WO2003064395A1 - Agents preventifs et therapeutiques destines a lutter contre des maladies neurodegeneratives - Google Patents

Agents preventifs et therapeutiques destines a lutter contre des maladies neurodegeneratives Download PDF

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Publication number
WO2003064395A1
WO2003064395A1 PCT/JP2003/000884 JP0300884W WO03064395A1 WO 2003064395 A1 WO2003064395 A1 WO 2003064395A1 JP 0300884 W JP0300884 W JP 0300884W WO 03064395 A1 WO03064395 A1 WO 03064395A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
group
alkyl
pyrazolin
methyl
Prior art date
Application number
PCT/JP2003/000884
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English (en)
Japanese (ja)
Inventor
Hiide Yoshino
Original Assignee
President Of National Center Of Neurology And Psychiatry
Mitsubishi Pharma Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by President Of National Center Of Neurology And Psychiatry, Mitsubishi Pharma Corporation filed Critical President Of National Center Of Neurology And Psychiatry
Priority to JP2003564018A priority Critical patent/JPWO2003064395A1/ja
Publication of WO2003064395A1 publication Critical patent/WO2003064395A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms

Definitions

  • the present invention relates to a preventive or therapeutic agent for a neurodegenerative disease.
  • a neurodegenerative disease The definition of a neurodegenerative disease is unclear, and if it were to be defined, clinical manifestations of disorders of one system (for example, the pyramidal tract, the posterior chordal system, the spinocerebellar system, etc.) alone or in combination
  • a disease that gradually develops and gradually progresses, and whose true cause is unknown, is collectively referred to as a neurodegenerative disease. [Kanazawa, Ichiro: Latest. College of Internal Medicine, 68: p. 3, Nakayama Shoten (1 997)].
  • intractable neurodegenerative diseases or immune neurological diseases include Guillain-Barre syndrome (GBS: Guil 1 ia nBarre Syndrome), chronic demyelinating inflammatory polyneuropathy (CI DP) : Chronic Demyelinating In Irammatory Pollyneuropathy), Fisher syndrome, spinocerebellar degeneration, and Alzheimer's disease.
  • GBS affects about 2 in 100,000 people, and not only does paralysis of the limbs progress, but a quarter of the patients cannot breathe and may need a ventilator.
  • CIDP chronic neurodegenerative disorder
  • the affected area is the motor paralysis of the extremities, sensory paralysis (dullness, abnormal sensation) due to impairment of the motor nerves connected to the limbs and trunk muscles from the spinal cord and the sensory nerves entering the spinal cord from the skin and joints. Etc.) occur.
  • cranial nerve dysfunction causes eye movement paralysis (such as diplopia) and, rarely, respiratory paralysis.
  • Spinocerebellar degeneration is a general term for an unexplained degenerative disease whose main symptom is cerebellar or spinal ataxia, and whose lesion is located in the nucleus or conduction pathway of the cerebellum or spinal cord.
  • the onset is slow but progressive, and some types of disease are hereditary. Head C T and MR I often cause atrophy of the cerebellum and brain stem.
  • the main symptom is cerebellar or retrospinal ataxia, but some types have autonomic and spastic paraplegia as the main symptoms, as well as pyramidal and extrapyramidal symptoms. In some cases, the symptoms are variable.
  • Alzheimer's disease is a progressive dementia that develops in the elderly (45-65 years old). Pathologically, there are numerous senile plaques and neurofibrillary tangles in the brain. Senile dementia due to so-called spontaneous aging, which occurs in the senile period of 65 years or older, is called Alzheimer-type senile dementia because there is no essential difference in pathological conditions. The number of patients with this disease is increasing with the elderly population, making it a socially important disease.
  • Treatment of immune neurological disorders includes corticosteroid therapy, plasma exchange therapy, and immunoglobulin intravenous therapy.
  • the efficacy of high-dose intravenous immunoglobulin therapy and simple plasmapheresis has been established, but there is no effective therapeutic agent using a compound, and the development of an immediate therapeutic agent is desired. Disclosure of the invention
  • An object of the present invention is to provide a medicament useful for preventing and / or treating a neurodegenerative disease, preferably a refractory neurodegenerative disease or an immune neurological disease.
  • the present inventors have found that a medicament containing a pyrazolone derivative or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient has an inhibitory action on 3-NT level increase in cerebrospinal fluid, The present inventors have found that they are useful as agents for preventing and treating neurodegenerative diseases, and completed the present invention.
  • R 1 represents a hydrogen atom, aryl, alkyl having 1 to 5 carbons or alkoxycarbonylalkyl having 3 to 6 carbons
  • R 2 represents a hydrogen atom, aryloxy, aryl mercapto, and carbon atoms having 1 to 5 carbon atoms
  • 5 represents alkyl or 1 to 3 hydroxyalkyl
  • R 1 and R 2 together represent alkylene having 3 to 5 carbon atoms
  • R 3 represents a hydrogen atom, and 1 to 5 carbon atoms.
  • the prophylactic or therapeutic agent for a neurodegenerative disease of the present invention comprises 3-methyl-1-phenyl-2-pyrazolin-15-one or a physiologically acceptable salt thereof, or a hydrate or solvent thereof. It contains a sum as an active ingredient.
  • the preventive or therapeutic agent for a neurodegenerative disease of the present invention is a 3-NT value increase inhibitor.
  • the neurodegenerative disease caused by an increase in 3-NT level in the cerebrospinal fluid is an intractable neurodegenerative disease or an immune neurological disease.
  • the refractory neurodegenerative disease or immune neurological disease is Guillain-Barre syndrome Group, chronic demyelinating inflammatory polyneuritic peripheral neuritis, Fisher syndrome, spinocerebellar degeneration, and Alzheimer's disease.
  • a pyrazolone derivative represented by the above formula (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof is contained as an active ingredient.
  • —An NT value increase inhibitor is provided.
  • a 3-NT value increase inhibitor comprising 3-methinolay 1-phenyl-12-pyrazolin-15-one or a physiologically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.
  • a mammal comprising a human containing an effective amount of the pyrazolone derivative represented by the above formula (I), a physiologically acceptable salt thereof, or a hydrate or solvate thereof.
  • a method for preventing or treating a neurodegenerative disease caused by an increase in 3-NT level in cerebrospinal fluid comprising a step of administering to a animal.
  • a pyrazolone derivative represented by the formula (I) or a physiology thereof for producing a preventive or therapeutic agent for a neurodegenerative disease caused by an increase in 3-NT level in cerebrospinal fluid.
  • the use of chemically acceptable salts, or hydrates or solvates thereof, is provided.
  • the agent for preventing or treating a neurodegenerative disease according to the present invention is a pyrazolone derivative represented by the formula (I) defined herein or a physiologically acceptable salt thereof, or Includes hydrates or solvates thereof. Among these, it is preferable to use the above-mentioned monohydrate of the pyrazopine derivative.
  • the compound represented by the formula (I) used in the present invention has the following formula
  • the aryl group in the definition of R 1 may be a monocyclic or polycyclic aryl group.
  • alkyl groups such as methyl and butyl groups, alkoxy groups such as methoxy and butoxy groups, halogen atoms such as chlorine atoms, and phenyl substituted with substituents such as hydroxyl groups.
  • halogen atoms such as chlorine atoms
  • phenyl substituted with substituents such as hydroxyl groups.
  • substituents such as hydroxyl groups.
  • substituents and the like The same applies to the aryl moiety in other substituents having an aryl moiety (such as an aryloxy group).
  • R ⁇ R 2 and alkyl groups of 1 to 5 carbon atoms in the definition of R 3 are straight chain, it may be either branched. Examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and the like. The same applies to the alkyl moiety in other substituents having an alkyl moiety (alkoxycarbonylalkyl group).
  • Examples of the alkoxycarbonylalkyl group having 3 to 6 carbon atoms in the definition of R 1 include a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, a methoxycarbonylethyl group, and a methoxycarbonylpropyl group. .
  • the aryloxy group in the definition of R 2 includes p_methylphenoxy group, p-methoxyphenoxy group, p-chlorophenoxy group, p-hydroxyphenoxy group and the like. And a p-methylphenylmercapto group, a p-methoxyphenylmercapto group, a p-chlorophenylmercapto group, and a p-hydroxyphenylmercapto group.
  • Examples of the hydroxyalkyl group having 1 to 3 carbon atoms in the definition of R 2 and R 3 include hydr Roxymethyl group, 2-hydroxyl group, 3-hydroxypropyl group and the like.
  • Examples of the cycloalkyl group having 5 to 7 carbon atoms in the definition of R 3 include a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
  • R 3 it is a alkoxy group having 1 to 5 carbon atoms in the substituent of the phenyl group, main butoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, Penchiruokishi group and the like, total
  • the alkoxycarbonyl group having 2 to 5 carbon atoms include a methoxycanolebonyl group, an ethoxycanoleboninole group, a propoxycarboninole group, and a butoxycarbonyl group, and an alkylmercapto group having 1 to 3 carbon atoms.
  • Examples thereof include a methyl mercapto group, an ethyl mercapto group, and a propyl mercapto group.
  • Examples of the alkylamino group having 1 to 4 carbon atoms include a methylamino group, an ethylamino group, a propylamino group, and a butylamino group.
  • As the aralkylamino group having a total of 2 to 8 carbon atoms a dimethylamino group, a getylamino group, Puropirua amino group, Jibuchiruamino group and the like.
  • the compound (I) suitably used as an active ingredient of the drug of the present invention for example, the following compounds can be mentioned.
  • a free form compound represented by the formula (I) is physiologically acceptable.
  • Salts may be used.
  • Physiologically acceptable salts include salts with mineral acids such as hydrochloric acid, sulfuric acid, hydrogen bromide, and phosphoric acid; methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, glycolic acid, and glucuronic acid.
  • Salts with organic acids such as maleic acid, fumaric acid, oxalic acid, ascorbic acid, citric acid, salicylic acid, nicotinic acid, tartaric acid; Salts with alkali metals such as sodium and potassium; Salts with earth metals; ammonia, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyxethylene) piperazine, 2-amino-1-methyl-11-propanol, ethanolamine, N— And salts with amines such as methylglutamine and L-glutamine. Further, a salt with an amino acid such as glycine may be used.
  • a hydrate of the compound represented by the above formula (I) or a physiologically acceptable salt thereof, or a compound represented by the above formula (I) or a compound thereof A solvate of a physiologically acceptable salt may be used.
  • the type of the organic solvent that forms the solvate is not particularly limited, and examples thereof include methanol, ethanol, ether, dioxane, and tetrahydrofuran.
  • the compound represented by the above formula (I) may have one or more asymmetric carbons depending on the type of the substituent, and may have a stereoisomer such as an optical isomer or a diastereomer. is there.
  • pure stereoisomers, arbitrary mixtures of stereoisomers, racemates and the like may be used.
  • the administration form of the agent for preventing or treating a neurodegenerative disease of the present invention is not particularly limited, and it can be administered orally-parenterally. Preferably, it may be administered parenterally, intravenously by injection or infusion.
  • the prophylactic or therapeutic agent for a neurodegenerative disease of the present invention one or more of the pyrazolone derivative of the formula (I) or a salt thereof may be administered as it is to a patient.
  • a pharmacologically and pharmaceutically acceptable additive and are preferably provided as a formulation in a form known to those skilled in the art.
  • compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, solutions, and syrups.
  • preparations suitable for parenteral administration include: Examples include injections, drops, and suppositories.
  • Formulations suitable for oral administration include, as excipients, excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegrants such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium; Disintegration aid; Binder such as hydroxypropynolecellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; Lubricant such as magnesium stearate or talc; Hydroxypropylmethylcellulose , Sucrose, polyethylene dalicol or titanium oxide; and base materials such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, and hard fat.
  • excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose
  • disintegrants such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium
  • Disintegration aid such as hydroxypropynolecellulose, hydroxypropylmethyl
  • Suitable formulations for injection or infusion include: solubilizing agents or solubilizing agents which can constitute aqueous or ready-to-use injections, such as distilled water for injection, physiological saline, propylene glycol, etc .; glucose, sodium chloride, Pharmaceutical additives such as D-mannitol, glycerin and other tonicity agents; pH regulators such as inorganic acids, organic acids, inorganic bases and organic bases can be used.
  • Formulations suitable for injection or infusion include dissolving agents or dissolving agents which can constitute aqueous or ready-to-use injections, such as distilled water for injection, physiological saline, and propylene glycol.
  • dissolving agents or dissolving agents which can constitute aqueous or ready-to-use injections, such as distilled water for injection, physiological saline, and propylene glycol.
  • isotonic agents such as glucose, sodium salt, D-mannitol, glycerin, etc .
  • additives for pharmaceutical preparations such as pH adjusters such as inorganic acids, organic acids, inorganic bases or organic bases may be added. Les ,.
  • a brain protectant (drip) containing the pyrazolone derivative of the formula (I) as an active ingredient is already used in clinical practice (generic name: edaravone, trade name)
  • the dose of the medicament of the present invention can be appropriately selected depending on the purpose of preventing or treating a neurodegenerative disease, the age and condition of a patient, and the like. : Ability to administer about L0 OmgZkg by injection or infusion It is preferable to orally administer about 0.1 to 100 mg / kg. In the case of administration by injection, it is preferable to use, for example, injections described in JP-A-63-132833.
  • the above compound as an active ingredient of the medicament of the present invention is highly safe (mouse intraperitoneal LD 5 2012 mgZk g; rat oral LD 50 3, 500mg / kg: . R egistryof To xic E ifectsof Ch em ical Su bstances, 1981–1982), has also been shown to be noncarcinogenic (National Cancer Institute Report, 89, 1978).
  • the agent of the present invention may be a neurodegenerative disease caused by an increase in 3-NT level in cerebrospinal fluid, preferably a refractory neurodegenerative disease or an immune neurological disease, more preferably Guillain-Barre syndrome group, or chronic demyelinating inflammation. It is effective for the prevention or treatment of polyneuritis nervosa, Fisher syndrome, spinocerebellar degeneration, or Alzheimer's disease. That is, the cryogen of the present invention can be administered prophylactically prior to the onset of the above-mentioned neurodegenerative disease.
  • the agent of the present invention can be administered to the patient for the purpose of reduction or the like.
  • the agent of the present invention is also useful as an inhibitor of 3-NT level elevation in cerebrospinal fluid.
  • the present invention will be described in more detail with reference to the following examples. It is not limited to the examples. Example
  • ALS patients were infused intravenously with edaravone at 30 mgZ days for 2 weeks, and cerebrospinal fluid was collected before and after administration, and the 3-NT value in the cerebrospinal fluid was measured by enzyme immunoassay.
  • a nitrotyrosine measurement kit (Cayman Chemical, domestic agent Funakoshi) was used for EIA measurement, and statistical analysis was performed by the usual paired t-test.
  • the pyrazolone derivative of the formula (I) described in the present specification has an action of suppressing an increase in 3-NT level in cerebrospinal fluid, it prevents neurodegenerative diseases, in particular, intractable neurodegenerative diseases or immune neurological diseases.
  • a highly safe drug useful as a therapeutic agent can be provided.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne la production de médicaments efficaces dans la prévention et/ou le traitement de maladies neurodégénératives, notamment des maladies neurodégénératives incurables ou immunes. Cette invention produit des agents préventifs ou thérapeutiques destinés à traiter des maladies neurodégénératives causées par du liquide céphalorachidien 3-NT(3-nitrotyrosine) augmenté qui contient en tant que principe actif des dérivés pyrazolone représentés par la formule générale (I) ou des sels acceptables sur le plan physiologique de ceux-ci, des hydrates ou des solvates des deux, dans laquelle R1 représente un hydrogène, un aryle ou analogue; R2 représente un hydrogène, un aryloxy ou analogue; R3 représente un phényle supportant un à trois substituants.
PCT/JP2003/000884 2002-01-31 2003-01-30 Agents preventifs et therapeutiques destines a lutter contre des maladies neurodegeneratives WO2003064395A1 (fr)

Priority Applications (1)

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JP2003564018A JPWO2003064395A1 (ja) 2002-01-31 2003-01-30 神経変性疾患の予防又は治療剤

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JP2002-24794 2002-01-31

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012210413A (ja) * 2010-04-13 2012-11-01 Baxter Internatl Inc アルツハイマー病の静脈内免疫グロブリン処置における脳室拡大速度の使用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0208874A1 (fr) * 1985-05-20 1987-01-21 Mitsubishi Kasei Corporation Agent prophylactique et thérapeutique pour maladies de circulation du sang
JPH11292764A (ja) * 1998-04-07 1999-10-26 Mitsui Chem Inc グルタミン酸類が関与する疾患の治療および／または予防薬
JP2001172258A (ja) * 1999-12-17 2001-06-26 Sumitomo Pharmaceut Co Ltd 神経網膜変性疾患の治療薬

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0208874A1 (fr) * 1985-05-20 1987-01-21 Mitsubishi Kasei Corporation Agent prophylactique et thérapeutique pour maladies de circulation du sang
JPH11292764A (ja) * 1998-04-07 1999-10-26 Mitsui Chem Inc グルタミン酸類が関与する疾患の治療および／または予防薬
JP2001172258A (ja) * 1999-12-17 2001-06-26 Sumitomo Pharmaceut Co Ltd 神経網膜変性疾患の治療薬

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012210413A (ja) * 2010-04-13 2012-11-01 Baxter Internatl Inc アルツハイマー病の静脈内免疫グロブリン処置における脳室拡大速度の使用
JP2013509985A (ja) * 2010-04-13 2013-03-21 バクスター、インターナショナル、インコーポレイテッド アルツハイマー病の静脈内免疫グロブリン処置における脳室拡大速度の使用

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