JP2004155661A - Prophylactic drug for sudden death - Google Patents
Prophylactic drug for sudden death Download PDFInfo
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- JP2004155661A JP2004155661A JP2002320077A JP2002320077A JP2004155661A JP 2004155661 A JP2004155661 A JP 2004155661A JP 2002320077 A JP2002320077 A JP 2002320077A JP 2002320077 A JP2002320077 A JP 2002320077A JP 2004155661 A JP2004155661 A JP 2004155661A
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- sudden death
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、突然死予防剤に関する。
【０００２】
【従来の技術】
心疾患、大動脈瘤、脳卒中、ポックリ病などを原因疾患とし、突然死が見られることがある（医科学大辞典、３５、ｐ３５−３６、野間惟道編、講談社）。突然死、特に原疾患が心疾患である突然死の予防としては、抗不整脈薬やベータ遮断薬の使用が試みられているが（Ｈｅａｒｔ Ｖｉｅｗ， Ｖｏｌ ２， Ｎｏ ７， １９９８， 江口潤司編、メジカルビュー社）、未だ画期的な治療法は見出されていない。
【０００３】
一方、一般式（Ｉ）で示される化合物は、Ｒｈｏキナーゼ、ミオシン軽鎖リン酸化酵素、プロテインキナーゼＣといったキナーゼ阻害活性を有し、血管平滑筋弛緩作用、血流増加作用、血圧低下作用、脳、心臓保護作用等を示し、血管拡張剤（特に、狭心症治療剤）、脳、心臓保護剤等において有効な物質であることは、既に公知である（特許文献１−７、非特許文献１−４）。
【特許文献１】
特開昭６１−１５２６５８号公報
【特許文献２】
特開昭６１−２２７５８１号公報
【特許文献３】
特開平２−２５６６１７号公報
【特許文献４】
特開平４−２６４０３０号公報
【特許文献５】
特開平６−０５６６６８号公報
【特許文献６】
特開平６−０８０５６９号公報
【特許文献７】
特開平７−８０８５４号公報、
【非特許文献１】
Ｂｒ． Ｊ． Ｐｈａｒｍａｃｏｌ．， ９８， １０９１ （１９８９）
【非特許文献２】
Ｊ． Ｐｈａｒｍａｃｏｌ． Ｅｘｐ． Ｔｈｅｒ．， ２５９， ７３８ （１９９１）
【非特許文献３】
Ｃｉｒｃｕｌａｔｉｏｎ， ９６， ４３５７ （１９９７）
【非特許文献４】
Ｃａｒｄｉｏｖａｓｃ． Ｒｅｓ．， ４３， １０２９ （１９９９）
しかし、虚血性心疾患に適用できる薬物が、同時に突然死にも有効であるとは必ずしもいえない上、一般式（Ｉ）で示される化合物が、突然死に有用である旨や、それを示唆する記載は認められない。
【０００４】
【発明が解決しようとする課題】
従来より、突然死を予防する医薬の提供が望まれていた。
【０００５】
【課題を解決するための手段】
本発明者らは、一般式（Ｉ）で示される化合物について、鋭意研究を重ねた結果、該化合物が上記血管平滑筋弛緩作用、血流増加作用、血圧低下作用、脳、心臓保護作用など、従来知られている作用からは全く予期できない突然死の予防効果を見出し、本発明を完成した。
すなわち、本発明は、下記一般式（Ｉ）
【０００６】
【化２】
（ただし、式中Ｒ１は水素原子または水酸基を表す）で示される化合物またはその酸付加塩もしくは水和物を有効成分とする、突然死予防剤である。
本突然死予防剤の投与対象者は、突然死を起こす可能性のある人である。例えば、突然死を起こしかけて、死に到らなかった患者等である。
本発明の一般式（Ｉ）で示される化合物は、公知の方法、例えば、Ｃｈｅｍ． Ｐｈａｒａｍ． Ｂｕｌｌ．， ４０， （３） ７７０−７７３ （１９９２）、特開昭６１−１５２６５８号公報等に記載されている方法に従って合成することができる。また、その酸付加塩は、薬学上許容される非毒性の塩が好ましく、例えば塩酸、臭化水素酸、リン酸、硫酸等の無機酸、および酢酸、クエン酸、酒石酸、乳酸、コハク酸、フマル酸、マレイン酸、メタンスルホン酸等の有機酸の塩を挙げることができる。水和物には、例えば１／２水和物、１水和物、３水和物がある。
【０００８】
本発明の、突然死予防剤を、投与に適した形の製剤として調整するのに際しては、上述の一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物と、公知の医薬上許容される担体とを混合すればよい。この担体としては、例えば、ゼラチン；乳糖、グルコース等の糖類；小麦、米、とうもろこし澱粉等の澱粉類；ステアリン酸等の脂肪酸；ステアリン酸カルシウム、ステアリン酸マグネシウム等の脂肪酸塩；タルク；植物油；ステアリンアルコール、ベンジルアルコール等のアルコール；ガム；ポリアルキレングリコール等が挙げられる。
【０００９】
また、液状担体としては、一般に水、生理食塩液、デキストロースまたは類似の糖溶液、エチレングリコール、プロピレングリコール、ポリエチレングリコール、ポリプロピレンルリコール等のグルコール類が挙げられる。カプセル剤となす場合には、通常ゼラチンを用いてカプセルを調整することが好ましい。
以上のような担体と一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物よりなる本発明の突然死予防剤中には、通常０．０１重量％以上、また８０重量％以下、好ましくは６０重量％以下の有効成分を含む例が挙げられる。
【００１０】
投与方法は、経口投与や非経口投与が挙げられる。経口投与に適した剤形としては、錠剤、カプセル剤、粉剤、顆粒剤、液剤、エリキシル剤等が挙げられ、非経口投与に適した剤形としては、液剤が挙げられる。
非経口的に筋肉内注射、静脈内注射、皮下注射で投与する場合、一般式（Ｉ）で示される化合物またはその酸付加塩もしくは水和物を等張にするために、食塩または、グルコース等の他の溶質を添加した無菌溶液として投与される。
【００１１】
注射により投与する場合には、滅菌水、塩酸リドカイン溶液（筋肉内注射用）、生理食塩液、ブドウ糖、静脈内注射用溶液、電解質溶液（静脈内注射用）等で溶解することも好ましい。このようにして溶解した場合には、通常０．０１重量％以上、また２０重量％以下、好ましくは０．１重量％以上、また１０重量％以下の有効成分を含むように調整されることがある。経口投与の液剤の場合、０．０１−２０重量％の有効成分を含む懸濁液またはシロップが好ましい例として挙げられる。この場合における担体としては、香料、シロップ、製剤的ミセル体等の水様賦形剤が挙げられる。
【００１２】
本発明の突然死予防剤の投与量は、被投与者の年齢、健康状態、体重、症状の程度、同時処置があるならばその種類、処置頻度、所望の効果の性質、あるいは投与経路や投与計画などによって異なるが、一般には、非経口投与で０．０１−２０ｍｇ／ｋｇ・日、経口投与で０．０２−４０ｍｇ／ｋｇ・日が挙げられる。
【００１３】
【実施例】
以下に実施例及び参考例を挙げ、この発明をさらに具体的に説明するが、本発明はこれらに限定されるものではない。
【００１４】
【実施例１】
ポックリ病患者の血漿成分を用いた、ブタ冠動脈過収縮モデルに対する作用
ポックリ病患者の血漿成分から、レムナントリポタンパク、超低比重リポ蛋白（ＶＬＤＬ）分画を分離した。ブタの左冠動脈前下降枝、及び回旋枝の近位部位にレムナントリポタンパクおよびＶＬＤＬを塗布した。１週間後、セロトニン（３〜１００ μｇ／ｋｇ）を冠動脈内投与することにより、レムナントリポタンパク部位において、顕著な冠動脈過収縮を認めた。
【００１５】
それに対し、セロトニン投与前に、一般式（Ｉ）（式中Ｒ１は水酸基）３０ μｇ／ｋｇを冠動脈内へ予め投与すると、セロトニン誘発の冠動脈過収縮の発生は、予防された。
【００１６】
【実施例２】
本発明の化合物の急性毒性試験を、ラット（Ｊｃｌ：Ｗｉｓｔａｒ，５週齢）およびマウス（Ｓｌｃ：ｄｄＹ，５週齢）を用いて実施した結果、低毒性であることが確認された。その結果を表１に示す。
【００１７】
【表１】
【実施例３】
製剤例（無菌注射剤）
下記表２の成分を注射用蒸留水に溶解し、その後、注射用蒸留水を添加し、
必要な最終重量とし、この溶液２ｍｌをアンプルに密封し、加熱滅菌した。
【００１９】
【表２】
【実施例４】
製剤例（錠剤）
下記表３の成分を含む錠剤を常法により調整した。
【００２１】
【表３】
【発明の効果】
本発明によれば、突然死予防剤が提供できる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an agent for preventing sudden death.
[0002]
[Prior art]
Caused by heart disease, aortic aneurysm, stroke, Pockli's disease, etc., sudden death may be seen (Digital Dictionary of Medical Science, 35, p35-36, edited by Nomichi Nomichi, Kodansha). In order to prevent sudden death, especially sudden death in which the underlying disease is heart disease, use of antiarrhythmic drugs and beta-blockers has been attempted (Heart View, Vol 2, No 7, 1998, edited by Junji Eguchi, Medical View). No innovative treatment has been found yet.
[0003]
On the other hand, the compound represented by the general formula (I) has kinase inhibitory activities such as Rho kinase, myosin light chain kinase, and protein kinase C, and has a vascular smooth muscle relaxing action, a blood flow increasing action, a blood pressure lowering action, It has already been known that it is a substance that exhibits a cardioprotective action and the like, and is an effective substance in vasodilators (especially therapeutic agents for angina pectoris), brain, cardioprotective agents, etc. (Patent Documents 1-7, Non-Patent Documents) 1-4).
[Patent Document 1]
JP-A-61-152658 [Patent Document 2]
Japanese Patent Application Laid-Open No. 61-227581 [Patent Document 3]
JP-A-2-256617 [Patent Document 4]
JP-A-4-264030 [Patent Document 5]
JP-A-6-056668 [Patent Document 6]
JP-A-6-080569 [Patent Document 7]
JP-A-7-80854,
[Non-patent document 1]
Br. J. Pharmacol. , 98, 1091 (1989).
[Non-patent document 2]
J. Pharmacol. Exp. Ther. , 259, 738 (1991)
[Non-Patent Document 3]
Circulation, 96, 4357 (1997).
[Non-patent document 4]
Cardiovasc. Res. , 43, 1029 (1999)
However, drugs that can be applied to ischemic heart disease are not necessarily effective for sudden death at the same time, and the compounds of the general formula (I) are useful for sudden death and a statement suggesting that they are useful for sudden death. It is not allowed.
[0004]
[Problems to be solved by the invention]
Conventionally, it has been desired to provide a medicine for preventing sudden death.
[0005]
[Means for Solving the Problems]
The present inventors have conducted intensive studies on the compound represented by the general formula (I), and as a result, it has been found that the compound has the above-mentioned vascular smooth muscle relaxing action, blood flow increasing action, blood pressure lowering action, brain, cardioprotective action and the like. The present invention has been found to have an effect of preventing sudden death, which is completely unexpected from the conventionally known effects, and completed the present invention.
That is, the present invention relates to the following general formula (I)
[0006]
Embedded image
Wherein R1 represents a hydrogen atom or a hydroxyl group, or an acid addition salt or hydrate thereof as an active ingredient.
The subject to whom this sudden death prevention agent is administered is a person who may cause sudden death. For example, a patient who died suddenly and did not die.
The compound represented by the general formula (I) of the present invention can be produced by a known method, for example, Chem. Pharm. Bull. , 40, (3) 770-773 (1992), JP-A-61-152658, and the like. The acid addition salt is preferably a pharmaceutically acceptable non-toxic salt, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, Salts of organic acids such as fumaric acid, maleic acid and methanesulfonic acid can be mentioned. Hydrates include, for example, hemihydrate, monohydrate and trihydrate.
[0008]
When the agent for preventing sudden death of the present invention is prepared as a preparation suitable for administration, the compound represented by the above general formula (I) or an acid addition salt or hydrate thereof is combined with a known pharmaceutical agent. What is necessary is just to mix with an acceptable carrier. Examples of the carrier include gelatin; sugars such as lactose and glucose; starches such as wheat, rice and corn starch; fatty acids such as stearic acid; fatty acid salts such as calcium stearate and magnesium stearate; talc; Benzyl alcohol and the like; gums; polyalkylene glycols and the like.
[0009]
The liquid carrier generally includes water, physiological saline, dextrose or a similar sugar solution, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol. When a capsule is prepared, it is usually preferable to prepare the capsule using gelatin.
In the agent for preventing sudden death of the present invention comprising the above carrier and the compound represented by the general formula (I) or an acid addition salt or hydrate thereof, usually 0.01% by weight or more and 80% by weight or less. And preferably contains 60% by weight or less of the active ingredient.
[0010]
The administration method includes oral administration and parenteral administration. Dosage forms suitable for oral administration include tablets, capsules, powders, granules, solutions, elixirs and the like, and dosage forms suitable for parenteral administration include liquid preparations.
When administered parenterally by intramuscular injection, intravenous injection, or subcutaneous injection, in order to make the compound represented by the general formula (I) or an acid addition salt or hydrate thereof isotonic, sodium chloride, glucose, etc. Administered as a sterile solution with the addition of other solutes.
[0011]
When administered by injection, it is also preferable to dissolve in sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, glucose, intravenous injection solution, electrolyte solution (for intravenous injection), and the like. When dissolved in this way, it is usually adjusted to contain 0.01% by weight or more and 20% by weight or less, preferably 0.1% by weight or more and 10% by weight or less of the active ingredient. is there. In the case of a liquid preparation for oral administration, a preferable example is a suspension or syrup containing 0.01 to 20% by weight of the active ingredient. In this case, the carrier includes aqueous excipients such as flavors, syrups, and pharmaceutical micelles.
[0012]
The dose of the agent for preventing sudden death of the present invention depends on the age, health condition, body weight, degree of symptom, type of concurrent treatment, if any, treatment frequency, nature of desired effect, or administration route or administration of the subject. In general, parenteral administration is 0.01-20 mg / kg-day, and oral administration is 0.02-40 mg / kg-day, depending on the plan.
[0013]
【Example】
Hereinafter, the present invention will be described more specifically with reference to Examples and Reference Examples, but the present invention is not limited thereto.
[0014]
Embodiment 1
Effect on Porcine Coronary Artery Hyperconstriction Model Using Plasma Component of Pokkuri Disease Patient Remnant lipoprotein and a very low density lipoprotein (VLDL) fraction were separated from the plasma component of a Pokkuri disease patient. Remnant lipoprotein and VLDL were applied to the left anterior descending coronary artery of the pig and the proximal site of the circumflex branch. One week later, by administering serotonin (3 to 100 μg / kg) into the coronary artery, significant coronary artery hyperconstriction was observed at the remnant lipoprotein site.
[0015]
In contrast, when 30 μg / kg of the general formula (I) (where R1 is a hydroxyl group) was administered to the coronary artery before administration of serotonin, the occurrence of serotonin-induced hyperconstriction of the coronary artery was prevented.
[0016]
Embodiment 2
The acute toxicity test of the compound of the present invention was performed using rats (Jcl: Wistar, 5 weeks old) and mice (Slc: ddY, 5 weeks old), and it was confirmed that the compounds had low toxicity. Table 1 shows the results.
[0017]
[Table 1]
Embodiment 3
Formulation example (sterile injection)
The components in Table 2 below were dissolved in distilled water for injection, and then distilled water for injection was added.
To the required final weight, 2 ml of this solution was sealed in an ampoule and heat sterilized.
[0019]
[Table 2]
Embodiment 4
Formulation example (tablet)
Tablets containing the components shown in Table 3 below were prepared by a conventional method.
[0021]
[Table 3]
【The invention's effect】
According to the present invention, an agent for preventing sudden death can be provided.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002320077A JP2004155661A (en) | 2002-11-01 | 2002-11-01 | Prophylactic drug for sudden death |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002320077A JP2004155661A (en) | 2002-11-01 | 2002-11-01 | Prophylactic drug for sudden death |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2004155661A true JP2004155661A (en) | 2004-06-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002320077A Pending JP2004155661A (en) | 2002-11-01 | 2002-11-01 | Prophylactic drug for sudden death |
Country Status (1)
| Country | Link |
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| JP (1) | JP2004155661A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006115245A1 (en) * | 2005-04-25 | 2006-11-02 | D. Western Therapeutics Institute, Inc. | 4-ethynylisoquinoline derivative and pharmaceutical preparation comprising the same |
| WO2006115244A1 (en) * | 2005-04-25 | 2006-11-02 | D. Western Therapeutics Institute, Inc. | 4-bromoisoquinoline derivative and pharmaceutical preparation comprising the same |
| WO2006115247A1 (en) * | 2005-04-25 | 2006-11-02 | D. Western Therapeutics Institute, Inc. | HIGHLY SELECTIVE Rho-KINASE INHIBITOR |
-
2002
- 2002-11-01 JP JP2002320077A patent/JP2004155661A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006115245A1 (en) * | 2005-04-25 | 2006-11-02 | D. Western Therapeutics Institute, Inc. | 4-ethynylisoquinoline derivative and pharmaceutical preparation comprising the same |
| WO2006115244A1 (en) * | 2005-04-25 | 2006-11-02 | D. Western Therapeutics Institute, Inc. | 4-bromoisoquinoline derivative and pharmaceutical preparation comprising the same |
| WO2006115247A1 (en) * | 2005-04-25 | 2006-11-02 | D. Western Therapeutics Institute, Inc. | HIGHLY SELECTIVE Rho-KINASE INHIBITOR |
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