Therapeutic agent for neurodegenerative disorder

Abstract

The present invention addresses the problem of providing a medicine that, despite of being a non-ergot dopamine agonist (DA), reduces the risk of the drowsiness side effect, and exhibits an excellent therapeutic effect on neurodegenerative disorders such as Parkinson's disease (PD). The present invention relates to a pharmaceutical composition for treating neurodegenerative diseases such as Parkinson's disease, the pharmaceutical composition comprising 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea or a pharmacologically acceptable salt thereof. The pharmaceutical composition is characterized by being orally administered at a daily dose of 0.25 mg to 2 mg in terms of free form.

Description

Neurodegenerative disease treatment

[0001] The present invention relates to a drug that reduces the risk of somnolence as a side effect caused by non-ergot dopamine agonists and exhibits excellent therapeutic effects against neurodegenerative diseases such as Parkinson's disease.

[0002] More specifically, the present invention relates to a pharmaceutical composition for treating a neurodegenerative disease, which comprises 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea or a pharmacologically acceptable salt thereof, and is characterized in that the pharmaceutical composition is orally administered once a day in an amount of 0.25 mg to 2 mg of the compound, calculated as the free form.

[0003] Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration and loss of dopamine neurons in the substantia nigra of the midbrain. The decline in dopamine causes slowly progressive motor disorders such as resting tremor, rigidity, akinesia, and impaired postural reflexes. Non-motor symptoms, such as autonomic nervous system symptoms, depression, sleep disorders, and dementia, also occur.

[0004] There is no cure for PD, and symptomatic medication aimed at alleviating symptoms is the primary treatment. Dopamine agonists (DAs) have a longer half-life in the blood than levodopa preparations, and have been reported to reduce the occurrence of motor complications such as wearing-off and dyskinesia, which are seen with levodopa preparations. DAs are classified into ergot-based and non-ergot-based DAs based on their chemical structure. Ergot-based DAs (e.g., cabergoline, pergolide) have been reported to cause valvular heart disease as a serious side effect, so non-ergot-based DAs (e.g., pramipexole, ropinirole) are widely used clinically.

[0005] However, caution is advised regarding the clinical application of non-ergot DAs, and "somnolence" is listed as a well-known adverse event associated with non-ergot DAs (Non-Patent Document 1). A meta-analysis of clinical trials has shown that non-ergot DAs have a higher risk of somnolence as a side effect compared to ergot DAs (Non-Patent Document 2), and that existing non-ergot DAs have a higher risk of somnolence as a side effect compared to placebos and the like (Non-Patent Documents 3 and 4).

[0006] For somnolence, reducing or discontinuing DAs has been considered, but there is insufficient evidence. The risk of worsening motor symptoms associated with dose reduction has also been noted (Non-Patent Document 1). It has been difficult to maintain sufficient therapeutic efficacy while reducing the risk of side effects with non-ergot DAs.

[0007] As mentioned above, there is a need for the development of new non-ergot DAs that reduce the risk of somnolence as a side effect and exhibit efficacy equal to or greater than that of existing DAs.

[0008] 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (hereinafter referred to as Compound 1), represented by the following formula (I), is described in Patent Documents 1, 2, and 3. Furthermore, the succinate salt of Compound 1 is described in Patent Document 3. Patent Documents 1, 2, and 3 describe that octahydrothienoquinoline derivatives including Compound 1 or pharmacologically acceptable salts thereof have dopamine D2 receptor agonistic activity and can be used as agents for the prevention or treatment of PD, restless legs syndrome, or hyperprolactinemia. Furthermore, Patent Documents 1, 2, and 3 describe that an orally administered preparation can be prepared so that the octahydrothienoquinoline derivative or a pharmacologically acceptable salt thereof is administered in a range of about 0.1 mg to about 300 mg. However, none of these documents describe that Compound 1 or a pharmacologically acceptable salt thereof reduces the risk of somnolence and exhibits excellent effects of improving neurodegenerative diseases such as PD.

[0009] (I)

[0010] International Publication No. 2012 / 124649 Patent No. 6177061 International Publication No. 2022 / 009815

[0011] Parkinson's Disease Clinical Practice Guidelines 2018, p.34-57, 217-219Stowe R, "The Cochrane database of systematic reviews", 2008, No. 2, CD006564Wu, Chunxiao, "Frontiers in Aging Neuroscience", 2022, Vol. 14, 831884Chen, Xiang-Ting, "Frontiers in neurology", 2023, Vol. 14, 1183823

[0012] An object of the present invention is to provide a drug that is a non-ergot DA, yet reduces the risk of somnolence as a side effect, and exhibits excellent therapeutic effects against neurodegenerative diseases such as PD.

[0013] The present inventors have conducted extensive research to solve the above-mentioned problems, and have surprisingly found that use of compound 1 or a pharmacologically acceptable salt thereof not only has a clear ameliorative effect on neurodegenerative diseases such as PD, but also reduces the risk of somnolence as a side effect.

[0014] That is, the present invention relates to the following [1] to [5], etc.: [1] A pharmaceutical composition for treating a neurodegenerative disease, comprising 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea or a pharmacologically acceptable salt thereof, wherein the compound is orally administered in a daily dose of 0.25 mg to 2 mg in terms of the free form. [2] The pharmaceutical composition according to [1] above, wherein the pharmacologically acceptable salt is the succinate salt of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea. [3] The pharmaceutical composition according to [1] or [2] above, wherein the daily dose is 0.25 mg to 1.5 mg, calculated as the free form, and is administered once daily. [4] The pharmaceutical composition according to any of [1] to [3] above, wherein the daily dose is 0.25 mg for the initial administration and 0.5 mg to 2 mg for subsequent administrations, calculated as the free form, and is administered once daily. [5] The pharmaceutical composition according to any one of [1] to [4] above, wherein the neurodegenerative disease is Parkinson's disease.

[0015] In another embodiment, the present invention relates to a method for treating a neurodegenerative disease, comprising administering to a patient a pharmaceutical composition containing a required amount of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea or a pharmacologically acceptable salt thereof, wherein the compound is orally administered in a daily dose of 0.25 mg to 2 mg, calculated as the free form.

[0016] In another embodiment, the present invention relates to use of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating a neurodegenerative disease, wherein the use comprises orally administering a daily dose of 0.25 mg to 2 mg of the compound, calculated as the free form.

[0017] The pharmaceutical composition of the present invention exhibits excellent therapeutic effects on neurodegenerative diseases such as PD and reduces the risk of somnolence as a side effect.

[0018] This figure shows the effect of improving motor symptoms in PD patients. The vertical axis shows the change from baseline (CFB) in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III total score. The horizontal axis shows the time of evaluation. "wk 1, 2, 3, 4, 5, 6, 7, 8, 10, 12" means 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12 weeks after the start of administration, respectively. "EoT (End of Treatment)" means the final evaluation during the treatment period. In the figure, black bars show the values ​​(mean ± standard deviation) for the Compound 2 administration group, and white bars show the values ​​(mean ± standard deviation) for the pramipexole hydrochloride hydrate extended-release tablet (PPX-LA) administration group. This figure shows the evaluation of somnolence in PD patients. The vertical axis shows the Epworth Sleepiness Scale (ESS) total score. The horizontal axis shows the time of evaluation. "Wk 0" refers to the start of administration, and "wk 4, 8, 12" refer to weeks 4, 8, and 12 after the start of administration, respectively. "EoT" refers to the final evaluation of the treatment period. In the figure, black bars represent the values ​​(mean ± standard deviation) of the Compound 2 administration group, and white bars represent the values ​​of the PPX-LA administration group. This figure shows the somnolence assessment of PD patients. The vertical axis represents the percentage of subjects with an ESS total score of 11 or more. The horizontal axis represents the time of assessment. "Wk 0" refers to the start of administration, and "wk 4, 8, 12" represent weeks 4, 8, and 12 after the start of administration, respectively. "EoT" refers to the final evaluation of the treatment period. In the figure, black bars represent the values ​​of the Compound 2 administration group, and white bars represent the values ​​of the PPX-LA administration group, respectively. This figure shows the effect of improving motor symptoms in PD patients. The vertical axis represents the change from baseline in the MDS-UPDRS Part III total score. The horizontal axis represents the time of assessment. "Wk 2, 4, 6, 8" refer to 2, 4, 6, and 8 weeks from the start of administration, respectively. "EoT" refers to the final evaluation of the treatment period. In the figure, black bars show values ​​(mean ± standard deviation) for the compound 2 administration group. This shows the somnolence evaluation of PD patients. The vertical axis shows the ESS total score. The horizontal axis shows the time of evaluation. "Wk 0" refers to the start of administration, and "wk 4, 8" refer to 4 and 8 weeks from the start of administration, respectively. "EoT" refers to the final evaluation of the treatment period.In the figure, black bars show values ​​(mean ± standard deviation) for the Compound 2 administration group. The figure shows the somnolence assessment of PD patients. The vertical axis shows the percentage of subjects with an ESS total score of 11 or more points. The horizontal axis shows the time of assessment. "wk 0" means the start of administration, and "wk 4, 8" means 4 and 8 weeks after the start of administration, respectively. "EoT" means the final evaluation of the treatment period. In the figure, black bars show values ​​for the Compound 2 administration group.

[0019] Hereinafter, embodiments of the present invention will be described in more detail.

[0020] In the present invention, each term has the following meaning unless otherwise specified.

[0021] In the present invention, compound 1 means "1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea." Note that compound 1 and "1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea" described in Patent Document 1 are the same compound.

[0022] In the present invention, Compound 1 can also be converted into a pharmacologically acceptable salt thereof according to a conventional method, if necessary. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; acid addition salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, and aspartic acid; salts with inorganic bases such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt; and salts with organic bases such as triethylamine, piperidine, morpholine, and lysine. Preferably, succinate salts are used. In the present invention, examples of the succinate salt of Compound 1 include a 1:1 salt of Compound 1 and succinic acid, and a 2:3 salt of Compound 1 and succinic acid (hereinafter, sometimes referred to as "2 / 3 succinate salt of Compound 1"), as described in Patent Document 3, and both salts are included.

[0023] In the present invention, "Compound 1 or a pharmacologically acceptable salt thereof" also includes solvates with pharmaceutically acceptable solvents such as water and ethanol.

[0024] Compound 1 of the present invention and its pharmacologically acceptable salts can be produced by known methods. For example, Compound 1 of the present invention can be produced by the method described in WO 2012 / 124649 (Patent Document 1), and the succinate of Compound 1 can be produced by the method described in WO 2022 / 009815 (Patent Document 3) or a method similar thereto.

[0025] The pharmaceutical composition of the present invention may be used in various dosage forms depending on the method of use, including, for example, oral administration forms such as powders, granules, fine granules, dry syrups, tablets, and capsules.

[0026] The pharmaceutical compositions of the present invention are prepared using Compound 1 or a pharmacologically acceptable salt thereof as an active ingredient and at least one pharmaceutical additive. These pharmaceutical compositions can also be prepared by appropriately mixing, diluting, or dissolving the pharmaceutical additive with a pharmaceutical additive according to the dosage form using a known pharmaceutical method. Examples of such pharmaceutical additives include excipients such as lactose, lubricants such as magnesium stearate, disintegrants such as carboxymethylcellulose, binders such as hydroxypropylmethylcellulose, surfactants such as macrogol, effervescent agents such as sodium bicarbonate, solubilizers such as cyclodextrin, acidulants such as citric acid, stabilizers such as sodium edetate, and pH adjusters such as phosphates.

[0027] In another embodiment, the pharmaceutical composition of the present invention is useful for treating neurodegenerative diseases. In the present invention, the neurodegenerative disease is not limited to those characterized by insidious onset, progression of cell death, and functional loss, and examples thereof include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, familial dementia, Alzheimer's disease, PD, Huntington's disease, multiple sclerosis, dementia with Lewy bodies, mild cognitive impairment, retinal neurodegeneration, amyotrophic lateral sclerosis, and frontotemporal dementia.

[0028] In another embodiment, the pharmaceutical composition of the present invention is useful as a therapeutic agent for PD, and has an effect of improving movement disorders (tremor, rigidity, bradykinesia, axial signs, etc.) associated with PD and / or an effect of reducing the risk of onset of non-motor symptoms (somnolence, gastrointestinal symptoms, psychiatric symptoms, etc.).

[0029] In one embodiment, the pharmaceutical composition of the present invention can reduce the risk of somnolence as a side effect during the treatment of PD depending on the embodiment, and therefore can also be used for PD patients who cannot obtain sufficient effects from existing non-ergot DAs because they cannot increase the dose due to the side effect of somnolence.

[0030] In the present invention, the effect of improving PD-associated motor disorders can be evaluated using scores known to those skilled in the art as assessment scales for PD motor symptoms, such as the MDS-UPDRS score, posturally unstable gait disorder (PIGD) score, and Schwab & England ADL scale.

[0031] The MDS-UPDRS score, one of the most representative indices, consists of four parts (i.e., Part I to Part IV), with Part I assessing cognitive function and mood disorders, Part II assessing activities of daily living, Part III assessing motor symptoms, and Part IV assessing motor complications. The score in Part III in particular is used to evaluate improvement in motor symptoms, with a decrease in the score from baseline indicating a greater improvement.

[0032] In the present invention, the daily dose of the active ingredient (Compound 1 or a pharmacologically acceptable salt thereof) for an adult can be determined in the range of 0.25 mg to 2 mg in terms of the free form when administered orally. The dose can be appropriately increased or decreased within the range of 0.25 mg to 2 mg in terms of the free form at the discretion of a physician based on the patient's age, weight, severity of the disease, occurrence of side effects, etc., and the daily dose can be administered once or in divided doses as appropriate.

[0033] The dosage of the pharmaceutical composition of the present invention is as follows: an initial dose of 0.25 mg of Compound 1 or a pharmacologically acceptable salt thereof, calculated as the free form, can be orally administered once daily. After the initial dose, the maintenance dose of the pharmaceutical composition can be determined by gradually increasing the dose within the range of 0.25 mg to 2 mg.

[0034] In one embodiment, Compound 1 or a pharmacologically acceptable salt thereof (e.g., Compound 2 described below) is administered as an initial dose at a dose that has clinically significant efficacy and does not cause side effects (e.g., 0.25 mg or less in free form equivalent as a daily oral dose), and the dose is increased by 0.25 mg or 0.5 mg once or twice or more at intervals of a certain observation period (e.g., 1 week, 2 weeks, or a combination thereof), and the occurrence of side effects (e.g., somnolence, gastrointestinal symptoms, psychiatric symptoms, etc.) is monitored. It can also be used in a gradual escalation regimen with a maintenance dose of a dose that shows efficacy (for example, an effect of improving movement disorders associated with neurodegenerative diseases) without causing any side effects (for example, a daily dose of 0.5 mg to 2 mg, 0.5 mg to 1.5 mg, 0.5 mg to 1 mg, 0.75 mg to 2 mg, 0.75 mg to 1.5 mg, 0.75 mg to 1 mg, 1 mg to 2 mg, 1 mg to 1.5 mg, 1.5 mg to 2 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, or 2.0 mg in terms of free form).

[0035] In one embodiment, the once-daily dose is initiated by oral administration of 0.25 mg of compound 1 or a pharmacologically acceptable salt thereof (e.g., compound 2 described below) in free form equivalent (at week 0), and the once-daily dose is increased to 0.5 mg at week 1. The once-daily dose is then increased by 0.5 mg every week thereafter, with a maintenance dose of 0.5 mg to 2 mg. Note that the doctor may decide to increase or decrease the escalation period, and the once-daily dose may be increased or decreased within the range of 0.25 mg to 2 mg.

[0036] In one embodiment, the once-daily dose is initiated by oral administration of 0.25 mg of Compound 1 or a pharmacologically acceptable salt thereof (e.g., Compound 2 described below) in free form equivalent as an initial dose (at week 0), and is then increased by 0.25 mg every two weeks as a once-daily dose, with a maintenance dose of 0.5 mg to 2 mg. Note that the escalation period may be increased or decreased at the discretion of the physician, and the once-daily dose may be increased or decreased within the range of 0.25 mg to 2 mg.

[0037] In one embodiment, the once-daily dose is initiated by oral administration of 0.25 mg of compound 1 or a pharmacologically acceptable salt thereof (e.g., compound 2 described below) in free form equivalent (at week 0), followed by 0.5 mg at week 1 and 1 mg at week 2. Thereafter, the once-daily dose is increased by 0.5 mg every two weeks, and a maintenance dose of 0.5 mg to 2 mg may be administered. Note that the doctor's discretion may determine whether the escalation period is longer or shorter, and the once-daily dose may be increased or decreased within the range of 0.25 mg to 2 mg.

[0038] In another embodiment, the pharmaceutical composition of the present invention exhibits an excellent therapeutic effect against PD and can reduce the risk of somnolence, which is one of the side effects of non-ergot DAs. In the present invention, reducing the risk of somnolence also includes maintaining the risk of somnolence as a side effect and not worsening the risk of somnolence as a side effect.

[0039] In the present invention, the "risk of somnolence" as a side effect of non-ergot DAs refers to the risk of daytime somnolence, which is a safety issue associated with non-ergot DAs. The degree of "reduction in the risk of somnolence" as a side effect of the pharmaceutical composition of the present invention can also be evaluated, for example, by the ESS total score. The ESS is a self-administered questionnaire in which subjects answer eight questions to assess their daytime sleepiness and tendency to fall asleep. The ESS score (the sum of the scores for eight items, each ranging from 0 to 3) ranges from 0 to 24, with a normal range of 10 points or less. The higher the ESS score, the higher the subject's average sleep tendency or daytime sleepiness in daily life (epworthsleepinessscale.com), and a score of 11 or more is considered pathological hypersomnia (Narcolepsy Diagnosis and Treatment Guidelines). The effect of the pharmaceutical composition of the present invention in "reducing the risk of somnolence as a side effect" can also be evaluated by, for example, a decrease in the incidence of adverse events and side effects compared to the incidence of adverse events and side effects caused by other non-ergot DAs, or a decrease in the incidence or degree of daytime somnolence compared to the frequency of daytime somnolence before administration of the pharmaceutical composition of the present invention.

[0040] The present invention will be described in more detail below based on examples, but the present invention is not limited thereto. In the examples, a 3 / 2 succinate salt of Compound 1 (referred to as Compound 2) was used as the active ingredient of the test drug. The dosage (dosage) refers to the dosage in free form (free form equivalent value) unless otherwise specified.

[0041] Example 1 Clinical Trial in PD Patients 1. Study Method: The efficacy, safety, and pharmacokinetics of Compound 2, administered orally at doses ranging from 0.25 mg to 1 mg once daily for 12 weeks, were investigated in 75 PD patients not receiving concomitant levodopa, using a randomized, open-label study with pramipexole as a comparator. The doses and administration methods are shown in Table 1. Compound 2 was administered orally once daily at a starting daily dose of 0.25 mg. At weeks 2, 4, and 6 of study drug administration, the daily dose was increased in increments of 0.5 mg, 0.75 mg, and 1 mg, unless a dose-escalation criterion was met (e.g., an adverse event causally related to the study drug was observed, or the investigator or subinvestigator determined there was a safety issue). If a criterion for dose escalation was met and it was determined possible to continue the clinical trial, the same dose was continued. Even if the same dose was continued, the dose was increased if the dose did not meet the criteria for dose escalation at the next dose escalation time (weeks 4 and 6). (Hereinafter, this is referred to as the Compound 2 group.) Pramipexole hydrochloride hydrate extended-release tablets (PPX-LA) were administered orally at a daily dose of 0.375 mg once daily. At weeks 1, 2, 3, 4, 5, and 6 of study drug administration, the daily dose was increased in increments of 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, and 4.5 mg (daily dose of 0.375 mg or 0.75 mg) in this order, unless the criteria for dose escalation were met. If the criteria for dose escalation were met and it was determined that the trial could be continued, the same dose was continued. Even if the same dose was administered continuously, the dose was increased if the criteria for disallowing dose increase were not met at the time of the next dose increase (2, 3, 4, 5, and 6 weeks). Hereafter, this group is referred to as the PPX-LA administration group.

[0042]

[0043] 2. Efficacy and safety evaluation items Efficacy evaluation items included summary statistics of the measured values ​​and the change from baseline (week 0) for the total score of the MDS-UPDRS score and the total score of each part. A larger change in the MDS-UPDRS Prat III total score (a lower score) indicates an improvement.

[0044] Safety evaluation items included the ESS total score, occurrence of adverse events, occurrence of side effects, etc. 3. Results The escalation and maintenance dose of Compound 2 were as shown in Table 2 below.

[0045] The MDS-UPDRS Part III total score decreased over time with increasing dose (Figure 1). The change from baseline in the MDS-UPDRS Part III total score at the end of the treatment period (mean ± standard deviation) was -11.5 ± 7.6 in the Compound 2 group and -12.9 ± 6.7 in the PPX-LA group, demonstrating symptomatic improvement in both groups. The ESS total score (mean ± standard deviation) remained stable in the Compound 2 group, from 5.8 ± 4.9 at Week 0 to 5.6 ± 5.7 at the end of the treatment period. The PPX-LA group showed a clear increase, from 6.1 ± 4.2 at Week 0 to 9.2 ± 5.7 at the end of the treatment period (Figure 2). The proportion of subjects with an ESS total score of 11 or more (cutoff criterion for pathological hypersomnia) was 21.6% (8 / 37 subjects) at Week 0 and 13.5% (5 / 37 subjects) at the final evaluation of the treatment period in the Compound 2 group, and 10.8% (4 / 37 subjects) at Week 0 and 38.9% (14 / 36 subjects) at the final evaluation of the treatment period in the PPX-LA group (Figure 3). The incidence of adverse events during the study drug administration period was 13.5% (5 / 37 subjects) in the Compound 2 group and 67.6% (25 / 37 subjects) in the PPX-LA group. The incidences of adverse events related to somnolence, psychiatric symptoms, and gastrointestinal symptoms are shown in Table 3. All adverse events were lower in the Compound 2 group, with the incidence of somnolence in particular being 2.7% (1 / 37 subjects) in the Compound 2 group and 29.7% (11 / 37 subjects) in the PPX-LA group.

[0046]

[0047] The results of Example 1 showed that the compound 2 administration group had a lower incidence of adverse events and side effects than the PPX-LA administration group, and also had a lower risk of side effects such as daytime somnolence, which is a safety issue with existing non-ergot DAs. This indicates that compound 2 clearly improves PD motor symptoms at a daily dose range of 0.25 mg to 1 mg, and can reduce the risk of side effects such as somnolence, despite being a non-ergot DA.

[0048] Example 2 Clinical Trial 2 in PD Patients 1. Study Method Seven PD patients not receiving concomitant levodopa were randomized, open-label, and the efficacy, safety, and pharmacokinetics of Compound 2 were evaluated in a once-daily oral dose ranging from 0.25 mg to 2 mg for 8 weeks. The doses and administration methods are shown in Table 4. Compound 2 was administered orally at a starting daily dose of 0.25 mg. At weeks 1, 2, 4, and 6 of study drug administration, the daily dose was increased in increments of 0.5 mg, 1 mg, 1.5 mg, and 2 mg (0.25 mg or 0.5 mg once-daily) unless the patient met the criteria for dose increment failure. If the patient met the criteria for dose increment failure and was deemed able to continue the clinical trial, the same dose was continued. Even if the same dose was administered continuously, the dose was increased if the criteria for disallowing dose increase were not met at the time of the next dose increase (2, 4, and 6 weeks).

[0049] 2. Evaluation Items Regarding Efficacy and Safety The evaluation items regarding efficacy and safety were the same as those in Example 1. 3. Results The gradual increase in Compound 2 was as shown in Table 5 below.

[0050] The MDS-UPDRS Part III total score decreased over time as the dose was gradually increased (Figure 4). The change from baseline in the MDS-UPDRS Part III total score (mean ± standard deviation) at the end of the treatment period was -15.1 ± 9.0. The ESS total score (mean ± standard deviation) was 7.7 ± 8.4 at Week 0 and 8.4 ± 9.0 at the end of the treatment period, showing no significant fluctuations (Figure 5). The proportion of subjects with an ESS total score of 11 or higher was 2 of 7 subjects (28.6%) at Week 0 and 2 of 7 subjects (28.6%) at the end of the treatment period (Figure 6). Regarding side effects during the treatment period, hallucinations and nausea were observed in 1 of 7 subjects, but these were all mild, and somnolence was not observed.

[0051] The results of Example 2 show that Compound 2 clearly improves the motor symptoms of PD even at a daily dose ranging from 0.25 mg to 2 mg, and no significant safety concerns were observed when the daily dose was increased to 2 mg.

[0052] Example 3 Clinical Trial 3 in PD Patients 1. Study Method: A randomized, double-blind study will be conducted to evaluate the efficacy, safety, and pharmacokinetics of Compound 2 administered at a daily dose ranging from 0.25 mg to 2 mg over 17 weeks in patients with early PD not receiving concomitant levodopa. Compound 2 will be administered orally starting at a daily dose of 0.25 mg. Unless the dose-escalation criteria are met at the time of dose escalation, the dose will be gradually increased from 0.25 mg to 2 mg as appropriate, at the physician's discretion, to determine the maintenance dose. If the dose-escalation criteria are met and it is determined that the trial can be continued, the same dose will be continued. Even if the same dose is continued, the dose will be increased if the dose-escalation criteria are not met at the next dose escalation. 2. Efficacy and Safety Evaluation Items: Efficacy evaluation items will include the change in the MDS-UPDRS Part II+III total score from baseline (Day 1) to Week 17. Safety evaluation items will include the ESS total score, the occurrence of adverse events, and the occurrence of side effects.

[0053] The purpose of Example 3 is to examine the efficacy and safety at each maintenance dose.

[0054] Example 4 Clinical trial in PD patients 4 1. Study method A randomized, double-blind study will be conducted to verify the efficacy and safety of Compound 2 when administered at a daily dose ranging from 0.25 mg to 2 mg over 17 weeks in PD patients concomitantly receiving levodopa. Patients will be confirmed to meet the following inclusion criteria: Patients diagnosed with Parkinson's disease according to the Parkinson's Disease Society Brain Bank clinical diagnostic criteria of the UK Parkinson's Disease Society Patients who are using levodopa or levodopa combinations and have motor complications such as wearing-off phenomenon or dyskinesia, or who have not fully responded to levodopa Patients with a revised Hoehn & Yahr severity classification (ON state) of 2 to 4 Patients with an MDS-UPDRS Part II (ON state) total score of 2 or more and an MDS-UPDRS Part III (ON state) total score of 12 or more Patients who are using levodopa or levodopa combinations and have had a stable dosage regimen for the 4 weeks prior to the start of the screening period Oral administration of Compound 2 will begin at a daily dose of 0.25 mg. At weeks 1, 2, 3, and 4 of the treatment period, unless the dose-increase prohibition criteria are met, the dose will be increased in increments of 0.5 mg / day, 1 mg / day, 1.5 mg / day, and 2 mg / day (0.25 mg / day or 0.5 mg / day) at the physician's discretion to determine the maintenance dose. If the dose-increase prohibition criteria are met and it is determined that the clinical trial can be continued, the same dose will be continued. Note that even if the same dose is continued, the dose will be increased if the dose-increase prohibition criteria are not met at the time of the next dose increase.

[0055] 2. Efficacy and safety evaluation items Efficacy evaluation items MDS-UPDRS Part II+III (ON state) total score Total scores for MDS-UPDRS Part I, II, III and IV (ON state) OFF time (time when Parkinson's symptoms are relatively mild because the levodopa being taken is working (can move freely, can move relatively easily on their own)) The following ON times (time when Parkinson's symptoms are severe because the levodopa being taken is not working (cannot move or cannot move easily)): ON time without dyskinesia ON time with dyskinesia that does not interfere with daily life ON time without dyskinesia that interferes with daily life ON time with dyskinesia that interferes with daily life PDQ-39 summary index PDSS-2 total score Revised Hoehn & Yahr severity classification, etc. Safety evaluation items Adverse events and side effects ESS total score, etc.

[0056] The pharmaceutical composition of the present invention is extremely useful as a therapeutic agent for neurodegenerative diseases such as Parkinson's disease.

Claims

1. A pharmaceutical composition for the treatment of neurodegenerative diseases, comprising 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea or a pharmaceutically acceptable salt thereof, wherein the compound is orally administered in an amount of 0.25 mg to 2 mg in terms of the free form as a daily dose.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is the succinate salt of 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4,4a,5,6,7,8,8a,9-octahydrothieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea.

3. The pharmaceutical composition according to claim 1, wherein the daily dose is 0.25 mg to 1.5 mg in terms of the free form and is administered once a day.

4. The pharmaceutical composition according to claim 1, wherein the daily dose is 0.25 mg in terms of the free form for the first administration and 0.5 mg to 2 mg for the administrations after the first administration, and is administered once a day.

5. The pharmaceutical composition according to claim 1, wherein the neurodegenerative disease is Parkinson's disease.

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