JP3070687B2 - Heart disease treatment - Google Patents
Heart disease treatmentInfo
- Publication number
- JP3070687B2 JP3070687B2 JP2192575A JP19257590A JP3070687B2 JP 3070687 B2 JP3070687 B2 JP 3070687B2 JP 2192575 A JP2192575 A JP 2192575A JP 19257590 A JP19257590 A JP 19257590A JP 3070687 B2 JP3070687 B2 JP 3070687B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- taurine
- present
- heart disease
- myocardial
- 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.)
- Expired - Lifetime
Links
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は優れた心筋の強化・保護作用を有するタウリ
ンジペプチドを有効成分として含有する心疾患治療剤に
関する。Description: FIELD OF THE INVENTION The present invention relates to a therapeutic agent for heart disease containing as an active ingredient a taurine dipeptide having an excellent myocardial strengthening / protecting action.
（従来の技術） 心筋細胞は心筋細胞膜を介してカルシウムイオン等の
恒常性を維持している。この細胞膜機能に障害がある場
合や、薬物など何らかの原因により過剰のカルシウムイ
オンが細胞内負荷されると（Ca2+−overload）、心筋細
胞は障害を受け、いわゆる心筋症と呼ばれる病変が生じ
たり、心筋壊死の原因となったりする。(Prior Art) Cardiomyocytes maintain homeostasis such as calcium ions through the cardiomyocyte membrane. If the cell membrane function is impaired or if excessive calcium ions are intracellularly loaded for some reason such as a drug (Ca 2+ -overload), the cardiomyocytes will be damaged, resulting in a lesion called so-called cardiomyopathy. , Causing myocardial necrosis.
摘出心筋を無カルシウム液で短時間灌流した後、カル
シウム含有液で再灌流を行うと、心筋の拘縮、電気的活
動の消失、細胞破壊、細胞内酵素の流出等が引き起こさ
れる。この現象はカルシウムパラドックスと呼ばれ、そ
の発生機序については上記のCa2+−overloadが重要な役
割を果たしていると考えられている。即ち、虚血−血液
再灌流時に生ずる心筋障害発生の要因の一つとしてCa2+
−overloadが示唆されている。カルシウムパラドックス
により心筋は最終的に不可逆的変化を生じるが、例えば
カルシウム拮抗剤等によりこの障害が軽減されることが
報告されている。When the isolated myocardium is perfused for a short time with a calcium-free solution and then reperfused with a calcium-containing solution, contracture of the myocardium, loss of electrical activity, cell destruction, and outflow of intracellular enzymes are caused. This phenomenon is called calcium paradox, and it is considered that the above Ca 2+ -overload plays an important role in the mechanism of its occurrence. That is, Ca 2+ is one of the factors of myocardial injury occurring during ischemia-blood reperfusion.
-Overload is suggested. It has been reported that calcium paradox eventually causes irreversible changes in the myocardium. For example, calcium antagonists and the like alleviate this disorder.
本発明者らは、本発明タウリンジペプチドがCa2+−ov
erload等による心筋障害や低カルシウム状態における心
筋機能低下に対して優れた心筋強化・保護作用を有する
ことを見出し本発明を完成した。The present inventors have found that the taurine dipeptide of the present invention is Ca2 + -ov
The present inventors have found that the present invention has an excellent myocardial strengthening / protective effect against myocardial damage due to erload and the like and myocardial dysfunction in a low calcium state, and completed the present invention.
（発明が解決しようとする問題点） 本発明の目的は、タウリンジペプチド又はその薬学的
に許容される塩を有効成分として含有する心疾患治療剤
を提供することにある。(Problems to be Solved by the Invention) An object of the present invention is to provide a therapeutic agent for heart disease, comprising a taurine dipeptide or a pharmaceutically acceptable salt thereof as an active ingredient.
（本発明を解決するための手段） 本発明は次の一般式（Ｉ）で表される化合物又はその
薬学的に許容される塩の少なくとも一種を有効成分とし
て含有する心疾患治療剤である。(Means for Solving the Present Invention) The present invention is a therapeutic agent for heart disease, which comprises at least one compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
Ｒ−NH−CH2−CH2−SO3H （Ｉ） 上記一般式（Ｉ）中、Ｒはアミノ酸残基を表し、好ま
しくは、グリシン、アラニン、バリン、ロイシン、イソ
ロイシン、セリン、スレオニン、メチオニン、プロリ
ン、ヒドロキシプロリン、アスパラギン酸、β−アスパ
ラギン酸、グルタミン酸、γ−グルタミン酸、フェニル
アラニン、チロシン等が挙げられる。R—NH—CH 2 —CH 2 —SO 3 H (I) In the general formula (I), R represents an amino acid residue, and is preferably glycine, alanine, valine, leucine, isoleucine, serine, threonine, or methionine. , Proline, hydroxyproline, aspartic acid, β-aspartic acid, glutamic acid, γ-glutamic acid, phenylalanine, tyrosine and the like.
本発明化合物中特に好ましい化合物を例示すれば以下
の通りである。Particularly preferred compounds among the compounds of the present invention are as follows.
1.グルシルタウリン 2.アラニルタウリン 3.バリルタウリン 4.ロイシルタウリン 5.イソロイシルタウリン 6.セリルタウリン 7.スレオニルタウリン 8.メチオニルタウリン 9.プロリルタウリン 10.ヒドロキシプロリルタウリン 11.アスパルチルタウリン 12.β−アスパルチルタウリン 13.グルタミルタウリン 14.γ−グルタミルタウリン酸 15.フェニルアラニルタウリン 16.チロシルタウリン 本発明タウリンジペプチドはその薬学的に許容される
塩を包含し、例えば、塩酸、硫酸、硝酸、臭化水素酸、
リン酸、ホウ酸、ギ酸、酢酸、ハロ酢酸、プロピオン
酸、グリコール酸、クエン酸、酒石酸、コハク酸、グル
コン酸、乳酸、マロン酸、フマール酸、アントラニル
酸、安息香酸、ケイ皮酸、ｐ−トルエンスルホン酸、ナ
フタレンスルホン酸、スルファニル酸等の酸との酸付加
塩、或いはナトリウム、カリウム等のアルカリ金属、カ
ルシウム、バリウム等のアルカリ土類金属、その他のア
ルミニウム等の金属との塩、又はアンモニウム、有機ア
ミンとの塩などが挙げられる。1. Glucyl taurine 2. Alanyl taurine 3. Valyl taurine 4. Leucyl taurine 5. Isoleucyl taurine 6. Seryl taurine 7. Threonyl taurine 8. Methionyl taurine 9. Prolyl taurine 10. Hydroxyprolyl Taurine 11. Aspartyl taurine 12. β-aspartyl taurine 13. Glutamyl taurine 14. γ-glutamyl tauric acid 15. Phenylalanyl taurine 16. Tyrosyl taurine The taurine dipeptide of the present invention includes a pharmaceutically acceptable salt thereof. For example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid,
Phosphoric acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p- Acid addition salts with acids such as toluenesulfonic acid, naphthalenesulfonic acid and sulfanilic acid, or salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and barium, and other metals such as aluminum, or ammonium And salts with organic amines.
又、本発明化合物はその金属錯化合物を包含し、例え
ば亜鉛、ニッケル、コバルト、銅、鉄等との錯化合物が
挙げられる。Further, the compound of the present invention includes its metal complex compound, for example, a complex compound with zinc, nickel, cobalt, copper, iron and the like.
これらの塩並びに金属錯化合物は公知の方法により遊
離の本発明タウリンジペプチドより製造でき、或いは相
互に変換することができる。These salts and metal complex compounds can be produced from the free taurine dipeptide of the present invention by known methods, or can be mutually converted.
本発明化合物において光学異性体が存在する場合に
は、本発明はそのいずれをも包含する。When optical isomers exist in the compound of the present invention, the present invention includes both of them.
本発明化合物は公知物質であり、例えば「Chem.Phar
m.Bull.36（１）,70−77（1988）」や「Chem.Pharm.Bul
l.36（８）,2796−2801（1988）」等の文献記載の方法
によって製造することができる。The compound of the present invention is a known substance, for example, "Chem.Phar
m.Bull. 36 (1), 70-77 (1988) "and" Chem. Pharm.
l. 36 (8), 2796-2801 (1988).
（作用） 次に本発明化合物の薬理作用について述べる。(Action) Next, the pharmacological action of the compound of the present invention will be described.
（１）心筋保護作用 ICR系の14乃至16日目妊娠マウスの胎児心臓を細裁
し、0.06％トリプシン−0.01％コラゲナーゼの酵素液を
添加して、37℃で10分間振盪しながら反応させ細胞を分
離した。これに10％仔牛血清を含むイーグルMEM培養液
を加え遠心した後、集めた細胞を培養液中に再分散させ
た。心筋細胞は繊維芽様細胞とは付着時間が違うことか
ら、再分散させた細胞液を37℃で95％空気−５％二酸化
炭素飽和水蒸気状態で１時間インキュベートし、繊維芽
細胞を除去した後、1mlあたり２×105乃至４×105個に
調製して40乃至44時間の前培養後、カルシウムパラドッ
クスの実験に用いた。(1) Cardioprotective action The fetal heart of pregnant mice on the 14th to 16th day of the ICR system was minced, and an enzyme solution of 0.06% trypsin-0.01% collagenase was added, and the mixture was reacted at 37 ° C. with shaking for 10 minutes. Was isolated. An Eagle MEM culture solution containing 10% calf serum was added thereto, followed by centrifugation, and the collected cells were redispersed in the culture solution. Cardiomyocytes have a different attachment time from fibroblast-like cells, so the redispersed cell solution is incubated at 37 ° C in 95% air-5% carbon dioxide saturated steam for 1 hour to remove fibroblasts. After preparing the cells at 2 × 10 5 to 4 × 10 5 cells per ml and pre-culturing for 40 to 44 hours, the cells were used for calcium paradox experiments.
培地を除去して被検薬を含むEGTA培地（Ca2+−free）
を1ml添加した後、20乃至22℃に10分間放置した。次い
で細胞を無EGTA培地（Ca2+−free）で洗った後、速やか
に被検薬を含む1mMCa2+培地を入れ、１分間後の細胞の
形態変化（水腫、風船様）を観察した。結果の一例を第
１表に示す。EGTA medium containing test drug after removing the medium (Ca 2+ -free)
Was added, and the mixture was allowed to stand at 20 to 22 ° C. for 10 minutes. Then, the cells were washed with an EGTA-free medium (Ca 2+ -free), and immediately 1 mM A Ca 2+ medium containing the test drug was added, and morphological changes (edema, balloon-like) of the cells were observed after 1 minute. An example of the results is shown in Table 1.
（２）心筋強化作用 心筋細胞の培地を低カルシウム培地（0.5mMCa2+）に
変えると細胞の拍動振幅が低下する。この低カルシウム
培地に被検薬を共存させて、心筋細胞の振幅低下に対す
る作用を調べた。 (2) Myocardial strengthening action When the medium for cardiomyocytes is changed to a low calcium medium (0.5 mM Ca 2+ ), the pulse amplitude of the cells decreases. The test drug was allowed to coexist in this low calcium medium, and the effect on the decrease in amplitude of cardiomyocytes was examined.
結果の一例を第１図に示す。 One example of the results is shown in FIG.
（効果） 第１表の試験結果から明らかなように、本発明タウリ
ンジペプチドはカルシウムパラドックスによる心筋の形
態変化に対して優れた防御作用を有する。また、第１図
に示すように、低カルシウム培地での心筋の拍動振幅の
低下を、本発明化合物は有意に軽減する。(Effects) As is clear from the test results in Table 1, the taurine dipeptide of the present invention has an excellent protective action against myocardial morphological changes caused by calcium paradox. In addition, as shown in FIG. 1, the compounds of the present invention significantly reduce a decrease in heart muscle pulsation amplitude in a low calcium medium.
このように、本発明化合物はCa2+−overload等による
心筋障害に対して優れた心筋保護作用を有すると共に、
低カルシウム状態における心筋の拍動振幅の低下を軽減
し、心筋機能を正常化する心筋強化作用を併せ有する。
従って、本発明タウリンジペプチドは、心筋梗塞等の虚
血性心疾患、心臓手術時の虚血状態などにおける心筋障
害並びに心不全、狭心症など種々の心疾患の治療、予防
薬剤として有用である。As described above, the compound of the present invention has an excellent myocardial protective action against myocardial damage due to Ca 2+ -overload and the like,
It also has a myocardial strengthening action that reduces a decrease in the heartbeat amplitude in a low calcium state and normalizes myocardial function.
Therefore, the taurine dipeptide of the present invention is useful as a therapeutic or prophylactic agent for ischemic heart disease such as myocardial infarction, myocardial damage in ischemic conditions during cardiac surgery, and various heart diseases such as heart failure and angina.
第１図は低カルシウム培地（0.5mMCa2+）における心筋
細胞の拍動振幅の変化を測定した結果を示したものであ
る。FIG. 1 shows the results of measuring changes in the pulsation amplitude of cardiomyocytes in a low calcium medium (0.5 mM Ca 2+ ).
───────────────────────────────────────────────────── フロントページの続き (72)発明者 家永 和治 兵庫県加東郡社町木梨字川北山442番１ 日本臓器製薬株式会社生物活性科学研 究所内 (56)参考文献 特公 昭49−4210（ＪＰ，Ｂ１) (58)調査した分野(Int.Cl.7，ＤＢ名) A61K 31/185 A61P 9/10 ＣＡ（ＳＴＮ) ＭＥＤＬＩＮＥ（ＳＴＮ)──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Kazuharu Ienaga 442-1, Kawakitayama, Kinashi, Shato-cho, Kato-gun, Hyogo Pref. (JP, B1) (58) Fields investigated (Int. Cl. 7 , DB name) A61K 31/185 A61P 9/10 CA (STN) MEDLINE (STN)
Claims (3)
くとも一種を有効成分として含有する心筋障害治療剤。1. A general formula (I): R-NH- CH 2 -CH 2 -SO 3 H (I) wherein, R represents an amino acid residue. ] A therapeutic agent for myocardial injury, comprising as an active ingredient at least one of the compounds represented by the formula: or a pharmaceutically acceptable salt thereof.
心筋障害治療剤。2. The method according to claim 1, which is a therapeutic agent for ischemic heart disease.
害治療剤。3. The method according to claim 1, which is a therapeutic agent for angina pectoris.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2192575A JP3070687B2 (en) | 1990-07-19 | 1990-07-19 | Heart disease treatment |
| DE69125216T DE69125216T2 (en) | 1990-07-19 | 1991-07-18 | Aminoalkanesulfonic acid derivatives and pharmaceutical compositions thereof for the prevention or treatment of heart diseases |
| EP91810580A EP0467856B1 (en) | 1990-07-19 | 1991-07-18 | Aminoalkanesulfonic acid derivatives and pharmaceutical compositions for use in preventing or treating heart diseases |
| AT91810580T ATE150301T1 (en) | 1990-07-19 | 1991-07-18 | AMINOALKANESULPHONIC ACID DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR PREVENTING OR TREATING HEART DISEASES |
| ES91810580T ES2100222T3 (en) | 1990-07-19 | 1991-07-18 | DERIVATIVES OF THE AMINOALCANSULFONICO ACID AND PHARMACEUTICAL COMPOUNDS TO USE TO PREVENT OR TREAT CARDIAC DISEASES. |
| US08/167,459 US5430052A (en) | 1990-07-19 | 1993-12-15 | Aminoalkanesulfonic acid derivatives and pharmaceutical compositions for use in preventing or treating heart diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2192575A JP3070687B2 (en) | 1990-07-19 | 1990-07-19 | Heart disease treatment |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0477423A JPH0477423A (en) | 1992-03-11 |
| JP3070687B2 true JP3070687B2 (en) | 2000-07-31 |
Family
ID=16293565
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2192575A Expired - Lifetime JP3070687B2 (en) | 1990-07-19 | 1990-07-19 | Heart disease treatment |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3070687B2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2529256A1 (en) * | 2003-06-23 | 2004-12-29 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
| JP4711857B2 (en) * | 2006-03-01 | 2011-06-29 | 日本クラウンコルク株式会社 | Spout for paper pack |
| CN101045346A (en) * | 2006-03-30 | 2007-10-03 | 冷鹭浩 | Ultrasonic welding structure plastic composite board |
| DK2089417T3 (en) | 2006-10-12 | 2015-03-23 | Bhi Ltd Partnership | Methods, Compounds, Compositions and Vehicles for Delivery of 3-Amion-1-Propanesulfonic Acid |
| JP4881333B2 (en) * | 2008-02-22 | 2012-02-22 | 株式会社ジェイ・イー・ジェイ | Resin plate |
-
1990
- 1990-07-19 JP JP2192575A patent/JP3070687B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0477423A (en) | 1992-03-11 |
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