Dose regimens for use of ly3154207 in the treatment of dopaminergic CNS disorders

Abstract

This invention relates to a dosage therapy and method for treating dopamine-induced central nervous system disorders using LY3154207 (also described as 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl] ethyl ketone) and / or pharmaceutical compositions thereof. This dosage therapy is applicable to dopamine-related CNS conditions including Parkinson's Disease, Alzheimer's Disease, Lewy body dementia (LBD), vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, sleep disorders, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addiction.

Description

Technical Field

[0001] This invention relates to a dosage therapy and method for treating dopamine-induced central nervous system disorders using LY3154207 (also described as 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl] ethyl ketone) and / or pharmaceutical compositions thereof. This dosage therapy is applicable to dopamine-related CNS conditions including Parkinson's Disease, Alzheimer's Disease, Lewy body dementia (LBD), vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, sleep disorders, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addiction. Prior Technology

[0002] Lewy body dementia (LBD) is a progressive brain disorder in which Lewy bodies (abnormal deposition of alpha-synuclein) accumulate in brain regions that regulate behavior, cognition, and movement. LBD is a general term encompassing two related conditions: Parkinson's disease dementia (PDD) and Lewy body dementia (DLB). Individuals with LBD may experience a range of symptoms affecting cognition, movement, sleep, mood, behavior, and autonomic dysfunction. Parkinson's disease (PD) is a recognized example of a dopamine-related CNS disorder caused by dysfunction and / or loss of dopamine neurons and disruption of normal dopamine signaling. PD is a progressive neurodegenerative motor disorder resulting from the degeneration of dopamine neurons in the substantia nigra and the formation of Lewy bodies due to reduced dopamine levels in the striatum. PD manifests as tremor and other motor symptoms (e.g., akinesia and bradykinesia, impaired balance) and non-motor symptoms (e.g., cognitive impairment, sleep disturbances, apathy, and depression). Executive function, visuospatial recognition, attention deficits, and memory and language deficits are the most frequently affected descriptive cognitive areas and are thought to be associated with dopamine deficiency in the frontal cortex and striatum, with early signs observed in 15% to 20% of individuals at the time of PD diagnosis. PD-related dementia has been reported in 30% of individuals with PD, with an incidence increasing with disease progression and a lifetime risk of up to 78%. The standard treatment for PD is an acetylcholinesterase inhibitor (AChEI), such as rivastigmine, which provides clinical benefit in a subgroup of individuals with moderate efficacy but may be associated with motor side effects. Rivastigmine is currently the only approved treatment for mild to moderate dementia associated with Parkinson's disease. Therefore, an effective, safe, and clinically well-tolerated treatment for PD and cognitive impairment caused by PDD remains unmet medical need.

[0003] Dopamine deficiency has also been observed in individuals with Alzheimer's disease (AD). AD is an age-related neurodegenerative disease characterized by a slow decline in cognitive and behavioral function, with memory loss as a hallmark symptom. Currently available treatments for AD offer moderate benefit in treating cognitive impairment in mild to moderate AD patients, and limited or no benefit for other symptoms such as insomnia, depressive symptoms, daytime alertness, apathy, sleep disturbances, memory impairment, executive function (planning / implementation of tasks), and hallucinations. Furthermore, effective, safe, and clinically well-tolerated treatments for AD and related cognitive impairments remain unmet medical needs.

[0004] The D1 subtype of dopamine receptors (D1) is the most abundant dopamine receptor in the central nervous system and plays a crucial role in multiple CNS functions, including motor activity, reward, and cognitive function. D1 receptors in the prefrontal cortex are essential for cognition. D1 receptor-mediated acetylcholine release occurs in various brain regions, particularly the hippocampus, and D1 receptors on the dendritic spines of cortical neurons are extremely important for intact working memory, attention, and executive function. For many years, attempts have been made to modulate dopamine signaling in dopamine-related CNS disorders using direct D1 receptor agonists; however, various D1 agonists have achieved very limited effectiveness due to a lack of efficacy, safety, and tolerability, with unacceptable adverse effects limiting their effectiveness. Furthermore, D1 agonists exhibit bell-shaped dose-response curves with respect to cognitive indicators, complicating and confusing clinical use. Therefore, previous efforts to develop clinically applicable direct D1 receptor agonists have been largely unsuccessful due to receptor desensitization, poor ADME / PK properties, and dose-limiting side effects such as hypotension. Direct-acting dopamine therapies have also been limited in efficacy, partly due to high-dose-related cognitive impairment, increased risk of seizures, and tolerance development. Thus, a significant unmet need remains for safe, effective, and clinically tolerable treatments for Parkinson's disease and other dopamine-induced CNS disorders.

[0005] LY3154207 is a positive stereotactic modulator of the dopamine D1 receptor (D1 PAM) and represents a potential first-in-class therapeutic agent for dementia and other dopamine-induced CNS disorders. LY3154207 (CAS registration number 1638667-79-4) can be chemically described as 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl] ethyl ketone, and structurally can be represented as: LY3154207 is available in crystalline form (see WO 2017 / 070068) and cocrystalline form, comprising 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl] acetone and 4-hydroxybenzoic acid (CAS Registry No. 1638669-32-5) (see WO 2014 / 193781). As a positive stereotactic modulator, also known as an "enhancer" of the dopamine D1 receptor subtype, LY3154207 exhibits high selectivity for D1. LY3154207 demonstrates a very weak direct activating effect on the D1 receptor, and is active only in the presence of dopamine, and is considered to be dependent on endogenous tone and subject to normal feedback control. Therefore, LY3154207 represents an innovative pharmacological agent and pathway for modulating the D1 signaling pathway in PD, AD and other dopamine-induced CNS disorders in which D1 signaling may be lacking.

[0006] LY3154207 exhibits a mechanism of action distinct from other dopamine-inducing agents, such as direct D1 receptor agonists. LY3154207 binds to a newly discovered ectopic binding site on the intracellular loop 2 of the D1 receptor, thereby increasing dopamine's affinity for the D1 receptor. To date, a literature search indicates that no human clinical studies have been published for any D1 PAM agent. Due to the complexity of dopamine signaling in normal physiology and clinical disease, and the lack of clinical pharmacological guidance from D1 orthotopic agonists, there remains a significant unmet need for clinical dosing therapy of D1 PAM. Specifically, there is an unmet need for clinical dosing therapy of LY3154207 that provides a combination of effective, safe, and clinically tolerable pharmacological efficacy for the treatment of PD, AD, and other dopamine-induced CNS disorders. Summary of the Invention

[0007] This invention provides a clinical therapeutic dosage therapy and method for treating dopamine-induced central nervous system disorders using LY3154207 and / or its pharmaceutical compositions. As defined herein, dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, sleep disorders, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction. In the dosage therapy of this invention, and as used herein, LY3154207 is any form of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl] ethyl ketone, including its crystalline and cocrystalline forms, particularly its benzoic acid cocrystalline form, and / or pharmaceutical compositions containing such agents. This invention provides a method of treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or a pharmaceutical composition thereof. The present invention further provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3154207 or a pharmaceutical composition thereof.

[0008] LY3154207 and the related D1 PAM compound referred to herein as DPTQ have been investigated in Phase I studies in healthy primate and / or human volunteers and PD patients, and LY3154207 has entered a Phase II clinical trial for Parkinson's disease dementia (referred to as PRESENCE, NCT03305809). Studies including those described in Example 1 (Phase I clinical trial of LY3154207) and Example 2 (spatial working memory in adult rhesus monkeys) have yielded the following conception: LY3154207, when used in a dose-therapy according to the present invention, can induce unexpectedly marked improvements in signs and symptoms of dopamine-induced CNS disorders, such as treatment of PD or AD dementia, cognitive enhancement, and / or sleep or appetite regulation. Therefore, when used in accordance with this dosage therapy, LY3154207 provides a means of modifying dopamine D1 signaling in a manner that is considered to provide an effective, safe and clinically tolerable treatment for a variety of dopamine-related CNS disorders.

[0009] The dosage therapy of this invention offers a method with unexpected and unpredictable advantages. Specifically, patients with dopamine-induced CNS require avoiding significant levels or risks of insomnia, agitation, and / or unwanted cardiovascular effects, such as increased pulse and blood pressure, while simultaneously requiring the benefits of beneficial LY3154207 activity, such as alertness, appetite regulation, and / or cognitive or motor control effects. The clinically applicable and desirable effects of LY3154207 in dopamine-induced CNS conditions, such as cognitive enhancement, motor function recovery, decreased appetite, and alertness or insomnia, have been unexpectedly found to be effectively separated from certain unwanted effects by using the clinical dosage therapy of this invention.

[0010] Therefore, this invention provides a daily administration of certain clinical doses of LY3154207 to achieve remission of signs and symptoms of dopamine-induced central nervous system disorders in patients, while avoiding other D1 PAM effects that would preempt these clinical benefits. Furthermore, this invention provides long-term daily administration of LY3154207 to enable patients with dopamine-induced central nervous system disorders to further utilize lower or higher doses of LY3154207 within the therapies of this invention, resulting in effective symptom remission for individual patients while avoiding undesirable effects.

[0011] For example, patients can benefit from the dosage therapy of the present invention, where the efficacy for insomnia and / or decreased appetite can be maximized by using higher doses, up to 75 mg of LY3154207 daily. In another embodiment, a low-dose therapy of up to 15 mg of LY3154207 daily provides patients with the benefits of cognitive enhancement without experiencing excessive arousal, agitation, and / or unwanted loss of appetite. Generally, the dosage therapy of the present invention provides patients with the benefits of D1 PAM activity while avoiding certain unwanted adverse cardiovascular activities observed clinically, and can represent D1 PAM as a class of targeted pharmacology. Furthermore, the dosage therapy of the present invention provides a way to treat patients with dopamine-induced CNS disorders while reducing the risk of drug-drug interactions with Cyp3A4 inhibitors.

[0012] Therefore, the present invention provides a daily oral dosing therapy of LY3154207 to patients suffering from dopamine-induced central nervous system disorders, the dosing therapy using certain specific doses of LY3154207 described in detail below.

[0013] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient daily a dose of about 0.5 mg to about 75 mg of LY3154207 or a pharmaceutical composition thereof, with a maximum total daily dose of 75 mg.

[0014] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3154207 or a pharmaceutical composition thereof.

[0015] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient daily a dose of LY3154207 or a pharmaceutical composition thereof selected from the group consisting of: 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

[0016] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or a pharmaceutical composition thereof, for at least 21 consecutive days.

[0017] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient daily at a dose of about 0.5 mg to about 15 mg, with a maximum total daily dose of 15 mg of LY3154207 or a pharmaceutical composition thereof, for at least 21 consecutive days.

[0018] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient daily at a dose selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg, wherein the patient is treated for at least 21 consecutive days.

[0019] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient daily a dose of about 0.5 mg to about 75 mg of LY3154207 or a pharmaceutical composition thereof, with a maximum total daily dose of 75 mg, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction.

[0020] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3154207 or a pharmaceutical composition thereof, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction.

[0021] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or a pharmaceutical composition thereof, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction, wherein the patient is treated for at least 21 consecutive days.

[0022] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient daily a dose of about 0.5 mg to about 15 mg of LY3154207 or a pharmaceutical composition thereof, with a maximum total daily dose of 15 mg, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction, wherein the patient is treated for at least 21 consecutive days.

[0023] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient a daily dose of about 0.5 mg of LY3154207 or a pharmaceutical composition thereof.

[0024] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering a dose of 1 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0025] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering a dose of 2 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0026] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering a dose of 3 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0027] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering a dose of 5 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0028] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering a dose of 10 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0029] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering a dose of 15 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0030] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering a dose of 20 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0031] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering to the patient a daily dose of 30 mg of LY3154207 or a pharmaceutical composition thereof.

[0032] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207, comprising administering 50 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0033] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3154207 as described in technical solution 1, comprising administering a dose of 75 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0034] In one embodiment, the present invention provides a method for treating a patient with Parkinson's disease using LY3154207, comprising administering to the patient a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or a pharmaceutical composition thereof.

[0035] In one embodiment, the present invention provides a method of treating a patient with Parkinson's disease using LY3154207, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3154207 or a pharmaceutical composition thereof.

[0036] In one embodiment, the present invention provides a method of treating a patient with Parkinson's disease using LY3154207, comprising administering to the patient daily a dose of LY3154207 or a pharmaceutical composition thereof selected from the group consisting of: 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0037] In one embodiment, the present invention provides a method of treating a patient with Parkinson's disease using LY3154207, comprising administering to the patient daily a dose of about 0.5 mg to about 75 mg of LY3154207 or a pharmaceutical composition thereof, wherein the patient meets the revised MDS criteria for PD and mild to moderate dementia, defined as cognitive decline between 10 and 23 by a MoCA score.

[0038] In one embodiment, the present invention provides a method of treating a patient with Parkinson's disease using LY3154207, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or a pharmaceutical composition thereof, for at least 21 consecutive days.

[0039] In one embodiment, the present invention provides a method of treating a patient with Alzheimer's disease using LY3154207, comprising administering to the patient daily a dose of about 0.5 mg to about 75 mg of LY3154207 or a pharmaceutical composition thereof, with a maximum total daily dose of 75 mg.

[0040] In one embodiment, the present invention provides a method of treating a patient with Alzheimer's disease using LY3154207, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3154207 or a pharmaceutical composition thereof.

[0041] In one embodiment, the present invention provides a method of treating a patient with Alzheimer's disease using LY3154207, comprising administering to the patient daily a dose of LY3154207 or a pharmaceutical composition thereof selected from the group consisting of: 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0042] In one embodiment, the present invention provides a method of treating a patient with Alzheimer's disease using LY3154207, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or a pharmaceutical composition thereof, for at least 21 consecutive days.

[0043] In one embodiment, the present invention provides a method for inducing weight loss in a patient using LY3154207, comprising administering to the patient a dose of about 0.5 mg to about 75 mg daily, with a maximum total daily dose of 75 mg of LY3154207 or a pharmaceutical composition thereof.

[0044] In one embodiment, the present invention provides a method for inducing weight loss in a patient using LY3154207, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3154207 or a pharmaceutical composition thereof.

[0045] In one embodiment, the present invention provides a method for inducing weight loss in a patient using LY3154207, comprising administering to the patient daily a dose of LY3154207 or a pharmaceutical composition thereof selected from the group consisting of: 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0046] In one embodiment, the present invention provides a method for inducing weight loss in a patient using LY3154207, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or a pharmaceutical composition thereof, for at least 21 consecutive days.

[0047] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3151944, comprising administering to the patient daily a dose of about 0.5 mg to about 75 mg of LY3151944 or a pharmaceutical composition thereof, with a maximum total daily dose of 75 mg.

[0048] In one embodiment, the present invention provides a method for treating a patient with dopamine-induced central nervous system disorders using LY3151944, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3151944 or a pharmaceutical composition thereof.

[0049] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering one or more doses of about 0.5 mg to about 75 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily, with a maximum total daily dose of 75 mg.

[0050] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering one or more doses of about 0.5 mg to about 15 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily, with a maximum total daily dose of 15 mg.

[0051] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily in doses selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0052] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering one or more doses of about 0.5 mg to about 75 mg daily to the patient for an extended period, with a maximum total daily dose of 75 mg of LY3154207 or a pharmaceutical composition thereof, wherein the patient is treated for at least 21 consecutive days.

[0053] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising one or more doses of about 0.5 mg to about 15 mg daily administered to the patient for an extended period of time, with a maximum total daily dose of 15 mg of LY3154207 or a pharmaceutical composition thereof.

[0054] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising daily long-term administration to the patient of LY3154207 or a pharmaceutical composition thereof selected from the group consisting of: 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0055] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction.

[0056] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising administering 0.5 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0057] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising administering a dose of 1 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0058] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising administering a dose of 2 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0059] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising administering a dose of 3 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0060] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising administering a dose of 5 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0061] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising administering a dose of 10 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0062] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising administering a dose of 15 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0063] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising administering a dose of 20 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0064] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising administering LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 30 mg daily.

[0065] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising administering 50 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0066] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, comprising administering a dose of 75 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0067] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, wherein the dopamine-induced central nervous system disorder is Parkinson's disease.

[0068] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, wherein the patient meets the revised MDS criteria for PD and mild to moderate dementia, defined as cognitive decline between 10 and 23 by means of a MoCA score.

[0069] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, wherein the dopamine-induced central nervous system disorder is Alzheimer's disease.

[0070] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiments, wherein the dopamine-induced central nervous system disorder is obesity.

[0071] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 15 mg, with a maximum total daily dose of 15 mg of LY3154207 or the pharmaceutical composition thereof.

[0072] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily in doses selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0073] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, for at least 21 consecutive days.

[0074] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 15 mg, with a maximum total daily dose of 15 mg, for at least 21 consecutive days.

[0075] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg, wherein the patient is treated for at least 21 consecutive days.

[0076] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or the pharmaceutical composition thereof, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction.

[0077] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 15 mg, with a maximum total daily dose of 15 mg of LY3154207 or the pharmaceutical composition thereof, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction.

[0078] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction, wherein the patient has been treated for at least 21 consecutive days.

[0079] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 15 mg, with a maximum total daily dose of 15 mg of LY3154207 or the pharmaceutical composition thereof, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction, wherein the patient has been treated for at least 21 consecutive days.

[0080] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient a dose of about 0.5 mg of LY3154207 or a pharmaceutical composition thereof daily.

[0081] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering 1 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0082] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering 2 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0083] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering 3 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0084] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering 5 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0085] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering 10 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0086] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering 15 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0087] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering 20 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0088] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 30 mg daily.

[0089] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering 50 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0090] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with dopamine-induced central nervous system disorders, comprising administering 75 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0091] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with Parkinson's disease, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or the pharmaceutical composition thereof.

[0092] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with Parkinson's disease, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3154207 or a pharmaceutical composition thereof.

[0093] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with Parkinson's disease, comprising administering to the patient daily in doses selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0094] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with Parkinson's disease, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or the pharmaceutical composition thereof, wherein the patient meets the revised MDS criteria for PD and mild to moderate dementia, defined as cognitive decline between 10 and 23 by a MoCA score.

[0095] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with Parkinson's disease, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, wherein the patient is treated for at least 21 consecutive days.

[0096] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with Alzheimer's disease, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or the pharmaceutical composition thereof.

[0097] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with Alzheimer's disease, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3154207 or the pharmaceutical composition thereof.

[0098] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with Alzheimer's disease, comprising administering to the patient daily in doses selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0099] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for treating a patient with Alzheimer's disease, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, wherein the patient is treated for at least 21 consecutive days.

[0100] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for inducing weight loss in a patient, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or a pharmaceutical composition thereof.

[0101] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for inducing weight loss in a patient, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3154207 or a pharmaceutical composition thereof.

[0102] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for inducing weight loss in a patient, comprising administering to the patient daily in doses selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0103] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for inducing weight loss in a patient, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, for at least 21 consecutive days.

[0104] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg.

[0105] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 15 mg, with a maximum total daily dose of 15 mg of LY3154207 or the pharmaceutical composition thereof.

[0106] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily in doses selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

[0107] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or the pharmaceutical composition thereof to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, wherein the patient is treated for at least 21 consecutive days.

[0108] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or the pharmaceutical composition thereof to the patient daily for an extended period of time at a dose of about 0.5 mg to about 15 mg, with a maximum total daily dose of 15 mg, wherein the patient is treated for at least 21 consecutive days.

[0109] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg, wherein the patient is treated for at least 21 consecutive days.

[0110] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or the pharmaceutical composition thereof, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction.

[0111] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 15 mg, with a maximum total daily dose of 15 mg of LY3154207 or the pharmaceutical composition thereof, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction.

[0112] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or the pharmaceutical composition thereof to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction, wherein the patient has been treated for at least 21 consecutive days.

[0113] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering to the patient daily at a dose of about 0.5 mg to about 15 mg, with a maximum total daily dose of 15 mg of LY3154207 or the pharmaceutical composition thereof, wherein the dopamine-induced central nervous system disorders are selected from the group consisting of: Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction, wherein the patient has been treated for at least 21 consecutive days.

[0114] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering 0.5 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0115] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering 1 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0116] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering 2 mg of LY3154207 or a pharmaceutical composition thereof to the patient daily.

[0117] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or a pharmaceutical composition thereof to the patient at a daily dose of 3 mg.

[0118] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or a pharmaceutical composition thereof to the patient at a daily dose of 5 mg.

[0119] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 10 mg daily.

[0120] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or a pharmaceutical composition thereof to the patient at a daily dose of 15 mg.

[0121] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or a pharmaceutical composition thereof to the patient at a daily dose of 20 mg.

[0122] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 30 mg daily.

[0123] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 50 mg daily.

[0124] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with dopamine-induced central nervous system disorders, comprising administering LY3154207 or a pharmaceutical composition thereof to the patient at a daily dose of 75 mg.

[0125] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with Parkinson's disease, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg.

[0126] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with Parkinson's disease, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3154207 or the pharmaceutical composition thereof.

[0127] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with Parkinson's disease, comprising administering to the patient daily in doses selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

[0128] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with Parkinson's disease, comprising administering LY3154207 or the pharmaceutical composition thereof to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, wherein the patient meets the revised MDS criteria for PD and mild to moderate dementia, defined as cognitive decline between 10 and 23 by a MoCA score.

[0129] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with Parkinson's disease, comprising administering LY3154207 or the pharmaceutical composition thereof to the patient daily for an extended period of time at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, wherein the patient is treated for at least 21 consecutive days.

[0130] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with Alzheimer's disease, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg.

[0131] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with Alzheimer's disease, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg of LY3154207 or the pharmaceutical composition thereof.

[0132] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with Alzheimer's disease, comprising administering to the patient daily at a dose selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0133] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for treating a patient with Alzheimer's disease, comprising administering LY3154207 or the pharmaceutical composition thereof to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, wherein the patient is treated for at least 21 consecutive days.

[0134] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for inducing weight loss in a patient, comprising administering to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg.

[0135] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for inducing weight loss in a patient, comprising administering to the patient a dose of about 0.5 mg to about 15 mg daily, with a maximum total daily dose of 15 mg.

[0136] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for inducing weight loss in a patient, comprising administering to the patient daily in doses selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0137] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for manufacturing a medicament for inducing weight loss in a patient, comprising administering LY3154207 or the pharmaceutical composition thereof to the patient daily at a dose of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, for a period of at least 21 consecutive days.

[0138] The following terms, as used above and throughout the scope of this invention, shall be understood to have the following meanings unless otherwise indicated:

[0139] "Pharmaceutical-acceptable carriers, diluents or excipients" are the media commonly accepted in this technology for delivering bioactive agents to mammals (e.g., humans).

[0140] "Dosage" refers to the predetermined amount or unit dose of LY3154207 calculated to produce an appropriate therapeutic effect in the patient. As used herein, "mg" means milligram. As used herein, the dosage range and provided dosage of LY3154207 represent the weight of the active pharmaceutical ingredient 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl] acetone, regardless of the form provided, such as free base, co-crystalline, or any other composition or form. Preferably, the unit dose consists of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl] acetone and 4-hydroxybenzoic acid in a co-crystalline form. As used herein, the term "about" means within a reasonable range of a specified value, such as by or after 10% of the specified value.

[0141] Methods for manufacturing and formulating LY3154207 and / or 2-(2,6-dichlorophenyl)-1-((1S,3R)-5-(2-hydroxy-2-methylpropyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)ethyl-1-one are known in the art and are illustrated, for example, in WO 2014 / 193781 and / or WO 2017 / 070068. Methods for preparing LY3154207 and its cocrystals, and certain formulations and dosage forms thereof, are known to those skilled in the art and are described in WO 2014193781 and / or WO 2017 / 070068. WO 2014 / 193781 discloses certain 3,4-dihydroisoquinoline-2(1H)-yl compounds as positive stereoisotropic modulators (PAMs) of the dopamine 1 receptor (D1), including 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl] ethyl ketone and co-crystalline forms comprising 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl] ethyl ketone and 4-hydroxybenzoic acid, and compositions thereof. WO 2017 / 070068 discloses a crystalline form of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl] acetone. LY3154207 is preferably formulated as a pharmaceutical composition for administration via any route that makes the compound biologically usable, including oral, intravenous, and transdermal routes. Preferably, such pharmaceutical compositions are intended for oral administration. LY3154207 can be administered alone or as a pharmaceutical composition having a pharmaceutically acceptable carrier, diluent, or excipient. Throughout the specification, when a composition is described as having, including, or containing a specific component, it is contemplated that the composition is substantially composed of or consists of said component. Such pharmaceutical compositions and methods of manufacturing them are known in this art (see, for example, Remington: The Science and Practice of Pharmacy, LV Allen, ed., 22nd ed., Pharmaceutical Press, 2012). In formulations, LY3154207 is typically mixed with excipients, diluted by the excipients, or sealed in such carriers, which may be in the form of capsules, pouches, paper, or other containers. When the excipients act as diluents, they may be solid, semi-solid, or liquid materials, acting as a mordant, carrier, or medium for the active ingredient.Therefore, formulations can take the following forms: tablets, pills, powders, lozenges, capsules, pods, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of an active compound, soft and hard gelatin capsules, gels, suppositories, sterile injectable solutions, and sterile packaged powders. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrups, and methylcellulose. Formulations may also include: lubricants such as talc, magnesium stearate, and mineral oil; humectants; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents. The compounds of this invention can be formulated to provide a rapid, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in this art. Those skilled in the art can easily select the appropriate form and administration method based on the specific characteristics of the chosen compound and / or form, the disease or condition to be treated, the stage of the disease or condition, and other relevant circumstances. The table below provides examples of selected unit dosage forms provided according to the dosage therapy of this invention in tablet form for oral administration. Those skilled in the art can use these examples, as well as readily known formulation methods, to provide additional formulations and / or unit dosage forms. [Unit dose] [1] [3] [5]

[10]

[25]

[30]

[50]

[75] [(mg LY3154207] [,] [Active Ingredients] [Components] [mg] [mg] [mg] [mg] [mg] [mg] [mg] [mg] LY3154207 - Benzoic acid co-crystal form (mg) 1.3 3.9 6.5 13.1 32.7 39.2 65.3 98 microcrystalline cellulose 116.8 112.3 109.7 126.4 81.1 142.8 162.2 243.3 Sodium croscarmellose 6.3 6.3 6.3 7.5 6.3 10 12.5 18.8 Sodium stearate fumarate 0.6 2.5 2.5 3 2.5 4 5 7.5 Silicon dioxide 0 0 0 0 2.5 4 5 7.5 Core tablet weight (mg): 125 125 125 150 125 200 250 375 Coating: 4 5 5 6 5 8 10 15

[0142] The unit dose of this invention is preferably formulated as a pharmaceutical composition, which is administered by any route that makes the compound biologically available; preferably, such compositions are for oral administration. As used herein, "administration / administering" includes administration of LY3154207 by the patient, and / or administration of LY3154207 by another person, and / or instruction and / or guidance for the patient to take LY3154207 according to a specific therapy. Preferably, LY3154207 is administered in the morning. Preferably, as indicated by the use of the term "daily," a specified unit dose of LY3154207 is taken once daily. Preferably, LY3154207 is taken daily. As used herein, "daily administration" includes administration of LY3154207 as a specific therapeutic therapy intended to provide the beneficial effects of long-term and regular administration of a prescribed dose of LY3154207. Specifically, "daily administration" includes continuous daily administration for at least twenty-one consecutive days, or the duration required to continuously prevent signs and symptoms of dopamine-induced CNS disorders in a patient. If a patient misses an occasional day, the patient may resume administration only on the second day after the scheduled administration, and this situation will continue to be referred to as "daily administration." As used herein, "daily" means administration once every 24 hours, or once every calendar day for LY3154207. As used herein, "daily" means continuous administration of LY3154207, wherein administration as used herein includes both when the patient administers a dose and / or when the patient is instructed to administer a dose as part of a therapeutic therapy. When a method is described as having, including, or comprising specific treatment steps, such methods are substantially composed of or comprised of said treatment steps. Furthermore, it should be understood that the order of steps or the order in which specific actions are performed is not important, as long as the invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

[0143] As used herein, the term "patient" refers to a human being to be treated with this dose of therapy who has a dopamine-related CNS disorder and therefore shares a common pathogenesis in which disorders of dopamine signaling are known to contribute to these disorders. As used herein, dopamine-related CNS disorders include (but are not limited to) Parkinson's disease, Alzheimer's disease, Lewy body dementia (LBD), vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, sleep disorders, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction. Identification of patients with these dopamine-related CNS disorders can be achieved using established methods known to those skilled in this technique.

[0144] In embodiments of the invention, the patient is a human being diagnosed with a medical risk, condition, or symptom (such as dopamine-induced CNS disorders) requiring treatment with the dosage therapy described herein. In cases where the symptom treatable by the methods of the invention is known to be an established and recognized classification (such as AD, PD, LBD), such classification can be found in various well-known medical texts. For example, the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), currently provides diagnostic tools for identifying a variety of the symptom described herein. Furthermore, the International Classification of Diseases, 10th revision (ICD-10) provides classifications for a variety of the symptom described herein. Those skilled in the art will recognize the existence of alternative nomenclature, disease classifications, and classification systems for the symptom described herein, including those described in DSM-5 and ICD-10, and that terminology and classification systems evolve with the development of medical science. Cognitive impairment in individuals with Parkinson's disease is generally referred to as neurocognitive disorder. The diagnostic criteria in the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) describe evidence of a significant decline in cognitive performance from previous levels (as recorded by neuropsychological testing of personal or informational problems), and that the cognitive deficit may or may not interfere with the independence of daily activities. This assessment indicates severe or mild neurocognitive disorder. As used herein, "weight loss" refers to weight loss and / or long-term weight management in which treatment helps maintain a healthy weight.

[0145] As used in this article, the term "treatment" is intended to refer to methods that may slow down, block, curb, control, or stop the progression of an existing condition and / or its symptoms, but not necessarily to the complete elimination of all symptoms.

[0146] The attending physician, if familiar with this technique, can easily determine the dosage of the dosage therapy provided herein by observing the results of self-treatment. When determining a specific dosage of LY3154207 from the dosage therapy of this invention, various factors are considered, including (but not limited to) the patient's dopamine-induced CNS disorder, the patient's weight, age, and general health; the extent or severity of involvement; the individual patient's response; the use of other concomitant medications; and other relevant circumstances.

[0147] The dosage therapy of this invention can be used in combination with other medications for the treatment / prevention / inhibition or improvement of dopamine-induced CNS symptoms. These other medications can be administered simultaneously or sequentially with LY3154207 via the therefore commonly used route and at the therefore commonly used dosage. For example, other active ingredients that can be combined with LY3154207 for the effective treatment of Parkinson's disease include (but are not limited to): (a) dopamine precursors, such as levodopa; melevodopa and etilevodopa; and (b) dopamine agonists, including pramipexole, ropinirole, apomorphine, rotigotine, bromocriptine, cabergoline, and pergolide. Simple Explanation of the Diagram

[0148] [picture] [1] [:] [Research] [HBEA] [Design] [,] [Among healthy volunteers] [D1] [Receptor] [Positive Stereotropic Agent] [LY3154207] [Single escalation dose study] [。] [ ] A safety review was conducted before each dose level was increased. b. Due to cardiovascular effects, the dose escalation stops at 200 mg. CSF = Cerebrospinal fluid; LY = LY3154207; PBO = Placebo; PK = Pharmacokinetics. [picture] [2] [:] [HBEB] [,] [Healthy males suffering from sleep deprivation] [(n=17)] [Middle] [1] [Period] [Single-dose randomized placebo-controlled] [4] [cycle] [Incomplete crossover study. Multiple sleep latency tests were conducted on healthy male individuals with sleep deprivation.] [(MSLT)] [Measured] [Single dose] [LY3154207] [right] [Efficacy for insomnia.] Sleep latency is the time (in minutes) from the start of MSLT to the first detected sleep. If the individual does not sleep during the MSLT period, a 20-minute sleep latency is recorded. CI = confidence interval; LS = least squares; MSLT = multiple sleep latency tests. [picture] [3] [:Research] [HBEC] [Of] [Designed for once-daily dosing] [LY3154207 ()] [exist] [part] [A] [middle]

[15] [、]

[30] [、]

[75] [or] [150 mg] [And in] [part] [B] [Medium to maximum] [75 mg] [Or placebo and continue]

[14] [Heaven] [Healthy Individual] [(] [part] [A)] [and suffering from] [PD] [Of] [Participants] [(] [part] [B)] [middle] [LY3154207] [Multiple escalation dose study] [(] [Randomized, double-blind, placebo-controlled, parallel-group study with multiple escalation doses] [)] [。] [ ] a. Each escalating dose group was started only after reviewing safety data from previous groups up to at least day 7. b. Participants with Parkinson's disease in group 6 received titrations to determine the efficacy of this dosing regimen (i.e., days 1–3: 15 mg; days 4–6: 30 mg; and days 7–14: 75 mg) on ​​cardiovascular effects. Note: All groups were administered for 14 days. CRU = Clinical Research Unit; LY = LY3154207; PBO = Placebo; PD = Parkinson's Disease; R = Randomized. [picture] [4] [:] [Research] [HBEC] [,] [PD] [Used by the patient] [LY3154207] [Treatment]

[14] [Motor symptoms in the body.] Participants with PD treated with LY3154207 were compared with those treated with placebo, with motor examination subscale scores measured by MDS-UPDRS Part III. Group 5 (LY 75 mg), Group 6 (LY 75 mg titration) (Participants with PD in Group 6 received 15 mg on days 1–3 and 30 mg on days 4–6), Group 5 / 6 (PBO). [picture] [5] [:] Spatial Working Memory of Adult Rhesus Monkeys [:] [Acute Administration of Vehicles] [,] [A set]

[10] [Only] [The animal in the] [1] [The materials provided by Heaven for the medium.] [picture] [6] [:] Spatial Working Memory of Adult Rhesus Monkeys [:] [Acute administration] [2.5 mg / kg DPTQ] [。] [ ] [picture] [7] [:] Spatial Working Memory of Adult Rhesus Monkeys [:] [in the] [5] [Day repeats] [2.5 mg / kg DPTQ] [The effect of dosage.] [ ] [picture] [8] [:] Spatial Working Memory of Adult Rhesus Monkeys [:] [DPTQ] [by] [0.1 mg / kg] [Efficacy when administered at low doses.] [ ] [picture] [9] [:] Spatial Working Memory of Adult Rhesus Monkeys [:] [1.0 mg / kg DPTQ] [Dose-to-Dose Pair] [The benefits of spatial working memory.] [ ] Implementation

[0149] This application claims the benefit of U.S. Provisional Applications Serial Nos. 62 / 781,251 and 62 / 904,048, filed on December 18, 2018 and September 23, 2019, respectively, under 35 USC §119(e), the disclosures of which are incorporated herein by reference.

[0150] [Example] [1] [:] [LY3154207] [Of] [I] [Expect] [Clinical Research] LY3154207 is currently undergoing a Phase 2 cognitive study in Lewy body dementia (NCT03305809). Prior data from three completed Phase I clinical pharmacology studies of LY3154207 (studies HBEA, HBEB, and HBEC) provide conceptual evidence for the use of LY3154207 to treat patients with dopamine-induced central nervous system disorders, involving daily administration of LY3154207 or pharmaceutical combinations thereof at doses of approximately 0.5 mg to approximately 75 mg, with a maximum total daily dose of 75 mg.

[0151] HBEA is a single-escalation dose study of the D1 receptor positive stereotactic modulator LY3154207 in healthy volunteers. The HBEA study aims to determine the safety, tolerability, and peripheral and central pharmacokinetics (PK) of a single escalation dose of LY3154207 in healthy individuals. The HBEB study aims to evaluate the efficacy of a single dose of LY3154207 on sleep latency, as measured by multiple sleep latency tests (MSLT), in sleep-deprived healthy men. HBEA is a phase 1, two-part, randomized, double-blind, placebo-controlled study in healthy men or women. Part A has a 3-cycle crossover design with 2 alternating single-dose escalation groups, and individuals are randomized in each dosing cycle to either LY3154207 (n=6) or placebo (n=3). Part B featured a cohort design with two cerebrospinal fluid (CSF) samples collected in a single cycle and at a single dose. Individuals were randomly assigned to either LY3154207 (n=8) or placebo (n=4) within their respective cohorts. The study design is shown in Figure 1.

[0152] [HBEA] [part] [A-] [Single incremental dose] [(SAD)] [)] [Research] [:] This is a phase 1 SAD crossover design for LY3154207 in healthy individuals across two dose-escalation alternating cohorts. Individuals were administered 25 mg, 75 mg, 100 mg, 150 mg, and 200 mg or placebo. Safety parameters assessed included adverse events (AEs), safety laboratory findings, vital signs, walking blood pressure monitoring (ABPM), and electrocardiogram (ECG). Individuals provided blood samples after administration to measure plasma LY3154207 concentrations for pharmacokinetic (PK) assessment.

[0153] Eighteen individuals were enrolled, with 17 completing the study. The mean age (SD) was 33.6 (13.0), 16 were male (89%), and 16 were white (89%). One individual withdrew due to anxiety after taking a 150 mg dose. A total of 111 treatment-related adverse events (AEs) occurred, most of which were mild (101 / 111). Insomnia, decreased appetite, anxiety, dizziness, headache, nausea, epigastric pain, and dysgeusia were the most common AEs, and most (69 / 111) occurred at doses ≥100 mg. Dose-related signals of increased pulse and blood pressure appeared and resolved within 24 hours. Cmax and AUC were proportional to the dose administered. The median tmax and t1 / 2 were approximately 2–3 and 12 hours, respectively. The urinary excretion of LY3154207 was 0.02%. LY3154207 demonstrated an acceptable safety profile and linear pharmacokinetic profile across a dose range of 25 mg to 200 mg. Data from Phase 1 healthy volunteers indicate that the dosage therapy of this invention can produce a decrease in appetite in dopamine-induced central nervous system disorders or healthy individuals. Data on dose-related signals indicating increased pulse and blood pressure also indicate that the dosage therapy of this invention can provide a modified combination of efficacy, safety, and clinical tolerability with LY3154207, which can avoid and / or minimize such undesirable effects. LY3154207 is well tolerated at doses ≥75 mg, and increased adverse events (AEs) are associated with central activation. In HBEA Part A, treatment-related adverse events (AEs) occurred primarily at doses ≥100 mg and were mostly mild. In HBEA Part B, treatment-related AEs occurred only at 75 mg (25% of individuals) and were all mild: increased energy, anxiety, decreased appetite, and dizziness. No serious or severe AEs occurred. While maintaining circadian rhythms, LY3154207 produced dose-related increases in blood pressure and pulse rate during walking blood pressure monitoring (ABPM). Dose-related increases in systolic and diastolic blood pressure and pulse rate were observed in the ABPM, peaking between 4 and 12 hours post-dose and mostly resolved within 24 hours. Based on ABPM, the 4- to 8-hour estimates of the difference between the least squared mean of LY3154207 200 mg and placebo corresponded to a pulse rate of 32 beats per minute (bpm) and systolic and diastolic blood pressures of 14 mm Hg and 10 mm Hg, respectively. The results are presented in Table A. [surface] [A] HBEA Part A placebo (N=18) LY 25 mg (N=6) LY 75 mg (N=6) LY 100 mg (N=8) LY 150 mg (N=9) LY 200 mg (N=6) Treatment-related adverse events (AEs), n (%) [Events] 5 (27.8) [6] 1 (16.7) [1] 4 (66.7) [8] 6 (75.0)

[17] 8 (88.9)

[34] 5 (83.3)

[18] Insomnia 0 0 1 [1] 4 [4] 3 [3] 3 [3] Decreased appetite 1 [1] 0 1 [1] 1 [1] 3 [3] twenty two] Anxiety a 0 0 0 twenty two] 3b [4] 1 [1] Dizziness a 0 0 twenty two] 1 [1] twenty two] 1 [1] Disgusting a 1 [1] 0 0 0 twenty two] twenty two] Taste disorder a 0 0 0 twenty two] twenty two] 0 Energy increase a 0 0 0 1 [1] 1 [1] 1 [1] Feeling hot 0 0 0 1 [1] 1 [1] 1 [1] Headache 0 0 1 [1] 0 twenty two] 0 There are at least 3 individuals with treatment-related adverse events (AEs). b. One individual discontinued LY3154207 150 mg due to anxiety-induced adverse events. AE = Adverse Event; LY = LY3154207.

[0154] LY3154207 at doses ≤75 mg has an acceptable safety and tolerability. While maintaining a circadian rhythm, LY3154207 produces dose-related increases in blood pressure and pulse rate as measured by ABPM.

[0155] [HBEA] [part] [B-] Cerebrospinal fluid Part B of HBEA is a study of the cerebrospinal fluid (CSF) and plasma pharmacokinetics (PK) profiles of healthy volunteers following a single dose of LY3154207. The objective of this study was to determine the CSF and plasma PK profiles of LY3154207 in healthy volunteers after a single-dose study. This study consisted of two cohorts of single-dose, single-cycle, placebo-controlled, randomized, double-blind, parallel-group studies. Individuals were randomized to 25 mg and 75 mg doses, and continuous blood and CSF samples were collected 2 hours before and 24 hours after administration to measure LY3154207 concentrations. Twenty-four individuals were enrolled, and all completed the study. The individuals had a mean age (SD) of 29.4 (9.8), and 22 were male (92%) and 22 were white (92%). LY3154207 concentrations were detectable in CSF up to 8 hours after the 25 mg dose and up to 24 hours after the 75 mg dose. At all doses, approximately 1% of the total plasma exposure to LY3154207 is obtained in the CSF. Central permeability of LY3154207 at 25 mg and 75 mg was confirmed by measuring LY3154207 in the CSF, thus demonstrating its use in dopamine-induced CNS disorders according to the dosage therapy of the present invention. LY3154207 exhibits linear plasma pharmacokinetic (PK) and central permeability. LY3154207 exhibits linear plasma PK, with a median time to maximum concentration (tmax) of approximately 2–3 hours, a terminal half-life (t1 / 2) of approximately 12 hours, significant clearance (CL / F) over the entire dose range of 19–25 L / h, and negligible renal elimination. The area under the concentration-time curve from time 0 to infinity (AUC0–∞) increases proportionally with the LY3154207 dose (from 25 to 200 mg). In CSF, the median tmax of LY3154207 was 3–4 hours and the t1 / 2 was 8 hours. Approximately 1% of the total plasma exposure to LY3154207 is obtained in CSF, with a CSF / unbound plasma ratio of 0.3. Therefore, central permeability of LY3154207 was confirmed by CSF pharmacokinetics at 25 mg and 75 mg doses of HBEA fraction B.

[0156] [HBEB] [Health Volunteer] [I] [Expect] [Sleep Latency Study] Dose-dependent activation adverse events were also observed in single-dose escalation studies. The efficacy of a single dose of LY3154207 for insomnia was investigated, measured using multiple sleep latency tests (MSLT) in healthy, sleep-deprived men. HBEB was a phase 1, single-dose, randomized, placebo-controlled, 4-cycle incomplete crossover study in 17 healthy, sleep-deprived men (n=17). Individuals were randomized to receive a single dose of placebo, LY3154207 15, 30, or 75 mg (double-blind), or modafinil (open-label control). During each cycle, individuals were approximately 26 hours sleep-deprived before administration and approximately 12 hours after administration. MSLT was performed every 2 hours until 10 hours after administration. Analysis based on a mixed-model repeated-measures approach included treatment, cycle, time, and the treatment-time interaction as fixed factors, and the individual as a random factor; total sleep latency was the average of the four post-administration sleep latencies. All individuals were randomized to receive four of the five available single-dose treatments (15, 30, or 75 mg LY3154207, placebo, or modafinil 200 mg), with all individuals receiving placebo. The clearance period was at least 7 days. MSLT was the primary assessment for insomnia. Secondary outcomes included the Karolinska Sleepiness Scale (KSS), EEG, and a simple response task. Blood samples were collected to measure plasma concentrations of LY3154207 and modafinil. Seventeen individuals were enrolled and received at least one dose of the study drug, with sixteen completing all four cycles of the trial. A dose-dependent increase was observed in the MSLT, with the least squares mean (95% CI) difference compared to placebo at 5.2 minutes (3.3, 7.1) for 75 mg, 3.2 minutes (1.4, 5.1) for 30 mg, and 1.3 minutes (-0.6, 3.2) for 15 mg, as shown in Figure 2. LY3154207 also exhibited a dose-dependent increase in alertness, as measured by the Karolinska Sleepiness Scale. PK was linear across the dose range, with Cmax and t1 / 2 at approximately 3 and 9 hours, respectively. These results are depicted in Figure 2. LY3144207 exacerbated insomnia in sleep-deprived healthy volunteers in the Phase 1 Sleep Latency Study (HBEB) (providing a human clinical indication of D1 receptor signaling involvement) and promoted wakefulness. Thus, central pharmacokinetic activity was confirmed by dose-dependent exacerbation of insomnia. The HBEB Stage I sleep latency study in healthy volunteers demonstrated that, according to the dosage therapy of the present invention, LY3154207 improved insomnia in a dose-dependent manner in healthy men with sleep deprivation, thereby confirming the use of LY3154207 in conditions associated with excessive daytime sleepiness and other dopamine-induced central nervous system disorders.

[0157] [HBEC] [,] [LY3154207] [Multiple escalation dose study] [:] In this randomized, double-blind, placebo-controlled, multiple-escalation parallel group study HBEC, healthy individuals (Part A) and participants with PD (Part B) received a once-daily dose of LY3154207 (15, 30, 75, or 150 mg in Part A and up to 75 mg in Part B) or placebo for 14 days, as shown in Figure 3.

[0158] The study results included 24-hour walking blood pressure monitoring (ABPM), treatment-induced adverse events (TEAEs), and pharmacokinetic (PK) assessments in both healthy individuals and participants with Parkinson's disease (PD). The Movement Disorder Society-United Parkinson's Disease Rating Scale (MDS-UPDRS) assessment was also used to evaluate the effect of LY3154207 on motor function in PD participants. The objective was to investigate the safety, tolerability, and pharmacokinetics (PK) of multiple daily oral administration of LY3154207 in healthy individuals (Part A) and in participants with PD (Part B).

[0159] [Research] [HBEC] [part] [A] [:] [From a health volunteer] [1] [Cognitive Outcomes and] [PD] [Used by the patient] [LY3154207] [Treatment]

[14] [Tianzhong's movement symptoms] In both healthy individuals and participants with Parkinson's disease (PD), most treatment-associated adverse events (TEAEs) were mild, with no severe or serious TEAEs or TEAEs leading to discontinuation. In PD participants receiving LY3154207, treatment-related adverse events (AEs) included upper abdominal pain (n=1), visual hallucinations (n=1), headache (n=1), and sensory dullness (n=1). In healthy individuals, the incidence of TEAEs showed a dose-dependent increase after repeated administrations of LY3154207. In healthy individuals receiving LY3154207, common treatment-related AEs (primarily at the 150 mg dose) included insomnia (n=4), dizziness (n=3), nervousness (n=3), palpitations (n=3), and nausea (n=2). The efficacy of LY3154207 on vital signs was less pronounced in PD participants compared to healthy individuals. Results are shown in Table B. Multiple once-daily doses of LY3154207, up to 150 mg in healthy individuals and up to 75 mg in participants with Parkinson's disease (PD), were well tolerated. Initial increases in SBP, DBP, and pulse rate were observed with repeated dosing in both healthy individuals and PD participants, but the adaptation effect was less pronounced in PD participants. The pharmacokinetic (PK) profile of LY3154207 was generally similar between healthy individuals and PD participants, but a slight increase in LY3154207 exposure was observed in PD participants. [surface] [B] healthy individuals Participants with PD PBO (N=12) LY 15 mg (N=9) LY 30 mg (N=9) LY 75 mg (N=9) LY 150 mg (N=9) total (N=48) PBO (N=8) LY 75 mg (N=9) LY 75 mg titration a (N=8) total (N= 25) Individuals with ≥1 TEAE, n (%) 5 (41.7) 4 (44.4) 5 (55.6) 3 (33.3) 8 (88.9) 25 (52.1) 3 (37.5) 6 (66.7) 5 (62.5) 14 (56.0) Number of TEAEs 5 6 5 6 35 57 5 14 7 26 Mild 5 6 5 6 35 57 4 13 6 twenty three moderate 0 0 0 0 0 0 1 1 1 3 Participants with PD received titrated doses: Days 1–3: 15 mg; Days 4–6: 30 mg; and Days 7–14: 75 mg. LY=LY3154207; PBO=placebo; PD=Parkinson's disease; TEAE=treatment-induced adverse events.

[0160] As shown in Figure 4, participants with PD treated with LY3154207 showed more consistent improvement in motor function test scores compared to those treated with placebo, as measured by MDS-UPDRS Part III, thus indicating potential efficacy in treating motor symptoms in PD.

[0161] PK parameters of LY3154207 in healthy individuals and participants with PD confirmed a dose-dependent increase in exposure and minimum cumulative dose after repeated dosing. LY3154207 exposure on day 14 after 75 mg of LY3154207 was shown to be increased by 25% and 42% in participants with PD, respectively, with Cmax and AUC(0-24). [surface] [C] Healthy individual (Day 14) Participants with PD (day 14) LY 15 mg (N=9) LY 30 mg (N=9) LY 75 mg (N=9) LY 150 mg (N=9) LY 75 mg (N=8) LY 75 mg titration a (N=8) Cmax, ng / mL 66.2 149 307 500 335 400 tmax, hours Median 2.0 2.0 2.0 3.0 2.0 2.5 AUC(0-24), ng [·]h / mL 492 1240 2220 4350 3050 3680 CLss / F,L / h 30.5 24.2 33.8 34.5 24.6 20.4 RA Cmax b 1.18 1.12 1.13 0.92 1.05 NC RA AUC(0-24) b 1.34 1.03 0.99 0.93 1.06 NC CLr, L / h NC 0.0036 0.0024 0.0034 NC NC a. Titration doses for participants with Parkinson's disease (PD): Days 1-3: 15 mg; Days 4-6: 30 mg; and Days 7-14: 75 mg. b. Cumulative ratio (Day 14: Day 1). Note: Unless otherwise stated, all reported values ​​in the table are geometric mean. AUC(0-24) = Area below the concentration-time curve from 0 to 24 hours; CLr = Renal clearance; CLss / F = Apparent total clearance of the drug at steady state after extravascular administration; Cmax = Maximum drug concentration; LY = LY3154207; NC = Not calculated; PD = Parkinson's disease; RA = Cumulative ratio (Day 14: Day 1); tmax = Time to reach maximum drug concentration.

[0162] In the Digit Symbol Substitution Test (DSST), all groups (including placebo) improved over time, with the largest improvement relative to baseline observed at day 13, indicating that the learning effect persisted at day 13. The 15 mg dose of LY3154207 (the lowest dose tested, LY) unexpectedly produced the highest mean change relative to baseline at both post-dosing time points. The Hopkins Verbal Learning Test (HVLT) provided some indication of an inverse dose-response relationship, with LY3154207 15 mg producing the largest mean improvement relative to baseline. This Phase 1 data from healthy volunteers suggests that low-dose range therapy (up to a maximum total daily dose of 15 mg) may provide cognitive-enhancing effects in individuals with dopamine-induced central nervous system disorders or healthy individuals.

[0163] Abbreviations: AUC(0-24) = Area under the concentration-time curve from 0 to 24 hours. AUC0-∞ = Area under the concentration-time curve from time 0 to infinity; CI = Confidence interval; CL / F = Apparent clearance; CLr = Renal clearance; CLss / F = Apparent total clearance of the drug at steady state after extravascular administration; Cmax = Maximum concentration; tmax = Time to reach maximum drug concentration; CSF = Cerebrospinal fluid; LS = Least squared; LY = LY3154207; MSLT = Multiple sleep latency test; PBO = Placebo; PK = Pharmacokinetics; t1 / 2 = Endpoint half-life; tmax = Time to maximum concentration. bpm = heart rate per minute; DBP = diastolic blood pressure; SBP = systolic blood pressure; LS = least squares; LY = LY3154207; MDS-UPDRS = Movement Disorders Association Combined Parkinson's Disease Rating Scale; NC = not calculated; PD = Parkinson's disease; RA = cumulative ratio (day 14:day 1); AE = adverse events; TEAE = treatment-induced adverse events.

[0164] [Example] [2] [:] Spatial Working Memory of Adult Rhesus Monkeys Core cognitive functions of working memory have been established to be highly dependent on D1 receptor signaling in the prefrontal cortex. While D1 agonists have been shown to cause medical problems due to overstimulation and tolerance, positive stereotactic modulators of D1 (PAMs) show promise in selectively enhancing relevant D1 activity in response to the spatiotemporal dynamics of dopamine transmission and thus avoiding these problems. A D1 PAM compound known as DPTQ or LY3151944 (2-(2,6-dichlorophenyl)-1-((1S,3R)-5-(2-hydroxy-2-methylpropyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)ethyl-1-one) is presented below and unexpectedly showed sustained improvement in spatial working memory in adult rhesus monkeys.

[0165] DPTQ showed a tendency to reduce spatial working memory performance in rhesus macaques at acute doses of 2.5 to 10 mg / kg IM, but had little effect on avoiding ketamine-induced cognitive deficits. However, despite this apparent lack of acute cognitive enhancement, attention should be paid to the surprisingly consistent and pronounced efficacy observed in tests conducted several days post-administration. Specifically, performance substantially decreased 24 to 48 hours after injection but significantly improved when tested 96 to 120 hours later.

[0166] Studies were conducted to evaluate the efficacy of low-dose DPTQ at 0.1, 1.0, and 10.0 mg / kg alone, as well as the efficacy of a single dose of 2.5 mg / kg repeated during delayed cognitive enhancement. A moderate dose-related factor was observed across the magnitude of cognitive decline and enhancement, providing crucial insights into treatment efficacy. It was found that repeating the 2.5 mg / kg dose during enhancement elicited a transient deficiency, which was subsequently replaced by long-term cognitive enhancement. This unique and unexpected finding highlights the effects of long-term and intermittent repeated administration.

[0167] Experimental Summary: A single dose of 2.5 mg / kg was administered to both aged and non-aged animals, with performance tracked daily for the first six days and subsequent surrogate days. This confirmed that we could reproduce the efficacy previously observed at the lowest possible dose. The efficacy of repeating this dose on day 5 (marked with 120 hours) was tested to determine (i) whether an immediate reduction in performance was still observed on day 2 and (ii) whether a relatively consistent and sustained improvement in performance was achieved with subsequent days of treatment. Because this dose also induced short-term performance deficits, the efficacy of single administrations at lower doses of 0.1 and 1.0 mg / kg was also tested.

[0168] Except for one stump-tailed macaque (macaca arctoides), all animals were rhesus macaques. Detailed animal statistics are provided for each group. Young animals were expected in each study; however, most were older, and females outnumbered males by two or three to one. The spatial delay response task was identified as one of the most reliable, sensitive, and valuable models for testing spatial working memory in primates. The spatial delay response task was rigorously administered in a fully systematic format that was uniform within, between, and across studies. The task was designed to normalize performance across animals, so all typically achieved ~70% accuracy. The spatial delay response task directly challenges the same spatial working memory circuits in both human and non-human primates, including the dorsolateral prefrontal cortex, posterior parietal cortex, and MD thalamus. The spatial delay response task is sensitive to various neuropharmacological manipulations (local or systemic administration of dopamine-containing, nicotinic, glutamine-containing, and GABA-containing agents). In this task, one of several well locations was baited with animal food and then covered with the same plaque. Subsequently, for one of five variable delays, the opaque barrier was lowered and then raised to allow the animal to respond to the well location for food. Animals were stabilized (65% to 75% accuracy ± ≤ 2.5%) by varying the number of wells and delay duration before any drug administration. Each testing phase consisted of 20 trials, with four trials (semi-randomized distribution) for each of the five delays ranging from 0, 1, 2, 3, and 4 N seconds, where N increases from 1 to 10 according to ability. The number of wells ranged from 2 to 7, and stability was thus achieved by gradually varying the number of wells and the N factor. The initial baseline was obtained during initial training and standardized through twenty phases, after which animals typically underwent regular testing to ensure reasonable baseline stability. The absolute minimum of three baseline phases was required before any experimental conditions. The animals were not lacking in food, and were rewarded with their favorite foods (such as raisin yogurt, gummy bears, and almonds) for correct responses, and were then fed their normal proportion of nutritional biscuits shortly after the cognitive test.

[0169] DPTQ was prepared as a 20% Captisol / PBS suspension at pH 8. Extreme care was required during sonication to protect the compound, and it was injected into the gluteus maximus muscle via a 21G subcutaneous needle (avoiding blockage) within 2 hours of preparation (keeping on ice). The carrier was frozen in sterile vials for up to one month. Animals were fully acclimatized to all procedures before inclusion in any study. Animals were allocated for basic research, with relevant allocations being semi-randomized between the carrier and treatment groups. The IM injection was administered in the animal's cage 1 hour prior to cognitive testing. Testing was conducted in a standard WGTA-designed attenuated chamber at a designated operating location adjacent to the animal shelter.

[0170] The efficacy of single-dose and DPTQ was observed over a 14-day period. The single-dose test was initially conducted at 2.5 mg / kg, compared to the median, and the same median data were reasonably applicable to subsequent tests conducted at single doses of 0.1 and 1.0 mg / kg DPTQ. Separate but overlapping baselines were used for both conditions.

[0171] Data from a group of 10 animals treated with the medium are shown in Figure 5. Group performance remained almost unchanged from baseline over the following two weeks, with an average group bias of only 5%. Treatment on day 1 produced non-persistent changes in cognitive performance.

[0172] Figure 6 shows the treatment data of a group of 9 animals treated with an acute dose of 2.5 mg / kg DPTQ. No immediate effect was observed on day 1, but the reduction in performance was evident on day 2 and stabilized on day 3 (ANOVA F[1,14] = 4.543, p = 0.051 from baseline). This significant cognitive impairment was followed by a sustained improvement in cognition from day 4 onwards (ANOVA F[1,14] = 45.061, p < 0.001 from baseline). Of the 9 animals, 5 were older and 4 were younger. By combining the scores on days 4, 5, and 6, we were able to compare the two groups. No significant difference was observed between them (ANOVA: F[1,22] = 0.066, p = 0.799). No acute effects of DPTQ were observed, but the impairment of approximately 10% became apparent on day 3, and then began to increase over a long period from day 4, again approaching 10%.

[0173] The efficacy of repeating the DPTQ on day 5 during the 14-day observation period was also evaluated. Figure 7 illustrates the efficacy of repeating the 2.5 mg / kg dose on day 5. In this study, the 2.5 mg / kg dose was administered acutely on day 1 (1 hour before the test) and subsequently on day 5 (immediately after the test) with either the carrier or an additional dose of 2.5 mg / kg. Animals were semi-randomized to receive either the carrier or the treatment first during the repeat administration. When the 2.5 mg / kg was administered again on day 5 as a second dose, we observed a second consecutive drop in efficacy on day 6 (Figure 7). Although the efficacy was not significantly lower than baseline, it showed a marked drop relative to the enhancement seen on the previous two days. Nevertheless, performance recovered within two days (ANOVA on day 4: f[1,10] = 15.564, p = 0.003) and remained high throughout the week (ANOVA on day 10: f[1,10] = 25.912, p < 0.001). Earlier attenuation was also observed on day 3, but not significantly. Following an acute dose on day 1, a sharp drop was also observed on day 3, followed by a rebound on day 4. However, after a repeat dose on day 5, a particularly sharp drop occurred on day 6, immediately followed by a week of enhancement.

[0174] To better understand the dynamic range of these effects, administration of a low dose of DPTQ at 0.1 mg / kg was evaluated. Figure 8 shows the effects of DPTQ when administered at a low dose of 0.1 mg / kg. No signs of attenuation were observed, but moderate enhancement was observed. Interestingly, in a group of 10 animals, no defects were observed on day 3, but rather moderate enhancement was observed, showing some persistence over the course of week 2 (Figure 8). Nevertheless, a significant improvement relative to baseline was observed on day 4 (ANOVA: F[1,18] = 24.132, p < 0.001). Within this group, there were 6 older animals and 4 younger animals. No significant difference was observed between them when these scores were compared on day 1 (ANOVA F[1,8] = 0.816, p = 0.393).

[0175] The efficacy of the DPTQ administered at a dose of 1.0 mg / kg on spatial working memory was evaluated. As shown in Figure 9, early deficits were not significant, and the enhancement at the 0.1 mg / kg dose appeared to be stronger and significant on day 5 (ANOVA F[1,14] = 22.449, p < 0.001). This group currently includes 6 aged animals and 2 non-aged animals, plus 2 additional non-aged animals that have not yet completed the study. No indication of any difference in scores was observed between the two age groups.

[0176] Therefore, DPTQ at doses of 1–10 mg / kg or lower improves spatial working memory (as even the lowest dose studied showed significant improvement). Surprisingly, cognitive-enhancing effects were observed at low doses of IM (0.1 and 1 mg / kg) in rhesus monkeys. High doses of DPTQ (2.5 mg / kg and above) showed a slight drop in performance during the first 48 hours, but then continued positive effects for at least 14 days. These data suggest that DPTQ and / or LY3154207 can enhance cognitive performance in primates in a time-dependent manner. This primate cognitive signal at 0.1 mg / kg (approximately equivalent to 1 mg of LY3154207 orally in humans) suggests that DPTQ can have cognitive-enhancing effects at lower doses without showing initial signs of diminishing efficacy, which is attributed to overactivation. The PK-PD synaptic estimate equates the DPTQ of a 1.0 mg / kg IM dose to 10 mg of LY3154207 in humans, and the DPTQ of a 2.5 mg / kg dose to 25 mg of LY3154207 in humans. Phase I clinical data for a 15 mg dose of LY3154207 also showed a trend toward better cognitive efficacy in the DSST task compared to higher doses.

[0177] These data, when viewed in conjunction with the data from the aforementioned Phase I study, lead to the following conclusions: the dosage therapy of this invention, at a low dose range of 0.5 mg to 15 mg, can effectively enhance specific D1 signaling-mediated responses (such as cognitive-enhancing effects) while avoiding the higher levels of stimulation observed at higher doses (such as 20 mg–75 mg), such excessive wakefulness promotion leading to insomnia, and / or certain unwanted dose-related cardiovascular effects (such as increased pulse rate and blood pressure), and reducing the risk of drug-drug interactions with Cyp3A4 inhibitors. More specifically, high dosing schedules of LY3154207 (greater than 75 mg daily) have been found to be associated with mild to moderate insomnia and agitation, and / or unwanted cardiovascular effects, with doses greater than 75 mg producing acute and / or persistent increases in BP and pulse rate. In the HBEB study, linear and dose-dependent efficacy on sleep latency was observed in healthy, sleep-deprived individuals receiving a single dose of LY3154207 within a dose range of 15 mg to 75 mg. The frequency of adverse events such as insomnia was observed to increase significantly at doses greater than 75 mg of LY3154207. Therefore, in this dosage therapy, 75 mg represents a surprising and unexpected separation between the appropriate and undesirable effects of LY3154207.

[0178] Therefore, the combined results of Phase I human and primate studies have yielded the following conclusions: This invention provides a modified clinical dosage therapy for treating dopamine-induced central nervous system disorders and a method of using LY3154207 and / or its pharmaceutical compositions. Specifically, daily administration of LY3154207 provides a modified method for reducing the signs and symptoms of dopamine-induced central nervous system disorders in a clinically advantageous manner, thereby achieving safe, tolerable, and effective relief of clinical symptoms and symptoms.

[0179] Specifically, this invention further provides a method of using low-dose dosing therapy, which is believed to promote the normalization of endogenous dopamine signaling in various dopamine-mediated disease conditions, with a lower tendency for certain effects (such as overstimulation) seen at higher doses, and a lower likelihood of developing tolerability and adverse effects associated with orthotopic D1 agonists. Due to this normalizing effect, the LY3154207 clinical dosing therapy of this invention, and specifically the low-dose therapy, provides a modified approach to treating a range of dopamine-mediated CNS deficiencies, with a surprising and unexpected combination of favorable human clinical pharmacological efficacy, safety, and tolerability.

[0180] LY3154207 is currently in a Phase 2 study (NCT03305809) investigating cognition in Lewy body dementia. The results of this clinical trial could further support the use of dosing therapy for dopamine-induced CNS disorders such as LBD, PD, and AD, and the unexpected and unforeseen advantages of dosage.

[0181] [Example] [3] [:] [For use] [PD] [Of] [Dosage-based therapy study] [-] [Research] [HBEH] [The solution] [,] [Also known as ""] [Presence] [」] The following provides some dosage regimens of the dosage therapy of the present invention for use in dosage therapy studies of PD. Those skilled in the art will be able to apply the teachings of this Example 3 and other disclosures provided herein to carry out additional dosage and dosage therapy similar studies of the present invention.

[0182] Well-tolerated treatments for cognitive impairment caused by PDD have not yet met medical needs. D1PAM should improve cognitive performance by enhancing the response to dopamine in the residual brain of individuals with PDD (or by administering levodopa). In addition, D1PAM should have a positive effect on motor deficits, depression, and daytime sleepiness observed in individuals with PD.

[0183] LY3154207 can improve various areas that are crucial for individuals with Lewy body dementia (including Parkinson's disease, motor symptoms, insomnia, and signs of mood and function). LY3154207 is being developed to treat the symptoms of cognitive impairment in dementia, where it can provide improvement over a relatively short period (12 weeks or less) with long-term daily administration. As a symptomatic agent, LY3154207 is essential because even when using agents that slow progression, patients continue to experience dementia symptoms. By enhancing the dopamine response (or administering levodopa) in the remaining brain of individuals with Parkinson's disease, LY3154207 is believed to improve cognitive performance and provide treatment for individuals with Parkinson's disease who have neurocognitive impairment. The ultimate goal of using LY3154207 is to improve cognition in PD dementia (including Lewy body dementia (DLB)) and provide additional benefits in terms of movement and / or insomnia.

[0184] The PRESENCE study evaluated three doses of LY3154207 (10 mg, 30 mg, and / or 75 mg orally daily (QD) or 50 mg based on an interim analysis) versus placebo over a 12-week treatment period. Primary outcome was a measure of cognition, and additional cognitive measures were assessed as key secondary endpoints. PRESENCE was a randomized, placebo-controlled trial in individuals with Parkinson's disease dementia to evaluate the safety and efficacy of LY3154207 (three doses of the investigational drug) in participants with mild to moderate Parkinson's disease dementia after 12 weeks of treatment. Primary outcome was a measure of cognition, and additional cognitive measures were assessed as key secondary endpoints. The D1 PAM mechanism can affect various areas crucial for individuals with Lewy body dementia, and measures of Parkinson's disease (including motor symptoms), insomnia, mood, and functioning will be assessed.

[0185] The HBEH study will include individuals meeting the criteria for Parkinson's disease (PD) (Postuma et al., 2015) and those with mild to moderate dementia as defined by the revised MDS criteria, which, in the researchers' view, has resulted in functional impairment and a MoCA score between 10 and 23 (Trzepacz et al., 2015). According to the revised MDS criteria, Parkinson's disease (PDD) can be diagnosed in the presence of dementia, regardless of the chronological order of dementia onset relative to PD diagnosis. Individuals diagnosed with Lewy body dementia (DLB) who meet the MDS PD criteria should be considered to also have PD. Therefore, individuals can have dementia before, at, or after a PD diagnosis. Unlike registration trials of symptomatic treatment for PDD (Emre et al., 2004), this study will also include individuals who, based on the chronological order of their dementia, will meet the traditional criteria for DLB (dementia before or within one year of the start of motor activity) (Mckeith et al., 2005). This criterion is the presence of dementia before or within one year of Parkinson's symptoms. The one-year rule is arbitrary and based on the historical reliability of PD not being associated with dementia; however, there is increasing controversy regarding the effectiveness of this traditional decomposition diagnostic approach (Berg et al., 2014). Supporting the proposed approach, both conditions share various clinical, genetic, and pathological features (Lippa et al., 2007; Postuma et al., 2009; Johansen et al., 2010). Both DLB and PDD are associated with similar cognitive impairments, including visual abnormalities and suggestive memory improvements. Both are associated with prominent psychosis, sedative sensitivity, and altered arousal. Prodromal symptom features (e.g., REM sleep behavior disorder, anosmia) are identical in both conditions. Nonmotor symptoms associated with depression, anxiety, autonomic dysfunction, and sleep disturbances occur with similar frequencies in both conditions. The same gene mutations (α-synuclein replication, glucocerebrosidase mutation) are associated with the progression of either condition. Ultimately, they result in shared lesions of α-synuclein and Lewy body formation in the brainstem and cortex. Therefore, studying HBEH aligns with current thinking on PDD and DLB, as, aside from the timing of cognitive impairment, they are clinically and pathologically indistinguishable and likely to respond to similar treatments (Aarsland et al., 2004; Ballard et al., 2006). Including a placebo as a control, and blinding investigators, field staff, and individuals, allows for unbiased assessment of the resulting safety data, enabling a more stable comparison between LY3154207 and placebo data. A comparison of three dose levels of LY3154207 was selected to assess the dose-exposure response to safety and efficacy.Initial consultations (3rd to 7th consultations) were conducted every week to provide a detailed assessment of the efficacy and safety of LY3154207 during the initial treatment period. A 12-week dosing duration was chosen, representing the minimum estimated duration when beneficial cognitive effects could be observed.

[0186] The primary objective tested the hypothesis that, compared to placebo, daily (QD) oral administration of LY3154207 at 10 mg, 30 mg, and / or 75 mg (or 50 mg based on the interim analysis) for 12 weeks would produce a significant improvement in cognition in individuals with mild to moderate PDD. The primary endpoint was the change in the CoA composite score of the CDR-CCB from baseline to week 12. Secondary objectives are described below. Secondary therapeutic goals Secondary efficacy indicators Evaluation of the overall efficacy of LY3154207 ADC-CGIC score from baseline to week 12 Evaluate the efficacy of LY3154207 on cognitive outcomes Changes in CDR-CCB PoA composite score from baseline to week 12 Evaluate the efficacy of LY3154207 on cognitive outcomes Changes in ADAS-Cog13 score from baseline to week 12 Evaluate the efficacy of LY3154207 on cognitive outcomes Changes in MoCA scores from screening to week 12 Evaluation of the efficacy of LY3154207 on symptoms of neuropsychiatric disorders Changes in NPI total project score and individual project score from baseline to week 12 Evaluation of the efficacy of LY3154207 on daytime sleepiness Changes in ESS score from baseline to week 12 Evaluate the efficacy of LY3154207 on the severity of PD. Change in MDS-UPDRS total score (sum of parts I-III) from baseline to week 12 Evaluate the efficacy of LY3154207 on functional outcomes Changes in PDAQ-15 overall score from baseline to week 12 Evaluate the effect of LY3154207 on language fluency Changes in D-KEFS Language Fluency Test Scores from Baseline to Week 12 [Security Goals] [Security Indicators] Evaluate the efficacy of LY3154207 on acute changes in vital signs on the first day of administration. The number of individuals who met clinically significant vital signs criteria at three consecutive time points during the third consultation (day 1 stopping rule). Evaluate the efficacy of LY3154207 on SBP on the first day of administration. The study investigated changes in outpatient SBP from 0 to 8 hours after drug administration on the first day of drug administration. Evaluate the effect of LY3154207 on pulse rate on the first day of administration. The study investigated the changes in outpatient pulse rate on the first day of drug administration from 0 to 8 hours after administration. Assess the efficacy of LY3154207 on SBP from baseline to week 12. Change in mean outpatient blood pressure from baseline to mean SBP at week 12 Evaluate the efficacy of LY3154207 on pulse rate from baseline to week 12. Change in mean outpatient pulse rate from baseline to mean pulse rate at week 12 [Pharmacokinetic Target:] [Pharmacokinetic Target:] Evaluation of the pharmacokinetic (PK) profile of LY3154207 in individuals with mild to moderate dementia caused by Parkinson's disease (PD). Steady-state trough plasma concentration of LY3154207 at week 12

[0187] Abbreviations: ADAS-Cog13 = 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale; ADCS-CGIC = Alzheimer's Disease Collaborative Research - Clinician's Overall Impression of Change; CDR-CCB = Cognitive Drug Research - Computerized Cognitive Database; CoA = Continuity of Attention; D-KEFS = Delis-Kaplan Executive Function System; ESS = Epworth Somnolence Scale; MDS-UPDRS = Movement Disorders Association Combined Parkinson's Disease Rating Scale; MoCA = Montreal Cognitive Assessment; NPI = Neuropsychiatric Inventory; PD = Parkinson's Disease; PDD = Parkinson's Disease Dementia; PDAQ-15 = Penn Parkinson's Daily Activities Questionnaire-15; PK = Pharmacokinetics; PoA = Attention; QD = Once a Day; SBP = Systolic Blood Pressure.

[0188] References: Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015;30(12):1591-1601. Trzepacz PT, Hochstetler H, Wang S, Walker B, Saykin AJ; Alzheimer's Disease Neuroimaging Initiative. Relationship between the Montreal Cognitive Assessment and Mini-mental State Examination for assessment of mild cognitive impairment in older adults. BMC Geriatr. 2015;15:107. Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, De Deyn PP, Durif F, Kulisevsky J, van Laar T, Lees A, Poewe W, Robillard A, Rosa MM, Wolters E, Quarg P, Tekin S, Lane R. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med. 2004;351(24):2509-2518. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasco D, Gotzer SCG, Gomez-Tzorto E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Schulzki JB, Trozski RH JQ, Yamada M; Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65(12):1863-1872. Berg D, Postuma RB, Bloem B, Chan P, Dubois B, Gasser T, Goetz CG, Halliday GM, Hardy J, Lang AE, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease. Mov Disord. 2014;29(4):454-462. Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ, Dickson DW, Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG, Growdon JH, Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM, Leverenz JB, Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton AB, Tanner CM, Trojanowski JQ, Wszolek ZK; DLB / PDD Working Group. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology. 2007;68(11):812-819. Postuma RB, Gagnon JF, Vendette M, Montplaisir JY. Idiopathic REM sleep behavior disorder in the transition to degenerative disease. Mov Disord. 2009;24(15):2225-2232. Johansen KK, White LR, Sando SB, Aasly JO. Biomarkers: Parkinson disease with dementia and dementia with Lewy bodies. Parkinsonism Relat Disord. 2010;16(5):307-315. Aarsland D, Ballard CG, Halliday G. Are Parkinson's disease with dementia and dementia with Lewy bodies the same entity? J Geriatr Psychiatry Neurol. 2004;17(3):137-145. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed Washington, DC; 2013. Ballard C, Ziabreva I, Perry R, Larsen JP, O'Brien J, McKeith I, Perry E, Aarsland D. Differences in neuropathologic characteristics across the Lewy body dementia spectrum. Neurology. 2006;67(11):1931-1934. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M., Leirer VO. Development and validation of a geriatric depression screening scale: A preliminary report. J Psychiatr Res. 1983;17:37-49. Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): Recent evidence and development of a shorter version. Clin Gerontologist. 1986;5:165-173.

[0189] Study Design Overview: The I7S-MC-HBEH (HBEH) study was a multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 2a study comparing three doses of LY3154207 (10, 30, or 75 mg orally once daily [QD] [interval-based analytic 50 mg]) with placebo in individuals with mild to moderate PDD over a 12-week period. The study included a screening period of at least 7 days and at most 14 days (from the first to the second visit), a pretreatment period of at least 11 days and at most 17 days (from the second to the third visit), a 12-week treatment period (from the third to the eleventh visit), and a 14-day safety follow-up period (from the eleventh to the 801st visit or early termination [ET] / discontinuation [DC] visits to the 801st visit). Individuals meeting the inclusion criteria will be randomly assigned in a 1:1:1:1 ratio to receive LY3154207 (10, 30, or 75 mg QD) or placebo. The primary objective of the study is to test the hypothesis that, in individuals with mild to moderate PDD, 12 weeks of LY3154207 administration will produce significant cognitive improvements compared to placebo, as measured by changes in the CoA composite score from baseline to week 12 using the Cognitive Drug Research Computerized Cognitive Bank (CDR-CCB). CoA has demonstrated significant therapeutic effects in previous trials in individuals with PDD (Wesnes et al., 2005; Rowan et al., 2007).

[0190] Treatment groups and duration: The HBEH study included oral QD administration of LY3154207 10 mg, 30 mg, and 75 mg (or 50 mg based on interim analysis) versus placebo for 12 weeks. Number of individuals: Approximately 400 individuals will be screened to achieve 340 randomizations and an estimated total of 85 evaluable individuals in each treatment group.

[0191] Statistical analysis: Efficacy Analysis: All individuals in the assessable patient population (EPP) will be considered for efficacy analysis. A primary analysis of CoA will be performed when all individuals have completed 12 weeks of treatment. CoA analysis will utilize a Bayesian MMRM model. Bayesian analysis can utilize non-prior information for all terms in the model. These will be a zero-centered diffuse normal distribution. The prior differentials will follow an inverse gamma distribution. Further details of the Bayesian analysis will be provided in SAP. The MMRM model will interpret longitudinal data assessed throughout the study (after administration at weeks 1, 2, 4, 6, 8, 10, and 12). The change in CoA from baseline to week 12 will be the dependent variable. The model will include fixed (baseline, treatment, consultation) and random effects (individual) and interaction terms (treatment at consultation, baseline at consultation). Unstructured differential structures will be applied to the model, but if they cannot converge, other suitable structures will be investigated. Primary comparisons will be made between the changes in the treatment and placebo at week 12 relative to baseline (difference of least squares). Secondary efficacy outcomes: Changes in the overall clinical impression of Alzheimer's Disease Collaborative Study (ADC-CGIC), CDR-CCB attention (PoA), the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), the Montreal Cognitive Assessment (MoCA), the Neuropsychiatric Inventory (NPI), the Epworth Sleepiness Scale (ESS), the Movement Disorders Association Combined Parkinson's Disease Rating Scale (MDS-UPDRS), the Penn Parkinson's Daily Activities Questionnaire-15 (PDAQ-15), and the Delis-Kaplan Executive Function System (D-KEFS) at week 12 relative to baseline will follow the same analytical methods as described above. Missing records in some scales (e.g., ADAS-Cog) will be estimated in detail as planned in the statistical analysis. For scales that are not fully estimated, if any item is missing, any total or sum including that item will be considered missing. No adjustment will be made for multiple comparisons.

[0192] Safety Analysis: The safety analysis is based on a safe population and will include the following list and / or overview: adverse events (AEs), serious adverse events (SAEs), treatment-induced adverse events (TEAEs), laboratory measurements, vital signs, electrocardiogram readings, and the number of individuals meeting clinically significant vital sign criteria at three consecutive time points at the third visit (Day 1 discontinuation rule). A mixed-model repeated-measures analysis will be used to compare changes in outpatient blood pressure (BP) and pulse rate measured on day 1 (V3) of study drug administration from pre-treatment to 8 hours post-administration. Two baselines will be considered for the analysis relative to baseline: the V3 pre-treatment value and the time-matched baseline at the second visit (hourly values ​​from 0 to 6 hours). For the second baseline, the V2 6-hour time point will be used as the baseline value for the V3, 7-hour, and 8-hour time points. Individual changes relative to baseline will be analyzed for each baseline pathway. Mixed-model repeated measurement analysis will also be used to compare changes in outpatient blood pressure and pulse rate from V2 (average 0 to 6 hours per day) to week 6 / 8 visit and week 12 / 11 visit (average 0 to 6 hours per day) to assess changes in blood pressure and pulse rate over 12 weeks of medication.

[0193] Pharmacokinetics (PK): Pharmacokinetic analysis will be performed on individuals who have received at least one dose of the study drug and have a measurable concentration. Model-based methods can be implemented using nonlinear mixed efficacy modeling (NONMEM) or other suitable software to estimate PK parameters.

[0194] Additional indicators and biomarker data collected during the study can be evaluated in a probing manner.

[0195] Interim Analysis: A safety interim analysis will be conducted on the number of individuals in each treatment group who met the clinically significant criteria for vital signs (Day 1 discontinuation rule) at three consecutive time points at the third visit. This analysis will be conducted after 50, 100, and 150 individuals have completed their third visit. If there is a >60% probability that the difference in the percentage of individuals meeting the Day 1 discontinuation rule is >0.3 compared to placebo for 75 mg LY3154207, the 75 mg dose level will be replaced with 50 mg for subsequent enrolled individuals. Individuals already at the 75 mg dose who have met the Day 1 discontinuation rule will remain at 75 mg. In cases where an unacceptable percentage of individuals meet the Day 1 discontinuation rule at other doses, the Internal Assessment Committee (IAC) may decide on dose adjustments for subsequent randomized individuals. Additional efficacy analyses may be conducted during these safety interim analyses. A safety and efficacy interim analysis will be conducted when 170 randomized individuals have completed their 11th visit (week 12) assessment. All potential efficacy analyses are available for internal decision-making, but there are no plans to discontinue the study.

[0196] The HBEH study will include men and women aged 40 to 85 years with mild to moderate PDD. Individuals are eligible for inclusion in the study only if they meet all of the following inclusion (first visit) criteria (note that inclusion criteria [6] through

[10] must be met or be in additional visit [s]): Individual type and disease characteristics: [1] Male and female individuals aged 40 to 85 years (inclusive). [2] Idiopathic PD according to MDS criteria with PD symptoms for at least 2 years (Postuma et al., 2015). [3] Dementia as defined by cognitive decline with functional impairment in the investigator's view. [4] MoCA score of 10 to 23 at screening. [5] Modified Hoehn and Yahr grades 1 to 4. [6] BP or pulse rate at the first and third consultations, as determined by three consecutive BP / pulse rate measurements taken while seated: For individuals under 60 years of age: while seated, mean systolic blood pressure (SBP) is less than or equal to 140 mmHg, mean diastolic blood pressure is less than or equal to 90 mmHg, and mean pulse rate is less than or equal to 90 beats per minute. Each of the three SBP measurements must be less than 180 mmHg. For individuals aged ≥60 years: while seated, mean SBP is less than or equal to 150 mmHg, mean diastolic BP is less than or equal to 90 mmHg, mean pulse rate is less than or equal to 90 beats / minute, and each of the three SBP measurements must be less than 180 mmHg.

[0197] The following assessments of PD severity and cognition, as well as the Columbia-Suicide Severity Rating Scale (C-SSRS), will be completed during the first consultation as part of the individual eligibility assessment: The Movement Disorders Society (MDS) clinical diagnostic criteria for Parkinson's disease (PD) for enrolled individuals will meet the MDS criteria for clinically probable PD (Postuma et al., 2015). Individuals must have bradykinesia with resting tremor and / or rigidity. Individuals must not have any of the absolute exclusion criteria described in Appendix 5. Individuals must not have more than two red markers; if one red marker is present, they must deviate from one supportive criterion, and if two red markers are present, they must deviate from two supportive criteria.

[0198] In addition to meeting the criteria for PD, individuals must also meet the criteria for dementia as described below (Montreal Cognitive Assessment [MoCA] scale). The MDS criteria do not consider dementia as an exclusion criterion for PD and therefore do not impose any time limit on the progression of dementia relative to the motor characteristics of PD.

[0199] Modified Hoehn and Yahr Scales: At screening, individuals must be in Hoehn and Yahr stages 1 through 4. The Hoehn and Yahr Scales (Hoehn and Yahr 1967) are used to describe the progression of PD symptoms. Originally described in 1967, the scale included stages 1 through 5. Later modifications added stages 1.5 and 2.5 to account for intermediate stages of PD. The modified Hoehn and Yahr scales are as follows: Stage 0: No signs of disease; Stage 1: Unilateral disease; Stage 1.5: Unilateral with axial involvement; Stage 2: Bilateral disease without balance impairment; Stage 2.5: Mild bilateral disease with recovery on traction tests; Stage 3: Mild to moderate bilateral disease; some postural instability; independent movement; Stage 4: Severe functional impairment; able to walk or stand without assistance; Stage 5: Wheelchair-bound or bedridden unless assisted.

[0200] Montreal Cognitive Assessment Scale: At the screening stage, selected individuals must have a MoCA score of 10 to 23.

[0201] The Geriatric Depression Scale: At screening, participants must have a Geriatric Depression Scale-Short-Term Form (GDS-S) score of ≤6. The GDS is a field survey questionnaire for depression in older adults (Yesavage et al., 1983). Users respond in "yes / no" format. Initially developed as a 30-item scale (long-term form), it was later shortened to a 15-item scale (short-term form), which can be completed in approximately 5 to 7 minutes (Sheikh and Yesavage, 1986). Of the 15 items, 10 "yes" responses indicate depression, and 5 "no" responses indicate depression.

[0202] The Columbia Suicide Severity Scale-Child Version (C-SSRS) is a scale for obtaining the incidence, severity, and frequency of suicidal ideation and behavior during the corresponding assessment period. A detailed description of the C-SSRS for screening assessment is included in Chapter 9.4.4. The "baseline" version of the C-SSRS will be used for screening, and the results will constitute the baseline assessment. The C-SSRS will be administered to individuals following cognitive and functional assessments. Individual responses will be considered when administering the scale. If an individual is found to have suicidal ideation or behavior at this baseline assessment, the individual will not be randomized and the study will be terminated.

[0203] [Example] [4 AD] [Of] [Protocol for Dosage Therapy Research] It is believed that LY3154207 effectively improves cognitive impairment in Alzheimer's disease by activating cortical neurons, increasing synaptic plasticity, and promoting neurotransmitter release. Other potential benefits of LY3154207 (such as reduced daytime sleepiness, improved mood and / or apathy, and purposeful behaviors leading to reduced apathy (via activation of cortical and striatal D1 receptors)) will also benefit the Alzheimer's population. Its efficacy in AD can be demonstrated in clinical studies lasting 24 weeks or longer in patients with mild to moderate AD (MMSE 13-26) administered at doses of approximately 0.5 mg to approximately 75 mg, with a maximum total daily dose of 75 mg of LY3154207 or its pharmaceutical combinations. Efficacy, safety, and tolerability will be assessed using methods known to those skilled in this technology, including, for example, ADAS-Cog13, MMSE, ADC-CGIC, ADC-ADL, AD-QOL, NPI, and ESS.

[0204] [Example] [5] [:] [Other dopamine-related] [CNS] [disease] Clinical studies can demonstrate its efficacy in a variety of other dopamine-induced CNS disorders, including vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, myofibromyalgia, cognitive impairment, sleep disorders, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, somnolence, apathy, and addiction. In these clinical studies, patients with these disorders were administered LY3154207 or its pharmaceutical combinations at doses of approximately 0.5 mg to approximately 75 mg, with a maximum total daily dose of 75 mg, and the efficacy, safety, and tolerability were assessed using methods known to those skilled in this art.

Claims

1. Use of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl] acetone (LY3154207) or a pharmaceutical composition thereof for the manufacture of a pharmaceutical product for the treatment of patients with Lewy body dementia, wherein the pharmaceutical product is intended to administer to the patient one or more doses of about 0.5 mg to about 75 mg daily, with a maximum total daily dose of 75 mg of LY3154207 or a pharmaceutical composition thereof.

2. As claimed in claim 1, wherein the pharmaceutical product is LY3154207 or a pharmaceutical composition thereof for administering to the patient daily in doses of about 0.5 mg to about 15 mg, with a maximum total daily dose of 15 mg.

3. As claimed in claim 1, wherein the pharmaceutical product is intended to administer to the patient daily in doses of LY3154207 or pharmaceutical compositions thereof selected from the group consisting of: 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg and 75 mg.

4. As claimed in claim 1, wherein the pharmaceutical product is for the long-term administration of one or more doses of about 0.5 mg to about 75 mg, with a maximum total daily dose of 75 mg, of LY3154207 or a pharmaceutical composition thereof to the patient, wherein the patient is treated for at least 21 consecutive days.

5. As claimed in claim 4, LY3154207 or its pharmaceutical composition thereof, wherein one or more doses are from about 0.5 mg to about 15 mg per day, with a maximum total dose of 15 mg per day, is intended for long-term administration to the patient.

6. As claimed in claim 4, wherein the pharmaceutical product is intended for long-term daily administration to the patient of LY3154207 or a pharmaceutical composition thereof selected from the group consisting of: 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg and 75 mg.

7. The use as claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 0.5 mg daily.

8. The use as claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 1 mg daily.

9. The use as claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 2 mg daily.

10. The use as claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 3 mg daily.

11. The use as claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 5 mg daily.

12. As claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 10 mg daily.

13. The use as claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 15 mg daily.

14. The use as claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a daily dose of 20 mg.

15. As claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a daily dose of 25 mg.

16. The use as claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a daily dose of 30 mg.

17. The use as claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 50 mg daily.

18. The use as claimed in claim 3, wherein the pharmaceutical product is used to administer LY3154207 or a pharmaceutical composition thereof to the patient at a dose of 75 mg daily.

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