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WO1998035671A1 - Medicaments pour lutter contre le parkinsonisme - Google Patents

Medicaments pour lutter contre le parkinsonisme Download PDF

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Publication number
WO1998035671A1
WO1998035671A1 PCT/JP1998/000517 JP9800517W WO9835671A1 WO 1998035671 A1 WO1998035671 A1 WO 1998035671A1 JP 9800517 W JP9800517 W JP 9800517W WO 9835671 A1 WO9835671 A1 WO 9835671A1
Authority
WO
WIPO (PCT)
Prior art keywords
lower alkyl
alkyl group
levodopa
parkinsonism
group
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1998/000517
Other languages
English (en)
Japanese (ja)
Inventor
Masaya Kato
Hiroshi Iwata
Hiroshi Narita
Taiichi Katayama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Tanabe Pharma Corp
Original Assignee
Tanabe Seiyaku Co Ltd
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 Tanabe Seiyaku Co Ltd filed Critical Tanabe Seiyaku Co Ltd
Priority to AU57810/98A priority Critical patent/AU5781098A/en
Publication of WO1998035671A1 publication Critical patent/WO1998035671A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms

Definitions

  • the present invention relates to an agent for treating parkinsonism. More specifically, the present invention provides an effective therapeutic agent for parkinsonium alone or in combination with levodopa.
  • Parkinsonism The treatment of Parkinson's disease and Parkinson's syndrome (hereinafter collectively referred to as Parkinsonism) has focused on the administration of levodopa (L-13,4-dihydroxyphenylalanine; L-DOPA), a precursor of dopamine. I have been. Levodopa, unlike dopamine, can cross the blood-brain barrier, is converted to dopamine in the brain, and is known to improve symptoms of parkinsonism.
  • L-DOPA levodopa
  • An object of the present invention is to provide a therapeutic agent for parkinsonism which has an effective pharmacological action even when administered alone for parkinsonism, and a levodopa action enhancer which is effective in treating parkinsonism as a concomitant agent with levodopa.
  • This technical problem is solved by the embodiments described in the claims.
  • the present invention has surprisingly solved the problem of the present invention in a naphthyloxazolidone derivative (Japanese Patent Application Laid-Open No. 5-155772) which is known to have an antidepressant action. O It is based on the finding that there are compounds that have
  • the present invention provides a compound of the general formula (1)
  • R 1 represents a lower alkyl group which may be substituted with a cycloalkyl group
  • R 2 represents a lower alkyl group.
  • a pharmacologically acceptable salt thereof as an active ingredient The present invention relates to a therapeutic agent for nism.
  • the present invention relates to a levodopa action enhancer comprising, as an active ingredient, a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method for treating parkinsonism, comprising administering to a patient having parkinsonism a therapeutically effective amount of a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method for enhancing the action of levodopa by administering a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof to a patient receiving levodopa.
  • the present invention relates to the use of a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof for producing a medicament effective for treating parkinsonium.
  • R 1 represents a lower alkyl group which may be substituted with a cycloalkyl group.
  • the cycloalkyl group preferably has 3 to 6 carbon atoms, and particularly preferably a cyclopropyl group.
  • the lower alkyl group includes 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and particularly preferably a methyl group.
  • R 2 represents a lower alkyl group, preferably having 1 to 6 carbon atoms, more preferably having 1 to 4 carbon atoms, and particularly preferably a methyl group.
  • the compound of the general formula (1) has optical isomers, and in the present invention, any of the isomers or a mixture thereof may be used.
  • Specific examples of preferred examples of the compound represented by the general formula (1) include a compound in which R 1 is a lower alkyl group substituted with a cyclopropyl group.
  • a compound in which R 2 is a methyl group is more preferable.
  • (R) -3- (6- (cyclopropylpyrmethoxy) -12-naphthyl) -5-methoxymethyl-2-oxazolidone is a preferred example.
  • the compound of the general formula (1) used in the present invention is a known substance and can be easily synthesized, for example, by the method described in JP-A-3-218367. Japanese Unexamined Patent Publication No.
  • the compound represented by the general formula (1) can be used as a therapeutic agent or a levodopa action enhancer of the present invention either in a free form or in the form of a pharmaceutically acceptable salt thereof.
  • the pharmacologically acceptable salt is not particularly limited, but is a salt with an inorganic or organic base, for example, an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal such as a calcium salt or a magnesium salt. Salts, ammonium salts and the like, or inorganic or organic acid addition salts such as hydrochloride, sulfate, acetate and benzenesulfonate. I can do it.
  • the therapeutic agent and the levodopa action enhancer of the present invention contain the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient as described above.
  • various pharmacological experiments using mice have shown that it has an effective pharmacological action as a therapeutic agent for parkinsonism alone or as a levodopa action enhancer when used in combination with levodopa.
  • the therapeutic agent and the levodopa action enhancer of the present invention are useful as a therapeutic agent for parkin finism in mammals, thereby providing an effective method for treating parkinsonism and a method for enhancing levodopa action.
  • it is useful because it can be expected to reduce the levodopa dose in patients receiving levodopa.
  • the compound of the general formula (1) is considered to be effective in treating Parkinsonism because it has any action.
  • the compound of the general formula (1) is useful even when administered alone as a therapeutic agent for parkinsonism due to the action of increasing the amount of dopamine in the striatum, and can be used as a levodopa action enhancer due to the action of enhancing levodopa. It is considered to be effective for treatment.
  • Parkinsonism is a disease involving degeneration and shedding of nerve cells. Therefore, administration of a compound having a nerve cell protective effect is expected to prevent the progression of parkinsonism.
  • the compound of the general formula (1) has been shown to have a life-prolonging effect in a low-pressure and low-oxygen state, and is considered to have a neuroprotective effect. .
  • Reserpine-induced akinesia is thought to be associated with parkinsonism akinesia.
  • the compound of the general formula (1) exhibits a strong antagonistic effect on reserpine-induced akinesia, which is more effective than the effects of amanthuin gin and deprenyl hydrochloride, which are used as a therapeutic agent for parkinsonism. Since it is powerful, it is considered to be effective as a therapeutic agent for parkinsonism.
  • the amount of the compound of the present invention to be administered in the treatment method of the present invention and the method for enhancing levodopa action varies depending on the age / weight / status of a patient with parkinsonism requiring the treatment, the degree of disease, and the like.
  • the compound of 1) or a pharmaceutically acceptable salt thereof is usually administered at 0.01 to 25 O mg Z kg per day.
  • the therapeutic agent and the levodopa action enhancer of the present invention are capable of being administered orally or parenterally. In particular, it is preferably administered orally.
  • the dosage form for oral administration may be a solid preparation such as tablets, powders, capsules, and granules, or a liquid preparation such as a solution or a suspension, together with a pharmaceutical carrier suitable for oral administration. It can be used as a pharmaceutical preparation.
  • Such pharmaceutical carriers include, for example, binders (syrup, gum arabic, gelatin, sorbite, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, phosphate, sorbite, glycine, etc.) Lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (potato starch, etc.) and wetting agents (sodium lauryl sulfate, etc.).
  • dosage forms for parenteral administration include, for example, distilled water for injection, physiological saline, and It is preferable to use an aqueous solution of dextrose or the like to prepare an injection or an infusion.
  • the compound of the general formula (1) has extremely low toxicity, and is an active ingredient of the present invention in five mice (SIc: ddY strain, male) (R) —3— [6- (cyclopropylmethine). Toxi) 12-naphthyl] -15-methoxymethyl-2-oxazolidone 2 / kg was orally administered and observed for 2 weeks. No deaths were observed.
  • parkinsonism is a general term for Parkinson's disease and Parkinson's syndrome as described above.
  • the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
  • the compound of the present invention (R) -3- [6- (cyclopropylmethoxy) -12-naphthyl] -15-methoxymethyl-2-oxazolidone used in each example is disclosed in Japanese Patent Application Laid-Open No. 3-218183.
  • the compound was synthesized according to the description in Example 27 of JP-A No. 67. Amandine gin hydrochloride and deprenyl hydrochloride, which are used as therapeutic agents for parkinsonism, were used as comparative control drugs.
  • the compound (R) -3- [6- (cyclopropylmethoxy) -2- (naphthyl) -1-5-methoxymethyl-2-oxazolidone of the compound of the present invention is converted to 0.5% carboxymethylcellulose Na (CMC. Na, And suspended orally at a dose of 1 OmgZkg to eight S1c: SD male rats (10 weeks old, Japan SLC, Inc.) in 8 animals per group. Two hours after administration, the brain tissue is excised, the striatum is divided and collected, Dopamine levels in stria were measured by high performance liquid chromatography-electrochemical detection.
  • the striatum was collected 4 hours after oral administration at a dose of 1 Omg / kg and the amount of dopamine was measured.
  • 0.5% of CMC. Na containing no drug was similarly administered.
  • the compound of the present invention increased the amount of cerebral striatal dopamine by about 15% as compared with the control group.
  • Deprenyl hydrochloride did not affect dopamine levels.
  • Test drug is the dose giving levodopa enhanced rate of 50% and ED 50, ED 5 assumes a probit interface model. Values and 95% confidence limits were calculated.
  • Repodopa enhancement rate (%) 100 x (the number of individuals in the group that showed excitement behavior 10)
  • Lepodopa was dissolved in physiological saline and administered intraperitoneally at a dose of 1 OmlZkg.
  • the compound of the present invention was suspended in 0.5% carboxymethylcellulose Na (CMC. Na, manufactured by Wako Pure Chemical Industries, Ltd.) and orally administered at a dose of 1 OmlZkg.
  • the comparative drug deprenyl hydrochloride was dissolved in distilled water and orally administered at a dose of 10 ml / kg.
  • As a control group 0.5% CMC. Na containing no drug was similarly administered.
  • the compound of the present invention increased the survival time by about 28% compared to the control group (p ⁇ 0.05). It is generally known that a drug that exerts a central inhibitory effect has a prolonged life effect (neurocellular protective effect) at the dose at which it is expressed. Limited. The fact that the compound of the present invention exhibited a life-prolonging effect at a dose in which central depression was not recognized indicates that the compound of the present invention is useful in clinically for diseases associated with neurological deficits such as parkinsonism. It suggests the possibility of having a transcellular protective effect.
  • Example 4 Example 4
  • Effect on akinesia is a dose for inhibiting the onset of symptoms in 50% of animals ED 5.
  • the ED 50 value was determined using a probit model.
  • a similar test was carried out using amandine gin hydrochloride and debrenyl hydrochloride as comparative control drugs.
  • reserpine manufactured by Sigma was prepared according to the method described in JP-B-32-145 and injected intraperitoneally at a dose of 10 m 1 / kg. That is, 12.5 cc of 1% orthophosphoric acid, 12.5 g of propylene glycol and 50 cc of distilled water are added to 25 Omg of reservin, and then 5.0 g of benzyl alcohol and distilled water are added to make the total amount. It was 500 cc.
  • the compound of the present invention was suspended in 0.5% carboxymethylcellulose Na (CMC.
  • a therapeutic agent effective for parkinsonism alone or in combination with levodopa has an effect of increasing the amount of dopamine in the striatum, an effect of enhancing levodopa, an effect of prolonging life under low pressure and hypoxia, and an effect of antagonizing reserpine-induced akinesia. It has excellent pharmacological effects.
  • a levodopa action enhancer effective for treating parkinsonism as a concomitant drug with levodopa.

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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)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne des médicaments pour lutter contre le parkinsonisme, présentant des effets pharmacologiques efficaces, même s'ils sont administrés seuls. L'invention concerne également des potentialisateurs de lévodopa efficaces en tant que médicament à utiliser en combinaison avec la lévodopa pour le traitement du parkinsonisme, chacun contenant, en tant que principe actif, des composés représentés par la formule (1) et leurs sels pharmaceutiquement acceptables. Dans la formule, R1 représente alkyle inférieur éventuellement substitué par cycloalkyle; et R2 représente alkyle inférieur.
PCT/JP1998/000517 1997-02-14 1998-02-06 Medicaments pour lutter contre le parkinsonisme Ceased WO1998035671A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57810/98A AU5781098A (en) 1997-02-14 1998-02-06 Remedies for parkinsonism

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/47042 1997-02-14
JP04704297A JP3865450B2 (ja) 1997-02-14 1997-02-14 パーキンソニズム治療剤

Publications (1)

Publication Number Publication Date
WO1998035671A1 true WO1998035671A1 (fr) 1998-08-20

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Application Number Title Priority Date Filing Date
PCT/JP1998/000517 Ceased WO1998035671A1 (fr) 1997-02-14 1998-02-06 Medicaments pour lutter contre le parkinsonisme

Country Status (3)

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JP (1) JP3865450B2 (fr)
AU (1) AU5781098A (fr)
WO (1) WO1998035671A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2386458C1 (ru) * 2008-09-04 2010-04-20 Государственное Учреждение Научный Центр Неврологии Российской Академии Медицинских Наук Способ лечения болезни паркинсона

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0401842D0 (sv) 2004-07-12 2004-07-12 Dizlin Medical Design Ab Infusion and injection solution of levodopa

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03218367A (ja) * 1989-10-26 1991-09-25 Tanabe Seiyaku Co Ltd ナフチルオキサゾリドン誘導体、その製法及びその合成中間体
JPH05155772A (ja) * 1991-04-25 1993-06-22 Tanabe Seiyaku Co Ltd 抗うつ剤
JPH07196634A (ja) * 1993-12-13 1995-08-01 F Hoffmann La Roche Ag オキサゾリジン−２−オン誘導体
WO1997017346A1 (fr) * 1995-11-09 1997-05-15 Synthelabo Composes derives de 3-(benzofuran-5-yl) oxazolidin-2-one, leur preparation et leur application en therapeutique
WO1997017347A1 (fr) * 1995-11-09 1997-05-15 Synthelabo Composes derives d'oxazolidin-2-one, leur preparation et leur application en therapeutique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03218367A (ja) * 1989-10-26 1991-09-25 Tanabe Seiyaku Co Ltd ナフチルオキサゾリドン誘導体、その製法及びその合成中間体
JPH05155772A (ja) * 1991-04-25 1993-06-22 Tanabe Seiyaku Co Ltd 抗うつ剤
JPH07196634A (ja) * 1993-12-13 1995-08-01 F Hoffmann La Roche Ag オキサゾリジン−２−オン誘導体
WO1997017346A1 (fr) * 1995-11-09 1997-05-15 Synthelabo Composes derives de 3-(benzofuran-5-yl) oxazolidin-2-one, leur preparation et leur application en therapeutique
WO1997017347A1 (fr) * 1995-11-09 1997-05-15 Synthelabo Composes derives d'oxazolidin-2-one, leur preparation et leur application en therapeutique

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2386458C1 (ru) * 2008-09-04 2010-04-20 Государственное Учреждение Научный Центр Неврологии Российской Академии Медицинских Наук Способ лечения болезни паркинсона

Also Published As

Publication number Publication date
JP3865450B2 (ja) 2007-01-10
JPH10226646A (ja) 1998-08-25
AU5781098A (en) 1998-09-08

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