JP2006143708A - Medicine for treating neurodegenerative disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine for effectively treating neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis or nervous dysfunction associated with cerebral infarction. <P>SOLUTION: A method for administering (2R)-2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof in combination with other drugs is provided. The method for combined use disclosed herein is extremely effective for prophylaxis, therapy and/or supplementation and/or enhancement of symptom progression inhibitory effects, improvement in drug kinetics and absorption or reduction in dose and adverse effects of the drug or prevention, etc., of development of drug resistance as compared with the case of single use thereof during the prophylaxis, therapy and/or symptom progression inhibition of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease or nervous dysfunction associated with the cerebral infarction. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a medicament for the treatment of neurodegenerative diseases.

  More specifically, (2R) -2-propyloctanoic acid and others for effectively treating neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and neurological dysfunction associated with cerebral infarction In combination with other drugs or treatment methods.

  In recent years, in pharmacotherapy of many diseases, prevention of treatment, supplementation and / or enhancement of treatment and / or symptom progression inhibition effect, improvement of pharmacokinetics / absorption, reduction of drug dose / side effects, or drug resistance Multi-drug combination therapy using a combination of a plurality of drugs having different mechanisms of action for the purpose of preventing expression and the like has been performed.

  By the way, Parkinson's disease is one of the typical neurodegenerative diseases of elderly people whose main symptoms are extrapyramidal abnormalities caused by degeneration and loss of dopamine nerves. The treatment of Parkinson's disease is generally performed by rehabilitation while performing pharmacotherapy, and the pharmacotherapy performed here is mainly dopamine replacement therapy, and a levodopa preparation is essential. However, by administration of levodopa, involuntary movement (dyskinesia), freezing phenomenon (freezing), psychiatric symptoms (excitement, insomnia, hallucinations, delusions, manic depression, etc.), digestive symptoms (nausea, vomiting, etc.), ineffective Wearing that may cause side effects such as stability, and if you continue to administer for a long period of time, depending on the degree of progression of the disease state, the duration of the drug effect will shorten, and if you do not gradually shorten the drug administration interval, seizure will occur Up and down (wearing off) phenomenon, on and off phenomenon in which symptoms suddenly and irregularly improve or worsen, and circadian improvement in exacerbations and exacerbations (up and down) ) It is known that phenomena occur. In addition, it is also known that a delayed on phenomenon that takes a long time to develop a drug effect even when a levodopa preparation is administered, and a no on phenomenon in which no drug effect is observed at all. . Therefore, in order to reduce the dose of levodopa and reduce side effects, a combination of a dopamine receptor agonist, dopamine release promoter, central anticholinergic agent, monoamine oxidase inhibitor, norepinephrine replacement drug, etc. Multi-drug combination therapy is used. In addition, β-receptor blockers and antidepressants may be used in combination with side effects such as arrhythmia, tremor and depression. However, even now, there is no radical treatment for neurodegenerative diseases including Parkinson's disease, and it is difficult to expect a dramatic therapeutic effect even if multidrug combination therapy is performed.

  Alzheimer's disease is a neurodegenerative disease that is thought to be caused by degeneration / dropout of acetylcholine neurons and monoamine neurons, and β amyloid, an endogenous protein, is considered to be a factor causing apoptosis. Acetylcholinesterase inhibitors are mainly used for pharmacotherapy of Alzheimer's disease, but as side effects associated with activation of acetylcholinergic nerves, gastrointestinal side effects such as diarrhea, anorexia, nausea and vomiting are known. In order to avoid these side effects, the so-called titration is started at a low dose at first and then a high dose after a certain period of time. Generally, acetylcholinesterase inhibitors are administered at a high dose. Since the therapeutic effect is higher as much as possible, it is preferable not to perform titration if immediate effect is expected.

  On the other hand, (2R) -2-propyloctanoic acid is useful as a therapeutic agent for neurodegenerative diseases, neurological dysfunction associated with stroke or cerebrospinal trauma, brain tumor, cerebrospinal disease associated with infection, Parkinson's disease, Parkinson's syndrome, etc. It is known (see, for example, Patent Documents 1 and 2).

  Further, it has been reported that these effects of (2R) -2-propyloctanoic acid are due to the function improving action of abnormally activated astrocytes based on the action of reducing the content of intracellular S100B (also referred to as S100β) ( For example, refer nonpatent literature 1).

  This S100B is one of the S100 proteins and is known to be present in high concentrations in glial cells and Schwann cells in the central and peripheral nervous systems, as well as in anterior pituitary cells and Langerhans cells. Since the S100B content in cerebrospinal fluid or blood increases in cerebral infarction, subarachnoid hemorrhage, head trauma, various neurodegenerative diseases, neurological complications after cardiopulmonary bypass surgery, Measuring medium S100 protein content has been reported to be useful in the diagnosis of brain lesions and neurological damage (Stroke, 28, 1956-1060, 1997).

  In addition, a method is known in which (2R) -2-propyloctanoic acid or a salt thereof is used as a therapeutic agent for cerebral ischemic disease together with a thrombolytic agent such as tissue plasminogen activator (see, for example, Patent Document 3). ).

  However, in these patent documents and non-patent documents, there is no description or suggestion regarding the combined use of (2R) -2-propyloctanoic acid and a drug other than a thrombolytic agent. There is no description or suggestion of effects on other diseases.

European Patent Publication No. 06322088 European Patent Publication No. 1174131 International Publication No. 03/007992 Pamphlet Tateishi. N, 8 others, Journal of cerebral blood flow & metabolism, Vol. 22, 723-734, 2002

  The subject of the present invention is an existing technique that has been conventionally used in the prevention, treatment and / or suppression of symptom progression of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and neurological dysfunction associated with cerebral infarction. To supplement and / or enhance drug prevention, treatment and / or symptom progression suppression effects, improve pharmacokinetics / absorption, reduce the dose / side effects of the drug, and prevent the development of drug resistance The object is to provide a medicament for the treatment of neurodegenerative diseases.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors surprisingly combined (2R) -2-propyloctanoic acid with therapeutic agents for various diseases described later, and thereby neurodegeneration. It has been found that remarkable therapeutic effects as described above can be obtained in the treatment of diseases (for example, by combining (2R) -2-propyloctanoic acid, it was observed with repeated administration of levodopa benserazide compound or bromocriptine mesylate Improvement of the wear-off phenomenon was recognized.) Further studies were made based on the findings to complete the present invention.

That is, the present invention
[1] For (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, and for neurodegenerative disease, motor neuropathy, demyelinating disease, cerebrovascular disorder, brain tumor, cerebrospinal trauma A pharmaceutical comprising a combination of a therapeutic agent for one or more diseases selected from the accompanying neurological dysfunction, cerebrospinal disease associated with infection, mental illness, epilepsy, dystonia, diabetes, diabetic complications and hyperlipidemia;
[2] The medicament according to [1] above, which is a combination of (2R) -2-propyloctanoic acid and a therapeutic agent for neurodegenerative diseases;
[3] The medicament according to [2], wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease and / or amyotrophic lateral sclerosis;
[4] The treatment for Parkinson's disease is levodopa, levodopa / benserazide, levodopa / carbidopa and / or bromocriptine mesylate, and the treatment for Alzheimer's disease is donepezil hydrochloride, memantine hydrochloride, rivastigmine tartrate, galantamine and / or Or the drug according to the above [3], which is tacrine and the therapeutic agent for amyotrophic lateral sclerosis is riluzole;
[5] The medicament according to [1] above, comprising a combination of (2R) -2-propyloctanoic acid and a therapeutic agent for cerebrovascular disorder;
[6] The medicament according to the above [5], wherein the cerebrovascular disorder is cerebral infarction;
[7] The medicament according to [6] above, wherein the therapeutic agent for cerebral infarction is alteplase, clopidogrel hydrogensulfate, edaravone and / or ozagrel sodium;
[8] (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, a dopamine receptor agonist, a dopamine release promoter, a dopamine uptake inhibitor, a dopamine agonist, a central anti-drug Choline drugs, aromatic L-amino acid decarboxylase inhibitors, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, norepinephrine supplements, acetylcholinesterase inhibitors, NMDA receptor antagonists, AMPA / kainic acid receptors Antagonist, GABA _A receptor modulator, GABA _B receptor modulator, adenosine A2A receptor blocker, apoptosis inhibitor, neuronal differentiation / regeneration promoter, neurotrophic factor, brain function activator, Rho-kinase inhibitor, Diuretics, β receptor blockers, calcium channel blockers, angiotensin converting enzyme inhibitors Angiotensin II receptor antagonist, sodium channel blocker, potassium channel opener, antiplatelet drug, anticoagulant drug, thrombolytic drug, cyclooxygenase-2 inhibitor, nonsteroidal anti-inflammatory drug, steroid drug, antioxidant drug, A pharmaceutical comprising a combination of at least one selected from immunosuppressants and vitamins;
[9] The medicament according to [1] or [8] above, which is a preventive, therapeutic and / or symptom progression inhibitor for neurodegenerative diseases;
[10] The medicament according to [9] above, wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or neurological dysfunction associated with cerebral infarction;
[11] For (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, and for neurodegenerative disease, motor neuropathy, demyelinating disease, cerebrovascular disorder, brain tumor, cerebrospinal trauma A pharmaceutical composition comprising a combination of a therapeutic agent for one or more diseases selected from the accompanying neurological dysfunction, cerebrospinal disease associated with infection, mental illness, epilepsy, dystonia, diabetes, diabetic complications and hyperlipidemia ;
[12] The pharmaceutical composition according to the above [11], comprising a combination of (2R) -2-propyloctanoic acid and a therapeutic agent for neurodegenerative disease and / or cerebrovascular disorder;
[13] The pharmaceutical composition according to the above [12], wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease and / or amyotrophic lateral sclerosis, and the cerebrovascular disorder is cerebral infarction;
[14] (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, a dopamine receptor agonist, a dopamine release promoter, a dopamine uptake inhibitor, a dopamine agonist, a central anti-drug Choline drugs, aromatic L-amino acid decarboxylase inhibitors, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, norepinephrine supplements, acetylcholinesterase inhibitors, NMDA receptor antagonists, AMPA / kainic acid receptors Antagonist, GABA _A receptor modulator, GABA _B receptor modulator, adenosine A2A receptor blocker, apoptosis inhibitor, neuronal differentiation / regeneration promoter, neurotrophic factor, brain function activator, Rho-kinase inhibitor, Diuretics, β receptor blockers, calcium channel blockers, angiotensin converting enzyme inhibition Drugs, angiotensin II receptor antagonists, sodium channel blockers, potassium channel openers, antiplatelet drugs, anticoagulants, thrombolytic drugs, cyclooxygenase-2 inhibitors, nonsteroidal anti-inflammatory drugs, steroid drugs, antioxidant drugs A pharmaceutical composition comprising a combination of one or more selected from immunosuppressants and vitamins;
[15] The pharmaceutical composition according to [11] or [14] above, which is a preventive, therapeutic and / or symptom progression inhibitor for neurodegenerative diseases;
[16] The pharmaceutical composition according to [15] above, wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or neurological dysfunction associated with cerebral infarction;
[17] A method for preventing, treating and / or suppressing symptom progression in a neurodegenerative disease in a mammal, comprising (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, and a nerve Degenerative disease, motor neuropathy, demyelinating disease, cerebrovascular disorder, brain tumor, neurological dysfunction associated with cerebrospinal trauma, cerebrospinal disease associated with infection, mental illness, epilepsy, dystonia, diabetes, diabetic complications and high fat A method comprising administering to a mammal in combination with a therapeutic agent for one or more diseases selected from blood serum;
[18] A method for preventing, treating and / or suppressing symptom progression in a neurodegenerative disease in a mammal, comprising (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, and dopamine Receptor agonist, dopamine release promoter, dopamine uptake inhibitor, dopamine agonist, central anticholinergic agent, aromatic L-amino acid decarboxylase inhibitor, monoamine oxidase inhibitor, catechol-O-methyltransferase inhibitor Norepinephrine replacement agent, acetylcholinesterase inhibitor, NMDA receptor antagonist, AMPA / kainic acid receptor antagonist, GABA _A receptor modulator, GABA _B receptor modulator, adenosine A2A receptor blocker, apoptosis inhibitor, Neural differentiation / regeneration promoter, neurotrophic factor, brain function activator, Rho-kinase Harmful drugs, diuretics, beta receptor blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, sodium channel blockers, potassium channel openers, antiplatelet drugs, anticoagulants, thrombolysis A method comprising administering to a mammal in combination with one or more selected from drugs, cyclooxygenase-2 inhibitors, non-steroidal anti-inflammatory drugs, steroid drugs, antioxidants, immunosuppressive drugs and vitamins;
[19] (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, and a neurodegenerative disease for producing a preventive, therapeutic and / or symptom progression inhibitor for neurodegenerative disease Motor neuropathy, demyelinating disease, cerebrovascular disorder, brain tumor, neurological dysfunction associated with cerebrospinal trauma, cerebrospinal disease associated with infection, mental illness, epilepsy, dystonia, diabetes, diabetic complications and hyperlipidemia And (20) (2R) -2-propyloctane for the manufacture of a prophylactic, therapeutic and / or symptom progression inhibitor for neurodegenerative diseases Acids, salts thereof, solvates thereof or prodrugs thereof, dopamine receptor agonists, dopamine release promoters, dopamine uptake inhibitors, dopamine agonists, central anticholinergic agents, Aromatic L-amino acid decarboxylase inhibitors, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, norepinephrine supplements, acetylcholinesterase inhibitors, NMDA receptor antagonists, AMPA / kainic acid receptor antagonists, GABA _A receptor modulator, GABA _B receptor modulator, adenosine A2A receptor blocker, apoptosis inhibitor, neuronal differentiation / regeneration promoter, neurotrophic factor, brain function activator, Rho-kinase inhibitor, diuretic, β receptor blocker, calcium channel blocker, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, sodium channel blocker, potassium channel opener, antiplatelet agent, anticoagulant, thrombolytic agent, cyclooxygenase-2 inhibitor Drugs, non-steroidal anti-inflammatory drugs, steroid drugs, Oxidizing agents, the use or the like of a combination of one or more selected from immunosuppressant and vitamins.

  In the present invention, (2R) -2-propyloctanoic acid is a compound represented by the formula (A)

(Where

Represents the β-configuration. )
It is a compound shown by these.

  The salt of (2R) -2-propyloctanoic acid is preferably a non-toxic and water-soluble salt, such as an alkali metal (for example, potassium, sodium, lithium, etc.) salt, an alkaline earth metal (for example, calcium). , Magnesium, etc.), ammonium salts (eg, tetramethylammonium salt, tetrabutylammonium salt, etc.), organic amines (eg, methylamine, dimethylamine, trimethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclopentyl) Amine, benzylamine, phenethylamine, dicyclohexylamine, dibenzylamine, N, N′-dibenzylethylenediamine, tris (hydroxymethyl) methylamine, N-methyl-D-glucamine, pyridine, picoli , Salts with piperidine, etc.), basic amino acids (e.g., arginine, lysine, ornithine, and salts with histidine, etc.). Among these salts, more preferred are, for example, alkali metal salts or salts with basic amino acids, and sodium salts are particularly preferred.

  The solvate of (2R) -2-propyloctanoic acid or a salt thereof is preferably a non-toxic and water-soluble solvate such as water, alcohol solvents (for example, methanol, ethanol, etc.), and the like. Is mentioned.

In the present invention, the prodrug of (2R) -2-propyloctanoic acid is a derivative of (2R) -2-propyloctanoic acid, as used by those skilled in the art, and is enzymatic or chemical in the body. Any compound can be used as long as it is converted to (2R) -2-propyloctanoic acid, and its structure is not particularly limited. Examples of the prodrug of (2R) -2-propyloctanoic acid include compounds in which a carboxy group is esterified (for example, methyl ester, ethyl ester, phenyl ester, carboxymethyl ester of (2R) -2-propyloctanoic acid , Dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester, cyclohexyloxycarbonylethyl ester Etc.), a compound in which the carboxy group is amidated (for example, methylamide, ethylamide, phenylamide, etc. of (2R) -2-propyloctanoic acid), an alcohol form in which carboxylic acid is reduced (for example, (2R) -2- Propyl octano Le) and the like. These compounds can be produced by known methods. In addition, the prodrug of (2R) -2-propyloctanoic acid is (2R) under physiological conditions as described in Yodogawa Shoten 1990, “Drug Development”, Volume 7 “Molecular Design”, pages 163-198. ) It may be changed to 2-propyloctanoic acid. Further, the prodrug of (2R) -2-propyloctanoic acid may be the above-mentioned salt or solvate (for example, solvate such as water, alcohol solvent (for example, ethanol)), etc. It may be labeled with an element (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

  In the present invention, “(2R) -2-propyloctanoic acid, salt, solvate or prodrug thereof” includes (2R) -2-propyloctanoic acid, (2R) -2-propyloctanoic acid. Of (2R) -2-propyloctanoic acid, phenethylamine salt of (2R) -2-propyloctanoic acid, (2R) -2-propyloctanoic acid methyl ester and the like are preferred, and (2R) -2-propyloctanoic acid is more preferred.

  (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof may be obtained by a method known per se, for example, European Patent No. 0632008, International Publication No. 99/58513, International Publication No. 00/48982, pamphlet, patent 3032447, patent 3084345, international publication 03/051852, pamphlet, international publication 04/110972 pamphlet, etc. Or Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Second Edition (Richard C. Larock, John Wiley and Sons Inc, 1999) [Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999) Can be produced by appropriately combining according to the method such as that described, or those methods. The product of the reaction is obtained by conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, column chromatography or washing, recrystallization, etc. Can be purified. Moreover, you may attach | subject to processes, such as freeze-drying, as desired.

  In the present invention, (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof is not limited to a substance that is substantially pure and a single substance, but may contain impurities (for example, production By-products derived from the process, solvents, raw materials, decomposition products, etc.) may be contained as long as they are acceptable as an active pharmaceutical ingredient. 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, Depending on the impurities contained, for example, heavy metals are about 20 ppm or less, optical isomers S is about 5% by mass (preferably about 1.49% by mass), and residual solvents 2-propanol and heptane are total. It is preferably about 5000 ppm or less and the water content is about 0.2 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.

  In the present invention, all isomers are included unless otherwise specified. For example, isomers (R, S form, α, β configuration, enantiomer, diastereomer), optically active form having optical activity (D, L, d, l form), chromatographic separation due to the presence of asymmetric carbon, etc. Polar bodies (high polar bodies, low polar bodies), mixtures of these in arbitrary proportions, and racemic mixtures are all included in the present invention.

  The present invention effectively prevents neurodegenerative diseases by combining the above “(2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof” with “another drug”. Disclosed is a method for treatment and / or suppression of symptom progression (hereinafter sometimes abbreviated as the method of the present invention). In such a method, “a pharmaceutical comprising a combination of (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof and another drug described later” is used.

  In the present invention, “(2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof and another drug described later” (hereinafter abbreviated as the pharmaceutical of the present invention). And (A) (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof (hereinafter sometimes abbreviated as “drug A”), (B) Any drug may be used as long as it is combined with another drug described below (hereinafter sometimes abbreviated as drug B). Drug A and drug B may be a combination of a plurality of drugs. The medicament of the present invention may be one containing drug A and drug B in the same pharmaceutical composition (so-called compounding agent), or may contain drug A and drug B in separate pharmaceutical compositions. Also good. When the drug A and the 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 administering at a time difference, drug A may be administered first and drug B may be administered later, or drug B may be administered first and drug A may be administered later. The administration method and the number of administrations per day may be the same or different. The weight ratio of drug A and drug B is not particularly limited.

  The method of the present invention is intended to prevent, treat and / or suppress the progression of neurodegenerative diseases. Here, the neurodegenerative disease is a nerve cell (central nervous system (for example, cranial nerve, spinal nerve), and / or peripheral nerve (for example, autonomic nervous system (for example, sympathetic nerve, parasympathetic nerve)), motor nervous system, perception It encompasses all diseases with degeneration of the nervous system)) and is not limited by its etiology. Specifically, it may be a disease generally regarded as a neurodegenerative disease, for example, Parkinson's disease, Parkinson's syndrome, striatal nigra degeneration, Huntington's disease, chorea-ataxia, progressive Supranuclear paralysis, diffuse Lewy body disease, basal ganglia degeneration, Alzheimer's disease, senile dementia, Pick's disease, frontotemporal dementia, familial dementia, spinocerebellar degeneration (eg, Olive Bridge) Cerebellar atrophy, late-onset cerebellar cortical atrophy, familial spinocerebellar ataxia (for example, Maccard Joseph disease, etc.), dentate nucleus red nucleus pallidus louis atrophy, familial spastic paraplegia, Friedreich disease Etc.), motor neuropathy (eg, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, etc.), demyelinating diseases (eg, multiple sclerosis, generalized sclerosis, acute disseminated brain) Myelitis, acute cerebellar inflammation, transverse myelitis, Guillain Valley As well as cerebrovascular disorders (eg, stroke, cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), transient cerebral ischemic attack, reperfusion injury, cerebral hemorrhage (eg, hypertensive intracerebral hemorrhage, spider) Etc.), brain tumors (eg, astrocytoma, brain abscess, etc.), blood volume reducing shock, traumatic shock, head injury and / or cerebrospinal trauma (eg, brain contusion, penetration, etc.) Neurological dysfunction associated with shear, compression, laceration, labor trauma, infant whiplash, etc., cerebrospinal disease associated with infection (eg meningitis, influenza encephalopathy, Creutzfeld-Jakob disease, dementia due to AIDS encephalopathy, etc.) ), Toxic substances (arsenic, cadmium, organic mercury, sarin, soman, tabun, VX gas, etc.), neurological dysfunction due to radiation, etc., mental disorders (eg neurosis, psychosomatic disorders, anxiety, schizophrenia, manic depression, etc.) , Epilepsy, image syndrome, dystonia, Down's syndrome, sleep disorders (e.g., hypersomnia, narcolepsy, sleep apnea syndrome, etc.) are also included, and the like.

  The neurodegenerative disease is preferably, for example, Parkinson's disease, Parkinson's syndrome, Huntington's disease, Alzheimer's disease, senile dementia, spinocerebellar degeneration, amyotrophic lateral sclerosis, demyelinating disease (eg, multiple sclerosis) Etc.), cerebrovascular disorder (eg, stroke, cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), transient ischemic attack, cerebral hemorrhage (eg, hypertensive intracerebral hemorrhage, subarachnoid hemorrhage, etc.), brain tumor -Neurological dysfunction associated with traumatic shock, head injury and / or cerebrospinal trauma (eg cerebral contusion, etc.), cerebrospinal disease associated with infection (eg meningitis, influenza encephalopathy, Creutzfeld-Jakob disease, Dementia due to AIDS encephalopathy), epilepsy and the like, more preferably, for example, Parkinson's disease, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, cerebrovascular Neurological dysfunction associated with harm (eg, stroke, cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), transient cerebral ischemic attack, cerebrospinal disease associated with infection (eg, meningitis, influenza encephalopathy, Creutzfeld-Jakob disease, dementia due to AIDS encephalopathy, etc.), epilepsy and the like, particularly preferably, for example, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, or neurological dysfunction associated with cerebral infarction.

  The method of the present invention can also prevent, treat and / or suppress symptom progression even in neurological dysfunction. The neurological dysfunction may be any neurological dysfunction. For example, consciousness disorder, bilateral limb paralysis, contralateral hemiplegia, alternating hemiplegia, sensory disturbance, transient Blindness (for example, transient cataract etc.), homonymous half-blindness, dizziness, nystagmus, double vision, aphasia, tinnitus, coma and the like. Preferably, these are neurological dysfunctions associated with the neurodegenerative diseases. The neurological dysfunction associated with the above-mentioned neurodegenerative diseases, for example, neurological dysfunction associated with cerebral infarction varies depending on the site of vascular occlusion, and the symptoms vary depending on the level to be impaired. It can be seen. In addition, the presence or absence of neurological dysfunction in cerebral infarction may be determined by various diagnostic tests known in the art for detecting neurological dysfunction. Specific examples of the diagnostic test include, for example, Glasgow Outcome Scale (GOS), Glasgow Coma Scale (GCS), Rankin Scale (RS), Modified Rankin Scale (modified Rankin) Scale: mRS), disability rating scale (DRS), NIH Stroke Scale (NIHSS), and the like, which can be performed using known methods. These diagnostic tests for detecting neurological dysfunction may be performed in appropriate combination with a test method for detecting physical brain abnormalities, for example, CAT scan, intracranial pressure measurement, or the like.

In the method of the present invention, (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or another drug combined with a prodrug thereof may be, for example, a cerebrovascular disorder (for example, stroke, cerebral infarction ( For example, cerebral thrombus, cerebral embolism, etc.), transient cerebral ischemic attack, reperfusion injury, cerebral hemorrhage (eg hypertensive intracerebral hemorrhage, subarachnoid hemorrhage, etc.), brain tumor (eg, astrocytoma, brain Abscesses, etc.) ・ Neural blood loss shock, traumatic shock, head injury and / or cerebrospinal trauma (eg, brain contusion, penetration, shear, compression, laceration, labor trauma, infant whiplash sway syndrome) Dysfunction, neurodegenerative diseases (eg Parkinson's disease, Parkinson's syndrome, striatal nigra degeneration, Huntington's disease, chorea-ataxia, progressive supranuclear palsy, diffuse lewy Somatic disease, basal ganglia degeneration, Alzheimer's disease, senile dementia, Pick's disease, frontotemporal lobar dementia, familial dementia, spinocerebellar degeneration (eg, Olive Bridge cerebellar atrophy, late cerebellum Cortical atrophy, familial spinocerebellar ataxia (eg, Maccard Joseph disease, etc.), dentate nucleus red nucleus pallidal atrophy, familial spastic paraplegia, Friedreich disease, etc.) Remedy for motor neuropathy (eg, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, etc.), demyelinating diseases (eg, multiple sclerosis, general sclerosis, acute disseminated brain Drugs for myelitis, acute encephalitis, transverse myelitis, Guillain-Barre syndrome, etc., cerebrospinal diseases associated with infections (eg meningitis, influenza encephalopathy, Creutzfeld-Jakob disease, dementia due to AIDS encephalopathy, etc.) ) Remedies, poisons (arsenic, cadmium, organic water) , Sarin, soman, tabun, VX gas, etc.) ・ treatment for neurological dysfunction due to radiation, etc., treatment for mental disorders (eg, neurosis, psychosomatic disorders, anxiety, schizophrenia, manic depression, etc.), epilepsy Therapeutic, mage syndrome, dystonia, Down's syndrome and / or sleep disorders (eg, hypersomnia, narcolepsy, sleep apnea syndrome, etc.), diabetes, diabetes complications Remedy and / or hyperlipidemia, dopamine receptor agonist (dopamine receptor stimulant), dopamine release promoter (dopamine secretion promoter or dopamine release promoter), dopamine uptake inhibitor, dopamine action Drugs, central anticholinergic drugs, aromatic L-amino acid decarboxylase inhibitors (DCI), monoamine oxidase (MAO-B) inhibitors, catechol-O-methyltolane Spherase (COMT) inhibitor, norepinephrine (noradrenaline) supplement, acetylcholinesterase inhibitor, NMDA (N-methyl-D-aspartate) receptor antagonist, AMPA (2-amino-3- (methyl-3-hydroxyiso) Oxazol-4-yl) propanoic acid) / kainic acid receptor antagonist, GABA _A receptor modulator (eg, GABA _A receptor agonist), GABA _B receptor modulator, adenosine A2A receptor blocker, nicotine Receptor modulator, neuronal nitric oxide synthase (n-NOS) inhibitor, β amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitor (eg, β secretase inhibitor, γ secretase inhibitor) , Β amyloid protein aggregation inhibitor, β amyloid degrading enzyme, β amyloid vaccine, etc.) Apoptosis inhibitor, neuronal differentiation / regeneration promoter, neurotrophic factor (eg, neurotrophin, TGF-β superfamily, neurokine family, growth factor, etc.), other brain function activator (eg, brain metabolism activator, Cerebral circulation improving drugs, etc.), Rho-kinase inhibitors, diuretics (eg thiazide diuretics, loop diuretics, potassium-sparing diuretics, etc.), β receptor blockers, calcium channel blockers (calcium antagonists) , Angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor antagonist, sodium channel blocker, potassium channel opener, antiplatelet agent, anticoagulant, thrombolytic agent, thromboxane A ₂ synthase inhibitor, matrix metallo Proteinase (MMP) inhibitor, cyclooxygenase (COX) -2 inhibitor, Teloidal anti-inflammatory drugs, steroid drugs, antioxidant drugs, vitamins, disease-modifying anti-rheumatic drugs, anti-cytokine drugs (eg, TNF inhibitors, MAP kinase inhibitors, etc.), sex hormones or derivatives thereof (eg, progesterone, Estradiol, estradiol benzoate, etc.), parathyroid hormone (eg, PTH, etc.) and calcium receptor antagonists.

Other preferable drugs include, for example, cerebrovascular disorders (eg, stroke, cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), transient ischemic attacks, cerebral hemorrhage (eg, hypertensive intracerebral hemorrhage, subarachnoid hemorrhage) Etc.), therapeutic agents for brain tumors, therapeutic agents for neurological dysfunction associated with cerebrospinal trauma (eg, cerebral contusion, etc.), neurodegenerative diseases (eg, Parkinson's disease, Parkinson's syndrome, Huntington's disease, Alzheimer's disease, Therapeutic agents for senile dementia, spinocerebellar degeneration, etc., therapeutic agents for motor neuropathy (eg, amyotrophic lateral sclerosis, etc.), therapeutic agents for demyelinating diseases (eg, multiple sclerosis, etc.), Therapeutic agents for cerebrospinal diseases associated with infections (eg meningitis, influenza encephalopathy, Creutzfeldt-Jakob disease, dementia due to AIDS encephalopathy), mental disorders (eg neurosis, psychosomatic disorders, anxiety, schizophrenia, Manic depression ), Epilepsy, dystonia, diabetes, diabetic complications and / or hyperlipidemia, dopamine receptor agonist, dopamine release promoter, 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) supplement, acetylcholinesterase inhibitor, NMDA (N-methyl-D-aspartate) receptor antagonist, AMPA (2-amino-3- (methyl-3-hydroxyisoxazol-4-yl) propane Acid) / kainate receptor antagonist, GABA _A receptor modulator (eg, GABA _A receptor production) Kinematics, etc.), GABA _B receptor modulators, adenosine A2A receptor blockers, β secretase inhibitors, β amyloid protein aggregation inhibitors, apoptosis inhibitors, neuronal differentiation / regeneration promoters, neurotrophic factors (eg neurotrophic) Fin, TGF-β superfamily, neurocaine family, growth factor, etc.), other brain function activators (eg, cerebral metabolic activators, cerebral circulation improvers, etc.), Rho-kinase inhibitors, diuretics (eg, thiazide) System diuretics, loop diuretics, potassium-sparing diuretics, etc.), beta receptor blockers, calcium channel blockers (calcium antagonists), angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, sodium channels Blockers, potassium channel openers, antiplatelet drugs, anticoagulants, thrombolytics, cyclooxygen And steroid (COX) -2 inhibitors, non-steroidal anti-inflammatory drugs, steroid drugs, antioxidants and vitamins, more preferably, for example, treatment of cerebrovascular disorders (eg, stroke, cerebral infarction, etc.) Drugs, therapeutic agents for neurological dysfunction associated with cerebrospinal trauma (eg, cerebral contusion, etc.), therapeutic agents for neurodegenerative diseases (eg, Parkinson's disease, Parkinson's syndrome, Huntington's disease, Alzheimer's disease, senile dementia, etc.), muscle atrophy Treatment of multiple lateral sclerosis, treatment of multiple sclerosis, treatment of mental disorders (eg neurosis, psychosomatic disorders, anxiety, schizophrenia, manic depression, etc.), treatment of epilepsy and / or Dystonia treatment, diabetes treatment, diabetic complications and / or hyperlipidemia treatment, dopamine receptor agonist, dopamine release promoter, dopamine uptake inhibitor, dopamine production Drugs, central anticholinergic drugs, aromatic L-amino acid decarboxylase inhibitors (DCI), monoamine oxidase (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, norepinephrine (noradrenaline) supplementation Drug, acetylcholinesterase inhibitor, NMDA (N-methyl-D-aspartate) receptor antagonist, β secretase inhibitor, β amyloid protein aggregation inhibitor, apoptosis inhibitor, neuronal differentiation / regeneration promoter, neurotrophic factor ( For example, neurotrophin, TGF-β superfamily, neurocaine family, growth factor, etc.), other brain function activators (eg, brain metabolism activators, cerebral circulation improvers, etc.), β receptor blockers, calcium channels Blocker (calcium antagonist), angiotensin converting enzyme (ACE) Examples include harmful drugs, angiotensin II receptor antagonists, antiplatelet drugs, anticoagulants, and thrombolytic drugs, and particularly preferably, for example, therapeutic drugs for cerebrovascular disorders (eg, stroke, cerebral infarction, etc.), neurodegenerative diseases (For example, Parkinson's disease, Parkinson's syndrome, Huntington's disease, Alzheimer's disease, etc.), amyotrophic lateral sclerosis, multiple sclerosis, epilepsy and / or diabetic complications Therapeutic agent, dopamine receptor agonist, dopamine release promoter, dopamine uptake inhibitor, dopamine agonist, central anticholinergic agent, aromatic L-amino acid decarboxylase inhibitor (DCI), monoamine oxidase (MAO-B) ) Inhibitors, catechol-O-methyltransferase (COMT) inhibitors, norepinephrine (noradrenaline) supplements, ACE Le cholinesterase inhibitors, neurotrophic factors and other brain function activation agents.

  In the present invention, the term “therapeutic agent” and “therapeutic agent” refers to a “progressive agent” that suppresses the progression of the disease state and suppresses the progression of the disease state, in addition to the so-called “therapeutic agent” and “therapeutic agent” that leads the disease state in the direction of healing. "Progress prevention agents", and also includes "prophylactic agents" and "preventive agents" that prevent the onset of the disease itself.

  In the present invention, as a therapeutic agent for stroke, for example, alteplase, argatroban, citicoline, clopidogrel hydrogen sulfate, DMP-647, dipyridamole, idebenone , Indobufen, monosialoganglioside GM1 (monosialoganglioside GM1), nimodipine, propentofylline, triflusal, monteplase, aspirin, nicotinic acid Abciximab, atorvastatin calcium, cilostazol, tinzaparin sodium, tirilazad mesylate, ximelagatlan ran), NXY-059, nalmefene, drotrecogin alfa, trafermin, ziconotide, CRL-5861, crobenetine, CS-747, odiparcil, UK -279276, desmoteplase, repinotan hydrochloride, enrasentan, zonampanel, LJP-1082, DP-b99, S-0139, Bay-59-7939, SGS-111, pamiteplase ), Eptotermin-α (eptotermin alfa), tacrolimus, dexanabinol, BB-10153, EN-100, delucemine hydrochloride, MLN-519, SB-249417, NV-04, Mi Microplasmin, Bay-44-2041, S-1746, E-2051, TS-011, ethyl icosapentate, sodium ozagrel, beraprost sodium, alprostadil Ticlopidine hydrochloride, sarpogrelate hydrochloride, warfarin (eg, warfarin potassium), heparin (eg, heparin sodium, heparin calcium), antithrombin drug ( For example, antithrombin III, hirudin), urokinase, nasaruplase, prourokinase, tissue plasminogen activator ( Examples include t-PA, plasminogen activator, tisokinase, nateplase, and streptokinase. As a therapeutic agent for stroke, preferably, for example, alteplase, argatroban, citicoline, clopidogrel hydrogen sulfate, DMP-647, dipyridamole, idebenone, indobufen (idebenone) indobufen), monosialoganglioside GM1 (monosialoganglioside GM1), nimodipine, propentofylline, triflusal, monteplase, aspirin, nicotinic acid, abiximab ), Atorvastatin calcium, cilostazol, tinzaparin sodium, tirilazad mesylate, ximelagatran, N XY-059, nalmefene, drotrecogin alfa, trafermin, ziconotide, CRL-5861, crobenetine, CS-747, odiparcil, UK-279276, Desmoteplase, repinotan hydrochloride, enrasentan, zonampanel, LJP-1082, DP-b99, S-0139, Bay-59-7939, SGS-111, pamiteplase, sodium ozagrelase More preferably, for example, alteplase, argatroban, citicoline, clopidogrel hydrogen sulfate, DMP-647, dipyridamo Dipyridamole, idebenone, indobufen, monosialoganglioside GM1, monosialoganglioside GM1, nimodipine, propentofylline, triflusal, monteplase, inspirin ), Nicotinic acid, sodium ozagrel.

  In the present invention, therapeutic agents for cerebral infarction include, for example, alteplase, citicoline, edaravone, ibudilast, triflusal, cilostazol, nicaraven, Examples thereof include clopidogrel hydrogen sulfate, sodium ozagrel, EAA-90, SUN-N4057, SUN-N8075, and BGC-728. Preferred therapeutic agents for cerebral infarction are, for example, alteplase, citicoline, edaravone, ibudilast, triflusal, cilostazol, nicaraven, clopidogrel hydrogensulfate (Clopidogrel hydrogen sulfate), sodium ozagrel, EAA-90, SUN-N4057, and more preferably, for example, alteplase, citicoline, edaravone, ibudilast, triflusar (Triflusal), cilostazol, nicaraven, sodium ozagrel.

  In the present invention, therapeutic agents for cerebral thrombosis include, for example, ozagrel, sodium ozagrel, ticlopidine, ticlopidine hydrochloride, fasudil, cilostazol, and monteplase. , Aspirin, ethyl icosapentate, beraprost sodium, alprostadil, dipyridamole, sarpogrelate hydrochloride, warfarin potassium (eg warfarin potassium) ), Heparin (eg heparin sodium, heparin calcium), antithrombin drugs (eg antithrommbin III, argatroban) (Argatroban), hirudin), urokinase, nasalplase (nasaruplase, prourokinase), tissue plasminogen activator (t-PA), tisokinase, alteplase, alteplase, nateplase), streptokinase, and pamiteplase. Preferably, as a therapeutic agent for cerebral thrombosis, for example, ozagrel, sodium ozagrel, ticlopidine, ticlopidine hydrochloride, fasudil, tissue plasminogen activator (t-PA), Alteplase.

  In the present invention, as a therapeutic agent for subarachnoid hemorrhage, for example, monosialoganglioside GM1 (monosialoganglioside GM1), tirilazad mesylate, nicaraven, sodium ozagrel, clazosentan, bosentan (Bosentan). As a therapeutic agent for subarachnoid hemorrhage, for example, monosialoganglioside GM1 (monosialoganglioside GM1), tirilazad mesylate, nicaraven, sodium ozagrel, clazosentan is more preferable. Are, for example, monosialoganglioside GM1, tirilazad mesylate, nicaraven, sodium ozagrel.

  In the present invention, as a therapeutic agent for Parkinson's disease and / or Parkinson's syndrome, for example, levodopa (L-dopa), levodopa benserazide (levodopa + benserazide, for example, levodopa benserazide (4: 1) combination ), Levodopa carbidopa formulation (levodopa + carbidopa), entacapone levodopa carbidopa formulation (entacapone + levodopa + carbidopa), melevodopa (melevodopa), melevodopa carbidopa formulation (melevodopa + carbidopa), bromocryptine mesylate ), Α-dihydroergocryptine, apomorphine, budipine, cabergoline, droxidopa, entacapone, lisuride, pergolide mesylate ) Piribedil, pramipexole, pramipexole hydrochloride hydrate, ropinirole hydrochloride, ropinirole, selegiline, deprenil, terguride, terguride tolcapone, rasagiline mesylate, talipexole, amantadine hydrochloride, trihexyphenidyl hydrochloride, biperiden, piroheptine hydrochloride, mazaticol hydrochloride ), Metixene hydrochloride, profenamine, riluzole, zonisamide, CEP-1347, safinamide, rotigotine (r) otigotine, NS-2330, sumanirole, etilevodopa, modafinil, olanzapine, bifeprunox, TCH-346, sarizotan hydrochloride, GDNF, istradefylin ), 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, VR-2006, PYM-50028, CERE-120, P63, MITO-4509, NLX-XI, safrazine, Examples include remacemide, lazabemide, mofegiline, other ergot alkaloid derivatives, and CGP-28014. As a therapeutic agent for Parkinson's disease and / or Parkinson's syndrome, for example, levodopa (L-dopa), levodopa benserazide (eg levodopa + benserazide, eg levodopa benserazide (4: 1)), levodopa・ Carbidopa formulation (levodopa + carbidopa), Entacapone, levodopa, carbidopa formulation (entacapone + levodopa + carbidopa), Melevodopa, melevodopa, carbidopa formulation (melevodopa + carbidopa), Bromocryptine mesylate (bromocryptine mesylate) -Dihydroergocryptine, apomorphine, budipine, cabergoline, droxidopa, entacapone, lisuride, pergolide mesylate, pergolide mesylate Piribedil, pramipexole, pramipexole hydrochloride hydrate, ropinirole hydrochloride, ropinirole, selegiline, terguride, tolcapone, mesylic acid Rasagiline (rasagiline mesylate), Talipexole, amantadine hydrochloride, trihexyphenidyl hydrochloride, biperiden, piroheptine hydrochloride, mazaticol hydrochloride, machiticol hydrochloride metixene hydrochloride), profenamine, riluzole, zonisamide, CEP-1347, safinamide, rotigotine, NS-2330, Nirol (sumanirole), etilevodopa, modafinil, olanzapine, bifeprunox, TCH-346, sarizotan hydrochloride, GDNF, istradefylline, panel Leteprinim potassium, GPI-1485, altinicline, Spheramine, ACP-103, SLV-308, Sch-63390, E-2007, SR-57667, fipamezole, BIA -202, AVE-1625, DAR-0100, and more preferably, for example, levodopa (L-dopa), levodopa + benserazide (eg levodopa benserazide (4: 1)) Arrangement Agent), levodopa carbidopa combination agent (levodopa + carbidopa), entacapone levodopa carbidopa combination agent (entacapone + levodopa + carbidopa), melevodopa (melevodopa), melevodopa carbidopa combination agent (melevodopa + carbidopa), bromocryptine mesilate mesylate), alpha-dihydroergocryptine, apomorphine, budipine, cabergoline, droxidopa, entacapone, lisuride, pergolide mesylate mesylate, piribedil, pramipexole, pramipexole hydrochloride hydrate, ropinirole hydrochloride, ropinirole, selegiline, terguride (ter guride, tolcapone, rasagiline mesylate, talipexole, amantadine hydrochloride, trihexyphenidyl hydrochloride, biperiden, pyroheptine hydrochloride, piroheptine hydrochloride Mazaticol hydrochloride, metixene hydrochloride, and profenamine. Particularly preferably, levodopa (levodopa, L-dopa), levodopa benserazide combination agent (levodopa + benserazide, for example, levodopa benserazide (4: 1) combination agent), levodopa carbidopa combination agent (levodopa + carbidopa), mesylic acid Bromocryptine mesylate, alpha-dihydroergocryptine, cabergoline, droxidopa, pergolide mesylate, pramipexole, pramipexole hydrochloride hydrate (pramipexole hydrochloride) ), Selegiline, talipexole, amantadine hydrochloride, trihexyphenidyl hydrochloride.

  In the present invention, examples of the therapeutic agent for Huntington's disease include riluzole, LAX-101, tetrabenazine, olanzapine, and glatiramer acetate. A preferred therapeutic agent for Huntington's disease is riluzole.

  In the present invention, the therapeutic agent for chorea includes, for example, taltirelin, NS-2330, T-2000, and talampanel. A preferable therapeutic agent for chorea is, for example, taltirelin.

  In the present invention, as a therapeutic agent for Alzheimer's disease, for example, α-dihydroergocryptine, donepezil hydrochloride, fraction F (Fraction F), galantamine, indeloxazine ), Memantine hydrochloride, nicergoline, nicergoline, phosphatidylserine, rivastigmine tartrate, ST-200, tacrine, cerebrolysin, huperzine A (Nefiracetam), celecoxib, olanzapine, neramexane, NS-2330, xaliproden hydrochloride, phenserine, statins, anapos Anapos, dronabinol, atorvastatin calcium, cevimeline hydrochloride, ethyl icosapentate, modafinil, rosiglitazone maleate, lovastatin, Rasagiline mesylate, R-flurbiprofen, EGb-761, AMPAlex, TCH-346, ganstigmine hydrochloride, colostrinin, nitroflurbiprofen Coluracetam, N-acetylcysteine, NC-531, S-8510, T-588, T-82, MEM-1003, IQ-201, ABT-089, iodochlorohydroxyl (Iodochlorhydroxyquin), SL-65.0155, SR-57667, SGS-742, leuprolide acetate, Ketasyn, PYM-50028, c-9136, AVE-1625, CPI-1189, EN-100, CERE-110, P58, PPI-1019, ladostigil hemitartrate, SB-399885, amyloid inhibiting peptides, GT-1061, ZT-1, MEM-1414, LY-450108, MIT-4509, AAB-001, c-7617, R-1485, R-1500, GSK-742457, zanapezil (TAK-147), aniracetam, idebenone, vinpocetine. As a therapeutic agent for Alzheimer's disease, for example, α-dihydroergocryptine, donepezil hydrochloride, fraction F (Fraction F), galantamine, indeloxazine, hydrochloric acid Memantine hydrochloride, nicergoline, phosphatidylserine, rivastigmine tartrate, ST-200, tacrine, cerebrolysin, huperzine A, nefiracetam Celecoxib, olanzapine, neramexane, NS-2330, xaliproden hydrochloride, phenserine, statins, anapos Dronabinol, atorvastatin calcium, cevimeline hydrochloride, ethyl icosapentate, modafinil, rosiglitazone maleate, lovastatin, rasagiline mesylate (Rasagiline mesylate), R-flurbiprofen (R-flurbiprofen), EGb-761, AMPAlex, TCH-346, ganstigmine hydrochloride (Cosstrinin), nitroflurbiprofen (nitroflurbiprofen), collucetam ( coluracetam), N-acetylcysteine, NC-531, S-8510, T-588, T-82, MEM-1003, IQ-201, ABT-089, iodochlorohydroxyquine (iodochlo) rhydroxyquin), SL-65.0155, SR-57667, SGS-742, leuprolide acetate, Ketasyn, PYM-50028, c-9136, AVE-1625, more preferably, for example, α -Dihydroergocryptine, donepezil hydrochloride, fraction F, galantamine, indeloxazine, memantine hydrochloride, nicergoline, phosphatidyl Serine (phosphatidylserine), rivastigmine tartrate, ST-200, tacrine, cerebrolysin, hyperzine A, nefiracetam.

  In the present invention, therapeutic agents for senile dementia include, for example, ST-200, zuclopenthixol acetate, zuclopenthixol decanoate, cerebrolysin, nefiracetam ( nefiracetam), rivastigmine tartrate, nebostinel, P58, LX-104. Preferably, as a therapeutic agent for senile dementia, for example, ST-200, zuclopenthixol acetate, zuclopenthixol decanoate, cerebrolysin, nefiracetam, Rivastigmine tartrate, more preferably, for example, ST-200, zuclopenthixol acetate, zuclopenthixol decanoate, cerebrolysin, nefiracetam ( nefiracetam).

  In the present invention, as a therapeutic agent for amyotrophic lateral sclerosis, for example, riluzole, edaravone, arimoclomol, xaliproden hydrochloride, TCH-346, superoxide dismutase (superoxide) dismutase), pentoxifylline, PYM-50018, EHT-0202, FP-0011, gabapentin, neurotrophic factor, mecasermin. Preferably, as a therapeutic agent for amyotrophic lateral sclerosis, for example, riluzole, edaravone, arimoclomol, xaliproden hydrochloride, TCH-346, superoxide dismutase, Pentoxifylline, more preferably, for example, riluzole.

  In the present invention, as a therapeutic agent for multiple sclerosis, for example, glatiramer acetate, interferon, baclofen, cannabis, corticotropin, mitoxantrone, Natalizumab, teriflunomide, alemtuzumab, daclizumab, dronabinol, levetiracetam, pirfenidone, abatacept F ABT-874, Anapos, NeuroVax, AnergiX, tiplimotide, laquinimod, TR-14035, E-2007, BX-471, mesoprum (me sopram), MBP-8298, Tovaxin, AVE-9897, Aimspro, ibudilast, alefacept, leflunomide, immunoglobulin, AGT-1, fluasterone ), MLN-3897, interferon receptor, ISIS-107248, interleukin-4, EMZ-701, AZD-4750, CNTO-1275, cladribine, T-0047, c- 6448. As a therapeutic agent for multiple sclerosis, for example, glatiramer acetate, interferon, baclofen, corticotropin, mitoxantrone, natalizumab, teriflunomide (teriflunomide) ), Alemtuzumab, daclizumab, dronabinol, levetiracetam, pirfenidone, abatacept, FTY-720, fampridine, AB-74 ), NeuroVax, AnergiX, tiplimotide, laquinimod, TR-14035, E-2007, BX-471, mesoram, MBP-8298, G Toxaxin, AVE-9897, Aimspro, and more preferably, for example, glatiramer acetate, interferon, baclofen, corticotropin, mitoxantrone ).

  In the present invention, the therapeutic agents for meningitis include, for example, ABLC, amphotericin B, cefozopran, cefpirome, fluconazole, hemophilus vaccine, meropenem ( meropenem), pneumococcal vaccine, opebecan, pleconaril, interferon, ravuconazole, SPD-703. As a therapeutic agent for meningitis, preferably, for example, ABLC, amphotericin B (cehotozopran), cefozopran (cefpirome), fluconazole (fluconazole), hemophilus vaccine (Haemophilus vaccine), meropenem, Pneumococcal vaccine, opebecan, pleconaril, interferon, rabuconazole, more preferably, for example, ABLC, amphotericin B, cefozopran, They are cefpirome, fluconazole, hemophilus vaccine, meropenem, pneumococcal vaccine.

  In the present invention, examples of the therapeutic agent for Creutzfeld-Jakob disease include sodium pentosan polysulfate sodium.

  In the present invention, examples of the therapeutic agent for dementia caused by AIDS encephalopathy include lexipafant, memantine hydrochloride, and CPI-1189.

  In the present invention, examples of the therapeutic agent for neurosis include TJ-15.

  In the present invention, the therapeutic agents for psychosomatic diseases include, for example, bromperidol, fltoprazepam, olanzapine, sultopride, sodium valproate, ziprasidone, Clopentixol (zuclopenthixol), zuclopenthixol acetate, zuclopenthixol decanoate, quetiapine fumarate fumarate, risperidone, prochlorperazine maleate (Prochlorperazine maleate), aripiprazole (aripiprazole), topiramate (topiramate), zonisamide (zonisamide), ACP-103, nebostinel (nebostinel), avaperidone hydrochloride (abaperidone hydrochloride), SLV-319, LU-31-130 . Preferable therapeutic agents for psychosomatic disorders include, for example, bromperidol, fltoprazepam, olanzapine, sultopride, valproate semisodium, ziprasidone, zuclopentiki Sole (zuclopenthixol), zuclopenthixol acetate, zuclopenthixol decanoate, quetiapine fumarate, risperidone, prochlorperazine maleate (prochlorperazine maleate) ), Aripiprazole, topiramate, zonisamide, more preferably bromperidol, fltoprazepam, olanzapine, sultopr, for example. ide), sodium valproate (valproate semisodium), ziprasidone, zuclopenthixol acetate, zuclopenthixol acetate, zuclopenthixol decanoate decanoate, fumaric acid Quetiapine (quetiapine fumarate), risperidone (risperidone), prochlorperazine maleate, and aripiprazole.

  In the present invention, examples of the anti-anxiety agents include fltoprazepam (flutoprazepam), diazepam (diazepam), lorazepam (lorazepam), bromazepam (bromazepam), prazepam, prothiazepam (clotiazepam), oxazepam (oxazepam), fludiazepam (fluzeazepam). fludiazepam, medazepam, chlordiazepoxide, alprazolam, etizolam, fluutazolam, mexazolam, cloxazolam, dioxazolam, epazolamium ), Ethyl loflazepate, and tandospiron citrate.

  In the present invention, the therapeutic agents for schizophrenia include, for example, amisulpride, aripiprazole, clozapine, nemonapride, olanzapine, perospirone, quetiapine fumarate fumarate), risperidone, talipexole, ziprasidone, zotepine, zuclopenthixol, zuclopenthixol acetate, zuclopenthixol acetate, zuclopenthixol decanoate (Zuclopenthixol decanoate), sertindole (sertindole), blonanserin (blonanserin), asenapine maleate (asenapine maleate), bifeprunox (bifeprunox), pramipexole (pramipexole), secretin, LAX-101, AMPAl ex, dexefaroxan, NE-100, ocaperidone, osanetant, osanetant, talnetant, SM-13396, eplivanserin, uridine, palindore fumarate ), Org-24448, SLV-313, SLV-310, ABT-089, D-serine, avaperidone hydrochloride, SB-399885, SSR-125047, EMR-62218, AVE-5997EF, ACR-16, TC-1698, SSR-146977, GSK-773812, GSK-742457, GSK-644784, and iloperidone are mentioned. Preferably, as a therapeutic drug for schizophrenia, for example, amisulpride, aripiprazole, clozapine, nemonapride, olanzapine, perospirone, quetiapine fumarate, Risperidone, talipexole, ziprasidone, zotepine, zuclopenthixol, zuclopenthixol acetate, zuclopenthixol acetate, zuclopenthixol decanoate ), Sertindole, blonanserin, asenapine maleate, bifeprunox, pramipexole, secretin, LAX-101, AMPAlex, de Xeffaroxan, NE-100, ocaperidone, osanetant, talnetant, SM-13396, eplivanserin, uridine, palindore fumarate, Org-24448, SLV-313, SLV-310, ABT-089, D-serine, more preferably, for example, amisulpride, aripiprazole, clozapine, nemonapride ( nemonapride, olanzapine, perospirone, quetiapine fumarate, risperidone, talipexole, ziprasidone, zotepine, zuclopenthixol, zuclopenthixol vinegar Zuclopenthixol (zuclopenthixol acetate), decanoic acid zuclopenthixol (zuclopenthixol decanoate), a sertindole (sertindole).

  In the present invention, for example, olanzapine, sodium valproate (valproate semisodium), quetiapine fumarate fumarate, risperidone, aripiprazole, ziprasidone, lithium (Lithium), topiramate. As a therapeutic agent for gonorrhea, for example, olanzapine, sodium valproate (valproate semisodium), quetiapine fumarate, risperidone, aripiprazole, ziprasidone, lithium It is.

  In the present invention, the therapeutic agent for depression includes, for example, escitalopram oxalate oxalate, alprazolam, amisulpride, amoxapine, bupropion, carbamazepine, citalopram bromate (Citalopram hydrobromide), dihydroergocryptine, fluoxetine, fluvoxamine, lithium, mianserin, milnacipran, minaprine, mirtazapine, Moclobemide, nefazodone hydrochloride, paroxetine, pirlindole, reboxetine, ST-200, sertraline, tianeptine tianeptine, trazodone, venlafaxine, fluoxetine + olanzapine (fluoxetine + olanzapine), olanzapine, lamotrigine, bilcoat (Virucort), duloxetine hydrochloride, selegiline (elegin) ), Gepirone-ER, imipramine hydrochloride, amitriptyline, trimipramine, clomipramine, nortriptyline, lofepramine, maprotiline, cetipline setiptiline), dosulepin, nomifensine, agomelatine, netamiftide, asenapine maleate, SR-58611, LA -101, DVS-233, mifepristone, ODS-II, quetiapine fumarate, levetiracetam, pramipexole, topiramate, vilazodone, enol-3- IPA (Enol-3-IPA), OPC-14523, carabersat, eplivanserin, saledutant, YKP10A, AR-A2, DOV-216303, triacetyluridine, (R) -sibutramine (R) -673, Org-34517, GW-597599, GW-353162, licarbazepine, SLV-308, SPD-421, isovaleramide, Org-24448 , Nebostine (Nebostinel), SA-4503, LX-105, SNE-2, NBI-34041, SSR-149415, SSR-146777, DOV-21947, R-1204, PRX-00023, Lu-AA-21004, GSK-679769, GSK-832396 may be mentioned. As a therapeutic agent for depression, for example, escitalopram oxalate oxalate, alprazolam, amisulpride, amoxapine, bupropion, carbamazepine, citalopram hydrobromide bromide ), Dihydroergocryptine, fluoxetine, fluvoxamine, lithium, mianserin, milnacipran, minaprine, mirtazapine, moclobemide ), Nefazodone hydrochloride, paroxetine, pirlindole, reboxetine, ST-200, sertraline, tianeptine , Trazodone, venlafaxine, fluoxetine + olanzapine (fluoxetine + olanzapine), olanzapine (lamanzagine), bilcoat (Virucort), duloxetine hydrochloride (duloxetine hydrochloride), selegiline (sele) Gepirone-ER, imipramine hydrochloride, amitriptyline, trimipramine, clomipramine, nortriptyline, lofepramine, maprotiline, titipiline ip , Dosulepin, nomifensine, agomelatine, netamiftide, asenapine maleate, SR-58611, LAX-10 , DVS-233, mifepristone, ODS-II, quetiapine fumarate, levetiracetam, pramipexole, topiramate, vilazodone, enol-3-IPA ( Enol-3-IPA), OPC-14523, carabersat, eplivanserin, saledutant, YKP10A, AR-A2, DOV-216303, triacetyluridine, (R ) -Sibutramine (R) -673, Org-34517, GW-597599, GW-353162, licarbazepine, SLV-308, more preferably, for example, escitalopram oxalate oxalate ), Alprazo Alprazolam, amisulpride, amoxapine, bupropion, carbamazepine, citalopram hydrobromide, dihydroergocryptine, fluoxetine, fluoxetine, fluoxetine , Lithium, mianserin, milnacipran, minaprine, mirtazapine, moclobemide, nefazodone hydrochloride, paroxetine, pirlindole , Reboxetine, ST-200, sertraline, tianeptine, trazodone, venlafaxine, fluoxetine + olanzapine (fluoxetine + o lanzapine), olanzapine, lamotrigine, billcoat (Virucort), duloxetine hydrochloride, selegiline, gepirone-ER (gepirone-ER), imipramine hydrochloride, amitriptyline ), Trimipramine, clomipramine, nortriptyline, lofepramine, maprotiline, setiptiline, dosulepin, nomifensine.

  In the present invention, the therapeutic agents for epilepsy include, for example, carbamazepine, chloral hydrate, clonazepam, diazepam, felbamate, fosphenytoin, gabapentin, gabapentin ), Lamotrigine, levetiracetam, lorazepam, oxcarbazepine, phenobarbitone sodium, phenobarbitone Na, tiagabine, topiramate, valproate semisodium ), Sodium valproate, vigabatrin, zonisamide, pregabalin, phenobarbital, primidone, phenytoin, etho Ethosuximide, rufinamide, harkoseride, BIA-2-093, safinamide, SPD-421, talampanel, NS-1209, retigabine, carabersat Valrocemide, YKP-509, E-2007, AMP-397, UCB-34714, T-2000, isovaleramide, Co-102862, GT-1061, ICA-69673, UCB-44212. As a therapeutic agent for epilepsy, for example, carbamazepine, chloral hydrate, clonazepam, diazepam, felbamate, fosphenytoin, gabapentin, lamotrigine (Lamotrigine), levetiracetam, lorazepam (lorazepam), oxcarbazepine (oxcarbazepine), phenobarbitone sodium, tiagabine, topiramate, sodium valproate (valproate semisodium), valproate Sodium valproate, vigabatrin, zonisamide, pregabalin, phenobarbital, primidone, phenytoin, ethossimi (Ethosuximide), rufinamide (rufinamide), harcoside (harkoseride), BIA-2-093, safinamide, SPD-421, talampanel, NS-1209, retigabine, carabersat Valrocemide, YKP-509, E-2007, AMP-397, UCB-34714, and more preferably, for example, carbamazepine, chloral hydrate, clonazepam, diazepam ( diazepam), felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, lorazepam (lorazepam), oxcarbazepine, phenobabiton sodium (phenoba) rbitone Na, tiagabine, topiramate, sodium valproate (valproate semisodium), valproate sodium, vigabatrin, zonisamide, pregabalin, phenobarbital Primidone, phenytoin, ethosuximide.

  In the present invention, examples of therapeutic agents for dystonia include AN-072, botulinum toxin.

  In the present invention, as a therapeutic agent for diabetes, for example, haste, mixed, intermediate and / or continuous insulin preparations (eg, human insulin preparations synthesized by genetic engineering using E. coli, yeast, bovine, swine, etc.) Insulin preparations extracted from the pancreas), sulfonylureas (eg, tolbutamide, chlorpropamide, glibenclamide, gliclazide, glimepiride, tolazamide, acetohexa Acetohexamide, gliclopiramide,) biguanide drugs (eg, phenformine, buformin hydrochloride, metformin hydrochloride), α-glucosidase inhibitors (eg, acarbose ( acarbose) Voglibose), insulin secretagogues (eg nateglinide), insulin sensitizers (eg troglitazone, pioglitazone hydrochloride, AR-H-039242, BMS-298585, BM) -13.258, CS-011, DRF-2593, EML-16336, FK-614, GI-262570, KRP-297, LM-4156, LY-510929, LY-518818, MBX-102, MX-6054, ONO -5816, YM-440), GLP-1 receptor agonist, amylin agonist, phosphotyrosine phosphatase inhibitor, dipeptidyl peptidase IV inhibitor, β3 adrenergic receptor agonist, gluconeogenesis inhibitor, SGLT (sodium-glucose co transporter) inhibitors.

  In the present invention, as therapeutic agents for diabetic complications, for example, aldose reductase inhibitors (for example, epalrestat, SNK-860, CT-112), neurotrophic factors (for example, NGF (Nerve Growth Factor: nerve) Growth factors), NT-3, BDNF (Brain Derived Neurotrophic Factor)), nerve regeneration promoters, PKC inhibitors, AGE inhibitors, active oxygen scavengers, and the like.

  In the present invention, as a therapeutic drug for hyperlipidemia, for example, a statin HMG-CoA reductase inhibitor (for example, pravastatin sodium, atorvastatin calcium, simvastatin, lovastatin ( lovastatin), cerivastatin, fluvastatin (fluvastatin, etc.), fibrate triglyceride lowering drugs (eg, clofibrate), bezafibrate, fenofibrate, simfibrate, clinofibrate Etc.), squalene synthase inhibitors, cholestyramin, nicotinic acid, and probucol.

  In the present invention, as a dopamine receptor agonist, for example, levodopa (L-dopa) preparation, bromocryptine mesylate, α-dihydroergocryptine, lisuride, Pergolide mesylate, talipexole, cabergoline, pramipexole, pramipexole hydrochloride hydrate, piribedil, ropinirole, terguride (Rotigotine), AF-14, A-68939, A-77636, SKF-38393, N-0434, PD-118440, NIH-10494, and amantadine hydrochloride.

  In the present invention, examples of the dopamine release promoter include amantadine hydrochloride.

  In the present invention, examples of the dopamine uptake inhibitor include GBR-12909, GBR-13069, GYKI-52895, and NS-2141.

  In the present invention, as the central anticholinergic agent, for example, trihexyphenidyl hydrochloride, biperiden, piroheptine hydrochloride, mazaticol hydrochloride, metixene hydrochloride, metixene hydrochloride, Profenamine is mentioned.

  In the present invention, examples of the aromatic L-amino acid decarboxylase inhibitor (DCI) include carbidopa and benserazide.

  In the present invention, monoamine oxidase (MAO-B) inhibitors include, for example, selegiline, deprenil, riluzole, safrazine, remacemide, lazabemide, mesyl Examples include acid rasagiline (rasagiline mesylate), zonisamide, AGN-1133, LU-53439, MD-280040, mofegiline, and other ergot alkaloid derivatives.

  In the present invention, examples of the catechol-O-methyltransferase (COMT) inhibitor include entacapone, tolcapone, and CGP-28014.

  In the present invention, examples of norepinephrine (noradrenaline) supplements include droxidopa.

  In the present invention, examples of the acetylcholinesterase inhibitor include donepezil hydrochloride, rivastigmine tartrate, galantamine, and zanapezil (TAK-147).

  In the present invention, examples of the NMDA (N-methyl-D-aspartic acid) receptor antagonist include (+)-(1S, 2S) -1- (4-hydroxy-phenyl) -2- (4-hydroxy). -4-phenylpiperidino) -1-yl) -1-propanol, (1S, 2S) -1- (4-hydroxy-3-methoxyphenyl) -2- (4-hydroxy-4-phenylpiperidino) ) -1-propanol.

  In the present invention, AMPA (2-amino-3- (methyl-3-hydroxyisoxazol-4-yl) propanoic acid) / kainic acid receptor antagonist includes, for example, 6-cyano-7-nitroquinoxaline-2 , 3-dione (CNQX), 6-nitro-7-sulfamoylbenzo [f] quinoxaline-2,3-dione (NBQX), 6,7-dinitroquinoxaline-2,3-dione (DNQX). .

In the present invention, GABA _A receptor modulators (e.g., GABA _A receptor agonists, etc.) as, for example, muscimol (muscimol), isoguvacine (Isoguvacine), clomethiazole, gaboxadol (4,5,6,7-tetrahydro Isoxazolo [5,4-c] pyridin-3-ol), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), fengabine (2-[(butylimino)-(2-chlorophenyl) Methyl] -4-chlorophenol), 3-aminopropanesulfonic acid, 3- (aminomethyl) -5-methylhexanoic acid.

  In the present invention, examples of the adenosine A2A receptor blocker include istradefylline.

  In the present invention, β-amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitor includes, for example, β-secretase inhibitor, γ-secretase inhibitor, β-amyloid protein aggregation inhibitor, β-amyloid degrading enzyme, β An amyloid vaccine etc. are mentioned.

  In the present invention, β-secretase inhibitors include, for example, 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- (4-biphenylyl) methoxy-2- (N, N-dimethylamino) methyltetralin, 6- (4-biphenylyl) methoxy-2- (N, N-dipropylamino) methyltetralin, 2- (N, N-dimethylamino) methyl-6- (4 '-Methoxybiphenyl-4-yl) methoxytetralin, 6- (4-biphenylyl) methoxy-2- [2- (N, N-diethylamino) ethyl] tetralin, 2- [2- (N, N-dimethylamino) Ethyl] -6- (4'-methylbiphenyl-4-yl) methoxytetralin, 2- [2- (N, N-dimethylamino) ethyl] -6- (4'-me Xibiphenyl-4-yl) methoxytetralin, 6- (2 ′, 4′-dimethoxybiphenyl-4-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- [4- (1,3-Benzodioxol-5-yl) phenyl] methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- (3 ′, 4′-dimethoxybiphenyl-4-yl) ) Methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, its optically active substance, its salt and its hydrate, OM99-2 (WO01 / 00663).

  In the present invention, β-amyloid protein aggregation inhibitors include, for example, PTI-00703, ALZHEMED (NC-531), PPI-368 (Special Tables Hei 11-514333), PPI-558 (Special Tables Hei 2001-500852), SKF-74652 (Biochem. J., 340 (1), 283-289, 1999).

  In the present invention, examples of the apoptosis inhibitor include CPI-1189, IDN-6556, and CEP-1347.

  In the present invention, examples of the neuronal differentiation / regeneration promoter include leteprinim potassium, xaliproden hydrochloride, and SB-216763.

  In the present invention, examples of the neurotrophic factor include neurotrophin (eg, NGF (Nerve Growth Factor), BDNF (Brain Derived Neurotrophic Factor), NT-3, NT-4). / 5, NT-6), TGF-β superfamily (for example, 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, neuroturin, artemin, persephin, GDF-1, GDF-8, GDF-15, inhibin α, inhibin β, DAF (dauer formation) 7) Neurokine family (for example, ciliary neurotrophic factor (CNTF), interleukin-6) Growth factors (e.g., IGF-1, b-FGF), or the like ABS-205 and the like.

  In the present invention, as other brain function activators (for example, cerebral metabolism activators, cerebral circulation improvers, etc.), for example, nicergoline, ibudilast, aniracetam, ifenprodil, vinpocetine (Vinpocetine), idebenone, memantine hydrochloride.

  In the present invention, examples of the Rho-kinase inhibitor include fasudil.

  In the present invention, examples of diuretics include thiazide diuretics, loop diuretics, potassium-sparing diuretics, xanthine derivatives (eg, sodium salicylate theobromine, calcium theobromine salicylate), acetazolamide and the like.

  In the present invention, the thiazide diuretics include, for example, chlorothiazide, benzthiazide, hydrochlorothiazide, hydroflumethiazide, trichlormethiazide, cyclothiazide, cyclothiazide, Examples include methiclothiazide, polythiazide, quinethazone, and metolazone.

  In the present invention, examples of the loop diuretic include furosemide, bumetanide, piretanide, and ethacrynic acid.

  In the present invention, examples of the potassium-retaining diuretic include spironolactone, potassium canrenoate, amiloride, and triamterene.

  In the present invention, β receptor blockers include, for example, propranolol, alprenolol, pindolol, timolol, carteolol, nadolol, nipradilol ), Tilisolol, atenolol, acebutolol, metoprolol, bisoprolol, betaxolol, labetalol, arotinolol, amosulalol.

  In the present invention, as calcium channel blockers (calcium antagonists), for example, nifedipine, nicardipine, nitrendipine, nilvadipine, nisoldipine, manidipine, benidipine ( benidipine, barnidipine, efonidipine, amlodipine, diltiazem, verapamil, clonidine hydrochloride.

  In the present invention, examples of the angiotensin converting enzyme (ACE) inhibitor include captopril, alacepril, lisinopril, enalapril, delapril, cilazapril, and imidapril. ), Perindopril, temocapril, and trandolapril.

  In the present invention, examples of the angiotensin II receptor antagonist include candesartan cilexetil, losartan, and valsartan.

  In the present invention, examples of the sodium channel blocker include ajmaline, procainamide hydrochloride, and riluzole.

  In the present invention, examples of the potassium channel opener include diazoxide, flupirtine, pinacidil, levcromacarim, rilmacalim, cromakalim, PCO-400, and SKP-450.

  In the present invention, examples of the antiplatelet drug include aspirin, ethyl icosapentate, sodium ozagrel, beraprost sodium, alprostadil, ticlopidine hydrochloride ), Cilostazol, dipyridamole, sarpogrelate hydrochloride.

  In the present invention, examples of the anticoagulant include warfarin (for example, warfarin potassium), heparin (for example, heparin sodium, heparin calcium), and an antithrombin drug (for example, an antithrombin drug). Thrombin III, argatroban, hirudin).

  In the present invention, examples of thrombolytic agents include urokinase, nasalplase (nasaruplase, prourokinase), tissue plasminogen activator (t-PA), tisokinase, alteplase, Examples include nateplase, monteplase, streptokinase, and pamiteplase.

  In the present invention, examples of the cyclooxygenase (COX) -2 inhibitor include celecoxib and rofecoxib.

  In the present invention, examples of the nonsteroidal anti-inflammatory drug include aspirin, mefenamic acid, diclofenac, fenbufen, indometacin, ibuprofen, ketoprofen. ), Naproxen, phenylbutazone, piroxicam, tenoxicam, celecoxib, and rofecoxib.

  In the present invention, examples of the steroid drug include prednisolone, methylprednisolone, triamcinolone, paramethasone, dexamethasone, betamethasone, cortisone, cortisone, and hydrocortisone. ).

  In the present invention, examples of the antioxidant include linolenic acid, icosapentaenoic acid, docosahexaenoic acid, ascorbic acid, and tocopherol acetate.

  In the present invention, examples of the immunosuppressant include azathioprine (trade names: Imran, azanine), mizoribine (trade name: predinin), methotrexate (trade names: methotrexate, rheumatorex), mycophenolate mofetil (trade name: Celcept) , Cyclophosphamide (trade name: Endoxan P), cyclosporin A (trade name: Neoral, Sandymun), FTY-720, tacrolimus hydrate (FK506, trade name: Prograf, Protopic), sirolimus (rapamycin), everolimus (Product name: Certican), Prednisolone (Product name: Predonin), Methylprednisolone (Product name: Medrol), Orthoclone OKT3 (Product name: Moronab CD3), Anti-human lymphocyte globulin (ALG, Product name: Earl Buri) ), Deoxyspergualin (DSG, hydrochloric gusperimus, trade name: Supanijin), and the like.

  In the present invention, examples of vitamins include ascorbic acid, tocopherol acetate, and mecobalamin.

  The above drugs combined with (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof are merely examples, and are not limited thereto. In addition, other drugs that can be combined with (2R) -2-propyloctanoic acid, its salt, its solvate or their prodrugs have been found to date based on the mechanism described above. This includes not only things but also those that will be found in the future.

  The present invention also includes the aforementioned “(2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof” and “therapeutic method (for example, a therapeutic method such as rehabilitation and surgical treatment)”. And a method for effectively preventing, treating and / or suppressing the progression of symptoms of neurodegenerative diseases is also disclosed. That is, (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof is applied to a neurodegenerative disease patient who has been or will be subjected to a therapeutic method such as rehabilitation or surgical treatment. By administering a drug, it is possible to obtain a better prevention, treatment and / or symptom progression-suppressing effect than when a surgical treatment is simply performed. For example, in patients with cerebral infarction, local thrombolytic therapy that introduces a microcatheter to the occluded site of the occluded blood vessel, dissolves the thrombus causing the occlusion with a thrombolytic agent such as urokinase, and reopens it. (Or local fibrinolytic therapy), PTA (angioplasty) to expand thrombus and stenosis with balloon catheter, stent placement to expand stenosis with metal stent, etc. are performed. Administration of (2R) -2-propyloctanoic acid, its salt, its solvate, or other prodrugs to patients who have undergone treatment can significantly suppress the onset of neuropathy caused by cerebral infarction it can.

[Application to pharmaceutical products]
The medicament of the present invention can be applied to mammals (humans and animals other than humans (for example, monkeys, sheep, cows, horses, dogs, cats, rabbits, rats, mice, etc.)) and the like. In particular, by administering orally or parenterally to mammals, preferably humans, it is possible to obtain a preferable prevention, treatment and / or symptom progression-suppressing effect on neurodegenerative diseases or diseases requiring neurological dysfunction or nerve regeneration. it can. That is, the indication of the medicament of the present invention includes, for example, neurodegenerative diseases (for example, Parkinson's disease, Parkinson's syndrome, striatal nigra degeneration, Huntington's disease, chorea-ataxia, progressive supranuclear palsy, Diffuse Lewy body disease, cortical basal ganglia degeneration, Alzheimer's disease, senile dementia, Pick's disease, frontotemporal dementia, familial dementia, spinocerebellar degeneration (eg, Olive Bridge cerebellar atrophy, Late-onset cerebellar cortical atrophy, familial spinocerebellar ataxia (eg, Maccard Joseph disease, etc.), erythrocytic red nucleus pallidus atrophy, familial spastic paraplegia, Friedreich's disease, etc.), exercise Neuropathy (eg, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, etc.), demyelinating diseases (eg, multiple sclerosis, generalized sclerosis, acute disseminated encephalomyelitis, acute Encephalitis, transverse myelitis, Guillain-Barré disease Group), cerebrovascular disorder (eg, stroke, cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), transient cerebral ischemic attack, reperfusion injury, cerebral hemorrhage (eg, hypertensive intracerebral hemorrhage, subarachnoid hemorrhage, etc.) Etc.) ・ Brain tumors (eg astrocytomas, brain abscesses, etc.) ・ Blood-decreasing shocks, traumatic shocks, head injuries and / or cerebrospinal traumas (eg, brain contusions, penetrations, shears, compressions, Neurological dysfunction associated with lacerations, labor trauma, infant whiplash syndrome, etc., cerebrospinal diseases associated with infections (eg meningitis, influenza encephalopathy, Creutzfeldt-Jakob disease, dementia due to AIDS encephalopathy), toxicants ( Arsenic, cadmium, organic mercury, sarin, soman, tabun, VX gas, etc.), neurological dysfunction due to radiation, mental illness (eg, neurosis, psychosomatic disorder, anxiety, schizophrenia, manic depression, etc.), epilepsy Mage syndrome, dystonia, Down syndrome, sleep disorders (eg, hypersomnia, narcolepsy, sleep apnea syndrome, etc.), neurological dysfunction (eg, impaired consciousness, bilateral quadriplegia, contralateral hemiplegia, alternating hemiplegia) , Sensory disorders, transient blindness (eg, transient cataract etc.), homonymous half-blindness, dizziness, nystagmus, double vision, aphasia, tinnitus, coma, etc.) or diseases requiring nerve regeneration.

  In the present invention, a disease requiring nerve regeneration means a disease in which the absolute number of nerve cells or glial cells is decreased due to the loss of nerve cells or glial cells, and normal nerve function is impaired, For example, the above-mentioned neurodegenerative diseases that have reached such a state can be mentioned. Here, “nerve regeneration” includes both “neurogenesis” and “nerve regeneration” which are terms used in the art. Nerve regeneration refers to at least partially reproducing the normal development process in the nerve, and is not influenced by the origin of the cells to be regenerated. Nerve regeneration includes tissue regeneration or functional regeneration, and also includes a neurotrophic factor-like action and a neurotrophic factor activity enhancing action.

  In the present invention, “prevention” refers to preventing the establishment of the disease itself, “treatment” refers to guiding the disease state in the direction of healing, and “symptom progression inhibition” refers to suppressing the progression / aggravation of symptoms and the disease state It means to keep the progress of.

  As described above, the medicament of the present invention may be administered in the form of a combination preparation in which both components are mixed in one preparation, or may be administered in separate preparations. When administered as separate preparations, they may be administered simultaneously or at a time difference. In addition, when administered at a time difference, (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof may be administered first, and another drug may be administered later. Other drugs may be administered first, and (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof may be administered later. The number of administrations may be the same or different. In addition, the weight ratio of (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof and another drug is not particularly limited.

  The dose of (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof and another drug varies depending on age, body weight, symptom, therapeutic effect, administration method, treatment time, etc. In the case of oral administration, it is usually administered once or several times a day in the range of 1 μg to 5000 mg per adult per person. In the case of parenteral administration, each adult is administered parenterally once to several times a day in the range of 0.1 ng to 500 mg each. The parenteral dosage form is preferably intravenous administration and is continuously administered intravenously in the range of 1 hour to 24 hours per day. Of course, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or administration beyond the range may be necessary.

  “(2R) -2-propyloctanoic acid, its salt, its solvate or prodrug thereof”, or “other drug”, or “(2R) -2-propyloctanoic acid, its salt, its solvate” Or a prodrug thereof and a preparation containing another drug in the same preparation orally ”, it is used as a solid preparation for internal use, a liquid preparation for internal use, etc. for oral administration.

  Examples of the solid preparation for internal use for oral administration include tablets, pills, capsules, powders, granules and the like. Tablets include sublingual tablets, buccal adhesive tablets, buccal quick disintegrating tablets 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 an excipient (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), a binder (for example, hydroxypropylcellulose, polyvinylpyrrolidone, metasilicic acid). Magnesium aluminate, etc.), disintegrating agents (eg, calcium calcium glycolate), lubricants (eg, magnesium stearate), stabilizers, solubilizing agents (eg, glutamic acid, aspartic acid, etc.), etc. , Formulated according to conventional methods. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. Also included are capsules of absorbable substances such as gelatin.

  The sublingual tablet is prepared according to a known method. For example, drugs (for example, lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.), binders (for example, hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrants ( For example, starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium, calcium calcium glycolate, etc.), lubricant (eg, magnesium stearate), swelling agent (eg, hydroxypropyl cellulose, hydroxypropyl methylcellulose) , Carbopol, carboxymethylcellulose, polyvinyl alcohol, xanthan gum, guar gum, etc.), swelling aids (eg glucose, fructose, mannitol, xylates) Erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid, arginine, etc.), stabilizer, solubilizer (eg, polyethylene glycol, propylene glycol, glutamic acid, aspartic acid, etc.) , Flavoring agents (for example, orange, strawberry, mint, lemon, vanilla, etc.) and the like, and formulated into a conventional method for use. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. Moreover, additives such as preservatives, antioxidants, colorants, sweeteners and the like that are commonly used can be added as necessary.

  The intraoral patch is prepared according to a known method. For example, drugs (for example, lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.), binders (for example, hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrants ( For example, starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium, calcium calcium glycolate, etc.), lubricant (eg, magnesium stearate), adhesive (eg, hydroxypropyl cellulose, hydroxypropyl methylcellulose) , Carbopol, carboxymethylcellulose, polyvinyl alcohol, xanthan gum, guar gum, etc.), adhesion aids (eg glucose, fructose, mannitol, xylates) Erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid, arginine, etc.), stabilizer, solubilizer (eg, polyethylene glycol, propylene glycol, glutamic acid, aspartic acid, etc.) , Flavoring agents (for example, orange, strawberry, mint, lemon, vanilla, etc.) and the like, and formulated into a conventional method for use. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. Moreover, additives such as preservatives, antioxidants, colorants, sweeteners and the like that are commonly used can be added as necessary.

  The intraoral quick disintegrating tablet is prepared according to a known method. For example, the drug is coated as it is or with an appropriate coating agent (for example, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, acrylic acid / methacrylic acid copolymer), or a plasticizer (for example, polyethylene glycol, triethyl citrate). To the drug substance powder or granulated powder particles subjected to the treatment, excipients (for example, lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.), binders (for example, hydroxypropyl cellulose, polyvinylpyrrolidone, Magnesium aluminate metasilicate), disintegrating agents (eg starch, L-hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, calcium calcium glycolate), lubricants For example, magnesium stearate), dispersion aid (for example, glucose, fructose, mannitol, xylitol, erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid, arginine, etc.), stabilizer , Mixed with solubilizing agents (eg, polyethylene glycol, propylene glycol, glutamic acid, aspartic acid, etc.), flavoring agents (eg, orange, strawberry, mint, lemon, vanilla, etc.), etc. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. If necessary, additives such as commonly used preservatives, antioxidants, colorants, sweeteners and the like can be added.

  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.

  “(2R) -2-propyloctanoic acid, its salt, its solvate or prodrug thereof”, or “other drug”, or “(2R) -2-propyloctanoic acid, its salt, its solvate” Or a prodrug thereof and other drug in the same preparation "are used as parenteral injection, external preparation, inhalant, suppository and the like.

  The injection for parenteral administration includes all injections. For example, an injection for muscle, an injection for intravenous injection, an intravenous infusion, and the like are included.

  Examples of injections for parenteral administration include solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use. An injection is prepared by dissolving, suspending or emulsifying a drug in a solvent. Examples of the solvent include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof. Furthermore, this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent, a preservative and the like. Also good. These are sterilized in the final step or prepared by aseptic manipulation. In addition, an aseptic solid preparation, for example, a freeze-dried product can be prepared and dissolved in aseptic distilled water for injection or other solvent before use.

  Examples of external preparations for parenteral administration include ointments, gels, creams, poultices, patches, liniments, sprays, sprays, aerosols, inhalants, eye drops, and nasal drops. Is included. These are prepared by a known method or a commonly used formulation.

  The ointment is prepared by a known or commonly used formulation. For example, the drug is prepared by mixing or melting the base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (E.g., beeswax, whale wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene) Recall, macrogol, etc.), vegetable oil (eg, castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oil (eg, mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancer, anti-rash agent Can be used alone or in admixture of two or more. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like may be included.

  The gel is prepared by a known or commonly used formulation. For example, it is prepared by melting a drug in a base. The gel base is selected from known or commonly used ones. For example, lower alcohol (eg, ethanol, isopropyl alcohol, etc.), gelling agent (eg, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agent (eg, triethanolamine, diisopropanolamine, etc.), Those selected from surfactants (for example, polyethylene glycol monostearate), gums, water, absorption promoters and anti-rash agents are used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The cream is prepared by a known or commonly used formulation. For example, it is prepared by melting or emulsifying a drug in a base. The cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (eg, 2-hexyldecanol, cetanol, etc.), emulsifiers (eg, polyoxy (Ethylene alkyl ethers, fatty acid esters, etc.), water, absorption accelerators, and rash prevention agents may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The poultice is prepared by a known or commonly used formulation. For example, it is prepared by melting a drug in a base, spreading it onto a support as a kneaded product. The poultice base is selected from known or commonly used ones. For example, thickeners (for example, polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (for example, urea, glycerin, propylene glycol, etc.), fillers (for example, kaolin, zinc oxide, Talc, calcium, magnesium, etc.), water, solubilizers, tackifiers and anti-rash agents are used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The patch is prepared by a known or commonly used formulation. For example, it is prepared by melting a drug in a base and spreading it on a support. The base for patch is selected from known or commonly used ones. For example, those selected from polymer bases, oils and fats, higher fatty acids, tackifiers and anti-rash agents may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The liniment is prepared by a known or commonly used formulation. For example, a drug selected from water, alcohol (eg, ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, soap, emulsifier, suspending agent, etc. alone, or dissolved, suspended or emulsified in two or more kinds Prepared. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  Sprays and sprays include buffers that provide isotonicity with stabilizers such as sodium bisulfite in addition to commonly used diluents, such as sodium chloride, sodium citrate or citric acid, etc. It may contain a tonicity agent. The preparation method of the spray is described in detail in, for example, US Pat. Nos. 2,868,691 and 3,095,355.

  Inhalants for parenteral administration include aerosols, inhalable powders or inhalable solutions, which are used by dissolving or suspending them in water or other suitable media at the time of use. It may be. These inhalants are prepared according to known methods. For example, in the case of inhalation solutions, preservatives (eg, benzalkonium chloride, parabens, etc.), colorants, buffering agents (eg, sodium phosphate, sodium acetate, etc.), isotonic agents (eg, chloride) Sodium, concentrated glycerin, etc.), thickeners (for example, cariboxyvinyl polymer, etc.), absorption accelerators, and the like are appropriately selected as necessary. In the case of powders for inhalation, lubricants (for example, stearic acid and its salts), binders (for example, starch, dextrin, etc.), excipients (for example, lactose, cellulose, etc.), colorants, antiseptics An agent (for example, benzalkonium chloride, paraben, etc.), an absorption accelerator and the like are appropriately selected as necessary. A nebulizer (for example, an atomizer, a nebulizer, etc.) is usually used when administering an inhalation solution, and an inhalation administration device for powdered drugs is usually used when administering an inhalable powder.

  As other dosage forms for parenteral administration, suppositories for rectal administration, pessaries for intravaginal administration, etc. prescribed by conventional methods are used.

[toxicity]
The toxicity of (2R) -2-propyloctanoic acid, its salt, its solvate or their prodrug was confirmed to be sufficiently low and safe enough for use as a pharmaceutical product. For example, in a single intravenous administration of (2R) -2-propyloctanoic acid in a dog, no death was observed even at 100 mg / kg.

  The present invention uses (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof in combination with the above-mentioned other drugs to effectively prevent, treat and / or treat neurodegenerative diseases. Alternatively, the present invention provides a method for suppressing symptom progression and a medicine used for the method. The method using the medicament disclosed in the present invention is extremely effective in preventing, treating and / or suppressing the progression of symptoms of neurodegenerative diseases, and can significantly improve various symptoms associated with those diseases.

  The method of the present invention, preferably the method using the medicament of the present invention is, for example, a neurodegenerative disease (for example, Parkinson's disease, Parkinson's syndrome, striatal nigra degeneration, Huntington's disease, chorea-ataxia, Progressive supranuclear paralysis, diffuse Lewy body disease, basal ganglia degeneration, Alzheimer's disease, senile dementia, Pick's disease, frontotemporal lobar dementia, familial dementia, spinocerebellar degeneration (eg, Olive bridge cerebellar atrophy, late cerebellar cortical atrophy, familial spinocerebellar ataxia (eg, Maccard Joseph disease, etc.), dentate nucleus red nucleus pallidus louis atrophy, familial spastic paraplegia, freed Reich's disease, etc.), motor neuropathy (eg, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, etc.), demyelinating diseases (eg, multiple sclerosis, general sclerosis, acute dissemination) Encephalomyelitis, acute cerebellar inflammation, transverse myelitis, gi Valley syndrome, etc.), cerebrovascular disorders (eg, stroke, cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), transient cerebral ischemic attack, reperfusion injury, cerebral hemorrhage (eg, hypertensive intracerebral hemorrhage, arachnoid membrane) Etc.), brain tumors (eg, astrocytoma, brain abscess, etc.), blood volume reducing shock, traumatic shock, head injury and / or cerebrospinal trauma (eg, brain contusion, penetration, shear)・ Neuronal dysfunction associated with compression / laceration, labor trauma, infant whiplash syndrome, etc., cerebrospinal disease associated with infection (eg, meningitis, influenza encephalopathy, Creutzfeldt-Jakob disease, dementia due to AIDS encephalopathy, etc.) , Toxic substances (arsenic, cadmium, organic mercury, sarin, soman, tabun, VX gas, etc.), neurological dysfunction due to radiation, etc., mental disorders (eg neurosis, psychosomatic disorders, anxiety, schizophrenia, manic depression ), Epilepsy, mage syndrome, dystonia, Down syndrome, sleep disorders (eg, hypersomnia, narcolepsy, sleep apnea syndrome, etc.), consciousness disorder, bilateral quadriplegia, contralateral hemiplegia, alternating hemiplegia, sensation Prevention of neurological dysfunctions such as disorders, transient blindness (eg, transient cataracts), homonymous half-blindness, dizziness, nystagmus, double vision, aphasia, tinnitus, coma, and even diseases that require nerve regeneration, In the treatment and / or suppression of symptom progression, prevention, treatment and / or supplementation and / or enhancement of symptom progression suppression effect, improvement of pharmacokinetics / absorption, or drug dosage / It is extremely effective for reducing side effects or preventing the development of drug resistance. For example, in the treatment of Parkinson's disease, combining (2R) -2-propyloctanoic acid is expected to improve the wear-off phenomenon, which is one of the side effects seen with repeated administration of levodopa benserazide or bromocriptine mesylate. it can.

  Below, although the method of this invention is explained in full detail, giving an Example and a formulation example, this invention is not limited to these. Of course, various conditions may be changed without departing from the scope of the present invention.

[Example]
In the examples shown below, the therapeutic effect of the medicament of the present invention was confirmed.

Example 1: Combined effect of an existing drug and (2R) -2-propyloctanoic acid in a rhesus monkey MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) -induced Parkinson's disease model (1-1 ) (2R) 2-propyloctanoic acid and levodopa / benserazide combination administration experiment (1-2) (2R) -2-propyloctanoic acid and bromocriptine mesylate administration experiment [Purpose]
After MPTP was administered to rhesus monkeys to induce certain Parkinson's disease-like symptoms, (2R) -2-propyloctanoic acid and levodopa benserazide or (2R) -2-propyloctanoic acid and bromocriptine mesylate for 3 months To evaluate the therapeutic effect of Parkinson's disease-like symptoms by continuous administration.

[experimental method]
1. Induction of Parkinson's disease-like symptoms by MPTP MPTP (0.5-1.0 mg / kg) is intravenously administered to rhesus monkeys, and the symptoms are visually observed 6 days later. If the Parkinson's disease-like symptom score is 3 or more, then MPTP (0.5 mg / kg) is intravenously administered once a week. If the Parkinson's disease-like symptom score is 2 or less, MPTP (0.5-1.0 mg / kg) is administered intravenously once a week until the Parkinson's disease-like symptom score is 3 or more, and the Parkinson's disease-like symptom score is 3 or more. If so, the subsequent MPTP administration is 0.5 mg / kg once a week. When the Parkinson's disease-like symptom score is 9 or more, administration of MPTP is discontinued. For animals with a score of 6 or less after 6 months from the initial administration of MPTP, MPTP (1.0 mg / kg) is intravenously administered once a week until the score reaches 8 or more. When the score is 7 or 8, MPTP (0.5 mg / kg) is intravenously administered once or twice a week until the score becomes 9 or more.

2. Test Entry Criteria Animals that have been stable for a Parkinson's disease-like symptom score of 9 or more after 2 months or more have passed since the first MPTP administration and 2 weeks or more have passed since the last MPTP administration are sequentially subjected to the test.

3. Grouping Before the grouping, the spontaneous exercise amount and the feeding operation time are evaluated, and each group is divided so that the measured values are equal. Also, the maximum change in Parkinson's disease-like symptom score after administration of the initial levodopa / benserazide compound or bromocriptine mesylate should be made equal. The maximum score change value is searched from the Parkinson's disease-like symptom observation point of Example 1-1 or 1-2.

[Evaluation methods]
Parkinson's disease-like symptoms are scored according to the evaluation scale of Akai T et al. (Akai T, Ozawa M, Yamaguchi M, Mizuta E and Kuno S, J Pharmacol Exp Ther, 273, 309-314 (1995)). To do. Observation is performed 3 times a week. The daily observation schedule is performed 5, 30, 60, 90, 120, and 180 minutes after administration of the test substance for Example 1-1, and before test substance administration for Example 1-2, the test substance. 60, 120, 180, 240, 300, 360, 420, 480 minutes after administration. The score of each evaluation point is averaged every week, and the total value is used as data.

[result]
In the levodopa benserazide (4: 1) combination drug (12.5 mg / kg) or bromocriptine mesylate (3 mg / kg) single administration experiment, a wearing-off phenomenon was observed as the administration period increased. When used in combination with 2-propyloctanoic acid (10 mg / kg), no wear-off phenomenon was observed.

[Formulation example]
Examples of the pharmaceutical preparation of the present invention are disclosed below, but the present invention is not limited to these.

Formulation Example 1 :
(2R) -2-propyloctanoic acid (100 g), levodopa (100 g), benserazide (25 g), carboxymethylcellulose calcium (20.0 g), magnesium stearate (10.0 g) and microcrystalline cellulose (870 g) were mixed by a conventional method. Thereafter, tableting was performed to obtain 10,000 tablets each containing 10 mg (2R) -2-propyloctanoic acid, 10 mg levodopa, and 2.5 mg benserazide.

Formulation Example 2 :
(2R) -2-propyloctanoic acid (100 g), bromocriptine mesylate (30 g), carboxymethylcellulose calcium (20.0 g), magnesium stearate (10.0 g) and microcrystalline cellulose (870 g) were mixed by a conventional method and then beaten. Tablets were obtained to give 10,000 tablets each containing 10 mg (2R) -2-propyloctanoic acid and 3 mg bromocriptine mesylate.

Formulation Example 3
(2R) -2-propyloctanoic acid (200 g), levodopa (200 g), benserazide (50 g), mannitol (2 kg) and distilled water (50 L) were mixed by a conventional method to obtain a homogeneous solution, and then a sterile filter (Durapore 0.22 μm membrane), filled into ampoules in 5 mL portions, autoclaved (123 ° C., 15 minutes), 20 mg (2R) -2-propyloctanoic acid, 20 mg levodopa and 5 mg in one ampule Ten thousand ampoules containing benserazide were obtained.

Formulation Example 4 :
(2R) -2-propyloctanoic acid (200 g), bromocriptine mesylate (60 g), mannitol (2 kg), and distilled water (50 L) were mixed by a conventional method to obtain a homogeneous solution, and then a sterile filter (Durapore 0.22 μm membrane), filled into ampoules in 5 mL portions, autoclaved at 123 ° C. for 15 minutes, and contains 20 mg of (2R) -2-propyloctanoic acid and 6 mg of bromocriptine mesylate in one ampule 10,000 ampoules were obtained.

The combination of the (2R) -2-propyloctanoic acid, its salt, its solvate or their prodrug of the present invention with the other drugs described above is used for neurodegenerative diseases (for example, Parkinson's disease, Parkinson's syndrome, striatum) Corpus nigra degeneration, Huntington's disease, chorea-ataxia, progressive supranuclear palsy, diffuse Lewy body disease, cortical basal ganglia degeneration, Alzheimer's disease, senile dementia, Pick's disease, frontotemporal Leaf type dementia, familial dementia, spinocerebellar degeneration (eg, Olive Bridge cerebellar atrophy, late cerebellar cortical atrophy, familial spinocerebellar ataxia (eg, Maccard Joseph disease), dentate nucleus Rheumatoid pallidus atrophy, familial spastic paraplegia, Friedreich's disease, etc.), motor neuropathy (eg, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, etc.), demyelination Diseases (eg, multiple sclerosis) , Generalized sclerosis, acute disseminated encephalomyelitis, acute cerebellar inflammation, transverse myelitis, Guillain-Barre syndrome, etc., cerebrovascular disorder (eg, stroke, cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), one Transient cerebral ischemic attack, reperfusion injury, cerebral hemorrhage (eg hypertensive intracerebral hemorrhage, subarachnoid hemorrhage, etc.), brain tumor (eg astrocytoma, brain abscess, etc.) Neurological dysfunction associated with traumatic shock, head injury and / or cerebrospinal trauma (eg, brain contusion, penetration, shear, compression, laceration, delivery trauma, infant whiplash syndrome), cerebrospinal disease associated with infection (For example, meningitis, influenza encephalopathy, Creutzfeld-Jakob disease, dementia due to AIDS encephalopathy, etc.), toxic substances (arsenic, cadmium, organic mercury, sarin, soman, tabun, VX gas, etc.), neurological dysfunction due to radiation, etc. , Mental disorders (eg, neurosis, psychosomatic disorders, anxiety, schizophrenia, manic depression), epilepsy, mage syndrome, dystonia, Down syndrome, sleep disorders (eg, hypersomnia, narcolepsy, sleep apnea syndrome, etc.) Etc.), disturbance of consciousness, bilateral limb paralysis, contralateral hemiplegia, alternating hemiplegia, sensory disturbance, transient blindness (eg, transient cataract), homonymous half-blindness, dizziness, nystagmus, double vision Prevention, treatment, and / or symptom progression compared to the use of these alone when preventing, treating, and / or suppressing symptom progression, such as neurological dysfunction such as aphasia, tinnitus, and coma, as well as diseases that require nerve regeneration It is extremely effective for complementation and / or enhancement of inhibitory effect, improvement of pharmacokinetics / absorption, reduction of drug dosage / side effects, prevention of drug resistance, etc. For example, in the treatment of Parkinson's disease, the combined use of (2R) -2-propyloctanoic acid improves the wear-off phenomenon, which is one of the side effects seen with repeated administration of levodopa-benserazide or bromocriptine mesylate. I can expect.

Claims (20)

  (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof, and neurodegenerative disease, motor neuropathy, demyelinating disease, cerebrovascular disorder, brain tumor, cerebrospinal trauma A pharmaceutical comprising a combination of a therapeutic agent for one or more diseases selected from disorders, cerebrospinal diseases associated with infectious diseases, mental disorders, epilepsy, dystonia, diabetes, diabetic complications and hyperlipidemia.   The medicament according to claim 1, wherein (2R) -2-propyloctanoic acid is combined with a therapeutic agent for neurodegenerative diseases.   The medicament according to claim 2, wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease and / or amyotrophic lateral sclerosis.   The treatment for Parkinson's disease is levodopa, levodopa / benserazide, levodopa / carbidopa, and / or bromocriptine mesylate. Alzheimer's treatment is donepezil hydrochloride, memantine hydrochloride, rivastigmine tartrate, galantamine, and / or tacrine. The medicament according to claim 3, wherein the therapeutic agent for amyotrophic lateral sclerosis is riluzole.   The medicament according to claim 1, comprising (2R) -2-propyloctanoic acid in combination with a therapeutic agent for cerebrovascular disorder.   The medicament according to claim 5, wherein the cerebrovascular disorder is cerebral infarction.   The medicament according to claim 6, wherein the therapeutic agent for cerebral infarction is alteplase, clopidogrel hydrogensulfate, edaravone and / or ozagrel sodium. (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, a dopamine receptor agonist, a dopamine release promoter, a dopamine uptake inhibitor, a dopamine agonist, a central anticholinergic agent, Aromatic L-amino acid decarboxylase inhibitors, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, norepinephrine supplements, acetylcholinesterase inhibitors, NMDA receptor antagonists, AMPA / kainic acid receptor antagonists, GABA _A receptor modulator, GABA _B receptor modulator, adenosine A2A receptor blocker, apoptosis inhibitor, neuronal differentiation / regeneration promoter, neurotrophic factor, brain function activator, Rho-kinase inhibitor, diuretic, β receptor blocker, calcium channel blocker, angiotensin converting enzyme inhibitor, anne Geotensin II receptor antagonist, sodium channel blocker, potassium channel opener, antiplatelet agent, anticoagulant, thrombolytic agent, cyclooxygenase-2 inhibitor, non-steroidal anti-inflammatory agent, steroid drug, antioxidant, immune A pharmaceutical comprising a combination of one or more selected from inhibitors and vitamins.   The medicament according to claim 1 or 8, which is a preventive, therapeutic and / or symptom progression inhibitor for neurodegenerative diseases.   The medicament according to claim 9, wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or neurological dysfunction associated with cerebral infarction.   (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof, and neurodegenerative disease, motor neuropathy, demyelinating disease, cerebrovascular disorder, brain tumor, cerebrospinal trauma A pharmaceutical composition comprising a combination of a therapeutic agent for one or more diseases selected from disorders, cerebrospinal diseases associated with infectious diseases, mental disorders, epilepsy, dystonia, diabetes, diabetic complications and hyperlipidemia.   The pharmaceutical composition according to claim 11, wherein (2R) -2-propyloctanoic acid is combined with a therapeutic agent for neurodegenerative disease and / or cerebrovascular disorder.   The pharmaceutical composition according to claim 12, wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease and / or amyotrophic lateral sclerosis, and the cerebrovascular disorder is cerebral infarction. (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, a dopamine receptor agonist, a dopamine release promoter, a dopamine uptake inhibitor, a dopamine agonist, a central anticholinergic agent, Aromatic L-amino acid decarboxylase inhibitors, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, norepinephrine supplements, acetylcholinesterase inhibitors, NMDA receptor antagonists, AMPA / kainic acid receptor antagonists, GABA _A receptor modulator, GABA _B receptor modulator, adenosine A2A receptor blocker, apoptosis inhibitor, neuronal differentiation / regeneration promoter, neurotrophic factor, brain function activator, Rho-kinase inhibitor, diuretic, β receptor blocker, calcium channel blocker, angiotensin converting enzyme inhibitor, anne Geotensin II receptor antagonist, sodium channel blocker, potassium channel opener, antiplatelet agent, anticoagulant, thrombolytic agent, cyclooxygenase-2 inhibitor, non-steroidal anti-inflammatory agent, steroid drug, antioxidant, immune A pharmaceutical composition comprising a combination of one or more selected from inhibitors and vitamins.   The pharmaceutical composition according to claim 11 or 14, which is a preventive, therapeutic and / or symptom progression inhibitor for neurodegenerative diseases.   The pharmaceutical composition according to claim 15, wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and / or neurological dysfunction associated with cerebral infarction.   A method for preventing, treating and / or suppressing the progression of symptoms in a mammal, comprising (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, a neurodegenerative disease, From motor neuropathy, demyelinating disease, cerebrovascular disorder, brain tumor, neurological dysfunction associated with cerebrospinal trauma, cerebrospinal disease associated with infection, mental illness, epilepsy, dystonia, diabetes, diabetic complications and hyperlipidemia A method comprising administering to a mammal in combination with a therapeutic agent for one or more selected diseases. A method for preventing, treating and / or inhibiting the progression of symptoms in a neurodegenerative disease in a mammal, comprising (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, and dopamine receptor operation Drugs, dopamine release promoters, dopamine uptake inhibitors, dopamine agonists, central anticholinergics, aromatic L-amino acid decarboxylase inhibitors, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, norepinephrine supplementation Drugs, acetylcholinesterase inhibitors, NMDA receptor antagonists, AMPA / kainic acid receptor antagonists, GABA _A receptor modulators, GABA _B receptor modulators, adenosine A2A receptor blockers, apoptosis inhibitors, neuronal differentiation / Regeneration promoting agent, neurotrophic factor, brain function activator, Rho-kinase inhibitor, Urine drug, beta receptor blocker, calcium channel blocker, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, sodium channel blocker, potassium channel opener, antiplatelet drug, anticoagulant drug, thrombolytic drug, cyclooxygenase -2 inhibitor, a non-steroidal anti-inflammatory drug, a steroid drug, an antioxidant, an immunosuppressive drug and a combination of one or more selected from vitamins and administering to a mammal.   (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof, or a prodrug thereof, and a neurodegenerative disease, motor nerve, for producing a prophylactic, therapeutic and / or symptom progression inhibitor for neurodegenerative disease Disease, demyelinating disease, cerebrovascular disorder, brain tumor, neurological dysfunction associated with cerebrospinal trauma, cerebrospinal disease associated with infection, mental illness, epilepsy, dystonia, diabetes, diabetic complications and hyperlipidemia Use in combination with a therapeutic agent for one or more diseases. (2R) -2-propyloctanoic acid, a salt thereof, a solvate thereof or a prodrug thereof, a dopamine receptor agonist, for producing a preventive, therapeutic and / or symptom progression inhibitor for neurodegenerative diseases, Dopamine release promoter, dopamine uptake inhibitor, dopamine agonist, central anticholinergic agent, aromatic L-amino acid decarboxylase inhibitor, monoamine oxidase inhibitor, catechol-O-methyltransferase inhibitor, norepinephrine replacement agent, Acetylcholinesterase inhibitor, NMDA receptor antagonist, AMPA / kainic acid receptor antagonist, GABA _A receptor modulator, GABA _B receptor modulator, adenosine A2A receptor blocker, apoptosis inhibitor, neuronal differentiation / regeneration promotion Medicine, neurotrophic factor, brain function activator, Rho-kinase inhibitor, diuretic, beta receptor Blocker, calcium channel blocker, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, sodium channel blocker, potassium channel opener, antiplatelet agent, anticoagulant, thrombolytic agent, cyclooxygenase-2 inhibitor, non Use of a combination with one or more selected from steroidal anti-inflammatory drugs, steroid drugs, antioxidants, immunosuppressants and vitamins.