WO2006043532A1 - Therapeutic agent for parkinson's disease - Google Patents

Therapeutic agent for parkinson's disease Download PDF

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Publication number
WO2006043532A1
WO2006043532A1 PCT/JP2005/019092 JP2005019092W WO2006043532A1 WO 2006043532 A1 WO2006043532 A1 WO 2006043532A1 JP 2005019092 W JP2005019092 W JP 2005019092W WO 2006043532 A1 WO2006043532 A1 WO 2006043532A1
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WO
WIPO (PCT)
Prior art keywords
parkinson
propyloctanoic acid
disease
acid
syndrome
Prior art date
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PCT/JP2005/019092
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French (fr)
Japanese (ja)
Inventor
Narito Tateishi
Souich Satoh
Taiji Shimoda
Rika Shinagawa
Shinichiro Abe
Masao Morimoto
Ken Mizushima
Akifumi Fujii
Yoshifumi Kagamiishi
Original Assignee
Ono Pharmaceutical Co., Ltd.
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Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Publication of WO2006043532A1 publication Critical patent/WO2006043532A1/en

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a method useful for the prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome, and the suppression of Z or symptom progression, and a medicament used therefor.
  • (2R) 2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof is combined with prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome.
  • the present invention relates to a method for effectively and effectively preventing and treating Parkinson's disease and Z or Parkinson's syndrome, and suppressing Z or symptom progression, and a pharmaceutical used for the same.
  • Parkinson's disease is caused by degeneration of the dopaminergic neuron, and extrapyramidal abnormalities (e.g. tremor, ataxia, muscular rigidity, posture maintenance disorder) that are clinically symptomatic. It is one of the typical neurodegenerative diseases and has been designated as a specific disease by the Ministry of Health and Welfare.
  • the treatment of Parkinson's disease is generally performed by rehabilitation while performing pharmacotherapy, but the pharmacotherapy performed here is dopamine replacement therapy, and a repodopa preparation is essential.
  • administration of levodopa preparations caused involuntary movements (dyskinesia), freezing phenomena (freezing), psychiatric symptoms (excitement, insomnia, hallucinations, delusions, manic depression, etc.), digestive symptoms (nausea, vomiting, etc.)
  • Side effects such as instability, delayed ed on phenomenon, no on phenomenon, etc. may appear. If continued administration for a long time, wearing off phenomenon, on-off ( On-off) phenomenon, up-and-down phenomenon, etc. are observed.
  • dopamine receptor agonists dopamine release promoters, central anticholinergics, in order to reduce the dose of levodopa and reduce side effects
  • Multi-drug combination therapy using a combination of monoamine oxyenzyme inhibitors, aromatic L amino acid decarboxylase inhibitors, norepinephrine replacement drugs, and antispasmodic drugs is being carried out.
  • side effects such as arrhythmia, tremor, and depression may be combined with
  • Parkinson's disease and other neurodegenerative diseases there is no radical treatment for single-agent administration, and it is not possible to suppress the decrease in efficacy, side effects, and progression of the disease caused by long-term administration as described above. In addition, it is difficult to expect a dramatic therapeutic effect even if multi-drug combination therapy is performed.
  • transplantation of cells with the ability to produce dopamine has been attempted, various treatment methods have been tried, but have not yet been established.
  • Parkinson's syndrome (parkinsonism) is a symptom of extrapyramidal abnormalities that are clinically characteristic of Parkinson's disease, although it has a different etiology from Parkinson's disease. It refers to all diseases that present. Basically, as with Parkinson's disease, the treatment centered on dominine replacement therapy is attempted, so it has the same problems as the above-mentioned Parkinson's disease treatment.
  • neurodegenerative diseases Alzheimer's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, olive bridge cerebellar atrophy
  • neurological dysfunction after stroke or cerebrospinal trauma demyelinating disease (multiple Sclerosis, etc.), brain tumor (astrocytoma, etc.), cerebrospinal disease associated with infection (meningitis, Crotsfeld-Jakob disease, AIDS dementia, etc.), Parkinson's disease, Parkinson's syndrome, etc. 2R)
  • 2-Propyloctanoic acid is known to be useful (see, for example, Patent Documents 1 and 2).
  • This SlOO jS is one of the S 100 proteins that are thought to be involved in various neurodegenerative diseases, and is present in high concentrations in glial cells and Schwann cells in the central and peripheral nervous systems. It is also known to be present in anterior pituitary cells and Langerhans cells, and the content of S100
  • (2R) -2 propyloctanoic acid or a salt thereof together with a thrombolytic agent such as tissue plasminogen activator beta, cerebral ischemic disease (cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, white matter abnormality)
  • tissue plasminogen activator beta tissue plasminogen activator beta
  • cerebral ischemic disease Cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, white matter abnormality
  • the administration method and dose of (2R) -2-propyloctanoic acid are in the range of lmg to 1000mg once per adult once to several times a day.
  • Patent Document 1 European Patent Publication No. 0632008
  • Patent Document 2 European Patent Publication No. 1174131
  • Patent Document 3 International Publication No. 03Z007992 Pamphlet
  • Non-patent literature l Tateishi. N and 8 others, Journal of cerebral blood flow & metabolism, 22 (6), 723-734, 2002 Year
  • a dose per administration is about 50 mg to about 120 mg, preferably about lOOmg in the treatment of Parkinson's disease and Parkinson's syndrome.
  • 2R propyloctanoic acid
  • the combined use of 2-propyloctanoic acid improved the wear-off phenomenon observed with repeated administration of bromocriptine mesylate, which is a combination of levodopa and benserazide.
  • Clinically sufficient therapeutic effect We found an effect that can be obtained.
  • the inventors of the present invention have completed the present invention through further studies based on the findings.
  • the present invention provides:
  • Propyloctanoic acid is orally administered, followed by approximately 400 mg of (2R) —2 propyloctanoic acid orally, followed by approximately 12 During the weekly dosing period, about 600 mg of (2R) -2 propyloctanoic acid is orally administered once a day during the dosing period, and once a day during the dosing period of about one week. About 400 mg of (2R) -2 propyloctanoic acid is orally administered, followed by about 200 mg of (2R) -2 per dose during a subsequent dosing period of about 1 week. -The pharmaceutical according to the above-mentioned [7], wherein propyloctanoic acid is orally administered;
  • levodopa preparations dopamine receptor agonists, dopamine release promoters, dopamine uptake inhibitors, dopamine agonists, central anticholinergics, aromatic L amino acid decarboxylase inhibitors, monoamine acids Enzyme inhibitor, catechol o methyltransferase inhibitor
  • a combination of one or more selected from a syn A2A receptor blocker, an apoptosis inhibitor, a neuronal differentiation and regeneration promoter, a neurotrophic factor, a brain function activator, a Rho kinase inhibitor, and a ⁇ receptor blocker [1] The medicine according to [1]
  • (2R) A drug that combines propyloctanoic acid and levodopa'benserazide (4: 1) in combination with the dose of (2R) —2-propyloctanoic acid.
  • (2R) A drug consisting of a combination of 2-propyloctanoic acid and levodopa-carbidopa (10: 1), and the dosage of (2R) -2-propyloctanoic acid.
  • (2R) A drug comprising a combination of 2-propyloctanoic acid and bromocriptine mesylate, wherein (2R) -2-propyloctanoic acid is administered at a dose of about 3 mg to about 60 mg per kg of patient body weight.
  • Lepodopa formulation, levodopa-benserazide compound and levodopa-carbidopa compound force One or more selected, and (2R) -2-propyloctanoic acid, its salt, its solvate or their pro A drug for the prevention, treatment and inhibition of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome for oral administration in combination with a drug, with a dosage of once a day during a dosage period of about 1 week, Approximately 200 mg of (2R) -2-propyloctanoic acid is administered orally, and approximately 400 mg of (2R) -2-propyl is administered once a day during the subsequent dosing period.
  • Octanoic acid was orally administered, followed by approximately 600 mg of (2R) -2-propyloctanoic acid per oral administration at a dosage of once a day during the subsequent 12-week dosing period. Once a day during the dosing period About 400 mg of (2R) -2 propyloctanoic acid is orally administered, followed by about 200 mg of (2R) -2 at a single dose per day during the subsequent dosing period of about 1 week.
  • a drug for reducing the dose of the drug which comprises administering an acid, a salt thereof, a solvate thereof or a prodrug thereof;
  • the aforementioned prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome are levodopa, levodopa 'benserazide, levodopa' carbidopa and Z or promocributin mesylate [16] or [17] the medicine according to [17];
  • composition according to [19] above, wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 50 mg to about 1200 mg;
  • composition according to [20] above, wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 10 Omg to about 600 mg;
  • composition according to [21], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 10 Omg, about 200 mg, about 300 mg, about 400 mg or about 600 mg. ;
  • composition according to the above [22], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per one time is about 60 Omg;
  • composition according to [27] wherein about 50 mg to about 1200 mg of (2R) -2 propyloctanoic acid or a salt thereof is orally administered;
  • (2R) 2-Propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof for the manufacture of a medicament for the prevention, treatment and prevention of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome Use of the drug in combination with prophylaxis, treatment and prevention of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome;
  • Prevention, treatment and inhibition of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome (2R) -2-Propyloctanoic acid, its salt, and its solvate for the prevention, treatment of Parkinson's disease and Z or Parkinson's syndrome Use of objects or their pro-drugs;
  • (2R) 2 Propyloctanoic acid, its salt, its solvate or prodrug thereof as an active ingredient, and prevention or treatment of Parkinson's disease and Z or Parkinson's syndrome characterized by oral administration And Z or a pharmaceutical thread and composition for symptom progression inhibition;
  • composition of [101], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 5 Omg to about 1200 mg;
  • composition of the above-mentioned [102], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 1 OO mg to about 600 mg;
  • composition of [103], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof is about 1 OO mg, about 200 mg, about 300 mg, about 400 mg, or about 600 mg;
  • composition of the above-mentioned [104], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 6 OO mg;
  • composition of [106], wherein the dosing period is from about 3 months to about 1 year;
  • (2R) —2 oral piroctanoic acid is orally administered, followed by oral administration of about 400 mg of (2R) -2 propyloctanoic acid once a day during the subsequent dosing period of about 1 week
  • oral administration about 400 mg of (2R) -2 propyloctanoic acid once a day during the subsequent dosing period of about 1 week
  • [110] wherein about 200 mg of (2R) -2-propylactanoic acid is orally administered at a dose of once a day during the subsequent dosing period of about 1 week.
  • Parkinson's disease and Z or Parkinson's syndrome and Z or symptom progression inhibitors are repodopa, dopamine receptor agonists, dopamine release promoters, dopamine uptake inhibitors, dopamine agonists, central anti-drugs Choline drugs, aromatic L-amino acid decarboxylase inhibitors, monoamine oxyenzyme inhibitors, catechol o methyltransferase inhibitors and norepinephrine supplements Medicine;
  • the prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome are levodopa, levodopa'benserazide, levodopa'carbidopa and Z or promocributin mesylate
  • apoptosis inhibitor for oral administration consisting of one or more selected Or prevention and treatment of Parkinson's syndrome and drugs to suppress epilepsy or symptom progression;
  • (2R) —2 oral piroctanoic acid is orally administered, followed by oral administration of about 400 mg of (2R) -2 propyloctanoic acid once a day during the subsequent dosing period of about 1 week
  • oral administration about 400 mg of (2R) -2 propyloctanoic acid once a day during the subsequent dosing period of about 1 week
  • about 200 mg of (2R) -2-propyloctanoic acid is orally administered once per day during the subsequent dosing period of about 1 week.
  • (2R)-2 Propyl octanoic acid and levodopa formulation, which is also a powerful drug
  • (2R) 2 Propyl octanoate dosage power About 3 mg to about 60 mg per kg patient body weight
  • (2R) -2 A drug consisting of a combination of propyloctanoic acid and levodopa'benserazide (4: 1), and the dosage of (2R) -2-propyloctanoic acid is about 3 mg per kg body weight of the patient.
  • (2R) -2 Medicament consisting of propyloctanoic acid and levodopa'carbidopa (10: 1) combination drug, and (2R) -2-propyloctanoic acid dose power About 3mg / kg of patient body weight
  • Lepodopa formulation, levodopa-benserazide compound and levodopa-carbidopa compound force One or more selected, and (2R) -2-propyloctanoic acid, its salts, its solvates or their pros A drug for the prevention, treatment and prevention of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome for oral administration consisting of a drug, which is administered once a day during a dosing period of about 1 week.
  • Approximately 200 mg (2R) -2-propyloctanoic acid is orally administered per dose, followed by approximately 400 mg (2R) -2 propyloctane per dose, once a day for the following dosing period
  • the drug is administered orally, followed by approximately 600 mg of (2R) -2 propruccinic acid per dose during the subsequent 12-week dosing period, followed by approximately 1 week of dosing 1 dose per day during the period
  • oral administration of about lOOmg to about 1200mg of (2R) -2 propyloctanoic acid per dose is performed once to 3 times a day, followed by about 1 week to During the dosing period of about 3 months, about 1 to 3 doses per day, orally about lOOmg to about 1200mg of (2R) -2 proprucanoic acid is administered orally, followed by about 1 week to about 3 [120]
  • the above-mentioned [120] characterized by orally administering about lOO mg to about 1200 mg of (2R) -2 propyloctanoic acid per dose during a monthly dosing period with 1 to 3 dosing times per day Listed medicines;
  • Concomitant drugs are repodopa, dopamine receptor agonist, dopamine release promoter, dopamine uptake inhibitor, dopaminergic agent, central anticholinergic agent, aromatic L-amino acid decarboxylase inhibitor (DCI), monoamine Acid-enzyme (MAO-B) inhibitor, catechol-O-methyltransferase (COMT) inhibitor, norepinephrine (noradrenaline) supplement, GA BA receptor modulator, GABA receptor modulator, adenosine A2A receptor blockade Medicine, apoto
  • Concomitant drugs are repodopa, dopamine receptor agonist, dopamine release promoter, dopamine uptake inhibitor, dopaminergic agent, central anticholinergic agent, aromatic L-amino acid decarboxylase inhibitor (DCI), monoamine Acid ⁇ enzyme (MAO- ⁇ ) inhibitor, catechol- ⁇ -methyltransferase (COMT) inhibitor, norepinephrine (noradrenaline) supplement, GA ⁇ receptor modulator, GABA receptor modulator, adenosine A2A receptor blockade Medicine, apoto
  • Concomitant medications are levodopa, levodopa / benserazide, levodopa carbidopa
  • agent according to the above [206] which is a mixture and Z or promocributine mesylate
  • (2R) 2 Propyloctanoic acid and levodopa formulation
  • (2R) -2 Dosyloctanoic acid dosage power About 3 mg to about 6 Omg per kg of patient body weight, levodopa
  • the dosage according to the above [211] which is about 3 mg to about 60 mg per kg body weight of the patient;
  • (2R) 2 Propyloctanoic acid and levodopa 'benserazide (4: 1) combination drug
  • (2R) 2-propyloctanoic acid dose power
  • Patient weight 1 kg The agent according to the above [211], which is about 3 mg to about 60 mg per dose and is about 2 mg to about 20 mg per kg of body weight of the patient, the dosage of levodono'benserazide (4: 1) combination;
  • (2R) 2 Propyloctanoic acid and bromocriptine mesylate combined to give (2R) -2-propyloctanoic acid dosage power of about 3 mg to about 60 mg per kg patient body weight ,
  • a method for preventing and Z or treating Parkinson's disease and Z or Parkinson's syndrome in a mammal comprising (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof,
  • a method for reducing the dose of a concomitant drug comprising administering to a mammal in combination with a therapeutic drug for Parkinson's disease and Z or Parkinson's syndrome;
  • a method of preventing and Z or treating Parkinson's disease and Z or Parkinson's syndrome in a mammal comprising (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, Parkinson's disease and Z or Parkinso
  • a method for improving the side effects of a concomitant drug comprising administering to a mammal in combination with a therapeutic agent for N syndrome;
  • (2R) -2 propyloctanoic acid, a salt, a solvate thereof or a prodrug thereof, and a therapeutic agent for Parkinson's disease and Z or Parkinson's syndrome Combined use of Parkinson's disease and Z or Parkinson's syndrome prevention and use of Z or therapeutic agents;
  • (2R) —2 oral piroctanoic acid is orally administered, followed by oral administration of about 400 mg of (2R) -2 propyloctanoic acid once a day during the subsequent dosing period of about 1 week
  • about 200 mg of (2R) -2-propylactanoic acid is orally administered once per day during the subsequent dosing period of about 1 week.
  • Concomitant drugs are repodopa, dopamine receptor agonist, dopamine release promoter, dopamine uptake inhibitor, dopaminergic agent, central anticholinergic agent, aromatic L amino acid decarboxylase inhibitor, monoamine tyrosine enzyme Inhibitor, catechol o methyltransferase inhibitor, norepinephrine replacement agent, GABA receptor modulator, GABA receptor modulator,
  • Nosin A2A receptor blocker apoptosis inhibitor, neuronal differentiation, regeneration promoter, neurotrophic factor, brain function activator, Rho kinase inhibitor, and ⁇ receptor blocker
  • One or more selected from drugs, adenosine A2A receptor blockers, apoptosis inhibitors, neuronal differentiation, regeneration promoters, neurotrophic factors, brain function activators, Rho kinase inhibitors and ⁇ receptor blockers The agent according to [301] above;
  • Parkinson's disease and Z or Is a prophylaxis, treatment and Z or symptom progression inhibitor for Parkinson's syndrome, and (2R) 1-2 propyloctanoic acid dosage power is about 3 mg to about 60 mg per kg body weight of the patient, and levodopa carbidopa (10: 1 ) Dosage power of the combination agent
  • (2R) 2 Propyloctanoic acid as an active ingredient which is administered in combination with bromocriptine mesylate, and prevents or treats Parkinson's disease and Z or Parkinson's syndrome and suppresses Z or symptom progression
  • the dose power of (2R) 2-pupruoctanoic acid is about 3 mg to about 60 mg per kg body weight of the patient, and the dose power of bromocriptine mesylate is about O.Olmg to about lmg per kg body weight of the patient.
  • (2R) 2 Contains propyloctanoic acid, its salt, its solvate or their prodrug as an active ingredient, and is selected from levodopa, levodopa 'benserazide and levodopa' carbidopa ' A prophylaxis or treatment of Parkinson's disease and Z or Parkinson's syndrome characterized by administration in combination with two or more species, and an inhibitor of Z or symptom progression, orally administered (2R) -2-propyloctanoic acid
  • the dose is about 200 mg once a day during the dosing period of about 1 week, about 400 mg once a day during the following dosing period of about 1 week, about 600 mg once a day during the dosing period of about 12 weeks, It relates to a drug that is about 400 mg once a day during the subsequent dosing period of about 1 week and about 200 mg once a day during the next dosing period of about 1 week.
  • (2R) -2 propyloctanoic acid is a compound represented by the formula (A)
  • the salt of (2R) -2 propyloctanoic acid is preferably a non-toxic and water-soluble salt, such as an alkali metal (eg, potassium, sodium, lithium, etc.) salt, an alkaline earth metal (eg, , Calcium, magnesium, etc.), ammonium salts (eg, tetramethyl ammonium salts, tetraptyl ammonium salts, etc.), organic amines (eg, methylamine, dimethylamine, trimethylamine, triethylamine) , Monoethanolamine, diethanolamine, triethanolamine, cyclopentylamine, benzylamine, phenethylamine, dicyclohexylamine, dibenzylamine, N, N'-dibenzylethylenediamine, tris (hydroxymethyl) methylamine, N-- Methyl D glucamine, pyridine, picoline, piperi And salts with basic amino acids (eg, arginine, ly
  • a solvate of (2R) -2 propyloctanoic acid or a salt thereof a non-toxic and water-soluble one is preferable.
  • a non-toxic and water-soluble one is preferable.
  • alcohol solvents for example, methanol, ethanol, etc.
  • the prodrug of (2R) -2-propyloctanoic acid is usually a derivative of (2R) 2-propyloctanoic acid, as used by those skilled in the art, and is enzymatic or chemical in the body.
  • the structure is not particularly limited as long as it is a compound that becomes (2R) -2-propyloctanoic acid by being converted to.
  • Examples of prodrugs of (2R) -2-propyloctanoic acid include compounds in which a carboxy group is esterified (for example, (2R) -2-propyloctanoic acid methyl ester, ethyl ester, phenol ester, carboxy Methyl ester, dimethylaminomethyl ester, pivalooxymethyl ester, ethoxycarbonyloxetyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3-dioxolene-4yl) methyl ester, or cyclohexoxyloxy Carbo-ruethyl ester, etc.), compounds in which the carboxy group is amidated (for example, methylamide, ethylamide, or phenylamide of (2R) -2-propyloctanoic acid), compounds in which the carboxy group is reduced, and Its protector (eg (2R)
  • (2R) -2-propyloctanol or (2R) -2-propyloctanol ester of acetic acid Etc.
  • These compounds can be produced by known methods.
  • (2R) -2-Propyloctanoic acid prodrugs are produced under physiological conditions as described in Yodogawa Shoten 1990, “Drug Development”, Vol. 7, “Molecular Design”, pages 163-198. ) It may be changed to 2-propyloctanoic acid.
  • the prodrug of (2R) -2-propyloctanoic acid may be an isotope which may be the above-mentioned salt or solvate (for example, solvate such as water, alcohol-based solvent (for example, ethanol)). It may be labeled with an element (for example, 3H, “C, 35 S, 125 1, etc.) or the like.
  • (2R) -2-propyloctanoic acid, a salt, a solvate thereof or a prodrug thereof includes (2R) -2-propyloctanoic acid, (2R) -2-propylo Sodium salt of stannic acid, phenethylamine salt of (2R) -2-propyloctanoic acid, (2R) 2-propyloctanoic acid methyl ester and the like are preferable, and (2R) -2-propyloctanoic acid is more preferable.
  • (2R) 2 Propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof is a method known per se, such as EP 0632008, WO 99/5 8513. , WO00 / 48982, pamphlet, patent 3032447, patent 3084345, WO03 / 051852, pamphlet, WO04 / 1 10972, etc.
  • Comprehensive ⁇ Organic ⁇ Transformations A Guide 'To ⁇ ⁇ ⁇ Functional ⁇ Group. Preparations, Second Edition (Richard C. Laroc, John Wyle ⁇ 7's Sands Inc, 1999)
  • Larock, John Wiley & Sons Inc, 1999)] Can be produced according to the methods described above, or by appropriately combining these methods.
  • the product of the reaction can be obtained by conventional purification means such as distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, column chromatography or washing, recrystallization, etc. It can refine
  • (2R) -2-propyloctanoic acid, its salt, its solvate or its are not limited to those that are substantially pure and single substances, but impurities (e.g., by-products, solvents, raw materials or degradation products derived from the manufacturing process) can be removed from the drug substance. If it is within the allowable range, it may be contained.
  • impurities e.g., by-products, solvents, raw materials or degradation products derived from the manufacturing process
  • the content of impurities acceptable as an active pharmaceutical ingredient varies depending on whether (2R) -2-propyloctanoic acid, its salt, its solvate or its prodrug is used.
  • heavy metal is about 20 ppm or less
  • optical isomer S is about 5% by mass (preferably about 1.49% by mass)
  • residual solvent 2-propanol is about 20 ppm or less. It is preferable that the total amount of heptane is about 5000ppm or less and the water content is about 0.2% by mass or less.
  • the optical purity of (2R) -2-propyloctanoic acid used in the present invention is preferably 99% ee or higher, more preferably 99.3% ee or higher.
  • isomers are included unless otherwise specified.
  • isomers R, S, ⁇ ,
  • optically active optically active substances D, L, d, 1
  • chromatographic separation due to the presence of asymmetric carbon etc.
  • Polar bodies high polar bodies, low polar bodies, mixtures of these in arbitrary proportions, racemic mixtures and the like are all included in the present invention.
  • the present invention provides the above-mentioned “(2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof” and “prevention, treatment and inhibition of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome.
  • a method of preventing and treating Parkinson's disease and Z or Parkinson's syndrome, and inhibiting Z or symptom progression (hereinafter sometimes abbreviated as the method of the present invention). is there.
  • “(2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, and prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome Is used for the prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome, and Z or symptom progression suppression medicine.
  • (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, and prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome Parkinson's disease and Z
  • a drug for preventing, treating and inhibiting Z or symptom progression (hereinafter sometimes abbreviated as a drug of the present invention) of (A) (2R) -2-propylotatanic acid, its A salt, a solvate thereof, or a prodrug thereof (hereinafter sometimes abbreviated as “drug A”) and (B) prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome (hereinafter referred to as “drug A”) (It may be abbreviated as drug B.) in combination with (C) Others if desired as long as it is a drug for the prevention, treatment and inhibition of Z or symptom progression of Parkinson's disease and
  • Drugs can also be administered in combination.
  • Drug B or drug C may itself be a combination of multiple drugs.
  • the medicament of the present invention may be one containing drug A and drug B in the same pharmaceutical composition (so-called combination drug), or one containing drug A and drug B in separate pharmaceutical compositions. Also good.
  • drug A and drug B are contained in separate pharmaceutical compositions, they may be administered at the same time or may be administered with a time difference.
  • drug A may be administered first and then drug B may be administered later, or drug B may be administered first and drug A may be administered later.
  • the method of administration and the number of administrations per day may be the same or different.
  • the mass ratio of drug A and drug B is not particularly limited. The same applies when the drug C is further combined, and it may be used as a compounding agent or as a separate pharmaceutical composition.
  • Parkinson's disease and / or Parkinson's syndrome used as drug B can be prevented, treated and Z or symptom progression inhibitor, for example, levodopa ⁇ , levodopa, no benserazide, Levodopa + benserazide, f ⁇ ! Jx.
  • Z or symptom progression inhibitor for example, levodopa ⁇ , levodopa, no benserazide, Levodopa + benserazide, f ⁇ ! Jx.
  • levodono 'benserazide (4: 1) formulation
  • levodono' carbidopa formulation (levodopa + carbidopa, eg levodono 'carbidopa (10: 1) formulation
  • Levodopa 'carbidopa (4: 1) combination entacapon' levodono 'carbidopa combination
  • entacapone + levodopa + carbid opa melevodono, (melevodopa), melevodono ⁇ ' norevidno eye il combination
  • melevodopa + carbido pa Bromocryptine mesylate, alpha-dihydroergocryptine, 7 ⁇ monolevine (apomorphine, bunghin) (budipin e), force benoregoline (cabergoline), droxidopa moth (droxidopa), entacapone (lisuride), pergolide mesylate
  • the prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome are, for example, levodopa (L dopa), levodopa 'benserazide combination (levodopa + benrazrazide, eg, levodono' benserazide (4: 1) formulation), levodono 'carbidopa (eg, levodopa + carbidopa, for example, levodono' carbidopa (10: 1) formulation, levodopa's power rubidopa (4: 1) formulation), entacapon, levodopa, carbidopa Combination drug (entacapone + le vodopa + carbidopa ;, melevodono, (melevodopa), melevodono, 'canorevidono eye ti combination melev odopa + carbidopa), menoleic acid bromo
  • Nan bromocryptine mesylate
  • —Nenhito Orenorego Cliff. Chin Alpha-dihydroergocryptine
  • Apomorphine Abumorphine
  • Budipine Cabergoline
  • Droxidopa Entacapone
  • Lisuride Pergolide mesylate, Pyrgolide mesylate All Jil (piribedil), pramipexole (pramipexole), pram ipexole hydrochloride hydrate, ropiirole hydrochloride, ropinirole hydrochloride, ropiirole (ropinirole), selegiline (selegiline) ), Tenoregrid (terguride), tonocapone (tolcap one), rasagiline mesylate, talipexole, amantadine hydrochloride, trihexyphenidyl hydrochloride, trihexyphenidyl hydrochloride biperiden), acid pyr
  • drugs that may be used as the drug C include, for example, levodopa preparations, dopamine receptor agonists (dopamine receptor stimulants), dopamine release promoters (dopamine secretion promoters or dopamine release promoters). Drugs), dopamine uptake inhibitors, dopamine agonists, central anticholinergic drugs, aromatic L amino acid decarboxylase inhibitors (DCI), monoamine oxidase (MAO-B) inhibitors, catechol O methyltransferase (COMT) Inhibitors, norepinephrine (noradrenaline) supplements, GABA
  • a receptor modulator e.g., a receptor modulator
  • GABA receptor agonist etc.
  • GABA receptor modulator adenosine A2A receptor blocker
  • Apoptosis inhibitor eg., neuronal differentiation / regeneration promoter, neurotrophic factor (eg, neurotrophin, TGF—8 super family, neuro force in family, growth factor, etc.), brain function enhancer (eg, activation of brain metabolism)
  • neurodegenerative diseases e.g., striatal substantia nigra degeneration, Huntington's disease, chorea, stereotaxic movement, progressive supranuclear palsy, diffuse Lewy body disease, basal ganglia
  • neurodegenerative diseases e.g., striatal substantia nigra degeneration, Huntington's disease, chorea, stereotaxic movement, progressive supranuclear palsy, diffuse Lewy body disease, basal ganglia
  • Degenerative disease e.g., Alzheimer's disease, senile dementia (dementia), Pick's disease, frontotemporal lobar dementia (dementia), familial dementia (dementia), spinocerebellar degeneration (
  • amyotrophic lateral sclerosis familial amyotrophic lateral sclerosis etc.
  • therapeutic drugs demyelinating diseases (e.g. multiple sclerosis, generalized sclerosis) Disease, acute disseminated encephalomyelitis, acute cerebellar inflammation, transverse myelitis, Guillain-Barre syndrome, etc.)
  • Drug cerebrovascular disorder (for example, stroke, cerebral infarction (for example, cerebral thrombus, cerebral embolism, etc.), transient ischemic attack, reperfusion disorder, cerebral hemorrhage (for example, hypertensive intracerebral hemorrhage, subarachnoid hemorrhage, etc.)
  • Therapeutic drugs brain tumors (eg astrocytoma, brain abscesses, etc.), hypotensive shock, traumatic shock, head injury and Z or cerebrospinal trauma (eg cerebral contusion / penetration) ⁇ Pressure ⁇ Treatment, neurological dysfunction associated with laceration, labor trauma, infant whiplash
  • Rotinase (MMP) inhibitor cycloxygenase (COX) -2 inhibitor, non-steroidal anti-inflammatory drug, steroid drug, antioxidant, vitamins, disease-modifying anti-rheumatic drug, immunosuppressant, anti Cytodynamic drugs (eg, TNF inhibitors, MAP kinase inhibitors, etc.), sex hormones or derivatives thereof (eg, progesterone, estradiol, estradiol benzoate, etc.), parathyroid hormone (eg, PTH), factor Xa Inhibitors, Factor 1 Vila inhibitors and glycerin preparations are also selected One or more drugs or combinations thereof.
  • MMP Rotinase
  • COX cycloxygenase
  • a dopamine receptor agonist for example, a levodopa (Lododon) preparation, bromocryptine mesylate, Hydroenoreco cliff.
  • Chin (Alpha—dihydroergocryptine, lisunde, pergolide mesylate, talipexole, cabergoline, pramipexole, pubipexole)
  • Ramipe xole hydrochloride hydrate pyrihen nore (pinbedil), lohi bi mouth ⁇ nore ijopinirole no, anogurido (terguride), rotigotine, AF-14, A-68939, A-77636, SKF- 38393, N-0434, PD-118440, NIH-10494, amantadine hydrochloride and the like.
  • examples of the dopamine release promoting agent include amantadine hydrochloride and the like.
  • examples of dopamine uptake inhibitors include GBR-12909, GBR-13 069, GYKI-52895, NS-2141 and the like.
  • central anticholinergic agent for example, trihexyphenidyl hydrochloride; biperiden, piroheptine hydrochloride, mazaticol hydrochloride, mazaticol hydrochloride, Examples thereof include methixene hydrochloride and profenamine.
  • aromatic L amino acid decarboxylase inhibitor examples include carbidopa, benserazide and the like.
  • monoamine oxidase (MAO-B) inhibitors include, for example, selegiline, deprenil, riluzole, safrazine, remacemide, rasabide, Lazabemide, jasagiline me sylate, zonisamide, AGN-1133, LU-53439, MD-280040, mofegiline, and other ergot alkaloid derivatives.
  • examples of the catechol-O-methyltransferase (COMT) inhibitor include entacapone, tolcapone, CGP-28014, and the like.
  • norepinephrine (noradrenaline) supplements include, for example, droxidopa.
  • a GABA receptor modulator for example, a GABA receptor agonist
  • examples of adenosine 2 receptor blockers include istradefylline and the like.
  • examples of the apoptosis inhibitor include CPI-1189, IDN-6556, CEP-1347 and the like.
  • examples of the nerve differentiation / regeneration promoting agent include leteprinim potassium, xaliproden hydrochloride, SB-216763 and the like.
  • neurotrophic factors include, for example, neurotrophin (eg, NG F (Nerve Growth Factor), BDNF (Brain Derived Neurotrophic Fact) or: Brain-derived neurotrophic factor), NT-3, NT-4 / 5, NT-6), TGF-j8 superfamily (eg, TGF- ⁇ 1, TGF- ⁇ 2, TGF- ⁇ 3, BMP) — 2, BMP— 3, BMP —4, BMP— 5, BMP— 6, BMP— 7, BMP— 8A, BMP— 8B, BMP—14 (GDF — 5), GDNF, neurturin, artemin, persephin, GDF— 1, GDF—8, GDF—15, in hibin, inhibin j8, DAF (dauer formation) 7), two euro force in-family (eg ciliary neurotrophic factor (CNTF), interleukin-6 etc.), proliferation Factors (for example, IGF 1, b-FGF and the like), ABS-205 and the like can be mentioned.
  • a brain function activator for example, a brain metabolism activator, a cerebral circulation improver, etc.
  • a brain function activator for example, a brain metabolism activator, a cerebral circulation improver, etc.
  • a brain function activator for example, a brain metabolism activator, a cerebral circulation improver, etc.
  • a brain function activator for example, -sergoline, ibudilast, arracetam (anirac etam)
  • Examples include pyrithioxine hydrochloride, y-aminobutyric acid, bifumelan hydrochloride, lisuride maleate, indeloxazine hydrochloride, and propentofylline.
  • Rho kinase inhibitor examples include fasudil and the like.
  • the 13 receptor blockers include, for example, propranolol, alprenolol, pindolol, timolol, timolol, car teolol , Nadronole (nadolol), nipradilole (nipradilol), chili solo monole (tilisolol), atenolol, acebutolol, metopronore (metprolol), bisopronore (bisoprolol), betaxololole (betaxololole) , Arotinolol, amosulalol and the like.
  • examples of therapeutic agents for Huntington's disease include riluzole, LAX-101, tetrabenazine, olanzapine, and glatiramer acetate.
  • examples of the therapeutic agent for chorea include taltirelin, NS-2330, T-2000, and talampanel.
  • Alzheimer's disease for example, ⁇ -dihydroergo Cliff. Chin (Alpha-dihydroergocryptine), Donepezil hydrochloride, Fraction F, Galantamine, Indeloxazin e, Memantine hydrochloride, Nicenorgoline, Phospha Examples include phosphatidylserine, rivastigmine tartrate, ST-200, tacrine, cerebrolysin, hyperenosin A, and nefiracetam.
  • therapeutic agents for senile dementia include, for example, ST-200, zuclopenthixol acetate, zucl openthixol decanoate, celebrity mouth finn (And erebrolysin), non-fifty IT gum (nefiracetam) and the like.
  • a therapeutic agent for amyotrophic lateral sclerosis for example, riluzole, edaravone, xaliproden hydrochloride, TCH-346, Superoxide dismutase, pentoxifylline, etc. are mentioned.
  • the therapeutic agents for multiple sclerosis include, for example, glatiramer acetate, interferon, baclofen, coroticotropin, mitoxantrone and the like. It is done.
  • examples of the therapeutic agent for stroke include alteplase, argatroban, citicoline, clopidogrel hydrogen sulfate, DMP-647, dipyridamole ( dipyridamole), itidebenone, indobufen, monosialoganglioside GM1 (monosialoganglios ide GM1), nimodipine, propentofylline, triflusal, monteplase, monteplase Examples include aspirin, nicotinic acid, sodium ozagrel and the like.
  • the therapeutic agents for cerebral infarction include, for example, citicoline, edaravone, ibudilast, triflusal, cilostazol, -nicaraven, Examples include sodium ozagrel.
  • the therapeutic agents for cerebral thrombosis include, for example, ozagrel, sodium ozagrel, ticlopidine, ticlopidine hydrochloride, fasudil, Examples thereof include tissue plasminogen activator (t-PA), alteplase, and synthetic antithrombin drugs (for example, gabexate mesylate, nafamostat mesylate, etc.).
  • therapeutic agents for subarachnoid hemorrhage include, for example, monosialoganglioside GM1 (monosialoganglioside GM1), tirilazad mesylate, nicaraven, sodium ozagrel ) And the like.
  • therapeutic agents for meningitis include, for example, ABLC, amphotericin B, cefozopran, cefirome, cefirome, fluconazole, hemo, Examples include Haemophilus vaccine, meropenem, and pneumococcal vaccine.
  • examples of therapeutic agents for Creutzfeldt-Jakob disease include sodium pentosan polysulfate sodium.
  • examples of therapeutic agents for dementia (dementia) caused by AIDS encephalopathy include lexipafant, memantine hydrochloride, CPI-1189, and the like.
  • examples of the therapeutic agent for neurosis include TJ-15.
  • the therapeutic agents for psychosomatic diseases include, for example, bromperidol, flutoprazepam, olanzapine, sultopr ide, sodium noreproate (valproate semisodium) , Ziprasidone, zuclopenthixol, zuclopenthixol aceta te, zuclopenthixol decanoate, quetiapine fumarate, risperidone, risper, risperidone Prochlorperazine maleate, rehizofuzo ⁇ aripiprazole, etc .;
  • an anxiety therapeutic agent for example, flutobazepam (11 utoprazepam),,-senose diazepam, P husenome (lorazepam), brom azepam, praseno Prazepam, clotiazepam, oxaz epam), funoresazenum (fludiazepam), medazepam, medorepam, chlordiazepoxide, anoleprazolam, etizolam, fonorezolam, folutazolam, lamazolam, lamazolam Oxazolam, dipotassium clorazepate, ethyl loflazepate, tandospiron citrate, etc.
  • a therapeutic drug for schizophrenia for example, amisulprid (aripiprazole), clozapine (clozapine), nemonapride (nemonapride), olanzapine (olanzapine) ), Perospirone, quetiapine fumarate (qu etiapine fumarate), risheridone, risperidone, guriheyaso ⁇ nore (talipexole), ziprasidone, zotepine, zukupentizo Examples include zuclopenthixol, zuclopenthixol acetate, zucl openthixol decanoate, sertindole and the like.
  • olanzapine for example, olanzapine, sodium valproate (valproate semisodium), quetiapine fumarate, quetiapine fumarate, risheritone ijisperidone, rehizofuzo ⁇ aripiprazole, and nno.
  • examples thereof include ziprasidon e and lithium.
  • a therapeutic agent for depression a tricyclic antidepressant, a tetracyclic antidepressant, a triazolopyridine antidepressant, a selective serotonin reuptake inhibitor (SSRI), serotone noradrenaline reuptake inhibitor (SNRI), and the like, specifically, for example, escitalopram oxalate oxalate, alprazolam, amisulpride, amoxapine, Bupropion, carbamazepine, citalopram hydrobromide, dihydroergocryptine, fluoxetine, fluvoxamine, lithium, selenium, erium Plan (milnacipran), naprine (minaprine), rutazapine, mirtazapine) (Moclo bemide), acid nefazodone (nefazodone hydrochloride), Bruno Rokiseten (paroxetine), Pirlindole (pir
  • Reno kunserin eplivanserin
  • saledeutant saredut ant
  • YKP10A eplivanserin
  • AR-A2 eplivanserin
  • DOV-216303 triacetyluridine
  • R-673 Org-34517, GW-597599, GW-353162, licarbazepine
  • SLV-308, SPD-421 isovaleramide ⁇ O rg-24448, nevostinel (Nebostinel), SA-4503, LX-105, SNEC-2, NBI-34041, SS R-149415, SSR-146977, DOV-21947, R-1204, PRX-00023, Lu-AA-21004, GSK-679769 GSK-823296, etc.
  • Escitalopram oxalate / 'norephunhum (alprazolam)
  • epilepsy treatment agents include, for example, carbamazepine, chloral hydrate, clonazepam, diazepam, felbamate, Fosphenytoi n, gabapentin, lamotrigine, levetiracetam, lorazepam, oxycarbazepine, phenobarbitone Na), tiagabine, topiramate, sodium noreproate (valproate semisodium), sodium noreproate, valproate sodium, vigabatrin, zonisamide, pregabalin, phenol (phenobarbital), primidone, primidone, fetoin, phenytoin), Ethosuximide, rufinamide, norkoseride, BIA-2-093, safinamide, SPD-421, talampanel, NS-1209, retigabine, carabe / Carabersat, valrocemide ⁇
  • examples of therapeutic agents for dystonia include AN-072, botulinum toxin and the like.
  • a therapeutic agent for diabetes for example, haste, mixed, intermediate and Z or continuous insulin preparations (for example, human insulin preparations genetically synthesized using Escherichia coli and yeast, U , Animal insulin preparations extracted from porcine spleen, etc.;), sulfo-lurea drugs (eg, tolbutamide, chlorpro pamide, glibenclamide, gliclazide, glimepiride ( glimep iride), tolazamide, tocehexamide, glic lopiramide, etc., biguanides (eg, phenformine, buformin hydrochloride, metformin hydrochloride, etc.) ), ⁇ -glucosidase inhibitors (eg, acarbose, voglibo Voglibose, etc.), insulin secretagogues (eg, nateglinide), insulin resistance improvers (eg, troglitazone, pioglit
  • aldose reductase inhibitors e.g., Eparuresutatsuto (mark a lrestat), SNK- 860, CT- 112 , etc.
  • neurotrophic factor e.g., NGF (Nerve Growth Factor), NT-3, BDNF (Brain Derived Neurotrophic Factor), etc.
  • nerve regeneration promoter e.g., PKC inhibitor, AGE inhibitor, activity
  • oxygen scavengers and duloxetine hydrochloride e.g., oxygen scavengers and duloxetine hydrochloride.
  • therapeutic agents for hyperlipidemia include, for example, statin HMG-CoA reductase inhibitors (for example, pravastatin sodium, atorvastatin calcium, simvastatin calcium, simvastatin ( simvastatin), lovastatin (1 ovastatin), rosnostatin (rosuvastatin), cerivastatin, funorenostatin (fluvastatin, etc.), fibrate triglyceride-lowering drugs (eg, clofibrate, bezafibrate, bezafibrate, bezafibrate Nofibrato, symfibrate, clinofibrate, etc., squalene synthase inhibitors, cholestyramin nicotinic acid, probucol, and the like.
  • statin HMG-CoA reductase inhibitors for example, pravastatin sodium, atorvastatin calcium, simvastatin calcium, simvastatin ( si
  • examples of the acetylcholinesterase inhibitor include donepezil hydrochloride, linostigmine tartrate, rivastigmine tartrate, galantamine, zanapezil ( TAK-147).
  • NMDA (N-methyl D-aspartate) receptor antagonists include, for example, (+)-(IS, 2S) —1— (4 hydroxy monophenyl) 2— (4 hydroxy 4 1-phenyl) 1 1) 1 1) propanol, (IS, 2S) — 1 1 (4-hydroxy 1-methoxyphenyl) 2— (4-hydroxy 1-vinyl biperidino) 1-propanol Etc.
  • AMPA (2 amino-3 (methyl-3 hydroxyisoxazol 4-yl) propanoic acid) Z kainate receptor antagonists include, for example, 6-cyan-7 nitroquinoxaline 3 dione (CNQX), 6 nitro 7-sulfamoylbe Nzo [f] quinoxaline 2,3 dione (NBQX), 6,7 dinitroquinoxaline 2,3-dione (DNQX) and the like.
  • ⁇ -amyloid protein production, secretion, accumulation, aggregation and sputum or deposition inhibitor include, for example, i3 secretase inhibitor, ⁇ -secretase inhibitor, 0 amyloid protein aggregation inhibitor, amyloid degrading enzyme, amyloid Examples include vaccines.
  • the diuretics include, for example, thiazide diuretics (for example, chlorothiazide, benzthiazide, hydrochlorthiazide, hydrofurolemethiazide). (Hydroflumethiazide), trichlorme thiazide, cyclothiazide, methyclothiazide, polythiazide, quinethazone, metolazone, etc., loop diuretics (eg , Furosemide, bumetanide, piretanide, etacrynic acid, etc., potassium-sparing diuretics (for example, spironolactone, potassium canrenoate, potassium ⁇ Lomi (a miloride), triamterene, etc.), xanthine derivatives (eg, sari Sodium Le acid and theobromine, calcium salicylate and theobromine etc.), Asetazoramido (acetazo lamide),
  • calcium channel blockers for example, nifedipine, nicardipine, nitrendipine, ninolevadipine, nisoldipine , Manidipine, benidipine, parndipine, efonidipine, amlodipine, diltiazem, verapamil, clonidine hydrochloride ) And the like.
  • angiotensin converting enzyme (ACE) inhibitors include, for example, captopril, alacepril, lisinopril, enalapril, delapril ), Cilazapril, imidapril, perindopril, temocapril, trandolapril, and the like.
  • examples of angiotensin II receptor antagonists include candesartan cilexetil, rosartan, valsartan, and the like.
  • sodium channel blockers examples include ajmaline, procainamide hydrochloride, riluzole and the like.
  • examples of the potassium channel opener include diazoxide, flupirtine, pinacidil, levcromacarim, rilmacalim, cromakalim, PCO-400, SKP-450 and the like.
  • antiplatelet agents include aspirin, icosapentaenoate, ethyl icosapentaenoate, sodium ozagrel, beraprost sodium, alprostadil. ), Ticlopidine hydrochloride, cilostazol, dipyridamole, sarpogrelate hydrochloride and the like.
  • examples of the anticoagulant include ⁇ rufaline (e.g., warfarin potassium), henoline (for example, heparin sodium, heparin sodium). Calcium (heparin calcium etc.), antithrombin drugs (for example, antithrombin III (antithrommbin III), argatroban (argatroban), hirudin (hirudin) etc.) etc. are mentioned.
  • ⁇ rufaline e.g., warfarin potassium
  • henoline for example, heparin sodium, heparin sodium
  • Calcium heparin calcium etc.
  • antithrombin drugs for example, antithrombin III (antithrommbin III), argatroban (argatroban), hirudin (hirudin) etc.
  • thrombolytic agents include, for example, urokinase, nasalplase (nasaruplase, prourokinase, etc.), tissue plasminogen protease (t-PA), tisokinase,reteplase (alteplase). ), Nateplase, monteplase, streptokinase, pamiteplase and the like.
  • examples of the cyclooxygenase (COX) -2 inhibitor include celecoxib, oral fuecoxib, and the like.
  • non-steroidal anti-inflammatory drugs include, for example, aspirin, mefenamic acid, diclofenac, fenbufen , Indometacin, ibuprofen, ketoprofen, naproxen, phenylbutazone, pirox icam, tenoxicam, meloxicam, celecoxib, celecoxib rofecoxib) and the like.
  • prednisolone prednisolone
  • main Chino Les prednisolone methylprednisolone
  • triamcinolone triamcinolone
  • Bruno Rametazo emissions paramethasone
  • Te 3 r Sametazon Te 3 r Sametazon
  • betamethasone betamethasone
  • conorethone cortisone
  • hydroconorethone hydrocortisone
  • hexestrone cortisone acetate and the like.
  • examples of the antioxidant include linolenic acid, icosapentaenoic acid, docosahexaenoic acid, ascorbic acid, tocopherolole acetate. (tocopherol acetate), edaravone and the like.
  • vitamins include ascorbic acid, tocopherol acetate, mecobalamin, and the like.
  • examples of the immunosuppressant include, for example, azathioprine (trade names: Imran, azanine), mizoribine (trade name: predinin), methotrexate (trade names: methotrexate, rheumatorex), mycophenolate mofuethyl (product) Name: Cercebut), Cyclophosphamide (Product name: Endoxan P), Cyclosporin A (Product name: Neoral, Sandimyun), FTY-720, Takuguchi Limus Hydrate (FK506, Product name: Prograf, Protopic), Sirolimus ( Rapamycin), Everolimus (Brand name: Certican), Prednisolone (Brand name: Predonin), Methylprednisolone (Brand name: Medrol), Orthoclone OKT3 (Brand name: Moronab CD3), Anti-human lymphocyte globulin (ALG, Brand name) : Earl Bryn), Deoxyspa
  • azathioprine trade
  • examples of the glycerin preparation include glycerol.
  • the medicament of the present invention provides the above-mentioned “prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome” in order to prevent, treat and suppress Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome.
  • drug B or desired
  • drug C etc. that are further combined with the above, combine (2R) -2-pyruoctanoic acid, its salt, solvate or prodrug thereof (drug A). It is a pharmaceutical with particular characteristics.
  • Combining drug A prevents and treats Parkinson's disease and Z or Parkinson's syndrome compared to traditionally used drugs (ie, drugs containing drug B and drugs combined with drug C) and Z or
  • drugs drugs containing drug B and drugs combined with drug C
  • drug (drug B or drug C) dose side effects are reduced, or resistance to drug (drug B or drug C) is prevented
  • Useful effects can be obtained.
  • drug A that is, (2R) -2-propyloctanoic acid, a salt thereof, a solvent thereof, or a drug combined with a prodrug thereof is collectively referred to as “concomitant drug”.
  • the “concomitant drug” may be, for example, the drug specifically listed as drug B, or the drug listed as drug C.
  • the concomitant drug the above-mentioned drugs specifically listed as drug B are preferably used.
  • drug A can be referred to as a drug for reducing the dose of a concomitant drug (preferably drug B) (or an agent that reduces the dose of the concomitant drug).
  • administration of a combination of drug A can reduce or eliminate the side effects observed in the state where no drug A is combined (that is, when a concomitant drug is administered alone).
  • drug A can be used as a drug for improving side effects of a concomitant drug (preferably drug B) (or an agent that improves the side effect of the concomitant drug).
  • a concomitant drug preferably drug B
  • an agent that improves the side effect of the concomitant drug e.g., drug B
  • drug A can be referred to as a medicament for enhancing the therapeutic effect of a concomitant drug (preferably drug B) (or an agent that enhances the therapeutic effect of the concomitant drug).
  • Combining drug A has these effects (i.e., reduced dosage, improved side effects, or There may be one kind of concomitant drug for obtaining an effect such as an enhanced therapeutic effect) or two or more kinds.
  • a drug of the present invention having such an action is obtained by combining Drug A
  • the combination of Drug A and the concomitant drug is ⁇
  • the effect obtained by the above-mentioned "medicine for reducing the dose of a concomitant drug” is preferably the dose of the concomitant drug when the concomitant drug is administered alone (when no drug A is combined) 1/2 (sometimes expressed as 1Z2) to 1/10 (sometimes expressed as 1Z10), more preferably 1/5 (sometimes expressed as 1Z5); ) To 1/10 or less, most preferably 1/10 or less. Since the dose of the concomitant drug is reduced by the “drug for reducing the dose of the concomitant drug”, favorable effects such as avoiding side effects derived from the concomitant drug can be expected.
  • the concomitant drug when the concomitant drug is administered alone, the dose of the concomitant drug cannot be increased due to its side effects, and the present invention has obtained such an effect even in cases where the desired therapeutic effect cannot be obtained.
  • This medicine can be administered safely and can supplement its therapeutic effect.
  • typical side effects that can be improved by the "medicament for improving side effects of concomitant drugs” include the following.
  • administration of a repodopa preparation may result in involuntary movements (dyskinesia), freezing phenomena (freezing), psychiatric symptoms (eg, excitement, insomnia, hallucinations, delusions, manic depression) , Gastrointestinal symptoms (eg nausea, vomiting, etc.), side effects such as drug instability, wear-off phenomenon, on-off phenomenon, delayed-on phenomenon, no-on phenomenon, up-and-down phenomenon
  • the above-mentioned “(2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof” is administered,
  • the wearing-off phenomenon means, for example, in the treatment of Parkinson's disease, a drug (for example, levodopa preparation, levodopa'benserazide combination agent, etc.) is administered for a long time. If you continue, the duration of the efficacy will be shortened or compared to the first time This refers to a phenomenon in which seizures occur if the drug efficacy is reduced and the drug administration interval is not shortened gradually. When the wear-off phenomenon occurs, the number of drug administrations increases as a result.
  • the “medicament for improving side effects of concomitant drugs” can also improve the warning-off phenomenon.
  • “improvement” means the expected wear-off phenomenon that occurs only after the wear-off phenomenon has been observed once the duration of the medicinal effect has returned, or when the initial effect has been restored. The case where it is never recognized is also included.
  • an on-off phenomenon (sometimes referred to as an on-off phenomenon).
  • Is for example, a phenomenon in which symptoms are suddenly and irregularly improved (on) or worsened (off) after a certain period of treatment with Parkinson's disease. May repeat. It is common in younger onset patients, long-term users of levodopa, or patients with high doses of levodopa, often with dyskinesia when on.
  • the “medicament for improving side effects of concomitant drugs” can also improve the on-off phenomenon.
  • “Improvement” here means that the on / off phenomenon that has been expected is only recognized, but the expected on / off phenomenon is not recognized even if the number of occurrences of the phenomenon subsequently decreases or disappears. , Including cases.
  • the delayed on phenomenon refers to, for example, a phenomenon in which time is required for administration of a repodopa preparation to exert its effect in the treatment of Parkinson's disease.
  • the “medicament for improving side effects of concomitant drugs” can also improve the delayed on phenomenon.
  • “Improvement” here means that a delayed on-on phenomenon is recognized once, but then the number of occurrences of the phenomenon is reduced or no longer occurs. The expected delayed on phenomenon is never recognized. Including cases.
  • the no on phenomenon refers to a phenomenon in which no therapeutic effect is observed even when a repodopa preparation is administered in the treatment of Parkinson's disease, for example.
  • the “medicine for improving side effects of concomitant drugs” can also improve the noon phenomenon.
  • “Improvement” here means an expected nodal phenomenon that occurs once a no-on phenomenon is recognized, but only after that the number of occurrences of the phenomenon decreases or disappears. This includes cases where the one-on phenomenon has never been observed.
  • the "up and down” phenomenon refers to a state in which circadian variability is observed in improvement and exacerbation of symptoms in, for example, Parkinson's disease.
  • the “medicament for improving side effects of concomitant drugs” can also improve the up-and-down phenomenon.
  • “improve” means that once an up-and-down phenomenon has been observed, the expected up-and-down phenomenon can be recognized only by the fact that the number of occurrences of the phenomenon decreases or does not occur. This includes cases where it is not possible.
  • the "concomitant drug” is preferably, for example, the above-mentioned drugs specifically listed as Drug B, or the following drugs listed as Drug C, that is, levodopa formulations, dopamine Receptor agonist (dopamine receptor stimulant), dopamine release enhancer (dopamine secretion enhancer or dopamine release enhancer), dopamine uptake inhibitor, dopamine agonist, central anticholinergic, aromatic L-amino acid decarboxylation Enzyme inhibitors (DCI), monoamine acid enzymes (MAO — B) inhibitors, catechol—O-methyltransferase (COMT) inhibitors, norepinephrine (noradrenaline) supplements, GABA receptor modulators (eg, GABA receptor) Body
  • GABA receptor modulators e.g., GABA receptor modulators, adenosine A2A receptor blockers, apoptosis inhibitors
  • Pesticides neuronal differentiation'regenerative promoters, neurotrophic factors (eg, neurotrophins, TGF-superfamily, neuropower infamily, growth factors), brain function activators (eg, brain metabolism activators, cerebral circulation) Remedy), Rho-kinase inhibitor, acetylcholinesterase inhibitor, etc., Parkinson's disease and Z or Parkinson's syndrome prevention, treatment and Z or symptom progression inhibitor, neurodegenerative disease therapeutic, motor neuropathy, Treatment for demyelinating disease, treatment for cerebrovascular disorder, treatment for brain tumor, treatment for neurological dysfunction associated with cerebrospinal trauma, treatment for cerebrospinal disease associated with infection, treatment for mental illness, treatment for epilepsy, dystonia Therapeutic, Diabetes, Diabetes complication, Hyperlipidemia, NMDA receptor antagonist, AMPAZ kainate receptor antagonist, Diuretic, Calcium channel blocker (Calcium antagonist), angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor antagonist, sodium channel blocker, potassium channel opener, beta receptor blocker,
  • the "concomitant drug” is more preferably, for example, the above-mentioned drugs specifically listed as drug B, or, for example, levodopa preparations, dopamine receptor agonists (dopamine) listed as drug C.
  • Receptor stimulants dopamine release enhancers (dopamine secretion enhancers or dopamine release enhancers), dopamine uptake inhibitors, dopamine agonists, central anticholinergics, aromatic L amino acid decarboxylase inhibitors (DCI) ), Monoamine oxidase (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, norepinephrine (noradrenaline) supplements, etc., prevention, treatment and Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome Inhibitory pharmacological power
  • dopamine release enhancers dopamine secretion enhancers or dopamine release enhancers
  • dopamine uptake inhibitors dopamine agonists
  • central anticholinergics aromatic L amino acid decarboxylase inhibitors (DCI)
  • DCI aromatic L amino acid decarboxylase inhibitors
  • MAO-B Monoamine oxidase
  • COMP catechol-O-
  • the “concomitant drug” is particularly preferably, for example, a repodopa preparation and a Z or aromatic L amino acid decarboxylase inhibitor (DCI) or a combination thereof (that is, a levodopa 'DCI combination agent), etc. Is mentioned.
  • the levodopa / DCI combination agent includes, for example, levodopa / benserazide combination agent (levodopa + benserazide, for example, levodono'benserazide (4: 1) combination agent), (Levodopa + carbidopa, for example, levodono'carbidopa (10: 1) formulation, levodopa'carbidopa (4: 1) formulation) and the like.
  • levodopa / benserazide combination agent levodopa + benserazide, for example, levodono'benserazide (4: 1) combination agent
  • Levodopa + carbidopa for example, levodono'carbidopa (10: 1) formulation, levodopa'carbidopa (4: 1) formulation
  • “concomitant drugs” are merely examples, and are not limited thereto.
  • “concomitant drugs” include not only those found so far, but also those that will be found in the future based on the above-mentioned mechanism.
  • these drugs may be administered in combination of any two or more.
  • the medicament of the present invention can be used to prevent or treat Parkinson's disease and Z or Parkinson's syndrome, as well as mammals (humans and non-human animals (for example, monkeys, hidges, bushes, horses, Inu, cat, rabbit, rat, mouse, etc.)).
  • the administration method may be any method as long as an effective amount of the drug can be administered in vivo, but systemic administration such as oral administration and intravenous administration is preferred, and oral administration is particularly preferred. .
  • “prevention” prevents the establishment of the disease itself.
  • ⁇ Treatment '' refers to guiding the disease state in the direction of healing
  • ⁇ Symptom progression suppression '' means symptomatic progression ⁇ Suppressing bad habits and stopping the progression of the disease state
  • Parkinson's syndrome Is not only Parkinson's disease, but also has a different etiology from Parkinson's disease, but is clinically characteristic of extrapyramidal abnormalities characteristic of Parkinson's disease (e.g. tremor, ataxia, muscle rigidity, It includes all diseases presenting with posture maintenance disorder.
  • Parkinson's syndrome is usually associated with idiopathic Parkinson's disease, neurodegenerative diseases (e.g., striatal nigra degeneration, Huntington's disease, chorea, stereotaxic movement, progressive supranuclear palsy, diffuse Lewy body disease, cerebral cortex.
  • idiopathic Parkinson's disease e.g., striatal nigra degeneration, Huntington's disease, chorea, stereotaxic movement, progressive supranuclear palsy, diffuse Lewy body disease, cerebral cortex.
  • Basilar degeneration Alzheimer's disease, senile dementia (dementia), Pick's disease, frontotemporal lobar dementia (dementia), familial dementia (dementia), spinocerebellar degeneration, Guam Island Parkinson dementia Parkinsonism associated with complex
  • Secondary Parkinsonism is further classified according to its cause.
  • the “(2R) -2-propyloctanoic acid, a salt, a solvate thereof or a prodrug thereof” and the “prevention of Parkinson's disease and Z or Parkinson's syndrome, “Treatment and Z or symptom progression inhibitors” (or other drugs if desired) are administered in vivo sequentially in any order or simultaneously.
  • a pharmaceutical composition comprising these drugs separately is used.
  • a force using a pharmaceutical composition containing these drugs separately, or one containing these drugs in the same pharmaceutical composition is used.
  • composition for oral administration containing (2R) 2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof, that is, “(2R) -2” used in the present invention.
  • (2R) 2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof that is, “(2R) -2” used in the present invention.
  • the pharmaceutical composition of the present invention is administered as a dosage form suitable for oral administration, for example, as a solid preparation for internal use or a liquid preparation for internal use.
  • Solid preparations for internal use for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules.
  • the drug is used as it is or is a vehicle or an excipient (eg, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), a binder (eg, hydroxypropylcellulose, polybule).
  • a coating agent for example, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • capsules of absorbable substances such as gelatin.
  • Soft capsules for oral administration can be produced according to known methods for producing soft capsules. Specifically, the drug and the film solution are subjected to a known capsule filling method such as a punching method (for example, a rotary die method) or a dropping method (for example, a seamless capsule method). Produced capsules can be produced by drying.
  • the capsenore agent of the present invention may be a seamless soft capsenole agent or a soft capsule with a cross.
  • the method for producing seamless capsules is described in detail in known literature, for example, Bioscience and Industry, 58, No. 7, pp. 31-34 (2000). Since this basic seamless capsule manufacturing method is already used industrially, mass production is easy.
  • the capsule of the present invention is composed of a content liquid and a capsule skin film in the same manner as a general soft capsule.
  • Capsule membranes are called capsule base materials (proteins (gelatin, collagen, etc.)), polysaccharides (starch, amylose, polygalataturonic acid, agar, carrageenan, gum arabic, dielan gum, xanthan gum, pectin Tin, alginic acid, etc.), biodegradable plastics (polylactic acid, polyhydroxybutyric acid, polydalamic acid, etc.), hardened fats and oils (such as butter, margarine, shortening, cocoa butter, etc.) Plasticizers (sugars such as glycerin, sorbitol, and polyethylene glycol, sugar alcohols, polyhydric alcohols, etc.) are essential ingredients, and perfumes (hatsu force oil, cinnamon oil, strawberry and other fruit essences and flavors, etc.) ), Preservatives (such as ethyl,
  • Pigment (yellow 4, yellow 5, red 3, blue 1, copper black fin, etc.), opacifier (titanium dioxide, bengara, etc.), solubility regulator (cellulose acetate phthalate, hydroxypropyl methylcellulose) Alkali metal salt, hydroxymethylcellulose acetate succinate alkali metal salt, alginic acid alkali salt, polyacrylic acid alkali metal salt, methylcellulose, carboxymethylcellulose, casein, collagen, agar powder, polyvinyl alcohol, pectin, etc.) .
  • the capsule film is preferably based on gelatin. Particularly preferred are those based on gelatin and containing glycerin as a plasticizer. Also, it may contain sorbitol as a plasticizer.
  • the capsule film can be produced using a film solution.
  • the film solution contains the above-mentioned film components and can be formed into a thin film in a molten state or a solution state, and further solidified by cooling and Z or drying after the film is formed. It can be used without particular limitation.
  • the additive is not particularly limited as long as it is an additive generally used in a preparation for oral administration.
  • an additive used in a soft capsule preparation or an oral solution is preferable.
  • Preservatives, surfactants, solubilizers, emulsifiers, solvents, pH adjusters, buffering agents, suspending agents, thickeners, stabilizers, solubilizing agents, etc. are used. These additives can be added in combination of two or more components as desired.
  • the preservatives and preservatives include benzoic acid, sodium benzoate, sodium sorbate, parabens (such as ethyl oxybenzoate, butyl pyloxybenzoate, and propyl paraoxybenzoate).
  • Surfactants, solubilizers, emulsifiers, and solvents include, for example, hydroxypropylmethylcellulose, polybutylpyrrolidone, sucrose fatty acid ester, Examples include oxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, glycerin, ethanol, propylene glycol, water (for example, distilled water for injection) and the like.
  • Examples of the pH regulator and buffer include bases such as inorganic acids or alkalis, such as hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, and organic acids such as citrate, malic acid, Examples thereof include tartaric acid, succinic acid, and salts thereof.
  • the pH adjustment may be performed according to a method for adjusting pH or a method analogous thereto, which is generally used in the technical field of oral solutions.
  • the suspending agent and thickening agent include gum arabic, crystalline cellulose, bee gum, xanthan gum, gelatin, metrose and its edible salt, carmellose and its edible salt, and the like.
  • the stabilizer include an edible salt of edetic acid, sodium chloride salt, and an edible salt of pyrosulfite.
  • the solubilizer include cyclodextrin and arginine.
  • Liquid preparations for internal use for oral administration include solutions, suspensions, emulsions, syrups, elixirs and the like.
  • the drug is prepared by dissolving, suspending or emulsifying in a commonly used diluent (for example, purified water, ethanol or a mixture thereof).
  • this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
  • the dosage form for administering the pharmaceutical composition of the present invention is not particularly limited as long as it is an orally administrable dosage form. It is preferable to use the capsule described above.
  • (2R) -2-Propyloctanoic acid, a salt thereof, a solvate thereof or a (2R) -2-propyloctanoic acid when orally administered to prevent or treat Parkinson's disease and Z or Parkinson's syndrome The dosage of these prodrugs varies depending on the patient's age, weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is not particularly limited as long as about 50 mg or more is orally administered. Specific medication for obtaining favorable preventive, therapeutic and Z or symptom progression inhibiting effects on the above diseases Examples of the period, number of doses, dose, and administration method include those exemplified below.
  • the administration period of the pharmaceutical composition of the present invention may be continuously administered for any number of days in order to obtain a preferable prevention, treatment and Z or symptom progression suppression effect for the above-mentioned diseases. If desired, it may be administered intermittently with an appropriate drug holiday.
  • the specific dosing period is, for example, about 1 month to about 15 years.
  • Preferred dosage periods are, for example, from about 3 months to about 5 years, more preferred dosage periods are, for example, from about 3 months to about 1 year, and particularly preferred dosage periods are, for example, from about 3 months to About 6 months.
  • the pharmaceutical composition of the present invention may be administered any number of times in order to obtain a preferable prevention, treatment and Z or symptom progression inhibitory effect on the above-mentioned diseases. It may also be changed depending on the patient's condition and other reasons.
  • the specific number of doses is, for example, 1 to 5 times a day.
  • the preferred dosing frequency is, for example, 1 to 3 times a day, and the more preferred dosing frequency is, for example, 1 to 2 times a day, and the particularly preferred dosing frequency is once a day.
  • the dose of the Japanese product or prodrug thereof is not particularly limited as long as it is about 50 mg or more per dose, but it has preferable prevention, treatment and Z or symptom progression inhibitory effects on the above-mentioned diseases.
  • More preferable doses include, for example, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 600 mg, and the most preferable dose includes, for example, about 600 mg.
  • a dosage smaller than the above dosage may be sufficient. It may be necessary beyond the scope.
  • the dosage shown above is preferred as the amount of (2R) -2-propyloctanoic acid.
  • a preferred method for oral administration of the pharmaceutical composition of the present invention for the prevention, treatment and suppression of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome is, for example, a dosage period of about 1 month to about 5 years.
  • the target dose maintenance dose
  • Dosing method to gradually increase the dose (this period is expressed as the dose escalation period), or the maintenance dose force to stop the administration and to gradually reduce the dose for any given period
  • an administration method (this period is expressed as a dose gradual period) and a combination of these administration methods.
  • a more preferred method is, for example, from about lOOmg to about 1200mg (2R) -2 per dose with a dose of 1 to 3 doses per day during a dosing period of about 3 months to about 5 years.
  • the most preferred method is, for example, from about 200 mg to about 600 mg of (2R) -2-propyloctane per dose during a dosing period of about 3 months to about 1 year, once or twice daily About 200 mg of (2R) -2-propylactanoic acid is administered orally for a period of about 1 week. During the dosing period, about 400 mg of (2R) -2-propyloctanoic acid is orally administered once a day, and once a day during the following 12-week dosing period.
  • Approximately 600 mg of (2R) -2-propyloctanoic acid per dose Is administered orally, followed by oral administration of about 400 mg (2R) -2-propyloctanoic acid per dose, once a day during the dosing period of about 1 week, followed by about 1 week of dosing
  • a method of orally administering about 200 mg of (2R) -2-propyloctanoic acid at a single dose per day during the period is included.
  • (2R) 2 Propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof and a concomitant drug (for example, the drug specifically listed as Drug B, or the drug listed as Drug C ),
  • a concomitant drug for example, the drug specifically listed as Drug B, or the drug listed as Drug C
  • the dose of concomitant drugs varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., and is particularly limited as long as the effective dose of each drug is administered orally. However, some examples of specific dosing period, dosing number, dose, and administration method for obtaining favorable, preventive, therapeutic and Z or symptom progression inhibiting effects on the above diseases are exemplified below.
  • the concomitant drug can be formulated and administered in accordance with a known formulation or the formulation of the pharmaceutical composition of the present invention, and can be added to the pharmaceutical composition of the present invention as a combination drug. You can also.
  • the administration method and dosage are, for example, that about 1OOmg to about 1OOOmg of levodopa per day is orally administered once to 3 times a day, and then 1 From about 200 mg to about 400 mg per day every day to 3 days, gradually increase from about 200 mg to about 400 mg per day, and after about 2 weeks to about 4 weeks, a maintenance dose of about lOOOmg to about 4000 mg per day is orally administered.
  • the administration method and dose are, for example, about 1 OOmg to about 1OOOmg of levodopa per day as the initial dose.
  • the administration method and dose are, for example, about 1 OO mg / day of levodopa equivalent per day as the initial dose. Orally administered 3 to 3 times, then gradually increase from about 100 mg to about 400 mg per day every 1 to 3 days, and after about 2 weeks to about 4 weeks, the maintenance dose is about 500 mg to about 2000 mg per day. Examples include oral administration. [0081] [Toxicity]
  • the toxicity of (2R) -2-propyloctanoic acid, its salt, its solvate or their prodrug is sufficiently low, and it is particularly useful as a pharmaceutical for mammals, particularly humans, with the administration method and dose of the present invention. As long as it is used, it can be judged to be sufficiently safe.
  • the present invention relates to (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof, and prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome And a method for effectively preventing and treating Parkinson's disease and Z or Parkinson's syndrome, and inhibiting Z or symptom progression, and a medicament used therefor.
  • the method using the pharmaceutical disclosed in the present invention is extremely effective in preventing and treating Parkinson's disease and Z or Parkinson's syndrome and suppressing the progression of Z or symptoms, and significantly improves various symptoms associated with these diseases. be able to.
  • (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a combination thereof in addition to the prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome
  • the prevention, treatment and Z or symptom progression-suppressing effects can be complemented and enhanced, or drug doses and side effects can be reduced compared to when these drugs are used alone.
  • the development of drug resistance can be prevented.
  • it avoids side effects such as the wear-off phenomenon often observed in the treatment of Parkinson's disease and Z or Parkinson's syndrome, complements and enhances the therapeutic effect, reduces drug dosage, or prevents the development of drug resistance. This is a very useful method.
  • Example 1 1 (2R) -2-Propyloctanoic acid and lepodopa 'benserazide combination drug administration experiment
  • MPTP (0.5-1.0mgZkg) is administered intravenously to zodiac monkeys, and symptoms are observed visually 6 days later. If the Parkinson's disease-like symptom score is 3 or higher, then MPTP (0.5 mg / kg) is administered intravenously once a week. When Parkinson's disease-like symptom score is 2 or less When Parkinson's disease-like symptom score is 3 or more, MPTP (0.5-1.0mgZkg) is administered intravenously once a week, and Parkinson's disease-like symptom score is 3 or more The subsequent MPTP administration is 0.5 mgZkg once a week. Discontinue administration of MPTP when the Parkinson's disease-like symptom score is 9 or higher.
  • MPTP (l.OmgZkg) is administered intravenously once a week until the score reaches 8 or more for animals with a score of 6 or less after 6 months. If the score is 7 or 8, administer MPTP (0.5 mgZkg) intravenously once or twice a week until the score reaches 9 or more.
  • Parkinson's disease-like symptoms are scored according to Akai T et al.'S evaluation scale shown in Table 1 (Akai T, Ozawa M, Yamaguchi M, Mizuta E and Kuno S, J Pharmacol Exp Ther, 273, 309-314 (1995)) To do. Observe 3 times a week. The daily observation schedule for Example 1 1 was 5, 30, 60, 90, 120, 180 minutes after oral administration of the test substance, and for Example 1 2 before oral administration of the test substance and oral administration of the test substance. After 60, 120, 180, 240, 300, 360, 420, 480 minutes. Every week [Averages of each evaluation point are averaged and the aggregated numerical value is used as data.
  • Eye movement Normal, 0 drop, 1; Closed eyes, 2 positions normal, 0 Torso abnormalities, + 1;
  • Example 1-1 the change in Parkinson's disease-like symptom score for each observation schedule obtained according to the evaluation method shown in Table 1 during the period from week 0 to week 12 after administration of the test substance (here In Table 2, the change value indicates the decrease from the initial value (9), and the larger the value, the better the symptoms.)
  • single administration indicates the change in score when only levodopa benserazide (4: 1) combination drug (12.5 mg / kg) is administered alone
  • “combination administration” indicates (2R) — 2 -Shows the change in score when propyloctanoic acid (lOmgZkg) and lepodopa'benserazide (4: 1) combination (12.5mg / kg) are administered in combination
  • Example 1-2 the change in Parkinson's disease-like symptom score in each observation schedule obtained according to the evaluation method shown in Table 1 during the period from week 0 to week 12 after administration of the test substance (here In Table 3, the change value refers to the decrease from the initial value (9). The larger the value, the better the symptoms.)
  • single administration indicates the change in the score when only promocributin mesylate (3 mgZkg) is administered alone
  • “combination administration” indicates that (2R) -2-propyloctanoic acid (lOmgZkg) and mesyl
  • the change value of the score when co-administered with acid bromocriptine (3mgZkg) is shown.
  • Parkinson's disease including juvenile Parkinsonism
  • levodopa's DCI combination drug the drug to be used is not particularly limited
  • Lepodopa 150-165 patients with Parkinson's disease (including juvenile parkinsonism) using DCI combination.
  • the entire schedule of the study period is divided into (1) observation period, (2) dose escalation period, (3) maintenance dose administration period, (4) dose gradual decrease period, and (5) post-observation period. O administered according to
  • the placebo group was designated as the “placebo group” or the “P group” in which all the placebo administration period, the maintenance dose administration period, and the dose reduction period were administered.
  • (2R) 2-Propyloctanoic acid lOOmgZl times Z daily administration in all periods of the maintenance dose period and the gradual decrease period
  • the “L group” and the group administered (2R) -2-propyloctanoic acid 600 mg Zl times Zl daily during the maintenance dose administration period were referred to as the “(2R) -2-propyloctanoic acid 600 mg administered group” or “H It shall be written as “group”.
  • Week 1 Placebo soft capsules ((2R) -2-propyloctanoic acid 100111 8 soft capsules and soft capsules that are visually indistinguishable) per capsule;
  • Week 2 4 capsenoles with placebo soft caps.
  • Week 1 (2R) -2-Propyloctanoic acid lOOmg soft capsules and 1 placebo soft capsenore per caps;
  • Week 2 1 capsule (2R) -2-propyloctanoic acid lOOmg soft capsule and 3 placebo soft capsenore.
  • Week 1 2 capsules of (2R) -2-propyloctanoic acid lOOmg per capsule; Week 2: 4 capsules of (2R) -2 propyloctanoic acid lOOmg per capsule
  • Administration Orally administered once a day after breakfast according to the following administration method.
  • Administration Orally administered once a day after breakfast according to the following administration method.
  • Week 2 (2R) -2-propyloctanoic acid lOOmg soft capsules and 1 placebo soft capsenore per capsule.
  • Week 1 4 capsules of (2R) -2 propyloctanoic acid lOOmg per capsule; Week 2: 2 capsules of (2R) -2-propyloctanoic acid lOOmg per capsule
  • Placebo group about 50 to 55 people
  • the dose of levodopa 'DCI combination drug that maintains a constant force for 4 weeks before the start of the observation period' should not be changed throughout the observation period to the dose gradual period.
  • administration of a new repodopa DCI combination is prohibited.
  • Lepodopa single agent (2) Monoamine oxidase (MAO-B) inhibitors (eg, selegiline hydrochloride); (3) Other (a) to (5) which are considered to affect the symptoms of Parkinson's disease (D) drugs; (a) antihypertensive drugs (eg, centrally acting drugs such as methyldopa, reserpine, etc.); (b) neuropsychiatric drugs (eg, phenothiazine drugs, petitlophenone drugs, benzamide drugs) , Calpipramine hydrochloride, carpipramine maleate, clocapramine hydrochloride, berospirone hydrochloride hydrate, mosapramine hydrochloride, oxipertin, olanzapine, zotepine, pimozide, taethiapine fumarate, risperidone, etc .; (c) anti-epileptic drugs (eg, zonisamide, Sodium
  • drugs other than the above prohibited drugs can be used.
  • Dopamine receptor agonists eg, promocriptine mesylate, pergolide mesylate, force bergolin, talipexol hydrochloride, pramipexole hydrochloride, etc.
  • central anticholinergic agents eg, tricholine hydrochloride
  • amantadine hydrochloride e.g, tricholine hydrochloride
  • antidepressants eg, tricyclic antidepressants, iv) hexifuezyl, pyroheptine hydrochloride, mazaticol hydrochloride, methixene hydrochloride, biperidene, prophenamine, etc.
  • Ring antidepressants eg, triazolopyridine antidepressants, selective serotonin reup
  • Evaluation method At the start of the observation period, at the end of the observation period, administration 2 (at the end of the dose escalation period), 4, 6, 8, 10, 12, 14 (at the end of the maintenance dose administration period), 16 (at the dose gradual decrease period) At the end of), 18, 20 and 24 weeks later (at the end of the post observation period), the severity of the observation items was evaluated according to Table 5 below.
  • Evaluation method At the end of the observation period, administration 2 (at the end of the dose escalation period), 4, 6, 8, 10, 12, 14 (at the end of the maintenance dose period), 16 (at the end of the gradual decrease period), The ratio of off-time and on-time to the waking time after each of 18, 20, and 24 weeks (at the end of the post-observation period) was obtained from the patient's symptom diary, and the changes were compared with those before the start of the dose escalation period.
  • Evaluation method The severity of the observation items in the post observation period was evaluated in the same manner as described above.
  • Evaluation method The off time and the ratio of the on time in the post-observation period were evaluated in the same manner as described above.
  • Evaluation method Increasing the amount of levodopa ⁇ DCI combination or administration of a new repodopa ⁇ DCI combination as an event, and using the number of days until the first event occurs for the post-observation starting power, the repodopa 'DCI for each treatment group The cumulative change rate for the use of the combination was calculated.
  • (2R) 2-Propyloctanoic acid is effective in treating patients with Parkinson's disease.
  • Gelatin (15 kg) and concentrated glycerin (4.5 kg) were mixed at 70 ° C. in the presence of purified water (15 kg) to obtain a uniform solution.
  • This solution and (2R) -2-propyloctanoic acid (0.6 kg) are put into a soft capsule filling machine (rotary soft capsule molding machine H-1 type; force mata) and filled with (2R) 2-propyloctanoic acid.
  • a soft capsule live ball was obtained.
  • the obtained raw spheres were sequentially subjected to tumbler drying and shelf drying to obtain the title soft capsule (3000 capsules) containing lOOmg of (2R) -2-propyloctanoic acid in one capsule.
  • (2R) 2-propyloctanoic acid (100 8 ), levodopa (100 8 ), benserazide (25 8 ), carboxymethylcellulose calcium (20.0 g), magnesium stearate (lO.Og) and microcrystalline cellulose ( 870 g) were mixed by a conventional method and then tableted to obtain 10,000 tablets each containing 10 mg of (2R) -2-propyloctanoic acid, 10 mg of levodopa and 2.5 mg of benserazide.
  • (2R) -2 After mixing 2-propyloctanoic acid (lOOg), bromocriptine mesylate (30 g), calcium calcium carbonate (20.0 g), magnesium stearate (10.0 g) and microcrystalline cellulose (870 g) by conventional method Tablets were obtained in a tablet containing 10 mg of (2R) 2 propyloctanoic acid and 3 mg of bromocriptine mesylate in one tablet.
  • Formulation Example 1 Manufacture of injection containing (2R) -2-propyloctanoic acid, levodopa, benserazide (2R) — 2-propyloctanoic acid (200 g), levodopa (200 g), benserazide (50 g), male
  • 2R 2-propyloctanoic acid
  • levodopa 200 g
  • benserazide 50 g
  • male After mixing with water (2 kg) and distilled water (50 L) by a conventional method, make a uniform solution, filter through a sterile filter (Deyurapore 0.22 ⁇ m membrane), fill each 5 mL ampoule, and sterilize under high pressure steam ( At 15O 0 C for 15 minutes, 10,000 ampoules containing 20 mg (2R) -2-propyloctanoic acid, 20 mg levodopa and 5 mg benserazide in one ampule were obtained.
  • (2R) 2-Propyloctanoic acid (200 g), bromocriptine mesylate (60 g), mantol (2 kg) and distilled water (50 L) were mixed by a conventional method to obtain a homogeneous solution. (Filtered with Deyurapore 0.22 m membrane), filled into ampoules in 5 mL portions, autoclaved (123 ° C, 15 min), 20 mg (2R) -2-propyloctanoic acid and 6 mg mesylic acid in one ampule Ten thousand ampoules containing bromocriptine were obtained.
  • the method disclosed in the present invention and the medicament used in the method have been used in conventional treatment of Parkinson's disease and Z or Parkinson's syndrome, and have improved the problems in the treatment method.
  • the obtained effect is remarkably excellent.
  • 2R -2-propyloctanoic acid, its salt, its solvate or their
  • prodrugs, prevention, treatment and supplementation and Z or enhancement of Z or symptom progression inhibitory effect drug dose'reduction of side effects, compared to the use of these concomitant drugs alone Or it is effective in preventing the development of drug resistance.
  • side effects such as wear-off phenomenon that are often observed, complement and enhance the therapeutic effect, reduce drug dosage, or prevent the development of drug resistance. It is extremely useful because it can.

Abstract

A medicine for the prevention, treatment, and/or symptom progress inhibition of Parkinson's disease and/or Parkinson's syndrome. It comprises a combination of (2R)-2-propyloctanoic acid, a salt or solvate thereof, or a prodrug of either with an agent for the prevention, treatment, and/or symptom progress inhibition of Parkinson's disease and/or Parkinson's syndrome. The medicine is highly effective in the prevention, treatment, and/or symptom progress inhibition of Parkinson's disease and/or Parkinson's syndrome. In particular, when the medicinal composition which is for oral administration, which contains (2R)-2-propyloctanoic acid, a salt or solvate thereof, or a prodrug of either as an active ingredient, is administered in combination with a levodopa preparation, levodopa/benserazide preparation, levodopa/carbidopa preparation, and/or bromocriptine mesilate in the manner and dose shown in the description, then effects unobtainable with conventional treatments can be produced, such as a dose reduction, alleviation of side effects, and therapeutic-effect enhancement.

Description

明 細 書  Specification
パーキンソン病治療剤  Parkinson's disease treatment
技術分野  Technical field
[oooi] 本発明は、パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症状進展抑制に有用な方法と、そのために用いる医薬に関する。  [oooi] The present invention relates to a method useful for the prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome, and the suppression of Z or symptom progression, and a medicament used therefor.
より詳しくは、 (2R) 2—プロピルオクタン酸、その塩、その溶媒和物またはそれら のプロドラッグと、パーキンソン病および Zまたはパーキンソン症候群の予防、治療お よび Zまたは症状進展抑制薬とを組み合わせて用い、効果的にパーキンソン病およ び Zまたはパーキンソン症候群を予防、治療および Zまたは症状進展抑制する方法 と、そのために用いる医薬等に関する。  More specifically, (2R) 2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof is combined with prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome. The present invention relates to a method for effectively and effectively preventing and treating Parkinson's disease and Z or Parkinson's syndrome, and suppressing Z or symptom progression, and a pharmaceutical used for the same.
背景技術  Background art
[0002] 近年、多くの疾患の薬物治療にぉ 、て、疾患の予防および Zまたは治療効果の補 完および Zまたは増強、薬物動態'吸収の改善、あるいは薬物の投与量'副作用の 軽減、もしくは薬物耐性の発現の防止等を目的として作用機序の異なる複数の薬物 を組み合わせて用いる多剤併用療法が行われて 、る。  [0002] In recent years, in pharmacotherapy for many diseases, prevention and supplementation and Z or enhancement of the effects of Z or treatment, pharmacokinetics 'improvement of absorption, or drug dosage' reduction of side effects, or For the purpose of preventing the development of drug resistance, etc., multi-drug combination therapy using a plurality of drugs having different action mechanisms is being performed.
パーキンソン病は、ドパミン神経の変性'脱落が原因でおこる、錐体外路系異常 (例 えば、振戦、無動、筋固縮、姿勢保持障害等)を臨床的主症状とする、高齢者の代 表的な神経変性疾患の一つであり、厚生省から特定疾患に指定されている。  Parkinson's disease is caused by degeneration of the dopaminergic neuron, and extrapyramidal abnormalities (e.g. tremor, ataxia, muscular rigidity, posture maintenance disorder) that are clinically symptomatic. It is one of the typical neurodegenerative diseases and has been designated as a specific disease by the Ministry of Health and Welfare.
[0003] パーキンソン病の治療は、薬物療法を行いながらリハビリテーションを行うのが一般 的であるが、ここで行われる薬物療法はドパミンの補充療法が中心で、レポドパ製剤 が必須のものとなっている。しかし、レポドパ製剤の投与によって、不随意運動（ジス キネジァ）、すくみ現象 (フリージング)、精神症状 (興奮、不眠、幻覚、妄想、躁うつ状 態等)、消化器症状 (悪心、嘔吐等)、薬効不安定等の副作用やディレイドオン (delay ed on)現象、ノーオン (no on)現象等が現れることがあり、さらに長期間投与し続ける と、ウエアリングオフ（wearing off)現象、オン—オフ（on- off)現象、アップアンドダウン（ up and down)現象等が認められる。そこで、レポドパ製剤の投与量を減量し、副作用 を減弱するために、ドパミン受容体作動薬、ドパミン遊離促進薬、中枢性抗コリン薬、 モノアミン酸ィ匕酵素阻害薬、芳香族 L アミノ酸脱炭酸酵素阻害薬、ノルェピネフリン 補充薬等や鎮痙薬を組み合わせて用いる多剤併用療法が行われている。また、不 整脈、ふるえ、うつ状態といった副作用に対しては |8受容体遮断薬や抗うつ薬等が 併用されることもある。し力しながら、現在でも、パーキンソン病をはじめ、他の神経変 性疾患に対する根治療法は無ぐ単剤投与では、前記したような長期投与による薬 効の減退、副作用、病気の進行を抑制できない等の問題が認められるし、また、多剤 併用療法を行ったとしても劇的な治療効果を期待することは困難である。ドパミン産 生能を有する細胞を移植すると ヽつた治療方法も試みられて ヽるがまだ確立されて いない。 [0003] The treatment of Parkinson's disease is generally performed by rehabilitation while performing pharmacotherapy, but the pharmacotherapy performed here is dopamine replacement therapy, and a repodopa preparation is essential. . However, administration of levodopa preparations caused involuntary movements (dyskinesia), freezing phenomena (freezing), psychiatric symptoms (excitement, insomnia, hallucinations, delusions, manic depression, etc.), digestive symptoms (nausea, vomiting, etc.) Side effects such as instability, delayed ed on phenomenon, no on phenomenon, etc. may appear. If continued administration for a long time, wearing off phenomenon, on-off ( On-off) phenomenon, up-and-down phenomenon, etc. are observed. Therefore, dopamine receptor agonists, dopamine release promoters, central anticholinergics, in order to reduce the dose of levodopa and reduce side effects, Multi-drug combination therapy using a combination of monoamine oxyenzyme inhibitors, aromatic L amino acid decarboxylase inhibitors, norepinephrine replacement drugs, and antispasmodic drugs is being carried out. In addition, side effects such as arrhythmia, tremor, and depression may be combined with | 8 receptor blockers and antidepressants. However, even with Parkinson's disease and other neurodegenerative diseases, there is no radical treatment for single-agent administration, and it is not possible to suppress the decrease in efficacy, side effects, and progression of the disease caused by long-term administration as described above. In addition, it is difficult to expect a dramatic therapeutic effect even if multi-drug combination therapy is performed. Although transplantation of cells with the ability to produce dopamine has been attempted, various treatment methods have been tried, but have not yet been established.
[0004] また、パーキンソン症候群（パーキンソ-ズム）は、パーキンソン病のみならず、パー キンソン病とは異なる病因を有しながらも、臨床的にパーキンソン病に特徴的な錐体 外路系異常の症状を呈する全ての疾患をいう。基本的にはパーキンソン病と同様、ド ノ ミンの補充療法を中心とした治療を試みるため、前記したパーキンソン病治療にお ける問題点と同じ問題点を有している。  [0004] Parkinson's syndrome (parkinsonism) is a symptom of extrapyramidal abnormalities that are clinically characteristic of Parkinson's disease, although it has a different etiology from Parkinson's disease. It refers to all diseases that present. Basically, as with Parkinson's disease, the treatment centered on dominine replacement therapy is attempted, so it has the same problems as the above-mentioned Parkinson's disease treatment.
[0005] 一方、神経変性疾患 (アルツハイマー病、筋萎縮性側索硬化症、進行性核上麻痺 、ォリーブ橋小脳萎縮症)、脳卒中や脳脊髄外傷後の神経機能障害、脱髄疾患 (多 発性硬化症等)、脳腫瘍 (星状膠細胞腫等)、感染症に伴う脳脊髄疾患 (髄膜炎、ク ロッツフェルド ヤコブ病、エイズ痴呆等）、パーキンソン病、パーキンソン症候群等 の治療薬として（2R)— 2—プロピルオクタン酸が有用であることが知られている（例え ば、特許文献 1および 2参照)。  [0005] On the other hand, neurodegenerative diseases (Alzheimer's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, olive bridge cerebellar atrophy), neurological dysfunction after stroke or cerebrospinal trauma, demyelinating disease (multiple Sclerosis, etc.), brain tumor (astrocytoma, etc.), cerebrospinal disease associated with infection (meningitis, Crotsfeld-Jakob disease, AIDS dementia, etc.), Parkinson's disease, Parkinson's syndrome, etc. 2R) —2-Propyloctanoic acid is known to be useful (see, for example, Patent Documents 1 and 2).
[0006] (2R)—2 プロピルオクタン酸のこれらの効果は、細胞内 S100 β含量の減少作 用に基づく異常活性ィ匕ァスト口サイトの機能改善作用によるものであると報告されて いる (例えば、非特許文献 1参照)。  [0006] These effects of (2R) -2 propyloctanoic acid have been reported to be due to the function-improving action of abnormally active first mouth sites based on the action of reducing intracellular S100 β content (eg, Non-patent document 1).
この SlOO jSは、種々の神経変性疾患に関与していると考えられている S 100タン パクの一つであり、中枢神経系および末梢神経系のグリア細胞およびシュワン細胞 に高濃度で存在する他、下垂体前葉細胞やランゲルハンス細胞にも存在することが 知られており、脳脊髄液中あるいは血中の S100 |8含量は、脳梗塞、クモ膜下出血、 頭部外傷、種々の神経変性疾患、心肺バイパス手術後の神経合併症等において上 昇するため、例えば、脳卒中において、血中 S100タンパク含量を測定することは、 脳病変および神経学的損傷の診断に有用であると報告されている (ストローク (Strok e) ,第 28卷， 1956〜1960頁, 1997年）。 This SlOO jS is one of the S 100 proteins that are thought to be involved in various neurodegenerative diseases, and is present in high concentrations in glial cells and Schwann cells in the central and peripheral nervous systems. It is also known to be present in anterior pituitary cells and Langerhans cells, and the content of S100 | 8 in cerebrospinal fluid or blood is related to cerebral infarction, subarachnoid hemorrhage, head trauma, various neurodegenerative diseases. In neurological complications after cardiopulmonary bypass surgery For example, in blood stroke, measuring blood S100 protein content has been reported to be useful in the diagnosis of brain lesions and neurological damage (Stroke, pp. 28, 1956). ~ 1960, 1997).
[0007] また、（2R)— 2 プロピルオクタン酸またはその塩を、組織プラスミノーゲンァクティ ベータ一等の血栓溶解剤とともに、脳虚血疾患 (脳梗塞、脳出血、くも膜下出血、白 質異常症等)の治療剤として用いる方法が知られている (例えば、特許文献 3参照)。 しかし、これらの特許文献および非特許文献には、 (2R)—2—プロピルオクタン酸 の投与方法および投与量について、成人 1人あたり 1回に lmg〜1000mgの範囲で 1 日 1回〜数回経口投与される力、 1回に 0.1mg〜100mgの範囲で 1日 1回〜数回非 経口投与される等の一般的な記載がなされているに過ぎず、ヒトのパーキンソン病患 者で有効性を示す投与方法および投与量等にっ 、ての具体的な記載は一切な 、。 また、（2R)— 2—プロピルオクタン酸と他のパーキンソン病治療薬とを併用すること 力 S、パーキンソン病の治療にあたって副作用の低減等に極めて有用であるとの記載 もない。 [0007] In addition, (2R) -2 propyloctanoic acid or a salt thereof, together with a thrombolytic agent such as tissue plasminogen activator beta, cerebral ischemic disease (cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, white matter abnormality) There are known methods for use as therapeutic agents for diseases and the like (for example, see Patent Document 3). However, in these patent documents and non-patent documents, the administration method and dose of (2R) -2-propyloctanoic acid are in the range of lmg to 1000mg once per adult once to several times a day. There is only a general description such as the power to be administered orally, 0.1 to 100 mg at a time, parenteral administration once to several times a day, and it is effective for human Parkinson's disease patients There is no specific description of the administration method and dose showing sex. In addition, there is no description that it is extremely useful for reducing side effects in the treatment of Parkinson's disease with the use of (2R) -2-propyloctanoic acid and other Parkinson's disease in combination.
[0008] 特許文献 1：欧州特許公開第 0632008号明細書  [0008] Patent Document 1: European Patent Publication No. 0632008
特許文献 2 :欧州特許公開第 1174131号明細書  Patent Document 2: European Patent Publication No. 1174131
特許文献 3：国際公開第 03Z007992号パンフレット  Patent Document 3: International Publication No. 03Z007992 Pamphlet
非特許文献 l :Tateishi. N、他 8名、ジャーナル'ォブ 'セレブラル'ブラッド'フロウ' アンド'メタボリズム (Journal of cerebral blood flow & metabolism) ,第 22 (6)卷， 723 〜734頁， 2002年  Non-patent literature l: Tateishi. N and 8 others, Journal of cerebral blood flow & metabolism, 22 (6), 723-734, 2002 Year
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0009] 一般に医薬品を高用量投与、あるいはたとえ低用量であっても長期間投与すると 副作用等が発現し、目的とする患者の治療に制限が発生し、十分な治療効果が得ら れないことが多い。とりわけパーキンソン病およびパーキンソン症候群の単剤薬物治 療においては、ウエアリングオフ現象、オン オフ現象等の副作用がしばしば認めら れるといった問題があり、また多剤併用療法を行ったとしても劇的な治療効果を期待 することは困難である。そこで、これらの問題を克服した臨床上十分に有効な薬剤の 開発が切望されていた。 [0009] In general, when a pharmaceutical is administered at a high dose or even at a low dose for a long period of time, side effects and the like occur, the treatment of the intended patient is limited, and a sufficient therapeutic effect cannot be obtained. There are many. In particular, single drug therapy for Parkinson's disease and Parkinson's syndrome has problems such as side effects such as wear-off phenomenon and on / off phenomenon, and dramatic treatment is possible even if multi-drug therapy is used. It is difficult to expect an effect. Therefore, a clinically effective drug that overcomes these problems Development was anxious.
課題を解決するための手段  Means for solving the problem
[0010] 本発明者らは、上記の問題を解決すべく鋭意検討を行った結果、パーキンソン病 およびパーキンソン症候群の治療において、 1回あたりの投与量が約 50mg〜約 120 0mg、好ましくは約 lOOmg〜約 600mgの（2R)—2 プロピルオクタン酸を他のパ 一キンソン病治療薬等と併用することにより、治療にあたって認められる種々の副作 用を軽減することができ（例えば、（2R)— 2—プロピルオクタン酸を併用することによ つて、レポドパ ·ベンセラジド配合剤ある 、はメシル酸ブロモクリプチンの反復投与で 見られたウエアリングオフ現象の改善が認められた。）、臨床上十分な治療効果が得 られるという効果を見出した。本発明者らはその知見に基づいてさらに検討を加える ことにより本発明を完成した。  [0010] As a result of intensive studies to solve the above problems, the present inventors have found that a dose per administration is about 50 mg to about 120 mg, preferably about lOOmg in the treatment of Parkinson's disease and Parkinson's syndrome. ~ About 600 mg of (2R) -2 propyloctanoic acid can be used in combination with other Parkinson's disease drugs to reduce the various side effects observed in treatment (for example, (2R) — The combined use of 2-propyloctanoic acid improved the wear-off phenomenon observed with repeated administration of bromocriptine mesylate, which is a combination of levodopa and benserazide.) Clinically sufficient therapeutic effect We found an effect that can be obtained. The inventors of the present invention have completed the present invention through further studies based on the findings.
[0011] すなわち、本発明は、  [0011] That is, the present invention provides:
[1] (2R) 2—プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッ グと、パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制薬とを組み合わせてなるパーキンソン病および/またはパーキンソ ン症候群の予防、治療および Zまたは症状進展抑制用医薬；  [1] (2R) Combining 2-propyloctanoic acid, its salt, its solvate or their prodrug with the prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome and Z or symptom progression inhibitor Drugs for prevention, treatment and Z or symptom progression prevention of Parkinson's disease and / or Parkinson's syndrome;
[ 2]経口投与用である前記 [ 1 ]記載の医薬；  [2] The medicament according to [1], which is for oral administration;
[3] 1回あたりの（2R)— 2 プロピルオクタン酸またはその塩の経口投与量が約 50 mg〜約 1200mgである前記 [2]記載の医薬；  [3] The medicament according to the above [2], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 50 mg to about 1200 mg;
[4] 1回あたりの（2R)— 2 プロピルオクタン酸またはその塩の経口投与量が約 100 mg〜約 600mgである前記 [3]記載の医薬；  [4] The medicament according to [3] above, wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 100 mg to about 600 mg;
[5]投薬期間が約 1ヶ月間〜約 5年間である前記 [2]記載の医薬；  [5] The medicament according to the above [2], wherein the dosing period is about 1 month to about 5 years;
[6]約 1ヶ月間〜約 5年間の投薬期間中、 1日 1回〜 5回の投薬回数で、 1回あたり約 [6] During the dosing period of about 1 month to about 5 years, about 1 to 5 doses per day, about once per dose
50mg〜約 1200mgの（2R)—2 プロピルオクタン酸またはその塩を経口投与するこ とを特徴とする前記 [5]記載の医薬； The pharmaceutical according to [5] above, wherein 50 mg to about 1200 mg of (2R) -2 propyloctanoic acid or a salt thereof is orally administered;
[7]約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 1 OOmg〜約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜 約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 200mg〜約 800 mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜約 3年間の投薬 期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 300mg〜約 1200mgの（2R)— 2 —プロピルオクタン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回 〜2回の投薬回数で、 1回あたり約 200mg〜約 800mgの（2R)—2 プロピルォクタ ン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回 数で、 1回あたり約 lOOmg〜約 400mgの（2R)—2 プロピルオクタン酸を経口投与 することを特徴とする前記 [6]記載の医薬； [7] During a dosing period of about 1 week to about 2 weeks, about 1 OO mg to about 400 mg of (2R) -2 propyloctanoic acid is orally administered at a dose of 1 to 2 times a day, During the subsequent dosing period of about 1 week to about 2 weeks, about 200 mg to about 800 per dose with 1 to 2 dosing times per day mg (2R) -2 propyloctanoic acid orally, followed by dosing once to twice a day for a dosing period of about 1 week to about 3 years, about 300 mg to about 1200 mg per dose ( 2R) — 2 -Propyloctanoic acid orally, followed by a dose of about 200 mg to about 800 mg (2R) per dose with a dosing frequency of 1 to 2 times a day for a subsequent dosing period of about 1 week to about 2 weeks —2 Propoctanic acid administered orally, followed by about 1 to 2 weeks of dosing for about 1 week to about 2 weeks, with about lOOmg to about 400 mg of (2R) —2 per dose The pharmaceutical according to [6] above, wherein propyloctanoic acid is orally administered;
[8]約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2 [8] About 200 mg of (2R) -2 per dose during a dosing period of about 1 week
—プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回 数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 12 週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 600mgの（2R)—2 プロ ピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数で、 1 回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間の 投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2—プロピルォ クタン酸を経口投与することを特徴とする前記 [7]記載の医薬； —Propyloctanoic acid is orally administered, followed by approximately 400 mg of (2R) —2 propyloctanoic acid orally, followed by approximately 12 During the weekly dosing period, about 600 mg of (2R) -2 propyloctanoic acid is orally administered once a day during the dosing period, and once a day during the dosing period of about one week. About 400 mg of (2R) -2 propyloctanoic acid is orally administered, followed by about 200 mg of (2R) -2 per dose during a subsequent dosing period of about 1 week. -The pharmaceutical according to the above-mentioned [7], wherein propyloctanoic acid is orally administered;
[9] さらに、レポドパ製剤、ドパミン受容体作動薬、ドパミン遊離促進薬、ドパミン取り 込み阻害薬、ドパミン作用薬、中枢性抗コリン薬、芳香族 L アミノ酸脱炭酸酵素阻 害薬、モノアミン酸ィ匕酵素阻害薬、カテコール o メチルトランスフェラーゼ阻害薬 [9] In addition, levodopa preparations, dopamine receptor agonists, dopamine release promoters, dopamine uptake inhibitors, dopamine agonists, central anticholinergics, aromatic L amino acid decarboxylase inhibitors, monoamine acids Enzyme inhibitor, catechol o methyltransferase inhibitor
、ノルェピネフリン補充薬、 GABA受容体調節薬、 GABA受容体調節薬、アデノ , Norepinephrine replacement drug, GABA receptor modulator, GABA receptor modulator, adeno
A B  A B
シン A2A受容体遮断薬、アポトーシス阻害薬、神経分化，再生促進薬、神経栄養因 子、脳機能賦活薬、 Rho キナーゼ阻害薬および β受容体遮断薬から選択される 1 種以上を組み合わせてなる前記 [1]記載の医薬； A combination of one or more selected from a syn A2A receptor blocker, an apoptosis inhibitor, a neuronal differentiation and regeneration promoter, a neurotrophic factor, a brain function activator, a Rho kinase inhibitor, and a β receptor blocker [1] The medicine according to [1]
[10]パーキンソン病および Ζまたはパーキンソン症候群の予防、治療および Ζまた は症状進展抑制薬が、レポドパ製剤、レポドパ 'ベンセラジド配合剤、レポドパ 'カル ビドパ配合剤および Ζまたはメシル酸プロモクリブチンである前記 [ 1 ]記載の医薬； [ 11 ] (2R)— 2—プロピルオクタン酸とレポドパ製剤とを組み合わせてなる医薬であ つて、（2R)— 2 プロピルオクタン酸の投与量力 患者の体重 lkgあたり約 3mg〜 約 60mgであって、レボドパ製剤の投与量力 患者の体重 lkgあたり約 3mg〜約 60 mgである前記 [10]記載の医薬； [10] Prevention, treatment and prevention of epilepsy or symptom progression for Parkinson's disease and epilepsy or Parkinson's syndrome are levodopa, levodopa 'benserazide, levodopa' carbidopa, and お よ び or promocributin mesylate [1] Drug described in [1]; [11] (2R) — A drug comprising a combination of 2-propyloctanoic acid and a repodopa preparation, and the dose power of (2R) -2-propyloctanoic acid is about 3 mg per kg body weight of the patient. ~ About 60 mg, dose power of levodopa formulation About 3 mg to about 60 mg / kg of patient body weight The medicament according to [10] above, which is mg;
[12] (2R)—2 プロピルオクタン酸とレボドパ 'ベンセラジド (4 : 1)配合剤とを組み 合わせてなる医薬であって、（2R)— 2—プロピルオクタン酸の投与量力 患者の体 重 lkgあたり約 3mg〜約 60mgであって、レボドノ 'ベンセラジド（4 : 1)配合剤の投与 量力 患者の体重 lkgあたり約 2mg〜約 20mgである前記 [10]記載の医薬；  [12] (2R) —A drug that combines propyloctanoic acid and levodopa'benserazide (4: 1) in combination with the dose of (2R) —2-propyloctanoic acid. The drug according to [10], wherein the dose is about 3 mg to about 60 mg per dose, and the dosage power of the combination drug of levodono'benserazide (4: 1) is about 2 mg to about 20 mg per kg body weight of the patient;
[ 13] (2R)— 2 プロピルオクタン酸とレボドパ ·カルビドパ（10 : 1)配合剤とを組み 合わせてなる医薬であって、（2R)— 2—プロピルオクタン酸の投与量力 患者の体 重 lkgあたり約 3mg〜約 60mgであって、レボドノ 'カルビドパ（10 : 1)配合剤の投与 量が、患者の体重 lkgあたり約 2mg〜約 15mgである前記 [10]記載の医薬； [13] (2R) — A drug consisting of a combination of 2-propyloctanoic acid and levodopa-carbidopa (10: 1), and the dosage of (2R) -2-propyloctanoic acid. The drug according to [10], wherein the dose is about 3 mg to about 60 mg per dose, and the dose of levodono carbidopa (10: 1) is about 2 mg to about 15 mg per kg of patient body weight;
[14] (2R) 2 プロピルオクタン酸とメシル酸ブロモクリプチンとを組み合わせてな る医薬であって、（2R)— 2—プロピルオクタン酸の投与量力 患者の体重 lkgあたり 約 3mg〜約 60mgであって、メシル酸ブロモクリプチンの投与量力 患者の体重 lkg あたり約 O.Olmg〜約 lmgである前記 [10]記載の医薬； [14] (2R) A drug comprising a combination of 2-propyloctanoic acid and bromocriptine mesylate, wherein (2R) -2-propyloctanoic acid is administered at a dose of about 3 mg to about 60 mg per kg of patient body weight. , The dose power of bromocriptine mesylate, the pharmaceutical agent according to the above [10], which is about O.Olmg to about lmg per kg body weight of the patient;
[15]レポドパ製剤、レポドパ ·ベンセラジド配合剤およびレポドパ ·カルビドパ配合剤 力 選ばれる 1種または 2種以上と、 (2R)—2—プロピルオクタン酸、その塩、その溶 媒和物またはそれらのプロドラッグとを組み合わせてなる経口投与用のパーキンソン 病および Zまたはパーキンソン症候群の予防、治療および Zまたは症状進展抑制用 医薬であって、約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mg の（2R)—2—プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1 回の投薬回数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与 し、続く約 12週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 600mgの（2R )—2—プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投 薬回数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く 約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2— プロピルオクタン酸を経口投与することを特徴とする医薬；  [15] Lepodopa formulation, levodopa-benserazide compound and levodopa-carbidopa compound force One or more selected, and (2R) -2-propyloctanoic acid, its salt, its solvate or their pro A drug for the prevention, treatment and inhibition of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome for oral administration in combination with a drug, with a dosage of once a day during a dosage period of about 1 week, Approximately 200 mg of (2R) -2-propyloctanoic acid is administered orally, and approximately 400 mg of (2R) -2-propyl is administered once a day during the subsequent dosing period. Octanoic acid was orally administered, followed by approximately 600 mg of (2R) -2-propyloctanoic acid per oral administration at a dosage of once a day during the subsequent 12-week dosing period. Once a day during the dosing period About 400 mg of (2R) -2 propyloctanoic acid is orally administered, followed by about 200 mg of (2R) -2 at a single dose per day during the subsequent dosing period of about 1 week. — A medicine characterized by oral administration of propyloctanoic acid;
[16]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制に際し、パーキンソン病および Zまたはパーキンソン症候群の予防 、治療および Zまたは症状進展抑制薬に加えて、さらに（2R)— 2—プロピルオクタン 酸、その塩、その溶媒和物またはそれらのプロドラッグを投与することを特徴とする、 当該薬の投与量低減用医薬； [16] In addition to Parkinson's disease and Z or Parkinson's syndrome prevention, treatment and prevention of Z or Parkinson's syndrome, Z or symptom progression, in addition to Parkinson's disease and Z or Parkinson's syndrome 2-propyloctane A drug for reducing the dose of the drug, which comprises administering an acid, a salt thereof, a solvate thereof or a prodrug thereof;
[ 17]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制に際し、パーキンソン病および Zまたはパーキンソン症候群の予防 [17] Prevention or treatment of Parkinson's disease and Z or Parkinson's syndrome, prevention of Parkinson's disease and Z or Parkinson's syndrome in the prevention of Z or symptom progression
、治療および Zまたは症状進展抑制薬に加えて、さらに（2R)— 2—プロピルオクタン 酸、その塩、その溶媒和物またはそれらのプロドラッグを投与することを特徴とする、 当該薬の副作用改善用医薬； , Treatment and administration of (2R) -2-propyloctanoic acid, its salt, its solvate or their prodrug in addition to Z or symptom progression inhibitor Pharmaceuticals;
[18]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制薬が、レポドパ製剤、レポドパ 'ベンセラジド配合剤、レポドパ 'カル ビドパ配合剤および Zまたはメシル酸プロモクリブチンである前記 [ 16]または [ 17] 記載の医薬；  [18] The aforementioned prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome are levodopa, levodopa 'benserazide, levodopa' carbidopa and Z or promocributin mesylate [16] or [17] the medicine according to [17];
[19] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグを有効成分として含有し、経口投与することを特徴とするパーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症状進展抑制用医薬糸且 成物；  [19] Prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome comprising (2R) 2 propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof as an active ingredient and orally administered And Z or a pharmaceutical thread and composition for symptom progression inhibition;
[20] 1回あたりの（2R)— 2 プロピルオクタン酸またはその塩の経口投与量が約 50 mg〜約 1200mgである前記 [19]記載の組成物；  [20] The composition according to [19] above, wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 50 mg to about 1200 mg;
[21 ] 1回あたりの（2R)— 2—プロピルオクタン酸またはその塩の経口投与量が約 10 Omg〜約 600mgである前記 [20]記載の組成物；  [21] The composition according to [20] above, wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 10 Omg to about 600 mg;
[22] 1回あたりの（2R)— 2—プロピルオクタン酸またはその塩の経口投与量が約 10 Omg、約 200mg、約 300mg、約 400mgまたは約 600mgである前記 [21]記載の組 成物；  [22] The composition according to [21], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 10 Omg, about 200 mg, about 300 mg, about 400 mg or about 600 mg. ;
[23] 1回あたりの（2R)— 2 プロピルオクタン酸またはその塩の経口投与量が約 60 Omgである前記 [22]記載の組成物；  [23] The composition according to the above [22], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per one time is about 60 Omg;
[24]投薬期間が約 1ヶ月間〜約 5年間である前記 [19]記載の組成物；  [24] The composition of the above-mentioned [19], wherein the dosing period is about 1 month to about 5 years;
[25]投薬期間が約 3ヶ月間〜約 1年間である前記 [24]記載の組成物；  [25] The composition of the above-mentioned [24], wherein the dosing period is about 3 months to about 1 year;
[26]投薬期間が約 3ヶ月間〜約 6ヶ月間である前記 [25]記載の組成物；  [26] The composition of the above-mentioned [25], wherein the dosing period is about 3 months to about 6 months;
[27]約 1ヶ月間〜約 5年間の投薬期間中、 1日 1回〜 5回の投薬回数で、 1回あたり 約 50mg〜約 1200mgの（2R)—2 プロピルオクタン酸またはその塩を経口投与す ることを特徴とする前記 [ 19]記載の組成物； [27] During a dosing period of about 1 month to about 5 years, 1 to 5 dosing times per day, per dose The composition according to [19] above, wherein about 50 mg to about 1200 mg of (2R) -2 propyloctanoic acid or a salt thereof is orally administered;
[28]約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 lOOmg〜約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜 約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 200mg〜約 800 mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜約 3年間の投薬 期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 300mg〜約 1200mgの（2R)— 2 —プロピルオクタン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回 〜2回の投薬回数で、 1回あたり約 200mg〜約 800mgの（2R)—2 プロピルォクタ ン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回 数で、 1回あたり約 lOOmg〜約 400mgの（2R)—2 プロピルオクタン酸を経口投与 することを特徴とする前記 [27]記載の組成物；  [28] Oral administration of about lOOmg to about 400mg (2R) -2 propyloctanoic acid per dose, followed by 1 to 2 doses per day during the dosing period of about 1 to 2 weeks During a dosing period of about 1 week to about 2 weeks, about 200 mg to about 800 mg of (2R) -2 propyloctanoic acid is orally administered, followed by about 1 During the dosing period of about 3 to 3 years, about 300 mg to about 1200 mg of (2R) -2-propyloctanoic acid is orally administered at a dosage of 1 to 2 times a day, followed by about 1 week to During the dosing period of about 2 weeks, about 200 mg to about 800 mg of (2R) -2 propoctoic acid is orally administered once a day or 2 times a day, followed by about 1 week to about 2 weeks The above-mentioned [27], wherein orally administered from about lOO mg to about 400 mg of (2R) -2 propyloctanoic acid per dose during a dosing period of 1 to 2 times per day composition ;
[29]約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R) - 2—プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回 数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 12 週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 600mgの（2R)—2 プロ ピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数で、 1 回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間の 投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2—プロピルォ クタン酸を経口投与することを特徴とする前記 [28]記載の組成物；  [29] About 200 mg of (2R) -2-propyloctanoic acid is orally administered once a day during the dosing period of about 1 week, followed by about 1 week of dosing period 1 About 400 mg of (2R) -2 propyloctanoic acid is orally administered once a day for about 12 weeks, and about once per day for about 12 weeks. 600 mg of (2R) -2 propyloctanoic acid is orally administered, followed by about 400 mg of (2R) -2 propyloctanoic acid orally once a day during the subsequent dosing period of about 1 week In the following [28], about 200 mg of (2R) -2-propylactanoic acid is orally administered once per day during the subsequent dosing period of about 1 week. Composition;
[30] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグと、パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zま たは症状進展抑制薬とを組み合わせて哺乳動物に投与することを特徴とするパーキ ンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症状進展 抑制方法； [30] (2R) 2 Propyloctanoic acid, salt, solvate or prodrug thereof combined with prophylaxis, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome A method for the prevention, treatment and suppression of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome, characterized by being administered to a mammal;
[31]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制に際し、パーキンソン病および Zまたはパーキンソン症候群の予防 [31] Prevention, treatment and prevention of Parkinson's disease and Z or Parkinsonism in Parkinson's disease and Z or Parkinsonism
、治療および Zまたは症状進展抑制薬に加えて、さらに（2R)— 2—プロピルオクタン 酸、その塩、その溶媒和物またはそれらのプロドラッグを投与することを特徴とする、 当該薬の投与量低減方法； In addition to treatment and Z or symptom progression inhibitors, in addition (2R) -2-propyloctane Administration of an acid, a salt thereof, a solvate thereof, or a prodrug thereof;
[32]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制に際し、パーキンソン病および Zまたはパーキンソン症候群の予防 、治療および Zまたは症状進展抑制薬に加えて、さらに（2R)— 2—プロピルオクタン 酸、その塩、その溶媒和物またはそれらのプロドラッグを投与することを特徴とする、 当該薬の副作用改善方法；  [32] In prevention, treatment and prevention of Z or symptom progression in Parkinson's disease and Z or Parkinson's syndrome, in addition to prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome, (2R) — A method for improving a side effect of the drug, comprising administering 2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof;
[33] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグを哺乳動物に経口投与することを特徴とするパーキンソン病および Zまたはパー キンソン症候群の予防、治療および zまたは症状進展抑制方法；  [33] (2R) 2 Propyloctanoic acid, its salt, its solvate or their prodrug is orally administered to mammals, preventing or treating Parkinson's disease and Z or Parkinson's syndrome Or a symptom progression suppression method;
[34]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制用医薬を製造するための、（2R)— 2—プロピルオクタン酸、その塩 、その溶媒和物またはそれらのプロドラッグと、パーキンソン病および Zまたはパーキ ンソン症候群の予防、治療および Zまたは症状進展抑制薬との組み合わせの使用； [35]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制の際に用いる、パーキンソン病および Zまたはパーキンソン症候群 の予防、治療および Zまたは症状進展抑制薬の投与量低減用医薬を製造するため の、（2R)—2—プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッ グの使用；  [34] (2R) —2-Propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof for the manufacture of a medicament for the prevention, treatment and prevention of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome Use of the drug in combination with prophylaxis, treatment and prevention of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome; [35] Prevention, treatment and inhibition of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome (2R) -2-Propyloctanoic acid, its salt, and its solvate for the prevention, treatment of Parkinson's disease and Z or Parkinson's syndrome Use of objects or their pro-drugs;
[36]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制の際に用いる、パーキンソン病および Zまたはパーキンソン症候群 の予防、治療および Zまたは症状進展抑制薬の副作用改善用医薬を製造するため の、（2R)—2—プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッ グの使用；  [36] Prevention, treatment of Parkinson's disease and Z or Parkinson's syndrome, prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome Use of (2R) -2-propyloctanoic acid, its salts, its solvates or their prodrugs for the production;
[37]経口投与用のパーキンソン病および Zまたはパーキンソン症候群の予防、治 療および Zまたは症状進展抑制用医薬を製造するための、 (2R) 2—プロピルオタ タン酸、その塩、その溶媒和物またはそれらのプロドラッグの使用；  [37] (2R) 2-propylotatanic acid, a salt thereof, a solvate thereof, or a pharmaceutical for the prevention, treatment and prevention of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome for oral administration Use of those prodrugs;
[38]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制薬の投与量を単独投与時の投与量の 2分の 1〜10分の 1に低減す る前記 [16]記載の医薬； [38] Prevention, treatment and Z or Parkinson's disease and Z or Parkinson's syndrome [16] The pharmaceutical agent according to [16], wherein the dosage of the symptom progression inhibitor is reduced to one-half to one-tenth of the dose when administered alone;
[39]副作用がウエアリングオフ現象、オンアンドオフ現象および Zまたはアップダウ ン現象である前記 [17]記載の医薬；  [39] The medicament according to [17], wherein the side effects are a wear ring-off phenomenon, an on-and-off phenomenon, and a Z or an up-down phenomenon;
[40]副作用がウエアリングオフ現象である前記 [39]記載の医薬；  [40] The medicament according to the above [39], wherein the side effect is a wear ring-off phenomenon;
[101] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグを有効成分として含有し、経口投与することを特徴とするパーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症状進展抑制用医薬糸且 成物； [101] (2R) 2 Propyloctanoic acid, its salt, its solvate or prodrug thereof as an active ingredient, and prevention or treatment of Parkinson's disease and Z or Parkinson's syndrome characterized by oral administration And Z or a pharmaceutical thread and composition for symptom progression inhibition;
[102] 1回あたりの（2R)— 2 プロピルオクタン酸またはその塩の経口投与量が約 5 Omg〜約 1200mgである前記 [ 101 ]記載の組成物；  [102] The composition of [101], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 5 Omg to about 1200 mg;
[103] 1回あたりの（2R)— 2 プロピルオクタン酸またはその塩の経口投与量が約 1 OOmg〜約 600mgである前記 [102]記載の組成物；  [103] The composition of the above-mentioned [102], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 1 OO mg to about 600 mg;
[104] 1回あたりの（2R)— 2 プロピルオクタン酸またはその塩の経口投与量が約 1 OOmg,約 200mg、約 300mg、約 400mgまたは約 600mgである前記 [103]記載の 組成物；  [104] The composition of [103], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof is about 1 OO mg, about 200 mg, about 300 mg, about 400 mg, or about 600 mg;
[105] 1回あたりの（2R)— 2 プロピルオクタン酸またはその塩の経口投与量が約 6 OOmgである前記 [104]記載の組成物；  [105] The composition of the above-mentioned [104], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 6 OO mg;
[106]投薬期間が約 1ヶ月間〜約 5年間である前記 [101]記載の組成物；  [106] The composition of [101], wherein the dosing period is from about 1 month to about 5 years;
[107]投薬期間が約 3ヶ月間〜約 1年間である前記 [106]記載の組成物；  [107] The composition of [106], wherein the dosing period is from about 3 months to about 1 year;
[108]投薬期間が約 3ヶ月間〜約 6ヶ月間である前記 [107]記載の組成物；  [108] The composition of [107], wherein the dosing period is from about 3 months to about 6 months;
[109]約 1ヶ月間〜約 5年間の投薬期間中、 1日 1回〜 5回の投薬回数で、 1回あたり 約 50mg〜約 1200mgの（2R)—2 プロピルオクタン酸またはその塩を経口投与す ることを特徴とする前記 [101]記載の組成物；  [109] Oral administration of about 50 mg to about 1200 mg of (2R) -2 propyloctanoic acid or a salt thereof at a dose of 1 to 5 doses per day during a dosing period of about 1 month to about 5 years The composition according to the above [101], which is administered;
[110]約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 lOOmg〜約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜 約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 200mg〜約 800 mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜約 3年間の投薬 期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 300mg〜約 1200mgの（2R)— 2 —プロピルオクタン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回 〜2回の投薬回数で、 1回あたり約 200mg〜約 800mgの（2R)—2 プロピルォクタ ン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回 数で、 1回あたり約 lOOmg〜約 400mgの（2R)—2 プロピルオクタン酸を経口投与 することを特徴とする前記 [109]記載の組成物； [110] Oral administration of about lOOmg to about 400mg of (2R) -2 propyloctanoic acid per dose, followed by one to two doses per day during a dosing period of about 1 to 2 weeks During a dosing period of about 1 week to about 2 weeks, about 200 mg to about 800 mg of (2R) -2 propyloctanoic acid is orally administered, followed by about 1 Medication for about 3 years per week During the period, about 300 mg to about 1200 mg of (2R) -2-propyloctanoic acid is orally administered at a dosage of 1 to 2 times a day, followed by a dosage period of about 1 week to about 2 weeks 1 to 2 times per day, about 200 mg to about 800 mg of (2R) -2-propylactanoic acid is orally administered, followed by about 1 week to about 2 weeks The composition according to the above [109], wherein about 1OOmg to about 400mg of (2R) -2 propyloctanoic acid is orally administered at a dosage of 1 to 2 times;
[111]約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R) —2—プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬 回数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 12週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 600mgの（2R)—2 プ 口ピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間の 投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2—プロピルォ クタン酸を経口投与することを特徴とする前記 [110]記載の組成物；  [111] About 200 mg of (2R) -2-propyloctanoic acid is administered orally once a day during a dosing period of about 1 week, followed by a dosing period of about 1 week Approximately 400 mg of (2R) -2 propyloctanoic acid is orally administered once a day for the number of doses, and about 600 mg per dose for the following 12-day dosing period. (2R) —2 oral piroctanoic acid is orally administered, followed by oral administration of about 400 mg of (2R) -2 propyloctanoic acid once a day during the subsequent dosing period of about 1 week In addition, the following [110], wherein about 200 mg of (2R) -2-propylactanoic acid is orally administered at a dose of once a day during the subsequent dosing period of about 1 week. Composition;
[112] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグと、パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zま たは症状進展抑制薬力 なる経口投与用パーキンソン病および Zまたはパーキンソ ン症候群の予防、治療および Zまたは症状進展抑制用医薬； [112] (2R) 2-Propyloctanoic acid, its salts, its solvates or their prodrugs, and oral administration to prevent or treat Parkinson's disease and Z or Parkinson's syndrome and to suppress Z or symptom progression For the prevention, treatment and Z or symptom progression inhibition of Parkinson's disease and Z or Parkinson's syndrome;
[113]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制薬がレポドパ製剤、ドパミン受容体作動薬、ドパミン遊離促進薬、ド パミン取り込み阻害薬、ドパミン作用薬、中枢性抗コリン薬、芳香族 L—アミノ酸脱炭 酸酵素阻害薬、モノアミン酸ィ匕酵素阻害薬、カテコール o メチルトランスフェラー ゼ阻害薬およびノルェピネフリン補充薬力 選択される 1種以上である前記 [112]記 載の医薬； [113] Prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome and Z or symptom progression inhibitors are repodopa, dopamine receptor agonists, dopamine release promoters, dopamine uptake inhibitors, dopamine agonists, central anti-drugs Choline drugs, aromatic L-amino acid decarboxylase inhibitors, monoamine oxyenzyme inhibitors, catechol o methyltransferase inhibitors and norepinephrine supplements Medicine;
[114]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制薬がレポドパ製剤、レポドパ 'ベンセラジド配合剤、レポドパ 'カルビ ドパ配合剤および Zまたはメシル酸プロモクリブチンである前記 [112]記載の医薬； [115] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグと、パーキンソン病、パーキンソン症候群、神経変性疾患、運動神経病、脱髄性 疾患、脳血管障害、脳腫瘍、脳脊髄外傷に伴う神経機能障害、感染症に伴う脳脊髄 疾患、精神疾患、てんかん、ジストニア、糖尿病、糖尿病合併症および高脂血症から 選択される 1種以上の疾患の予防、治療および Zまたは症状進展抑制薬からなる経 口投与用パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Z または症状進展抑制用医薬； [114] The prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome are levodopa, levodopa'benserazide, levodopa'carbidopa and Z or promocributin mesylate [112] The medicament according to [112]; [115] (2R) 2 propyloctanoic acid, a salt thereof, a solvate thereof or a prodola thereof Parkinson's disease, Parkinson's syndrome, neurodegenerative disease, motor neuropathy, demyelinating disease, cerebrovascular disorder, brain tumor, neurological dysfunction associated with cerebrospinal trauma, cerebrospinal disease associated with infection, mental illness, epilepsy Prevention, treatment of one or more diseases selected from dystonia, diabetes, diabetic complications and hyperlipidemia and prevention or treatment of Parkinson's disease for oral administration consisting of Z or symptom progression inhibitor, and Z or Parkinson's syndrome And Z or drugs for inhibiting symptom progression;
[116] (2R) ー2—プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグと、 GABA受容体調節薬、 GABA受容体調節薬、アデノシン A2A受容体遮  [116] (2R) -2-Propyloctanoic acid, its salt, its solvate or their prodrug, GABA receptor modulator, GABA receptor modulator, adenosine A2A receptor blockade
A B  A B
断薬、アポトーシス阻害薬、神経分化および Zまたは再生促進薬、神経栄養因子、 脳機能賦活薬、 Rho—キナーゼ阻害薬、アセチルコリンエステラーゼ阻害薬、 NMD A受容体拮抗薬、 AMPAZカイニン酸受容体拮抗薬、利尿薬、カルシウムチャネル 遮断薬、アンジォテンシン変換酵素阻害薬、アンジォテンシン Π受容体拮抗薬、ナト リウムチャネル遮断薬、カリウムチャネル開口薬、 β受容体遮断薬、抗血小板薬、抗 凝固薬、血栓溶解薬、シクロォキシゲナーゼー 2阻害薬、非ステロイド性抗炎症薬、 ステロイド薬、抗酸ィ匕薬およびビタミン類力 選択される 1種以上とからなる経口投与 用パーキンソン病および Ζまたはパーキンソン症候群の予防、治療および Ζまたは 症状進展抑制用医薬； Withdrawal, apoptosis inhibitor, neuronal differentiation and Z or regeneration promoter, neurotrophic factor, brain function activator, Rho-kinase inhibitor, acetylcholinesterase inhibitor, NMD A receptor antagonist, AMPAZ kainate receptor antagonist , Diuretics, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin Π receptor antagonists, sodium channel blockers, potassium channel openers, β receptor blockers, antiplatelet drugs, anticoagulants , Thrombolytics, cycloxygenase-2 inhibitors, non-steroidal anti-inflammatory drugs, steroid drugs, anti-acid drugs and vitamins power Parkinson's disease for oral administration consisting of one or more selected Or prevention and treatment of Parkinson's syndrome and drugs to suppress epilepsy or symptom progression;
[ 117] 1回あたりの（ 2R)— 2—プロピルオクタン酸またはその塩の経口投与量が約 5 Omg〜約 1200mgである前記 [112]、 [115]または [116]記載の医薬；  [117] The medicament according to [112], [115] or [116] above, wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 5 Omg to about 1200 mg;
[ 118] 1回あたりの（2R)— 2—プロピルオクタン酸またはその塩の経口投与量が約 1 OOmg〜約 600mgである前記 [117]記載の医薬； [118] The medicament according to the above [117], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 1 OO mg to about 600 mg;
[119]投薬期間が約 1ヶ月間〜約 5年間である前記 [112]、 [115]または [116]記載の 医薬；  [119] The medicament according to [112], [115] or [116] above, wherein the dosing period is from about 1 month to about 5 years;
[120]約 1ヶ月間〜約 5年間の投薬期間中、 1日 1回〜 5回の投薬回数で、 1回あたり 約 50mg〜約 1200mgの（2R)—2—プロピルオクタン酸またはその塩を経口投与す ることを特徴とする前記 [112]、 [115]または [116]記載の医薬；  [120] About 50 mg to about 1200 mg of (2R) -2-propyloctanoic acid or a salt thereof at a dose of 1 to 5 times a day during a dosing period of about 1 month to about 5 years The medicament according to [112], [115] or [116], which is orally administered;
[121]約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 lOOmg〜約 400mgの（2R)—2—プロピルオクタン酸を経口投与し、続く約 1週間〜 約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 200mg〜約 800 mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜約 3年間の投薬 期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 300mg〜約 1200mgの（2R)— 2 —プロピルオクタン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回 〜2回の投薬回数で、 1回あたり約 200mg〜約 800mgの（2R)—2 プロピルォクタ ン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回 数で、 1回あたり約 lOOmg〜約 400mgの（2R)—2 プロピルオクタン酸を経口投与 することを特徴とする前記 [120]記載の医薬； [121] oral administration of about lOOmg to about 400mg of (2R) -2-propyloctanoic acid per dose with a dosing frequency of 1 to 2 times a day during a dosing period of about 1 week to about 2 weeks; About 1 week During a dosing period of about 2 weeks, about 200 mg to about 800 mg of (2R) -2 propyloctanoic acid is orally administered once a day or twice a day, followed by about 1 week to about 3 During the annual dosing period, about 300 mg to about 1200 mg of (2R) -2-propyloctanoic acid is orally administered once a day or twice a day, followed by about 1 week to about 2 weeks During the dosing period, oral administration of about 200 mg to about 800 mg of (2R) -2-propyloctanoic acid per dose, once a day or twice a day, followed by a dosing period of about 1 week to about 2 weeks The pharmaceutical agent according to the above [120], wherein about 1OOmg to about 400mg of (2R) -2-propyloctanoic acid is orally administered at a dosage of 1 to 2 times a day;
[122]約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R) —2—プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬 回数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 12週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 600mgの（2R)—2 プ 口ピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間の 投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2—プロピルォ クタン酸を経口投与することを特徴とする前記 [121]記載の医薬；  [122] About 200 mg of (2R) -2-propyloctanoic acid is administered orally at a single dosing frequency per day during the dosing period of about 1 week, followed by a dosing period of about 1 week Approximately 400 mg of (2R) -2 propyloctanoic acid is orally administered once a day for the number of doses, and about 600 mg per dose for the following 12-day dosing period. (2R) —2 oral piroctanoic acid is orally administered, followed by oral administration of about 400 mg of (2R) -2 propyloctanoic acid once a day during the subsequent dosing period of about 1 week In the above-mentioned [121], wherein about 200 mg of (2R) -2-propyloctanoic acid is orally administered once per day during the subsequent dosing period of about 1 week. Medicine;
[123]併用薬の投与量低減剤である前記 [112]、 [115]または [116]記載の医薬； [ 124]併用薬の投与量を併用薬単独投与時の投与量の 2分の 1〜 10分の 1に低減 することを特徴とする前記 [123]記載の医薬； [123] The drug according to the above [112], [115] or [116], which is a dose reducing agent for a concomitant drug; [124] the dose of the concomitant drug is half of the dose when the concomitant drug is administered alone The pharmaceutical according to [123], which is reduced to ˜1 / 10;
[125]併用薬の副作用改善剤である前記 [112]、 [115]または [116]記載の医薬； [125] The medicament according to [112], [115] or [116], which is an agent for improving side effects of concomitant drugs;
[126]副作用がウエアリングオフ現象、オン一オフ現象、ディレイドオン現象、ノーオン 現象、ジスキネジァおよび Zまたはすくみ現象である前記 [125]記載の医薬； [126] The medicament according to [125], wherein the side effect is a wear ring-off phenomenon, an on-off phenomenon, a delayed on phenomenon, a no-on phenomenon, dyskinesia, and Z or freezing phenomenon;
[127]併用薬のウエアリングオフ現象改善剤である前記 [126]記載の医薬；  [127] The medicament according to [126] above, which is an agent for improving the wear-off phenomenon of a concomitant drug;
[128]併用薬がレポドパ製剤、レポドパ ·ベンセラジド配合剤、レポドパ'カルビドパ配 合剤および Zまたはメシル酸ブロモクリプチンである前記 [123]または [125]記載の 医薬；  [128] The drug according to [123] or [125], wherein the concomitant drug is a levodopa preparation, a levodopa-benserazide combination agent, a levodopa carbidopa combination agent and Z or bromocriptine mesylate;
[129] (2R)—2 プロピルオクタン酸とレポドパ製剤と力もなる医薬であって、（2R) 2 プロピルオクタン酸の投与量力 患者の体重 lkgあたり約 3mg〜約 60mgであ つて、レポドパ製剤の投与量力 患者の体重 lkgあたり約 3mg〜約 60mgである前記 [128]記載の医薬； [129] (2R) -2 Propyl octanoic acid and levodopa formulation, which is also a powerful drug, (2R) 2 Propyl octanoate dosage power About 3 mg to about 60 mg per kg patient body weight The dosage according to the repodopa preparation, wherein the drug is about 3 mg to about 60 mg per kg body weight of the patient;
[130] (2R)—2 プロピルオクタン酸とレボドパ 'ベンセラジド（4 : 1)配合剤とからな る医薬であって、（2R)— 2—プロピルオクタン酸の投与量力 患者の体重 lkgあたり 約 3mg〜約 60mgであって、レボドパ 'ベンセラジド（4 : 1)配合剤の投与量力 患者 の体重 lkgあたり約 2mg〜約 20mgである前記 [128]記載の医薬；  [130] (2R) -2 A drug consisting of a combination of propyloctanoic acid and levodopa'benserazide (4: 1), and the dosage of (2R) -2-propyloctanoic acid is about 3 mg per kg body weight of the patient. The pharmaceutical agent according to the above [128], which is about 60 mg and has a dosage strength of a combination of levodopa and benserazide (4: 1) of about 2 mg to about 20 mg per kg body weight of the patient;
[131] (2R)—2 プロピルオクタン酸とレボドパ 'カルビドパ（10 : 1)配合剤とからなる 医薬であって、（2R)— 2—プロピルオクタン酸の投与量力 患者の体重 lkgあたり約 3mg〜約 60mgであって、レボドノ 'カルビドパ（10 : 1)配合剤の投与量力 患者の 体重 lkgあたり約 2mg〜約 15mgである前記 [128]記載の医薬； [131] (2R) -2 Medicament consisting of propyloctanoic acid and levodopa'carbidopa (10: 1) combination drug, and (2R) -2-propyloctanoic acid dose power About 3mg / kg of patient body weight The pharmaceutical agent according to the above [128], which is about 60 mg, and the dosage power of the combination of levodono and carbidopa (10: 1) is about 2 mg to about 15 mg per kg body weight of the patient;
[132] (2R) 2 プロピルオクタン酸とメシル酸ブロモクリプチンとからなる医薬であ つて、（2R)— 2 プロピルオクタン酸の投与量力 患者の体重 lkgあたり約 3mg〜 約 60mgであって、メシル酸ブロモクリプチンの投与量力 患者の体重 lkgあたり約 0. Olmg〜約 lmgである前記 [128]記載の医薬； [132] (2R) 2-propyloctanoic acid and bromocriptine mesylate, (2R) -2 propyloctanoic acid dosage power of about 3 mg to about 60 mg per kg of patient body weight, bromocriptine mesylate The drug according to the above [128], which is about 0. Olmg to about 1 mg per 1 kg body weight of the patient;
[133]レポドパ製剤、レポドパ ·ベンセラジド配合剤およびレポドパ ·カルビドパ配合剤 力 選ばれる 1種または 2種以上と、 (2R)—2—プロピルオクタン酸、その塩、その溶 媒和物またはそれらのプロドラッグとからなる経口投与用パーキンソン病および Zま たはパーキンソン症候群の予防、治療および Zまたは症状進展抑制用医薬であって 、約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2— プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数 で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 12週 間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 600mgの（2R)—2 プロピ ルォクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回 あたり約 400mgの（2R)— 2 プロピルオクタン酸を経口投与し、続く約 1週間の投 薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2—プロピルォクタ ン酸を経口投与することを特徴とする医薬；  [133] Lepodopa formulation, levodopa-benserazide compound and levodopa-carbidopa compound force One or more selected, and (2R) -2-propyloctanoic acid, its salts, its solvates or their pros A drug for the prevention, treatment and prevention of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome for oral administration consisting of a drug, which is administered once a day during a dosing period of about 1 week. Approximately 200 mg (2R) -2-propyloctanoic acid is orally administered per dose, followed by approximately 400 mg (2R) -2 propyloctane per dose, once a day for the following dosing period The drug is administered orally, followed by approximately 600 mg of (2R) -2 propruccinic acid per dose during the subsequent 12-week dosing period, followed by approximately 1 week of dosing 1 dose per day during the period Approximately 400 mg of (2R) -2 propyloctanoic acid orally, followed by approximately 200 mg of (2R) -2-propyloctane per dose, once a day during the next week of administration A medicine characterized by orally administering an acid;
[134] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグを有効成分として含有する医薬組成物を経口投与することを特徴とする哺乳動 物におけるパーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症状進展抑制方法； [134] (2R) 2-propyloctanoic acid, a salt thereof, a solvate thereof, or a pharmaceutical composition containing the prodrug thereof as an active ingredient is orally administered. Prevention, treatment and Z or symptom progression suppression of Parkinson's disease and Z or Parkinson's syndrome in the body;
[135] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグと、パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zま たは症状進展抑制薬力 なる医薬を経口投与することを特徴とする哺乳動物におけ るパーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは 症状進展抑制方法；  [135] (2R) 2-Propyloctanoic acid, its salt, its solvate, or their prodrug, and a drug that prevents or treats Parkinson's disease and Z or Parkinson's syndrome and suppresses Z or symptom progression A method for the prevention, treatment and inhibition of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome in mammals, characterized by oral administration;
[136]経口投与用のパーキンソン病および Zまたはパーキンソン症候群の予防、治 療および Zまたは症状進展抑制剤を製造するための（2R)— 2—プロピルオクタン酸 、その塩、その溶媒和物またはそれらのプロドラッグを有効成分として含有する医薬 組成物の使用；  [136] (2R) —2-Propyloctanoic acid, a salt thereof, a solvate thereof or the like to prevent or treat Parkinson's disease and Z or Parkinson's syndrome for oral administration and to produce a Z or symptom progression inhibitor Use of a pharmaceutical composition containing a prodrug of
[137]経口投与用のパーキンソン病および Zまたはパーキンソン症候群の予防、治 療および Zまたは症状進展抑制剤を製造するための、（2R)— 2—プロピルオクタン 酸、その塩、その溶媒和物またはそれらのプロドラッグと、パーキンソン病および Zま たはパーキンソン症候群の予防、治療および Zまたは症状進展抑制薬力 なる医薬 の使用；  [137] Prevention or treatment of Parkinson's disease and Z or Parkinson's syndrome for oral administration and (2R) -2-propyloctanoic acid, its salt, its solvate or Their prodrugs and the use of drugs that prevent or treat Parkinson's disease and Z or Parkinson's syndrome and prevent Z or symptom progression;
[138]約 1週間〜約 3ヶ月間の投薬期間中、 1日 1回〜 3回の投薬回数で、 1回あたり 約 lOOmg〜約 1200mgの（2R)— 2 プロピルオクタン酸を経口投与し、続く約 1週 間〜 3ヶ月間の投薬期間中、 1日 1回〜 3回の投薬回数で、 1回あたり約 lOOmg〜約 1200mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜約 3年間の 投薬期間中、 1日 1回〜 3回の投薬回数で、 1回あたり約 lOOmg〜約 1200mgの（2R )—2 プロピルオクタン酸を経口投与し、続く約 1週間〜約 3ヶ月間の投薬期間中、 1日 1回〜 3回の投薬回数で、 1回あたり約 lOOmg〜約 1200mgの（2R)—2 プロピ ルォクタン酸を経口投与し、続く約 1週間〜約 3ヶ月間の投薬期間中、 1日 1回〜 3回 の投薬回数で、 1回あたり約 lOOmg〜約 1200mgの（2R)—2 プロピルオクタン酸 を経口投与することを特徴とする前記 [120]記載の医薬；  [138] During a dosing period of about 1 week to about 3 months, orally administered about lOOmg to about 1200 mg of (2R) -2-propyloctanoic acid per dose, with 1 to 3 dosing times per day, During the subsequent dosing period of about 1 week to 3 months, oral administration of about lOOmg to about 1200 mg of (2R) -2 propyloctanoic acid per dose is performed once to 3 times a day. During the dosing period of 1 week to about 3 years, oral administration of about lOOmg to about 1200mg of (2R) -2 propyloctanoic acid per dose is performed once to 3 times a day, followed by about 1 week to During the dosing period of about 3 months, about 1 to 3 doses per day, orally about lOOmg to about 1200mg of (2R) -2 proprucanoic acid is administered orally, followed by about 1 week to about 3 [120] The above-mentioned [120], characterized by orally administering about lOO mg to about 1200 mg of (2R) -2 propyloctanoic acid per dose during a monthly dosing period with 1 to 3 dosing times per day Listed medicines;
[201] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグと、パーキンソン病および Zまたはパーキンソン症候群の予防および Zまたは治 療薬とを組み合わせてなるパーキンソン病および Zまたはパーキンソン症候群の予 防および Zまたは治療剤； [201] (2R) 2 Propyloctanoic acid, salt, solvate or prodrug thereof, and prevention and Z or treatment of Parkinson's disease and Z or Parkinson's syndrome Preventive and Z or therapeutic agent for Parkinson's disease and Z or Parkinson's syndrome in combination with therapies;
[202]併用薬の投与量低減剤である前記 [201]記載の剤；  [202] The agent according to the above [201], which is a dose reducing agent for a concomitant drug;
[203]併用薬の投与量を併用薬単独投与時の投与量の 1Z2〜： LZ10に低減する 剤である前記 [202]記載の剤；  [203] The agent according to the above [202], which is an agent that reduces the dose of the concomitant drug to 1Z2 to: LZ10 when the concomitant drug is administered alone;
[204]併用薬がレポドパ製剤、ドパミン受容体作動薬、ドパミン遊離促進薬、ドパミン 取り込み阻害薬、ドパミン作用薬、中枢性抗コリン薬、芳香族 L—アミノ酸脱炭酸酵素 阻害薬 (DCI)、モノアミン酸ィ匕酵素（MAO— B)阻害薬、カテコール— O—メチルト ランスフェラーゼ (COMT)阻害薬、ノルェピネフリン (ノルアドレナリン)補充薬、 GA BA受容体調節薬、 GABA受容体調節薬、アデノシン A2A受容体遮断薬、アポト [204] Concomitant drugs are repodopa, dopamine receptor agonist, dopamine release promoter, dopamine uptake inhibitor, dopaminergic agent, central anticholinergic agent, aromatic L-amino acid decarboxylase inhibitor (DCI), monoamine Acid-enzyme (MAO-B) inhibitor, catechol-O-methyltransferase (COMT) inhibitor, norepinephrine (noradrenaline) supplement, GA BA receptor modulator, GABA receptor modulator, adenosine A2A receptor blockade Medicine, apoto
A B A B
一シス阻害薬、神経分化，再生促進薬、神経栄養因子、脳機能賦活薬、 Rho—キナ ーゼ阻害薬および β受容体遮断薬から選択される 1種以上である前記 [202]記載の 剤； The agent according to the above [202], which is at least one selected from a single cis inhibitor, a neuronal differentiation, regeneration promoting agent, a neurotrophic factor, a brain function activator, a Rho-kinase inhibitor, and a β receptor blocker. ;
[205]併用薬がレポドパ製剤、レポドパ .ベンセラジド配合剤、レポドパ .カルビドパ配 合剤および Ζまたはメシル酸プロモクリブチンである前記 [202]記載の剤；  [205] The agent according to [202], wherein the concomitant drug is a repodopa preparation, a levodopa benserazide combination agent, a levodopa carbidopa combination agent, and sputum or promocributine mesylate;
[206]併用薬の副作用改善剤である前記 [201]記載の剤； [206] The agent according to [201], which is an agent for improving side effects of concomitant drugs;
[207]副作用がウエアリングオフ現象、オンアンドオフ現象および Ζまたはアップアン ドダウン現象である前記 [206]記載の剤；  [207] The agent according to [206], wherein the side effects are a wear ring-off phenomenon, an on-and-off phenomenon, and a wrinkle or up-and-down phenomenon;
[208]併用薬のウエアリングオフ現象改善剤である前記 [207]記載の剤；  [208] The agent according to [207] above, which is an agent for improving the wear-off phenomenon of a concomitant drug;
[209]併用薬がレポドパ製剤、ドパミン受容体作動薬、ドパミン遊離促進薬、ドパミン 取り込み阻害薬、ドパミン作用薬、中枢性抗コリン薬、芳香族 L—アミノ酸脱炭酸酵素 阻害薬 (DCI)、モノアミン酸ィ匕酵素（MAO— Β)阻害薬、カテコール— Ο—メチルト ランスフェラーゼ (COMT)阻害薬、ノルェピネフリン (ノルアドレナリン)補充薬、 GA ΒΑ受容体調節薬、 GABA受容体調節薬、アデノシン A2A受容体遮断薬、アポト[209] Concomitant drugs are repodopa, dopamine receptor agonist, dopamine release promoter, dopamine uptake inhibitor, dopaminergic agent, central anticholinergic agent, aromatic L-amino acid decarboxylase inhibitor (DCI), monoamine Acid 匕 enzyme (MAO- Β) inhibitor, catechol- Ο-methyltransferase (COMT) inhibitor, norepinephrine (noradrenaline) supplement, GA ΒΑ receptor modulator, GABA receptor modulator, adenosine A2A receptor blockade Medicine, apoto
A B A B
一シス阻害薬、神経分化，再生促進薬、神経栄養因子、脳機能賦活薬、 Rho—キナ ーゼ阻害薬および β受容体遮断薬から選択される 1種以上である前記 [206]記載の 剤； The agent according to the above [206], which is at least one selected from a single cis inhibitor, a neuronal differentiation, regeneration promoting agent, a neurotrophic factor, a brain function activator, a Rho-kinase inhibitor, and a β receptor blocker. ;
[210]併用薬がレポドパ製剤、レポドパ ·ベンセラジド配合剤、レポドパ'カルビドパ配 合剤および Zまたはメシル酸プロモクリブチンである前記 [206]記載の剤； [210] Concomitant medications are levodopa, levodopa / benserazide, levodopa carbidopa The agent according to the above [206], which is a mixture and Z or promocributine mesylate;
[211]パーキンソン病および Zまたはパーキンソン症候群の治療薬がレポドパ製剤、 レポドパ .ベンセラジド配合剤、レポドパ ·カルビドパ配合剤および/またはメシル酸 ブロモクリプチンである前記 [202]または [206]記載の剤； [211] The agent according to the above [202] or [206], wherein the therapeutic agent for Parkinson's disease and Z or Parkinson's syndrome is a repodopa preparation, a levodopa benserazide combination preparation, a levodopa carbidopa combination preparation and / or bromocriptine mesylate;
[212] (2R) 2 プロピルオクタン酸とレポドパ製剤とを組み合わせてなる剤であつ て、（2R)— 2 プロピルオクタン酸の投与量力 患者の体重 lkgあたり約 3mg〜約 6 Omgであって、レボドパ製剤の投与量力 患者の体重 lkgあたり約 3mg〜約 60mg である前記 [211]記載の剤；  [212] (2R) 2 Propyloctanoic acid and levodopa formulation, (2R) -2 Dosyloctanoic acid dosage power About 3 mg to about 6 Omg per kg of patient body weight, levodopa The dosage according to the above [211], which is about 3 mg to about 60 mg per kg body weight of the patient;
[213] (2R)—2 プロピルオクタン酸とレボドパ 'ベンセラジド（4 : 1)配合剤とを組み 合わせてなる剤であって、（2R)— 2—プロピルオクタン酸の投与量力 患者の体重 1 kgあたり約 3mg〜約 60mgであって、レボドノ 'ベンセラジド（4 : 1)配合剤の投与量 力 患者の体重 lkgあたり約 2mg〜約 20mgである前記 [211]記載の剤；  [213] (2R) —2 Propyloctanoic acid and levodopa 'benserazide (4: 1) combination drug, (2R) — 2-propyloctanoic acid dose power Patient weight 1 kg The agent according to the above [211], which is about 3 mg to about 60 mg per dose and is about 2 mg to about 20 mg per kg of body weight of the patient, the dosage of levodono'benserazide (4: 1) combination;
[214] (2R)—2 プロピルオクタン酸とレボドパ 'カルビドパ（10 : 1)配合剤とを組み 合わせてなる剤であって、（2R)— 2—プロピルオクタン酸の投与量力 患者の体重 1 kgあたり約 3mg〜約 60mgであって、レボドノ 'カルビドパ（10： 1)配合剤の投与量 力 患者の体重 lkgあたり約 2mg〜約 15mgである前記 [211]記載の剤； [214] (2R) -2 Propyloctanoic acid combined with levodopa'carbidopa (10: 1) combination, and (2R) — 2-propyloctanoic acid dose power Patient weight 1 kg The agent according to the above [211], which is about 3 mg to about 60 mg per dose and is about 2 mg to about 15 mg per kg of body weight of the patient, the dosage of levodono carbidopa (10: 1) combination drug;
[215] (2R) 2 プロピルオクタン酸とメシル酸ブロモクリプチンとを組み合わせてな る剤であって、（2R)— 2—プロピルオクタン酸の投与量力 患者の体重 lkgあたり約 3mg〜約 60mgであって、メシル酸ブロモクリプチンの投与量力 患者の体重 lkgあ たり約 O.Olmg〜約 lmgである前記 [211]記載の剤； [215] (2R) 2 Propyloctanoic acid and bromocriptine mesylate combined to give (2R) -2-propyloctanoic acid dosage power of about 3 mg to about 60 mg per kg patient body weight , The dosage strength of bromocriptine mesylate, the agent according to the above [211], which is about O.Olmg to about lmg per lkg body weight of the patient;
[216]哺乳動物におけるパーキンソン病および Zまたはパーキンソン症候群を予防 および Zまたは治療する方法であって、（2R)— 2—プロピルオクタン酸、その塩、そ の溶媒和物またはそれらのプロドラッグと、パーキンソン病および Zまたはパーキンソ ン症候群の治療薬とを組み合わせて、哺乳動物に投与することを含む併用薬の投与 量低減方法；  [216] A method for preventing and Z or treating Parkinson's disease and Z or Parkinson's syndrome in a mammal, comprising (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, A method for reducing the dose of a concomitant drug comprising administering to a mammal in combination with a therapeutic drug for Parkinson's disease and Z or Parkinson's syndrome;
[217]哺乳動物におけるパーキンソン病および Zまたはパーキンソン症候群を予防 および Zまたは治療する方法であって、（2R)— 2—プロピルオクタン酸、その塩、そ の溶媒和物またはそれらのプロドラッグと、パーキンソン病および Zまたはパーキンソ ン症候群の治療薬とを組み合わせて、哺乳動物に投与することを含む併用薬の副作 用改善方法； [217] A method of preventing and Z or treating Parkinson's disease and Z or Parkinson's syndrome in a mammal, comprising (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, Parkinson's disease and Z or Parkinso A method for improving the side effects of a concomitant drug comprising administering to a mammal in combination with a therapeutic agent for N syndrome;
[218]併用薬の投与量低減剤を製造するための、 （2R)—2 プロピルオクタン酸、 その塩、その溶媒和物またはそれらのプロドラッグと、パーキンソン病および Zまたは パーキンソン症候群の治療薬とを組み合わせてなるパーキンソン病および Zまたは パーキンソン症候群の予防および Zまたは治療剤の使用；  [218] (2R) -2 propyloctanoic acid, a salt, a solvate thereof or a prodrug thereof, and a therapeutic agent for Parkinson's disease and Z or Parkinson's syndrome Prevention of Parkinson's disease and Z or Parkinson's syndrome, and the use of Z or therapeutic agent comprising:
[219]併用薬の副作用改善剤を製造するための、 （2R)—2 プロピルオクタン酸、 その塩、その溶媒和物またはそれらのプロドラッグと、パーキンソン病および Zまたは パーキンソン症候群の治療薬とを組み合わせてなるパーキンソン病および Zまたは パーキンソン症候群の予防および Zまたは治療剤の使用； [219] (2R) -2 propyloctanoic acid, a salt, a solvate thereof or a prodrug thereof, and a therapeutic agent for Parkinson's disease and Z or Parkinson's syndrome Combined use of Parkinson's disease and Z or Parkinson's syndrome prevention and use of Z or therapeutic agents;
[220]併用薬の治療効果増強剤である前記 [201]記載の剤； [220] The agent described in [201] above, which is a therapeutic effect enhancer of a concomitant drug;
[301] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグを有効成分として含有し、パーキンソン病および Zまたはパーキンソン症候群の 予防、治療および Zまたは症状進展抑制薬と組み合わせて投与することを特徴とす るパーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは 症状進展抑制剤； [301] (2R) 2 Propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof as an active ingredient, and a preventive, therapeutic and Z or symptom progression inhibitor for Parkinson's disease and Z or Parkinson's syndrome Parkinson's disease and Z or Parkinson's syndrome prevention, treatment and Z or symptom progression inhibitor characterized by administration in combination;
[302]投与が経口投与である前記 [301]記載の剤；  [302] The agent according to the above [301], wherein the administration is oral administration;
[303] 1回あたりの（2R)— 2 プロピルオクタン酸またはその塩の経口投与量が約 5 Omg〜約 1200mgである前記 [302]記載の剤；  [303] The agent according to the above [302], wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 5 Omg to about 1200 mg;
[304] 1回あたりの（2R)— 2 プロピルオクタン酸またはその塩の経口投与量が約 1 [304] The oral dose of (2R) —2 propyloctanoic acid or its salt per dose is about 1
OOmg〜約 600mgである前記 [303]記載の剤； The agent according to the above [303], which is OO mg to about 600 mg;
[305]投薬期間が約 1ヶ月間〜約 5年間である前記 [302]記載の剤；  [305] The agent of [302], wherein the dosing period is from about 1 month to about 5 years;
[306]約 1ヶ月間〜約 5年間の投薬期間中、 1日 1回〜 5回の投薬回数で、 1回あたり 約 50mg〜約 1200mgの（2R)—2 プロピルオクタン酸またはその塩を経口投与す ることを特徴とする前記 [302]記載の剤；  [306] About 50 mg to about 1200 mg of (2R) -2 propyloctanoic acid or its salt is orally administered once a day to 5 times during a dosing period of about 1 month to about 5 years The agent according to the above [302], which is administered;
[307]約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 lOOmg〜約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜 約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 200mg〜約 800 mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜約 3年間の投薬 期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 300mg〜約 1200mgの（2R)— 2 —プロピルオクタン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回 〜2回の投薬回数で、 1回あたり約 200mg〜約 800mgの（2R)—2 プロピルォクタ ン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回 数で、 1回あたり約 lOOmg〜約 400mgの（2R)—2 プロピルオクタン酸を経口投与 することを特徴とする前記 [306]記載の剤； [307] Oral administration of about lOOmg to about 400mg of (2R) -2 propyloctanoic acid per dose, followed by 1 to 2 doses per day during a dosing period of about 1 week to about 2 weeks About 200 mg to about 800 per dose during the dosing period of about 1 week to about 2 weeks, with 1 to 2 doses per day mg (2R) -2 propyloctanoic acid orally, followed by dosing once to twice a day for a dosing period of about 1 week to about 3 years, about 300 mg to about 1200 mg per dose ( 2R) — 2 -Propyloctanoic acid orally, followed by a dose of about 200 mg to about 800 mg (2R) per dose with a dosing frequency of 1 to 2 times a day for a subsequent dosing period of about 1 week to about 2 weeks —2 Propoctanic acid administered orally, followed by about 1 to 2 weeks of dosing for about 1 week to about 2 weeks, with about lOOmg to about 400 mg of (2R) —2 per dose The agent according to the above [306], wherein propyloctanoic acid is orally administered;
[308]約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R) —2—プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬 回数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 12週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 600mgの（2R)—2 プ 口ピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間の 投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2—プロピルォ クタン酸を経口投与することを特徴とする前記 [307]記載の剤；  [308] About 200 mg of (2R) -2-propyloctanoic acid is orally administered at a single dosing frequency per day during a dosing period of about 1 week, and during the following dosing period of about 1 week, 1 Approximately 400 mg of (2R) -2 propyloctanoic acid is orally administered once a day, and approximately 600 mg per dose during the subsequent 12-week dosing period. (2R) —2 oral piroctanoic acid is orally administered, followed by oral administration of about 400 mg of (2R) -2 propyloctanoic acid once a day during the subsequent dosing period of about 1 week In the above-mentioned [307], about 200 mg of (2R) -2-propylactanoic acid is orally administered once per day during the subsequent dosing period of about 1 week. Agent;
[309]併用薬の投与量を低減する剤である前記 [301]記載の剤； [309] The agent described in [301] above, which is an agent for reducing the dose of a concomitant drug;
[310]併用薬の投与量を併用薬単独投与時の投与量の 2分の 1〜 10分の 1に低減 する前記 [309]記載の剤； [310] The agent according to [309], wherein the dose of the concomitant drug is reduced to one-half to one-tenth of the dose when the concomitant drug is administered alone;
[311]併用薬の副作用を改善する剤である前記 [301]記載の剤；  [311] The agent according to the above [301], which is an agent for improving side effects of a concomitant drug;
[312]副作用がウエアリングオフ現象、オンアンドオフ現象および Zまたはアップアン ドダウン現象である前記 [311]記載の剤；  [312] The agent according to [311] above, wherein the side effects are wear ring-off phenomenon, on-and-off phenomenon and Z or up-and-down phenomenon;
[313]副作用がウエアリングオフ現象である前記 [312]記載の剤；  [313] The agent according to [312], wherein the side effect is a wear ring-off phenomenon;
[314]併用薬がレポドパ製剤、ドパミン受容体作動薬、ドパミン遊離促進薬、ドパミン 取り込み阻害薬、ドパミン作用薬、中枢性抗コリン薬、芳香族 L アミノ酸脱炭酸酵素 阻害薬、モノアミン酸ィ匕酵素阻害薬、カテコール o メチルトランスフェラーゼ阻害 薬、ノルェピネフリン補充薬、 GABA受容体調節薬、 GABA受容体調節薬、アデ  [314] Concomitant drugs are repodopa, dopamine receptor agonist, dopamine release promoter, dopamine uptake inhibitor, dopaminergic agent, central anticholinergic agent, aromatic L amino acid decarboxylase inhibitor, monoamine tyrosine enzyme Inhibitor, catechol o methyltransferase inhibitor, norepinephrine replacement agent, GABA receptor modulator, GABA receptor modulator,
A B  A B
ノシン A2A受容体遮断薬、アポトーシス阻害薬、神経分化，再生促進薬、神経栄養 因子、脳機能賦活薬、 Rho キナーゼ阻害薬および β受容体遮断薬から選択され る 1種以上である前記 [309]または [311]記載の剤； Nosin A2A receptor blocker, apoptosis inhibitor, neuronal differentiation, regeneration promoter, neurotrophic factor, brain function activator, Rho kinase inhibitor, and β receptor blocker The agent according to [309] or [311], which is one or more of;
[315]併用薬がレポドパ製剤、レポドパ ·ベンセラジド配合剤、レポドパ'カルビドパ配 合剤および Zまたはメシル酸ブロモクリプチンである前記 [309]または [311]記載の 剤；  [315] The agent according to [309] or [311], wherein the concomitant drug is a levodopa preparation, a levodopa-benserazide combination agent, a levodopa carbidopa combination agent and Z or bromocriptine mesylate;
[316]パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制薬が、レポドパ製剤、ドパミン受容体作動薬、ドパミン遊離促進薬、 ドパミン取り込み阻害薬、ドパミン作用薬、中枢性抗コリン薬、芳香族 L アミノ酸脱 炭酸酵素阻害薬、モノアミン酸ィ匕酵素阻害薬、カテコール O メチルトランスフェラ ーゼ阻害薬、ノルェピネフリン補充薬、 GABA受容体調節薬、 GABA受容体調節  [316] Prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome and inhibitors of Z or symptom progression are levodopa, dopamine receptor agonists, dopamine release promoters, dopamine uptake inhibitors, dopamine agonists, central anti-drugs Choline drugs, aromatic L amino acid decarboxylase inhibitors, monoamine acid enzyme inhibitors, catechol O methyltransferase inhibitors, norepinephrine supplements, GABA receptor modulators, GABA receptor modulators
A B  A B
薬、アデノシン A2A受容体遮断薬、アポトーシス阻害薬、神経分化，再生促進薬、神 経栄養因子、脳機能賦活薬、 Rho キナーゼ阻害薬および β受容体遮断薬から選 択される 1種以上である前記 [301]記載の剤； One or more selected from drugs, adenosine A2A receptor blockers, apoptosis inhibitors, neuronal differentiation, regeneration promoters, neurotrophic factors, brain function activators, Rho kinase inhibitors and β receptor blockers The agent according to [301] above;
[317]パーキンソン病および Ζまたはパーキンソン症候群の予防、治療および Ζまた は症状進展抑制薬が、レポドパ製剤、レポドパ 'ベンセラジド配合剤、レポドパ 'カル ビドパ配合剤および Ζまたはメシル酸プロモクリブチンである前記 [301]記載の剤； [318] (2R)—2 プロピルオクタン酸を有効成分として含有し、レポドパ製剤と組み 合わせて投与することを特徴とするパーキンソン病および Ζまたはパーキンソン症候 群の予防、治療および Ζまたは症状進展抑制剤であって、 (2R) 2—プロピルオタ タン酸の投与量が、患者の体重 lkgあたり約 3mg〜約 60mgであって、レボドパ製剤 の投与量が、患者の体重 lkgあたり約 3mg〜約 60mgである前記 [317]記載の剤； [319] (2R)—2 プロピルオクタン酸を有効成分として含有し、レボドパ 'ベンセラジ ド (4： 1)配合剤と組み合わせて投与することを特徴とするパーキンソン病および Zま たはパーキンソン症候群の予防、治療および Zまたは症状進展抑制剤であって、 (2 R)—2 プロピルオクタン酸の投与量力 患者の体重 lkgあたり約 3mg〜約 60mg であって、レポドパ 'ベンセラジド (4 : 1)配合剤の投与量力 患者の体重 lkgあたり約 2mg〜約 20mgである前記 [317]記載の剤；  [317] Said prevention, treatment and prevention of epilepsy or symptom progression of Parkinson's disease and epilepsy or Parkinson's syndrome are levodopa, levodopa 'benserazide, levodopa' carbidopa and パ or promocributin mesylate [301] The agent according to [301]; [318] (2R) -2 Prevention and treatment of Parkinson's disease and epilepsy or Parkinson's syndrome group characterized by comprising propyloctanoic acid as an active ingredient and administered in combination with a repodopa preparation And a sputum or symptom progression inhibitor, wherein the dose of (2R) 2-propylotatanate is about 3 mg to about 60 mg per kg of patient body weight, and the dose of levodopa is about 1 kg of patient body weight The agent according to the above [317], which is about 3 mg to about 60 mg; [319] (2R) -2 containing propyloctanoic acid as an active ingredient, and containing levodopa'benserazide (4: 1) (2R) -2 Propyloctanoic acid dosage power Patient weight, prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome characterized by administration in combination with an agent The agent according to the above [317], which is about 3 mg to about 60 mg per kg, and has a dosage power of lepodopa'benserazide (4: 1) combination, about 2 mg to about 20 mg per kg body weight of the patient;
[320] (2R)—2 プロピルオクタン酸を有効成分として含有し、レポドパ 'カルビドパ（ [320] (2R) —2 Contains propyloctanoic acid as an active ingredient, and levodopa carbidopa (
10： 1)配合剤と組み合わせて投与することを特徴とするパーキンソン病および Zまた はパーキンソン症候群の予防、治療および Zまたは症状進展抑制剤であって、 (2R )一 2 プロピルオクタン酸の投与量力 患者の体重 lkgあたり約 3mg〜約 60mgで あって、レポドパ 'カルビドパ（10 : 1)配合剤の投与量力 患者の体重 lkgあたり約 2 mg〜約 15mgである前記 [317]記載の剤； 10: 1) Parkinson's disease and Z or Is a prophylaxis, treatment and Z or symptom progression inhibitor for Parkinson's syndrome, and (2R) 1-2 propyloctanoic acid dosage power is about 3 mg to about 60 mg per kg body weight of the patient, and levodopa carbidopa (10: 1 ) Dosage power of the combination agent The agent according to the above [317], which is about 2 mg to about 15 mg per kg body weight of the patient;
[321] (2R) 2 プロピルオクタン酸を有効成分として含有し、メシル酸ブロモクリプ チンと組み合わせて投与することを特徴とするパーキンソン病および Zまたはパーキ ンソン症候群の予防、治療および Zまたは症状進展抑制剤であって、 (2R) 2—プ 口ピルオクタン酸の投与量力 患者の体重 lkgあたり約 3mg〜約 60mgであって、メ シル酸ブロモクリプチンの投与量力 患者の体重 lkgあたり約 O.Olmg〜約 lmgであ る前記 [317]記載の剤；  [321] (2R) 2 Propyloctanoic acid as an active ingredient, which is administered in combination with bromocriptine mesylate, and prevents or treats Parkinson's disease and Z or Parkinson's syndrome and suppresses Z or symptom progression The dose power of (2R) 2-pupruoctanoic acid is about 3 mg to about 60 mg per kg body weight of the patient, and the dose power of bromocriptine mesylate is about O.Olmg to about lmg per kg body weight of the patient. An agent according to [317] above;
[322] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグを有効成分として含有し、レポドパ製剤、レポドパ 'ベンセラジド配合剤およびレ ボドパ 'カルビドパ配合剤から選ばれる 1種または 2種以上と組み合わせて投与する ことを特徴とするパーキンソン病および Zまたはパーキンソン症候群の予防、治療お よび Zまたは症状進展抑制剤であって、（2R)— 2—プロピルオクタン酸の経口投与 量が、約 1週間の投薬期間中は 1日 1回約 200mg、続く約 1週間の投薬期間中は 1 日 1回約 400mg、続く約 12週間の投薬期間中は 1日 1回約 600mg、続く約 1週間の 投薬期間中は 1日 1回約 400mg、続く約 1週間の投薬期間中は 1日 1回約 200mgで ある剤等に関する。  [322] (2R) 2 Contains propyloctanoic acid, its salt, its solvate or their prodrug as an active ingredient, and is selected from levodopa, levodopa 'benserazide and levodopa' carbidopa ' A prophylaxis or treatment of Parkinson's disease and Z or Parkinson's syndrome characterized by administration in combination with two or more species, and an inhibitor of Z or symptom progression, orally administered (2R) -2-propyloctanoic acid The dose is about 200 mg once a day during the dosing period of about 1 week, about 400 mg once a day during the following dosing period of about 1 week, about 600 mg once a day during the dosing period of about 12 weeks, It relates to a drug that is about 400 mg once a day during the subsequent dosing period of about 1 week and about 200 mg once a day during the next dosing period of about 1 week.
本発明において、（2R)—2 プロピルオクタン酸とは、式 (A)  In the present invention, (2R) -2 propyloctanoic acid is a compound represented by the formula (A)
[化 1]
Figure imgf000023_0001
[Chemical 1]
Figure imgf000023_0001
(式中、  (Where
[化 2]  [Chemical 2]
は j8—配置を表す。 ) で示される化合物である。 Represents the j8-configuration. ) It is a compound shown by these.
[0016] (2R)—2 プロピルオクタン酸の塩としては、毒性のない、水溶性のものが好ましく 、例えば、アルカリ金属（例えば、カリウム、ナトリウム、リチウム等）の塩、アルカリ土類 金属（例えば、カルシウム、マグネシウム等）の塩、アンモ-ゥム塩 (例えば、テトラメチ ルアンモ -ゥム塩、テトラプチルアンモ-ゥム塩等）、有機アミン (例えば、メチルァミン 、ジメチルァミン、トリメチルァミン、トリエチルァミン、モノエタノールァミン、ジエタノー ルァミン、トリエタノールァミン、シクロペンチルァミン、ベンジルァミン、フエネチルアミ ン、ジシクロへキシノレアミン、ジベンジルァミン、 N, N'—ジベンジルエチレンジァミン 、トリス（ヒドロキシメチル）メチルァミン、 N—メチル D グルカミン、ピリジン、ピコリ ン、ピぺリジン等）との塩、塩基性アミノ酸 (例えば、アルギニン、リジン、オル-チン、 ヒスチジン等）との塩等が挙げられる。これらの塩のうちょり好ましくは、例えば、アル カリ金属塩または塩基性アミノ酸との塩等であり、とりわけナトリウム塩が好ましい。  [0016] The salt of (2R) -2 propyloctanoic acid is preferably a non-toxic and water-soluble salt, such as an alkali metal (eg, potassium, sodium, lithium, etc.) salt, an alkaline earth metal (eg, , Calcium, magnesium, etc.), ammonium salts (eg, tetramethyl ammonium salts, tetraptyl ammonium salts, etc.), organic amines (eg, methylamine, dimethylamine, trimethylamine, triethylamine) , Monoethanolamine, diethanolamine, triethanolamine, cyclopentylamine, benzylamine, phenethylamine, dicyclohexylamine, dibenzylamine, N, N'-dibenzylethylenediamine, tris (hydroxymethyl) methylamine, N-- Methyl D glucamine, pyridine, picoline, piperi And salts with basic amino acids (eg, arginine, lysine, orthine, histidine, etc.). Among these salts, preferred are, for example, alkali metal salts or salts with basic amino acids, and sodium salts are particularly preferred.
[0017] (2R)—2 プロピルオクタン酸またはその塩の溶媒和物としては、毒性のない、水 溶性のものが好ましぐ例えば、水、アルコール系溶媒 (例えば、メタノール、エタノー ル等)等の溶媒和物が挙げられる。  [0017] As a solvate of (2R) -2 propyloctanoic acid or a salt thereof, a non-toxic and water-soluble one is preferable. For example, water, alcohol solvents (for example, methanol, ethanol, etc.), etc. Of the solvates.
本発明において、（2R)— 2—プロピルオクタン酸のプロドラッグとは、通常、当業者 によって用いられるように、 (2R) 2—プロピルオクタン酸の誘導体であって、体内 で酵素的または化学的に変換されることで（2R)— 2—プロピルオクタン酸となる化合 物であればよぐその構造は特に限定されるものではない。（2R)— 2—プロピルオタ タン酸のプロドラッグとしては、例えば、カルボキシ基がエステルイ匕された化合物（例 えば、（2R)— 2—プロピルオクタン酸のメチルエステル、ェチルエステル、フエ-ル エステル、カルボキシメチルエステル、ジメチルァミノメチルエステル、ピバロイルォキ シメチルエステル、エトキシカルボニルォキシェチルエステル、フタリジルエステル、（ 5—メチルー 2 ォキソ 1, 3 ジォキソレンー4 ィル)メチルエステル、またはシク 口へキシルォキシカルボ-ルェチルエステル等）、カルボキシ基がアミド化された化 合物（例えば、（2R)—2—プロピルオクタン酸のメチルアミド、ェチルアミド、またはフ ェニルアミド等）、カルボキシ基が還元されたィ匕合物およびその保護体 (例えば、（2R In the present invention, the prodrug of (2R) -2-propyloctanoic acid is usually a derivative of (2R) 2-propyloctanoic acid, as used by those skilled in the art, and is enzymatic or chemical in the body. The structure is not particularly limited as long as it is a compound that becomes (2R) -2-propyloctanoic acid by being converted to. Examples of prodrugs of (2R) -2-propyloctanoic acid include compounds in which a carboxy group is esterified (for example, (2R) -2-propyloctanoic acid methyl ester, ethyl ester, phenol ester, carboxy Methyl ester, dimethylaminomethyl ester, pivalooxymethyl ester, ethoxycarbonyloxetyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3-dioxolene-4yl) methyl ester, or cyclohexoxyloxy Carbo-ruethyl ester, etc.), compounds in which the carboxy group is amidated (for example, methylamide, ethylamide, or phenylamide of (2R) -2-propyloctanoic acid), compounds in which the carboxy group is reduced, and Its protector (eg (2R
)—2—プロピルォクタノール、または酢酸の（2R)—2—プロピルォクタ-ルエステル 等)等が挙げられる。これらの化合物は公知の方法によって製造することができる。ま た、（2R)— 2 プロピルオクタン酸のプロドラッグは、廣川書店 1990年刊「医薬品の 開発」第 7卷「分子設計」 163〜198頁に記載されているような、生理的条件で (2R) 2—プロピルオクタン酸に変化するものであってもよい。さらに（2R)— 2—プロピル オクタン酸のプロドラッグは前記した塩あるいは溶媒和物（例えば、水、アルコール系 溶媒 (例えば、エタノール等)等の溶媒和物等)等であってもよぐ同位元素 (例えば、 3H、 "C、 35S、 1251等)等で標識されていてもよい。 ) —2-propyloctanol, or (2R) -2-propyloctanol ester of acetic acid Etc.). These compounds can be produced by known methods. In addition, (2R) -2-Propyloctanoic acid prodrugs are produced under physiological conditions as described in Yodogawa Shoten 1990, “Drug Development”, Vol. 7, “Molecular Design”, pages 163-198. ) It may be changed to 2-propyloctanoic acid. Further, the prodrug of (2R) -2-propyloctanoic acid may be an isotope which may be the above-mentioned salt or solvate (for example, solvate such as water, alcohol-based solvent (for example, ethanol)). It may be labeled with an element (for example, 3H, “C, 35 S, 125 1, etc.) or the like.
[0018] 本発明において、（2R)— 2 プロピルオクタン酸、その塩、その溶媒和物またはそ れらのプロドラッグとしては、（2R)— 2—プロピルオクタン酸、（2R)— 2—プロピルォ クタン酸のナトリウム塩、（2R)— 2—プロピルオクタン酸のフエネチルァミン塩、（2R) 2—プロピルオクタン酸メチルエステル等が好ましく、（2R)— 2—プロピルオクタン 酸がより好ましい。 [0018] In the present invention, (2R) -2-propyloctanoic acid, a salt, a solvate thereof or a prodrug thereof includes (2R) -2-propyloctanoic acid, (2R) -2-propylo Sodium salt of stannic acid, phenethylamine salt of (2R) -2-propyloctanoic acid, (2R) 2-propyloctanoic acid methyl ester and the like are preferable, and (2R) -2-propyloctanoic acid is more preferable.
[0019] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグ は、それ自体公知の方法、例えば、欧州特許第 0632008号明細書、国際公開第 99/5 8513号パンフレット、国際公開第 00/48982号パンフレット、特許第 3032447号明細書 、特許第 3084345号明細書、国際公開第 03/051852号パンフレット、国際公開第 04/1 10972号パンフレット等に記載された方法、これらに準ずる方法、またはコンプリヘン シヴ ·オーガニック ·トランスフォーメーションズ：ァ ·ガイド 'トゥ^ ~ ·ファンクショナル ·グ ループ.プレパレーシヨンズ、セカンド ·エディション（リチャード c.ラロック、ジョンワイ リ ~~ 7ン サンズ Inc, 1999) [し omprehensive Organic Transformations ： A uuide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)]に記載された方法等に従って、またはそれらの方法を適宜組み合わせる ことで製造することができる。反応の生成物は通常の精製手段、例えば、常圧下また は減圧下における蒸留、シリカゲルまたはケィ酸マグネシウムを用いた高速液体クロ マトグラフィー、薄層クロマトグラフィー、あるいはカラムクロマトグラフィーまたは洗浄、 再結晶等の方法により精製することができる。また所望によって、凍結乾燥等の処理 に付してもよい。  [0019] (2R) 2 Propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof is a method known per se, such as EP 0632008, WO 99/5 8513. , WO00 / 48982, pamphlet, patent 3032447, patent 3084345, WO03 / 051852, pamphlet, WO04 / 1 10972, etc. Or Comprehensive · Organic · Transformations: A Guide 'To ^ ~ · Functional · Group. Preparations, Second Edition (Richard C. Laroc, John Wyle ~~ 7's Sands Inc, 1999) [Omprehensive Organic Transformations: A uuide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)] Can be produced according to the methods described above, or by appropriately combining these methods. The product of the reaction can be obtained by conventional purification means such as distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, column chromatography or washing, recrystallization, etc. It can refine | purify by the method of. If desired, it may be subjected to treatment such as freeze-drying.
[0020] 本発明において、（2R)— 2—プロピルオクタン酸、その塩、その溶媒和物またはそ れらのプロドラッグは、実質的に純粋で単一な物質であるものに限定されず、不純物 (例えば、製造工程に由来する副生成物、溶媒、原料または分解物等)を、医薬品原 薬として許容される範囲であれば含有して ヽてもよ ヽ。医薬品原薬として許容される 不純物の含有量は、（2R)—2—プロピルオクタン酸を用いるかその塩を用いるかそ の溶媒和物を用いる力またはそのプロドラッグを用いるかでも異なるし、また、その含 有される不純物によって異なる力 例えば、重金属は約 20ppm以下、光学異性体で ある S体は約 5質量％ (好ましくは約 1.49質量％)以下、残留溶媒である 2—プロパノ ールゃヘプタンは合計約 5000ppm以下、水分は約 0.2質量％以下であることが好ま しい。また本発明に用いる（2R)—2—プロピルオクタン酸の光学純度は 99%ee以上 であることが好ましぐ 99.3%ee以上がより好適である。 In the present invention, (2R) -2-propyloctanoic acid, its salt, its solvate or its These prodrugs are not limited to those that are substantially pure and single substances, but impurities (e.g., by-products, solvents, raw materials or degradation products derived from the manufacturing process) can be removed from the drug substance. If it is within the allowable range, it may be contained. The content of impurities acceptable as an active pharmaceutical ingredient varies depending on whether (2R) -2-propyloctanoic acid, its salt, its solvate or its prodrug is used. For example, heavy metal is about 20 ppm or less, optical isomer S is about 5% by mass (preferably about 1.49% by mass), and residual solvent 2-propanol is about 20 ppm or less. It is preferable that the total amount of heptane is about 5000ppm or less and the water content is about 0.2% by mass or less. The optical purity of (2R) -2-propyloctanoic acid used in the present invention is preferably 99% ee or higher, more preferably 99.3% ee or higher.
[0021] 本発明にお 、ては、特に指示しない限り異性体はこれをすベて包含する。例えば、 不斉炭素の存在等による異性体 (R、 S体、 α、 |8配置、ェナンチォマー、ジァステレ ォマー）、旋光性を有する光学活性体 (D、 L、 d、 1体)、クロマトグラフ分離による極性 体 (高極性体、低極性体)、これらの任意の割合の混合物、ラセミ混合物等は、すべ て本発明に含まれる。 In the present invention, all isomers are included unless otherwise specified. For example, isomers (R, S, α , | 8 configuration, enantiomers, diastereomers), optically active optically active substances (D, L, d, 1), chromatographic separation due to the presence of asymmetric carbon, etc. Polar bodies (high polar bodies, low polar bodies), mixtures of these in arbitrary proportions, racemic mixtures and the like are all included in the present invention.
本発明は、前記「（2R)—2—プロピルオクタン酸、その塩、その溶媒和物またはそ れらのプロドラッグ」と「パーキンソン病および Zまたはパーキンソン症候群の予防、 治療および Zまたは症状進展抑制薬」とを組み合わせて投与し、パーキンソン病お よび Zまたはパーキンソン症候群を予防、治療および Zまたは症状進展抑制する方 法 (以下、本発明の方法と略記する場合がある。）を開示するものである。かかる方法 においては、「（2R)—2—プロピルオクタン酸、その塩、その溶媒和物またはそれら のプロドラッグと、パーキンソン病および Zまたはパーキンソン症候群の予防、治療お よび Zまたは症状進展抑制薬とを組み合わせてなるパーキンソン病および Zまたは パーキンソン症候群の予防、治療および Zまたは症状進展抑制用医薬」が用いられ る。  The present invention provides the above-mentioned “(2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof” and “prevention, treatment and inhibition of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome. A method of preventing and treating Parkinson's disease and Z or Parkinson's syndrome, and inhibiting Z or symptom progression (hereinafter sometimes abbreviated as the method of the present invention). is there. In such a method, “(2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, and prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome Is used for the prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome, and Z or symptom progression suppression medicine.
[0022] 本発明において、「（2R)— 2—プロピルオクタン酸、その塩、その溶媒和物または それらのプロドラッグと、パーキンソン病および Zまたはパーキンソン症候群の予防、 治療および Zまたは症状進展抑制薬とを組み合わせてなるパーキンソン病および Z またはパーキンソン症候群の予防、治療および Zまたは症状進展抑制用医薬」（以 下、本発明の医薬と略記する場合がある。）とは、（A)前記（2R)—2—プロピルオタ タン酸、その塩、その溶媒和物またはそれらのプロドラッグ (以下、薬物 Aと略記する 場合がある。）と、（B)パーキンソン病および Zまたはパーキンソン症候群の予防、治 療および Zまたは症状進展抑制薬 (以下、薬物 Bと略記する場合がある。）とを組み 合わせた、パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症状進展抑制用の医薬であればよぐ所望によって、（C)その他の薬物（以 下、薬物 Cと略記する場合がある。）をさらに組み合わせて投与することもできる。薬 物 Bや薬物 Cは、それ自体複数の薬物の組み合わせであってもよい。本発明の医薬 は、薬物 Aと薬物 Bを同一医薬組成物中に含むもの（いわゆる配合剤）であってもよ いし、また薬物 Aと薬物 Bを別々の医薬組成物に含むものであってもよい。薬物 Aと 薬物 Bを別々の医薬組成物に含む場合は、同時に投与してもよいし、また時間差を おいて投与してもよい。時間差をおいて投与する場合は、薬物 Aを先に投与して薬 物 Bを後に投与してもよ 、し、薬物 Bを先に投与して薬物 Aを後に投与しても構わな い。投与方法や 1日あたりの投与回数は同じでも異なっていてもよい。また、薬物 Aと 薬物 Bの質量比も特に限定されない。薬物 Cをさらに組み合わせる場合も同様であり 、配合剤として用いてもよいし、別々の医薬組成物として用いてもよい。 [0022] In the present invention, "(2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, and prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome"Parkinson's disease and Z Or, “a drug for preventing, treating and inhibiting Z or symptom progression” (hereinafter sometimes abbreviated as a drug of the present invention) of (A) (2R) -2-propylotatanic acid, its A salt, a solvate thereof, or a prodrug thereof (hereinafter sometimes abbreviated as “drug A”) and (B) prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome (hereinafter referred to as “drug A”) (It may be abbreviated as drug B.) in combination with (C) Others if desired as long as it is a drug for the prevention, treatment and inhibition of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome. Drugs (hereinafter sometimes abbreviated as “drug C”) can also be administered in combination. Drug B or drug C may itself be a combination of multiple drugs. The medicament of the present invention may be one containing drug A and drug B in the same pharmaceutical composition (so-called combination drug), or one containing drug A and drug B in separate pharmaceutical compositions. Also good. When drug A and drug B are contained in separate pharmaceutical compositions, they may be administered at the same time or may be administered with a time difference. When administration is performed with a time lag, drug A may be administered first and then drug B may be administered later, or drug B may be administered first and drug A may be administered later. The method of administration and the number of administrations per day may be the same or different. Further, the mass ratio of drug A and drug B is not particularly limited. The same applies when the drug C is further combined, and it may be used as a compounding agent or as a separate pharmaceutical composition.
本発明において、薬物 Bとして用いられる、パーキンソン病および/またはパーキン ソン症候群の予防、治療および Zまたは症状進展抑制薬としては、例えば、レポドパ (levodopa^ ード、ノ )、レボド、ノ ·ベンセラジド、酉己合剤 (levodopa + benserazide、 f^!jx. ば、レボドノ 'ベンセラジド（4 : 1)配合剤）、レボドノ 'カルビドパ配合剤（levodopa + c arbidopa、例えば、レボドノ 'カルビドパ（10 : 1)配合剤、レボドパ 'カルビドパ（4 : 1) 配合剤）、ェンタカポン'レボドノ 'カルビドパ配合剤（entacapone + levodopa + carbid opa)、メレボドノ、 (melevodopa)、メレボドノヽ'カノレビドノ 目 il合剤 (melevodopa + carbido pa)、メシノレ酸ブロモクリプチン（bromocryptine mesylate)、 aージヒドロエノレゴクリプ チン (Alpha— dihydroergocryptineノ、 7 ヽモノレフイン (apomorphineノ、ブンヒン (budipin e)、力べノレゴリン (cabergoline)、ドロキシドノヽ (droxidopa)、ェンタカポン (entacapone) 、リスリド（lisuride)、メシル酸ペルゴリド（pergolide mesylate)、ピリべジル（piribedil)、 プラミぺキソ一ノレ (pramipexole)、塩酸プラミぺキソ一ノレ水和物 (pramipexole hydrochl oride hydrate)、 酸ロビニローノレ、 ropinirole hydrochloride)、ロビニローノレ (ropinirol e)、セレギリン (selegiline)、デプレ二ノレ (deprenil)、テノレグリド (terguride)、トノレカポン (tolcapone)、メシノレ酸ラサギリン (rasagiline mesylate;、タリぺキソ一ノレ (talipexole)、 塩酸ァマンタジン (amantadine hydrochloride) ,塩酸トリへキシフエ-ジノレ (trihexyphe nidyl hydrochloride)、ビヘリプン (biperiden)、塩酸ピロヘプナン (piroheptine hydroc hloride)、塩酸マザチコ一ノレ (mazaticol hydrochloride)、塩酸メチキセン (metixene hy arochlonde)、フ—口フエナ ン (profenamine)、リノレン ~~ノレ (riluzole)、ゾ-サ ト (zonisa mide)、 CEP- 1347、サフイナミド（safinamide)、ロチゴチン（rotigotine)、 NS- 2330、スマ -ローノレ (sumanirole)、ェチレボドノ (etilevodopa)、モダフィ-ノレ (modafinil)、オラン ザピン（olanzapine)、ビフエプルノクス（bifeprunox)、 TCH- 346、塩酸サリゾタン（sariz otan hydrochloride)、 GDNF、イストラデフイリン（istradefylline)、タランパネル（talam panel)、レテプリ-ムカリウム（leteprinim potassium)、 GPI- 1485、アルチ-クリン（altini cline)、スフエラミン（Spheramine)、 ACP- 103、 SLV- 308、 Sch- 63390、 E- 2007、 SR- 57 667、フィパメゾール（fipamezole)、 BIA- 3- 202、 AVE- 1625、 DAR- 0100、 VR- 2006、 P YM- 50028、 CERE- 120、 P63、 MITO- 4509、 NLX- XI、サフラジン（safrazine)、レマセ ミド (remacemide)、フザべミド (lazabemide)、モフエギリン (mofegiline)、その他の麦角 アルカロイド誘導体、 CGP-28014等が挙げられる。該パーキンソン病および Zまたは パーキンソン症候群の予防、治療および Zまたは症状進展抑制薬として好ましくは、 例えば、レボドパ（levodopa、 L ドパ）、レボドパ 'ベンセラジド配合剤（levodopa + be nserazide、例えば、レボドノ 'ベンセラジド（4 : 1)配合剤）、レボドノ 'カルビドパ配合 剤（levodopa + carbidopa,例えば、レボドノ 'カルビドパ（10 : 1)配合剤、レボドパ '力 ルビドパ（4 : 1)配合剤）、ェンタカポン ·レボドパ ·カルビドパ配合剤 (entacapone + le vodopa + carbidopa;、メレボドノ、 (melevodopa)、メレボドノ、'カノレビドノ 目 ti合剤 melev odopa + carbidopa)、メンノレ酸ブロモクリフ。ナン (bromocryptine mesylate)、 —ンヒト 口エノレゴクリフ。チン (Alpha- dihydroergocryptine)、アポモノレフイン (apomorphine)、ブ ジピン (budipine)、力べノレゴリン (cabergoline)、ドロキシドノ (droxidopa)、ェンタカポ ン (entacapone)、リスリド (lisuride)、メシル酸ペルゴリド (pergolide mesylate)、ピリべ ジル（piribedil)、プラミぺキソール（pramipexole)、塩酸プラミぺキソ一ル水和物（pram ipexole hydrochloride hydrate)、塩酸ロピ-口 ~~ノレ (ropinirole hydrochloride)、ロピ- ローノレ (ropinirole)、セレギリン (selegiline)、テノレグリド (terguride)、トノレカポン (tolcap one)、メシル酸ラサギリン（rasagiline mesylate)、タリぺキソール（talipexole)、塩酸ァ マンタジン (amantadine hydrochloride)、塩酸トリへキシフエ-ジノレ (trihexyphenidyl h ydrochloride)、ビヘリテン (biperiden)、； 酸ピロへプチン、 piroheptine hydrochloride )、塩酸マザチコ一ノレ (mazaticol hydrochloride)、塩酸メチキセン (metixene hydrochl orideノ、プロフエナ^ン、 profenamineノ、リノレゾ ~~ノレ、 riluzoleノ、ゾ-サミド、 zonisamideノ 、 CEP- 1347、サフイナミド（safinamide)、口チゴチン（rotigotine)、 NS- 2330、スマ-口 一ノレ (sumanirole)、ェチレボドノ (etilevodopa)、モダフィ-ノレ (modafinil)、オランザピ ン（olanzapine)、ビフエプルノクス (bifeprunox)、 TCH- 346、塩酸サリゾタン（sarizotan hydrochloride)、 GDNF、イストラデフイリン（istradefylline)、タランパネル（talampanel レテプリ-ムカリウム（leteprinim potassium)、 GPI- 1485、アルチ-クリン（altinicline )、スフエラミン（Spheramine)、 ACP- 103、 SLV- 308、 Sch- 63390、 E- 2007、 SR- 57667、 フィパメゾール (fipamezole)、 BIA-3-202、 AVE-1625、 DAR-0100等であり、より好まし くは、例えば、レボドパ（levodopa、 L—ドパ）、レボドノ 'ベンセラジド配合剤（levodopa + benserazide、例えば、レボドノ 'ベンセラジド（4 : 1)配合剤）、レボドノ 'カルビドパ 配合剤（levodopa + carbidopa、例えば、レボドノ 'カルビドパ（10 : 1)配合剤、レボド パ ·カルビドパ（4 : 1)配合剤）、ェンタカポン ·レボドパ ·カルビドパ配合剤 (entacapon e + levodopa + carbidopa)、メレボドノ、、melevodopa)、メレボドノ、'カノレビドノヽ酉己合剤 ( melevoaopa + carbidopa)、メンノレ酸ブロモグリフ。テン (bromocryptine mesylate)、 ― ジヒドロエノレゴクリフ。チン (Alpha— dihydroergocryptine)、アポモノレフイン (apomorphine )、ブジピン（budipine)、力べノレゴリン（cabergoline)、ドロキシドパ (droxidopa)、ェンタ カポン (entacapone)、リスリド (lisuride)、メシル酸ペルゴリド (pergolide mesylate)、ピリ ベジル（piribedil)、プラミぺキソール（pramipexole)、塩酸プラミぺキソ一ル水和物（pr amipexole hydrochloride hydrate)、 酸ロヒ -ニ口 ~~ノレ (ropinirole nydrochlonde)、口 ピ-ローノレ (ropinirole)、セレギリン (selegiline)、テノレグリド (terguride)、トノレカポン (to lcapone)、メシノレ酸ラサギリン (rasagiline mesylate)、タリぺキソ一ノレ (talipexole)、 ¾. 酸ァマンタジン (amantadine hydrochloride)、塩酸トリへキシフエニジノレ (trihexypheni dyl hydrochloride八ビぺリデン (biperiden)、 酸ピロヘプナン (piroheptine hydrochl oride)、塩酸マザチコ一ノレ (mazaticol hydrochloride)、塩酸メチキセン (metixene hyd rochloride)、プロフエナミン（profenamine)等である。とりわけ好ましくは、レボドパ（lev odopa、：Lード、ノく)、レボド、ノ .ベンセラジド、酉己合剤 (levodopa + benserazide、 ί列; 1ί 、レ ボドパ ·ベンセラジド（4 : 1)配合剤）、レボドパ ·カルビドパ配合剤 (levodopa + carbido pa、例えば、レポドパ 'カルビドパ（10： 1)配合剤、レポドパ 'カルビドパ（4 : 1)配合剤 )、メシノレ酸ブロモクリプチン（bromocryptine mesylate)、 aージヒドロエノレゴタリプチ ン ( Aipha-dihydroergocryptine 、力へノレコリン (caoergoline 、 ドロキンドノぺ (aroxidopa )、メシル酸ペルゴリド (pergolide mesylate)、プラミぺキソ一ノレ (pramipexole)、塩酸プ ラミぺキソーノレ水和物 ^pramipexole hydrochloride hydrateリ、セレ： ^リン selegiline)、 タリぺキソ一ノレ (talipexole)、塩酸ァマンタジン (amantadine hydrochloride)、塩酸トリ へキシフエ-ジル（trihexyphenidyl hydrochloride)等であり、中でも、レボドノ （levodo pa、：Lード、ノく)、レボド、ノ .ベンセラジド、酉己^ · (levodopa + benserazide、 ί列; 1ί 、レボ ドパ ·ベンセラジド（4 : 1)配合剤）、レボドパ ·カルビドパ配合剤 (levodopa + carbidopa 、例えば、レポドパ 'カルビドパ（10： 1 )配合剤、レポドパ 'カルビドパ (4： 1)配合剤） 等が好ましい。 In the present invention, Parkinson's disease and / or Parkinson's syndrome used as drug B can be prevented, treated and Z or symptom progression inhibitor, for example, levodopa ^, levodopa, no benserazide, Levodopa + benserazide, f ^! Jx. For example, levodono 'benserazide (4: 1) formulation), levodono' carbidopa formulation (levodopa + carbidopa, eg levodono 'carbidopa (10: 1) formulation , Levodopa 'carbidopa (4: 1) combination), entacapon' levodono 'carbidopa combination (entacapone + levodopa + carbid opa), melevodono, (melevodopa), melevodono カ' norevidno eye il combination (melevodopa + carbido pa , Bromocryptine mesylate, alpha-dihydroergocryptine, 7 ヽ monolevine (apomorphine, bunghin) (budipin e), force benoregoline (cabergoline), droxidopa moth (droxidopa), entacapone (lisuride), pergolide mesylate (pergolide mesylate), piribedil (piribedil), Pramipexole, pramipexole hydrochl oride hydrate, ropinirole hydrochloride, ropinirole hydrochloride, selegiline, deprenil, Terguride, tolcapone, rasagiline mesylate; talipexole, amantadine hydrochloride, trihexyphe nidyl hydrochloride, periden bibien , Piroheptine hydrochloride (piroheptine hydroc hloride), mazaticol hydrochloride, metixene hy arochlonde, profenamine, linolene to riluzole, zonisa mide ), CEP-1347, safinamide, rotigotine, NS-2330, Suma-Ronole (sumanirole), Bodno (etilevodopa), modafinil, olanzapine, bifeprunox, TCH-346, sarizotan hydrochloride, GDNF, istradefylline, talam panel , Leteprinim potassium, GPI-1485, altini cline, spheramine, ACP-103, SLV-308, Sch-63390, E-2007, SR-57 667, fipamezole ), BIA-3-202, AVE-1625, DAR-0100, VR-2006, PYM-50028, CERE-120, P63, MITO-4509, NLX-XI, safrazine, remacemide, Examples include fazabemide, mofegiline, other ergot alkaloid derivatives, and CGP-28014. Preferably, the prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome are, for example, levodopa (L dopa), levodopa 'benserazide combination (levodopa + benrazrazide, eg, levodono' benserazide (4: 1) formulation), levodono 'carbidopa (eg, levodopa + carbidopa, for example, levodono' carbidopa (10: 1) formulation, levodopa's power rubidopa (4: 1) formulation), entacapon, levodopa, carbidopa Combination drug (entacapone + le vodopa + carbidopa ;, melevodono, (melevodopa), melevodono, 'canorevidono eye ti combination melev odopa + carbidopa), menoleic acid bromocliff. Nan (bromocryptine mesylate), —Nenhito Orenorego Cliff. Chin (Alpha-dihydroergocryptine), Apomorphine, Abumorphine, Budipine, Cabergoline, Droxidopa, Entacapone, Lisuride, Pergolide mesylate, Pyrgolide mesylate All Jil (piribedil), pramipexole (pramipexole), pram ipexole hydrochloride hydrate, ropiirole hydrochloride, ropinirole hydrochloride, ropiirole (ropinirole), selegiline (selegiline) ), Tenoregrid (terguride), tonocapone (tolcap one), rasagiline mesylate, talipexole, amantadine hydrochloride, trihexyphenidyl hydrochloride, trihexyphenidyl hydrochloride biperiden), acid pyroheptine, piroheptine hydrochloride), mazaticol hydrochloride, metixene hydrochloride (metixene hydrochl orideno, profenamine, profenamine, linolezo ~~ nore, riluzoleno, zo-samide, zonisamide , CEP-1347, safinamide, rotigotine, NS-2330, sumairole, sumanirole, echile Dono (etilevodopa), modafinil, olanzapine, bifeprunox, TCH-346, sarizotan hydrochloride, GDNF, istradefylline, talampanel Leteprinim potassium, GPI-1485, altinicline, Spheramine, ACP-103, SLV-308, Sch-63390, E-2007, SR-57667, fipamezole, BIA-3 -202, AVE-1625, DAR-0100, etc., more preferably, for example, levodopa (L-dopa), levodono 'benserazide combination agent (levodopa + benserazide, eg levodono' benserazide (4: 1) Formulations), levodono carbidopa (eg levodopa + carbidopa, for example, levodono carbidopa (10: 1) formulation, levodopa carbidopa (4: 1) formulation), entacapon Bodopa and carbidopa combination agent (entacapon e + levodopa + carbidopa), melevodono, melevodono, 'canolevidono ヽ 酉 self combination (melevoaopa + carbidopa), menoleic acid bromoglyph. Ten (bromocryptine mesylate),-dihydroenoregocliff. Chin (Alpha— dihydroergocryptine), Apomorphine, abumorphine, babipine, cabergoline, droxidopa, entacapone, lisuride, pergolide mesylate, pyrigolide mesylate, pergolide mesylate (Piribedil), pramipexole, pramiipexole hydrochloride hydrate, acid rohi-niguchi ~~ nore (ropinirole nydrochlonde), mouth pirinoleole (ropinirole), selegiline ( selegiline), tenoregrid (terguride), tonocapone (to lcapone), rasagiline mesylate, talipexole, ¾. Amantadine hydrochloride, trihexypheni dyl hydrochloride, biperiden, piroheptine hydrochl oride, mazaticol hydrochloride, metixene hyd romin, prometh Particularly preferred are levodopa, levodopa, benserazide, levodopa, levodopa, benserazide, levodopa and benserazide, levodopa 4: 1) Formulation), levodopa carbidopa formulation (levodopa + carbidopa, eg Lepodopa 'carbidopa (10: 1) formulation, Lepodopa' carbidopa (4: 1) formulation), bromocryptine mesylate ), A-dihydroenoregotaliptin (Aipha-dihydroergocryptine), force herecholine (caoergoline, drokindnope (aroxidopa), Pergolide mesylate, pramipexole, pramipexole hydrochloride ^ pramipexole hydrochloride hydrate, sele: ^ phosphorus selegiline, talipexole, amantadine hydrochloride amantadine hydrochloride), trihexyphenidyl hydrochloride, etc., among others, levodopa, levodopa, benserazide, levodopa Column: 1ί, levodopa-benserazide (4: 1) formulation), levodopa-carbidopa formulation (levodopa + carbidopa, eg, levodopa 'carbidopa (10: 1) formulation, levodopa' carbidopa (4: 1) formulation Agent) and the like.
本発明において、薬物 Cとして用いてもよいその他の薬物としては、例えば、レボド パ製剤、ドパミン受容体作動薬 (ドパミン受容体刺激薬)、ドパミン遊離促進薬 (ドパミ ン分泌促進薬あるいはドパミン放出促進薬)、ドパミン取り込み阻害薬、ドパミン作用 薬、中枢性抗コリン薬、芳香族 L アミノ酸脱炭酸酵素阻害薬 (DCI)、モノアミン酸 化酵素（MAO— B)阻害薬、カテコール O メチルトランスフェラーゼ（COMT)阻 害薬、ノルェピネフリン (ノルアドレナリン)補充薬、 GABA  In the present invention, other drugs that may be used as the drug C include, for example, levodopa preparations, dopamine receptor agonists (dopamine receptor stimulants), dopamine release promoters (dopamine secretion promoters or dopamine release promoters). Drugs), dopamine uptake inhibitors, dopamine agonists, central anticholinergic drugs, aromatic L amino acid decarboxylase inhibitors (DCI), monoamine oxidase (MAO-B) inhibitors, catechol O methyltransferase (COMT) Inhibitors, norepinephrine (noradrenaline) supplements, GABA
A受容体調節薬 (例えば、 A receptor modulator (e.g.,
GABA受容体作動薬等）、 GABA受容体調節薬、アデノシン A2A受容体遮断薬GABA receptor agonist, etc.), GABA receptor modulator, adenosine A2A receptor blocker
A B A B
、アポトーシス阻害薬、神経分化 ·再生促進薬、神経栄養因子 (例えば、ニューロトロ フィン、 TGF— |8スーパーファミリー、ニューロ力インファミリー、増殖因子等）、脳機 能賦活薬 (例えば、脳代謝賦活薬、脳循環改善薬等)、 Rho キナーゼ阻害薬およ び 13受容体遮断薬等のパーキンソン病および Zまたはパーキンソン症候群の予防、 治療および Zまたは症状進展抑制薬、神経変性疾患 (例えば、線条体黒質変性症、 ハンチントン病、舞踏病 無定位運動症、進行性核上麻痺、びまん性レビー小体病 、大脳皮質基底核変性症、アルツハイマー病、老年性痴呆 (認知症）、ピック病、前 頭側頭葉型痴呆症 (認知症）、家族性痴呆症 (認知症）、脊髄小脳変性症 (例えば、 ォリーブ橋小脳萎縮症、晚発性小脳皮質萎縮症、家族性脊髄小脳失調症 (例えば、 マツカードジヨセフ病等)、歯状核赤核淡蒼球ルイ体萎縮症、家族性痙性対麻痺、フ リードライヒ病等)等)治療薬、運動神経病 (例えば、筋萎縮性側索硬化症、家族性筋 萎縮性側索硬化症等)治療薬、脱髄性疾患 (例えば、多発性硬化症、汎発硬化症、 急性散在性脳脊髄炎、急性小脳炎、横断性脊髄炎、ギラン ·バレー症候群等)治療 薬、脳血管障害 (例えば、脳卒中、脳梗塞 (例えば、脳血栓、脳塞栓等)、一過性脳 虚血発作、再灌流障害、脳出血 (例えば、高血圧性脳内出血、クモ膜下出血等)等） 治療薬、脳腫瘍 (例えば、星状膠細胞腫、脳膿瘍等)治療薬、血液量減少性ショック 、外傷性ショック、頭部損傷および Zまたは脳脊髄外傷 (例えば、脳挫傷 ·貫入 'せん 断 ·圧迫 ·裂傷、分娩時外傷、乳児むち打ち揺さぶり症候群等）に伴う神経機能障害 の治療薬、感染症に伴う脳脊髄疾患 (例えば、髄膜炎、インフルエンザ脳症、クロイツ フェルド ヤコブ病、エイズ脳症による痴呆等）の治療薬、毒物（ヒ素、カドミウム、有 機水銀、サリン、ソマン、タブン、 vxガス等） '放射線等による神経機能障害の治療薬 、精神疾患 (例えば、神経症、心身症、不安、統合失調症、躁うつ病等)治療薬、て んかん、メージ症候群、ジストニア、ダウン症および Zまたは睡眠障害 (例えば、過眠 、ナルコレプシ一、睡眠時無呼吸症候群等)の治療薬、糖尿病、糖尿病合併症およ び Zまたは高脂血症の治療薬、降圧薬、アセチルコリンエステラーゼ阻害薬、 NMD A (N—メチル—D—ァスパラギン酸)受容体拮抗薬、 AMPA (2—アミノー 3— (メチ ルー 3—ヒドロキシイソォキサゾールー 4 ィル）プロパン酸） Zカイニン酸受容体拮 抗薬、ニコチン受容体調節薬、神経型一酸化窒素合成酵素 (n— NOS)阻害薬、 β アミロイドタンパクの産生、分泌、蓄積、凝集および Ζまたは沈着抑制薬 (例えば、 β セクレターゼ阻害剤、 γセクレターゼ阻害作用剤、 /3アミロイドタンパク凝集抑制薬、 βアミロイド分解酵素、 βアミロイドワクチン等）、利尿薬 (例えば、チアジド系利尿薬、 ループ利尿薬、カリウム保持性利尿薬等）、カルシウムチャネル遮断薬 (カルシウム拮 抗薬)、アンジォテンシン変換酵素 (ACE)阻害薬、アンジォテンシン II受容体拮抗 薬、ナトリウムチャネル遮断薬、カリウムチャネル開口薬、 β受容体遮断薬、抗血小板 薬、抗凝固薬、血栓溶解薬、トロンボキサン Α合成酵素阻害薬、マトリックスメタロブ , Apoptosis inhibitor, neuronal differentiation / regeneration promoter, neurotrophic factor (eg, neurotrophin, TGF—8 super family, neuro force in family, growth factor, etc.), brain function enhancer (eg, activation of brain metabolism) Prevention of Parkinson's disease and Z or Parkinson's syndrome, such as Rho kinase inhibitors and 13 receptor blockers, Treatment and Z or symptom progression inhibitors, neurodegenerative diseases (e.g., striatal substantia nigra degeneration, Huntington's disease, chorea, stereotaxic movement, progressive supranuclear palsy, diffuse Lewy body disease, basal ganglia Degenerative disease, Alzheimer's disease, senile dementia (dementia), Pick's disease, frontotemporal lobar dementia (dementia), familial dementia (dementia), spinocerebellar degeneration (eg, Olive Bridge cerebellar atrophy) , Cerebellar cortical atrophy, familial spinocerebellar ataxia (e.g., Matsucard Dijosef disease, etc.), erythrocytic red nuclei Ryukyu atrophy, familial spastic paraplegia, Friedreich disease Etc.) Therapeutic drugs, motor neuropathies (e.g. amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis etc.) therapeutic drugs, demyelinating diseases (e.g. multiple sclerosis, generalized sclerosis) Disease, acute disseminated encephalomyelitis, acute cerebellar inflammation, transverse myelitis, Guillain-Barre syndrome, etc.) Drug, cerebrovascular disorder (for example, stroke, cerebral infarction (for example, cerebral thrombus, cerebral embolism, etc.), transient ischemic attack, reperfusion disorder, cerebral hemorrhage (for example, hypertensive intracerebral hemorrhage, subarachnoid hemorrhage, etc.) ) Therapeutic drugs, brain tumors (eg astrocytoma, brain abscesses, etc.), hypotensive shock, traumatic shock, head injury and Z or cerebrospinal trauma (eg cerebral contusion / penetration) · Pressure · Treatment, neurological dysfunction associated with laceration, labor trauma, infant whiplash syndrome, etc., cerebrospinal disease associated with infection (eg meningitis, influenza encephalopathy, Creutzfeldt-Jakob disease, dementia due to AIDS encephalopathy) ) Therapeutic agents, poisons (arsenic, cadmium, organic mercury, sarin, soman, tabun, vx gas, etc.) 'therapeutic agents for neurological dysfunction caused by radiation, etc., mental disorders (eg, neurosis, psychosomatic disorders, anxiety, schizophrenia, (E.g., manic depression), treatment for epilepsy, mage syndrome, dystonia, Down syndrome and Z or sleep disorders (e.g. hypersomnia, narcolepsy, sleep apnea syndrome, etc.), diabetes, diabetic complications and And Z or hyperlipidemia treatment, antihypertensive, acetylcholinesterase inhibitor, NMD A (N-methyl-D-aspartate) receptor antagonist, AMPA (2-amino-3- (methyl 3-hydroxyiso) Oxazol-4-yl) propanoic acid) Z-kainic acid receptor antagonist, nicotinic receptor modulator, neuronal nitric oxide synthase (n—NOS) inhibitor, β amyloid protein production, secretion, accumulation , Aggregation and sputum or deposition inhibitors (eg, β-secretase inhibitor, γ-secretase inhibitor, / 3 amyloid protein aggregation inhibitor, β-amyloid degrading enzyme, β-amyloid vaccine, etc.), diuresis Drugs (for example, thiazide diuretics, loop diuretics, potassium-sparing diuretics), calcium channel blockers (calcium Anti-agents), angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, sodium channel blockers, potassium channel openers, beta receptor blockers, antiplatelet drugs, anticoagulants, thrombolysis Drugs, thromboxane Α synthase inhibitors, matrix metallobes
2  2
ロティナーゼ（MMP)阻害剤、シクロォキシゲナーゼ（COX)—2阻害薬、非ステロイ ド性抗炎症薬、ステロイド薬、抗酸化薬、ビタミン類、疾患修飾性抗リウマチ薬、免疫 抑制薬、抗サイト力イン薬 (例えば、 TNF阻害薬、 MAPキナーゼ阻害薬等）、性ホル モンまたはその誘導体 (例えば、プロゲステロン、エストラジオール、安息香酸エストラ ジオール等）、副甲状腺ホルモン (例えば、 PTH等）、ファクター Xa阻害薬、ファクタ 一 Vila阻害薬およびグリセリン製剤等力も選ばれる 1種または 2種以上の薬物または それらの配合剤等が挙げられる。  Rotinase (MMP) inhibitor, cycloxygenase (COX) -2 inhibitor, non-steroidal anti-inflammatory drug, steroid drug, antioxidant, vitamins, disease-modifying anti-rheumatic drug, immunosuppressant, anti Cytodynamic drugs (eg, TNF inhibitors, MAP kinase inhibitors, etc.), sex hormones or derivatives thereof (eg, progesterone, estradiol, estradiol benzoate, etc.), parathyroid hormone (eg, PTH), factor Xa Inhibitors, Factor 1 Vila inhibitors and glycerin preparations are also selected One or more drugs or combinations thereof.
[0025] 本発明にお 、て、ドパミン受容体作動薬 (ドパミン受容体刺激薬)としては、例えば 、レボドパ（levodopa、 L—ドノく）製剤、メシル酸ブロモクリプチン（bromocryptine mesyl ate)、 —シヒドロエノレコクリフ。チン (Alpha— dihydroergocryptineノ、リスリト (lisunde)、 メシル酸ペルゴリド (pergolide mesylate)、タリぺキソ一ノレ (talipexole)、カベルゴリン (c abergoline)、プラミぺキソ一ノレ (.pramipexole)、 酸プブミぺキソ一ノレ水禾ロ物 ramipe xole hydrochloride hydrate;、ピリヘンノレ (pinbedil)、ロヒ二口 ~~ノレ ijopiniroleノ、ァノレ グリド（terguride)、ロチゴチン（rotigotine)、 AF- 14、 A- 68939、 A- 77636、 SKF- 38393 、 N- 0434、 PD- 118440、 NIH- 10494、塩酸アマンタジン（amantadine hydrochloride) 等が挙げられる。 In the present invention, as a dopamine receptor agonist (dopamine receptor stimulant), for example, a levodopa (Lododon) preparation, bromocryptine mesylate, Hydroenoreco cliff. Chin (Alpha—dihydroergocryptine, lisunde, pergolide mesylate, talipexole, cabergoline, pramipexole, pubipexole) Ramipe xole hydrochloride hydrate ;, pyrihen nore (pinbedil), lohi bi mouth ~~ nore ijopinirole no, anogurido (terguride), rotigotine, AF-14, A-68939, A-77636, SKF- 38393, N-0434, PD-118440, NIH-10494, amantadine hydrochloride and the like.
本発明にお 、て、ドパミン遊離促進薬 (ドパミン分泌促進薬あるいはドパミン放出促 進薬）としては、例えば、塩酸アマンタジン（amantadine hydrochloride)等が挙げられ る。  In the present invention, examples of the dopamine release promoting agent (dopamine secretion promoting agent or dopamine release promoting agent) include amantadine hydrochloride and the like.
[0026] 本発明において、ドパミン取り込み阻害薬としては、例えば、 GBR-12909, GBR-13 069、 GYKI-52895, NS-2141等が挙げられる。  In the present invention, examples of dopamine uptake inhibitors include GBR-12909, GBR-13 069, GYKI-52895, NS-2141 and the like.
本発明において、中枢性抗コリン薬としては、例えば、塩酸トリへキシフエ-ジル (tri hexyphenidyl hydrochloride;、ビぺリデン (biperiden)、 酸ピロヘプナン (piroheptine hydrochloride)、塩酸マザチコ一ノレ (mazaticol hydrochloride)、塩酸メチキセン (meti xene hydrochloride)、プロフエナミン (profenamine)等が挙げられる。 本発明において、芳香族 L アミノ酸脱炭酸酵素阻害薬 (DCI)としては、例えば、 カルビドパ（carbidopa)、ベンセラジド (benserazide)等が挙げられる。 In the present invention, as the central anticholinergic agent, for example, trihexyphenidyl hydrochloride; biperiden, piroheptine hydrochloride, mazaticol hydrochloride, mazaticol hydrochloride, Examples thereof include methixene hydrochloride and profenamine. In the present invention, examples of the aromatic L amino acid decarboxylase inhibitor (DCI) include carbidopa, benserazide and the like.
本発明において、モノアミン酸ィ匕酵素（MAO— B)阻害薬としては、例えば、セレギ リン（selegiline)、デプレ-ル（deprenil)、リルゾール（riluzole)、サフラジン（safrazine) 、レマセミド remacemide)、ラサべミド (lazabemide)、メシノレ酸ラサギリン (jasagiline me sylate)、ゾ-サミド（zonisamide)、 AGN- 1133、 LU- 53439、 MD- 280040、モフエギリン (mofegiline)、その他の麦角アルカロイド誘導体等が挙げられる。  In the present invention, monoamine oxidase (MAO-B) inhibitors include, for example, selegiline, deprenil, riluzole, safrazine, remacemide, rasabide, Lazabemide, jasagiline me sylate, zonisamide, AGN-1133, LU-53439, MD-280040, mofegiline, and other ergot alkaloid derivatives.
[0027] 本発明において、カテコール— O—メチルトランスフェラーゼ（COMT)阻害薬とし ては、例えば、ェンタカポン（entacapone)、トルカポン（tolcapone)、 CGP- 28014等が 挙げられる。 [0027] In the present invention, examples of the catechol-O-methyltransferase (COMT) inhibitor include entacapone, tolcapone, CGP-28014, and the like.
本発明において、ノルェピネフリン (ノルアドレナリン)補充薬としては、例えば、ドロ キシドパ (droxidopa)等が挙げられる。  In the present invention, norepinephrine (noradrenaline) supplements include, for example, droxidopa.
本発明において、 GABA受容体調節薬 (例えば、 GABA受容体作動薬等)とし  In the present invention, a GABA receptor modulator (for example, a GABA receptor agonist)
A A  A A
ては、例えば、ムシモール（muscimol)、イソグバシン（isoguvacine)、クロメチアゾーノレ 、ガボキサドール（4, 5, 6, 7—テトラヒドロイソォキサゾロ [5, 4— c]ピリジンー3—ォ 一ル）、ガナキソロン（3 α ヒドロキシ一 3 j8—メチル 5 α—プレダナン一 20—オン )、フェンガビン（2 [ (ブチノレイミノ）一（2 クロ口フエ二ノレ)メチノレ ]ー4ークロロフエノ 一ル）、 3—ァミノプロパンスルホン酸、 3—（アミノメチル）ー5—メチルへキサン酸等 が挙げられる。  For example, muscimol, isoguvacine, chromethiazone, gaboxadol (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol), Ganaxolone (3 α-hydroxy 1 3 j8-methyl 5 α-predanane 1 20-one), Fengabine (2 [(butinoreimino) 1 (2 cloenophenenole) methinole] -4-chlorophenol), 3-aminopropane Examples thereof include sulfonic acid and 3- (aminomethyl) -5-methylhexanoic acid.
[0028] 本発明にお 、て、アデノシン Α2Α受容体遮断薬としては、例えば、イストラデフイリ ン（istradefylline)等が挙げられる。  In the present invention, examples of adenosine 2 receptor blockers include istradefylline and the like.
本発明において、アポトーシス阻害薬としては、例えば、 CPI-1189、 IDN-6556、 CE P-1347等が挙げられる。  In the present invention, examples of the apoptosis inhibitor include CPI-1189, IDN-6556, CEP-1347 and the like.
本発明において、神経分化'再生促進薬としては、例えば、レテプリニムカリウム (le teprinim potassium) ,塩酸キサリプローデン（xaliproden hydrochloride) , SB- 216763 等が挙げられる。  In the present invention, examples of the nerve differentiation / regeneration promoting agent include leteprinim potassium, xaliproden hydrochloride, SB-216763 and the like.
[0029] 本発明において、神経栄養因子としては、例えば、ニューロトロフィン (例えば、 NG F (Nerve Growth Factor:ネ申経成長因子)、 BDNF (Brain Derived Neurotrophic Fact or :脳由来神経栄養因子）、 NT— 3、 NT- 4/5, NT— 6)、 TGF— j8スーパーファ ミリ一（例えば、 TGF— β 1、 TGF - β 2、 TGF— β 3、 BMP— 2、 BMP— 3、 BMP —4、 BMP— 5、 BMP— 6、 BMP— 7、 BMP— 8A、 BMP— 8B、 BMP—14 (GDF — 5)、 GDNF、 neurturin, artemin、 persephin、 GDF— 1、 GDF— 8、 GDF— 15、 in hibin , inhibin j8、 DAF (dauer formation) 7)、二ユーロ力インファミリー（例えば、 毛様体神経栄養因子 (CNTF)、インターロイキン— 6等）、増殖因子 (例えば、 IGF 1、 b— FGF等）、 ABS-205等が挙げられる。 In the present invention, neurotrophic factors include, for example, neurotrophin (eg, NG F (Nerve Growth Factor), BDNF (Brain Derived Neurotrophic Fact) or: Brain-derived neurotrophic factor), NT-3, NT-4 / 5, NT-6), TGF-j8 superfamily (eg, TGF-β1, TGF-β2, TGF-β3, BMP) — 2, BMP— 3, BMP —4, BMP— 5, BMP— 6, BMP— 7, BMP— 8A, BMP— 8B, BMP—14 (GDF — 5), GDNF, neurturin, artemin, persephin, GDF— 1, GDF—8, GDF—15, in hibin, inhibin j8, DAF (dauer formation) 7), two euro force in-family (eg ciliary neurotrophic factor (CNTF), interleukin-6 etc.), proliferation Factors (for example, IGF 1, b-FGF and the like), ABS-205 and the like can be mentioned.
[0030] 本発明にお ヽて、脳機能賦活薬 (例えば、脳代謝賦活薬、脳循環改善薬等)として は、例えば、 -セルゴリン（nicergoline)、イブジラスト（ibudilast)、ァ-ラセタム（anirac etam)、ィフェンプロジノレ（ifenprodil)、ビンポセチン（vinpocetine)、イデべノン（ideben one)、塩酸メマンチン（memantine hydrochloride)、ホパンテン酸カノレシゥム、塩酸ァ マンタジン、塩酸メクロフエノキサート、メシル酸ジヒドロエルゴトキシン、塩酸ピリチォ キシン、 y—ァミノ酪酸、塩酸ビフエメラン、マレイン酸リスリド、塩酸インデロキサジン 、プロペントフイリン等が挙げられる。 [0030] In the present invention, as a brain function activator (for example, a brain metabolism activator, a cerebral circulation improver, etc.), for example, -sergoline, ibudilast, arracetam (anirac etam) ), Ifenprodil, vinpocetine, idebenone, memantine hydrochloride, canolesium hopantenate, amantadine hydrochloride, meclofenoxate hydrochloride, dihydroergotoxin mesylate, Examples include pyrithioxine hydrochloride, y-aminobutyric acid, bifumelan hydrochloride, lisuride maleate, indeloxazine hydrochloride, and propentofylline.
本発明において、 Rho キナーゼ阻害薬としては、例えば、ファスジル (fasudil)等 が挙げられる。  In the present invention, examples of the Rho kinase inhibitor include fasudil and the like.
[0031] 本発明にお!/、て、 13受容体遮断薬としては、例えば、プロプラノロール (propranolol )、アルプレノロール（alprenolol)、ピンドロール（pindolol)、チモロール（timolol)、力 ノレテオローノレ (carteolol)、ナドローノレ (nadolol)、ニプラジローノレ (nipradilol)、チリソロ 一ノレ（tilisolol)、ァテノロ一ノレ（atenolol)、ァセブトローノレ（acebutolol)、メトプロローノレ (metprolol) ,ビソプロローノレ (bisoprolol)、ベタキソローノレ (betaxolol)、ラベタローノレ (1 abetalol)、ァロチノロール（arotinolol)、ァモスラロール（amosulalol)等が挙げられる。 本発明において、ハンチントン病の治療薬としては、例えば、リルゾール (riluzole)、 LAX-101、テトラべナジン（tetrabenazine)、オランザピン（olanzapine)、酢酸グラチラ マー (glatiramer acetate)等が挙げられる。 [0031] In the present invention, the 13 receptor blockers include, for example, propranolol, alprenolol, pindolol, timolol, timolol, car teolol , Nadronole (nadolol), nipradilole (nipradilol), chili solo monole (tilisolol), atenolol, acebutolol, metopronore (metprolol), bisopronore (bisoprolol), betaxololole (betaxololole) , Arotinolol, amosulalol and the like. In the present invention, examples of therapeutic agents for Huntington's disease include riluzole, LAX-101, tetrabenazine, olanzapine, and glatiramer acetate.
[0032] 本発明にお!/、て、舞踏病の治療薬としては、例えば、タルチレリン (taltirelin)、 NS- 2330, T- 2000、タランパネル (talampanel)等が挙げられる。  [0032] In the present invention, examples of the therapeutic agent for chorea include taltirelin, NS-2330, T-2000, and talampanel.
本発明において、アルツハイマー病の治療薬としては、例えば、 α—ジヒドロエルゴ クリフ。チン (Alpha— dihydroergocryptine)、塩酸ドネぺジノレ (donepezil hydrochloride)、 フラクション F (Fraction F)、ガランタミン（galantamine)、インデロキサジン（indeloxazin e)、塩酸メマンチン (memantine hydrochloride)、ニセノレゴリン (nicergoline)、ホスファ チジルセリン（phosphatidylserine)、酒石酸リバスチグミン（rivastigmine tartrate)、 ST -200、タクリン (tacrine)、セレブ口ライシン (Cerebrolysin)、ヒュぺノレジン A (huperzine A)、ネフイラセタム（nefiracetam)等が挙げられる。 In the present invention, as a therapeutic agent for Alzheimer's disease, for example, α-dihydroergo Cliff. Chin (Alpha-dihydroergocryptine), Donepezil hydrochloride, Fraction F, Galantamine, Indeloxazin e, Memantine hydrochloride, Nicenorgoline, Phospha Examples include phosphatidylserine, rivastigmine tartrate, ST-200, tacrine, cerebrolysin, hyperenosin A, and nefiracetam.
本発明において、老年性痴呆 (認知症)の治療薬としては、例えば、 ST-200,酢酸 ズクロペンチキソール（zuclopenthixol acetate)、デカン酸ズクロペンチキソール（zucl openthixol decanoateノ、セレブ口フィンン (し erebrolysin)、不フィフ ITグム (nefiracetam )等が挙げられる。  In the present invention, therapeutic agents for senile dementia (dementia) include, for example, ST-200, zuclopenthixol acetate, zucl openthixol decanoate, celebrity mouth finn (And erebrolysin), non-fifty IT gum (nefiracetam) and the like.
[0033] 本発明にお 、て、筋萎縮性側索硬化症の治療薬としては、例えば、リルゾール (rilu zole)、エダラボン (edaravone)、塩酸キサリプロ一テン (xaliproden hydrochloride)、 T CH- 346、スーパーォキシドジスムターゼ（superoxide dismutase)、ペントキシフィリン（ pentoxifylline)等が挙げられる。  [0033] In the present invention, as a therapeutic agent for amyotrophic lateral sclerosis, for example, riluzole, edaravone, xaliproden hydrochloride, TCH-346, Superoxide dismutase, pentoxifylline, etc. are mentioned.
本発明において、多発性硬化症の治療薬としては、例えば、酢酸ダラチラマー (gla tiramer acetate)、インターフェロン (interferon)、ノ クロフェン (baclofen)、コノレチコトロ ピン（corticotropin)、ミトキサントロン（mitoxantrone)等が挙げられる。  In the present invention, the therapeutic agents for multiple sclerosis include, for example, glatiramer acetate, interferon, baclofen, coroticotropin, mitoxantrone and the like. It is done.
[0034] 本発明にお 、て、脳卒中の治療薬としては、例えば、アルテプラーゼ (alteplase)、 アルガトロバン（argatroban)、シチコリン（citicoline)、硫酸水素クロピドグレル（clopido grel hydrogen sulfate)、 DMP- 647、ジピリダモーノレ (dipyridamole)、ィテベノン (idebe none)、インドブフェン (indobufen)、モノシァロガングリオシド GM1 (monosialoganglios ide GM1)、二モジピン（nimodipine)、プロペントフイリン（propentofylline)、トリフルサ ール（triflusal)、モンテプラーゼ（monteplase)、アスピリン（aspirin)、ニコチン酸（nicot inic acid)、ォザダレルナトリウム（sodium ozagrel)等が挙げられる。  [0034] In the present invention, examples of the therapeutic agent for stroke include alteplase, argatroban, citicoline, clopidogrel hydrogen sulfate, DMP-647, dipyridamole ( dipyridamole), itidebenone, indobufen, monosialoganglioside GM1 (monosialoganglios ide GM1), nimodipine, propentofylline, triflusal, monteplase, monteplase Examples include aspirin, nicotinic acid, sodium ozagrel and the like.
本発明において、脳梗塞の治療薬としては、例えば、シチコリン (citicoline)、ェダラ ボン（edaravone)、イブジラスト (ibudilast)、トリフルサール (triflusal)、シロスタゾール（ cilostazol)、 -カラベン (nicaraven)、ォザグレノレナトリウム (sodium ozagrel)等が挙げ られる。 [0035] 本発明にお 、て、脳血栓の治療薬としては、例えば、ォザダレル (ozagrel)、ォザグ レルナトリウム（sodium ozagrel)、チクロピジン（ticlopidine)、塩酸チクロピジン（ticlopi dine hydrochloride)、ファスジル（fasudil)、組織プラスミノーゲンァクティベータ一（t— PA)、アルテプラーゼ（alteplase)、合成抗トロンビン薬（例えば、メシル酸ガべキサー ト、メシル酸ナファモスタツト等)等が挙げられる。 In the present invention, the therapeutic agents for cerebral infarction include, for example, citicoline, edaravone, ibudilast, triflusal, cilostazol, -nicaraven, Examples include sodium ozagrel. [0035] In the present invention, the therapeutic agents for cerebral thrombosis include, for example, ozagrel, sodium ozagrel, ticlopidine, ticlopidine hydrochloride, fasudil, Examples thereof include tissue plasminogen activator (t-PA), alteplase, and synthetic antithrombin drugs (for example, gabexate mesylate, nafamostat mesylate, etc.).
本発明において、クモ膜下出血の治療薬としては、例えば、モノシァロガンダリオシ ド GM1 (monosialoganglioside GM1)、メシノレ酸チリラザド (tirilazad mesylate)、二カラ ベン（nicaraven)、ォザグレルナトリウム（sodium ozagrel)等が挙げられる。  In the present invention, therapeutic agents for subarachnoid hemorrhage include, for example, monosialoganglioside GM1 (monosialoganglioside GM1), tirilazad mesylate, nicaraven, sodium ozagrel ) And the like.
[0036] 本発明にお 、て、髄膜炎の治療薬としては、例えば、 ABLC、アムホテリシン B (am photericin B)、セフォゾプラン (cefozopran)、セフピロム (ceftirome)、フノレコナゾ一ノレ (fluconazole)、へモフィフスワクテン (Haemophilus vaccine)、メロへネム、meropenem) 、肺炎球菌ワクチン (pneumococcal vaccine)等が挙げられる。 [0036] In the present invention, therapeutic agents for meningitis include, for example, ABLC, amphotericin B, cefozopran, cefirome, cefirome, fluconazole, hemo, Examples include Haemophilus vaccine, meropenem, and pneumococcal vaccine.
本発明において、クロイツフェルド一ヤコブ病の治療薬としては、例えば、ペントサ ンポリ硫酸ナトリウム（pentosan polysulfate sodium)等が挙げられる。  In the present invention, examples of therapeutic agents for Creutzfeldt-Jakob disease include sodium pentosan polysulfate sodium.
本発明において、エイズ脳症による痴呆 (認知症）の治療薬としては、例えば、レキ シパファント（lexipafant)、塩酸メマンチン（memantine hydrochloride)、 CPI- 1189等が 挙げられる。  In the present invention, examples of therapeutic agents for dementia (dementia) caused by AIDS encephalopathy include lexipafant, memantine hydrochloride, CPI-1189, and the like.
[0037] 本発明において、神経症の治療薬としては、例えば、 TJ- 15等が挙げられる。  [0037] In the present invention, examples of the therapeutic agent for neurosis include TJ-15.
本発明において、心身症の治療薬としては、例えば、ブロンペリドール (bromperidol )、フル卜プラゼノ ム (flutoprazepam)、オランザピン (olanzapine)、スル卜プリド (sultopr ide)、ノ ノレプロ酸ナトリウム (valproate semisodium)、ジプラシドン (ziprasidone)、ズク 口ペンチキソーノレ（zuclopenthixol)、酢酸ズクロペンチキソーノレ（zuclopenthixol aceta te)、デカン酸ズクロペンチキソール（zuclopenthixol decanoate)、フマル酸ケチアピン (quetiapine fumarate)、リスペリドン (risperidone)、マレイン酸プロクロルペラジン (pro chlorperazine maleate)、 リヒゾフゾ ~~ノレ (aripiprazole)等; 0举げられる。  In the present invention, the therapeutic agents for psychosomatic diseases include, for example, bromperidol, flutoprazepam, olanzapine, sultopr ide, sodium noreproate (valproate semisodium) , Ziprasidone, zuclopenthixol, zuclopenthixol aceta te, zuclopenthixol decanoate, quetiapine fumarate, risperidone, risper, risperidone Prochlorperazine maleate, rehizofuzo ~ aripiprazole, etc .;
[0038] 本発明において、不安の治療薬 (抗不安薬)としては、例えば、フルトブラゼパム (11 utoprazepam)、、, - セノヽム diazepam)、 Pフセノヽム (lorazepam)、ブロマゼ ヽム (brom azepam)、プラセノヽム (prazepam)、ク Pチ ゼノヽム clotiazepam)、才キサセノ ム (oxaz epam)、フノレジァゼノ ム (fludiazepam)、メダゼパム (medazepam)、クロノレジァゼポキシ ド (chlordiazepoxide)、ァノレプラゾラム (alprazolam)、ェチゾラム (etizolam)、フノレタゾ ラム (folutazolam)、メキサゾラム (mexazolam)、クロキサゾラム (cloxazolam)、ォキサゾ ラム (oxazolam)、クロラゼプ酸二カリウム (dipotassium clorazepate)、ロフラゼプ酸ェ チル（ethyl loflazepate)、タエン酸タンドスピロン（tandospiron citrate)等が挙げられる [0038] In the present invention, as an anxiety therapeutic agent (anti-anxiety agent), for example, flutobazepam (11 utoprazepam),,-senose diazepam, P husenome (lorazepam), brom azepam, praseno Prazepam, clotiazepam, oxaz epam), funoresazenum (fludiazepam), medazepam, medorepam, chlordiazepoxide, anoleprazolam, etizolam, fonorezolam, folutazolam, lamazolam, lamazolam Oxazolam, dipotassium clorazepate, ethyl loflazepate, tandospiron citrate, etc.
[0039] 本発明にお 、て、統合失調症の治療薬としては、例えば、アミスルプリド (amisulprid e)ゝァリピプラゾーノレ (aripiprazole)、クロザピン (clozapine)、ネモナプリド (nemonapri de)、オランザピン（olanzapine)、ぺロスピロン（perospirone)、フマル酸ケチアピン（qu etiapine fumarate)、リスへリドン、 risperidone)、グリへやソ ~~ノレ (talipexole)、シプフンド ン (ziprasidone)、ゾテピン (zotepine)、ズクロペンチキソーノレ (zuclopenthixol)、酢酸 ズクロペンチキソール（zuclopenthixol acetate)、デカン酸ズクロペンチキソール（zucl openthixol decanoate)、セルチンドール (sertindole)等力 S挙げられる。 [0039] In the present invention, as a therapeutic drug for schizophrenia, for example, amisulprid (aripiprazole), clozapine (clozapine), nemonapride (nemonapride), olanzapine (olanzapine) ), Perospirone, quetiapine fumarate (qu etiapine fumarate), risheridone, risperidone, guriheyaso ~~ nore (talipexole), ziprasidone, zotepine, zukupentizo Examples include zuclopenthixol, zuclopenthixol acetate, zucl openthixol decanoate, sertindole and the like.
本発明において、躁病の治療薬としては、例えば、オランザピン (olanzapine)、バル プロ酸ナトリウム (valproate semisodium)、フマノレ酸ケチアピン (quetiapine fumarate) 、 リスヘリトン ijisperidone)、 リヒゾフゾ ~~ノレ (aripiprazole)、ンノ。フン rン (ziprasidon e)、リチウム（lithium)等が挙げられる。  In the present invention, for example, olanzapine, sodium valproate (valproate semisodium), quetiapine fumarate, quetiapine fumarate, risheritone ijisperidone, rehizofuzo ~ aripiprazole, and nno. Examples thereof include ziprasidon e and lithium.
[0040] 本発明において、うつ病の治療薬 (抗うつ薬）としては、三環系抗うつ薬、四環系抗 うつ薬、トリァゾロピリジン系抗うつ薬、選択的セロトニン再取り込み阻害剤（SSRI)、 セロト-ン.ノルアドレナリン再取り込み阻害剤（SNRI)等が挙げられ、具体的には、 例えば、シユウ酸エスシタロプラム (escitalopram oxalate) ,ァノレプラゾラム (alprazolam )、アミスルプリド（amisulpride)、ァモキサピン（amoxapine)、ブプロピオン（bupropion) 、カノレノマゼピン (carbamazepine)、臭素酸シタロフフム (citalopram hydrobromide)、 ジヒドロエノレゴクリプチン（dihydroergocryptine)、フノレォキセチン（fluoxetine)、フノレボ キサミン（fluvoxamine)、リチウム（lithium)、ミアンセリン（mianserin)、ミノレナシプラン（ milnacipran)、 ナプリン (minaprine)、 ルタザピン、 mirtazapine)、モク口べ ト (moclo bemide)、 酸ネファゾドン (nefazodone hydrochloride)、ノ ロキセテン (paroxetine)、 ピルリンドール（pirlindole)、レボキセチン（reboxetine)、 ST- 200、セルトラリン（sertrali ne)、チアネプチン（tianeptine)、トラゾドン（trazodone)、ベンラフアキシン（venlafaxine )、フノレォキセチン +オランザピン (fluoxetine + olanzapine)、オランザピン (olanzapine )、ラモトリジン (lamotrigine)、ビノレコート (Virucort)、塩酸デュロキセチン (duloxetine hydrochloride)、セレギリン（selegiline)、ゲピロン一 ER (gepirone-ER)、塩酸イミプラミ ン (lmipramine hydrochlorideノ、 トリプチリン (amitriptylineノ、トリミフフ ン (tnmipra mine) ,クロミプラミン（clomipramine)、ノノレトリプチリン（nortriptyline)、口フエプラミン（1 ofepramine)、マプロチリン（maprotiline)、セチプチリン（setiptiline)、ドスレピン（dosul epin 、ノミフェンシン、 nomifensine)、アコメフチン (agomelatine)、不タミフチド (netamif tide)、マレイン酸ァセナピン（asenapine maleate)、 SR- 58611、 LAX- 101、 DVS- 233、 ミフェプリストン（mifepristone)、 ODS- II、フマル酸ケチアピン（quetiapine fomarate)、 レべチフセタム (levetiracetamリ、フフミぺキソーノレ ramipexoleリ、トヒフメート（topiram ate) ,ヴイラゾドン（vilazodone)、エノールー 3— IPA (Enoト 3- IPA)、 OPC- 14523、力 ラベノレサート (carabersat)ゝエフ。リノくンセリン (eplivanserin)、サレデユータント (saredut ant)、 YKP10A、 AR- A2、 DOV- 216303、トリァセチルゥリジン（triacetyluridine)、（R) —シブトラミン（(R)- sibutramine)、 R- 673、 Org- 34517、 GW- 597599、 GW- 353162、リ カルバゼピン（licarbazepine)、 SLV- 308、 SPD- 421、イソバレラミド（isovaleramide)ゝ O rg- 24448、ネボスチネル（nebostinel)、 SA- 4503、 LX- 105、 SNEC- 2、 NBI- 34041、 SS R- 149415、 SSR- 146977、 DOV- 21947、 R- 1204、 PRX- 00023、 Lu-AA- 21004、 GSK- 679769、 GSK-823296等が挙げられ、好ましくは、例えば、シユウ酸エスシタロプラム（ escitalopram oxalate)、 /'ノレプフンフム (alprazolam)、 スノレプリ r (amisulpndeノ、 モキサピン (amoxapine)、ブプロピオン (bupropion)、カノレノマゼピン (carbamazepine )、臭素酸シタロプラム（citalopram hydrobromide)、ジヒドロエルゴクリプチン（dihydro ergocryptine)、フノレォキセチン (fluoxetine)、フノレボキサミン (fluvoxamine)、リチウム (1 ithiumノ、 ンセリン (mianserin)、 ノレナンフフン (milnacipran)、 ナプリン (minaprine )、ミノレタザピン (mirtazapine)、モク口べミド (moclobemide)、塩酸ネファゾドン (nefazod one hydrochloride)、ノ ロキセチン (paroxetine)、ピルリンドール (pirlindole)、レボキ セチン（reboxetine)、 ST- 200、セルトラリン（sertraline)、チアネプチン（tianeptine)、ト ラゾドン（trazodone)、ベンラフアキシン（venlafaxine)、フルォキセチン +オランザピン (fluoxetine + olanzapine)、才ランザピン (olanzapine)、ラモトリジン (lamotrigine)、ビ ノレコート (Vimcort)ゝ塩酸デュロキセチン (duloxetine hydrochloride)、セレギリン (sele giline)、ゲピロン一 ER (gepirone— ER)、； 酸づ プフ ン (imipramine hydrochloride;、 アミトリプチリン (amitriptyline)、トリミプラミン (trimipramine)、クロミプラミン (clomiprami ne)、ノノレトリプチリン (nortriptyline)、口フエプラミン (lofepramine)、マプロチリン (mapr otiline)、セチプチリン（setiptiline)、ドスレピン（dosulepin)、ノミフェンシン（nomifensin e)等である。 [0040] In the present invention, as a therapeutic agent for depression (antidepressant), a tricyclic antidepressant, a tetracyclic antidepressant, a triazolopyridine antidepressant, a selective serotonin reuptake inhibitor ( SSRI), serotone noradrenaline reuptake inhibitor (SNRI), and the like, specifically, for example, escitalopram oxalate oxalate, alprazolam, amisulpride, amoxapine, Bupropion, carbamazepine, citalopram hydrobromide, dihydroergocryptine, fluoxetine, fluvoxamine, lithium, selenium, erium Plan (milnacipran), naprine (minaprine), rutazapine, mirtazapine) (Moclo bemide), acid nefazodone (nefazodone hydrochloride), Bruno Rokiseten (paroxetine), Pirlindole (pirlindole), reboxetine (reboxetine), ST- 200, sertraline (Sertrali ne), tianeptine, trazodone, venlafaxine, funoleoxetine + olanzapine, olanzapine, lamotrigine, vinolecoat (Virucoret), duloxine hydrochloride, duloxine hydrochloride Selegiline, gepirone-ER, imipramine hydrochloride, triptyline, amitriptyline, tnmipra mine, clomipramine, nortriptyline, oral phepramine (1 ofepramine), maprotiline (maprotiline), cetiptiline (setiptiline), dosulpin (dosul epin, nomifensine), acomeftine (agomelatine), inamififide (netamif tide), asenapine maleate L, SR-611 -101, DVS-233, Mifepris Mifepristone, ODS-II, quetiapine fomarate, levetifacetam, ramipexole, topiram ate, virazodone, enol 3—IPA (Eno 3) IPA), OPC-14523, force Rabenoresert (carabersat) ゝ F. Reno kunserin (eplivanserin), saledeutant (saredut ant), YKP10A, AR-A2, DOV-216303, triacetyluridine, (R) — Sibutramine ((R) -sibutramine), R-673, Org-34517, GW-597599, GW-353162, licarbazepine, SLV-308, SPD-421, isovaleramide ゝ O rg-24448, nevostinel (Nebostinel), SA-4503, LX-105, SNEC-2, NBI-34041, SS R-149415, SSR-146977, DOV-21947, R-1204, PRX-00023, Lu-AA-21004, GSK-679769 GSK-823296, etc., preferably, for example, Escitalopram oxalate, / 'norephunhum (alprazolam), snolepri r (amisulpnde, moxapine, bupropion), canorenozepine (carbamazepine), citalopram hydrodigo hydrodiide , Funoleoxetine, flunoxamine, lithium (1 ithium, nianserin), norennanfunn (milnacipran), minaprine, minoletazapine, moclobemdon, nezozodone hydrochloride), noroxetine, parirdole, reboxetine, ST-200, sertraline, tianeptine, trazodone, venlafaxine, fluoxetine + Olanzapine (fluoxetine + olanzapine), aged lanzapine (olanzapine), lamotrigine, vinorecoat (dimoxetine hydrochloride), selegiline (sele giline), gepirone-ER (gepirone-ER), (imipramine hydrochloride ;, amitriptyline, trimipramine, clomipramine, nortriptyline, lofepramine, mapr otiline, setiptiline, dosulepin , Nomifensin and the like.
本発明において、てんかんの治療薬 (抗てんかん薬）としては、例えば、カルバマゼ ピン (carbamazepine)、抱水クロラー/レ、 chloral hydrate)、クロナセノヽム (clonazepam) 、ジァゼパム（diazepam)、フエノレバメート（felbamate)、フォスフエニトイン（fosphenytoi n)、ガノ ペンチン (gabapentin)、ラモトリシン（lamotrigine)、レべチラセタム (levetirace tam)、口ラゼ/ ム (lorazepam)、ォキシ力ノレノ ゼピン (oxcarbazepine)、フエノノ レビト ンナトリウム (phenobarbitone Na)、チアガビン（tiagabine)、トピラメート（topiramate)、 ノ レプロ酸ナトリウム (valproate semisodium)、ノ ノレプロ酸ナトリウム、 valproate sodiu m)、ビガバトリン（vigabatrin)、ゾニサミド（zonisamide)、プレガパリン（pregabalin)、フ エノノ ルビターノレ (phenobarbital)、プリミドン、 primidoneリ、フエエトイン、 phenytoin)、 エトスクシミド (ethosuximide)、ノレフイナミド (rufinamide)、ノヽーコセリド (harkoseride)、 BIA- 2- 093、サフイナミド（safinamide)、 SPD- 421、タランパネル（talampanel)、 NS- 120 9、レチガビン (retigabine)、カラべ/レサート (carabersat)、バル口セミド (valrocemide) ゝ YKP- 509、 E- 2007、 AMP- 397、 UCB- 34714、 T- 2000、イソバレラミド（isovaleramide )、 Co- 102862、 GT- 1061、 ICA- 69673、 UCB- 44212、メホバルビタール、メタルビター ル、エトトイン、トリメタジオン、ァセチルフエネトライド、ァセタゾラミド等が挙げられ、好 ましくは、例えば、カノレノ マゼピン (carbamazepine)、抱水クロラーノレ chloral hydrate )、ク C2ナ ム clonazepam)、シァセノヽム (diazepam;、フエ/レノ、メート (felbamate 、 フォスフエニトイン（fosphenytoin)、ガパペンチン（gabapentin)、ラモトリジン（lamotrigi ne)、レべチラセタム (levetiracetam)、ロラゼパム (lorazepam)、ォキシ力ノレノ ゼピン (o xcarbazepine)、フエノノ ルビトンナトリウム (phenobarbitone Na)、チアガビン (tiagabin e)、トピラメート (topiramate)、ノ ノレプロ酸ナトリウム (valproate semisodium)、ノ ノレプロ 酸ナトリウム (valproate sodium)、ビガノ トリン (vigabatrin)、ゾ-サミド (zonisamide)、 プレガパリン（pregabalin)、フエノバルビタール（phenobarbital)、プリミドン（primidone) 、フエ-トイン (phenytoin)、エトスクシミド (ethosuximide)、ノレフイナ ド (rufinamide)、 ハーコセリド（harkoseride)、 BIA- 2- 093、サフイナミド（safinamide)、 SPD- 421、タラン ノネル（talampanel)、 NS- 1209、レチガビン（retigabine)、カラベルサート（carabersat) 、バル口セミド（valrocemide)、 YKP- 509、 E- 2007、 AMP- 397、 UCB- 34714等であり、 より好ましくは、例えば、カルバマゼピン（carbamazepine)、抱水クロラール（chloral hy drate)、クロナゼノ ム (clonazepam)、ジァゼノ ム (diazepam)、フエノレノメート (felbamat e)、フォスフエ-トイン（fosphenytoin)、ガバペンチン（gabapentin)、ラモトリジン（lamot rigine)、レべチラセタム (levetiracetam)、ロラゼノ ム (lorazepam)、ォキシカノレノ ゼピ ン（oxcarbazepine)、フエノバルビトンナトリウム（phenobarbitone Na)、チアガビン（tiag abine)、トピラメート（topiramate)、ノ ノレプロ酸ナトリウム (^valproate semisodium)、ノ レ プロ酸ナトリウム (valproate sodium)、ビガノ トリン (vigabatrin)、ゾ-サミド (zonisamide )、プレガバリン（pregabalin)、フエノバルビタール（phenobarbital)、プリミドン（primido ne)、フエ-トイン（phenytoin)、エトスクシミド（ethosuximide)等である。 In the present invention, epilepsy treatment agents (antiepileptic drugs) include, for example, carbamazepine, chloral hydrate, clonazepam, diazepam, felbamate, Fosphenytoi n, gabapentin, lamotrigine, levetiracetam, lorazepam, oxycarbazepine, phenobarbitone Na), tiagabine, topiramate, sodium noreproate (valproate semisodium), sodium noreproate, valproate sodium, vigabatrin, zonisamide, pregabalin, phenol (phenobarbital), primidone, primidone, fetoin, phenytoin), Ethosuximide, rufinamide, norkoseride, BIA-2-093, safinamide, SPD-421, talampanel, NS-1209, retigabine, carabe / Carabersat, valrocemide ゝ YKP-509, E-2007, AMP-397, UCB-34714, T-2000, isovaleramide, Co-102862, GT-1061, ICA-69673, UCB -44212, mehobarbital, metal bital, ethotoin, trimethadione, acetylphenelide, acetazolamide, etc., preferably, for example, canoreno mazepine (carbamazepine), chloranohydrate chloral hydrate, ku C2 nam clonazepam), shiasenome (diazepam;), Hue / Leno, mate (felbamate, fosphenytoin, gabapentin, lamotrigine, lamotrigin) Chirasetamu (levetiracetam), lorazepam (lorazepam), Okishi force Noreno Zepin (o xcarbazepine), Fuenono ruby tons sodium (phenobarbitone Na), tiagabine (tiagabin e), topiramate (topiramate), sodium Bruno Norepuro acid (valproate semisodium), Bruno Norepuro Sodium valproate, vigabatrin, zonisamide, pregabalin, phenobarbital, primidone, phenytoin, ethosuximide, norefina Rufinamide, harkoseride, BIA-2-093, safinamide, SPD-421, taran panel, NS-1209, retigabine, carabersat, baluchimide ( va lrocemide), YKP-509, E-2007, AMP-397, UCB-34714, etc., more preferably, for example, carbamazepine, chloral hydrate, clonazepam, diazeno. (Diazepam), phenolate (felbamat e), fosphenytoin, gabapentin, lamotrigine, levetirace Levetiracetam, lorazepam, oxcarbazepine, phenobarbitone sodium, tiag abine, topiramate, sodium noreproate (^ valproate semisodium) Sodium proate (valproate sodium), biganobatrin (vigabatrin), zoisamide (zonisamide), pregabalin (pregabalin), phenobarbital (phenobarbital) (primido ne), phenytoin (phenytoin), ethosuximide (ethosuximide) Etc.
本発明において、ジストニアの治療薬としては、例えば、 AN-072,ボツリヌストキシ ン（botulinum toxin)等が挙げられる。  In the present invention, examples of therapeutic agents for dystonia include AN-072, botulinum toxin and the like.
本発明において、糖尿病の治療薬としては、例えば、速攻型、混合型、中間型およ び Zまたは持続型インスリン製剤 (例えば、大腸菌、イーストを用い、遺伝子工学的 に合成したヒトインスリン製剤、ゥシ、ブタの脾臓カゝら抽出された動物インスリン製剤等 ；)、スルホ -ルゥレア薬（例えば、トルプタミド（tolbutamide)、クロルプロパミド（chlorpro pamide)、グリベンクラミド (glibenclamide)、グリクラジド (gliclazide)、グリメピリド (glimep iride)、トラザミド（tolazamide)、ァセトへキサミド（acetohexamide)、グリクロビラミド（glic lopiramide)等）、ビグアナイド薬（例えば、フェンホルミン（phenformine)、塩酸ブホルミ ン (buformin hydrochloride)、 酸メトホノレミン (metformin hydrochloride)等)、 α—グ ルコシダーゼ阻害薬（例えば、ァカルボース（acarbose)、ボグリボース（voglibose)等） 、インスリン分泌促進薬 (例えば、ナテグリニド (nateglinide)等）、インスリン抵抗性改 善薬（例えば、トログリタゾン（troglitazone)、塩酸ピオグリタゾン（pioglitazone hydroch loride)等）、 GLP—l受容体ァゴニスト、アミリンァゴニスト、ホスホチロシンホスファタ ーゼ阻害薬、ジぺプチジルぺプチダーゼ IV阻害薬、 β 3アドレナリン受容体ァゴニス ト、糖新生阻害薬、 SGLT (sodium- glucose cotransporter)阻害薬等が挙げられる。 In the present invention, as a therapeutic agent for diabetes, for example, haste, mixed, intermediate and Z or continuous insulin preparations (for example, human insulin preparations genetically synthesized using Escherichia coli and yeast, U , Animal insulin preparations extracted from porcine spleen, etc.;), sulfo-lurea drugs (eg, tolbutamide, chlorpro pamide, glibenclamide, gliclazide, glimepiride ( glimep iride), tolazamide, tocehexamide, glic lopiramide, etc., biguanides (eg, phenformine, buformin hydrochloride, metformin hydrochloride, etc.) ), Α-glucosidase inhibitors (eg, acarbose, voglibo Voglibose, etc.), insulin secretagogues (eg, nateglinide), insulin resistance improvers (eg, troglitazone, pioglitazone hydrochloride (pioglitazone hydroch) loride)), GLP-1 receptor agonist, amylin agonist, phosphotyrosine phosphatase inhibitor, dipeptidyl peptidase IV inhibitor, β 3 adrenergic receptor agonist, gluconeogenesis inhibitor, SGLT (sodium- glucose cotransporter) inhibitors and the like.
[0043] 本発明にお 、て、糖尿病合併症の治療薬としては、例えば、アルドース還元酵素 阻害薬（例えば、ェパルレスタツト（印 alrestat)、 SNK- 860、 CT- 112等）、神経栄養因 子（例えば、 NGF (Nerve Growth Factor:神経成長因子）、 NT— 3、 BDNF (Brain D erived Neurotrophic Factor：脳由来神経栄養因子）等）、神経再生促進薬、 PKC阻 害薬、 AGE阻害薬、活性酸素消去薬、塩酸デュロキセチン等が挙げられる。 [0043] Te you, in the present invention, as a therapeutic agent for diabetic complications, for example, aldose reductase inhibitors (e.g., Eparuresutatsuto (mark a lrestat), SNK- 860, CT- 112 , etc.), neurotrophic factor (For example, NGF (Nerve Growth Factor), NT-3, BDNF (Brain Derived Neurotrophic Factor), etc.), nerve regeneration promoter, PKC inhibitor, AGE inhibitor, activity Examples include oxygen scavengers and duloxetine hydrochloride.
[0044] 本発明において、高脂血症の治療薬としては、例えば、スタチン系 HMG— CoA還 元酵素阻害薬（例えば、プラバスタチンナトリウム（pravastatin sodium)、アト口パスタ チンカノレシゥム (atorvastatin calcium)、シンバスタチン (simvastatin)、ロバスタチン (1 ovastatin)、ロスノ スタチン (rosuvastatin)、セリバスタチン (cerivastatin)、フノレノ スタ チン (fluvastatin)等）、フイブラート系トリグリセリド低下作用薬 (例えば、クロフイブラー ト（clofibrate)、ベザフイブラート（bezafibrate)、フエノフイブラート、シンフイブラート（si mfibrate)、クリノフイブラート（clinofibrate)等）、スクワレン合成酵素阻害薬、コレスチ ラミン (cholestyramin)ゝニコチン酸 (nicotinic acid)、プロブコール (probucol)等が挙 げられる。  [0044] In the present invention, therapeutic agents for hyperlipidemia include, for example, statin HMG-CoA reductase inhibitors (for example, pravastatin sodium, atorvastatin calcium, simvastatin calcium, simvastatin ( simvastatin), lovastatin (1 ovastatin), rosnostatin (rosuvastatin), cerivastatin, funorenostatin (fluvastatin, etc.), fibrate triglyceride-lowering drugs (eg, clofibrate, bezafibrate, bezafibrate, bezafibrate Nofibrato, symfibrate, clinofibrate, etc., squalene synthase inhibitors, cholestyramin nicotinic acid, probucol, and the like.
[0045] 本発明にお 、て、アセチルコリンエステラーゼ阻害薬としては、例えば、塩酸ドネべ シノレ (donepezil hydrochloride)、酒石酸リノくスチク ン、 rivastigmine tartrate)、力フン タミン（galantamine)、ザナぺジル (TAK-147)等が挙げられる。  [0045] In the present invention, examples of the acetylcholinesterase inhibitor include donepezil hydrochloride, linostigmine tartrate, rivastigmine tartrate, galantamine, zanapezil ( TAK-147).
本発明にお 、て、 NMDA (N メチル D ァスパラギン酸)受容体拮抗薬として は、例えば、 （+ ) - (IS, 2S)—1— (4 ヒドロキシ一フエ-ル） 2— (4 ヒドロキシ 4一フエ-ルビペリジノ）一 1ーィル）一 1一プロパノール、 （IS, 2S)— 1一 （4ーヒド 口キシ一 3—メトキシフエ-ル） 2— (4—ヒドロキシ一 4—フエ-ルビペリジノ） 1— プロパノール等が挙げられる。  In the present invention, NMDA (N-methyl D-aspartate) receptor antagonists include, for example, (+)-(IS, 2S) —1— (4 hydroxy monophenyl) 2— (4 hydroxy 4 1-phenyl) 1 1) 1 1) propanol, (IS, 2S) — 1 1 (4-hydroxy 1-methoxyphenyl) 2— (4-hydroxy 1-vinyl biperidino) 1-propanol Etc.
[0046] 本発明において、 AMPA (2 アミノー 3 （メチルー 3 ヒドロキシイソォキサゾー ルー 4 ィル)プロパン酸) Zカイニン酸受容体拮抗薬としては、例えば、 6—シァノ —7 ニトロキノキサリン一 2, 3 ジオン（CNQX)、 6 ニトロ一 7—スルファモイルべ ンゾ [f]キノキサリン 2, 3 ジオン（NBQX)、 6, 7 ジニトロキノキサリン 2, 3— ジオン (DNQX)等が挙げられる。 [0046] In the present invention, AMPA (2 amino-3 (methyl-3 hydroxyisoxazol 4-yl) propanoic acid) Z kainate receptor antagonists include, for example, 6-cyan-7 nitroquinoxaline 3 dione (CNQX), 6 nitro 7-sulfamoylbe Nzo [f] quinoxaline 2,3 dione (NBQX), 6,7 dinitroquinoxaline 2,3-dione (DNQX) and the like.
本発明において、 βアミロイドタンパクの産生、分泌、蓄積、凝集および Ζまたは沈 着抑制薬としては、例えば、 i3セクレターゼ阻害薬、 γセクレターゼ阻害作用薬、 0 アミロイドタンパク凝集抑制薬、 アミロイド分解酵素、 アミロイドワクチン等が挙げ られる。  In the present invention, β-amyloid protein production, secretion, accumulation, aggregation and sputum or deposition inhibitor include, for example, i3 secretase inhibitor, γ-secretase inhibitor, 0 amyloid protein aggregation inhibitor, amyloid degrading enzyme, amyloid Examples include vaccines.
[0047] 本発明にお 、て、利尿薬としては、例えば、チアジド系利尿薬 (例えば、クロ口チア ジド（chlorothiazide)、べンズチアジド（benzthiazide)、ヒドロクロ口チアジド（hydrochlor othiazide)、ヒドロフノレメチアジド（hydroflumethiazide)、トリクロノレメチアジド（trichlorme thiazide)、シクロチアジド（cyclothiazide)、メチクロチアジド（methyclothiazide)、ポリ チアジド (polythiazide)、キネタゾン (quinethazone)、メトラゾン (metolazone)等)、ル ープ利尿薬（例えば、フロセミド（forosemide)、ブメタエド（bumetanide)、ピレタニド（pi retanide)、エタクリン酸（ethacrynic acid)等）、カリウム保持性利尿薬（例えば、スピロ ノラタトン (spironolactone)、カンレノ酸カリウム (potassium canrenoate)、ア^ロフイド (a miloride)、トリアムテレン（triamterene)等）、キサンチン誘導体（例えば、サリチル酸 ナトリウムテオブロミン、サリチル酸カルシウムテオブロミン等）、ァセタゾラミド（acetazo lamide)等が挙げられる。  In the present invention, the diuretics include, for example, thiazide diuretics (for example, chlorothiazide, benzthiazide, hydrochlorthiazide, hydrofurolemethiazide). (Hydroflumethiazide), trichlorme thiazide, cyclothiazide, methyclothiazide, polythiazide, quinethazone, metolazone, etc., loop diuretics (eg , Furosemide, bumetanide, piretanide, etacrynic acid, etc., potassium-sparing diuretics (for example, spironolactone, potassium canrenoate, potassium ^ Lomi (a miloride), triamterene, etc.), xanthine derivatives (eg, sari Sodium Le acid and theobromine, calcium salicylate and theobromine etc.), Asetazoramido (acetazo lamide), and the like.
[0048] 本発明にお 、て、カルシウムチャネル遮断薬 (カルシウム拮抗薬）としては、例えば 、二フエジピン（nifedipine)、二カルジピン（nicardipine)、ニトレンジピン（nitrendipine) 、ニノレバジピン (nilvadipine)、ニソノレジピン (nisoldipine)、マニジピン (manidipine)、ベ -ジピン（benidipine)、パル-ジピン（barnidipine)、エホ-ジピン（efonidipine)、アム ロジピン（amlodipine)、ジルチアゼム（diltiazem)、ベラパミル（verapamil)、塩酸クロ- ジン（clonidine hydrochloride)等が挙げられる。  [0048] In the present invention, as calcium channel blockers (calcium antagonists), for example, nifedipine, nicardipine, nitrendipine, ninolevadipine, nisoldipine , Manidipine, benidipine, parndipine, efonidipine, amlodipine, diltiazem, verapamil, clonidine hydrochloride ) And the like.
[0049] 本発明にお 、て、アンジォテンシン変換酵素 (ACE)阻害薬としては、例えば、カブ トプリル（captopril)、ァラセプリル（alacepril)、リシノプリノレ（lisinopril)、ェナラブリノレ（e nalapril)、デラプリル（delapril)、シラザプリル（cilazapril)、イミダプリル（imidapril)、ぺ リンドプリル（perindopril)、テモカプリル（temocapril)、トランドラプリル（trandolapril) 等が挙げられる。 本発明において、アンジォテンシン II受容体拮抗薬としては、例えば、カンデサル タンシレキセチノレ (candesartan cilexetil)、ロサノレタン (losartan)、 ノ レサノレタン (valsa rtan)等が挙げられる。 [0049] In the present invention, angiotensin converting enzyme (ACE) inhibitors include, for example, captopril, alacepril, lisinopril, enalapril, delapril ), Cilazapril, imidapril, perindopril, temocapril, trandolapril, and the like. In the present invention, examples of angiotensin II receptor antagonists include candesartan cilexetil, rosartan, valsartan, and the like.
[0050] 本発明にお!/、て、ナトリウムチャネル遮断薬としては、例えば、アジマリン（ajmaline) 、塩酸プロ力インアミド（procainamide hydrochloride) ,リルゾール（riluzole)等が挙げ られる。  [0050] Examples of sodium channel blockers according to the present invention include ajmaline, procainamide hydrochloride, riluzole and the like.
本発明において、カリウムチャネル開口薬としては、例えば、ジァゾキシド、フルピ ルチン、ピナシジル、レブクロマカリム、リルマカリム、クロマカリム、 PCO-400、 SKP-45 0等が挙げられる。  In the present invention, examples of the potassium channel opener include diazoxide, flupirtine, pinacidil, levcromacarim, rilmacalim, cromakalim, PCO-400, SKP-450 and the like.
本発明において、抗血小板薬としては、例えば、アスピリン (aspirin)、ィコサペンタ ェン酸ェチノレ (ethyl icosapentaenoate)、ォサグレノレナトリウム (sodium ozagrel)、ベラ プロストナトリウム（beraprost sodium)、アルプロスタジル（alprostadil)、塩酸チクロピ ジン (ticlopidine hydrochloride)、シロスタゾーノレ (cilostazol)、ジピリダモーノレ (dipyrid amole)、塩酸サノレポグレラート (sarpogrelate hydrochloride)等が挙げられる。  In the present invention, examples of antiplatelet agents include aspirin, icosapentaenoate, ethyl icosapentaenoate, sodium ozagrel, beraprost sodium, alprostadil. ), Ticlopidine hydrochloride, cilostazol, dipyridamole, sarpogrelate hydrochloride and the like.
[0051] 本発明において、抗凝固薬としては、例えば、ヮルフアリン (例えば、ヮルフアリンカリ ゥム (warfarin potassium)等)、へノ リン (f列えば、、へノ《リンナトリウム (heparin sodium) 、へパリンカルシウム（heparin calcium)等）、抗トロンビン薬（例えば、アンチトロンビン III (antithrommbin III)、アルガトロバン（argatroban)、ヒルジン（hirudin)等）等が挙げ られる。 [0051] In the present invention, examples of the anticoagulant include ヮ rufaline (e.g., warfarin potassium), henoline (for example, heparin sodium, heparin sodium). Calcium (heparin calcium etc.), antithrombin drugs (for example, antithrombin III (antithrommbin III), argatroban (argatroban), hirudin (hirudin) etc.) etc. are mentioned.
本発明において、血栓溶解薬としては、例えば、ゥロキナーゼ（urokinase)、ナサル プラーゼ（nasaruplase、プロゥロキナーゼ（prourokinase)等）、組織プラスミノーゲンァ タティベータ一（t— PA)、チソキナーゼ（tisokinase)、アルテプラーゼ（alteplase)、ナ テプラーゼ (nateplase)、モンテプラーゼ (monteplase)、ストレプトキナーゼ (streptoki nase)、 ノ ミテプラーゼ（pamiteplase)等が挙げられる。  In the present invention, thrombolytic agents include, for example, urokinase, nasalplase (nasaruplase, prourokinase, etc.), tissue plasminogen protease (t-PA), tisokinase, alteplase (alteplase). ), Nateplase, monteplase, streptokinase, pamiteplase and the like.
[0052] 本発明にお 、て、シクロォキシゲナーゼ (COX)— 2阻害薬としては、例えば、セレ コキシブ（celecoxib)、口フエコキシブ (rofecoxib)等が挙げられる。 [0052] In the present invention, examples of the cyclooxygenase (COX) -2 inhibitor include celecoxib, oral fuecoxib, and the like.
本発明において、非ステロイド性抗炎症薬としては、例えば、アスピリン (aspirin)、メ フエナム酸（mefenamic acid)、ジクロフェナク（diclofenac)、フェンブフェン（fenbufen) 、インドメタシン（indometacin)、イブプロフェン（ibuprofen)、ケトプロフェン（ketoprofen ) ,ナプロキセン (naproxen) ,フエ-ルブタゾン (phenylbutazone)、ピロキシカム (pirox icam)、テノキシカム（tenoxicam)、メロキシカム、セレコキシブ (celecoxib)、口フエコキ シブ (rofecoxib)等が挙げられる。 In the present invention, non-steroidal anti-inflammatory drugs include, for example, aspirin, mefenamic acid, diclofenac, fenbufen , Indometacin, ibuprofen, ketoprofen, naproxen, phenylbutazone, pirox icam, tenoxicam, meloxicam, celecoxib, celecoxib rofecoxib) and the like.
[0053] 本発明にお 、て、ステロイド薬としては、例えば、プレドニゾロン（prednisolone)、メ チノレプレドニゾロン (methylprednisolone)、トリアムシノロン (triamcinolone)、ノ ラメタゾ ン (paramethasone)、テ3 rサメタゾン (dexamethasone)、ベタメタゾン (betamethasone 、コノレチゾン (cortisone)、ヒドロコノレチゾン (hydrocortisone)、へキセストローノレ、酢酸 コルチゾン等が挙げられる。 [0053] Te you, to the present invention, as the steroids, for example, prednisolone (prednisolone), main Chino Les prednisolone (methylprednisolone), triamcinolone (triamcinolone), Bruno Rametazo emissions (paramethasone), Te 3 r Sametazon (dexamethasone), Examples thereof include betamethasone (betamethasone, conorethone (cortisone), hydroconorethone (hydrocortisone), hexestrone, cortisone acetate and the like.
本発明において、抗酸化薬としては、例えば、リノレン酸 (linolenic acid)、ィコサぺ ンタエン酸 (icosapentaenoic acid)、ドコサへキサェン酸 (docosahexaenoic acid)、ァス コノレビン酸 (ascorbic acid)、酢酸トコフェローノレ (tocopherol acetate)、エダラボン等 が挙げられる。  In the present invention, examples of the antioxidant include linolenic acid, icosapentaenoic acid, docosahexaenoic acid, ascorbic acid, tocopherolole acetate. (tocopherol acetate), edaravone and the like.
本発明において、ビタミン類としては、例えば、ァスコルビン酸（ascorbic acid)、酢 酸トコフェローノレ (tocopherol acetate)、メコノ ラミン (mecobalamin)等が挙げられる。  In the present invention, examples of vitamins include ascorbic acid, tocopherol acetate, mecobalamin, and the like.
[0054] 本発明において、免疫抑制薬としては、例えば、ァザチォプリン (商品名：イムラン、 ァザニン）、ミゾリビン (商品名：プレディニン）、メトトレキサート（商品名：メトトレキセー ト、リウマトレックス）、ミコフエノール酸モフエチル（商品名：セルセブト）、シクロホスフ アミド（商品名：エンドキサン P)、シクロスポリン A (商品名：ネオーラル、サンディミユン ) , FTY- 720,タク口リムス水和物（FK506、商品名：プログラフ、プロトピック）、シロリ ムス（ラパマイシン）、エベロリムス（商品名：サーティカン）、プレドニゾロン（商品名：プ レドニン）、メチルプレドニゾロン（商品名：メドロール）、オルソクローン OKT3 (商品名 ：モロナブ CD3)、抗ヒトリンパ球グロブリン (ALG、商品名：アールブリン）、デォキシス パーガリン (DSG、塩酸ダスペリムス、商品名：スパ-ジン)等が挙げられる。  [0054] In the present invention, examples of the immunosuppressant include, for example, azathioprine (trade names: Imran, azanine), mizoribine (trade name: predinin), methotrexate (trade names: methotrexate, rheumatorex), mycophenolate mofuethyl (product) Name: Cercebut), Cyclophosphamide (Product name: Endoxan P), Cyclosporin A (Product name: Neoral, Sandimyun), FTY-720, Takuguchi Limus Hydrate (FK506, Product name: Prograf, Protopic), Sirolimus ( Rapamycin), Everolimus (Brand name: Certican), Prednisolone (Brand name: Predonin), Methylprednisolone (Brand name: Medrol), Orthoclone OKT3 (Brand name: Moronab CD3), Anti-human lymphocyte globulin (ALG, Brand name) : Earl Bryn), Deoxyspa -Garin (DSG, Dasperimus hydrochloride, trade name: Spergin) and the like.
[0055] 本発明において、グリセリン製剤としては、例えば、グリセオール等が挙げられる。  [0055] In the present invention, examples of the glycerin preparation include glycerol.
本発明の医薬は、パーキンソン病および Zまたはパーキンソン症候群を予防、治療 および Zまたは症状進展抑制するために、前記「パーキンソン病および Zまたはパ 一キンソン症候群の予防、治療および Zまたは症状進展抑制薬」（薬物 B)や、所望 によってさらに組み合わせるその他の薬物 (薬物 C)等にカ卩え、前記「（2R)—2—プ 口ピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグ」（薬物 A)を組 み合わせることに特徴を有する医薬である。薬物 Aを組み合わせることによって、従 来用いられていた医薬 (すなわち、薬物 Bを含む医薬や、さらに薬物 Cを組み合わせ た医薬）に比べ、パーキンソン病および Zまたはパーキンソン症候群の予防、治療お よび Zまたは症状進展抑制効果を補完および Zまたは増強したり、薬物 (薬物 Bや 薬物 C)の投与量 ·副作用を軽減したり、もしくは薬物 (薬物 Bや薬物 C)に対する耐性 の発現を防止したりするといつた有用な効果 (特に、投与量低減、副作用改善、治療 効果増強等、好ましくは、投与量低減、副作用改善等)を得ることができる。なお、本 発明においては、薬物 A、すなわち（2R)— 2—プロピルオクタン酸、その塩、その溶 媒和物またはそれらのプロドラッグと組み合わせる薬物は、その全てを総じて「併用 薬」と称する場合がある。すなわち、該「併用薬」は、例えば、薬物 Bとして具体的に列 記した前記の薬物であってもよいし、また、薬物 Cとして列記した前記の薬物であって もよい。併用薬として好ましくは、薬物 Bとして具体的に列記した前記の薬物等が用 いられる。 The medicament of the present invention provides the above-mentioned “prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome” in order to prevent, treat and suppress Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome. (Drug B) or desired In combination with other drugs (drug C) etc. that are further combined with the above, combine (2R) -2-pyruoctanoic acid, its salt, solvate or prodrug thereof (drug A). It is a pharmaceutical with particular characteristics. Combining drug A prevents and treats Parkinson's disease and Z or Parkinson's syndrome compared to traditionally used drugs (ie, drugs containing drug B and drugs combined with drug C) and Z or When supplementation and / or enhancement of the symptom progression inhibitory effect, drug (drug B or drug C) dose, side effects are reduced, or resistance to drug (drug B or drug C) is prevented Useful effects (especially dose reduction, side effect improvement, therapeutic effect enhancement, etc., preferably dose reduction, side effect improvement, etc.) can be obtained. In the present invention, drug A, that is, (2R) -2-propyloctanoic acid, a salt thereof, a solvent thereof, or a drug combined with a prodrug thereof is collectively referred to as “concomitant drug”. There is. That is, the “concomitant drug” may be, for example, the drug specifically listed as drug B, or the drug listed as drug C. As the concomitant drug, the above-mentioned drugs specifically listed as drug B are preferably used.
このように、薬物 Aを組み合わせて投与することで、薬物 Aを組み合わせな 、状態（ すなわち、併用薬単独投与時)で得られる薬効を維持したまま (あるいは薬効をさら に高めつつ）、併用薬の投与量を低減させることができる。このような場合、薬物 Aは 、併用薬 (好ましくは薬物 B)の投与量低減用医薬 (もしくは、併用薬の投与量を低減 する剤）ということができる。同様に、薬物 Aを組み合わせて投与することで、薬物 Aを 組み合わせない状態 (すなわち、併用薬単独投与時）に見られていた副作用を軽減 、あるいは解消することができる。このような場合、薬物 Aは、併用薬 (好ましくは薬物 B)の副作用改善用医薬 (もしくは、併用薬の副作用を改善する剤) t 、うことができる 。また同様に、薬物 Aを組み合わせて投与することで、薬物 Aを組み合わせない状態 (すなわち、併用薬単独投与時）に見られていた治療効果を増強することができる。こ のような場合、薬物 Aは、併用薬 (好ましくは薬物 B)の治療効果増強用医薬 (もしくは 、併用薬の治療効果を増強する剤）ということができる。薬物 Aを組み合わせることに よってこれらの効果 (すなわち、投与量が低減される、副作用が改善される、もしくは 治療効果が増強される等の効果)を得るための併用薬は一種であってもよいし、また 二種以上であってもよ 、。薬物 Aを組み合わせることでこのような作用を有する本発 明の医薬が得られた場合、薬物 Aと併用薬の組み合わせはそれぞれ、「併用薬の投 与量低減剤」、「併用薬の副作用改善剤」、「併用薬の治療効果増強剤」ということが できる。 In this way, by administering the drug A in combination, the drug combination is maintained without maintaining the drug effect obtained in the state (ie, when the concomitant drug is administered alone) (or while further improving the drug effect). Dosage can be reduced. In such a case, drug A can be referred to as a drug for reducing the dose of a concomitant drug (preferably drug B) (or an agent that reduces the dose of the concomitant drug). Similarly, administration of a combination of drug A can reduce or eliminate the side effects observed in the state where no drug A is combined (that is, when a concomitant drug is administered alone). In such a case, drug A can be used as a drug for improving side effects of a concomitant drug (preferably drug B) (or an agent that improves the side effect of the concomitant drug). Similarly, by administering the drug A in combination, the therapeutic effect seen in the state where the drug A is not combined (that is, when the concomitant drug is administered alone) can be enhanced. In such a case, drug A can be referred to as a medicament for enhancing the therapeutic effect of a concomitant drug (preferably drug B) (or an agent that enhances the therapeutic effect of the concomitant drug). Combining drug A has these effects (i.e., reduced dosage, improved side effects, or There may be one kind of concomitant drug for obtaining an effect such as an enhanced therapeutic effect) or two or more kinds. When a drug of the present invention having such an action is obtained by combining Drug A, the combination of Drug A and the concomitant drug is `` Dose reduction agent for concomitant drug '', `` Improved side effect of concomitant drug, respectively '' Agents ”and“ therapeutic effect enhancers of concomitant drugs ”.
[0057] 本発明において、前記「併用薬の投与量低減用医薬」によって得られる効果として 好ましくは、併用薬の投与量を併用薬単独投与時 (薬物 Aを組み合わせな 、場合） の投与量の 2分の 1 (1Z2と表記する場合もある。）〜10分の 1 (1Z10と表記する場 合もある。）以下に、より好ましくは 5分の 1 (1Z5と表記する場合もある。；)〜 10分の 1 以下に、最も好ましくは 10分の 1以下に低減するものである。「併用薬の投与量低減 用医薬」によって、併用薬の投与量が下がるので、併用薬に由来する副作用の回避 等の好ましい効果が期待できる。また、併用薬単独投与時にはその副作用のために 併用薬の投与量を増量することができず、望ましい治療効果を得ることができなかつ たような症例に対しても、かかる効果を得た本発明の医薬は安全に投与することがで き、その治療効果を補うことができる。  [0057] In the present invention, the effect obtained by the above-mentioned "medicine for reducing the dose of a concomitant drug" is preferably the dose of the concomitant drug when the concomitant drug is administered alone (when no drug A is combined) 1/2 (sometimes expressed as 1Z2) to 1/10 (sometimes expressed as 1Z10), more preferably 1/5 (sometimes expressed as 1Z5); ) To 1/10 or less, most preferably 1/10 or less. Since the dose of the concomitant drug is reduced by the “drug for reducing the dose of the concomitant drug”, favorable effects such as avoiding side effects derived from the concomitant drug can be expected. In addition, when the concomitant drug is administered alone, the dose of the concomitant drug cannot be increased due to its side effects, and the present invention has obtained such an effect even in cases where the desired therapeutic effect cannot be obtained. This medicine can be administered safely and can supplement its therapeutic effect.
[0058] 本発明において、「併用薬の副作用改善用医薬」が改善しうる副作用として、代表 的なものには以下のものが挙げられる。例えば、パーキンソン病の治療においては、 レポドパ製剤を投与することによって、不随意運動 (ジスキネジァ）、すくみ現象 (フリ 一ジング)、精神症状 (例えば、興奮、不眠、幻覚、妄想、躁うつ状態等)、消化器症 状 (例えば、悪心、嘔吐等）、薬効不安定といった副作用の他、ウエアリングオフ現象 、オン一オフ現象、ディレイドオン現象、ノーオン現象、アップアンドダウン（up and do wn)現象等の副作用が生じることが知られている力 該レボドパ製剤と組み合わせて 、前記「（2R)— 2—プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロド ラッグ」を投与することにより、レポドパ製剤の投与に起因するこれらの副作用を改善 することが可能となる。 [0058] In the present invention, typical side effects that can be improved by the "medicament for improving side effects of concomitant drugs" include the following. For example, in the treatment of Parkinson's disease, administration of a repodopa preparation may result in involuntary movements (dyskinesia), freezing phenomena (freezing), psychiatric symptoms (eg, excitement, insomnia, hallucinations, delusions, manic depression) , Gastrointestinal symptoms (eg nausea, vomiting, etc.), side effects such as drug instability, wear-off phenomenon, on-off phenomenon, delayed-on phenomenon, no-on phenomenon, up-and-down phenomenon In combination with the levodopa preparation, the above-mentioned “(2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof” is administered, These side effects resulting from the administration of the drug product can be improved.
[0059] 本発明にお!/、て、ウエアリングオフ（wearing off)現象とは、例えば、パーキンソン病 の治療において、薬物（例えば、レポドパ製剤、レポドパ 'ベンセラジド配合剤等）を 長期間投与し続けると、薬効の持続時間が短縮したり、あるいは初回投与時に比べ て薬効が減弱し、薬物の投与間隔を次第に短くしなければ発作が起きるようになる現 象等をいう。ウエアリングオフ現象が起こると、結果として薬物の投与回数が増加する 本発明において、「併用薬の副作用改善用医薬」は、ゥヱァリングオフ現象を改善 することもできる。ここで「改善する」とは、一度ウエアリングオフ現象が認められた後に 薬効の持続時間が再び復帰することや、初回投与時の薬効まで回復する等だけで なぐ予想されたウエアリングオフ現象が一度も認められない場合をも包含する。 [0059] In the present invention, the wearing-off phenomenon means, for example, in the treatment of Parkinson's disease, a drug (for example, levodopa preparation, levodopa'benserazide combination agent, etc.) is administered for a long time. If you continue, the duration of the efficacy will be shortened or compared to the first time This refers to a phenomenon in which seizures occur if the drug efficacy is reduced and the drug administration interval is not shortened gradually. When the wear-off phenomenon occurs, the number of drug administrations increases as a result. In the present invention, the “medicament for improving side effects of concomitant drugs” can also improve the warning-off phenomenon. Here, “improvement” means the expected wear-off phenomenon that occurs only after the wear-off phenomenon has been observed once the duration of the medicinal effect has returned, or when the initial effect has been restored. The case where it is never recognized is also included.
[0060] 本発明にお!/、て、オン オフ（on-off)現象（オンアンドオフ現象と称することもある。 [0060] In the present invention, an on-off phenomenon (sometimes referred to as an on-off phenomenon).
)とは、例えば、パーキンソン病の治療において、レポドパ製剤の服薬一定期間後、 急激かつ不規則に症状が改善 (オン)したり、増悪 (オフ）したりする現象をいい、一日 に何回も繰り返すこともある。若年発症者、レポドパ製剤長期服用者あるいはレボド パ製剤の投与量の多い患者によく見られ、オン時にジスキネジァを伴うことが多い。 本発明において、「併用薬の副作用改善用医薬」は、オン—オフ現象を改善するこ ともできる。ここで「改善する」とは、一度オン オフ現象が認められながらもその後該 現象の起きる回数が減少したりあるいは起きなくなったりすることだけでなぐ予想さ れたオン オフ現象が一度も認められな 、場合も包含する。  ) Is, for example, a phenomenon in which symptoms are suddenly and irregularly improved (on) or worsened (off) after a certain period of treatment with Parkinson's disease. May repeat. It is common in younger onset patients, long-term users of levodopa, or patients with high doses of levodopa, often with dyskinesia when on. In the present invention, the “medicament for improving side effects of concomitant drugs” can also improve the on-off phenomenon. “Improvement” here means that the on / off phenomenon that has been expected is only recognized, but the expected on / off phenomenon is not recognized even if the number of occurrences of the phenomenon subsequently decreases or disappears. , Including cases.
本発明において、ディレイドオン（delayed on)現象とは、例えば、パーキンソン病の 治療において、レポドパ製剤を投与して力も効果が発現するまでに時間を要する現 象を指す。  In the present invention, the delayed on phenomenon refers to, for example, a phenomenon in which time is required for administration of a repodopa preparation to exert its effect in the treatment of Parkinson's disease.
[0061] 本発明において、「併用薬の副作用改善用医薬」は、ディレイドオン現象を改善す ることもできる。ここで「改善する」とは、一度ディレイドオン現象が認められながらもそ の後該現象の起きる回数が減少したりあるいは起きなくなったりすることだけでなぐ 予想されたディレイドオン現象が一度も認められない場合も包含する。  In the present invention, the “medicament for improving side effects of concomitant drugs” can also improve the delayed on phenomenon. “Improvement” here means that a delayed on-on phenomenon is recognized once, but then the number of occurrences of the phenomenon is reduced or no longer occurs. The expected delayed on phenomenon is never recognized. Including cases.
本発明において、ノーオン (no on)現象とは、例えば、パーキンソン病の治療にお いて、レポドパ製剤を投与しても、治療効果が全く認められない現象を指す。  In the present invention, the no on phenomenon refers to a phenomenon in which no therapeutic effect is observed even when a repodopa preparation is administered in the treatment of Parkinson's disease, for example.
本発明において、「併用薬の副作用改善用医薬」は、ノーオン現象を改善すること もできる。ここで「改善する」とは、一度ノーオン現象が認められながらもその後該現象 の起きる回数が減少したりあるいは起きなくなったりすることだけでなぐ予想されたノ 一オン現象が一度も認められな 、場合も包含する。 In the present invention, the “medicine for improving side effects of concomitant drugs” can also improve the noon phenomenon. “Improvement” here means an expected nodal phenomenon that occurs once a no-on phenomenon is recognized, but only after that the number of occurrences of the phenomenon decreases or disappears. This includes cases where the one-on phenomenon has never been observed.
[0062] 本発明にお!/、て、アップアンドダウン (up and down)現象とは、例えば、パーキンソ ン病において、症状の改善と増悪に日内変動が認められる状態をいう。  [0062] In the present invention, the "up and down" phenomenon refers to a state in which circadian variability is observed in improvement and exacerbation of symptoms in, for example, Parkinson's disease.
本発明において、「併用薬の副作用改善用医薬」は、アップアンドダウン現象を改 善することもできる。ここで「改善する」とは、一度アップアンドダウン現象が認められな がらもその後該現象の起きる回数が減少したりあるいは起きなくなったりすることだけ でなぐ予想されたアップアンドダウン現象が一度も認められない場合も包含する。  In the present invention, the “medicament for improving side effects of concomitant drugs” can also improve the up-and-down phenomenon. Here, “improve” means that once an up-and-down phenomenon has been observed, the expected up-and-down phenomenon can be recognized only by the fact that the number of occurrences of the phenomenon decreases or does not occur. This includes cases where it is not possible.
[0063] 本発明にお 、て、「併用薬」として好ましくは、例えば、薬物 Bとして具体的に列記し た前記の薬物や、薬物 Cとして列記した以下の薬物、すなわち、レポドパ製剤、ドパミ ン受容体作動薬 (ドパミン受容体刺激薬)、ドパミン遊離促進薬 (ドパミン分泌促進薬 あるいはドパミン放出促進薬)、ドパミン取り込み阻害薬、ドパミン作用薬、中枢性抗 コリン薬、芳香族 L—アミノ酸脱炭酸酵素阻害薬 (DCI)、モノアミン酸ィ匕酵素 (MAO — B)阻害薬、カテコール— O—メチルトランスフェラーゼ（COMT)阻害薬、ノルェピ ネフリン (ノルアドレナリン)補充薬、 GABA受容体調節薬 (例えば、 GABA受容体 [0063] In the present invention, the "concomitant drug" is preferably, for example, the above-mentioned drugs specifically listed as Drug B, or the following drugs listed as Drug C, that is, levodopa formulations, dopamine Receptor agonist (dopamine receptor stimulant), dopamine release enhancer (dopamine secretion enhancer or dopamine release enhancer), dopamine uptake inhibitor, dopamine agonist, central anticholinergic, aromatic L-amino acid decarboxylation Enzyme inhibitors (DCI), monoamine acid enzymes (MAO — B) inhibitors, catechol—O-methyltransferase (COMT) inhibitors, norepinephrine (noradrenaline) supplements, GABA receptor modulators (eg, GABA receptor) Body
A A  A A
作動薬等)、 GABA受容体調節薬、アデノシン A2A受容体遮断薬、アポトーシス阻  Agonists, etc.), GABA receptor modulators, adenosine A2A receptor blockers, apoptosis inhibitors
B  B
害薬、神経分化'再生促進薬、神経栄養因子 (例えば、ニューロトロフィン、 TGF- スーパーファミリー、ニューロ力インファミリー、増殖因子等）、脳機能賦活薬 (例え ば、脳代謝賦活薬、脳循環改善薬等)、 Rho—キナーゼ阻害薬、アセチルコリンエス テラーゼ阻害薬等のパーキンソン病および Zまたはパーキンソン症候群の予防、治 療および Zまたは症状進展抑制薬、神経変性疾患治療薬、運動神経病治療薬、脱 髄性疾患治療薬、脳血管障害治療薬、脳腫瘍治療薬、脳脊髄外傷に伴う神経機能 障害の治療薬、感染症に伴う脳脊髄疾患の治療薬、精神疾患治療薬、てんかん治 療薬、ジストニア治療薬、糖尿病治療薬、糖尿病合併症治療薬、高脂血症治療薬、 NMDA受容体拮抗薬、 AMPAZカイニン酸受容体拮抗薬、利尿薬、カルシウムチ ャネル遮断薬 (カルシウム拮抗薬)、アンジォテンシン変換酵素 (ACE)阻害薬、アン ジォテンシン II受容体拮抗薬、ナトリウムチャネル遮断薬、カリウムチャネル開口薬、 β受容体遮断薬、抗血小板薬、抗凝固薬、血栓溶解薬、シクロォキシゲナーゼ (CO X)— 2阻害薬、非ステロイド性抗炎症薬、ステロイド薬、抗酸ィ匕薬およびビタミン類か ら選ばれる 1種または 2種以上の薬物またはそれらの配合剤等が挙げられる。 Pesticides, neuronal differentiation'regenerative promoters, neurotrophic factors (eg, neurotrophins, TGF-superfamily, neuropower infamily, growth factors), brain function activators (eg, brain metabolism activators, cerebral circulation) Remedy), Rho-kinase inhibitor, acetylcholinesterase inhibitor, etc., Parkinson's disease and Z or Parkinson's syndrome prevention, treatment and Z or symptom progression inhibitor, neurodegenerative disease therapeutic, motor neuropathy, Treatment for demyelinating disease, treatment for cerebrovascular disorder, treatment for brain tumor, treatment for neurological dysfunction associated with cerebrospinal trauma, treatment for cerebrospinal disease associated with infection, treatment for mental illness, treatment for epilepsy, dystonia Therapeutic, Diabetes, Diabetes complication, Hyperlipidemia, NMDA receptor antagonist, AMPAZ kainate receptor antagonist, Diuretic, Calcium channel blocker (Calcium antagonist), angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor antagonist, sodium channel blocker, potassium channel opener, beta receptor blocker, antiplatelet agent, anticoagulant, thrombus Soluble drugs, cycloxygenase (CO X) -2 inhibitors, non-steroidal anti-inflammatory drugs, steroid drugs, anti-acid drugs and vitamins 1 type or 2 or more types of drugs chosen from these, or those compounding agents.
[0064] 本発明において、「併用薬」としてより好ましくは、例えば、薬物 Bとして具体的に列 記した前記の薬物や、薬物 Cとして列記した、例えば、レポドパ製剤、ドパミン受容体 作動薬 (ドパミン受容体刺激薬)、ドパミン遊離促進薬 (ドパミン分泌促進薬あるいはド パミン放出促進薬)、ドパミン取り込み阻害薬、ドパミン作用薬、中枢性抗コリン薬、芳 香族 L アミノ酸脱炭酸酵素阻害薬 (DCI)、モノアミン酸化酵素 (MAO— B)阻害薬 、カテコール— O—メチルトランスフェラーゼ（COMT)阻害薬、ノルェピネフリン（ノル アドレナリン)補充薬等のパーキンソン病および Zまたはパーキンソン症候群の予防 、治療および Zまたは症状進展抑制薬力 選ばれる 1種または 2種以上の薬物また はそれらの配合剤等が挙げられる。 [0064] In the present invention, the "concomitant drug" is more preferably, for example, the above-mentioned drugs specifically listed as drug B, or, for example, levodopa preparations, dopamine receptor agonists (dopamine) listed as drug C. Receptor stimulants), dopamine release enhancers (dopamine secretion enhancers or dopamine release enhancers), dopamine uptake inhibitors, dopamine agonists, central anticholinergics, aromatic L amino acid decarboxylase inhibitors (DCI) ), Monoamine oxidase (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, norepinephrine (noradrenaline) supplements, etc., prevention, treatment and Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome Inhibitory pharmacological power One or two or more selected drugs or combinations thereof may be mentioned.
本発明において、「併用薬」としてとりわけ好ましくは、例えば、レポドパ製剤および Zまたは芳香族 L アミノ酸脱炭酸酵素阻害薬 (DCI)またはそれらの配合剤 (すな わち、レポドパ 'DCI配合剤）等が挙げられる。  In the present invention, the “concomitant drug” is particularly preferably, for example, a repodopa preparation and a Z or aromatic L amino acid decarboxylase inhibitor (DCI) or a combination thereof (that is, a levodopa 'DCI combination agent), etc. Is mentioned.
[0065] 本発明にお 、て、レポドパ · DCI配合剤としては、例えば、レポドパ ·ベンセラジド配 合剤（levodopa + benserazide,例えば、レボドノ 'ベンセラジド（4 : 1)配合剤）、レボド ノ 'カルビドパ配合剤（levodopa + carbidopa、例えば、レボドノ 'カルビドパ（10 : 1) 配合剤、レポドパ'カルビドパ (4： 1)配合剤）等が挙げられる。 In the present invention, the levodopa / DCI combination agent includes, for example, levodopa / benserazide combination agent (levodopa + benserazide, for example, levodono'benserazide (4: 1) combination agent), (Levodopa + carbidopa, for example, levodono'carbidopa (10: 1) formulation, levodopa'carbidopa (4: 1) formulation) and the like.
もちろん、以上の「併用薬」は例示であって、これらに限定されるものではない。また 、「併用薬」には、上記したメカニズムに基づいて、現在までに見出されているものだ けでなく今後見出されるものも含まれる。さらにこれらの薬物は、任意の 2種以上を組 み合わせて投与してもよい。  Of course, the above “concomitant drugs” are merely examples, and are not limited thereto. In addition, “concomitant drugs” include not only those found so far, but also those that will be found in the future based on the above-mentioned mechanism. Furthermore, these drugs may be administered in combination of any two or more.
[0066] [医薬品への適用] [0066] [Application to pharmaceutical products]
本発明の医薬は、パーキンソン病および Zまたはパーキンソン症候群の予防、治 療および Zまたは症状進展抑制を目的として哺乳動物 (ヒトおよびヒト以外の動物 (例 えば、サル、ヒッジ、ゥシ、ゥマ、ィヌ、ネコ、ゥサギ、ラット、マウス等)）等に投与される 。その投与方法は有効量の薬物を生体内に投与できる方法であればどのようなもの であってもよいが、経口投与や静脈内投与のような全身投与が好ましぐとりわけ経 口投与が好ましい。なお、本発明において、「予防」とは疾患の成立そのものを予防 することを、「治療」とは病態を治癒の方向へ導くことを、「症状進展抑制」とは症状の 進展 ·悪ィ匕を抑制し病態の進行をとどめることを意味し、また、パーキンソン症候群と は、パーキンソン病のみならず、パーキンソン病とは異なる病因を有しながらも、臨床 的にパーキンソン病に特徴的な錐体外路系異常の症状 (例えば、振戦、無動、筋固 縮、姿勢保持障害等)を呈する全ての疾患を包含する。パーキンソン症候群は、通常 の特発性パーキンソン病、神経変性疾患 (例えば、線条体黒質変性症、ハンチントン 病、舞踏病 無定位運動症、進行性核上麻痺、びまん性レビー小体病、大脳皮質 基底核変性症、アルツハイマー病、老年性痴呆 (認知症）、ピック病、前頭側頭葉型 痴呆症 (認知症）、家族性痴呆症 (認知症）、脊髄小脳変性症、グアム島パーキンソ ン痴呆複合等）に伴うパーキンソニズムおよび特定の原因によって生じる二次性パー キンソニズムに分けられ、二次性パーキンソ-ズムはその原因によってさらに (i)多発 性脳梗塞'脳腫瘍等の脳血管障害による脳血管性パーキンソ-ズム、 (ii)ウィルス性 脳炎後パーキンソ-ズム、 (iii)ドパミン拮抗薬等の抗精神病薬等による薬剤性パー キンソニズム、（iv)—酸ィ匕炭素、マンガン中毒等による中毒性パーキンソ-ズム、（V) 無酸素脳症の後遺症や副甲状腺機能低下による代謝性パーキンソニズム、 (vi)慢 性硬膜下血腫やボクサー痴呆等の外傷性パーキンソニズム等に分類される。 The medicament of the present invention can be used to prevent or treat Parkinson's disease and Z or Parkinson's syndrome, as well as mammals (humans and non-human animals (for example, monkeys, hidges, bushes, horses, Inu, cat, rabbit, rat, mouse, etc.)). The administration method may be any method as long as an effective amount of the drug can be administered in vivo, but systemic administration such as oral administration and intravenous administration is preferred, and oral administration is particularly preferred. . In the present invention, “prevention” prevents the establishment of the disease itself. `` Treatment '' refers to guiding the disease state in the direction of healing, `` Symptom progression suppression '' means symptomatic progression · Suppressing bad habits and stopping the progression of the disease state, and Parkinson's syndrome Is not only Parkinson's disease, but also has a different etiology from Parkinson's disease, but is clinically characteristic of extrapyramidal abnormalities characteristic of Parkinson's disease (e.g. tremor, ataxia, muscle rigidity, It includes all diseases presenting with posture maintenance disorder. Parkinson's syndrome is usually associated with idiopathic Parkinson's disease, neurodegenerative diseases (e.g., striatal nigra degeneration, Huntington's disease, chorea, stereotaxic movement, progressive supranuclear palsy, diffuse Lewy body disease, cerebral cortex. Basilar degeneration, Alzheimer's disease, senile dementia (dementia), Pick's disease, frontotemporal lobar dementia (dementia), familial dementia (dementia), spinocerebellar degeneration, Guam Island Parkinson dementia Parkinsonism associated with complex) and secondary Parkinsonism caused by a specific cause. Secondary Parkinsonism is further classified according to its cause. (I) Multiple cerebral infarction 'Cerebrovascular due to cerebrovascular disorders such as brain tumors (Ii) viral post-encephalitis parkinsonism, (iii) drug-related parkinsonism with antipsychotics such as dopamine antagonists, (iv) —acidic carbon, in manganese (V) Metabolic parkinsonism due to anaerobic encephalopathy sequelae or parathyroid hypofunction, (vi) Traumatic parkinsonism such as chronic subdural hematoma or boxer dementia The
前記したように、本発明の医薬においては、前記「（2R)— 2 プロピルオクタン酸、 その塩、その溶媒和物またはそれらのプロドラッグ」と、前記「パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症状進展抑制薬」（あるい は所望によってさらにその他の薬物）は、任意の順で逐次に、または同時に生体内 に投与される。任意の順で逐次に投与される場合は、これらの薬物を別々に含む医 薬組成物が用いられる。同時に生体内に投与される場合は、これらの薬物を別々に 含む医薬組成物を用いる力、または同一医薬組成物中にこれらの薬物を含むものが 用いられる。以下、本発明で用いられる、 (2R) 2—プロピルオクタン酸、その塩、そ の溶媒和物またはそれらのプロドラッグを含有する経口投与用医薬組成物、すなわ ち、「（2R)— 2—プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラ ッグを有効成分として含有し、経口投与することを特徴とするパーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症状進展抑制用医薬糸且 成物」（以下、「本発明の医薬組成物」と略記する場合がある。）について詳述する。 As described above, in the medicament of the present invention, the “(2R) -2-propyloctanoic acid, a salt, a solvate thereof or a prodrug thereof” and the “prevention of Parkinson's disease and Z or Parkinson's syndrome, “Treatment and Z or symptom progression inhibitors” (or other drugs if desired) are administered in vivo sequentially in any order or simultaneously. When administered sequentially in any order, a pharmaceutical composition comprising these drugs separately is used. When administered in vivo at the same time, a force using a pharmaceutical composition containing these drugs separately, or one containing these drugs in the same pharmaceutical composition is used. Hereinafter, a pharmaceutical composition for oral administration containing (2R) 2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof, that is, “(2R) -2” used in the present invention. —Prophyloctanoic acid, its salts, its solvates or their prodrugs as active ingredients, and prevention or treatment of Parkinson's disease and Z or Parkinson's syndrome characterized by oral administration Pharmaceutical thread The “composition” (hereinafter sometimes abbreviated as “the pharmaceutical composition of the present invention”) will be described in detail.
[0068] 本発明の医薬組成物は、経口投与に適した剤形、例えば、経口投与のための内服 用固形剤や内服用液剤等として投与される。  [0068] The pharmaceutical composition of the present invention is administered as a dosage form suitable for oral administration, for example, as a solid preparation for internal use or a liquid preparation for internal use.
経口投与のための内服用固形剤には、錠剤、丸剤、カプセル剤、散剤、顆粒剤等 が含まれる。カプセル剤には、ハードカプセルおよびソフトカプセルが含まれる。 このような内服用固形剤においては、薬物はそのまま力 または賦形剤 (例えば、ラ クトース、マン-トール、グルコース、微結晶セルロース、デンプン等）、結合剤（例え ば、ヒドロキシプロピルセルロース、ポリビュルピロリドン、メタケイ酸アルミン酸マグネ シゥム等）、崩壊剤（例えば、繊維素グリコール酸カルシウム等）、滑沢剤（例えば、ス テアリン酸マグネシウム等）、安定剤、溶解補助剤（例えば、グルタミン酸、ァスパラギ ン酸等)等と混合され、常法に従って製剤化して用いられる。また、必要によりコーテ イング剤（例えば、白糖、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピル メチルセルロースフタレート等）で被覆して 、てもよ 、し、また 2以上の層で被覆して いてもよい。さらにゼラチンのような吸収されうる物質のカプセルも包含される。  Solid preparations for internal use for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules. In such a solid preparation for internal use, the drug is used as it is or is a vehicle or an excipient (eg, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), a binder (eg, hydroxypropylcellulose, polybule). Pyrrolidone, magnesium metasilicate aluminate, etc.), disintegrant (eg, calcium calcium glycolate), lubricant (eg, magnesium stearate), stabilizer, solubilizer (eg, glutamic acid, asparagine) Acid) and the like, and formulated into a conventional method. If necessary, it may be coated with a coating agent (for example, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Also included are capsules of absorbable substances such as gelatin.
[0069] 経口投与のためのソフトカプセル剤（以下、「本発明のカプセル剤」と略記すること がある。 )は、公知のソフトカプセル剤の製造方法に準じて製造することができる。具 体的には、薬物と皮膜用溶液とを、例えば、打ち抜き法 (例えば、ロータリーダイ法等 )もしくは滴下法 (例えば、シームレスカプセル法等)等の公知のカプセル充填法に付 し、さらに得られたカプセルを乾燥することによって製造することができる。本発明の カプセノレ剤は、シームレスソフトカプセノレ剤であってもよぐまた、 ϋぎ目のあるソフト カプセル剤であってもよい。シームレスカプセル剤の製造方法は、公知の文献、例え ば、バイオサイエンスとインダストリ一、 58卷、 7号、 31〜34頁（2000年刊）に詳細に 記載されて 、る。この基本的なシームレスカプセル剤の製造方法は既に工業的に使 用されている方法であるため、大量生産は容易である。  [0069] Soft capsules for oral administration (hereinafter sometimes abbreviated as "capsules of the present invention") can be produced according to known methods for producing soft capsules. Specifically, the drug and the film solution are subjected to a known capsule filling method such as a punching method (for example, a rotary die method) or a dropping method (for example, a seamless capsule method). Produced capsules can be produced by drying. The capsenore agent of the present invention may be a seamless soft capsenole agent or a soft capsule with a cross. The method for producing seamless capsules is described in detail in known literature, for example, Bioscience and Industry, 58, No. 7, pp. 31-34 (2000). Since this basic seamless capsule manufacturing method is already used industrially, mass production is easy.
[0070] 本発明のカプセル剤は、一般的なソフトカプセル剤と同様に、内容液とカプセル皮 膜によって構成される。カプセル皮膜は、カプセル基剤と呼ばれるカプセル皮膜の主 体となる物質 (蛋白質 (ゼラチン、コラーゲン等）、多糖類 (デンプン、アミロース、ポリ ガラタツロン酸、寒天、カラギナン、アラビアガム、ジエランガム、キサンタンガム、ぺク チン、アルギン酸等）、生分解性プラスチック (ポリ乳酸、ポリヒドロキシ酪酸、ポリダル タミン酸等）、硬化油脂 (バター、マーガリン、ショートニング、カカオバター等の中鎖 脂肪酸のトリグリセリドゃジグリセリド等)等）と、可塑剤（グリセリン、ソルビトール、ポリ エチレングリコール等の糖、糖アルコール、多価アルコール等）とを必須成分とし、所 望によって、香料 (ハツ力油、桂皮油、ストロベリーその他の果実エッセンスやフレー バー等）、防腐剤 (パラヒドロキシ安息酸ェチル、ノ ラヒドロキシ安息香酸プロピル等）[0070] The capsule of the present invention is composed of a content liquid and a capsule skin film in the same manner as a general soft capsule. Capsule membranes are called capsule base materials (proteins (gelatin, collagen, etc.)), polysaccharides (starch, amylose, polygalataturonic acid, agar, carrageenan, gum arabic, dielan gum, xanthan gum, pectin Tin, alginic acid, etc.), biodegradable plastics (polylactic acid, polyhydroxybutyric acid, polydalamic acid, etc.), hardened fats and oils (such as butter, margarine, shortening, cocoa butter, etc.) Plasticizers (sugars such as glycerin, sorbitol, and polyethylene glycol, sugar alcohols, polyhydric alcohols, etc.) are essential ingredients, and perfumes (hatsu force oil, cinnamon oil, strawberry and other fruit essences and flavors, etc.) ), Preservatives (such as ethyl parahydroxybenzoate, propyl norahydroxybenzoate)
、色素 (黄色 4号、黄色 5号、赤色 3号、青色 1号、銅クロ口フィン等)、不透明化剤（二 酸化チタン、ベンガラ等）、溶解度調節剤（セルロースアセテートフタレート、ヒドロキ シプロピルメチルセルロースのアルカリ金属塩、ヒドロキシメチルセルロースアセテート サクシネートのアルカリ金属塩、アルギン酸アルカリ塩、ポリアクリル酸アルカリ金属塩 、メチルセルロース、カルボキシメチルセルロース、カゼイン、コラーゲン、寒天末、ポ リビニールアルコール、ぺクチン等）等を含んで 、てもよ 、。 , Pigment (yellow 4, yellow 5, red 3, blue 1, copper black fin, etc.), opacifier (titanium dioxide, bengara, etc.), solubility regulator (cellulose acetate phthalate, hydroxypropyl methylcellulose) Alkali metal salt, hydroxymethylcellulose acetate succinate alkali metal salt, alginic acid alkali salt, polyacrylic acid alkali metal salt, methylcellulose, carboxymethylcellulose, casein, collagen, agar powder, polyvinyl alcohol, pectin, etc.) .
[0071] 本発明のカプセル剤にぉ 、て、カプセル皮膜は、ゼラチンを基剤とするものが好ま しい。特に、ゼラチンを基剤とし、可塑剤としてグリセリンを含むものが好ましい。また 可塑剤として、さらにソルビトールを含んで 、てもよ 、。  [0071] In the capsule of the present invention, the capsule film is preferably based on gelatin. Particularly preferred are those based on gelatin and containing glycerin as a plasticizer. Also, it may contain sorbitol as a plasticizer.
カプセル皮膜は、皮膜用溶液を用いて製造することができる。皮膜用溶液は、前記 した皮膜用の成分を含有し、かつ溶融状態または溶液状態で薄い皮膜に形成するこ とができ、さらに皮膜の形成後に冷却および Zまたは乾燥することによって固化する ものであれば特に制限なく用いることができる。  The capsule film can be produced using a film solution. The film solution contains the above-mentioned film components and can be formed into a thin film in a molten state or a solution state, and further solidified by cooling and Z or drying after the film is formed. It can be used without particular limitation.
[0072] 添加剤としては、一般的に経口投与用製剤に用いられる添加剤であれば特に限定 されないが、例えば、ソフトカプセル製剤や経口液剤に用いられる添加剤等が好まし ぐ例えば、防腐剤、保存剤、界面活性剤、可溶化剤、乳化剤、溶剤、 pH調節剤、緩 衝剤、懸濁剤、粘稠剤、安定化剤、溶解補助剤等が用いられる。これらの添加剤は、 所望によって、 2以上の成分を組み合わせ、添加することができる。防腐剤、保存剤と しては、例えば、安息香酸、安息香酸ナトリウム、ソルビン酸ナトリウム、パラベン類（ パラォキシ安息香酸ェチル、パラォキシ安息香酸プチル、パラォキシ安息香酸プロ ピル等)等が挙げられる。界面活性剤、可溶化剤、乳化剤、溶剤としては、例えば、ヒ ドロキシプロピルメチルセルロース、ポリビュルピロリドン、ショ糖脂肪酸エステル、ポリ ォキシエチレン硬化ヒマシ油類、ポリソルベート 80、ポリエチレングリコール、グリセリ ン、エタノール、プロピレングリコール、水（例えば、注射用蒸留水等)等が挙げられる 。 pH調節剤、緩衝剤としては、例えば、無機の酸またはアルカリ等の塩基、例えば、 塩酸、水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム等、さらに有機酸、例え ば、クェン酸、リンゴ酸、酒石酸あるいはコハク酸またはその塩類等を挙げることがで きる。 pHの調整は、一般に経口液剤の技術分野で汎用されている pHを調整する方 法またはこれに準ずる方法に従って行えばよい。懸濁剤、粘稠剤としては、例えば、 アラビアゴム、結晶セルロース、ビーガム、キサンタンガム、ゼラチン、メトロースおよび その可食性塩、カルメロースおよびその可食性塩等が挙げられる。安定化剤としては 、例えば、ェデト酸の可食性塩、塩ィ匕ナトリウム、ピロ亜硫酸の可食性塩等が挙げら れる。溶解補助剤としては、例えば、シクロデキストリンやアルギニン等が挙げられる。 これらの添加剤は、一般的に経口投与製剤に通常用いられる割合で配合される。ま た、上記以外にも、公知の文献、例えば、薬事日報社 2000年刊「医薬品添加物辞典 」（日本医薬品添加剤協会編集)等に記載されているような添加剤を用いてもよい。 [0072] The additive is not particularly limited as long as it is an additive generally used in a preparation for oral administration. For example, an additive used in a soft capsule preparation or an oral solution is preferable. Preservatives, surfactants, solubilizers, emulsifiers, solvents, pH adjusters, buffering agents, suspending agents, thickeners, stabilizers, solubilizing agents, etc. are used. These additives can be added in combination of two or more components as desired. Examples of the preservatives and preservatives include benzoic acid, sodium benzoate, sodium sorbate, parabens (such as ethyl oxybenzoate, butyl pyloxybenzoate, and propyl paraoxybenzoate). Surfactants, solubilizers, emulsifiers, and solvents include, for example, hydroxypropylmethylcellulose, polybutylpyrrolidone, sucrose fatty acid ester, Examples include oxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, glycerin, ethanol, propylene glycol, water (for example, distilled water for injection) and the like. Examples of the pH regulator and buffer include bases such as inorganic acids or alkalis, such as hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, and organic acids such as citrate, malic acid, Examples thereof include tartaric acid, succinic acid, and salts thereof. The pH adjustment may be performed according to a method for adjusting pH or a method analogous thereto, which is generally used in the technical field of oral solutions. Examples of the suspending agent and thickening agent include gum arabic, crystalline cellulose, bee gum, xanthan gum, gelatin, metrose and its edible salt, carmellose and its edible salt, and the like. Examples of the stabilizer include an edible salt of edetic acid, sodium chloride salt, and an edible salt of pyrosulfite. Examples of the solubilizer include cyclodextrin and arginine. These additives are generally blended in proportions usually used for oral preparations. In addition to the above, additives such as those described in publicly known documents such as “Pharmaceutical Additives Dictionary” (edited by the Japan Pharmaceutical Additives Association), etc., published in 2000 by Yakuji Nippo may be used.
[0073] 経口投与のための内服用液剤は、水剤、懸濁剤、乳剤、シロップ剤、エリキシル剤 等を含む。このような液剤においては、薬物を、一般的に用いられる希釈剤（例えば 、精製水、エタノールまたはそれらの混液等）に溶解、懸濁または乳化して調製する 。さらにこの液剤は、湿潤剤、懸濁化剤、乳化剤、甘味剤、風味剤、芳香剤、保存剤 、緩衝剤等を含有していてもよい。  [0073] Liquid preparations for internal use for oral administration include solutions, suspensions, emulsions, syrups, elixirs and the like. In such a liquid preparation, the drug is prepared by dissolving, suspending or emulsifying in a commonly used diluent (for example, purified water, ethanol or a mixture thereof). Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
[0074] 本発明の医薬組成物を投与するための剤形は、経口投与できる剤形であれば特 に限定されないが、前記疾患に対する好ましい予防、治療および Zまたは症状進展 抑制効果を得るために、前記したカプセル剤を用いることが好ま 、。  [0074] The dosage form for administering the pharmaceutical composition of the present invention is not particularly limited as long as it is an orally administrable dosage form. It is preferable to use the capsule described above.
本発明の医薬組成物をパーキンソン病および Zまたはパーキンソン症候群の予防 、治療および Zまたは症状進展抑制のために経口投与する際の（2R)— 2—プロピ ルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグの投与量は、患者 の年齢、体重、症状、治療効果、投与方法、処理時間等により異なるが、 1回あたり 約 50mg以上を経口投与する方法であれば特に限定されな 、。前記疾患に対する 好ましい予防、治療および Zまたは症状進展抑制効果を得るための、具体的な投薬 期間、投薬回数、投与量、投与方法としては、以下に例示するものが挙げられる。 (2R) -2-Propyloctanoic acid, a salt thereof, a solvate thereof or a (2R) -2-propyloctanoic acid when orally administered to prevent or treat Parkinson's disease and Z or Parkinson's syndrome The dosage of these prodrugs varies depending on the patient's age, weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is not particularly limited as long as about 50 mg or more is orally administered. Specific medication for obtaining favorable preventive, therapeutic and Z or symptom progression inhibiting effects on the above diseases Examples of the period, number of doses, dose, and administration method include those exemplified below.
[0075] 本発明の医薬組成物の投薬期間は、前記の疾患に対する好ましい予防、治療およ び Zまたは症状進展抑制効果を得るために、任意の日数、継続して投薬しても構わ ない。また所望によって適当な休薬期間をおいて、間歇的に投与しても構わない。具 体的な投薬期間としては、例えば、約 1ヶ月間〜約 15年間である。好ましい投薬期間 は、例えば、約 3ヶ月間〜約 5年間であり、より好ましい投薬期間は、例えば、約 3ヶ月 間〜約 1年間であり、とりわけ好ましい投薬期間は、例えば、約 3ヶ月間〜約 6ヶ月間 である。 [0075] The administration period of the pharmaceutical composition of the present invention may be continuously administered for any number of days in order to obtain a preferable prevention, treatment and Z or symptom progression suppression effect for the above-mentioned diseases. If desired, it may be administered intermittently with an appropriate drug holiday. The specific dosing period is, for example, about 1 month to about 15 years. Preferred dosage periods are, for example, from about 3 months to about 5 years, more preferred dosage periods are, for example, from about 3 months to about 1 year, and particularly preferred dosage periods are, for example, from about 3 months to About 6 months.
本発明の医薬組成物の投薬回数は、前記の疾患に対する好ましい予防、治療およ び Zまたは症状進展抑制効果を得るために、任意の回数、投薬しても構わない。ま た、患者の容態やその他の理由によって変更しても構わない。具体的な投薬回数と しては、例えば、 1日 1回〜 5回である。好ましい投薬回数は、例えば、 1日 1回〜 3回 であり、より好ましい投薬回数は、例えば、 1日 1回〜 2回であり、とりわけ好ましい投 薬回数は、 1日 1回である。  The pharmaceutical composition of the present invention may be administered any number of times in order to obtain a preferable prevention, treatment and Z or symptom progression inhibitory effect on the above-mentioned diseases. It may also be changed depending on the patient's condition and other reasons. The specific number of doses is, for example, 1 to 5 times a day. The preferred dosing frequency is, for example, 1 to 3 times a day, and the more preferred dosing frequency is, for example, 1 to 2 times a day, and the particularly preferred dosing frequency is once a day.
[0076] 本発明の医薬組成物をパーキンソン病および Zまたはパーキンソン症候群の予防 、治療および Zまたは症状進展抑制のために経口投与する際の（2R)— 2—プロピ ルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグの投与量は、前述し たように、 1回あたり約 50mg以上であれば特に限定されないが、前記の疾患に対す る好ましい予防、治療および Zまたは症状進展抑制効果を得るために、例えば、約 5 Omg〜約 1200mg等を投与することが好ましい。より具体的な投与量としては、例え ば、約 lOOmg〜約 600mg等が挙げられる。より好ましい投与量としては、例えば、約 100mg、約 200mg、約 300mg、約 400mgまたは約 600mg等力挙げられ、最も好 ましい投与量としては、例えば、約 600mg等が挙げられる。し力しながら前記の疾患 に対する好ましい予防、治療および Zまたは症状進展抑制効果を得る投与量は、種 々の条件によって変動するので、上記投与量より少ない量で十分な場合もあるし、ま た範囲を越えて必要な場合もある。また、（2R)— 2—プロピルオクタン酸の塩を投与 する場合は、（2R)— 2—プロピルオクタン酸の量として上記に示した投与量が好適 である。 本発明の医薬組成物をパーキンソン病および Zまたはパーキンソン症候群の予防 、治療および Zまたは症状進展抑制のために経口投与する際の好ましい方法として は、例えば、約 1ヶ月間〜約 5年間の投薬期間中、 1日 1回〜 5回の投薬回数で、 1回 あたり約 50mg〜約 1200mgの（2R)—2—プロピルオクタン酸またはその塩を、経口 投与する方法等が挙げられる。その際、目標とする投与量 (維持投与量)を最初から 最後まで増減させずに投与する方法だけでなぐそれより少量の初回投与量より始め て維持投与量まで任意の投与期間を力けて投与量を漸増していく投与方法 (この期 間を投与量漸増期と表現する)や、あるいは投与を中止するにあたり維持投与量力も 任意の投与期間を力けて投与量を漸減していくといつた投与方法 (この期間を投与 量漸減期と表現する）、およびそれらを組み合わせた投与方法も好ましい。より好まし い方法としては、例えば、約 3ヶ月間〜約 5年間の投薬期間中、 1日 1回〜 3回の投 薬回数で、 1回あたり約 lOOmg〜約 1200mgの（2R)—2—プロピルオクタン酸を経 口投与する方法や、約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数 で、 1回あたり約 lOOmg〜約 400mgの（2R)—2—プロピルオクタン酸を経口投与し 、続く約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 200mg〜約 800mgの（2R)—2—プロピルオクタン酸を経口投与し、続く約 1週間〜 約 3年間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 300mg〜約 120 Omgの（2R)—2—プロピルオクタン酸を経口投与し、続く約 1週間〜約 2週間の投薬 期間中、 1曰 1回〜 2回の投薬回数で、 1回あたり約 200mg〜約 800mgの（2R)— 2 —プロピルオクタン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回 〜2回の投薬回数で、 1回あたり約 lOOmg〜約 400mgの（2R)—2—プロピルォクタ ン酸を経口投与する方法等が挙げられる。最も好ましい方法としては、例えば、約 3ケ 月間〜約 1年間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 200mg 〜約 600mgの（2R)— 2—プロピルオクタン酸を経口投与する方法や、約 1週間の 投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2—プロピルォ クタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あた り約 400mgの（2R)—2—プロピルオクタン酸を経口投与し、続く約 12週間の投薬期 間中、 1日 1回の投薬回数で、 1回あたり約 600mgの（2R)—2—プロピルオクタン酸 を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 400 mgの（2R)—2—プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1 日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2—プロピルオクタン酸を経口 投与する方法等が挙げられる。 [0076] (2R) -2-Propyloctanoic acid, a salt thereof, and a solvent thereof when the pharmaceutical composition of the present invention is orally administered for the prevention, treatment, and suppression of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome As described above, the dose of the Japanese product or prodrug thereof is not particularly limited as long as it is about 50 mg or more per dose, but it has preferable prevention, treatment and Z or symptom progression inhibitory effects on the above-mentioned diseases. For example, it is preferable to administer about 5 Omg to about 1200 mg. More specific doses include, for example, about 10 mg to about 600 mg. More preferable doses include, for example, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 600 mg, and the most preferable dose includes, for example, about 600 mg. However, since the dosage for obtaining a favorable prevention, treatment and Z or symptom progression-suppressing effect for the above-mentioned diseases varies depending on various conditions, a dosage smaller than the above dosage may be sufficient. It may be necessary beyond the scope. In addition, when a salt of (2R) -2-propyloctanoic acid is administered, the dosage shown above is preferred as the amount of (2R) -2-propyloctanoic acid. A preferred method for oral administration of the pharmaceutical composition of the present invention for the prevention, treatment and suppression of Z or symptom progression of Parkinson's disease and Z or Parkinson's syndrome is, for example, a dosage period of about 1 month to about 5 years. Among them, there is a method of orally administering about 50 mg to about 1200 mg of (2R) -2-propyloctanoic acid or a salt thereof at a dosage of 1 to 5 times a day. At that time, the target dose (maintenance dose) can be administered without increasing or decreasing from the beginning to the end. Dosing method to gradually increase the dose (this period is expressed as the dose escalation period), or the maintenance dose force to stop the administration and to gradually reduce the dose for any given period Preferred is an administration method (this period is expressed as a dose gradual period) and a combination of these administration methods. A more preferred method is, for example, from about lOOmg to about 1200mg (2R) -2 per dose with a dose of 1 to 3 doses per day during a dosing period of about 3 months to about 5 years. -Oral administration of propyloctanoic acid or about 1 to 2 doses per day during a dosing period of about 1 to 2 weeks (2R) —2 —Propyloctanoic acid orally, followed by a dosing period of about 1 week to about 2 weeks, with about 1 to 2 doses per day, about 200 mg to about 800 mg of (2R) —2-propyl Oral administration of octanoic acid, followed by dosing from 1 to 2 times a day for about 1 week to about 3 years, about 300 mg to about 120 Omg (2R) -2-propyloctane Acid is administered orally, followed by about 1 to 2 doses during the subsequent dosing period of about 1 to 2 weeks, with about 200 mg to about 800 mg of (2R) -2-propyloctanoic acid per dose Oral administration and oral administration of about lOOmg to about 400mg of (2R) -2-propylactanoic acid per dose in the subsequent dosing period of about 1 to 2 weeks And the like. The most preferred method is, for example, from about 200 mg to about 600 mg of (2R) -2-propyloctane per dose during a dosing period of about 3 months to about 1 year, once or twice daily About 200 mg of (2R) -2-propylactanoic acid is administered orally for a period of about 1 week. During the dosing period, about 400 mg of (2R) -2-propyloctanoic acid is orally administered once a day, and once a day during the following 12-week dosing period. Approximately 600 mg of (2R) -2-propyloctanoic acid per dose Is administered orally, followed by oral administration of about 400 mg (2R) -2-propyloctanoic acid per dose, once a day during the dosing period of about 1 week, followed by about 1 week of dosing For example, a method of orally administering about 200 mg of (2R) -2-propyloctanoic acid at a single dose per day during the period is included.
[0078] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグ と併用薬 (例えば、薬物 Bとして具体的に列記した前記の薬物や、薬物 Cとして列記 した前記の薬物)とを組み合わせて投与する場合、併用薬の投与量は、年齢、体重、 症状、治療効果、投与方法、処理時間等により異なり、それぞれの薬物の有効量を 経口投与する方法であれば特に限定されな 、が、前記疾患に対する好ま 、予防、 治療および Zまたは症状進展抑制効果を得るための、具体的な投薬期間、投薬回 数、投与量、投与方法について、いくつかを以下に例示する。なお、併用薬は、公知 の処方や本発明の医薬組成物の処方に準じて製剤化して投与することもできるし、ま た、配合剤として本発明の医薬組成物中に加え、投与することもできる。  [0078] (2R) 2 Propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof and a concomitant drug (for example, the drug specifically listed as Drug B, or the drug listed as Drug C ), The dose of concomitant drugs varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., and is particularly limited as long as the effective dose of each drug is administered orally. However, some examples of specific dosing period, dosing number, dose, and administration method for obtaining favorable, preventive, therapeutic and Z or symptom progression inhibiting effects on the above diseases are exemplified below. The concomitant drug can be formulated and administered in accordance with a known formulation or the formulation of the pharmaceutical composition of the present invention, and can be added to the pharmaceutical composition of the present invention as a combination drug. You can also.
[0079] 例えば、併用薬としてレポドパを用いる際のその投与方法および投与量は、例えば 、初回量として 1日あたり約 lOOmg〜約 lOOOmgのレボドパを 1日 1回〜 3回経口投与 し、次いで 1日〜 3日毎に 1日あたり約 200mg〜約 400mgずつ漸増し、約 2週間〜 約 4週間後からは維持量として 1日あたり約 lOOOmg〜約 4000mgを経口投与する方 法等が挙げられる。  [0079] For example, when levodopa is used as a concomitant drug, the administration method and dosage are, for example, that about 1OOmg to about 1OOOmg of levodopa per day is orally administered once to 3 times a day, and then 1 From about 200 mg to about 400 mg per day every day to 3 days, gradually increase from about 200 mg to about 400 mg per day, and after about 2 weeks to about 4 weeks, a maintenance dose of about lOOOmg to about 4000 mg per day is orally administered.
[0080] 例えば、併用薬としてレポドパ 'ベンセラジド (4 : 1)配合剤を用いる際のその投与方 法および投与量は、例えば、初回量として 1日あたり約 lOOmg〜約 lOOOmgのレボド パ相当量を 1日 1回〜 3回経口投与し、次いで 1日〜 3日毎に 1日あたり約 100mg〜 約 400mgずつ漸増し、約 2週間〜約 4週間後からは維持量として 1日あたり約 1000 mg〜約 4000mgを経口投与する方法等が挙げられる。  [0080] For example, when using levodopa 'benserazide (4: 1) combination drug as a concomitant drug, the administration method and dose are, for example, about 1 OOmg to about 1OOOmg of levodopa per day as the initial dose. Oral administration once to 3 times a day, then gradually increase by about 100 mg to about 400 mg per day every 1 to 3 days, and after about 2 weeks to about 4 weeks as a maintenance dose about 1000 mg to about 1000 mg per day Examples include a method of orally administering about 4000 mg.
例えば、併用薬としてレポドパ 'カルビドパ（10 : 1)配合剤を用いる際のその投与方 法および投与量は、例えば、初回量として 1日あたり約 lOOmg〜約 lOOOmgのレボド パ相当量を 1日 1回〜 3回経口投与し、次いで 1日〜 3日毎に 1日あたり約 100mg〜 約 400mgずつ漸増し、約 2週間〜約 4週間後からは維持量として 1日あたり約 500m g〜約 2000mgを経口投与する方法等が挙げられる。 [0081] [毒性] For example, when using a combination drug of levodopa and carbidopa (10: 1) as a concomitant drug, the administration method and dose are, for example, about 1 OO mg / day of levodopa equivalent per day as the initial dose. Orally administered 3 to 3 times, then gradually increase from about 100 mg to about 400 mg per day every 1 to 3 days, and after about 2 weeks to about 4 weeks, the maintenance dose is about 500 mg to about 2000 mg per day. Examples include oral administration. [0081] [Toxicity]
(2R)—2—プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグ の毒性は十分に低いものであり、特に本発明の投与方法および投与量で哺乳動物、 特にヒトに医薬品として使用する限り、十分安全であると判断できる。  The toxicity of (2R) -2-propyloctanoic acid, its salt, its solvate or their prodrug is sufficiently low, and it is particularly useful as a pharmaceutical for mammals, particularly humans, with the administration method and dose of the present invention. As long as it is used, it can be judged to be sufficiently safe.
発明の効果  The invention's effect
[0082] 本発明は、 (2R)—2 プロピルオクタン酸、その塩、その溶媒和物またはそれらの プロドラッグと、パーキンソン病および Zまたはパーキンソン症候群の予防、治療およ び Zまたは症状進展抑制薬とを組み合わせて用い、効果的にパーキンソン病および Zまたはパーキンソン症候群を予防、治療および Zまたは症状進展抑制する方法と 、そのために用いる医薬を提供するものである。本発明で開示する医薬を用いた方 法は、パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまた は症状進展抑制に際して、極めて有効であり、それらの疾患に伴う諸症状を顕著に 改善することができる。  [0082] The present invention relates to (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof, and prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome And a method for effectively preventing and treating Parkinson's disease and Z or Parkinson's syndrome, and inhibiting Z or symptom progression, and a medicament used therefor. The method using the pharmaceutical disclosed in the present invention is extremely effective in preventing and treating Parkinson's disease and Z or Parkinson's syndrome and suppressing the progression of Z or symptoms, and significantly improves various symptoms associated with these diseases. be able to.
本発明で開示するように、パーキンソン病および Zまたはパーキンソン症候群の予 防、治療および Zまたは症状進展抑制薬に加えて（2R)—2—プロピルオクタン酸、 その塩、その溶媒和物またはそれらのプロドラッグを投与することで、それらの薬物を 単独で用いた場合に比べて、予防、治療および Zまたは症状進展抑制効果を補完 および Zまたは増強したり、薬物の投与量 ·副作用を軽減したり、あるいは薬物耐性 の発現を防止したりすることができる。特に、パーキンソン病および Zまたはパーキン ソン症候群の治療においてしばしば認められるウエアリングオフ現象等の副作用を回 避し、治療効果を補完 '増強し、薬物投与量を軽減し、もしくは薬物耐性の発現を防 止することができるので極めて有用な方法である。  As disclosed in the present invention, (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a combination thereof, in addition to the prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome By administering prodrugs, the prevention, treatment and Z or symptom progression-suppressing effects can be complemented and enhanced, or drug doses and side effects can be reduced compared to when these drugs are used alone. Alternatively, the development of drug resistance can be prevented. In particular, it avoids side effects such as the wear-off phenomenon often observed in the treatment of Parkinson's disease and Z or Parkinson's syndrome, complements and enhances the therapeutic effect, reduces drug dosage, or prevents the development of drug resistance. This is a very useful method.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0083] 以下に、本発明の新規な投与方法および投与量を用いた、 (2R) 2 プロピルォ クタン酸の、（1)パーキンソン病モデル動物に対する効果と（2)パーキンソン病患者 に対する臨床効果とを、実施例および製剤例を挙げて詳述するが、本発明はこれら に限定されるものではない。また、当然ではある力 本発明の範囲を逸脱しない範囲 で変化させてもよい。 [0084] 実施例 1 [0083] The following is a description of (2) the effects of (2R) 2 propyloctanoic acid on (1) Parkinson's disease model animals and (2) the clinical effects on Parkinson's disease patients using the novel administration method and dose of the present invention. The present invention will be described in detail with reference to Examples and Preparation Examples, but the present invention is not limited thereto. Naturally, a certain force may be changed without departing from the scope of the present invention. [0084] Example 1
ァカゲザノレ MPTP (1—メチル一4—フエニル一 1, 2, 3, 6—テトラヒドロピリジン）誘 発パーキンソン病モデルにおける既存薬と（2R)— 2—プロピルオクタン酸の併用効 果  Acquired Nore MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) -induced Parkinson's disease model in combination with (2R) -2-propyloctanoic acid
実施例 1一 1 : (2R)—2—プロピルオクタン酸とレポドパ 'ベンセラジド配合剤との併 用投与実験  Example 1 1 1: (2R) -2-Propyloctanoic acid and lepodopa 'benserazide combination drug administration experiment
実施例 1一 2 : (2R)—2—プロピルオクタン酸とメシル酸ブロモクリプチンとの併用 投与実験  Example 1 1 2: (2R) -2-Propyloctanoic acid and bromocriptine mesylate combination administration experiment
[0085] [目的] [0085] [Purpose]
ァカゲザルに MPTPを投与し、一定のパーキンソン病様症状を誘発した後に（2R) —2—プロピルオクタン酸とレボドパ'ベンセラジド配合剤、または（2R)—2—プロピ ルオクタン酸とメシル酸プロモクリブチンを 3ヶ月間連続併用経口投与してパーキンソ ン病様症状の治療効果を検討する。  After MPTP was administered to akage monkeys and certain Parkinson's disease-like symptoms were induced, (2R) -2-propyloctanoic acid and levodopa'benserazide or (2R) -2-propyloctanoic acid and promocributine mesylate To examine the therapeutic effect of Parkinson's disease-like symptoms by continuous oral administration for 3 months.
[0086] [実験方法] [0086] [Method of experiment]
1. MPTPによるパーキンソン病様症状の惹起  1. Induction of Parkinson's disease-like symptoms by MPTP
MPTP (0.5〜1.0mgZkg)をァカゲザルに静脈内投与し、その 6日後に症状を目 視で観察する。パーキンソン病様症状スコアが 3以上だった場合、その後 MPTP (0.5 mg/kg)を週 1回静脈内投与する。パーキンソン病様症状スコアが 2以下の場合、 パーキンソン病様症状スコアが 3以上になるまで週 1回 MPTP (0.5〜1.0mgZkg)を 静脈内投与し、パーキンソン病様症状スコアが 3以上になった場合、その後の MPT P投与を週 1回 0.5mgZkgとする。パーキンソン病様症状スコアが 9以上になった時 点で MPTPの投与を中止する。なお、 MPTP初回投与力 6ヶ月経過した個体でス コアが 6以下の動物については、スコアが 8以上になるまで MPTP (l.OmgZkg)を週 1回静脈内投与する。また、スコアが 7および 8になった場合 MPTP (0.5mgZkg)を スコアが 9以上になるまで週 1〜2回静脈内投与を行う。  MPTP (0.5-1.0mgZkg) is administered intravenously to zodiac monkeys, and symptoms are observed visually 6 days later. If the Parkinson's disease-like symptom score is 3 or higher, then MPTP (0.5 mg / kg) is administered intravenously once a week. When Parkinson's disease-like symptom score is 2 or less When Parkinson's disease-like symptom score is 3 or more, MPTP (0.5-1.0mgZkg) is administered intravenously once a week, and Parkinson's disease-like symptom score is 3 or more The subsequent MPTP administration is 0.5 mgZkg once a week. Discontinue administration of MPTP when the Parkinson's disease-like symptom score is 9 or higher. In addition, MPTP (l.OmgZkg) is administered intravenously once a week until the score reaches 8 or more for animals with a score of 6 or less after 6 months. If the score is 7 or 8, administer MPTP (0.5 mgZkg) intravenously once or twice a week until the score reaches 9 or more.
2.試験エントリー基準  2. Exam entry criteria
初回 MPTP投与から 2ヶ月間以上および最終の MPTP投与から 2週間以上経過し た動物で、パーキンソン病様症状スコアが 9以上を安定して示す動物を順次試験に 供する。 Sequentially test animals with stable Parkinson's disease-like symptom score of 9 or more that have passed 2 months or more after the first MPTP administration and 2 weeks or more after the last MPTP administration. Provide.
3.群分け  3.Grouping
群分け前に自発運動量および摂餌動作時間の評価を行い、測定した数値が均等 となるように各群に振り分ける。また、初回レポドパ 'ベンセラジド配合剤またはメシル 酸プロモクリブチン投与後のパーキンソン病様症状スコア最大変化値も均等になるよ うにする。スコア最大変化値は、実施例 1—1または 1—2のパーキンソン病様症状観 察ポイントから検索する。  Evaluate the amount of locomotor activity and feeding time before grouping, and assign to each group so that the measured values are equal. The maximum change in Parkinson's disease-like symptom score after administration of the first repodopa benserazide or promocributin mesylate should be made equal. The maximum score change value is searched from the observation points for Parkinson's disease-like symptoms in Example 1-1 or 1-2.
[0087] [評価方法] [0087] [Evaluation Method]
パーキンソン病様症状を表 1に示す Akai Tらの評価スケール（Akai T, Ozawa M, Yamaguchi M, Mizuta E and Kuno S, J Pharmacol Exp Ther, 273, 309—314 (1995)) に準じてスコア化する。観察は、 1週間に 3回行う。一日の観察スケジュールは、実施 例 1 1については被験物質経口投与後 5、 30、 60、 90、 120、 180分に行い、実 施例 1 2については被験物質経口投与前、被験物質経口投与後 60、 120、 180、 240、 300、 360、 420、 480分【こ行う。 1週 毎【こ各評価ポイントのス を平均し、 集計した数値をデータとする。  Parkinson's disease-like symptoms are scored according to Akai T et al.'S evaluation scale shown in Table 1 (Akai T, Ozawa M, Yamaguchi M, Mizuta E and Kuno S, J Pharmacol Exp Ther, 273, 309-314 (1995)) To do. Observe 3 times a week. The daily observation schedule for Example 1 1 was 5, 30, 60, 90, 120, 180 minutes after oral administration of the test substance, and for Example 1 2 before oral administration of the test substance and oral administration of the test substance. After 60, 120, 180, 240, 300, 360, 420, 480 minutes. Every week [Averages of each evaluation point are averaged and the aggregated numerical value is used as data.
[表 1] 行動 スコア  [Table 1] Behavior score
警戒動作 ι 常， 0 低下， 1 ；欠如， 2  Vigilance ι Normal, 0 drop, 1 ； Lack, 2
頭の動き 正常， 0 低下， 1 ；欠如， 2  Head movement normal, 0 decreased, 1; lack, 2
目の動き （視線 まばたき） 正常， 0 低下， 1 ； 目を閉じている， 2 *** 正常， 0 胴体部の異常， + 1 ；手足の異常，  Eye movement (blink of eyes) Normal, 0 drop, 1; Closed eyes, 2 positions normal, 0 Torso abnormalities, + 1;
かなり異常， 3  Quite abnormal, 3
平衔性 正常， 0 ；障害 無動作， 2  Flatness normal, 0; fault no action, 2
安静時動作 正常， 0 ；やや緩徐， 1 ；屮程度の運動緩徐， 2 運動緩徐， 3 ；無動， 4  Resting behavior Normal, 0: Slightly slow, 1: Slow movement slow, 2 Motor slow, 3; No movement, 4
外刺激に対する反応 正常， 0 低下， 1 ；緩徐， λ ' ；欠如， 3 う〔ゝ 正常， 0 欠如， 1  Response to external stimulus Normal, 0 decrease, 1 ： Slow, λ ′;
振戦 なし， 0 中程度， 1 ；重篤， 2  No tremor, 0 moderate, 1; severe, 2
[0088] [結果] 実施例 1— 1において、被験物質投与後 0週目から 12週目までの期間中、表 1に示 す評価方法に従って得た、それぞれの観察スケジュールでのパーキンソン病様症状 スコアの変化値 (ここで変化値とは、初期値 (9)からの減少分を指し、この値が大きい ほど症状が改善されていることを示す。）を表 2に示す。表中、「単独投与」は、レボド パ ·ベンセラジド (4： 1)配合剤 (12.5mg/kg)のみ単独投与した時のスコアの変化値 を示し、「併用投与」は、（2R)— 2—プロピルオクタン酸（lOmgZkg)とレポドパ 'ベ ンセラジド (4： 1)配合剤 (12.5mg/kg)とを併用投与した時のスコアの変化値を示す [0088] [Result] In Example 1-1, the change in Parkinson's disease-like symptom score for each observation schedule obtained according to the evaluation method shown in Table 1 during the period from week 0 to week 12 after administration of the test substance (here In Table 2, the change value indicates the decrease from the initial value (9), and the larger the value, the better the symptoms.) In the table, “single administration” indicates the change in score when only levodopa benserazide (4: 1) combination drug (12.5 mg / kg) is administered alone, and “combination administration” indicates (2R) — 2 -Shows the change in score when propyloctanoic acid (lOmgZkg) and lepodopa'benserazide (4: 1) combination (12.5mg / kg) are administered in combination
[表 2] [Table 2]
Figure imgf000060_0001
表 2に示すように、レポドパ ·ベンセラジド (4： 1)配合剤 (12.5mg/kg)の単独投与 実験では、投与期間が長くなるに従って (特に投与後 7週目以降顕著に)ウエアリング オフ現象が認められた力 (2R)— 2—プロピルオクタン酸（lOmgZkg)を併用投与 した時にはウエアリングオフ現象は認められないばかりか、治療効果の増強さえ認め られた。
Figure imgf000060_0001
As shown in Table 2, wearing levodopa benserazide (4: 1) alone (12.5 mg / kg) alone In the experiment, the wear-off phenomenon occurred as the administration period increased (especially after 7 weeks of administration) (2R) —administered with 2-propyloctanoic acid (lOmgZkg) At the same time, the wear ring-off phenomenon was not observed, and even the therapeutic effect was enhanced.
実施例 1—2において、被験物質投与後 0週目から 12週目までの期間中、表 1に示 す評価方法に従って得た、それぞれの観察スケジュールでのパーキンソン病様症状 スコアの変化値 (ここで変化値とは、初期値 (9)からの減少分を指し、この値が大きい ほど症状が改善されていることを示す。）を表 3に示す。表中、「単独投与」は、メシル 酸プロモクリブチン（3mgZkg)のみ単独投与した時のスコアの変化値を示し、「併用 投与」は、 (2R)— 2—プロピルオクタン酸（lOmgZkg)とメシル酸ブロモクリプチン（ 3mgZkg)とを併用投与した時のスコアの変化値を示す。  In Example 1-2, the change in Parkinson's disease-like symptom score in each observation schedule obtained according to the evaluation method shown in Table 1 during the period from week 0 to week 12 after administration of the test substance (here In Table 3, the change value refers to the decrease from the initial value (9). The larger the value, the better the symptoms.) In the table, “single administration” indicates the change in the score when only promocributin mesylate (3 mgZkg) is administered alone, and “combination administration” indicates that (2R) -2-propyloctanoic acid (lOmgZkg) and mesyl The change value of the score when co-administered with acid bromocriptine (3mgZkg) is shown.
[表 3] [Table 3]
Figure imgf000061_0001
表 3に示すように、メシル酸プロモクリブチン（3mgZkg)の単独投与実験では、投 与期間が長くなるに従って (特に投与後 8週目以降顕著に)ウエアリングオフ現象が 認められたが、（2R)— 2—プロピルオクタン酸（lOmgZkg)を併用投与した時には ウエアリングオフ現象は認められな力つた。
Figure imgf000061_0001
As shown in Table 3, in the single administration experiment of promocributine mesylate (3 mgZkg), wear-off phenomenon was observed as the administration period increased (especially after 8 weeks of administration), 2R) -2 When 2-propyloctanoic acid (lOmgZkg) was administered in combination The wear ring-off phenomenon was unacceptable.
[0090] 実施例 2  [0090] Example 2
臨床試験として、レポドパ 'DCI配合剤（用いる薬物は特に限定しない。）を使用し ているパーキンソン病患者 (若年性パーキンソ-ズムを含む。）を対象に、以下の条 件で二重盲検無作為化並行群間比較試験を実施した。  As a clinical trial, patients with Parkinson's disease (including juvenile Parkinsonism) who are using levodopa's DCI combination drug (the drug to be used is not particularly limited) are unblinded under the following conditions: A randomized parallel group comparison study was conducted.
<対象 >  <Target>
レポドパ . DCI配合剤を使用して 、るパーキンソン病 (若年性パーキンソニズムを含 む。；)患者 150〜165名。  Lepodopa. 150-165 patients with Parkinson's disease (including juvenile parkinsonism) using DCI combination.
<用法 ·用量 >  <Dosage and administration>
(A)プラセボ投与；  (A) placebo administration;
(B) (2R) — 2—プロピルオクタン酸 lOOmgZl回 Z1日投与；および  (B) (2R) — 2-Propyloctanoic acid lOOmgZl times Z daily administration; and
(C) (2R) ー2—プロピルォクタン酸600111871回71日投与。 (C) (2R) -2-propyloctanoic acid 600111 8 71 doses for 71 days.
<投与期間 >  <Dose period>
試験期間全日程を、（1)観察期、（2)投与量漸増期、（3)維持量投与期、（4)投与 量漸減期、および (5)後観察期にわけ、以下の投与スケジュールに従って投与を行 つた o  The entire schedule of the study period is divided into (1) observation period, (2) dose escalation period, (3) maintenance dose administration period, (4) dose gradual decrease period, and (5) post-observation period. O administered according to
なお、本実施例においては、投与量漸増期、維持量投与期および投与量漸減期 の全ての期間でプラセボ投与のみを行った群を「プラセボ群」もしくは「P群」と、投与 量漸増期、維持量投与期および投与量漸減期の全ての期間で (2R)— 2—プロピル オクタン酸 lOOmgZl回 Z1日投与を行った群を「（2R)—2—プロピルオクタン酸 100 mg投与群」もしくは「L群」と、維持量投与期に（2R)— 2—プロピルオクタン酸 600mg Zl回 Zl日投与を行った群を「（2R)— 2—プロピルオクタン酸 600mg投与群」もしく は「H群」と表記するものとする。  In this example, the placebo group was designated as the “placebo group” or the “P group” in which all the placebo administration period, the maintenance dose administration period, and the dose reduction period were administered. (2R) —2-Propyloctanoic acid lOOmgZl times Z daily administration in all periods of the maintenance dose period and the gradual decrease period, the “(2R) -2-propyloctanoic acid 100 mg administration group” or The “L group” and the group administered (2R) -2-propyloctanoic acid 600 mg Zl times Zl daily during the maintenance dose administration period were referred to as the “(2R) -2-propyloctanoic acid 600 mg administered group” or “H It shall be written as “group”.
[0091] く投与スケジユーノレ > [0091] Special administration schedule>
( 1 )観察期：投与量漸増期開始前 4週間  (1) Observation period: 4 weeks before the start of the dose escalation period
投与:行わない。  Administration: Not performed.
(2)投与量漸増期：2週間  (2) Dose escalation period: 2 weeks
投与：以下の投与方法に従い、 1日 1回朝食後に経口投与した。 [プラセボ群] Administration: Orally administered once a day after breakfast according to the following administration method. [Placebo group]
1週目： 1回あたりプラセボソフトカプセル（（2R)—2—プロピルォクタン酸1001118ソフ トカプセルと外観上識別不能なソフトカプセル)を 2カプセル； Week 1: Placebo soft capsules ((2R) -2-propyloctanoic acid 100111 8 soft capsules and soft capsules that are visually indistinguishable) per capsule;
2週目： 1回あたりプラセボソフトカプセノレを 4カプセノレ。 Week 2: 4 capsenoles with placebo soft caps.
[ (2R) 2—プロピルオクタン酸 lOOmg投与群] [(2R) 2-propyloctanoic acid lOOmg administration group]
1週目： 1回あたり（2R)—2—プロピルオクタン酸 lOOmgソフトカプセルを 1カプセル と、プラセボソフトカプセノレを 1カプセノレ；  Week 1: (2R) -2-Propyloctanoic acid lOOmg soft capsules and 1 placebo soft capsenore per caps;
2週目： 1回あたり（2R)—2—プロピルオクタン酸 lOOmgソフトカプセルを 1カプセル と、プラセボソフトカプセノレを 3カプセノレ。  Week 2: 1 capsule (2R) -2-propyloctanoic acid lOOmg soft capsule and 3 placebo soft capsenore.
[ (2R) 2 プロピルオクタン酸 600mg投与群]  [(2R) 2-propyloctanoic acid 600mg administration group]
1週目： 1回あたり（2R)—2—プロピルオクタン酸 lOOmgソフトカプセルを 2カプセル； 2週目： 1回あたり（2R)—2 プロピルオクタン酸 lOOmgソフトカプセルを 4カプセル  Week 1: 2 capsules of (2R) -2-propyloctanoic acid lOOmg per capsule; Week 2: 4 capsules of (2R) -2 propyloctanoic acid lOOmg per capsule
(3)維持量投与期：12週間 (3) Maintenance dose administration period: 12 weeks
投与：以下の投与方法に従い、 1日 1回朝食後に経口投与した。 Administration: Orally administered once a day after breakfast according to the following administration method.
[プラセボ群] [Placebo group]
1回あたりプラセボソフトカプセノレを 6カプセノレ。  6 capsenore placebo soft capsenore per dose.
[ (2R) 2—プロピルオクタン酸 lOOmg投与群] [(2R) 2-propyloctanoic acid lOOmg administration group]
1回あたり（2R)—2—プロピルオクタン酸 lOOmgソフトカプセルを 1カプセルと、プラ セボソフトカプセルを 5カプセル。  One (2R) -2-propyloctanoic acid lOOmg soft capsule and 5 placebo soft capsules.
[ (2R) 2 プロピルオクタン酸 600mg投与群]  [(2R) 2-propyloctanoic acid 600mg administration group]
1回あたり（2R)— 2 プロピルオクタン酸 lOOmgソフトカプセルを 6カプセル。  (2R) —2 propyloctanoic acid lOOmg soft capsules for 6 capsules.
(4)投与量漸減期：2週間  (4) Dose gradual period: 2 weeks
投与：以下の投与方法に従い、 1日 1回朝食後に経口投与した。 Administration: Orally administered once a day after breakfast according to the following administration method.
[プラセボ群] [Placebo group]
1週目： 1回あたりプラセボソフトカプセノレを 4カプセノレ；  Week 1: 4 capsenoles with placebo soft caps
2週目： 1回あたりプラセボソフトカプセノレを 2カプセノレ。 2nd week: 2 capsules with 1 placebo soft capsule.
[ (2R) 2—プロピルオクタン酸 lOOmg投与群] 1週目： 1回あたり（2R)—2—プロピルオクタン酸 lOOmgソフトカプセルを 1カプセル と、プラセボソフトカプセルを 3カプセル； [(2R) 2-propyloctanoic acid lOOmg administration group] Week 1: (2R) -2-propyloctanoic acid 1 lOOmg soft capsule and 3 placebo soft capsules per dose;
2週目： 1回あたり（2R)—2—プロピルオクタン酸 lOOmgソフトカプセルを 1カプセル と、プラセボソフトカプセノレを 1カプセノレ。  Week 2: (2R) -2-propyloctanoic acid lOOmg soft capsules and 1 placebo soft capsenore per capsule.
[ (2R) 2 プロピルオクタン酸 600mg投与群]  [(2R) 2-propyloctanoic acid 600mg administration group]
1週目： 1回あたり（2R)—2 プロピルオクタン酸 lOOmgソフトカプセルを 4カプセル; 2週目： 1回あたり（2R)—2—プロピルオクタン酸 lOOmgソフトカプセルを 2カプセル  Week 1: 4 capsules of (2R) -2 propyloctanoic acid lOOmg per capsule; Week 2: 2 capsules of (2R) -2-propyloctanoic acid lOOmg per capsule
(5)後観察期：投与量漸減期終了後 8週間 (5) Post observation period: 8 weeks after the end of the dose gradual reduction period
投与:行わない。 Administration: Not performed.
<投与スケジュールの概略 > <Outline of administration schedule>
前記投与スケジュールの概略を以下の表 4に示す。  The outline of the administration schedule is shown in Table 4 below.
[表 4] [Table 4]
Figure imgf000064_0001
Figure imgf000064_0001
<症例数 > (A)プラセボ群：約 50〜 55名； <Number of cases> (A) Placebo group: about 50 to 55 people;
(B) (2R)— 2 プロピルオクタン酸 lOOmg投与群：約 50〜55名；  (B) (2R) — 2-propyloctanoic acid lOOmg group: about 50 to 55 people;
(C) (2R)— 2 プロピルオクタン酸 600mg投与群：約 50〜55名。  (C) (2R) —2-propyloctanoic acid 600 mg administration group: about 50 to 55 people.
<併用薬および併用療法 > <Combination drugs and combination therapy>
本試験は、レポドパ 'DCI配合剤を使用しているパーキンソン病 (若年性パーキンソ -ズムを含む）患者を対象に、 (2R) 2—プロピルオクタン酸またはその塩の臨床効 果を確認するものであるため、併用薬の使用および併用療法の実施に関しては、以 下の規定に準じて行った。  This study is to confirm the clinical efficacy of (2R) 2-propyloctanoic acid or its salt in patients with Parkinson's disease (including juvenile parkinsonism) using levodopa's DCI combination drug. Therefore, the use of concomitant drugs and the use of concomitant therapy were performed according to the following rules.
[併用薬および併用療法に関する規定] [Regulations for concomitant drugs and concomitant therapy]
レポドパ 'DCI配合剤は、観察期開始の 4週間前力も一定に保たれている用法'用 量を、観察期間〜投与量漸減期間を通じて変更しないこととする。また、新たにレポ ドパ 'DCI配合剤を投与することは禁止する。後観察期間においては、症状が悪化し 、その程度が本試験の継続に支障を来すような場合には、レポドパ 'DCI配合剤を増 量もしくは新たにレポドパ · DCI配合剤を投与することを可能とする。  The dose of levodopa 'DCI combination drug that maintains a constant force for 4 weeks before the start of the observation period' should not be changed throughout the observation period to the dose gradual period. In addition, administration of a new repodopa DCI combination is prohibited. During the post-observation period, if the symptoms worsen and the extent of this may interfere with the continuation of this study, increase the dose of levodopa's DCI combination or a new levodopa / DCI combination. Make it possible.
投与量漸増期開始力も後観察期終了まで、ジスキネジァゃ精神症状などドパミン 過量のために発現したと思われる症状が発現し、かつ、その程度が本試験の継続に 支障を来すような場合には、レポドパ 'DCI配合剤を減量することは可能とする。なお 、一度減量したレポドパ 'DCI配合剤は観察期開始時点の用量まで増量可能とする 下記（1)〜 (4)の薬物および治療法は、治験期間中 (観察期開始から後観察期終 了まで)を通じて併用を禁止する。 (1)レポドパ単剤； (2)モノアミン酸化酵素（MAO —B)阻害薬 (例:塩酸セレギリン等）；（3)その他パーキンソン病の症候に影響を及ぼ すと考えられる以下の（a)〜（d)の薬物；（a)降圧薬 (例:メチルドパ、レセルピン等の 中枢性に作用するもの等）；（b)精神神経用薬 (例：フエノチアジン系薬物、プチロフ エノン系薬物、ベンズアミド系薬物、塩酸カルピプラミン、マレイン酸カルピプラミン、 塩酸クロカプラミン、塩酸べロスピロン水和物、塩酸モサプラミン、ォキシペルチン、ォ ランザピン、ゾテピン、ピモジド、フマル酸タエチアピン、リスペリドン等）；（c)抗てんか ん薬 (例:ゾニサミド、バルプロ酸ナトリウム等）；（d)消ィ匕器系用薬 (例:スルピリド、リン ゴ酸クレポプリド、メトクロブラミド等）；（4)現在開発中で薬効の定まっていない他の全 ての薬物；（5)定位脳手術等のパーキンソン病の外科的治療。 In the case of dyskinesia, symptoms such as psychiatric symptoms that may have occurred due to an overdose of dopamine, and the extent of this may interfere with the continuation of this study. It is possible to reduce the weight of Lepodopa's DCI combination. The levodopa DCI combination once reduced can be increased up to the dose at the start of the observation period. The drugs and treatments (1) to (4) below are during the trial period (from the start of the observation period to the end of the later observation period). Use is prohibited. (1) Lepodopa single agent; (2) Monoamine oxidase (MAO-B) inhibitors (eg, selegiline hydrochloride); (3) Other (a) to (5) which are considered to affect the symptoms of Parkinson's disease (D) drugs; (a) antihypertensive drugs (eg, centrally acting drugs such as methyldopa, reserpine, etc.); (b) neuropsychiatric drugs (eg, phenothiazine drugs, petitlophenone drugs, benzamide drugs) , Calpipramine hydrochloride, carpipramine maleate, clocapramine hydrochloride, berospirone hydrochloride hydrate, mosapramine hydrochloride, oxipertin, olanzapine, zotepine, pimozide, taethiapine fumarate, risperidone, etc .; (c) anti-epileptic drugs (eg, zonisamide, Sodium valproate, etc.); (d) anti-inflammatory drugs (eg sulpiride, phosphorus) (4) All other drugs that are currently under development and are not well-defined; (5) Surgical treatment of Parkinson's disease such as stereotactic brain surgery.
治験期間中 (観察期開始から後観察期終了まで)は、原則として前記の併用禁止 薬以外の薬物は使用可能とする。  In principle, during the trial period (from the beginning of the observation period to the end of the later observation period), drugs other than the above prohibited drugs can be used.
下記（1)〜（5)の薬物は、観察期開始の 4週間前力も用法'用量を変えることなく使 用している場合は併用を認め、治験期間中 (観察期開始力も後観察期終了まで)を 通じて同一薬剤を使用し、用法'用量を変更しないこととする。また、新たに下記の薬 物を投与することは禁止する。 (1)ドパミン受容体作動薬 (例:メシル酸プロモクリプチ ン、メシル酸ぺルゴリド、力べルゴリン、塩酸タリぺキソール、塩酸プラミぺキソール等） ； (2)中枢性抗コリン薬 (例:塩酸トリへキシフエ-ジル、塩酸ピロヘプチン、塩酸マザ チコール、塩酸メチキセン、ビペリデン、プロフエナミン等）；（3)塩酸ァマンタジン；（4 )ドロキシドパ、（5)抗うつ薬 (例：三環系抗うつ薬、四環系抗うつ薬、トリァゾロピリジン 系抗うつ薬、選択的セロトニン再取り込み阻害剤（SSRI)、セロトニン'ノルアドレナリ ン再取り込み阻害剤 (SNRI)等)。  The drugs listed in (1) to (5) below can be used together for 4 weeks before the start of the observation period without changing the dosage. The same drug should be used throughout the above and the dosage should not be changed. In addition, administration of the following new drugs is prohibited. (1) Dopamine receptor agonists (eg, promocriptine mesylate, pergolide mesylate, force bergolin, talipexol hydrochloride, pramipexole hydrochloride, etc.); (2) central anticholinergic agents (eg, tricholine hydrochloride) (3) amantadine hydrochloride; (4) droxidopa, (5) antidepressants (eg, tricyclic antidepressants, iv) hexifuezyl, pyroheptine hydrochloride, mazaticol hydrochloride, methixene hydrochloride, biperidene, prophenamine, etc.) Ring antidepressants, triazolopyridine antidepressants, selective serotonin reuptake inhibitors (SSRI), serotonin noradrenaline reuptake inhibitors (SNRI), etc.).
パーキンソン病のリハビリテーションは、観察期開始前力もの継続に限り併用可能と する。  Rehabilitation for Parkinson's disease can be used only for the duration of the observation period.
チトクロム P450 2C9アイソザィムの阻害薬と併用禁忌もしくは併用注意とされる薬 物を併用する場合は、十分な観察を行うこととする。  When a cytochrome P450 2C9 isozyme inhibitor is used together with a contraindicated or concomitant drug, careful observation should be performed.
<評価項目 > <Evaluation item>
[有効性評価項目]  [Effectiveness evaluation items]
主要評価項目 Primary endpoint
(1)日本語版 UPDRS (Unified Parkinson's Disease Rating Scale) Part III 評価方法:観察期開始時、観察期終了時、投与 2 (投与量漸増期終了時)、 4、 6、 8 (1) Japanese version UPDRS (Unified Parkinson's Disease Rating Scale) Part III Evaluation method: At the start of the observation period, at the end of the observation period, administration 2 (at the end of the dose escalation period), 4, 6, 8
、 10、 12、 14 (維持量投与期終了時)、 16 (投与量漸減期終了時)、 18、 20および 210, 12, 14 (at the end of the maintenance dose period), 16 (at the end of the dose gradual period), 18, 20, and 2
4週後（後観察期終了時）において、 日本語版 UPDRS Part III (神経治療、 17卷、 57After 4 weeks (at the end of the post observation period), the Japanese version of UPDRS Part III (neurotherapy, 17 、, 57
7〜591頁、 2000年参照）に従って観察項目の重症度を評価した。 7-591, see 2000). The severity of the observed items was evaluated.
副次評価項目 Secondary endpoint
(1)日本語版 UPDRS Part I、 Π、 IVおよびトータルスコア 評価方法：主要評価項目と同様に評価を行った。 (1) Japanese version UPDRS Part I, IV, IV and total score Evaluation method: Evaluation was performed in the same manner as the main evaluation items.
(2)改訂 Hoehn & Yahr重症度のスコア  (2) Revised Hoehn & Yahr severity score
評価方法:観察期開始時、観察期終了時、投与 2 (投与量漸増期終了時)、 4、 6、 8 、 10、 12、 14 (維持量投与期終了時)、 16 (投与量漸減期終了時)、 18、 20および 2 4週後（後観察期終了時）において、以下の表 5に従って観察項目の重症度を評価し た。 Evaluation method: At the start of the observation period, at the end of the observation period, administration 2 (at the end of the dose escalation period), 4, 6, 8, 10, 12, 14 (at the end of the maintenance dose administration period), 16 (at the dose gradual decrease period) At the end of), 18, 20 and 24 weeks later (at the end of the post observation period), the severity of the observation items was evaluated according to Table 5 below.
[表 5] 改 fj—Hoeh" ¾ Y'nlirの fe度分 [Table 5] Revised fj—Hoeh "¾ Y'nlir's fe degree
0 ： } .—キンノニズムなし  0:} .— No kinnonism
i ： 一翻性ハーキン ニズム  i: Transverse Herkinism
i ^ ： ー删性,' '；ーキン:ノニズム +体 ^陣害 ( tiecr. ri : 'ど）  i ^:-Inferiority, '';-Kin: Nonism + body ^ camp (tiecr. ri: ')
： 雨翻性 ·.一キンノニっ " だが平衡陣害なし  : Rain reversal ·.
： 輕度両删性.' '；一キンソニズム +後方突進があるが自分で立ち直れる  ： Degree of ambiguity. '' ； One Kinsonism + Backward rush but you can recover by yourself
3 ： 11- Ψ等度 ーキンソ二ズム +平囊陣 ¾肉体 1こ 1 i介助不要  3 ： 11- Ψ Equal-Kinsonism + Hiraisojin ¾ Body 1 1 No assistance required
： 中等度 キン'ノニズム +平籠陣甚 1：庭 では独立生 ¾可能 : Moderate Kin'Nonism + Heijinjin 1: Independent in the garden ¾ possible
： 高度 ' h—キ：'ソニフ ，歩 ffli介 しでどう か可能 : Altitude 'h-ki:' Something is possible via Sonif, Affle
： 高度のバーキンソニズム、介助すゎぱ歩行可能  : Advanced Birkinsonism, assisted walking
5 ： 介助なしでは、翠德子またはぺッドに寝たぎり《介翁で ¾歩 ί'ϊは困隱》  5: Without assistance, you can lie on a lion or a bed.
(3)オフ時間（症状日記を使用） (3) Off time (use symptom diary)
評価方法:観察期終了時、投与 2 (投与量漸増期終了時)、 4、 6、 8、 10、 12、 14 (維 持量投与期終了時)、 16 (投与量漸減期終了時)、 18、 20および 24週後 (後観察期 終了時)の各々起きている時間に対するオフ時間ならびにオン時間の割合を患者の 症状日記から求め、その変化を投与量漸増期投与開始前と比較した。 Evaluation method: At the end of the observation period, administration 2 (at the end of the dose escalation period), 4, 6, 8, 10, 12, 14 (at the end of the maintenance dose period), 16 (at the end of the gradual decrease period), The ratio of off-time and on-time to the waking time after each of 18, 20, and 24 weeks (at the end of the post-observation period) was obtained from the patient's symptom diary, and the changes were compared with those before the start of the dose escalation period.
(4)後観察期における日本語版 UPDRS Part I、 II、 III、 IVおよびトータルスコア 評価方法：後観察期における観察項目の重症度を前記と同様に評価した。  (4) Japanese version UPDRS Part I, II, III, IV and total score in the post observation period Evaluation method: The severity of the observation items in the post observation period was evaluated in the same manner as described above.
(5)後観察期における改訂 Hoehn & Yahr重症度のスコア  (5) Revised Hoehn & Yahr severity score in the post observation period
評価方法：後観察期における観察項目の重症度を前記と同様に評価した。 Evaluation method: The severity of the observation items in the post observation period was evaluated in the same manner as described above.
(6)後観察期におけるオフ時間 (症状日記を使用）  (6) Off-time in the post-observation period (use symptom diary)
評価方法:後観察期におけるオフ時間ならびにオン時間の割合を前記と同様に評価 した。 Evaluation method: The off time and the ratio of the on time in the post-observation period were evaluated in the same manner as described above.
(7)後観察期にお ヽてレボドパ · DCI配合剤の増量もしくは新たにレポドパ · DCI配 合剤を投与するまでの期間 (7) Increased dose of levodopa / DCI combination or newly added levodopa / DCI Time to administer the mixture
評価方法：レポドパ · DCI配合剤の増量もしくは新たなレポドパ · DCI配合剤の投与を イベントとし、後観察開始日力も最初のイベントが発生するまでの日数を用いて、投 与群ごとのレポドパ 'DCI配合剤の使用に対する累積変更率を算出した。 Evaluation method: Increasing the amount of levodopa · DCI combination or administration of a new repodopa · DCI combination as an event, and using the number of days until the first event occurs for the post-observation starting power, the repodopa 'DCI for each treatment group The cumulative change rate for the use of the combination was calculated.
[安全性評価項目] [Safety evaluation items]
有害事象の発現率とその内容 (症状、因果関係等)、臨床検査値の推移等 解析： Incidence rate and content of adverse events (symptoms, causality, etc.), changes in clinical laboratory values, etc. Analysis:
上記の主要評価項目および副次的評価項目で（2R)— 2—プロピルオクタン酸投 与による治療効果を評価した。  The therapeutic effects of (2R) -2-propyloctanoic acid administration were evaluated using the above primary and secondary endpoints.
成績： Grade:
成績を以下に示す。  The results are shown below.
[有効性評価項目] [Effectiveness evaluation items]
(2R) 2—プロピルオクタン酸はパーキンソン病患者の治療にぉ 、て有効である。  (2R) 2-Propyloctanoic acid is effective in treating patients with Parkinson's disease.
[安全性評価項目] [Safety evaluation items]
(2R) 2—プロピルオクタン酸はパーキンソン病患者の治療にぉ 、て安全である。 製剤例  (2R) 2-Propyloctanoic acid is safe for treating Parkinson's disease patients. Formulation example
(1) (2R) 2—プロピルオクタン酸含有ソフトカプセルの製造  (1) Production of (2R) 2-propyloctanoic acid-containing soft capsules
製剤例 1 : (2R)—2—プロピルオクタン酸 lOOmgソフトカプセルの製造 Formulation Example 1: Production of (2R) -2-propyloctanoic acid lOOmg soft capsule
ゼラチン（15kg)および濃グリセリン (4.5kg)を、精製水（15kg)の存在下、 70°Cで 混和し、均一な溶液を得た。この溶液および（2R)—2—プロピルオクタン酸 (0.6kg) を、ソフトカプセル充填機（ロータリー式軟カプセル成型機 H—1型;力マタ）に投入し 、 (2R) 2—プロピルオクタン酸を充填したソフトカプセルの生球を得た。得られた 生球を、タンブラ乾燥および棚乾燥に順次付すことにより、 1カプセル中に lOOmgの (2R)—2 プロピルオクタン酸を含有する表題のソフトカプセル剤（3000カプセル）を 得た。  Gelatin (15 kg) and concentrated glycerin (4.5 kg) were mixed at 70 ° C. in the presence of purified water (15 kg) to obtain a uniform solution. This solution and (2R) -2-propyloctanoic acid (0.6 kg) are put into a soft capsule filling machine (rotary soft capsule molding machine H-1 type; force mata) and filled with (2R) 2-propyloctanoic acid. A soft capsule live ball was obtained. The obtained raw spheres were sequentially subjected to tumbler drying and shelf drying to obtain the title soft capsule (3000 capsules) containing lOOmg of (2R) -2-propyloctanoic acid in one capsule.
製剤例 2 : (2R)—2 プロピルオクタン酸 150mgソフトカプセルの製造 Formulation Example 2: (2R) -2 Propyloctanoic acid 150mg soft capsule production
前記と同様にして、 1カプセル中に 150mgの（2R)—2 プロピルオクタン酸を含有 する表題のソフトカプセル剤（2000カプセル）を得た。 製剤例 3 : (2R)—2 プロピルオクタン酸 200mgソフトカプセルの製造 前記と同様にして、 1カプセル中に 200mgの（2R)—2—プロピルオクタン酸を含有 する表題のソフトカプセル剤（2000カプセル）を得た。 In the same manner as described above, the title soft capsule (2000 capsules) containing 150 mg of (2R) -2-propyloctanoic acid in one capsule was obtained. Formulation Example 3: Production of (2R) -2 propyloctanoic acid 200 mg soft capsule In the same manner as described above, the title soft capsule (2000 capsules) containing 200 mg of (2R) -2-propyloctanoic acid in one capsule was obtained. It was.
製剤例 4 : (2R)—2 プロピルオクタン酸 300mgソフトカプセルの製造  Formulation Example 4: (2R) -2 Propyloctanoic acid 300mg soft capsule production
前記と同様にして、 1カプセル中に 300mgの（2R)—2 プロピルオクタン酸を含有 する表題のソフトカプセル剤（2000カプセル）を得た。  In the same manner as described above, the title soft capsule (2000 capsules) containing 300 mg of (2R) -2-propyloctanoic acid in one capsule was obtained.
製剤例 5 : (2R)—2 プロピルオクタン酸 600mgソフトカプセルの製造  Formulation Example 5: (2R) -2 Propyloctanoic acid 600 mg soft capsule production
前記と同様にして、 1カプセル中に 600mgの（2R)—2 プロピルオクタン酸を含有 する表題のソフトカプセル剤（2000カプセル）を得た。  In the same manner as described above, the title soft capsule (2000 capsules) containing 600 mg of (2R) -2-propyloctanoic acid in one capsule was obtained.
製剤例 6 : (2R)—2 プロピルオクタン酸 50mgソフトカプセルの製造  Formulation Example 6: (2R) -2 Propyloctanoic acid 50mg soft capsule production
前記と同様にして、 1カプセル中に 50mgの（2R)—2 プロピルオクタン酸を含有 する表題のソフトカプセル剤（2000カプセル）を得た。  In the same manner as described above, the title soft capsule (2000 capsules) containing 50 mg of (2R) -2-propyloctanoic acid in one capsule was obtained.
[0096] (2) (2R)— 2 プロピルオクタン酸含有錠剤の製造 [0096] (2) (2R) — Manufacture of 2-propyloctanoic acid-containing tablets
製剤例 1 : (2R)—2—プロピルオクタン酸、レポドパ、ベンセラジド含有錠剤の製造 Formulation Example 1: Production of (2R) -2-propyloctanoic acid, repodopa, benserazide-containing tablets
(2R) 2—プロピルォクタン酸（1008)、レボドパ（1008)、べンセラジド（258)、カ ルボキシメチルセルロースカルシウム（20.0g)、ステアリン酸マグネシウム（lO.Og)およ び微結晶セルロース（870g)を常法により混合した後打錠して、一錠中に lOmgの（2 R)—2 プロピルオクタン酸、 lOmgのレボドパおよび 2.5mgのベンセラジドを含有す る錠剤 1万錠を得た。 (2R) 2-propyloctanoic acid (100 8 ), levodopa (100 8 ), benserazide (25 8 ), carboxymethylcellulose calcium (20.0 g), magnesium stearate (lO.Og) and microcrystalline cellulose ( 870 g) were mixed by a conventional method and then tableted to obtain 10,000 tablets each containing 10 mg of (2R) -2-propyloctanoic acid, 10 mg of levodopa and 2.5 mg of benserazide.
製剤例 2 : (2R)—2—プロピルオクタン酸、メシル酸プロモクリブチン含有錠剤の製造 Formulation Example 2: Production of tablets containing (2R) -2-propyloctanoic acid and promocributine mesylate
(2R)— 2 プロピルオクタン酸（lOOg)、メシル酸ブロモクリプチン（30g)、カルボ キシメチルセルロースカルシウム（20.0g)、ステアリン酸マグネシウム（10.0g)および微 結晶セルロース（870g)を常法により混合した後打錠して、一錠中に lOmgの（2R) 2 プロピルオクタン酸および 3mgのメシル酸ブロモクリプチンを含有する錠剤 1万 錠を得た。 (2R) -2 After mixing 2-propyloctanoic acid (lOOg), bromocriptine mesylate (30 g), calcium calcium carbonate (20.0 g), magnesium stearate (10.0 g) and microcrystalline cellulose (870 g) by conventional method Tablets were obtained in a tablet containing 10 mg of (2R) 2 propyloctanoic acid and 3 mg of bromocriptine mesylate in one tablet.
[0097] (3) (2R)— 2 プロピルオクタン酸含有注射剤の製造  [0097] (3) (2R) — Production of 2-propyloctanoic acid-containing injection
製剤例 1 : (2R)—2—プロピルオクタン酸、レポドパ、ベンセラジド含有注射剤の製造 (2R)— 2 プロピルオクタン酸（200g)、レボドパ（200g)、ベンセラジド（50g)、マ ン-トール (2kg)および蒸留水（50L)を常法により混合した後、均一な溶液とし、無 菌フィルター（デユラポア 0.22 μ mメンブレン）で濾過後、 5mLずつアンプルに充填し 、高圧蒸気滅菌（123°C、 15分間）して、 1アンプル中 20mgの（2R)— 2—プロピル オクタン酸、 20mgのレボドパおよび 5mgのベンセラジドを含有するアンプル 1万本を 得た。 Formulation Example 1: Manufacture of injection containing (2R) -2-propyloctanoic acid, levodopa, benserazide (2R) — 2-propyloctanoic acid (200 g), levodopa (200 g), benserazide (50 g), male After mixing with water (2 kg) and distilled water (50 L) by a conventional method, make a uniform solution, filter through a sterile filter (Deyurapore 0.22 μm membrane), fill each 5 mL ampoule, and sterilize under high pressure steam ( At 15O 0 C for 15 minutes, 10,000 ampoules containing 20 mg (2R) -2-propyloctanoic acid, 20 mg levodopa and 5 mg benserazide in one ampule were obtained.
製剤例 2 : (2R)—2—プロピルオクタン酸、メシル酸プロモクリブチン含有注射剤の製 造 Formulation Example 2: Production of injection containing (2R) -2-propyloctanoic acid and promocributine mesylate
(2R)— 2—プロピルオクタン酸（200g)、メシル酸ブロモクリプチン（60g)、マン-ト ール (2kg)および蒸留水（50L)を常法により混合した後、均一な溶液とし、無菌フィ ルター（デユラポア 0.22 mメンブレン）で濾過後、 5mLずつアンプルに充填し、高圧 蒸気滅菌（123°C、 15分間）して、 1アンプル中 20mgの（2R)—2—プロピルオクタン 酸および 6mgのメシル酸ブロモクリプチンを含有するアンプル 1万本を得た。  (2R) — 2-Propyloctanoic acid (200 g), bromocriptine mesylate (60 g), mantol (2 kg) and distilled water (50 L) were mixed by a conventional method to obtain a homogeneous solution. (Filtered with Deyurapore 0.22 m membrane), filled into ampoules in 5 mL portions, autoclaved (123 ° C, 15 min), 20 mg (2R) -2-propyloctanoic acid and 6 mg mesylic acid in one ampule Ten thousand ampoules containing bromocriptine were obtained.
産業上の利用可能性 Industrial applicability
本発明で開示する方法、ならびにその方法で用いる医薬は、従来のパーキンソン 病および Zまたはパーキンソン症候群治療で用いられて 、た治療方法における問題 点を改善したものであり、該投与方法および投与量で得られる効果は著しく優れたも のである。本発明で開示するように、パーキンソン病および Zまたはパーキンソン病 症候群の予防、治療および Zまたは症状進展抑制薬に加えて（2R)— 2—プロピル オクタン酸、その塩、その溶媒和物またはそれらのプロドラッグを投与することで、そ れらの併用薬を単独で用いた場合に比べて、予防、治療および Zまたは症状進展 抑制効果の補完および Zまたは増強、薬物の投与量'副作用の軽減、もしくは薬物 耐性の発現の防止等に対して有効である。特に、パーキンソン病およびパーキンソン 症候群の治療において、しばしば認められるウエアリングオフ現象等の副作用を回避 し、治療効果を補完 '増強し、薬物投与量を軽減し、もしくは薬物耐性の発現を防止 することができるので極めて有用である。  The method disclosed in the present invention and the medicament used in the method have been used in conventional treatment of Parkinson's disease and Z or Parkinson's syndrome, and have improved the problems in the treatment method. The obtained effect is remarkably excellent. As disclosed in the present invention, in addition to the prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's disease syndrome, (2R) -2-propyloctanoic acid, its salt, its solvate or their By administering prodrugs, prevention, treatment and supplementation and Z or enhancement of Z or symptom progression inhibitory effect, drug dose'reduction of side effects, compared to the use of these concomitant drugs alone Or it is effective in preventing the development of drug resistance. In particular, in the treatment of Parkinson's disease and Parkinson's syndrome, it is possible to avoid side effects such as wear-off phenomenon that are often observed, complement and enhance the therapeutic effect, reduce drug dosage, or prevent the development of drug resistance. It is extremely useful because it can.

Claims

請求の範囲 The scope of the claims
[1] (2R) 2—プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグ と、パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは 症状進展抑制薬とを組み合わせてなるパーキンソン病および/またはパーキンソン 症候群の予防、治療および Zまたは症状進展抑制用医薬。  [1] (2R) Parkinson which is a combination of 2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, and prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome and a Z or symptom progression inhibitor A drug for prevention, treatment and Z or symptom progression suppression of diseases and / or Parkinson's syndrome.
[2] 経口投与用である請求項 1記載の医薬。  [2] The medicament according to claim 1, which is for oral administration.
[3] 1回あたりの（2R)—2 プロピルオクタン酸またはその塩の経口投与量が約 50mg 〜約 1200mgである請求項 2記載の医薬。  [3] The medicament according to claim 2, wherein the oral dose of (2R) -2 propyloctanoic acid or a salt thereof per administration is about 50 mg to about 1200 mg.
[4] 1回あたりの（2R)—2—プロピルオクタン酸またはその塩の経口投与量が約 100m g〜約 600mgである請求項 3記載の医薬。  [4] The medicament according to claim 3, wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 100 mg to about 600 mg.
[5] 投薬期間が約 1ヶ月間〜約 5年間である請求項 2記載の医薬。  [5] The medicament according to claim 2, wherein the dosing period is from about 1 month to about 5 years.
[6] 約 1ヶ月間〜約 5年間の投薬期間中、 1日 1回〜 5回の投薬回数で、 1回あたり約 5 Omg〜約 1200mgの（2R)—2—プロピルオクタン酸またはその塩を経口投与するこ とを特徴とする請求項 5記載の医薬。  [6] About 5 Omg to about 1200 mg of (2R) -2-propyloctanoic acid or a salt thereof at a dosage of 1 to 5 times a day during a dosage period of about 1 month to about 5 years 6. The medicament according to claim 5, which is orally administered.
[7] 約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 100 mg〜約 400mgの（2R)— 2 プロピルオクタン酸を経口投与し、続く約 1週間〜約 2 週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 200mg〜約 800mg の（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜約 3年間の投薬期間 中、 1日 1回〜 2回の投薬回数で、 1回あたり約 300mg〜約 1200mgの（2R)— 2 プ 口ピルオクタン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2 回の投薬回数で、 1回あたり約 200mg〜約 800mgの（2R)—2 プロピルオクタン 酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数 で、 1回あたり約 lOOmg〜約 400mgの（2R)—2 プロピルオクタン酸を経口投与す ることを特徴とする請求項 6記載の医薬。  [7] During the dosing period of about 1 week to about 2 weeks, about 100 mg to about 400 mg of (2R) -2-propyloctanoic acid is orally administered at a dose of 1 to 2 times a day, During the subsequent dosing period of about 1 week to about 2 weeks, about 200 mg to about 800 mg of (2R) -2 propyloctanoic acid is orally administered at a dosage of 1 to 2 times a day, followed by about 1 During the dosing period of about 3 years per week, oral administration of about 300 mg to about 1200 mg of (2R) —2 oral piroctanoic acid per dose, with 1 to 2 dosing times per day, followed by about 1 week to During a dosing period of about 2 weeks, about 200 mg to about 800 mg of (2R) -2 propyloctanoic acid is orally administered once a day or twice a day, followed by about 1 week to about 2 weeks 7. The pharmaceutical composition according to claim 6, wherein from about 1OOmg to about 400mg of (2R) -2 propyloctanoic acid is orally administered once per day during the dosing period of .
[8] 約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)— 2— プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数 で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 12週 間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 600mgの（2R)—2 プロピ ルォクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回 あたり約 400mgの（2R)— 2 プロピルオクタン酸を経口投与し、続く約 1週間の投 薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2—プロピルォクタ ン酸を経口投与することを特徴とする請求項 7記載の医薬。 [8] Approximately 200 mg of (2R) -2-propyloctanoic acid is orally administered once a day during the dosing period of about 1 week, followed by 1 About 400 mg of (2R) -2 propyloctanoic acid is orally administered once a day for about 12 weeks, and about once per day for about 12 weeks. 600mg (2R) -2 propi Lucotanic acid is administered orally, followed by about 400 mg of (2R) -2-propyloctanoic acid per dose for the following weekly dosing period, followed by administration for about 1 week. 8. The medicine according to claim 7, wherein about 200 mg of (2R) -2-propyloctanoic acid is orally administered once per day during the drug period.
[9] さらに、レポドパ製剤、ドパミン受容体作動薬、ドパミン遊離促進薬、ドパミン取り込 み阻害薬、ドパミン作用薬、中枢性抗コリン薬、芳香族 L アミノ酸脱炭酸酵素阻害 薬、モノアミン酸ィ匕酵素阻害薬、カテコール—O メチルトランスフェラーゼ阻害薬、 ノルェピネフリン補充薬、 GABA受容体調節薬、 GABA受容体調節薬、アデノシ [9] In addition, levodopa preparations, dopamine receptor agonists, dopamine release promoters, dopamine uptake inhibitors, dopamine agonists, central anticholinergics, aromatic L amino acid decarboxylase inhibitors, monoamine acids Enzyme inhibitor, catechol-O methyltransferase inhibitor, norepinephrine replacement agent, GABA receptor modulator, GABA receptor modulator, adenosine
A B  A B
ン A2A受容体遮断薬、アポトーシス阻害薬、神経分化，再生促進薬、神経栄養因子 、脳機能賦活薬、 Rho キナーゼ阻害薬および β受容体遮断薬から選択される 1種 以上を組み合わせてなる請求項 1記載の医薬。  A combination of one or more selected from an A2A receptor blocker, an apoptosis inhibitor, a neuronal differentiation / regeneration promoter, a neurotrophic factor, a brain function activator, a Rho kinase inhibitor, and a β receptor blocker 1. The medicine according to 1.
[10] パーキンソン病および Ζまたはパーキンソン症候群の予防、治療および Ζまたは症 状進展抑制薬が、レポドパ製剤、レポドパ 'ベンセラジド配合剤、レポドパ 'カルビドパ 配合剤および Ζまたはメシル酸プロモクリブチンである請求項 1記載の医薬。  [10] The prevention, treatment and prevention of epilepsy or symptom progression of Parkinson's disease and epilepsy or Parkinson's syndrome are levodopa, levodopa 'benserazide, levodopa' carbidopa 'and お よ び or promocributin mesylate 1. The medicine according to 1.
[11] (2R) 2 プロピルオクタン酸とレポドパ製剤とを組み合わせてなる医薬であって 、（2R)— 2 プロピルオクタン酸の投与量力 患者の体重 lkgあたり約 3mg〜約 60 mgであって、レボドパ製剤の投与量力 患者の体重 lkgあたり約 3mg〜約 60mgで ある請求項 10記載の医薬。  [11] (2R) 2 Propyl octanoic acid and a levodopa preparation, wherein (2R) -2 propyloctanoic acid is administered at a dose of about 3 mg to about 60 mg per kg of patient weight, 11. The pharmaceutical composition according to claim 10, wherein the dosage is about 3 mg to about 60 mg per kg body weight of the patient.
[12] (2R)—2 プロピルオクタン酸とレボドパ 'ベンセラジド (4 : 1)配合剤とを組み合わ せてなる医薬であって、（2R)— 2—プロピルオクタン酸の投与量力 患者の体重 lkg あたり約 3mg〜約 60mgであって、レボドノ 'ベンセラジド（4 : 1)配合剤の投与量が、 患者の体重 lkgあたり約 2mg〜約 20mgである請求項 10記載の医薬。  [12] (2R) —A drug that combines propyloctanoic acid and levodopa'benserazide (4: 1) combination, and (2R) —dosage of 2-propyloctanoic acid per lkg of patient body weight 11. The medicament according to claim 10, wherein the dose is about 3 mg to about 60 mg, and the dosage of levodono'benserazide (4: 1) is about 2 mg to about 20 mg per kg body weight of the patient.
[13] (2R)—2 プロピルオクタン酸とレボドパ 'カルビドパ（10 : 1)配合剤とを組み合わ せてなる医薬であって、（2R)— 2—プロピルオクタン酸の投与量力 患者の体重 lkg あたり約 3mg〜約 60mgであって、レボドパ 'カルビドパ（10 : 1)配合剤の投与量が、 患者の体重 lkgあたり約 2mg〜約 15mgである請求項 10記載の医薬。  [13] (2R) —A drug comprising a combination of propyloctanoic acid and levodopa'carbidopa (10: 1), with the ability to administer (2R) -2-propyloctanoic acid per lkg of patient body weight 11. The medicament according to claim 10, wherein the dose is about 3 mg to about 60 mg, and the dose of levodopa'carbidopa (10: 1) combination is about 2 mg to about 15 mg per kg patient body weight.
[14] (2R)—2 プロピルオクタン酸とメシル酸ブロモクリプチンとを組み合わせてなる医 薬であって、（2R)— 2 プロピルオクタン酸の投与量力 患者の体重 lkgあたり約 3 mg〜約 60mgであって、メシル酸ブロモクリプチンの投与量力 患者の体重 lkgあた り約 O.Olmg〜約 lmgである請求項 10記載の医薬。 [14] (2R) -2 A medicine composed of a combination of propyloctanoic acid and bromocriptine mesylate. (2R) -2 Dosage power of propyloctanoic acid About 3 per kg of patient body weight 11. The medicament according to claim 10, which has a dosage power of bromocriptine mesylate from about O.Olmg to about 1 mg per kg body weight of the patient.
[15] レポドパ製剤、レポドパ ·ベンセラジド配合剤およびレポドパ ·カルビドパ配合剤から 選ばれる 1種または 2種以上と、 (2R) 2—プロピルオクタン酸、その塩、その溶媒 和物またはそれらのプロドラッグとを組み合わせてなる経口投与用のパーキンソン病 および Zまたはパーキンソン症候群の予防、治療および Zまたは症状進展抑制用医 薬であって、約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの (2R)—2—プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回 の投薬回数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し 、続く約 12週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 600mgの（2R) —2—プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬 回数で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2—プ 口ピルオクタン酸を経口投与することを特徴とする医薬。  [15] One or more selected from levodopa, levodopa-benserazide and levodopa-carbidopa, (2R) 2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof An orally administered combination of Parkinson's disease and Z or Parkinson's syndrome prevention, treatment and Z or suppression of symptom progression, in a dosage period of about 1 week, 1 dose per day, 1 Approximately 200 mg of (2R) -2-propyloctanoic acid per dose, followed by approximately 400 mg of (2R) -2-propyloctane per dose during the subsequent dosing period of about 1 week The oral administration of acid, followed by oral administration of about 600 mg (2R) -2-propyloctanoic acid per dose for the following 12 week dosing period, once a day, followed by about 1 week 1 dose per day during the period About 400 mg of (2R) -2 propyloctanoic acid is orally administered, and about 200 mg of (2R) -2 is administered once a day during the subsequent dosing period of about 1 week. —Pharmaceuticals characterized by oral administration of oral pyroctanoic acid.
[16] パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症 状進展抑制に際し、パーキンソン病および Zまたはパーキンソン症候群の予防、治 療および Zまたは症状進展抑制薬にカ卩えて、さらに（2R)—2—プロピルオクタン酸、 その塩、その溶媒和物またはそれらのプロドラッグを投与することを特徴とする、当該 薬の投与量低減用医薬。  [16] In preventing or treating Parkinson's disease and Z or Parkinson's syndrome and inhibiting Z or symptomatic progression, in addition to Parkinson's disease and Z or Parkinson's syndrome prevention, treatment and Z or symptom progression inhibitory drugs, (2R ) —2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof, which is administered.
[17] パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症 状進展抑制に際し、パーキンソン病および Zまたはパーキンソン症候群の予防、治 療および Zまたは症状進展抑制薬にカ卩えて、さらに（2R)—2—プロピルオクタン酸、 その塩、その溶媒和物またはそれらのプロドラッグを投与することを特徴とする、当該 薬の副作用改善用医薬。  [17] In prevention, treatment and suppression of Z or symptom progression in Parkinson's disease and Z or Parkinson's syndrome, in addition to prevention, treatment and Z or symptom progression inhibitor in Parkinson's disease and Z or Parkinson's syndrome, (2R ) —2-Propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof, which is administered.
[18] パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症 状進展抑制薬が、レポドパ製剤、レポドパ 'ベンセラジド配合剤、レポドパ 'カルビドパ 配合剤および Zまたはメシル酸ブロモクリプチンである請求項 16または 17記載の医 薬。 [18] The prevention, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome are repodopa, levodopa 'benserazide combination, levodopa' carbidopa combination 'and Z or bromocriptine mesylate. The medicine according to 17.
[19] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグ を有効成分として含有し、経口投与することを特徴とするパーキンソン病および Zま たはパーキンソン症候群の予防、治療および Zまたは症状進展抑制用医薬糸且成物 [19] Prevention of Parkinson's disease and Z or Parkinson's syndrome comprising (2R) 2 propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof as an active ingredient and orally administered, Medicinal yarn and composition for treatment and suppression of Z or symptom progression
[20] 1回あたりの（2R)—2 プロピルオクタン酸またはその塩の経口投与量が約 50mg[20] The oral dose of (2R) -2 propyloctanoic acid or its salt is about 50 mg per dose.
〜約 1200mgである請求項 19記載の組成物。 20. A composition according to claim 19 which is from about 1200 mg.
[21] 1回あたりの（2R)— 2 プロピルオクタン酸またはその塩の経口投与量が約 100m g〜約 600mgである請求項 20記載の組成物。 21. The composition according to claim 20, wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 100 mg to about 600 mg.
[22] 1回あたりの（2R)—2—プロピルオクタン酸またはその塩の経口投与量が約 100m g、約 200mg、約 300mg、約 400mgまたは約 600mgである請求項 21記載の組成 物。 [22] The composition of claim 21, wherein the oral dose of (2R) -2-propyloctanoic acid or a salt thereof per administration is about 100 mg, about 200 mg, about 300 mg, about 400 mg or about 600 mg.
[23] 1回あたりの（2R)—2 プロピルオクタン酸またはその塩の経口投与量が約 600m gである請求項 22記載の組成物。  [23] The composition according to claim 22, wherein the oral dose of (2R) -2 propyloctanoic acid or a salt thereof per administration is about 600 mg.
[24] 投薬期間が約 1ヶ月間〜約 5年間である請求項 19記載の組成物。 24. The composition of claim 19, wherein the dosing period is from about 1 month to about 5 years.
[25] 投薬期間が約 3ヶ月間〜約 1年間である請求項 24記載の組成物。 25. The composition of claim 24, wherein the dosing period is from about 3 months to about 1 year.
[26] 投薬期間が約 3ヶ月間〜約 6ヶ月間である請求項 25記載の組成物。 26. The composition of claim 25, wherein the dosing period is from about 3 months to about 6 months.
[27] 約 1ヶ月間〜約 5年間の投薬期間中、 1日 1回〜 5回の投薬回数で、 1回あたり約 5 Omg〜約 1200mgの（2R)—2—プロピルオクタン酸またはその塩を経口投与するこ とを特徴とする請求項 19記載の組成物。 [27] About 5 Omg to about 1200 mg of (2R) -2-propyloctanoic acid or a salt thereof at a dosage of 1 to 5 times a day during a dosage period of about 1 month to about 5 years 20. The composition according to claim 19, which is orally administered.
[28] 約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 100 mg〜約 400mgの（2R)— 2 プロピルオクタン酸を経口投与し、続く約 1週間〜約 2 週間の投薬期間中、 1日 1回〜 2回の投薬回数で、 1回あたり約 200mg〜約 800mg の（2R)—2 プロピルオクタン酸を経口投与し、続く約 1週間〜約 3年間の投薬期間 中、 1日 1回〜 2回の投薬回数で、 1回あたり約 300mg〜約 1200mgの（2R)— 2 プ 口ピルオクタン酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2 回の投薬回数で、 1回あたり約 200mg〜約 800mgの（2R)—2 プロピルオクタン 酸を経口投与し、続く約 1週間〜約 2週間の投薬期間中、 1日 1回〜 2回の投薬回数 で、 1回あたり約 lOOmg〜約 400mgの（2R)—2 プロピルオクタン酸を経口投与す ることを特徴とする請求項 27記載の組成物。 [28] oral administration of about 100 mg to about 400 mg of (2R) -2-propyloctanoic acid per dose, with a dosing frequency of 1 to 2 times a day during a dosing period of about 1 week to about 2 weeks; During the subsequent dosing period of about 1 week to about 2 weeks, about 200 mg to about 800 mg of (2R) -2 propyloctanoic acid is orally administered at a dosage of 1 to 2 times a day, followed by about 1 During the dosing period of about 3 years per week, oral administration of about 300 mg to about 1200 mg of (2R) —2 oral piroctanoic acid per dose, with 1 to 2 dosing times per day, followed by about 1 week to During a dosing period of about 2 weeks, about 200 mg to about 800 mg of (2R) -2 propyloctanoic acid is orally administered once a day or twice a day, followed by about 1 week to about 2 weeks 1 to 2 doses per day during the dosing period, orally administer about lOOmg to about 400mg of (2R) -2 propyloctanoic acid per dose 28. The composition of claim 27.
[29] 約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2— プロピルオクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数 で、 1回あたり約 400mgの（2R)—2 プロピルオクタン酸を経口投与し、続く約 12週 間の投薬期間中、 1日 1回の投薬回数で、 1回あたり約 600mgの（2R)—2 プロピ ルォクタン酸を経口投与し、続く約 1週間の投薬期間中、 1日 1回の投薬回数で、 1回 あたり約 400mgの（2R)— 2 プロピルオクタン酸を経口投与し、続く約 1週間の投 薬期間中、 1日 1回の投薬回数で、 1回あたり約 200mgの（2R)—2—プロピルォクタ ン酸を経口投与することを特徴とする請求項 28記載の組成物。  [29] Approximately 200 mg of (2R) -2-propyloctanoic acid is orally administered once a day during a dosing period of about 1 week, followed by 1 About 400 mg of (2R) -2 propyloctanoic acid is orally administered once a day for about 12 weeks, and about once per day for about 12 weeks. 600 mg of (2R) -2 proproctanoic acid is administered orally, followed by about 400 mg of (2R) -2 propyloctanoic acid orally, once a day during the subsequent dosing period of about 1 week The oral administration of about 200 mg of (2R) -2-propyloctanoic acid per dose is carried out once a day during the next week of administration. Composition.
[30] (2R) 2 プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグ と、パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは 症状進展抑制薬とを組み合わせて哺乳動物に投与することを特徴とするパーキンソ ン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症状進展抑制 方法。  [30] (2R) 2 Propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof is combined with prophylaxis, treatment and Z or symptom progression inhibitor of Parkinson's disease and Z or Parkinson's syndrome in mammals A method for the prevention, treatment and suppression of Z or symptom progression of Parkinson's disease and Z or Parkinsonism, characterized by administration.
[31] パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症 状進展抑制に際し、パーキンソン病および Zまたはパーキンソン症候群の予防、治 療および Zまたは症状進展抑制薬にカ卩えて、さらに（2R)—2—プロピルオクタン酸、 その塩、その溶媒和物またはそれらのプロドラッグを投与することを特徴とする、当該 薬の投与量低減方法。  [31] In preventing or treating Parkinson's disease and Z or Parkinson's syndrome, and in suppressing Z or symptom progression, in addition to Parkinson's disease and Z or Parkinson's syndrome prevention, treatment and Z or symptom progression inhibiting drugs, (2R ) —2-Propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof.
[32] パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症 状進展抑制に際し、パーキンソン病および Zまたはパーキンソン症候群の予防、治 療および Zまたは症状進展抑制薬にカ卩えて、さらに（2R)—2—プロピルオクタン酸、 その塩、その溶媒和物またはそれらのプロドラッグを投与することを特徴とする、当該 薬の副作用改善方法。  [32] In preventing or treating Parkinson's disease and Z or Parkinson's syndrome and suppressing Z or symptomatic progression, in addition to Parkinson's disease and Z or Parkinson's syndrome prevention, treatment and Z or symptom progression inhibiting drugs, (2R ) —————————————————————————————————— Propyl drug administration
[33] (2R) 2—プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグ を哺乳動物に経口投与することを特徴とするパーキンソン病および Zまたはパーキン ソン症候群の予防、治療および Zまたは症状進展抑制方法。  [33] (2R) Prevention, treatment and Z of Parkinson's disease and Z or Parkinson's syndrome characterized by orally administering 2-propyloctanoic acid, its salt, its solvate or their prodrug to a mammal Or a symptom progression suppression method.
[34] パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症 状進展抑制用医薬を製造するための、（2R)—2—プロピルオクタン酸、その塩、そ の溶媒和物またはそれらのプロドラッグと、パーキンソン病および Zまたはパーキンソ ン症候群の予防、治療および Zまたは症状進展抑制薬との組み合わせの使用。 [34] Prevention, treatment and Z or symptom of Parkinson's disease and Z or Parkinson's syndrome (2R) -2-propyloctanoic acid, its salts, solvates or prodrugs thereof, and prevention, treatment and Z of Parkinson's disease and Z or Parkinson's syndrome Or use in combination with symptom progression inhibitors.
[35] パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症 状進展抑制の際に用いる、パーキンソン病および Zまたはパーキンソン症候群の予 防、治療および Zまたは症状進展抑制薬の投与量低減用医薬を製造するための、 ( 2R)—2—プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグの 使用。 [35] For prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome, for prevention and treatment of Parkinson's disease and Z or Parkinson's syndrome, and for reducing dosage of Z or symptom progression inhibitor Use of (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof for the manufacture of a medicament.
[36] パーキンソン病および Zまたはパーキンソン症候群の予防、治療および Zまたは症 状進展抑制の際に用いる、パーキンソン病および Zまたはパーキンソン症候群の予 防、治療および Zまたは症状進展抑制薬の副作用改善用医薬を製造するための、 ( [36] Prevention, treatment of Parkinson's disease and Z or Parkinson's syndrome, and prevention or treatment of Parkinson's disease and Z or Parkinson's syndrome, drugs for improving side effects of Z or symptom progression inhibitor For manufacturing the (
2R)—2—プロピルオクタン酸、その塩、その溶媒和物またはそれらのプロドラッグの 使用。 2R) —Use of 2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof.
[37] 経口投与用のパーキンソン病および Zまたはパーキンソン症候群の予防、治療お よび Zまたは症状進展抑制用医薬を製造するための、（2R)— 2—プロピルオクタン 酸、その塩、その溶媒和物またはそれらのプロドラッグの使用。  [37] (2R) — 2-Propyloctanoic acid, its salts, and its solvates for the prevention, treatment of Parkinson's disease and Z or Parkinson's syndrome for oral administration, and the manufacture of drugs for inhibiting Z or symptom progression Or the use of their prodrugs.
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