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WO2025143100A1 - Agent thérapeutique pour trouble neurodégénératif - Google Patents

Agent thérapeutique pour trouble neurodégénératif Download PDF

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Publication number
WO2025143100A1
WO2025143100A1 PCT/JP2024/046107 JP2024046107W WO2025143100A1 WO 2025143100 A1 WO2025143100 A1 WO 2025143100A1 JP 2024046107 W JP2024046107 W JP 2024046107W WO 2025143100 A1 WO2025143100 A1 WO 2025143100A1
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Prior art keywords
dose
compound
pharmaceutical composition
somnolence
disease
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English (en)
Japanese (ja)
Inventor
貴生 降旗
由洋 佐▲桑▼
純一 及川
裕子 梅澤
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Kissei Pharmaceutical Co Ltd
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Kissei Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a drug that reduces the risk of somnolence, a side effect caused by non-ergot dopamine agonists, and has excellent therapeutic effects against neurodegenerative diseases such as Parkinson's disease.
  • the present invention relates to a pharmaceutical composition for treating a neurodegenerative disease, which contains 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 at a dose of 0.25 mg to 2 mg of the compound calculated as the free form.
  • Parkinson's disease is a neurodegenerative disease in which dopamine neurons in the substantia nigra of the midbrain degenerate and fall out, and the decrease in dopamine causes slowly progressing motor disorders such as resting tremor, rigidity, akinesia, and impaired postural reflexes.
  • motor disorders such as resting tremor, rigidity, akinesia, and impaired postural reflexes.
  • non-motor symptoms such as autonomic symptoms, depression, sleep disorders, and dementia occur concomitantly, which precede the motor disorders.
  • DAs Dopamine agonists
  • DAs are classified into ergot-based and non-ergot-based DAs based on differences in chemical structure, and since ergot-based DAs (cabergoline, pergolide, etc.) have been reported to cause valvular heart disease as a serious side effect, non-ergot DAs (pramipexole, ropinirole, etc.) are widely used in clinical practice.
  • 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, etc. (Non-Patent Documents 3 and 4).
  • Non-Patent Document 1 It has been difficult to maintain sufficient therapeutic effect while reducing the risk of side effects with non-ergot DAs.
  • compound 1 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. Also, a 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 a dopamine D2 receptor agonist action and can be used as an agent for preventing or treating PD, restless legs syndrome, or hyperprolactinemia. Patent Documents 1, 2, and 3 also state that an oral preparation can be prepared so that the octahydrothienoquinoline derivative or a pharmacologically acceptable salt thereof is administered in the range of about 0.1 mg to about 300 mg. However, none of these documents state that Compound 1 or a pharmacologically acceptable salt thereof reduces the risk of somnolence and exerts an excellent effect of improving neurodegenerative diseases such as PD.
  • the objective of the present invention is to provide a drug that is a non-ergot DA, reduces the risk of somnolence as a side effect, and has excellent therapeutic effects against neurodegenerative diseases such as PD.
  • the inventors conducted intensive research to solve the above problems, and as a result, they surprisingly found that the use of compound 1 or a pharmacologically acceptable salt thereof not only has a clear improving effect on neurodegenerative diseases such as PD, but also reduces the risk of somnolence as a side effect.
  • 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 an amount of 0.25 mg to 2 mg per day in terms of the free form.
  • 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, characterized in that a daily dose of 0.25 mg to 2 mg of the compound calculated as the free form is orally administered.
  • the present invention relates to the 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, characterized in that a daily dose of 0.25 mg to 2 mg of the compound in terms of free form is orally administered.
  • the pharmaceutical composition of the present invention exhibits excellent therapeutic effects against neurodegenerative diseases such as PD, and also reduces the risk of the side effect of somnolence.
  • the vertical axis shows the change from baseline (CFB: Change from Baseline) 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 from the start of administration, respectively.
  • "EoT (End of Treatment)” means the final evaluation time of the treatment period.
  • black bars show the values (mean ⁇ standard deviation) of the compound 2 administration group
  • white bars show the values of the pramipexole hydrochloride hydrate extended-release tablet (PPX-LA) administration group.
  • the vertical axis shows the Epworth Sleepiness Scale (ESS) total score.
  • the horizontal axis shows the time of evaluation.
  • "wk 0" means the time at which administration began, and "wk 4, 8, 12” mean 4, 8, and 12 weeks after administration began, respectively.
  • "EoT” means the final evaluation during the treatment period.
  • black bars show the values (mean ⁇ standard deviation) of the compound 2-administered group, and white bars show the values of the PPX-LA-administered group.
  • the vertical axis indicates the percentage of subjects with an ESS total score of 11 or more points.
  • the horizontal axis indicates the time of assessment.
  • wk 0 means the time at which administration began
  • wk 4, 8, 12 means 4, 8, and 12 weeks after administration began, respectively.
  • EoT means the final assessment time of the treatment period.
  • black bars indicate the values for the compound 2 administration group
  • white bars indicate the values for the PPX-LA administration group. This shows the effect of improving motor symptoms in PD patients.
  • the vertical axis shows the change from baseline in the MDS-UPDRS Part III total score.
  • the horizontal axis shows the time of evaluation.
  • wk 2, 4, 6, 8 means 2, 4, 6, and 8 weeks, respectively, from the start of administration.
  • EoT means the final evaluation of the treatment period.
  • the black bars show the values (mean ⁇ standard deviation) of the compound 2 administration group.
  • the vertical axis indicates the ESS total score.
  • the horizontal axis indicates the time of evaluation.
  • "wk 0" means the time of 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.
  • the black bars show the values (mean ⁇ standard deviation) of the compound 2 administration group.
  • the vertical axis indicates the percentage of subjects with an ESS total score of 11 or more points.
  • the horizontal axis indicates the time of assessment.
  • "wk 0" means the time of initiation 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.
  • black bars show the values for the compound 2 administration group.
  • 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.”
  • 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.
  • Compound 1 can be converted into its pharmacologically acceptable salt according to a conventional method, if necessary.
  • 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 salts, sodium salts, potassium salts, calcium salts, and magnesium salts; and salts with organic bases such as triethylamine, piperidine,
  • Succinic acid salts are preferred.
  • examples of the succinate salt of compound 1 include the salt of compound 1 and succinic acid in a ratio of 1:1 and 2:3 (hereinafter sometimes referred to as "2/3 succinate salt of compound 1") described in Patent Document 3, and both salts are included.
  • Compound 1 or a pharmacologically acceptable salt thereof also includes solvates with medicamentously acceptable solvents such as water and ethanol.
  • Compound 1 of the present invention and its pharmacologically acceptable salts can be produced by known methods.
  • compound 1 of the present invention can be produced by the method described in WO 2012/124649 (Patent Document 1), and the succinate salt of compound 1 can be produced by the method described in WO 2022/009815 (Patent Document 3) or a method similar thereto.
  • the pharmaceutical composition of the present invention may be used in various dosage forms depending on the method of use.
  • dosage forms include oral administration agents such as powders, granules, fine granules, dry syrups, tablets, and capsules.
  • 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 with pharmaceutical additives using methods known in pharmaceutical formulations according to the dosage form.
  • pharmaceutical additives include excipients such as lactose, lubricants such as magnesium stearate, disintegrants such as carboxymethylcellulose, binders such as hydroxypropylmethylcellulose, surfactants such as macrogol, foaming 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.
  • the pharmaceutical composition of the present invention is useful for treating neurodegenerative diseases.
  • the neurodegenerative disease is not limited to those characterized by insidious onset and 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.
  • 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 developing non-motor symptoms (somnolence, gastrointestinal symptoms, psychiatric symptoms, etc.).
  • movement disorders tremor, rigidity, bradykinesia, axial signs, etc.
  • non-motor symptoms somnolence, gastrointestinal symptoms, psychiatric symptoms, etc.
  • 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 can therefore be used for PD patients who are unable to obtain sufficient efficacy from existing non-ergot DAs because they cannot increase the dosage due to the side effect of somnolence.
  • the effect of improving motor disorders associated with PD can be evaluated using scores known to those skilled in the art as an assessment scale for PD motor symptoms. Examples include the MDS-UPDRS score, the Postural Instability Gait Disorder (PIGD) score, and the Schwab & England ADL scale.
  • scores known to those skilled in the art as an assessment scale for PD motor symptoms. Examples include the MDS-UPDRS score, the Postural Instability Gait Disorder (PIGD) score, and the Schwab & England ADL scale.
  • the MDS-UPDRS score one of the most representative indices, consists of four parts (i.e., Parts I to IV). Part I evaluates cognitive function and mood disorders, Part II evaluates activities of daily living, Part III evaluates motor symptoms, and Part IV evaluates motor complications. The score in Part III in particular is used to evaluate improvement in motor symptoms, and a lower score from baseline indicates a greater improvement.
  • 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 the physician based on the patient's age, weight, degree of disease, occurrence of side effects, etc., and the daily dose can be administered once or in divided doses as appropriate.
  • 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 a day.
  • the maintenance dose of this pharmaceutical composition can be determined by gradually increasing the dose within the range of 0.25 mg to 2 mg as appropriate.
  • compound 1 or a pharmacologically acceptable salt thereof is administered as an initial dose at a dose that has clinically significant efficacy and does not cause side effects (e.g., oral administration, daily dose of 0.25 mg or less in terms of free form), and the dose is increased by 0.25 mg or 0.5 mg once or twice or more at regular follow-up periods (e.g., 1 week, 2 weeks, or a combination thereof) to monitor the occurrence of side effects (e.g., somnolence, gastrointestinal symptoms, psychiatric symptoms, etc.).
  • side effects e.g., oral administration, daily dose of 0.25 mg or less in terms of free form
  • a maintenance dose at a dose that shows no current efficacy e.g., improvement of movement disorders associated with neurodegenerative diseases
  • a maintenance dose at a dose that shows no current efficacy e.g., improvement of movement disorders associated with neurodegenerative diseases
  • a maintenance dose at a dose that shows no current efficacy e.g., improvement of movement disorders associated with neurodegenerative diseases
  • the once-daily dose is started with 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 at week 1, the once-daily dose is 0.5 mg, and thereafter the once-daily dose is increased by 0.5 mg every week, with a maintenance dose of 0.5 mg to 2 mg being administered.
  • the doctor may decide to increase or decrease the gradual increase period, and may also decide to increase or decrease the once-daily dose within the range of 0.25 mg to 2 mg.
  • the once-daily dose is started with 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 then increased by 0.25 mg once-daily every two weeks, with a maintenance dose of 0.5 mg to 2 mg being administered.
  • the doctor may decide to increase or decrease the escalation period, and may increase or decrease the once-daily dose within the range of 0.25 mg to 2 mg.
  • the once-daily dose is started with 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 the initial dose (at week 0), with the once-daily dose being 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 can be administered. The doctor may increase or decrease the gradual increase period, and the once-daily dose may be increased or decreased within the range of 0.25 mg to 2 mg.
  • a pharmacologically acceptable salt thereof e.g., compound 2 described below
  • 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.
  • 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.
  • the "risk of somnolence as a side effect" due to non-ergot DA means the risk of daytime somnolence, which is a safety issue for non-ergot DA.
  • the degree of "reduction in the risk of somnolence as a side effect" due to the pharmaceutical composition of the present invention can also be evaluated, for example, by the ESS total score.
  • the ESS is a scale in which subjects evaluate their daytime sleepiness and tendency to fall asleep by answering eight questions in a self-administered questionnaire.
  • the ESS score (total score of eight items, each item from 0 to 3) ranges from 0 to 24, with a normal range of 10 points or less.
  • 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 reduction in the incidence rate of adverse events and side effects compared to the incidence rate of other non-ergot DAs, or a reduction in the incidence rate or degree of somnolence compared to the frequency of daytime somnolence before administration of the pharmaceutical composition of the present invention.
  • a 2/3 succinate salt of Compound 1 (referred to as Compound 2) was used as the active ingredient of the test drug.
  • the dosage refers to the dosage in free form (free form equivalent value) unless otherwise specified.
  • Example 1 Clinical trial in PD patients 1 The efficacy, safety, and pharmacokinetics of Compound 2, administered at doses of 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 at a daily dose of 0.25 mg once a day, and at the time points of 2, 4, and 6 weeks of administration of the investigational drug, unless the criteria for dose increment were met (when adverse events causally related to the investigational drug were observed, when the investigator or the subinvestigator judged there to be a safety problem, etc.), the daily dose was increased by one step (0.25 mg per day) in the order of 0.5 mg, 0.75 mg, and 1 mg, and administered orally once a day. If the criteria for dose increment were met and it was judged possible to continue the clinical trial, the same dose was continued. Note that even if the same dose was continued, the dose was increased if the criteria for dose increment were not met at the time of the next dose increment (4 and 6 weeks).
  • Pramipexole hydrochloride hydrate extended-release tablets were orally administered once daily at a daily dose of 0.375 mg, and at the time points of 1, 2, 3, 4, 5, and 6 weeks of administration of the study drug, unless the criteria for non-escalation were met, the daily dose was increased in steps (0.375 mg or 0.75 mg per day) in the order of 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, and 4.5 mg, and administered orally once daily. If the criteria for non-escalation were met and it was determined that the clinical trial could be continued, the same dose was continued. Even if the same dose was continued, the dose was increased if the criteria for non-escalation were not met at the time of the next dose increase (2, 3, 4, 5, and 6 weeks). Hereinafter, this is referred to as the PPX-LA administration group.
  • Efficacy evaluation items included the total score of the MDS-UPDRS score and the total score of each part, and the measured values and summary statistics of the change from baseline (week 0) were evaluated. The greater the change in the MDS-UPDRS Prat III total score (the lower the score), the greater the improvement.
  • Safety evaluation items included the ESS total score, occurrence of adverse events, and occurrence of side effects. 3. Results The escalation and maintenance doses of Compound 2 were as shown in Table 2 below.
  • 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 final evaluation of the treatment period was -11.5 ⁇ 7.6 in the compound 2 group and -12.9 ⁇ 6.7 in the PPX-LA group, and both groups showed improvement in symptoms.
  • the ESS total score (mean ⁇ SD) in the compound 2 group was 5.8 ⁇ 4.9 at week 0 and 5.6 ⁇ 5.7 at the final evaluation of the treatment period, showing no change.
  • the score was 6.1 ⁇ 4.2 at week 0 and 9.2 ⁇ 5.7 at the final evaluation of the treatment period, showing a clear increase (Figure 2).
  • the proportion of subjects with an ESS total score of 11 points or more (cutoff criterion for pathological hypersomnia) in the compound 2 group was 21.6% (8/37 cases) at week 0 and 13.5% (5/37 cases) at the final evaluation of the treatment period, and in the PPX-LA group, it was 10.8% (4/37 cases) at week 0 and 38.9% (14/36 cases) at the final evaluation of the treatment period (Figure 3).
  • the incidence of side effects during the administration of the study drug was 13.5% (5/37 cases) in the Compound 2 group and 67.6% (25/37 cases) in the PPX-LA group.
  • the incidence of side effects related to somnolence, psychiatric symptoms, and gastrointestinal symptoms is shown in Table 3. All side effects were low in the Compound 2 group, and the incidence of "somnolence" in particular was 2.7% (1/37 cases) in the Compound 2 group and 29.7% (11/37 cases) in the PPX-LA group.
  • Example 1 show that the compound 2 group had a lower incidence of adverse events and side effects compared to the PPX-LA 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 shows that compound 2 clearly improves motor symptoms of PD at a daily dose range of 0.25 mg to 1 mg, and that it is able to reduce the risk of side effects such as somnolence, despite being a non-ergot DA.
  • Example 2 Clinical trial in PD patients 2 1. Study method Seven PD patients not receiving concomitant levodopa were orally administered Compound 2 at a daily dose ranging from 0.25 mg to 2 mg once a day for 8 weeks. The efficacy, safety, and pharmacokinetics of the compound were examined in a randomized, open-label manner. The doses and administration methods are shown in Table 4. Compound 2 was orally administered once a day at a daily dose of 0.25 mg, and was increased in steps (0.25 mg or 0.5 mg once a day) to 0.5 mg, 1 mg, 1.5 mg, and 2 mg at each time point of 1, 2, 4, and 6 weeks of administration of the study drug, unless the criteria for dose increment were met.
  • the same dose was continued. Even if the same dose was continued, the dose was increased if the criteria for dose increment were not met at the time of the next dose increment (2, 4, and 6 weeks).
  • 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 at the final evaluation of the treatment period (mean ⁇ SD) was -15.1 ⁇ 9.0.
  • the ESS total score (mean ⁇ SD) showed no significant change, being 7.7 ⁇ 8.4 at Week 0 and 8.4 ⁇ 9.0 at the final evaluation of the treatment period (Fig. 5).
  • the proportion of subjects with an ESS total score of 11 points or more was 2 of 7 (28.6%) at Week 0 and 2 of 7 (28.6%) at the final evaluation of the treatment period (Fig. 6).
  • Example 2 show that Compound 2 shows a clear effect of improving motor symptoms of PD even at a daily dose range of 0.25 mg to 2 mg, and no significant safety concerns were observed when the daily dose was increased to 2 mg.
  • Example 3 Clinical trial in PD patients 3 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 a 17-week period in patients with early PD not receiving concomitant levodopa.
  • Compound 2 will be orally administered at a daily dose of 0.25 mg, and the maintenance dose will be determined by the doctor's discretion, gradually increasing the dose from 0.25 mg to 2 mg as appropriate, unless the patient meets the criteria for not being able to increase the dose at the time of the dose increase. If the patient meets the criteria for not being able to increase the dose and it is determined that the clinical trial can be continued, the same dose will be continued.
  • 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, occurrence of adverse events, occurrence of side effects, etc.
  • Example 3 The purpose of Example 3 is to examine the efficacy and safety of each maintenance dose.
  • Example 4 Clinical trial in PD patients4 1. Study Method: The efficacy and safety of Compound 2 administered at a daily dose ranging from 0.25 mg to 2 mg over a 17-week period in PD patients concomitantly receiving levodopa will be evaluated using a randomized, double-blind study. Eligible patients will be confirmed to meet the following inclusion criteria.
  • the same dose will be continued. Note that even if the same dose is continued, the dose will be increased if the patient does not meet the criteria for non-increase at the time of the next dose increase.
  • the following on-times times when Parkinson's symptoms are severe (unable to move or unable to move easily) due to the ineffectiveness of the levodopa medication): 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
  • the pharmaceutical composition of the present invention is extremely useful as a therapeutic agent for neurodegenerative diseases such as Parkinson's disease.

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  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention aborde le problème de la fourniture d'un médicament qui, bien qu'il soit un agoniste de dopamine non ergot (DA), réduit le risque de l'effet secondaire de somnolence, et présente un excellent effet thérapeutique sur des troubles neurodégénératifs tels que la maladie de Parkinson (PD). La présente invention concerne une composition pharmaceutique pour le traitement de maladies neurodégénératives telles que la maladie de Parkinson, la composition pharmaceutique comprenant de la 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-méthyl-4,4a,5,6,7,8,8a,9-octahydrothiéno[3,2-g]quinoléin-6-yl]carbonyl}-3-[2-(diméthylamino)éthyl]-1-propylurée ou un sel pharmacologiquement acceptable de celle-ci. La composition pharmaceutique est caractérisée en ce qu'elle est administrée par voie orale à une dose quotidienne de 0,25 mg à 2 mg en termes de forme libre.
PCT/JP2024/046107 2023-12-28 2024-12-26 Agent thérapeutique pour trouble neurodégénératif Pending WO2025143100A1 (fr)

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JP2023-223448 2023-12-28
JP2023223448 2023-12-28

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WO2025143100A1 true WO2025143100A1 (fr) 2025-07-03

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012124649A1 (fr) * 2011-03-14 2012-09-20 キッセイ薬品工業株式会社 Nouveau dérivé octahydrothiénoquinoline, composition pharmaceutique comprenant le dérivé, et utilisation de ceux-ci
JP7187733B2 (ja) * 2020-07-06 2022-12-12 キッセイ薬品工業株式会社 オクタヒドロチエノキノリン化合物のコハク酸塩及びその結晶

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012124649A1 (fr) * 2011-03-14 2012-09-20 キッセイ薬品工業株式会社 Nouveau dérivé octahydrothiénoquinoline, composition pharmaceutique comprenant le dérivé, et utilisation de ceux-ci
JP7187733B2 (ja) * 2020-07-06 2022-12-12 キッセイ薬品工業株式会社 オクタヒドロチエノキノリン化合物のコハク酸塩及びその結晶

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