pharmaceutically active ingredients.

Example 7 d: the method of embodiment 6d wherein the additional pharmaceutically active ingredient is a stimulant.

Example 8 d: the method of embodiment 6d, wherein the additional pharmaceutically active ingredient is selected from the group consisting of: levodopa; a combination of levodopa and pergolide; a combination of levodopa and cabergoline; a combination of levodopa and ropinirole; a combination of levodopa and carbidopa; a combination of levodopa and entacapone; a combination of levodopa and benserazide; a combination of levodopa and pramipexole; or a pharmaceutically acceptable salt thereof.

Example 9 d: the method according to any one of embodiments 1d to 8d, wherein the method is combined with psychotherapy or behavioral therapy, in particular behavioral therapy, such as cognitive behavioral therapy focused on sleep hygiene regulations (e.g. wherein behavioral therapy is computer-assisted therapy).

Example 10 d: the method according to any one of embodiments 3d to 9d, wherein excessive daytime sleepiness is concomitant with one or more sleep disorders associated with parkinson's disease, such as fast eye movement, e.g. fast eye movement sleep behaviour disorder.

Example 11 d: the method according to any one of embodiments 1d to 10d, wherein compound (I) is administered in an amount of 0.1 mg/day to 50 mg/day, in particular 1 mg/day to 20 mg/day, such as 5 mg/day, 10 mg/day or 20 mg/day, in particular 10 mg/day.

Example 12 d: the method according to any one of embodiments 1d to 11d, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered orally.

Example 13 d: the method according to any one of embodiments 1d to 12d, wherein parkinson's disease is co-morbid with a psychotic disorder such as depression, anxiety or psychosis.

Example 14 d: the method according to any one of embodiments 1d to 13d, wherein parkinson's disease is early, intermediate or advanced parkinson's disease, in particular advanced parkinson's disease.

Example (e):

example 1 e: a method for promoting wakefulness in a parkinson's disease subject in need thereof, which comprises administering to said subject a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

Example 2 e: a method of treating impaired cognitive function associated with parkinson's disease in a subject in need thereof, said method comprising administering to said subject a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, in particular wherein cognitive function comprises a cognitive domain selected from the group consisting of: impaired learning, impaired psychomotor function, impaired attention, impaired sustained attention, impaired working memory, impaired episodic memory, and impaired executive function, each of which is associated with parkinson's disease; particularly attention associated with parkinson's disease.

Example 3 e: a method for treating excessive daytime sleepiness associated with parkinson's disease in a subject in need thereof, said method comprising administering to said subject a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

Example 4 e: a method for treating excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease in a subject in need thereof, which comprises administering to said subject a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

Example 5 e: the method according to any one of embodiments 1e to 4e, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional pharmaceutically active ingredients.

Example 6 e: the method of embodiment 5e wherein the additional pharmaceutically active ingredient is a stimulant.

Example 7 e: the method of embodiment 5e, wherein the additional pharmaceutically active ingredient is selected from the group consisting of: levodopa; a combination of levodopa and pergolide; a combination of levodopa and cabergoline; a combination of levodopa and ropinirole; a combination of levodopa and carbidopa; a combination of levodopa and entacapone; a combination of levodopa and benserazide; a combination of levodopa and pramipexole; or a pharmaceutically acceptable salt thereof.

Example 8 e: the method according to any one of embodiments 1e to 7e, wherein the method is combined with psychotherapy or behavioral therapy, in particular behavioral therapy, such as cognitive behavioral therapy focused on sleep hygiene regulations (e.g. wherein behavioral therapy is computer-assisted therapy).

Example 9 e: the method according to any one of embodiments 3e to 8e, wherein excessive daytime sleepiness is concomitant with one or more sleep disorders associated with parkinson's disease, such as fast eye movement, e.g. fast eye movement sleep behaviour disorder.

Example 10 e: the method according to any one of embodiments 1e to 9e, wherein compound (I) is administered in an amount of 0.1 mg/day to 50 mg/day, in particular 1 mg/day to 20 mg/day, such as 5 mg/day, 10 mg/day or 20 mg/day, in particular 10 mg/day.

Example 11 e: the method according to any one of embodiments 1e to 10e, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered orally.

Example 12 e: the method according to any one of embodiments 1e to 11e, wherein parkinson's disease is co-morbid with a psychiatric disorder such as depression, anxiety or psychosis.

Example 13 e: the method according to any one of embodiments 1e to 12e, wherein parkinson's disease is early, intermediate or advanced parkinson's disease, in particular advanced parkinson's disease.

Example (f):

example 1 f: a method for promoting wakefulness in a parkinson's disease subject in need thereof, which comprises administering to said subject a pharmaceutical combination comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and at least one additional pharmaceutically active ingredient.

Example 2 f: a method of treating impaired cognitive function associated with parkinson's disease in a subject in need thereof, said method comprising administering to said subject a pharmaceutical combination comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and at least one additional pharmaceutically active ingredient, in particular wherein cognitive function comprises a cognitive domain selected from the group consisting of: impaired learning, impaired psychomotor function, impaired attention, impaired sustained attention, impaired working memory, impaired episodic memory, and impaired executive function, each of which is associated with parkinson's disease; particularly attention associated with parkinson's disease.

Example 3 f: a method for treating excessive daytime sleepiness associated with parkinson's disease in a subject in need thereof, said method comprising administering to said subject a pharmaceutical combination comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and at least one additional pharmaceutically active ingredient.

Example 4 f: a method for treating excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease in a subject in need thereof, which comprises administering to the subject a pharmaceutical combination comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient.

Example 5 f: the method according to any one of embodiments 1f to 4f, wherein the further pharmaceutically active ingredient is a pro-wakefuling agent.

Example 6 f: the method according to any one of embodiments 1f to 4f, wherein the additional pharmaceutically active ingredient is selected from the group consisting of: levodopa; a combination of levodopa and pergolide; a combination of levodopa and cabergoline; a combination of levodopa and ropinirole; a combination of levodopa and carbidopa; a combination of levodopa and entacapone; a combination of levodopa and benserazide; a combination of levodopa and pramipexole; or a pharmaceutically acceptable salt thereof.

Example 7 f: the method according to any one of embodiments 1f to 6f, wherein the method is combined with psychotherapy or behavioral therapy, in particular behavioral therapy, such as cognitive behavioral therapy focused on sleep hygiene regulations (e.g. wherein behavioral therapy is computer-assisted therapy).

Example 8 f: the method according to any one of embodiments 3f to 7f, wherein excessive daytime sleepiness is concomitant with one or more sleep disorders associated with parkinson's disease, such as fast eye movement, e.g. fast eye movement sleep behaviour disorder.

Example 9 f: the method according to any one of embodiments 1f to 8f, wherein compound (I) is administered in an amount of 0.1 mg/day to 50 mg/day, in particular 1 mg/day to 20 mg/day, such as 5 mg/day, 10 mg/day or 20 mg/day, in particular 10 mg/day.

Example 10 f: the method according to any one of embodiments 1f to 9f, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered orally.

Example 11 f: the method according to any one of embodiments 1 f-10 f, wherein parkinson's disease is co-morbid with a psychiatric disorder such as depression, anxiety or psychosis.

Example 12 f: the method according to any one of embodiments 1 f-11 f, wherein parkinson's disease is early, intermediate or advanced parkinson's disease, in particular advanced parkinson's disease.

Example (g):

example lg: use of compound (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of promoting wakefulness in parkinson's disease patients.

Example 2 g: use of compound (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of impaired cognitive function associated with parkinson's disease; such as impaired learning, psychomotor function, attention, sustained attention, working memory, episodic memory, and executive function, each of which is associated with parkinson's disease; particularly attention associated with parkinson's disease.

Example 3 g: use of compound (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of excessive sleepiness associated with parkinson's disease.

Example 4 g: use of compound (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease.

Example 5 g: use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament according to any one of embodiments 1g to 4g, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.

Example 6 g: use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament according to any one of embodiments 1g to 4g, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional pharmaceutically active ingredients.

Example 7 g: use of compound (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament according to example 6g, wherein the further pharmaceutically active ingredient is a pro-wakening agent.

Example 8 g: use of compound (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament according to embodiment 6g, wherein the additional pharmaceutically active ingredient is selected from the group consisting of: levodopa; a combination of levodopa and pergolide; a combination of levodopa and cabergoline; a combination of levodopa and ropinirole; a combination of levodopa and carbidopa; a combination of levodopa and entacapone; a combination of levodopa and benserazide; a combination of levodopa and pramipexole; or a pharmaceutically acceptable salt thereof.

Example 9 g: use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament according to any one of embodiments 1g to 8g, wherein the use is in combination with psychotherapy or behavioral therapy, in particular behavioral therapy, such as cognitive behavioral therapy focused on sleep hygiene regulations (e.g. wherein the behavioral therapy is computer-assisted therapy).

Example 10 g: use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament according to any one of embodiments 3g to 9g, wherein excessive daytime sleepiness is concomitant with one or more sleep disorders associated with parkinson's disease, such as rapid eye movement, e.g. a rapid eye movement sleep behaviour disorder.

Example 11 g: use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament according to any one of embodiments 1 to 10g, wherein compound (I) is administered in an amount of 0.1 to 50 mg/day, in particular 1 to 20 mg/day, such as 5, 10 or 20 mg/day, in particular 10 mg/day.

Example 12 g: use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament according to any one of embodiments 1g to 11g, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered orally.

Example 13 g: use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament according to any one of embodiments 1g to 12g, wherein parkinson's disease is co-morbid with a psychotic disorder such as depression, anxiety or psychosis.

Example 14 g: use of compound (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament according to any one of embodiments 1 to 13g, wherein parkinson's disease is early, intermediate or advanced parkinson's disease, in particular advanced parkinson's disease.

Example (h):

example 1 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment of promoting wakefulness in parkinson's disease patients.

Example 2 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment of impaired cognitive function associated with parkinson's disease; such as impaired learning, psychomotor function, attention, sustained attention, working memory, episodic memory, and executive function, each of which is associated with parkinson's disease; particularly attention associated with parkinson's disease.

Example 3 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment of excessive daytime sleepiness associated with parkinson's disease.

Example 4 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment of excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease.

Example 5 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the manufacture of a medicament according to any one of embodiments 1h to 4h, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional pharmaceutically active ingredients.

Example 6 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the manufacture of a medicament according to example 5h, wherein the further pharmaceutically active ingredient is a wakefulness-promoting agent.

Example 7 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the manufacture of a medicament according to embodiment 5h, wherein the additional pharmaceutically active ingredient is selected from the group consisting of: levodopa; a combination of levodopa and pergolide; a combination of levodopa and cabergoline; a combination of levodopa and ropinirole; a combination of levodopa and carbidopa; a combination of levodopa and entacapone; a combination of levodopa and benserazide; a combination of levodopa and pramipexole; or a pharmaceutically acceptable salt thereof.

Example 8 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the manufacture of a medicament according to any one of embodiments 1h to 7h, wherein the use is in combination with psychotherapy or behavioral therapy, in particular behavioral therapy, such as cognitive behavioral therapy focused on sleep hygiene regulations (e.g., wherein the behavioral therapy is computer-assisted therapy).

Example 9 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the manufacture of a medicament according to any one of embodiments 3h to 8h, wherein excessive daytime sleepiness is concomitant with one or more sleep disorders associated with parkinson's disease, such as fast eye movement, e.g. fast eye movement sleep behaviour disorder.

Example 10 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, for the manufacture of a medicament according to any one of embodiments 1h to 9h, wherein compound (I) is administered in an amount of 0.1 mg/day to 50 mg/day, in particular 1 mg/day to 20 mg/day, such as 5 mg/day, 10 mg/day or 20 mg/day, in particular 10 mg/day.

Example 11 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the manufacture of a medicament according to any one of embodiments 1h to 10h, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered orally.

Example 12 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the manufacture of a medicament according to any one of embodiments 1h to 11h, wherein parkinson's disease is co-morbid with a psychotic disorder such as depression, anxiety or psychosis.

Example 13 h: use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the manufacture of a medicament according to any one of embodiments 1h to 12h, wherein parkinson's disease is early, intermediate or advanced parkinson's disease, in particular advanced parkinson's disease.

Example (j):

example 1 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient in the manufacture of a medicament for the treatment of promoting wakefulness in parkinson's disease patients.

Example 2 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient in the manufacture of a medicament for the treatment of impaired cognitive function associated with parkinson's disease; such as impaired learning, psychomotor function, attention, sustained attention, working memory, episodic memory, and executive function, each of which is associated with parkinson's disease; particularly attention associated with parkinson's disease.

Example 3 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the manufacture of a medicament for the treatment of excessive daytime sleepiness associated with parkinson's disease.

Example 4 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the manufacture of a medicament for the treatment of excessive daytime sleepiness associated with dopamine replacement therapy in parkinson's disease.

Example 5 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the manufacture of a medicament according to any one of embodiments 1j to 4j, wherein the further pharmaceutically active ingredient is a wakefulness-promoting agent.

Example 6 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the manufacture of a medicament according to any one of embodiments 1j to 4j, wherein the further pharmaceutically active ingredient is selected from the group consisting of: levodopa; a combination of levodopa and pergolide; a combination of levodopa and cabergoline; a combination of levodopa and ropinirole; a combination of levodopa and carbidopa; a combination of levodopa and entacapone; a combination of levodopa and benserazide; a combination of levodopa and pramipexole; or a pharmaceutically acceptable salt thereof.

Example 7 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the manufacture of a medicament according to any one of embodiments 1j to 6j, wherein the use is in combination with a psychotherapy combination or a behavioral therapy, in particular a behavioral therapy, such as a cognitive behavioral therapy focused on sleep hygiene regulations (e.g. wherein the behavioral therapy is a computer-assisted therapy).

Example 8 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the manufacture of a medicament according to any one of embodiments 3j to 7j, wherein excessive daytime sleepiness is concomitant with one or more sleep disorders associated with parkinson's disease, such as fast eye movement, e.g. fast eye movement sleep behaviour disorder.

Example 9 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the manufacture of a medicament according to any one of embodiments 1j to 8j, wherein compound (I) is administered in an amount of 0.1 mg/day to 50 mg/day, in particular 1 mg/day to 20 mg/day, such as 5 mg/day, 10 mg/day or 20 mg/day, in particular 10 mg/day.

Example 10 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the manufacture of a medicament according to any one of embodiments 1j to 9j, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered orally.

Example 11 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the manufacture of a medicament according to any one of embodiments 1j to 10j, wherein parkinson's disease is co-morbid with a psychotic disorder such as depression, anxiety or psychosis.

Example 12 j: use of a pharmaceutical combination comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically active ingredient for the manufacture of a medicament according to any one of embodiments 1j to 11j, wherein parkinson's disease is early, intermediate or advanced parkinson's disease, in particular advanced parkinson's disease.

General terms

The term "parkinson's disease" (PD) as used herein should be understood, for example, according to the Hoehn and Yahr scale [ e.g. in Neurology, 1967, 17 (5): 427-442; or Mov disorder [ dyskinesia ] 9 months 2004; 19(9): 1020-8], which is incorporated herein by reference. In one embodiment, "PD" as used herein refers to "early PD," intermediate PD, "and" late PD. As used herein, the term "early PD" refers to phases 1 and 2, the term "intermediate PD" refers to phase 3, and the term "late PD" refers to phases 4 and 5; wherein the staging is determined according to the Hoehn and Yahr scale [ Neurology ], 1967, 17 (5): 427-442]. In one embodiment, PD is referred to as "early PD". In another embodiment, PD is referred to as "intermediate PD". In yet another embodiment, PD is referred to as "late PD".

As used herein, the term "parkinson's disease patient" or "patient with parkinson's disease" refers to a patient diagnosed with parkinson's disease, for example as defined above. In one embodiment, it refers to a parkinson's disease patient (e.g., as defined herein) who is excessively sleepy during the day (e.g., as defined herein).

As used herein, the term "daytime excessive sleepiness associated with parkinson's disease (EDS)" is understood to be defined, for example, in terms of the ICSD-3 standard (i.e., in accordance with the International Classification of Sleep Disorders [ International Sleep disorder Classification ] -third edition) with respect to sleepiness due to medical Disorders, such as parkinson's disease-induced sleepiness. The ICSD-3 standard, defined in relation to the hypersomnia due to medical disorders (incorporated herein by reference), relates to four diagnostic criteria that the diagnosis needs to meet (i.e. all a-D below): (A) patients have an uninhibited need for sleep on a daily basis or daytime sleepiness for at least 3 months, (B) daytime sleepiness is due to a serious underlying physical or neurological condition, (C) if multiple sleep latency tests [ MSLT ] are performed, the mean sleep latency is less than 8 minutes and less than two sleep REM episodes (soramp) are observed, and (D) these symptoms cannot be better explained with another untreated sleep disorder, psychiatric disorder or drug treatment or effect of the drug. Excessive daytime sleepiness may be assessed with MSLT (e.g., determining mean (± SD) MSLT latency), e.g., as objective sleepiness, as suggested by the relevant guidelines [ Littner et al, Sleep ], 2005, 28(1), 113-sec 121 ]. Alternatively, excessive daytime sleepiness can be assessed using the Epworth Sleepiness Scale (ESS) [ Sleep ], 1991, 14, 540-; com ], which is a self-administered 8 questionnaire whose scores are explained as follows: normal daytime sleepiness is 0-5 minutes lower, normal daytime sleepiness is 6-10 minutes higher, mild daytime excessive sleepiness is 11-12 minutes, moderate daytime sleepiness is 13-15 minutes, and severe daytime sleepiness is 16-24 minutes. In one embodiment, as used herein, the term "excessive daytime sleepiness" (EDS) should be understood as an ESS score ≧ 13.

As used herein, the term "dopamine replacement therapy" refers to a primary symptom treatment for PD based on (i) a drug that replaces or increases the level of endogenous dopamine (e.g., levodopa (levodopa or L-DOPA)) or (ii) administration of a dopamine receptor agonist (e.g., apomorphine).

As used herein, the term "Parkinson's disease-induced daytime excessive sleepiness associated with dopamine replacement therapy" is understood to be defined, for example, in terms of drug-or substance-induced hypersomnia, such as hypersomnia due to dopamine replacement therapy, according to the ICSD-3 standard (i.e., according to the International Classification of Sleep Disorders [ International Classification of Sleep Disorders ] -3 rd edition: American Academy of Sleep Medicine [ American society for Sleep Medicine ], 2014). The ICSD-3 standard (incorporated herein by reference) defined for drug or substance induced hypnagogic disorders relates to three diagnostic criteria (i.e. all a-C below) that a diagnosis needs to meet: (A) patients have daily uninhibited sleep needs or daytime sleepiness, (B) daytime sleepiness is a result of current drug or substance use or inactivation of a pro-wake drug or substance, (C) these symptoms cannot be better explained by another untreated sleep disorder, physical or neurological disorder, or psychological disorder.

As used herein, the term "PD-associated sleep disorder" refers specifically to a) insomnia, such as insomnia associated or not associated with Rapid Eye Movement (REM), sleep-related respiratory disorders, and sleep-related movement disorders, such as Restless Leg Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD) ]; and b) sudden sleep attacks.

As used herein, the terms "Rapid Eye Movement (REM) Sleep behavior disorder", "rapid eye movement Sleep behavior disorder", or "RDB" are defined, for example, with reference to the ICSD-3 standard (International Classification of Sleep Disorders Classification, 3 rd edition: american society for Sleep medicine, 2014), which is incorporated herein by reference.

As used herein, the term "restless leg syndrome" is defined with reference to, for example, the ICSD-3 standard, which is incorporated herein by reference.

As used herein, the term "sleep-related breathing disorder" is defined, for example, with reference to the ICSD-3 standard, which is incorporated herein by reference.

As used herein, the term "insomnia" is defined, for example, with reference to the ICSD-3 standard, which is incorporated herein by reference.

As used herein, the term "periodic limb movement disorder" is defined, for example, with reference to the ICSD-3 standard, which is incorporated herein by reference.

As used herein, the term "sleep-related dyskinesia" is defined, for example, with reference to the ICSD-3 standard, which is incorporated herein by reference.

As used herein, the term "sudden onset of sleep" refers to the onset of a Sudden Onset of Sleep (SOS) that is generally free of warning signals.

As used herein, the term "Mental disorder" shall be in accordance with, for example, the Diagnostic and Statistical Manual of Mental Disorders 5^thEdition [ diagnostic and statistical manual for mental disorders 5 th Edition](DSM-5), which is incorporated herein by reference.

As used herein, the term "depression" is to be understood as a depressive disorder, e.g. according to the criteria defined in DMS-5, which is incorporated herein by reference.

As used herein, the term "anxiety disorder" is to be understood as an anxiety disorder, for example according to the criteria defined in DMS-5, which is incorporated herein by reference.

As used herein, the term "psychosis" is to be understood as a mental disorder arising from another physical condition, e.g., according to the criteria defined in DMS-5, which is incorporated herein by reference.

As used herein, the term "circadian sleep-wake rhythm" refers to the circadian rhythm (i.e., the "internal clock" that regulates, for example, sleep patterns such as when to fall asleep and when to wake up every 24 hours, with the normal circadian clock set by a light-dark cycle over 24 hours).

As used herein, the term "wake-promoting agent" refers to an agent capable of reducing excessive daytime sleepiness, e.g., as compared to the excessive daytime sleepiness observed without treatment. For example, the wakefulness-promoting agent is selected from the group consisting of modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, sorafenib, and sodium oxybate, or a pharmaceutically acceptable salt thereof; in particular sorafenib, modafinil or armodafinil or pharmaceutically acceptable salts thereof.

As used herein, the term "promoting arousal" refers to a reduction in excessive daytime sleepiness, as measured, for example, by the Epworth sleepiness scale (e.g., a reduction in score > 2) or by an arousal maintenance test (e.g., an increase in sleep latency of at least 0.5 minutes), as compared to the excessive daytime sleepiness observed without treatment. In one embodiment, as used herein, the term "for promoting arousal" is understood to mean "a treatment for promoting arousal" or "a method of treatment for promoting arousal". In another embodiment, the term "treatment for promoting wakefulness" as used herein is understood to mean "a method of treatment for promoting wakefulness".

The term "sleep-inducing agent" refers to a compound capable of inducing sleep and/or improving the quality of sleep in a patient.

As used herein, the term "cognitive function" refers to the ability to, for example, concentrate, remember things, make decisions, solve problems, or think. The cognitive function includes one or more cognitive domains selected from the group consisting of learning, psychomotor function, attention, sustained attention, working memory, episodic memory, and executive function. In a particular embodiment, it comprises one or more cognitive domains selected from the group consisting of psychomotor function, attention, sustained attention, working memory, episodic memory and executive function; more particularly, a cognitive domain selected from the group consisting of psychomotor function, attention, sustained attention, working memory, episodic memory, and executive function.

The term "impaired cognitive function" refers to a defect in one or more cognitive domains associated with cognitive function, in particular a defect in one or more cognitive domains selected from the group consisting of: learning (i.e., impaired learning), psychomotor function (i.e., impaired psychomotor function), attention (i.e., impaired attention), sustained attention (i.e., impaired sustained attention), working memory (i.e., impaired working memory), situational memory (i.e., impaired situational memory), and executive function (i.e., impaired executive function); for example, as measured by symbolic digital modal testing (SDMT; see Smith, 1968) and computerized testing (e.g., Cho et al, 2011 or Grove et al, 2014). In a particular embodiment, impaired cognitive function refers to impaired attention, impaired sustained attention, or impaired psychomotor function. In another specific embodiment, it refers to impaired learning, impaired episodic memory, impaired working memory, or impaired executive function.

As used herein, the term "attention" refers to, but is not limited to, the ability to selectively focus on one aspect of an environment while ignoring other things. For example, it can be tested by authentication (e.g., by a differential test)https：//cogstate.com/cognitive- tests/identification/) It is measured.

As used herein, the term "psychotherapy" refers to, but is not limited to, a standard counseling session, e.g., once per week, e.g., focusing on

As used herein, the term "behavioral therapy" refers to, but is not limited to, cognitive behavioral therapy (e.g., Koychev et al, Evid Based Ment Health, 2017, 20(1), 15-20), particularly focused on sleep hygiene rules.

As used herein, the term "sleep hygiene rules" refers to sleep practices and habits, for example, by following conventions that improve nighttime sleep quality and daytime alertness (e.g., by regular bedtime, by limiting daytime sleepiness to 30 minutes, etc.).

In one embodiment, the term "psychotherapy" or "behavioral therapy" includes light therapy (e.g., light therapy using 400 to 760nm visible radiation), thoughts (e.g., physical scanning meditation), or awareness training (e.g., self awareness training).

As used herein, the term "computer-assisted" in the expression "behavioral therapy is computer-assisted therapy" refers to a behavioral therapy that includes the use of electronic tools (such as online tools, smartphones, wireless devices, or health apps). In one embodiment, the term "computer-assisted" in the expression "psychosocial therapy or behavioral therapy as used herein is understood to be" computer-implemented "(i.e., psychosocial therapy or behavioral therapy is computer-implemented therapy, i.e., provided by a computerized device, such as a mobile device), e.g., selected from the group consisting of a smartphone, a notebook, a tablet, and a wearable computer [ e.g., a smartwatch (such as an apple watch, a samsung Gear smartwatch, a LG G watch, a sony smartwatch) or a computer wristband (i.e., a smartwristband), particularly a smartphone ], as used herein with respect to a disease or disorder, the term" treat (therapy or treatment) "refers in one embodiment to alleviating the disease or disorder (i.e., slowing or preventing or reducing the development of the disease or at least one clinical symptom thereof.) in another embodiment, "treating" or "treatment" refers to reducing or improving at least one physical parameter, including those that are not discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating a disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter), or both. As used herein, for example, with respect to symptoms of a disorder, the term "alleviating" or "alleviating" refers to reducing at least one of the frequency and amplitude of symptoms of the disorder in a patient. In one embodiment, the term "method for the treatment (or method for treating)" as used herein refers to "method for treating".

As used herein, bid ═ b.i.d ═ twice a day, for example in the morning and in the evening (approximately 12 hours apart).

As used herein, the term "patient" refers to a subject who is ill and would benefit from treatment. As used herein, the term "elderly patient" refers to patients six and fifteen years of age or older.

As used herein, the term "subject" refers to a mammal, preferably a human (male or female).

As used herein, such a subject (patient) is "in need of treatment" if the subject would benefit biologically, medically or in quality of life from such treatment.

The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that will elicit the biological or medical response of a subject (e.g., ameliorating symptoms, alleviating a disorder, etc.). The term "pharmaceutical composition" is defined herein to mean a mixture or solution containing at least one active ingredient or therapeutic agent to be administered to a subject for the treatment of a particular condition (i.e., a disease, disorder or condition or at least one clinical symptom thereof) affecting the subject.

The term "pharmaceutical composition" is defined herein to mean a mixture or solution containing at least one active ingredient or therapeutic agent to be administered to a subject for the treatment of a particular condition (i.e., a disease, disorder or condition or at least one clinical symptom thereof) affecting the subject.

As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorants, dyes, and the like, and combinations thereof, as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, raminten Pharmaceutical Sciences, 22 th edition Mack Printing Company, 2013, pp 1049-1070). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

The terms "drug", "active substance", "active ingredient", "pharmaceutically active ingredient", "active agent" or "therapeutic agent" are to be understood as meaning a compound, in particular of the type specified herein, in free form or in pharmaceutically acceptable salt form.

The term "combination" or "pharmaceutical combination" refers to a fixed combination of unit dosage forms (e.g., capsules, tablets, caplets or granules), an unfixed combination, or a kit of parts for combined administration in which a compound of the invention and one or more combination partners (e.g., another drug as specified herein, also referred to as additional "pharmaceutically active ingredient", "therapeutic agent" or "adjuvant") may be administered separately, either simultaneously or at separate times, particularly where such time intervals allow the combination partners to exhibit cooperation, e.g., a synergistic effect. The terms "co-administration" or "combined administration" and the like as used herein are intended to encompass administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or simultaneously. The term "fixed combination" means that the active ingredients (e.g. a compound of the invention and one or more combination partners) are both administered to the patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that the active ingredients (e.g., a compound of the invention and one or more combination partners) are both administered to a patient as separate entities either simultaneously or sequentially without specific time constraints, wherein such administration provides therapeutically effective levels of both compounds in the patient.

The compounds of the invention may be administered separately, by the same or different route of administration as the other agents, or together in the same pharmaceutical composition. In the combination therapies of the invention, the compounds of the invention and the other therapeutic agents may be produced and/or formulated by the same or different manufacturers. In addition, the compounds of the present invention and other therapeutic agents may be brought together in a combination therapy in the following manner: (i) prior to dispensing the combination product to a physician (e.g., a kit where the compound of the invention and other therapeutic agent are included); (ii) shortly before administration, by the physician himself (or under the direction of the physician); (iii) in the patient itself, for example during the sequential administration of the compound of the invention and the other therapeutic agent.

In particular, as used herein (e.g., in any of the examples above herein, or any claim herein below), reference to a combination with an additional active agent refers, for example, to a combination with at least one additional active agent, e.g., selected from the group consisting of: levodopa, a combination of levodopa and pergolide, a combination of levodopa and cabergoline, a combination of levodopa and ropinirole, a combination of levodopa and carbidopa, a combination of levodopa and entacapone, a combination of levodopa and benserazide, a combination of levodopa and pramipexole, amantadine, selegiline, rasagiline, entacapone, ramelteone, melatonin, zolpidem, eszopiclone, zopiclone, brotizolam, trazodone, doxepin, darifenacin, solifenadine, tolterodine, pregabalin, gabapentin ester, paroxetine, donepezil, rivastigmine, desipramine, clonazepam, lorazepam, triazolam, temazepam, flumazepam, cabergoline, levuline, triptorelin, tipepilin, pergoline, pramipexole, cabergoline, pramipexole, clethole, lorazepam, and levamitriptonile, Ropinirole, carbidopa, benserazide, clozapine, quetiapine, pimavanserin, duloxetine, mirtazapine, nortriptyline, venlafaxine, modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, sodium oxybate; or a pharmaceutically acceptable salt thereof; in particular modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, alprazolam, sorafenib and sodium oxybate; or a pharmaceutically acceptable salt thereof.

As used herein, the terms "a" and "an", "the", and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

As used herein, the compounds of the present invention, as used above and below, referred to as compounds (I), are 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate having the following formula:

it can be prepared as described in WO 2014/013469, for example in example 1.5. WO 2014/013469 (which is incorporated herein by reference) also describes its biological data in vitro, according to pages 40 to 42, as well as its solid forms such as the free form in crystalline form, i.e. example ii.1.1 (i.e. the a form in free form) and example ii.1.2 (i.e. the B form in free form), and salts, e.g. citrate (i.e. example ii.2.1: the a form of citrate; example ii.2.2: the B form of citrate), hydrochloride (i.e. example ii.4.1: the a form of hydrochloride; example ii.4.2: the B form of hydrochloride), fumarate (i.e. example ii.3.1: the a form of fumarate; example ii.3.2: the B form of fumarate), including formulations thereof. As used herein, 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate or a pharmaceutically acceptable salt thereof refers in particular to the free form (such as the free a or B form), the citrate salt (such as the a or B form of the citrate salt), the hydrochloride salt (such as the a or B form of the hydrochloride salt), the fumarate salt (such as the a or B form of the fumarate salt). In one embodiment, the compound 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate of the present invention is in the free form as form a. In another embodiment, the compound 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate of the present invention is in the free form as form B.

In one embodiment, 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate is also intended to represent an isotopically labeled form. Isotopically-labeled compounds have the structure shown in the formula except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into compounds of the invention include, for example, isotopes of hydrogen, i.e., compounds having the formula:

wherein R is₀、R’₀、R”₀、R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₇、R₁₈、R₁₉、R₂₀、R₂₁、R₂₂、R₂₃、R₂₄、R₂₅And R₂₆Each independently selected from H or deuterium; with the proviso that at least one deuterium is present in the compound. In other embodiments, multiple deuterium atoms are present in the compound. In one embodiment, for example, R0, R' 0, and R "0 are deuterium atoms. In another embodiment, for example, R12 is a deuterium atom. In yet another embodiment, for example, R1 and R2 are deuterium. In yet another embodiment, for example, R13 through R18 are deuterium atoms.

In addition, certain isotopes, particularly deuterium (i.e., deuterium) are incorporated²H or D) may provide certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improvement in therapeutic index or tolerability. It is to be understood that deuterium is considered in this context to be a substituent of the compounds of the invention. The concentration of deuterium can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the abundance of an isotope and the natural abundance of a given isotope. If a substituent in a compound of the invention is represented as deuterium, the isotopic enrichment factor of the compound for each designated deuterium atom is at least 3500 (52.5% deuterium incorporated per designated deuterium atom), at least 4000 (60% deuterium incorporated), at least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated), at least 6466.7 (97% deuterium incorporated), at least 6600 (99% deuterium incorporated), or at least 6633.3 (99.5% deuterium incorporated). It is to be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

Isotopologues which can be incorporated in the compounds of the inventionOther examples of elements include isotopes of hydrogen (other than deuterium), carbon, nitrogen, oxygen, and fluorine, such as³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸F. Thus, it is to be understood that the present invention includes incorporation of one or more of any of the foregoing isotopes (including, for example, radioactive isotopes (such as³H and¹⁴C) or in the presence of a non-radioactive isotope (e.g. of a non-radioactive isotope)²H and¹³C) the compound of (1). Such isotopically labeled compounds are useful in metabolic studies (using¹⁴C) Reaction kinetics study (e.g. with²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including drug or substrate tissue distribution assays, or for radiotherapy of a patient. In particular, it is possible to use, for example,¹⁸f or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described for the preparation of compounds of the present invention by employing an appropriate isotopically-labeled reagent in place of the non-labeled reagent employed previously.

As used herein, the term "free form" refers to a compound in non-salt form, such as the base free form or acid free form of the corresponding compound, e.g. a compound as indicated herein (e.g. compound (I) or another pharmaceutically active ingredient, such as e.g. a wakefulness-promoting agent as defined herein).

As used herein, the term "salt" or "salt form" refers to an acid addition salt or a base addition salt of the corresponding compound, e.g. a compound as indicated herein (e.g. compound (I) or another pharmaceutically active ingredient, such as e.g. a wakefulness-promoting agent as defined herein). "salts" include in particular "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound, and such salts are typically not biologically or otherwise undesirable. A compound as specified herein (e.g. compound (I) or another pharmaceutically active ingredient, such as e.g. an arousal agent as defined herein) may form an acid and/or base salt by the presence of an amino and/or carboxyl group or similar groups thereof. The compounds of the present invention are capable of forming acid addition salts by the presence of an amino group similar thereto, such as the citrate, hydrochloride, fumarate, adipate, maleate or sebacate salts thereof; in particular the citrate, hydrochloride and fumarate salts thereof. Thus, as used herein, the term pharmaceutically acceptable salt of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate refers to a pharmaceutically acceptable acid addition salt of 1- (1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic Table of the elements. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); a cyclic amine; basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

Pharmaceutically acceptable salts can be synthesized from basic or acidic moieties by conventional chemical methods. In general, these salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base form of the compound with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or an organic solvent or a mixture of both. Generally, where feasible, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of other suitable salts can be found, for example: "Remington's Pharmaceutical Sciences [ Remington Pharmaceutical Sciences ]", Mack Printing Company 22 th edition [ Mark publishing Co. (2013); and Stahl and Wermuth, "Handbook of Pharmaceutical Salts: properties, Selection, and Use [ handbook of salts of pharmaceutical salts: properties, selections and uses ] "(Wiley-VCH, Weinheim [ Weili-VCH Press ], Weinheim, 2011, 2nd edition).

The compounds specified herein (e.g. compound (I) or another pharmaceutically active ingredient, such as e.g. a wakefulness-promoting agent as defined herein) may be administered by conventional routes, in particular orally, such as in the form of tablets, capsules, caplets or granules, which may be manufactured according to Pharmaceutical techniques known in the art (e.g. "Remington essences of pharmaceuticals [ leimington Pharmaceutical base ]", 2013, 1 st edition, editors of Linda Felton, Pharmaceutical Press [ Pharmaceutical Press ] publication 2012, ISBN 9780857111050; in particular chapter 30), wherein the Pharmaceutical Excipients are e.g. as described in "Handbook of Pharmaceutical Excipients [ Handbook of Pharmaceutical Excipients ], 2012, 7 th edition, Raymond c.rowe, Paul j.sheskey, Walter g.cook and martian e.fenton editor, ISBN 9780857110275".

The pharmaceutical composition or combination of the invention may be in unit dosage form (e.g. tablets or capsules) comprising compound (I) in an amount of from 0.1mg to 50mg, especially from 1mg to 20mg, such as 5mg, 10mg or 20mg, especially 10mg (referring to the amount of compound (I) in free form and if a salt thereof is used, the amount will be adjusted accordingly; especially compound (I) in free form, such as in free form a or in free form B). For the above-mentioned use/treatment method, the appropriate dosage may vary depending on various factors such as, for example, age, body weight, sex, administration route or salt used. A specified daily dose is 0.1 mg/day to 50 mg/day, in particular 1 mg/day to 20 mg/day, such as 5 mg/day, 10 mg/day or 20 mg/day, in particular 10 mg/day of compound (I) [ refers to the amount of compound (I) in free form, and if a salt thereof is used, the amount will be adjusted accordingly, in a patient weighing, for example, 50-70 kg; in particular, compound (I) is in free form, such as in free form a or in free form B ].

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abbreviations:

ACN acetonitrile

DEG C

EDTA ethylene diamine tetraacetic acid

ESS Epworth somnolence scale

FA Formaldehyde

g

h hours

H₂O water

HPLC high pressure liquid chromatography

HPLC-MS high pressure liquid chromatography-mass spectrometry

Institutional animal Care and use Committee for IACUC

IC₅₀Inhibitor concentration leading to 50% inhibition

IV is i.v. intravenous

PO ═ p.o. orally

Kd equilibrium dissociation constant

Kg kilogram

Ki equilibrium inhibitor constant

LCMS liquid chromatography mass spectrometry

MCP modeling multiple comparison program-modeling

MeOH methanol

min for

mL to mL

mM millimole

mm

MS mass spectrometry

ng nan Ke

NH₃Ammonia

NH₄OAC ammonium acetate

PK pharmacokinetics

RO receptor occupancy

rpm revolutions per minute

sec second

Tris Tris (hydroxymethyl) aminomethane

T1/2 half-life

Micromolar at μ M

Micron diameter of

v/v volume/volume

Example (c):

example 1: receptor Occupancy (RO) study

An open label, adaptive design study was conducted in healthy volunteers using Positron Emission Tomography (PET) and radioligand (Naja @)¹¹C]MK-8278 characterizes regional cerebral H3 receptor occupancy after a single dose of Compound (I) (Van Laere, K.J. et al, Journal of Nuclear Medicine],2014, 55: 65-72). The main objective of this study was to assess the plasma concentration (EC) of compound (I) which resulted in 50% H3 receptor occupancy in the brain₅₀). A total of 6 subjects were enrolled in the study and two subjects were scanned in each of the three cohorts. Prior to administration of Compound (I), each subject was subjected to a baseline PET scan to evaluate in the absence of Compound (I)¹¹C]Binding of MK-8278 to H3R. The subjects then received a single oral dose of compound (I) followed by two post-dose PET scans. Subjects in cohort 1 received a single oral dose of 300mg of compound (I), corresponding to a single Maximum Tolerated Dose (MTD) determined from the phase I study after a single oral dose of compound (I). These subjects performed two post-dose PET scans at 3 and 27 hours post-dose. The dose and scan time for the subsequent cohort are selected based on interim data analysis after completion of one or more previous cohorts. Subjects in cohorts 2 and 3 received single oral doses of 10mg and 0.3mg, respectively. Compound (I) was administered in the form of capsules in cohorts 1 and 2, while cohort 3 received compound (I) in the form of an oral solution. In part 3 of the FIH study (diet)Substance and formulation effects) no clinically relevant PK differences were observed after administration of compound (I) in capsules or oral solution. The first post-dose PET scans of cohorts 2 and 3 were obtained at 3 hours post-dose, respectively, and the second at 27 and 8 hours post-dose, respectively.

The baseline acquired PET images show the expected heterogeneous signal with the highest volume of distribution (V) in the nucleocapsid_T) Second, the caudate nucleus, anterior cingulate gyrus, most neocortical areas, midbrain and cerebellum. The binding is to a known profile of the H3 receptor and previously¹¹C]MK-8278 data is consistent (Van Laere, K.J. et al, Journal of Nuclear Medicine],2014, 55: 65-72). Analysis of brain using different modeling methods¹¹C]Kinetics of MK-8278, such as single and double tissue chamber (1TC, 2TC) models, multilinear analysis (MA 1; Icise, M., et al, Journal of Cerebral Blood Flow and Metabolism],2002, 22: 1271-1281) and Logan graphical method (Logan, J. et al, Journal of Cerebral Blood Flow and Metabolism],1990, 10(5): 740-747). All methods produced similar results, but the 2TC model was best suited to derive region V_TThe value is obtained. Tissue time-activity curves (TAC) were generated for all scans, characterized by a peak at about 5-15 minutes post injection followed by elution. After administration of Compound (I), the composition¹¹C]Region binding of MK-8278 is reduced compared to the baseline scan, indicating that compound (I) binds to the target. Occupancy profiles proposed by Lassen (Lassen, N.A. et al, Journal of Cerebral Blood Flow and Metabolism [ J. Nam. Blood Flow and Metabolism ]],1995, 15(1): 152-165; cunningham, V.J., et al, Journal of Cerebral Blood Flow and Metabolism],2010, 30(1): 46-50) was used to estimate the whole brain H3 receptor occupancy for each post-dose PET scan. The method also provides for the non-displaceable component (V)_ND) Is evaluated in accordance with the above.

Occupancy estimates were plotted against corresponding plasma concentration data (measured at the beginning of the PET scan after each dose) to characterize the relationship between plasma concentration of compound (I) and H3 receptor occupancy. The relationship of RO to concentration was analyzed using Emax model:

RO＝(Emax*Cp)/(Cp+EC₅₀)

wherein RO ═ receptor occupancy; emax ═ maximum receptor occupancy; plasma concentration of compound (I) during PET scan; EC (EC)₅₀Plasma concentration that resulted in 50% of the maximum change in RO.

In both subjects in the first cohort, RO was greater than 95% at both 3 and 27 hours post-dose. In the second cohort, RO was similarly higher at 3 hours post-dose, but decreased at 27 hours post-dose. The RO values for the third cohort were generally lower than for the other groups, especially at 8 hours post-dose. A clear relationship was observed in this study between plasma concentrations of compound (I) and the resulting H3 receptor occupancy estimates, strongly supporting a direct PK-RO relationship. The PK-RO relationship described using the Emax model provides an Emax of 96.1% and an EC₅₀The concentration was 0.29ng/mL (FIG. 1).

This study demonstrated that compound (I) binds to H3 receptors in the human brain and allows the establishment of a plasma PK-brain RO relationship.

Example 2: single and multiple escalation dose (SAD) studies in healthy volunteers

Study section 1 (SAD) and section 2 (MAD) evaluated the safety, tolerability, and PK of increasing single and multiple oral doses of compound (I) in healthy volunteers, respectively.

2.1 data used in PK model

The PK data (time-varying drug concentration) for part 1 and part 2 of the phase I study were used for model development:

1) part 1 is the "single ascending dose" part; 8 different cohorts were used, each cohort consisting of 6 active drug subjects and 2 placebo subjects. The doses used in these 8 cohorts were 0.3, 1, 3, 10, 30, 100, 300 and 800 mg. The administration is carried out at a time equal to 0 hour. Additional data from part 3 of the phase I study (mechanical biomarker study, 100mg single dose) were merged with this group.

2) Part 2 is the "multiple ascending dose" part; 4 different cohorts were used, each cohort consisting of 9 active drug subjects and 3 placebo subjects. The doses used in the 4 cohorts were 10, 30, 50 and 100 mg. Once daily (morning) at times equal to 0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 days.

Any outliers were not considered in this study. Data below the limit of quantitation were excluded from the analysis.

2.2 data on nighttime sleep duration in sleep diary

The safety (nocturnal sleep disturbance) of compound (I) was assessed using the nocturnal sleep duration data (total nocturnal sleep time over time) of part 1 and part 2 of the phase I study:

1) part 1 is the "single ascending dose" part; 8 different cohorts were used, each cohort consisting of 6 active drug subjects and 2 placebo subjects. The doses used in these 8 cohorts were 0.3, 1, 3, 10, 30, 100, 300 and 800 mg. The administration is carried out at a time equal to 0 hour. Sleep duration data were collected before and 24 hours after dosing. Additional data from part 3 of the phase I study (mechanical biomarker study, 100mg single dose) were merged with this group.

2) Part 2 is the "multiple ascending dose" part; 4 different cohorts were used, each cohort consisting of 9 active drug subjects and 3 placebo subjects. The doses used in the 4 cohorts were 10, 30, 50 and 100 mg. Once daily (morning) at times equal to 0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 days. Sleep duration data was collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 days post-dose.

Example 3: dose selection for the daytime excessive sleepiness in Parkinson's disease (EDS PD) study

Data from phase I SAD and MAD studies (example 2: PK) and data from PET study RO (example 1) were used to establish a quantitative non-linear mixed effects model that correlated PK-RO for compound (I). Model prediction was based on 10,000 simulated subjects.

RO should be high enough for the H3R inverse agonist to reach full potency for the entire duration of action desired; 80% RO at maximum drug concentration (Cmax) is required, but higher (. gtoreq.90) is preferred (Iannone, R. et al, Clinical Pharmacology and Therapeutics [ Clinical Pharmacology and Therapeutics)],2010, 88(6): 831-839). On the other hand, after the desired duration of action, the RO should be low enough to avoid nighttime sleep disturbances; while the level of RO responsible for sleep disturbance is not known, nighttime RO > 70% may be associated with insomnia ((R))Pharmaceutical Research [ Pharmaceutical Research ], et al],2014, 31: 489-499). Thus, to minimize sleep disturbance, RO should be as high as possible during the duration of action and as low as possible in anticipation of sleep.

In the EDS PD study, compound (I) will be administered to the patient in the morning. The dose administered should provide sufficient RO over the expected duration of action (12 hours) while keeping nocturnal sleep disturbance at a minimum level.

The 10mg dose is expected to be the lowest dose that provides sufficient efficacy while having minimal impact on the duration of nighttime sleep. The efficacy of the 20mg dose is expected to be similar to 10mg, but the potential safety profile is not very different without major tolerability issues (the highest tolerated repeat dose is 50mg in the healthy volunteer study). The model predicts that in 90% of subjects, a dose of 10mg results in RO ≧ 90% at 12 hours post-dose, and RO ≧ 80% at 13-17 hours post-dose. Whereas the 10mg dose in the FIH study showed comparable interference with nighttime sleep duration as placebo, it was not expected to cause severe nighttime sleep interference

Description of PK model

Modeling strategy

Analysis was performed using a MODESM high performance computing environment using NONMEM VII version 3 (Icon Development Solutions, Ellico Kett, Md., USA). The Pirana software was used for model editing and submitting the models to cluster runs. All model constructions were performed using a First Order Conditional Estimation and Interaction (FOCEi) method.

Structural model

The concentration of compound (I) was fitted using a two-chamber model combining zero-order and first-order absorption. Treatment kinetics were modeled using parametric methods involving apparent oral clearance (CL/F), apparent central volume (Vc/F), apparent interventricular clearance (Q/F), and apparent peripheral volume (Vp/F). The absorption process is characterized using the duration of the zeroth order absorption (D), the first order absorption rate constant (Ka), and the absorption delay parameter (Lag)).

Model of random effects

Pharmacokinetic parameters Vc/F, CL/F, Vp/F and K_aIs modeled using multiplicative exponential stochastic effects of the form:

where θ is the population-typical value of the parameter and η_iRepresents a random effect between subjects, which explains the ith individual as zero mean and a variance of ω²Is measured in a single cell. The covariance between the parameters Vc/F, CL/F and Vp/F is used.

The residual variability was modeled using a proportional error model:

Y_ij＝F_ij×(1+ε_ij)

wherein Y is_ijRepresenting the observed concentration of the ith individual at time j. F_ijRepresenting the corresponding predicted concentration based on a pharmacokinetic model. Epsilon_ijRepresents the proportional residual random effect, assuming that its mean is zero and its variance is sigma²。

Estimation of model parameters

Table 1: estimation of parameters for PK models

Parameter (Unit)	Estimation (RSE)
		VC/F(L)	121(3.35％)
VP/F(L)	18.4(13.18％)
		Q/F(L/hr)	1.26(17.35％)
CL/F(L/hr)	22.8(4.85％)
		Ka(1/hr)	2.44(15.68％)
Hysteresis (hours)	0.214(6.76％)
		D (hours)	0.108(92.1％)
Unexplained variability (%)	34.8(4.09％)
		ω	％CV(RSE)
Vc/F	23.71(13.42％)
		Vp/F	46.48(13.69％)
CL/F	40.37(7.33％)
		Ka	145(8.59％)
Correlation of omega	％CV(RSE)
		Vc/F～CL/F	89.12(10.41％)
Vc/F～Vp/F	68.34(11.88％)
		Vp/F～CL/F	54.36(12.56％)

RSE: relative standard error (SE/variance estimate) reported as approximate standard deviation scale/2;

CV: coefficient of variation

K_a: first order absorption rate constant

Hysteresis: delay of absorption

V_c: center volume

V_p: peripheral volume

Q: clearance rate between chambers

F: bioavailability of

CL: central clearance rate

D: duration of zero order absorption

PK-RO model description

The PK model is correlated with the RO model to generate a PK-RO model. The RO equation used (as described above) is as follows:

RO＝(Emax*Cp)/(Cp+EC₅₀)

wherein RO ═ receptor occupancy (%); emax 96.16; cp-compound (I) concentration (ng/mL) in the central compartment of the model; EC (EC)₅₀＝0.29ng/mL。

Example 4: radioactive binding assay

Human histamine H3 receptor membrane (PerkinElmer) was coupled with 1.0nM [ deg. ] C [ PerkinElmer ] with or without an increase in the concentration of ligand competing for binding of the H3 receptor³H]-N-alpha-methyl histamine (Perkin Elmer) were incubated together. Binding incubation at 28 ℃ in a final volume of 0.1ml of buffer (50mM Tris pH 7.5, 5mM MgCl)₂) For 120 minutes. Thiamphetamine (10. mu.M) was used to define non-specific binding.

All binding reactions were stopped by transferring 70 μ l binding reactions from the reaction plates to a filter plate (Zeba 96 well rotary desalting plate, seemer Scientific) followed by centrifugation at 1000g for 2 min to collect the radioligand bound protein. 200 μ l microscint-40 was added to determine the bound radiolabel by Wallac Microbeta Trilux 2450 (Perkin Elmer). IC was determined by GraphPad Prism for all radioligand competition binding assays₅₀Value and Hill slope: log (inhibitor) is related to the response, with a variable slope. Ki was measured using Cheng and Prusoff, biochem]1973.22(23), 3099 and 3108: ki ═ IC₅₀/{1+ ([ radioligand ]]/Kd)}。

As a result:

the compound (I), PIRISANTE and baffiryn inhibit³H]-binding of N- α -methyl histamine at human recombinant H3R. The Ki values obtained from these binding experiments for LML134, Pirisperidone and bafferson were 8.5, 153 and 102nM, respectively.

And (4) conclusion:compound (I) exhibits low nanomolar affinity for the human H3 receptor. The affinity was 18 times higher than for piosant and 12 times higher than for baffe.

Example 5:

5.1. rat PK and PD (tele-methylhistamine)

Male Sprague-Dawley rats (Shanghai SLAC Laboratory Animal Co., LTD) of 6-7 weeks of age were selected. Animals were kept in a temperature and humidity controlled environment for 12h light/dark. All animals had free access to food and water. All procedures have been approved by the institutional animal care and use committee of wisdom chemistry, inc (ChemPartner co., LTD) (IACUC protocol No.: a998HL 0002).

For IV or PO experiments, the compounds were dissolved in citrate buffer (pH 3.5). The bolus intravenous dose was administered intravenously on the dorsum of the foot and the PO dose was administered by oral gavage.

For sampling, the animals were restrained by hand. Blood samples were collected via the tail vein prior to dosing (approximately 150 μ L/sample) and post-dose in the PO and IV arms. Blood samples were placed in tubes containing EDTA and centrifuged at 2000g for 5 minutes at 4 ℃ to obtain plasma samples within 15 minutes after sampling. After centrifugation, the resulting plasma was transferred to a new tube and snap frozen in dry ice, before being transferred to a-80 ℃ freezer for biological analysis.

Plasma concentrations of the compounds were determined by high performance liquid chromatography-mass spectrometry (HPLC-MS/MS) using an Agilent 6410 triple quadrupole mass spectrometer (mobile phase A: H)₂O-0.025％FA-1mM NH₄OAC, mobile phase B: MeOH-0.025% FA-1mM NH₄OAC, column: ultimate XB-C18 (2.1X 50mm, 5 μm, flow rate 0.45mL/min, box temperature 40 ℃) and dexamethasone was used asIs an internal standard product.

Aliquots of 30 μ L of plasma samples were mixed with 30 μ L IS (dexamethasone, 300ng/mL) followed by 150 μ L Acetonitrile (ACN) for protein precipitation. Briefly, the mixture was vortexed for 2 minutes and then centrifuged at 12000rpm for 5 minutes. mu.L of the supernatant was injected onto LC-MS/MS for analysis.

PK parameters are composed ofProfessional 6.2 was determined by non-compartmental analysis. The time point for determining the terminal T1/2 was selected by the best fit model of WinNonlin. Manual selection of time points was used when the best-fit model was not considered to be optimal by visual inspection.

For the biological analysis of brain tissue, samples of t-methyl histamine were further processed.

One aliquot of the stock solution was diluted with ethanol/phosphate buffer (85: 15, v/v) at pH 7.4 to give a series of working solutions. The brain homogenate was centrifuged at 12000rpm for 5 minutes at 4 ℃. Then 10. mu.L of the supernatant of the brain homogenate sample was added to 60. mu.L of internal standard (d 3-1-methyl histamine, 20 ng/mL). The mixture was vortexed for 2 minutes and centrifuged at 12000rpm for 5 minutes at 4 ℃. Finally, 60. mu.L of the supernatant was added and 3. mu.L of the supernatant was injected into LC-MS/MS for analysis (Agilent 6410, triple quadrupole mass spectrometer, mobile phase A: H₂0-0.1％NH₃And the mobile phase B: methanol-0.1% NH₃And (3) chromatographic column: ultimate XB-C18 (2.1X 50mm, 5 μm, flow rate: 0.45mL/min, temperature: 40 ℃ C.).

5.2. Ex vivo receptor occupancy assay

Male Sprague-Dawley rats (from Shanghai SLAC laboratory animals Co., Ltd.) were selected for 5-6 weeks of age. Animals were housed in a temperature and humidity controlled environment and were fed ad libitum and drunk water during a 12h light/dark cycle. All procedures have been approved by the Institutional Animal Care and Use Committee of Intelligent chemical, Inc. (Institutional Animal Care and Use Committee of Chempartner Co., LTD) (IACUC protocol No.: A998HL 0076).

The compounds were dissolved in 50mM citrate buffer (pH 3.5) or saline. The compound is then gradually diluted with vehicle to final concentration. Animals were dosed p.o. or i.v. at 1ml/kg body weight.

At each time point, rats were decapitated immediately. The whole brain was taken out and washed by immersing in pre-cooled saline. After drying on filter paper, the frontal cortex was dissected with a double blade at an angle of about 30 ° starting from 1/3 in the rat forebrain (the weight of most brain tissue is about 70 ± 10 mg). Brain tissue was transferred to pre-weighed tubes with homogenizer beads. The tube was weighed again and the tissue net weight was recorded. Tissue sampling was performed on ice at 1 minute intervals. Then, 50mM HEPES (Life Technologies) was added) Buffer (equivalent to 3.75. mu.l/mg tissue weight) followed by homogenization (frequency 30/sec, duration 20 sec, tissue grinder (tissue Lyser), Qiagen).

As described above, a crude tissue homogenate sample of the frontal cortex of rat was used as described above³H]-N- α -methyl histamine as radioligand to measure H3 receptor binding. The protein concentration of each sample was determined by Pierce BCA protein assay kit (Thermo).

Adding the cortex homogenate to a slurry containing³H]N-. alpha. -methyl histamine (0.1nM) in a volume of 0.2ml (final protein concentration 4. mu.g/. mu.l) in 96-well plates, incubated at 28 ℃ for 15 minutes, and stopped by rapid filtration using filter plates (Millipore) multi-screen GF/B plates). The filter was washed 3 times with ice cold wash buffer (50mM Tris, pH 7.5) and 250. mu.l of Microscint-40 was added, followed by determination of bound radiolabel with Wallac Microbeta Trilux 2450 (Perkin Elmer). Nonspecific binding was determined in the presence of 10. mu.M thiopropionamide. Each data point was obtained from a total of at least four animals. Determining the value of the specific [ 2] calculated with respect to the carrier-treated sample³H]Inhibition of NAMH binding to provide an indication of the receptor occupancy of the compound. Using GraphPad Prism dose-dependent% RO and time course were analyzed. Dose response was fitted using GraphPad Prism: log (inhibitor) is related to the response, with a variable slope.

As a result:

rat PK

After administration of 10mg/kg of the different compounds, the total brain exposure of baffiryn was very high, the total brain exposure of compound (I) was at a moderate level, and the total brain exposure of peliostat was very low (fig. 2). For compound (I), brain exposure dropped to 21ng/g at the 4h time point and approached the limit of detection at 8 h. In contrast, the decline rate of exposure for pisifert and baffiryun was much slower, and higher baffiryun brain exposure could be detected at the 8h time point (fig. 2). These results suggest that the rapid brain penetration of bafferson and compound (I) will produce a central effect immediately after a single compound administration. For pelioside, it may be necessary to repeat the cycle of compound administration until a level sufficient to inhibit the H3 receptor is reached in the brain. Furthermore, the rapid decrease in brain exposure of compound (I) compared to bafferson does not lead to RO at a later point in time and therefore will cause less insomnia in the clinical setting.

Ex vivo receptor occupancy studies in rats

Prior to the experiment, the dose of each compound that resulted in an occupancy of H3 receptor of 80% -90% 1H after compound administration after oral administration was determined. A suitable dose of LML134 and bafferson was found to be 10mg/kg, while a suitable dose of peliostat was found to be 300 mg/kg.

Using these data, Receptor Occupancy (RO) time course studies were performed for all three compounds (fig. 3).

The initial RO of LML134 was 95% at the 1h time point and dropped to 39% at 4 h. At 8h, almost no RO was detected.

Despite the high dose of 300mg/kg of pricint, initial RO at 0.5h hardly reached 90%, and after a slight decrease of RO at the time point of 2h, a considerable (40%) RO was observed at 8h after compound administration.

Initial RO for baffersun was high (90%), but the decline in RO was slow and 37% RO was still detected at 7 h.

And (4) conclusion:

compound (I) and baffersyn showed higher initial RO compared to peliostat. Of all three compounds tested, only compound (I) rapidly dropped RO within 8H, indicating that compound (I) rapidly detached from H3R. In a clinical setting, compound (I) will be administered in the morning and the lack of H3 inhibition is expected to reduce the arousal associated with this mechanism (and during the required day) after 8-10 hours. As a result, the impact on sleep onset is less and the incidence of insomnia will be minimized.

Ex vivo PD assay

The purpose of these experiments was to evaluate the H3 RO-dependent pharmacodynamic readout, which is an inactive metabolite of histamine, t-methyl histamine (tMeHA). The dose of each compound was selected based on the results obtained in the PK experiment, which showed that oral administration of 10mg/kg of compound (I), pirisin and bafferson caused a large amount of brain exposure.

After oral administration of 10mg/kg of compound (I) (fig. 4, upper panel), levels of tMeHA increased from 30 minutes, peaked at 2h and remained slightly elevated at 8 h. the duration of the increase in tMeHA was longer than the rapid decrease in RO (fig. 3, upper panel), which may be due to the longer half-life of tMeHA compared to histamine. After release, the half-life of histamine is approximately 20 minutes. Histamine is converted to the inactive metabolite tMeHA by the enzyme histamine-N-methyltransferase. tMeHA in the brain undergoes oxidative deamination by monoamine oxidase (MAO-B) and aldehyde dehydrogenase, resulting in the formation of t-methyl-imidazole acetic acid, a process with a half-life of about 2-3 hours. Deconvolution of the PD data indicated that histamine was released for about 2h after compound administration, but this PD marker remained elevated for up to 8h due to the slower metabolism of the measured tMeHA.

After oral administration of 10mg/kg of pirisinterate, no increase in tMeHA above baseline levels was observed. At the 4h time point, the pirisint treated group tended to maintain the same level of tMeHA as the earlier time point, while tMeHA decreased in the vehicle group.

10mg/kg baffirperson resulted in a delayed increase in tMeHA, observed only 1h after administration, and remained high throughout the 8h observation period, with no signs of any decline.

Conclusion

A large difference in the profile of compound (I) was observed compared to the long lasting PK, RO and PD profiles of baffirsen and peliostat. Compound (I) has short duration PK and excellent brain penetration, which is observed immediately after compound administration. This PK is well reflected in the RO time course starting with high receptor occupancy, which is required for efficacy, falling back to 50% and 0% at 4h and 8h, respectively, in rats. As a result of receptor occupancy, histamine is released and then becomes its inactive metabolite, t-methyl histamine. These PD effects are also very transient, consistent with transient PK and RO. Given the PK, RO and PD characteristics of compound (I), the compound is expected to translate clinically into a fast-acting, highly active wake-up effect without causing insomnia at bedtime due to the short duration of efficacy of the compound. In summary, therefore, less insomnia and less other side effects, such as a vivid dreaming caused by long-duration RO, are expected for compound (I) compared to baffirsen and prilosartan. The presented pirisinte data show that repeated applications are required to establish a central level high enough to cause H3 inhibition, and that this level is also high at night, remaining almost unchanged.

Example 6: clinical research

Study of

A randomized, double-blind, placebo-controlled, multicenter, seamless, combined proof-of-concept and dose-ranging study to evaluate the safety, pharmacokinetics and efficacy of compound (I) in patients with parkinson's disease who are hypersomnic during the day.

Purpose of study

The primary objective of this study was to evaluate the safety, efficacy and characterization of dose-response relationships of compound (I) to patient reported sleepiness (as measured by the Epworth Sleepiness Scale (ESS)) in Parkinson's Disease (PD) patients.

Study goals and endpoints

All study objectives will be evaluated based on the combined results of part A and part B

Design of research

Overall study design:

the study was a seamless, joint, non-definitive Ph2a or concept validation (PoC) and Ph2b or Dose Range Finding (DRF) study for PD patients with Excessive Daytime Sleepiness (EDS). The study is divided into two parts. Part a is a PoC study aimed at providing early evidence of the safety and efficacy of compound (I) in PD patients with EDS. Part B will provide additional data to establish dose response relationships for compound (I) in the same patient population.

Once the projected patient population completes section A, interim analysis will be performed. The recruitment work was not stopped during the interim analysis, i.e., once a sufficient number of patients were recruited into part a, recruitment would continue into part B of the study. If compound (I) does not show any prohibitive safety or tolerability signals in part a and has clinically significant efficacy according to interim analysis results, part B of the study will proceed. The results of the entire study (part a + part B) will be used in combination to estimate the dose of the Ph3 study using MCP modeling.

Safety, tolerability, and efficacy data will be reviewed by the non-blind external Data Monitoring Committee (DMC) every 6 months and at mid-term analysis.

The study will employ a randomized, double-blind, placebo-controlled, parallel-group, multicenter design. All study procedures were the same for both study sections, so only one evaluation schedule would be used.

Approximately 301 patients will be enrolled in the study: part A was included in 112 patients, and part B in 189 patients.

In part A, patients will be randomized to one of three treatment groups at a 2: 1 ratio:

placebo

Compound (I), D3[10mg ], once daily in the morning

Compound (I), D5[20mg ], once daily in the morning

In part B, patients will be randomized to one of six treatment groups at a ratio of 1: 2: 1:

placebo

Compound (I), D1[2mg ], once daily in the morning

Compound (I), D2[5mg ], once daily in the morning

Compound (I), D3[10mg ], once daily in the morning

Compound (I), D4[15mg ], once daily in the morning

Compound (I), D5[20mg ], once daily in the morning

Study period and related procedures:

the initial screening period of up to 28 days includes screening for eligibility, including assessment of the severity of drowsiness [ ESS and clinical global impression severity (CGI-S) ], PD stage, and overall health status through examination of vital signs, ECG, laboratory examinations, and physical examinations listed in the assessment schedule. For a portion of patients, a practice session of attention and cognitive testing will also be conducted during a screening visit.

Eligible patients will be required to return to the center on day 1 for baseline follow-up. During the baseline visit, all security and efficacy assessments will be completed as specified in the assessment schedule, including the ESS. At the selected site, a subset of patients (approximately 50% of all patients, proportionally allocated to the two study segments) will also participate in other assessments aimed at providing their alertness and sleep metrics, respectively, by neuropsychological testing and physical activity recording. Hereinafter, this subset of patients will be referred to as the body motion record subset. With the patient in the 'ON' state, the patients in the active state subset will complete the attention and cognition tests during the baseline visit, except for all other safety and efficacy assessments specified in the assessment schedule. After all baseline assessments are completed, the patient may leave the center and return to dosing the next morning.

Patients will receive the first study dose at around 09:00 am on day 1. After all safety and PK assessments were completed (PK sampling just prior to dosing) and deemed satisfactory by the investigator, the patient could be off-center.

During the outpatient period (days 2 to 27), patients will take study medication at home shortly after waking up in the morning, except day 14, when patients will take study medication in the morning at the doctor's office.

Safety will be assessed on days 7 and 14 along with PK on day 14 (PK samples before and 2 and 4 hours post dose) as specified by the assessment schedule. In addition, efficacy assessments (all patients undergoing ESS assessments while performing cognitive and attention tests in a subset of physical activity records) will also be performed on day 14. During the outpatient period, the patient will also be required to complete a daily sleep diary. Patients in the actigraphy subset will also be required to wear portable activity monitors (actigraphy) to measure the number and duration of scheduled daytime sleepiness and unintentional sleep episodes and to assess their nighttime sleep.

Patients will return to the center on day 28 for final safety and efficacy assessments and PK sampling as specified by the assessment schedule (2 and 4 hours before and after dosing). Study medication will be taken in the office on the morning of day 28. ESS will be administered at the same time of day as during the baseline visit. When the patient is in the 'ON' state, the patients in the subset of actigraphy records will also be subjected to cognitive and attention tests in the same manner and at the same time of day as during baseline. Researchers must make reasonable efforts to perform these tests at the same time as the anti-parkinson drugs are used during baseline. The security assessment will be made as specified in the assessment schedule. If all safety assessments are completed and satisfactory results are obtained, the patient may be off-center. After the last dose of study medication, the patient will return to the center for a safety follow-up 7-14 days later (days 35-42). If all safety assessments are completed and satisfactory results are obtained, the patient will be removed from the study.

If the patient has an assistant, the patient assistant will be required to complete "significant additional ESS" at baseline, day 14 and day 28. The scale may be done during a face-to-face visit at a clinical center or by telephone. However, for each patient assistant, the scale must be completed in the same manner throughout the study. The patient assistant is a person willing to participate in the study and able to understand and follow the study program in the local language and to provide informed consent to themselves. The patient assistant need not be a primary or formal caregiver, and may include family members or other individuals who assist the patient in their activities of daily living. The patient assistant need not be resident at the same premises as the patient, but needs to be co-located with the patient for a sufficient amount of time (a minimum of 2 days per week) to be able to reliably assess the patient's somnolence.

If the patient lives near the clinical center, there is no need to stay in the center overnight before or after other hospitalizations. However, for all centers, if the patient resides at a distance from the clinical center, the patient and patient assistants will be left to stay in a hotel at or near the center. Long morning traffic and thus short overnight sleep before the evaluation day must be avoided.

Group of people

The study population will include PD patients with excessive daytime sleepiness. Patients enrolled in study part a were not eligible for study part B.

Inclusion criteria

1. Signed informed consent must be provided prior to participation in the study.

2.30 years old and female patients

3. Patients with clinically established parkinson's disease.

4. The anti-parkinson drugs (total daily dose and dosing regimen) must remain stable for at least four weeks prior to baseline and must not change any foreseeable changes over the duration of the study.

5. Excessive daytime sleepiness and a history (at least 3 months) with an ESS score of > 13 at screening.

6. Outpatients who live in the community (patients who are not admitted to a nursing home).

7. Can communicate well with researchers to understand and comply with research requirements.

8. If the patient is using any psychotropic drug that may affect daytime sleepiness, the daily dose and course of sedatives, hypnotics and anxiolytics must remain stable for at least 4 weeks, the antidepressants and antipsychotics should remain stable for at least 8 weeks before baseline, and there should be no changes foreseen over the duration of the study. If the patient is taking quetiapine only in the evening, the patient may be selected for use of quetiapine.

Statistical model, hypothesis, and analysis method

The study will be conducted in two parts. Part a will contain a no-use assessment to assess the efficacy of compound (I) at doses of 10mg and 20mg compared to placebo.

Analysis of part a:

the primary goal was to assess the performance of ESS after the end of the treatment period (i.e., study day 28). An intermediate analysis (placebo: compound (I)10 mg: compound (I)20 mg: 56: 28) will be performed on 112 patients. A mixed effects model (MMRM; e.g., Mallinckrodt CH, Clark WS, David SR (2001) Accounting for drop bias using mixed effects models; Journal of Biopharmaceutical Statistics; 11: 9-21) that will perform repeated measurements on ESS data. The MMRM model will contain treatment group, baseline ESS score, visit, sleep laboratory availability of treatment center, levodopa/dopamine agonist use, and treatment group x visit as covariates with an unstructured covariance matrix.

And (3) performing useless analysis: if the change from baseline ESS score is improved by less than 1 unit, the study will be stopped for uselessness. To assess the uselessness, the combined therapeutic effect of 10mg of compound (I) and 20mg of compound (I) in the MMRM model described above was compared to placebo. Least squares mean square error of the combination treatment with placebo will be evaluated to check for non-usefulness.

Analysis of part B: the null hypothesis of a flat dose-response curve with respect to change in ESS score from baseline was tested using MCP Mod method against a one-sided surrogate hypothesis of a non-constant dose-response curve at a significance level of 5% (e.g., EMA, Qualification option on MCP-Mod [ MCP-Mod Qualification ], date: EMA/CHMP/SAWP/757052/2013, 1-23 days 2014).

Thus, the following invalid and alternative hypotheses will be examined:

·H₀₁: compound (I) has no dose-response relationship (i.e. the dose-response relationship is flat).

·H₁₁: compound (I) exhibits a dose-response relationship (i.e., dose-response relationship is not flat).

The output of the mixed effects model (MMRM) based on repeated measurements was applied to the general MCP-Mod (Pinheiro et al, Stat in Med [ medical statistics ], 2014, 33(10), 1646-1661). The MMRM model will contain treatment group, baseline ESS score, visit, sleep laboratory availability of treatment center, levodopa/dopamine agonist use, and treatment group x visit as covariates with an unstructured covariance matrix. To perform universal MCP-Mod, the least squares mean and associated covariance matrix at each individual dose on day 28 would be obtained from MMRM.

For each candidate model, the contrast test statistics will be derived based on linear combinations of treatment estimates for each dose. The contrast factor will be selected to maximize the efficacy of detecting the predetermined candidate model. For this purpose, Emax, S-type E will be selected_maxLinear and beta dose response shape. For the Emax model, ED will be used₅₀For the S-type Emax model, 2.5 (ED) will be used₅₀H) three shapes of (5, 5), (7.5, 5) and (13, 10), and for β -model (2, 1), the scale accompanying parameter (24) is used.

The formula for these models is as follows:

table 1 candidate dose response model for dose selection hypothesis

The same shape will be used for comparison. All the contrasts will be combined into one contrast matrix. The global test decision is based on the maximum of all comparative test statistics. The critical value q for controlling the type I error rate can be derived from the fact that the comparative test statistics approximately follow a multivariate t distribution. If the maximum contrast test statistic exceeds the threshold value q, the overall null hypothesis for the constant dose response curve will be negated and further evaluation steps can be followed to determine the dose response curve and the dose that will achieve the target clinical effect.

The dose response curve will be estimated using bootstrap and confidence intervals derived. Bootstrap simulations will be performed using the obtained estimated multivariate normal distributions for different doses and the estimated covariance matrix from MMRM analysis. A generalized least squares fit using the resulting modeled values will be used (Pinheiro et al, Stat in Med [ medical statistics ], 2014, 33(10), 1646-.

Sample size calculation

The sample size for the garbage evaluation is based on:

a less than 1 unit improvement in change from baseline ESS score compared to placebo is justified for the following reasons:

A. from the existing literature and published articles, 1 unit of ESS improvement is considered to be the least evidence of efficacy relative to placebo.

B. At a given sample size (i.e., 112), any chance of missing a true effect amount of 2.5 units or more is less than 10%. The following table is calculated based on the run characteristics of the garbage rule (ESS score SD 6).

Table 2 operating characteristics: garbage rule

The sample size for dose finding was based on:

the primary objective of this study was to characterize the dose-response relationship between compound (I) doses (2, 5, 10, 15 and 20mg) and placebo for primary efficacy parameter ESS measurements 28 days after randomization. The sample size for the primary analysis was determined using software ADDPLAN DF (version 4.0) and mean efficacy function settings and model-based comparisons.

Sample size was developed to test dose response with at least 95% efficacy and 5% unilateral alpha. Assuming no change in ESS in the placebo group, the maximum therapeutic effect of compound (I) is expected to be 3 points higher than placebo after 28 days.

Due to the two-stage design, the final (unbalanced) dispensing ratio was predicted to be 11: 6: 7, corresponding to treatment group placebo: 2 mg: 5 mg: 10 mg: 15 mg: 20 mg. The initial randomization of patients in part a will be 56: 28, corresponding to treatment group placebo: 10 mg: 20 mg. The initial dose randomly assigned to part a will then be slightly higher and proportional to the other doses in part B.

Under these assumptions, a sample size of a total of 301 subjects was required, randomized to 77: 42: 49 subjects, corresponding to placebo: 2mg, 5mg, 10mg, 15mg and 20mg for treating arm diseases.

Table 3 sensitivity of efficacy to changes under the assumption of N301

Calculations were performed using ADDPLAN-DF version 4.0.

The efficacy calculation does not take into account the intermediate stage of uselessness, which has little impact on the overall efficacy.