WO2003078401A1 - Agent prophylactique et/ou therapeutique conçu pour un trouble cerebral ischemique hypoxique - Google Patents

Agent prophylactique et/ou therapeutique conçu pour un trouble cerebral ischemique hypoxique Download PDF

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Publication number
WO2003078401A1
WO2003078401A1 PCT/JP2003/003067 JP0303067W WO03078401A1 WO 2003078401 A1 WO2003078401 A1 WO 2003078401A1 JP 0303067 W JP0303067 W JP 0303067W WO 03078401 A1 WO03078401 A1 WO 03078401A1
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WO
WIPO (PCT)
Prior art keywords
pyrazolin
methyl
group
phenyl
carbon atoms
Prior art date
Application number
PCT/JP2003/003067
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English (en)
Japanese (ja)
Inventor
Tomoaki Ikeda
Tsuyomu Ikenoue
Original Assignee
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 Mitsubishi Pharma Corporation filed Critical Mitsubishi Pharma Corporation
Priority to AU2003213364A priority Critical patent/AU2003213364A1/en
Publication of WO2003078401A1 publication Critical patent/WO2003078401A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a medicament useful for preventing or treating hypoxic-ischemic encephalopathy, more preferably neonatal hypoxic-ischemic encephalopathy.
  • the fetus performs gas exchange in the uterus by the placenta, but when delivery approaches and labor becomes severe, gas exchange in the placenta stops.
  • the partial pressure of carbon dioxide (PC o 2 ) in the fetal blood increases and the partial pressure of oxygen (PO 2 ) decreases.
  • spontaneous respiration starts at the time of childbirth, so that the partial pressure of carbon dioxide (PC o 2 ) decreases and the partial pressure of oxygen (PO 2 ) increases and returns to normal.
  • aloprinol xanthine oxidase inhibitor
  • deferoxamine iron chelating agent
  • vitamin c vitamin E
  • antioxidants all of these compounds have reached clinical trials as prophylactic agents for hypoxic-ischemic encephalopathy. None has been found.
  • 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, carbon number 1 to R 1 and R 2 together represent alkylene having 3 to 5 carbon atoms
  • R 3 represents a hydrogen atom, alkyl having 1 to 5 carbon atoms, , Cycloalkyl having 5 to 7 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, benzyl, naphthyl or phenyl, or alkoxy having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, total carbon number Alkoxycarbonyl having 2 to 5 carbon atoms, alkyl mercapto having 1 to 3 carbon atoms, alkylamino having 1 to 4 carbon atoms, dialkylamino having 2 to 8 carbon atoms, halogen atom, trifluor
  • Japanese Patent Publication No. 5-315152 Japanese Patent Publication No. 5-315152
  • an inhibitory effect on lipid peroxide production a compound of Japanese Patent Publication No. 5-31528, Example 1
  • an anti-ulcer effect Japanese Patent Publication No. 3-215425
  • an effect of suppressing blood glucose elevation Japanese Unexamined Patent Application Publication No. 3-215426
  • various diseases and disorders that cause cerebral dysfunction are described as the brain function normalizing action (Japanese Patent Publication No. 5-315253), but these diseases are all intrinsic factors. It is understood to be due to.
  • An object of the present invention is to provide a medicament useful for prevention and / or treatment of hypoxic-ischemic encephalopathy.
  • the inventors of the present invention have made intensive efforts to solve the above-mentioned problems. And / or found to be useful for treatment, and completed the present invention.
  • the present invention relates to the following prophylactic and / or therapeutic agents for hypoxic-ischemic encephalopathy. '
  • a preventive and / or therapeutic agent for hypoxic-ischemic encephalopathy comprising, as an active ingredient, a substance selected from the group consisting of an acceptable salt thereof, an arbitrary hydrate thereof, and an arbitrary solvate thereof. .
  • hypoxic-ischemic encephalopathy is neonatal hypoxic-ischemic encephalopathy.
  • Birazolone derivative represented by the above formula (I) and a physiologically acceptable salt thereof, and any hydrates and any hydrates thereof, for the production of the above prophylactic and / or therapeutic agents Use of a substance selected from the group consisting of solvates.
  • a method for preventing and / or treating hypoxic-ischemic encephalopathy comprising a pyrazolone derivative represented by the above formula (I), a physiologically acceptable salt thereof, and any hydrate thereof. And administering a prophylactically and / or therapeutically effective amount of a substance selected from the group consisting of any solvates thereof to mammals including humans.
  • the pyrazolone derivative of the formula (I) contained in the prophylactic and / or therapeutic agent for hypoxic-ischemic encephalopathy of the present invention can be synthesized by any suitable method. Examples of preferable synthetic methods Examples thereof include a method described in JP-A-62-108814.
  • a pyrazolone derivative of the above formula (I) in a free form may be used as an active ingredient of the prophylactic and / or therapeutic agent for hypoxic-ischemic encephalopathy of the present invention.
  • any hydration of the above pyrazolone derivative or physiologically acceptable salt Or any solvate thereof can also be used.
  • the pyrazolone derivative has a tautomer (() or (1 ′)) represented by the chemical structural formula shown in the upper part of column 5 of JP-B-5-311523. Any of these isomers may be used as an active ingredient of the medicament of the present invention.
  • examples of the aryl group in the definition of R 1 include a phenyl group and a phenyl group substituted with a substituent such as a methyl group, a butyl group, a methoxy group, a butoxy group, a chlorine atom and a hydroxyl group.
  • a substituent such as a methyl group, a butyl group, a methoxy group, a butoxy group, a chlorine atom and a hydroxyl group.
  • Examples of the alkyl group having 1 to 5 carbon atoms in the definition of RR 2 and R 3 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. Is mentioned.
  • Examples of the alkoxycarbonylalkyl group having a total of 3 to 6 carbon atoms in the definition of R 1 include a methoxycanoleponylmethyl group, an ethoxycarbonylmethyl group, a propoxycanoleponylmethyl group, a methoxycarbonylethyl group, and a methoxycarbonylpropyl group. And the like.
  • the aryloxy group in the definition of R 2 includes a phenoxy group, a p-methylphenoxy group, a p-methoxyphenoxy group, a p-chlorophenoxy group, a p-hydroxyphenoxy group, and the like. Examples include a phenylmercapto group, a p-methylphenylmercapto group, a p-methoxyphenylmercapto group, a p-chlorobutyrmercapto 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 a hydroxymethyl group, a 2-hydroxyethyl group, a 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.
  • the alkoxycarbonyl group having 2 to 5 include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group.
  • the alkylmercapto group having 1 to 3 carbon atoms include a methylmercapto group, Ethyl mercapto group, propyl mercapto group, and the like.
  • the alkylamino group having 1 to 4 carbon atoms include a methylamino group, an ethylamino group, a propylamino group, a butylamino group, and the like.
  • Dialkylamino groups include dimethylamino group,
  • an acid addition salt or a base addition salt can be used.
  • mineral salts such as hydrochloride, sulfate, hydrobromide, or phosphate; methanesulfonate, paratoluenesulfonate, acetate, oxalate, citrate, malate
  • organic salts such as fumarate; metal salts such as sodium, potassium or magnesium salts; ammonium salts; or organic amine salts such as ethanolanol or 2-amino-2-methyl-1-propanol.
  • the type of salt is not particularly limited as long as it is physiologically acceptable.
  • the compound of formula (I) as an active ingredient, a physiologically acceptable salt thereof, and a hydrate or a hydrate thereof are provided.
  • One or more of the substances selected from the group consisting of these solvates may be administered to the patient as they are, but preferably the pharmacologically and pharmaceutically And a pharmaceutical composition in a form well known to those skilled in the art. Should be provided as a thing.
  • Pharmaceutically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegrants, binders, lubricants, coatings, pigments, diluents, bases, solvents
  • a peptizer or a solubilizing agent, a tonicity agent, a pH regulator, a stabilizer, a propellant, an adhesive, or the like can be used.
  • Examples of pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, and syrups.
  • Pharmaceutical compositions suitable for parenteral administration Examples thereof include an injection, a drip, and a suppository.
  • compositions suitable for oral administration include, as excipients, excipients such as pudose, lactose, D-mannitol, starch, and crystalline cellulose; carboxymethyl cellulose, starch, and calcium carboxymethyl cellulose.
  • Disintegrant or disintegration aid such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone or gelatin; lubricant such as magnesium stearate or talc; hydroxypropylmethylcellulose, sucrose, polyethylene Coating agents such as glycol or titanium oxide; bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, dextrin, glycerin, purified water, and hard fat can be used.
  • compositions suitable for injection or infusion include solubilizing agents or solubilizing agents which can constitute aqueous or ready-to-use injectables such as distilled water for injection, physiological saline, and oral pyrendalcol; glucose, chloride Pharmaceutical additives such as isotonic agents such as sodium, D-mannitol and glycerin; pH regulators such as inorganic acids, organic acids, inorganic bases and organic bases can be used.
  • compositions suitable for injection or infusion include solubilizers or dissolution aids that can constitute aqueous or ready-to-use injections, such as distilled water for injection, physiological saline, and oral pyrendalcol; glucose, Pharmaceutical additives such as isotonic agents such as sodium chloride, D-mannitol, and glycerin; PH regulators such as inorganic acids, organic acids, inorganic bases and organic bases may be added.
  • Brain protective agents containing the compound of the above formula (I) as an active ingredient are already available. (Generic name “Edaravone”, trade name “Radicat”: manufactured and sold by Mitsubishi Pharma Corporation) as a preventive and / or therapeutic agent for hypoxic-ischemic encephalopathy of the present invention.
  • the above commercial preparations can be used as they are.
  • hypoxic-ischemic encephalopathy includes neonatal hypoxic-ischemic encephalopathy.
  • the administration form of the preventive and / or therapeutic agent for hypoxic-ischemic encephalopathy of the present invention is not particularly limited, and it can be administered orally or parenterally. Preferably, it is administered parenterally, for example, intravenously by injection or infusion.
  • parenterally for example, intravenously by injection or infusion.
  • the medicament of the present invention prophylactically intravenously, intraarterially or intracardially to patients who have suffered massive bleeding or acute circulatory failure due to accidents or the like. If a considerable amount of bleeding is expected at the time of surgery, prior to the operation, the drug of the present invention should be administered orally by parenteral administration such as injection or infusion.
  • parenteral administration such as injection or infusion.
  • intravenously, intraarterially or intracardially by injection for the purpose of preventing the worsening of symptoms or reducing the symptoms.
  • the dose of the medicament of the present invention can be appropriately selected depending on the purpose of prevention or treatment of hypoxic-ischemic encephalopathy, the age and condition of the patient, and the like.
  • For administration by injection it is preferable to use, for example, injections described in JP-A-63-132833.
  • the above compound which is an active ingredient of the medicament of the present invention, is highly safe (LD 5 intraperitoneally administered to mice; 2012 mg / kg; LD orally administered to rats; 3,500 mg / kg: Registry of Toxiceffects of Chemical Sub stances, 1981-1982), and has also been shown to be non-carcinogenic (National Caneer Institute Report, 89, 1978).
  • LD 5 intraperitoneally administered to mice; 2012 mg / kg; LD orally administered to rats; 3,500 mg / kg: Registry of Toxiceffects of Chemical Sub stances, 1981-1982
  • mice Seven-day Wistar rats were used. Pregnant rats were purchased (Kudo Co., Ltd.), and the newborn rats that gave birth were divided into an experimental group and a control group on day 7 of life. Only rats in the normal weight range were used for the experiments. In addition, it was adjusted to have 7 to 12 pups per parent rat.
  • LeViline Levin, S., Am. J. Pathol., 36 (1960) 1-17 was used.
  • Ota et al.'S method (Ota, A., I keda, ⁇ ⁇ , I kenoue, T., To shimori, K., Am. J. Obset Gyn ecol, 177 (1997) 519-26)
  • the evaluation was judged as having neuropathy of 50% or more of the hemisphere area (severe), 25-50% (moderate), less than 25% (mild) and no neuropathy.
  • the test was performed using M a n n -W h i t n e y t e st, and p ⁇ 0.05 was significant.
  • the evaluation sites were the cerebral cortex, hippocampus (C A1, C A3, dentate gyrus), thalamus, and striatum.
  • Severe Neuropathy is recognized in 50% or more of the hemisphere area
  • the medicament of the present invention are useful in the prevention and ⁇ or treatment of hypoxic-ischemic encephalopathy c

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

Abstract

L'invention concerne un médicament destiné à être utilisé pour prévenir et/ou traiter des troubles cérébraux ischémiques hypoxiques, en particulier des troubles liés au travail que présentent les nouveau-nés. Ce médicament contient, en tant qu'ingrédient actif, une substance sélectionnée dans le groupe comprenant le composé 3-méthyl-1-phényl-2-pyrazolin-5-one, des dérivés de pyrazolone qui sont des analogues de celui-ci, leurs sels physiologiquement acceptables et n'importe quels hydrates ou solvants de ceux-ci.
PCT/JP2003/003067 2002-03-15 2003-03-14 Agent prophylactique et/ou therapeutique conçu pour un trouble cerebral ischemique hypoxique WO2003078401A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003213364A AU2003213364A1 (en) 2002-03-15 2003-03-14 Preventive and/or therapeutic agent for hypoxic ischemic brain disorder

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JP2002071595A JP2005343789A (ja) 2002-03-15 2002-03-15 低酸素性虚血性脳障害予防・治療剤
JP2002-71595 2002-03-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2677318A1 (fr) * 2011-02-16 2013-12-25 CellSeed Inc. Agent de marquage pour analyse des modifications post-traductionnelles de la sérine et de la thréonine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111116608B (zh) * 2020-01-10 2022-02-11 南京医科大学 一类具有自由基清除作用的n-苄基苯胺衍生物及其药物用途

Citations (1)

* 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

Patent Citations (1)

* 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

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ESPINOZA M.I. ET AL.: "Mechanisms of asphyxial brain damage and possible pharmacologic interventions, in the fetus", AM. J. OBSTET. GYNECOL., vol. 164, no. 6, pages 1582 - 1591, XP002968492 *
IKEDA TOMOAKI ET AL.: "Effect of the free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), on hypoxia-ischemia-induced brain injury in neonatal rats", NEUROSCIENCE LETTERS, vol. 329, no. 1, 2002, pages 33 - 36, XP002968490 *
KEIICHI SHINTOMI ET AL.: "Nicergoline ni kansuru yakurigaku-teki kenkyu (dai II ho)", NICHIYAKU ZASSHI, vol. 87, 1986, pages 427 - 434, XP002968496 *
RAJU T.N. ET AL.: "Effect of nimodipine on systemic, renal and cerebral haemodynamics after a mild hypoxic-ischaemic insult in newborn piglets", PHARMACOLOGICAL RESEARCH, vol. 33, no. 1, 1996, pages 5 - 12, XP002968497 *
WATANABE T. ET AL.: "Preventive effect of MCI-186 on 15-HPETE induced vascular endothelial cell injury in vitro", PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS, vol. 73, 1988, pages 81 - 87, XP002968491 *
WU TAI-WING ET AL.: "MCI-186: further histochemical and biochemical evidence of neuroprotection", LIFE SCIENCES, vol. 67, no. 19, 2000, pages 2387 - 2392, XP002968493 *
YOSHITAKE OMAE ET AL.: "Shikei dentatsu busshitsu kenren tanpaku no nonai donyu ni yoru shinseishi kyoketsusei noshogai no yobo", THE JOURNAL OF THE JAPAN PEDIATRIC SOCIETY, vol. 105, no. 3, 2001, pages 412, XP002968495 *
YOSHITAKE OMAE ET AL.: "Shinkei dentatsu busshitsu hoshutsu kanren tanpaku no nonai donyu ni yoru shinseishi kyoketsusei noshogai no yobo to chiryo", JOURNAL OF JAPAN SOCIETY FOR PREMATURE AND NEWBORN MEDICINE, vol. 12, no. 3, 2000, pages 368, XP002968494 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2677318A1 (fr) * 2011-02-16 2013-12-25 CellSeed Inc. Agent de marquage pour analyse des modifications post-traductionnelles de la sérine et de la thréonine
EP2677318A4 (fr) * 2011-02-16 2014-10-22 Cellseed Inc Agent de marquage pour analyse des modifications post-traductionnelles de la sérine et de la thréonine
JP6013197B2 (ja) * 2011-02-16 2016-10-25 株式会社セルシード セリン、スレオニンの翻訳後修飾解析用標識剤

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AU2003213364A1 (en) 2003-09-29

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