JPH10226646A - Therapeutic agent of parkinsonism - Google Patents
Therapeutic agent of parkinsonismInfo
- Publication number
- JPH10226646A JPH10226646A JP9047042A JP4704297A JPH10226646A JP H10226646 A JPH10226646 A JP H10226646A JP 9047042 A JP9047042 A JP 9047042A JP 4704297 A JP4704297 A JP 4704297A JP H10226646 A JPH10226646 A JP H10226646A
- Authority
- JP
- Japan
- Prior art keywords
- parkinsonism
- levodopa
- therapeutic agent
- administered
- compound
- 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.)
- Granted
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
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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
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、パーキンソニズム
治療剤に関する。さらに詳しくは、パーキンソニズムに
対して単独もしくはレボドパとの併用で有効な治療剤が
提供される。TECHNICAL FIELD The present invention relates to a therapeutic agent for parkinsonism. More specifically, a therapeutic agent effective for parkinsonism alone or in combination with levodopa is provided.
【０００２】[0002]
【従来の技術】パーキンソン病およびパーキンソン症候
群（以下、パーキンソニズムと総称する）の治療は、こ
れまでドパミンの前駆体であるレボドパ（Ｌ−３，４−
ジヒドロキシフェニルアラニン；Ｌ−ＤＯＰＡ）の投与
を中心に行われてきた。レボドパは、ドパミンと異なり
血液脳関門を通過でき、脳内でドパミンに変換され、パ
ーキンソニズムの症状を改善することが知られている。
しかし、投与されたレボドパのほとんどは末梢組織で急
速にドパミンに変換され、脳内に取り込まれるレボドパ
の量が少ないことから、脳線条体で不足したドパミンを
補充するためにはレボドパの大量投与が必須とされてい
る。また、レボドパは消化器症状（悪心、嘔吐等）、循
環器症状（起立性低血圧等）、精神症状（興奮、不穏
等）、神経症状（異常不随意運動等）等の副作用を発現
するという問題があり、レボドパに替わるパーキンソニ
ズム治療剤、またはレボドパ投与量を軽減させる併用剤
の開発が期待されている。2. Description of the Related Art The treatment of Parkinson's disease and Parkinson's syndrome (hereinafter collectively referred to as Parkinsonism) has been carried out by using levodopa (L-3,4-) which is a precursor of dopamine.
Dihydroxyphenylalanine (L-DOPA). Levodopa, unlike dopamine, can cross the blood-brain barrier, is converted to dopamine in the brain, and is known to improve the symptoms of parkinsonism.
However, most of the administered levodopa is rapidly converted to dopamine in peripheral tissues, and the amount of levodopa taken up in the brain is small, so large amounts of levodopa are administered to replace dopamine deficient in the striatum of the brain Is required. Levodopa also produces side effects such as gastrointestinal symptoms (nausea, vomiting, etc.), cardiovascular symptoms (orthostatic hypotension, etc.), mental symptoms (excitation, restlessness, etc.), and neurological symptoms (abnormal involuntary movement, etc.). There is a problem, and development of a therapeutic agent for parkinsonism that replaces levodopa or a combination drug that reduces the dose of levodopa is expected.
【０００３】[0003]
【発明が解決しようとする課題】本発明の目的は、パー
キンソニズムに対して単独投与でも有効な薬理作用を有
するパーキンソニズム治療剤を提供することにある。本
発明の他の目的は、レボドパの併用剤としてパーキンソ
ニズムの治療に有効なレボドパ作用増強剤が提供され
る。SUMMARY OF THE INVENTION 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. Another object of the present invention is to provide a levodopa action enhancer which is effective for treating parkinsonism as a combination drug of levodopa.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、前記課題
を解決するために鋭意検討した結果、抗うつ作用を有す
ることが知られているナフチルオキサゾリドン誘導体
（特開平５−１５５７７２号公報）の中に、意外にも本
発明の目的を達成しえる薬理作用を有する化合物が存在
することを見いだし、本発明を完成するに到った。Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that naphthyl oxazolidone derivatives which are known to have antidepressant action (Japanese Patent Laid-Open No. 5-155772). Among them, the present inventors have found that there is a compound having a pharmacological action capable of surprisingly achieving the object of the present invention, and completed the present invention.
【０００５】即ち、本発明の要旨は、一般式（１）That is, the gist of the present invention is that the general formula (1)
【０００６】[0006]
【化３】 Embedded image
【０００７】（式中、Ｒ1 はシクロアルキル基で置換さ
れていてもよい低級アルキル基、Ｒ2は低級アルキル基
を表す。）で示される化合物又はその薬理的に許容し得
る塩を有効成分とするパーキンソニズム治療剤に関す
る。本発明はさらに、一般式（１）で示される化合物又
はその薬理的に許容し得る塩を有効成分とするレボドパ
作用増強剤に関する。Wherein R 1 represents a lower alkyl group which may be substituted by a cycloalkyl group, and R 2 represents a lower alkyl group, or a pharmaceutically acceptable salt thereof as an active ingredient. Parkinsonism therapeutic agent. The present invention further 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.
【０００８】[0008]
【発明の実施の形態】一般式（１）において、Ｒ1 はシ
クロアルキル基で置換されていてもよい低級アルキル基
を表す。シクロアルキル基としては炭素数３〜６のもの
が好ましく、特にシクロプロピル基が好ましい。低級ア
ルキル基としては炭素数１〜６が挙げられ、特にメチル
基が好ましい。Ｒ2 は低級アルキル基を表し、炭素数１
〜６が好ましく、特にメチル基が好ましい。一般式
（１）の化合物には、光学異性体が存在するが、本発明
ではいずれの異性体であってもよく又はその混合物であ
ってもよい。BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (1), R 1 represents a lower alkyl group which may be substituted with a cycloalkyl group. As the cycloalkyl group, one having 3 to 6 carbon atoms is preferable, and a cyclopropyl group is particularly preferable. The lower alkyl group has 1 to 6 carbon atoms, and a methyl group is particularly preferable. R 2 represents a lower alkyl group and has 1 carbon atom
To 6 are preferable, and a methyl group is particularly preferable. 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.
【０００９】一般式（１）の化合物の好適例を具体的に
挙げると、Ｒ1 がシクロプロピル基で置換された低級ア
ルキル基である化合物が好ましく、この場合、さらにＲ
2 がメチル基である化合物が好ましい。即ち、例えば
（Ｒ）−３−〔６−（シクロプロピルメトキシ）−２−
ナフチル〕−５−メトキシメチル−２−オキサゾリドン
が好適例として挙げられる。その他にも、（Ｒ）−３−
〔６−（ｎ−プロポキシ）−２−ナフチル〕−５−メト
キシメチル−２−オキサゾリドン、（Ｒ）−３−〔６−
（ｎ−ブトキシ）−２−ナフチル〕−５−メトキシメチ
ル−２−オキサゾリドン、（Ｒ）−３−（６−エトキシ
−２−ナフチル）−５−メトキシメチル−２−オキサゾ
リドン等の化合物も好適なものとして挙げられる。本発
明で用いる一般式（１）の化合物は、既知物質であり、
例えば特開平３−２１８３６７号公報に記載の方法によ
り容易に合成することができる。Specific examples of preferred compounds of the general formula (1) include those wherein R 1 is a lower alkyl group substituted by a cyclopropyl group.
Compounds in which 2 is a methyl group are preferred. That is, for example, (R) -3- [6- (cyclopropylmethoxy) -2-
Naphthyl] -5-methoxymethyl-2-oxazolidone is a preferred example. In addition, (R) -3-
[6- (n-propoxy) -2-naphthyl] -5-methoxymethyl-2-oxazolidone, (R) -3- [6-
Compounds such as (n-butoxy) -2-naphthyl] -5-methoxymethyl-2-oxazolidone and (R) -3- (6-ethoxy-2-naphthyl) -5-methoxymethyl-2-oxazolidone are also suitable. Are listed. The compound of the general formula (1) used in the present invention is a known substance,
For example, it can be easily synthesized by the method described in JP-A-3-21867.
【００１０】一般式（１）の化合物は、遊離の形でもま
たその薬理的に許容し得る塩の形でも本発明の治療剤ま
たはレボドパ作用増強剤として用いることができる。薬
理的に許容し得る塩としては、特に限定されるものでは
ないが、無機又は有機塩基との塩、例えばナトリウム
塩、カリウム塩の如きアルカリ金属塩、カルシウム塩、
マグネシウム塩の如きアルカリ土類金属塩、アンモニウ
ム塩等、あるいは無機又は有機酸付加塩、例えば塩酸
塩、硫酸塩、酢酸塩、ベンゼンスルホン酸塩等があげら
れる。The compound of the general formula (1) can be used as a therapeutic agent or a levodopa action enhancer of the present invention in a free form or in the form of a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts are not particularly limited, and salts with inorganic or organic bases, such as sodium salts, alkali metal salts such as potassium salts, calcium salts,
Examples thereof include alkaline earth metal salts such as magnesium salts, ammonium salts and the like, and inorganic or organic acid addition salts such as hydrochloride, sulfate, acetate and benzenesulfonate.
【００１１】本発明の治療剤およびレボドパ作用増強剤
は、前記のような一般式（１）の化合物又はその薬理的
に許容し得る塩を有効成分とするものであり、次のよう
な各種の薬理実験によりパーキンソニズム治療薬として
単独投与で、あるいはレボドパとの併用時にはレボドパ
作用増強剤として有効な薬理作用を有することが示され
ている。特に、レボドパ作用増強剤として使用する場合
は、レボドパ投与量を軽減させることが期待できるので
有用である。The therapeutic agent and the levodopa action enhancer of the present invention comprise the above-mentioned compound of the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmacological experiments have shown that it has an effective pharmacological action as a levodopa action enhancer when administered alone as a therapeutic agent for parkinsonism or when used in combination with levodopa. In particular, when used as a levodopa action enhancer, it is useful because it can be expected to reduce the dose of levodopa.
【００１２】（１）脳線条体内ドパミン量の増加作用、
レボドパ増強作用 脳内のドパミン量を増加させる薬物またはレボドパの作
用を増強させる薬物は、パーキンソニズムの治療に有効
であると考えられているが、一般式（１）の化合物は、
いずれの作用も有することから、パーキンソニズムの治
療に有効であると考えられる。即ち、一般式（１）の化
合物は、脳線条体内ドパミン量の増加作用によりパーキ
ンソニズム治療剤として単独投与でも有用であると共
に、レボドパ増強作用によりレボドパ作用増強剤として
使用できるのでパーキンソニズムの治療に有効であると
考えられる。(1) an action of increasing the amount of dopamine in the striatum;
Levodopa enhancing action Drugs that increase the amount of dopamine in the brain or drugs that enhance the action of levodopa are thought to be effective in treating Parkinsonism, but the compound of general formula (1)
Since it has both effects, it is considered to be effective for treating Parkinsonism. That is, 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 of the brain, and can be used as a levodopa action enhancer due to the action of enhancing levodopa, thereby treating parkinsonism. Is considered to be effective.
【００１３】（２）低圧低酸素状態での延命効果 パーキンソニズムは神経細胞の変性・脱落を伴う疾患で
あるため、神経細胞保護作用を有する化合物を投与する
ことにより、パーキンソニズムの進行を防ぐ作用が期待
される。一般式（１）の化合物は、低圧低酸素状態で延
命効果が認められており、神経細胞保護作用を有するも
のと考えられるので、この点からもパーキンソニズムの
治療剤として有効であると考えられる。(2) Life extension effect under low pressure and low oxygen state Parkinsonism is a disease accompanied by degeneration and loss of nerve cells. Therefore, administration of a compound having a nerve cell protective effect prevents the progression of parkinsonism. There is expected. 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 neuronal protective effect. From this point of view, it is considered that the compound is also effective as a therapeutic agent for parkinsonism. .
【００１４】（３）レセルピン誘発無動症拮抗作用 レセルピンに誘発される無動症はパーキンソニズムの無
動と関連があると考えられている。一般式（１）の化合
物は、レセルピンに誘発される無動症に対して強い拮抗
作用を示し、その作用はパーキンソニズム治療剤として
用いられている塩酸アマンタジン、塩酸デプレニル等の
作用よりも強力であることから、パーキンソニズム治療
剤として有効であると考えられる。(3) Antagonism of reserpine-induced akinesia It is believed that reserpine-induced akinesia is associated with parkinsonism akinesia. The compound of the general formula (1) shows a strong antagonistic effect on reserpine-induced akinesia, which is more potent than the effects of amantadine hydrochloride, deprenyl hydrochloride, etc., which are used as a therapeutic agent for parkinsonism. Therefore, it is considered to be effective as a therapeutic agent for parkinsonism.
【００１５】本発明の治療剤およびレボドパ作用増強剤
の投与量は、患者の年齢・体重・状態あるいは疾患の程
度などにより異なるが、一般式（１）の化合物又はその
薬理的に許容し得る塩を通常１日当たり０．０１〜２５
０ｍｇ／ｋｇ投与する。本発明の治療剤およびレボドパ
作用増強剤は、経口的にも非経口的にも投与することが
できるが、とりわけ、経口的に投与するのが好ましい。The dose of the therapeutic agent and the levodopa action enhancer of the present invention varies depending on the age, weight, condition and degree of disease of the patient, but the compound of the general formula (1) or a pharmaceutically acceptable salt thereof. Is usually 0.01 to 25 per day
Administer 0 mg / kg. Although the therapeutic agent and the levodopa action enhancer of the present invention can be administered orally or parenterally, it is particularly preferable to administer orally.
【００１６】経口投与する場合の剤形は、錠剤、散剤、
カプセル剤、顆粒剤の如き固形剤であってもよく、溶
液、懸濁液の如き液剤であってもよく、経口投与に適し
た医薬担体と共に、医薬製剤として使用することができ
る。かかる医薬担体としては、例えば、結合剤（シロッ
プ、アラビアゴム、ゼラチン、ソルビット、トラガン
ト、ポリビニルピロリドン等）、賦形剤（乳糖、砂糖、
コーンスターチ、リン酸カリウム、ソルビット、グリシ
ン等）、滑沢剤（ステアリン酸マグネシウム、タルク、
ポリエチレングリコール、シリカ等）、崩壊剤（バレイ
ショデンプン等）及び湿潤剤（ラウリル硫酸ナトリウム
等）があげられる。For oral administration, dosage forms include tablets, powders,
It may be a solid preparation such as a capsule or a granule, or a liquid preparation such as a solution or a suspension, and may be used as a pharmaceutical preparation together with a pharmaceutical carrier suitable for oral administration. Such pharmaceutical carriers include, for example, binders (syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar,
Corn starch, potassium phosphate, sorbite, glycine, etc.), lubricants (magnesium stearate, talc,
Polyethylene glycol, silica, etc.), disintegrants (potato starch, etc.) and wetting agents (sodium lauryl sulfate, etc.).
【００１７】一方、非経口投与する場合の剤形は、例え
ば、注射用蒸留水、生理食塩水、ブドウ糖水溶液等を用
いて、注射剤や点滴注射剤とするのが好ましい。On the other hand, for parenteral administration, the dosage form is preferably an injection or drip injection using, for example, distilled water for injection, physiological saline, aqueous glucose solution or the like.
【００１８】また、一般式（１）の化合物は、毒性が極
めて低く、マウス（Ｓｌｃ：ｄｄＹ系、雄性）５匹に本
発明の有効成分である（Ｒ）−３−〔６−（シクロプロ
ピルメトキシ）−２−ナフチル〕−５−メトキシメチル
−２−オキサゾリドン２ｇ／ｋｇを経口投与し、２週間
観察したが、死亡例は観察されなかった。また、その薬
理作用は顕著であり、後述の実施例で示すようにパーキ
ンソニズムに対する治療剤として使用されている塩酸ア
マンタジン及び塩酸デプレニルと比較してより際立った
効果を示すので、パーキンソニズム治療剤またはレボド
パ作用増強剤として有用性が高い。なお、本明細書にお
いて、パーキンソニズムとは前記のようにパーキンソン
病とパーキンソン症候群の総称である。Further, the compound of the general formula (1) has extremely low toxicity, and the compound (R) -3- [6- (cyclopropyl), which is an active ingredient of the present invention, is present in five mice (Slc: ddY strain, male). Methoxy) -2-naphthyl] -5-methoxymethyl-2-oxazolidone was orally administered at 2 g / kg, and observed for 2 weeks. No deaths were observed. Further, since its pharmacological action is remarkable and shows a more prominent effect as compared with amantadine hydrochloride and deprenyl hydrochloride which are used as therapeutic agents for parkinsonism, as shown in Examples below, the therapeutic agent for parkinsonism or It is highly useful as a levodopa action enhancer. In this specification, parkinsonism is a general term for Parkinson's disease and Parkinson's syndrome as described above.
【００１９】[0019]
【実施例】以下、実施例により本発明をさらに詳しく説
明するが、本発明はこれらの実施例によりなんら限定さ
れるものではない。なお、各実施例で用いる本発明化合
物である（Ｒ）−３−〔６−（シクロプロピルメトキ
シ）−２−ナフチル〕−５−メトキシメチル−２−オキ
サゾリドンは、特開平３−２１８３６７号公報の実施例
２７の記載に従って合成した。また、比較対照薬として
は、パーキンソニズム治療剤として使用されている塩酸
アマンタジン及び塩酸デプレニルを用いた。EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention. In addition, the compound of the present invention (R) -3- [6- (cyclopropylmethoxy) -2-naphthyl] -5-methoxymethyl-2-oxazolidone used in each Example is described in JP-A-3-21867. Synthesized according to the description in Example 27. In addition, amantadine hydrochloride and deprenyl hydrochloride used as therapeutic agents for parkinsonism were used as comparative control drugs.
【００２０】実施例１ラット脳線条体内ドパミン量の増加作用 本発明化合物の（Ｒ）−３−〔６−（シクロプロピルメ
トキシ）−２−ナフチル〕−５−メトキシメチル−２−
オキサゾリドンを０．５％カルボキシメチルセルロース
Ｎａ（ＣＭＣ．Ｎａ、和光純薬工業社製）に懸濁し、１
０ｍｇ／ｋｇの用量で、１群８匹のＳｌｃ：ＳＤ系雄性
ラット（１０週齢、日本エスエルシー社）に経口投与し
た。投与２時間後に脳組織を摘出し、線条体を分割採取
し、脳線条体内ドパミン量を高速液体クロマトグラフィ
ー−電気化学的検出法で測定した。比較対照薬として塩
酸デプレニルを用い、１０ｍｇ／ｋｇの用量で同様にし
て経口投与の４時間後に脳線条体を採取してドパミン量
を測定した。対照群として薬物を含有しない０．５％の
ＣＭＣ．Ｎａを同様に投与した。その結果、表１に示す
ように、本発明化合物は脳線条体ドパミン量を対照群と
比較して約１５％増加させた。塩酸デプレニルはドパミ
ン量に影響を与えなかった。Example 1 Effect of increasing dopamine levels in rat striatum of the rat. (R) -3- [6- (Cyclopropylmethoxy) -2-naphthyl] -5-methoxymethyl-2-
Oxazolidone was suspended in 0.5% carboxymethylcellulose Na (CMC.Na, manufactured by Wako Pure Chemical Industries, Ltd.) and
Eight Slc: SD male rats (10 weeks old, Japan SLC) were orally administered at a dose of 0 mg / kg to 8 Slc: SD male rats per group. Two hours after the administration, the brain tissue was excised, the striatum was sampled, and the amount of dopamine in the striatum was measured by high performance liquid chromatography-electrochemical detection. Using deprenyl hydrochloride as a comparative drug, the striatum was collected 4 hours after oral administration at a dose of 10 mg / kg and the amount of dopamine was measured. As a control, 0.5% CMC. Na was administered similarly. As a result, as shown in Table 1, the compound of the present invention increased the amount of brain striatal dopamine by about 15% as compared with the control group. Deprenyl hydrochloride did not affect dopamine levels.
【００２１】[0021]
【表１】 [Table 1]
【００２２】実施例２レボドパ増強作用 １群１０匹のＣＤ−１系雄性マウス（５週齢、チャール
ズリバー・ジャパン社）に本発明化合物の（Ｒ）−３−
〔６−（シクロプロピルメトキシ）−２−ナフチル〕−
５−メトキシメチル−２−オキサゾリドンまたは比較対
照薬の塩酸デプレニルを経口投与し、その６０分後レボ
ドパ（Ｌ−３，４−ジヒドロキシフェニルアラニン：シ
グマ社）１５０ｍｇ／ｋｇを腹腔内投与した。さらにそ
の３０分後から２０分間、興奮行動出現の有無を観察
し、以下の式に基づいてレボドパ増強率（％）を算出し
た。被検薬が５０％のレボドパ増強率を与える用量をＥ
Ｄ50とし、プロビットモデルを想定してＥＤ50値及び９
５％信頼限界を算出した。 レボドパ増強率（％）＝１００×（その群で興奮行動を
示した個体数／１０） なお、レボドパは、生理食塩水に溶解し、１０ｍｌ／ｋ
ｇの用量で腹腔内投与した。本発明化合物は０．５％
カルボキシメチルセルロース Ｎａ（ＣＭＣ．Ｎａ，和
光純薬工業社製）に懸濁し、１０ｍｌ／ｋｇの用量で経
口投与した。比較対照薬の塩酸デプレニルは蒸留水に溶
解して１０ｍｌ／ｋｇの用量で経口投与した。また、対
照群として薬物を含有しない０．５％ＣＭＣ．Ｎａを同
様にして投与した。その結果、本発明化合物投与群では
興奮行動がみられ、そのＥＤ50値は５．９０ｍｇ／ｋｇ
であり、レボドパ増強作用が認められた。一方、塩酸デ
プレニルではレボドパ増強作用は弱く、そのＥＤ50値は
１００ｍｇ／ｋｇより大きかった。また対照群では興奮
行動はみられなかった。Example 2 Levodopa potentiating action One group of 10 CD-1 male mice (5 weeks old, Charles River Japan) was treated with the compound of the present invention (R) -3-
[6- (Cyclopropylmethoxy) -2-naphthyl]-
5-Methoxymethyl-2-oxazolidone or a comparative drug, deprenyl hydrochloride, was orally administered, and 60 minutes later, 150 mg / kg of levodopa (L-3,4-dihydroxyphenylalanine: Sigma) was intraperitoneally administered. From 30 minutes later, the presence or absence of the appearance of the excitatory behavior was observed for 20 minutes, and the levodopa enhancement rate (%) was calculated based on the following equation. The dose at which the test drug gives 50% levodopa enhancement
And D 50, ED 50 values and 9 assume the probit model
A 5% confidence limit was calculated. Levodopa enhancement rate (%) = 100 × (the number of individuals exhibiting an excitatory behavior / 10) The levodopa was dissolved in physiological saline and 10 ml / k
It was administered intraperitoneally at a dose of g. 0.5% of the compound of the present invention
It was suspended in carboxymethylcellulose Na (CMC.Na, manufactured by Wako Pure Chemical Industries, Ltd.) and orally administered at a dose of 10 ml / kg. 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 was administered in the same manner. As a result, an excitatory behavior was observed in the group administered with the compound of the present invention, and the ED 50 value was 5.90 mg / kg.
And a levodopa enhancing effect was observed. On the other hand, deprenyl hydrochloride had a weak levodopa enhancing effect, and its ED 50 value was greater than 100 mg / kg. No excitement was observed in the control group.
【００２３】実施例３低圧低酸素状態での延命効果 １群１０匹のＣＤ−１系雄性マウス（５週齢、チャール
ズリバー・ジャパン社）に本発明化合物の（Ｒ）−３−
〔６−（シクロプロピルメトキシ）−２−ナフチル〕−
５−メトキシメチル−２−オキサゾリドンを経口投与
（１００ｍｇ／ｋｇ）し、その３０分後にマウスを低圧
低酸素状態（１７０〜１７２ｍｍＨｇ）のチャンバー内
に入れ、体動・呼吸が認められなくなるまでの時間（生
存時間）を測定した。対照群として薬物を含有しない
０．５％ＣＭＣ．Ｎａを同様にして投与した。その結
果、本発明化合物は生存時間を対照群に比して約２８％
延長した（ｐ＜０．０５）。一般に中枢抑制作用を発現
する薬物は、その発現用量において延命効果（神経細胞
保護作用）を示すことが知られているが、中枢抑制作用
に基づく神経細胞保護作用は臨床では危険を伴い、使用
は制限されている。本発明化合物が中枢抑制の認められ
ない用量において延命効果を示したことは、本発明化合
物が臨床においてパーキンソニズムのような神経脱落を
伴う疾患に対して有用な神経細胞保護作用を有する可能
性を示唆するものである。Example 3 Effect of Prolonging Life Under Low Pressure and Hypoxia One group of 10 CD-1 male mice (5 weeks old, Charles River Japan) was treated with the compound of the present invention (R) -3-
[6- (Cyclopropylmethoxy) -2-naphthyl]-
After oral administration of 5-methoxymethyl-2-oxazolidone (100 mg / kg), 30 minutes later, the mice were placed in a chamber under low pressure and low oxygen (170 to 172 mmHg), and the time until no movement or respiration was observed (Survival time) was measured. As a control group, 0.5% CMC. Na was administered in the same manner. As a result, the compound of the present invention exhibited a survival time of about 28% as compared with the control group.
Prolonged (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 suggests that the compound of the present invention may have a useful neuroprotective effect against diseases associated with neurological deficits such as parkinsonism in clinical practice. Suggestive.
【００２４】実施例４レセルピン誘発無動症拮抗作用 Ｗｏｒｍｓらの方法〔Ｊ．Ｐｈａｒｍ．Ｅｘｐ．Ｔｈｅ
ｒ．，２４０，２４１−２４９（１９８７）〕に準じ
て、以下のような方法で行った。１群１０匹のＣＤ−１
系雄性マウス（５週齢、チャールズリバー・ジャパン
社）に本発明化合物の（Ｒ）−３−〔６−（シクロプロ
ピルメトキシ）−２−ナフチル〕−５−メトキシメチル
−２−オキサゾリドンを経口投与し、その直後レセルピ
ンを腹腔内投与（５ｍｇ／ｋｇ）した。無動症はレセル
ピン投与２時間後に、白紙上に描いた直径９．５ｃｍの
円の中央に動物を置いたとき円内に１５秒以上留まれば
陽性と判定した。無動症に対する作用は、症状の発現を
５０％の動物において抑制する用量をＥＤ50値とし、プ
ロビットモデルを用いてＥＤ50値を求めた。また、比較
対照薬として塩酸アマンタジンおよび塩酸デプレニルを
用い、同様にして試験を行った。Example 4 Antagonism of reserpine-induced akinesia The method of Worms et al. [J. Pharm. Exp. The
r. , 240, 241-249 (1987)]. 10 CD-1s per group
A male mouse (5 weeks old, Charles River Japan) was orally administered with the compound of the present invention (R) -3- [6- (cyclopropylmethoxy) -2-naphthyl] -5-methoxymethyl-2-oxazolidone. Immediately thereafter, reserpine was intraperitoneally administered (5 mg / kg). The akinesia was determined to be positive if the animal remained at the center of a 9.5 cm diameter circle drawn on white paper 2 hours after reserpine administration for 15 seconds or more. Regarding the effect on akinesia, the dose that suppresses the onset of symptoms in 50% of animals was defined as the ED 50 value, and the ED 50 value was determined using a probit model. The test was carried out in the same manner using amantadine hydrochloride and deprenyl hydrochloride as comparative control drugs.
【００２５】なお、レセルピン（シグマ社製）は特公昭
３２−１１４５号公報記載の方法に従い、注射液を調製
し１０ｍｌ／ｋｇの用量で腹腔内投与した。すなわち、
レセルピン２５０ｍｇに１％正燐酸１６．２ｃｃとプロ
ピレングリコール１２．５ｇ及び蒸留水５０ｃｃを加
え、次いでベンジルアルコール５．０ｇと蒸留水を追加
して全量を５００ｃｃとした。また、本発明化合物は
０．５％ カルボキシメチルセルロース Ｎａ（ＣＭ
Ｃ．Ｎａ，和光純薬工業社製）に懸濁し、塩酸アマンタ
ジンおよび塩酸デプレニルは蒸留水に溶解し、いずれも
１０ｍｌ／ｋｇの用量で経口投与した。用量は全てフリ
ー体の重量として表した。その結果、塩酸アマンタジン
のＥＤ50は４２．９ｍｇ／ｋｇであり、塩酸デプレニル
のＥＤ50は１４．４ｍｇ／ｋｇであるのに対し、本発明
化合物のＥＤ50は３．３ｍｇ／ｋｇであり、いずれの比
較対照薬よりも強力であったことからレセルピン誘発無
動症に対する優れた拮抗作用が認められた。In addition, reserpine (manufactured by Sigma) was prepared according to the method described in Japanese Patent Publication No. 32-1145, and an injectable solution was prepared and administered intraperitoneally at a dose of 10 ml / kg. That is,
To 250 mg of reserpine, 16.2 cc of 1% orthophosphoric acid, 12.5 g of propylene glycol and 50 cc of distilled water were added, and then 5.0 g of benzyl alcohol and distilled water were added to make the total amount 500 cc. The compound of the present invention is 0.5% carboxymethylcellulose Na (CM
C. Na, manufactured by Wako Pure Chemical Industries, Ltd.), amantadine hydrochloride and deprenyl hydrochloride were dissolved in distilled water, and all were orally administered at a dose of 10 ml / kg. All doses were expressed as free body weight. As a result, the ED 50 of amantadine hydrochloride was 42.9 mg / kg and the ED 50 of deprenyl hydrochloride was 14.4 mg / kg, whereas the ED 50 of the compound of the present invention was 3.3 mg / kg. The superior antagonism against reserpine-induced akinesia was confirmed because the drug was more potent than the control drug.
【００２６】[0026]
【発明の効果】本発明により、パーキンソニズムに対し
て単独もしくはレボドパとの併用で有効な治療剤が提供
される。特に本発明の治療剤は、脳線条体内ドパミン量
の増加作用、レボドパ増強作用、低圧低酸素状態での延
命効果、さらにレセルピン誘発無動症拮抗作用を有して
おり、パーキンソニズムの治療に優れた薬理作用を発揮
する。また、本発明により、レボドパとの併用剤として
パーキンソニズムの治療に有効なレボドパ作用増強剤が
提供される。Industrial Applicability According to the present invention, there is provided a therapeutic agent effective for parkinsonism alone or in combination with levodopa. Particularly, the therapeutic agent of the present invention has an effect of increasing the amount of dopamine in the striatum, an effect of enhancing levodopa, an effect of prolonging the life in low-pressure hypoxia, and a reserpine-induced akinetic antagonism, and is useful for treating parkinsonism. Exhibits excellent pharmacological action. Further, according to the present invention, there is provided a levodopa action enhancer which is effective for treating parkinsonism as a concomitant drug with levodopa.
Claims (4)
い低級アルキル基、Ｒ2は低級アルキル基を表す。）で
示される化合物又はその薬理的に許容し得る塩を有効成
分とするパーキンソニズム治療剤。1. A compound of the general formula (1) Wherein R 1 represents a lower alkyl group optionally substituted by a cycloalkyl group, and R 2 represents a lower alkyl group; or a pharmacologically acceptable salt thereof as an active ingredient. Nism treatment.
級アルキル基である請求項１記載のパーキンソニズム治
療剤。2. The therapeutic agent for parkinsonism according to claim 1, wherein R 1 is a lower alkyl group substituted with a cyclopropyl group.
プロピルメトキシ）−２−ナフチル〕−５−メトキシメ
チル−２−オキサゾリドンである請求項１記載のパーキ
ンソニズム治療剤。3. The therapeutic agent for parkinsonism according to claim 1, wherein the active ingredient is (R) -3- [6- (cyclopropylmethoxy) -2-naphthyl] -5-methoxymethyl-2-oxazolidone.
い低級アルキル基、Ｒ2は低級アルキル基を表す。）で
示される化合物又はその薬理的に許容し得る塩を有効成
分とするレボドパ作用増強剤。4. A compound of the general formula (1) Wherein R 1 represents a lower alkyl group which may be substituted with a cycloalkyl group, and R 2 represents a lower alkyl group; or a pharmaceutically acceptable salt thereof as an active ingredient. Action enhancer.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04704297A JP3865450B2 (en) | 1997-02-14 | 1997-02-14 | Parkinsonism treatment |
| PCT/JP1998/000517 WO1998035671A1 (en) | 1997-02-14 | 1998-02-06 | Remedies for parkinsonism |
| AU57810/98A AU5781098A (en) | 1997-02-14 | 1998-02-06 | Remedies for parkinsonism |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP04704297A JP3865450B2 (en) | 1997-02-14 | 1997-02-14 | Parkinsonism treatment |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH10226646A true JPH10226646A (en) | 1998-08-25 |
| JP3865450B2 JP3865450B2 (en) | 2007-01-10 |
Family
ID=12764120
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP04704297A Expired - Fee Related JP3865450B2 (en) | 1997-02-14 | 1997-02-14 | Parkinsonism treatment |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP3865450B2 (en) |
| AU (1) | AU5781098A (en) |
| WO (1) | WO1998035671A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8735382B2 (en) | 2004-07-12 | 2014-05-27 | Dizlin Medical Design Ab | Infusion and injection solution of levodopa |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5182296A (en) * | 1989-10-26 | 1993-01-26 | Tanabe Seiyaky Co., Ltd. | Naphthyloxazolidone derivatives |
| JP2551298B2 (en) * | 1991-04-25 | 1996-11-06 | 田辺製薬株式会社 | Antidepressant |
| TW286317B (en) * | 1993-12-13 | 1996-09-21 | Hoffmann La Roche | |
| FR2741072B1 (en) * | 1995-11-09 | 1997-12-12 | Synthelabo | OXAZOLIDIN-2-ONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2741071B1 (en) * | 1995-11-09 | 1997-12-12 | Synthelabo | DERIVATIVES OF 3- (BENZOFURAN-5-YL) OXAZOLIDIN-2-ONE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
-
1997
- 1997-02-14 JP JP04704297A patent/JP3865450B2/en not_active Expired - Fee Related
-
1998
- 1998-02-06 WO PCT/JP1998/000517 patent/WO1998035671A1/en active Application Filing
- 1998-02-06 AU AU57810/98A patent/AU5781098A/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8735382B2 (en) | 2004-07-12 | 2014-05-27 | Dizlin Medical Design Ab | Infusion and injection solution of levodopa |
| US9248113B2 (en) | 2004-07-12 | 2016-02-02 | Dizlin Medical Design Ab | Infusion and injection solution of Levodopa |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3865450B2 (en) | 2007-01-10 |
| AU5781098A (en) | 1998-09-08 |
| WO1998035671A1 (en) | 1998-08-20 |
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