JPS61277617A - Inhibitor of blood platelet aggregation - Google Patents
Inhibitor of blood platelet aggregationInfo
- Publication number
- JPS61277617A JPS61277617A JP11653885A JP11653885A JPS61277617A JP S61277617 A JPS61277617 A JP S61277617A JP 11653885 A JP11653885 A JP 11653885A JP 11653885 A JP11653885 A JP 11653885A JP S61277617 A JPS61277617 A JP S61277617A
- Authority
- JP
- Japan
- Prior art keywords
- platelet aggregation
- gliotoxin
- blood platelet
- active ingredient
- inhibitor
- 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.)
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、血小板凝集を抑制するのに有効な式:
で示されるグリオトキシン(Gliotoxin)を有
効成分として含有する抗血小板凝集剤に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antiplatelet aggregation agent containing as an active ingredient gliotoxin, which is effective in inhibiting platelet aggregation and is represented by the formula: Gliotoxin.
血小板の凝集作用が誘引して起きる血栓性疾患(脳梗塞
、一過性虚血発作、心筋梗塞、狭心症等)は、近年、高
年金層人口が増加し、食生活、社会環境が変化するのに
伴い、欧米諸国と同様、わが国においてもますます増加
することが予測されている。Thrombotic diseases (cerebral infarction, transient ischemic attack, myocardial infarction, angina pectoris, etc.) caused by the aggregation of platelets are caused by an increase in the elderly population and changes in dietary habits and social environment. It is predicted that the number of cases will continue to increase in Japan as well as in Western countries.
また、前述の疾患以外にも、血小板凝集は、動脈硬化症
、ガンの転移等の疾病にも深い関わりを持つことが報告
されているなど、臨床分野で注目を集めている。そのた
め、これまでに、国内外を問わず、多くの研究者によっ
て有効な血小板凝集阻害剤を開発すべく、種々の研究が
行なわれているが、未だ満足なものが得られていないの
が現状である。In addition to the above-mentioned diseases, platelet aggregation is also attracting attention in the clinical field, as it has been reported that it is closely related to diseases such as arteriosclerosis and cancer metastasis. Therefore, various studies have been carried out by many researchers in Japan and abroad to develop effective platelet aggregation inhibitors, but the current situation is that nothing satisfactory has been obtained yet. It is.
本発明の目的は、上述のよ5な現状に鑑み、特に、血栓
性疾患について、それが、発生後においては充分な治療
効果が期待できない点を考慮し、該疾患の主要因の1つ
と考えられる血小板凝集に注目し、抗血小板凝集剤を提
供し、該疾患を予防せんとするものである。In view of the above-mentioned current situation, the purpose of the present invention is to treat thrombotic diseases, which are considered to be one of the main causes of these diseases, in particular, considering the fact that sufficient therapeutic effects cannot be expected after they occur. The aim is to provide an anti-platelet aggregation agent to prevent this disease.
本発明者らは、血小板凝集阻害作用を指標として、血小
板に特異的に作用する薬剤の開発という観点から鋭意研
究の結果、カビ(アスはルギルス・7ミガタス・フレセ
ニナスCAIII)θrgillusfumigatu
s Freseninus) )の培養液上清が強力な
活性を示すことを見い出し、その成分を分離、同定する
という一連の研究により、極めて有力な血小板凝集阻害
作用を有する活性物質、グリオトキシンを見い出すこと
に成功した。As a result of intensive research from the viewpoint of developing a drug that specifically acts on platelets using platelet aggregation inhibition as an indicator, the present inventors discovered that the fungus θrgillus fumigatu (Rugilus 7migatus Freseninus CAIII)
After discovering that the culture supernatant of S. Freseninus (S. Successful.
さらに本発明者らは、該グリ・^6シ・について、薬理
・毒性等の一連の試験を行い、この化合物が臨床的見地
からも、血小板凝集の抑制に優れた効果を有することを
見い出し、本発明を完成するに至った。Furthermore, the present inventors conducted a series of pharmacological and toxicological tests on Gly^6S, and found that this compound has an excellent effect on inhibiting platelet aggregation from a clinical standpoint. The present invention has now been completed.
すなわち、本発明の目的は、優れた血小板凝集を抑制す
る効果を有するグリオトキシンを有効成分として含有す
る抗血小板凝集剤を提供することにある。That is, an object of the present invention is to provide an antiplatelet aggregation agent containing gliotoxin as an active ingredient, which has an excellent effect of inhibiting platelet aggregation.
上記のグリオトキシンは既にワイドリングらによって単
離されており、〔フイトパンロジー(ph、ytopa
thology) 27、P1175(1937) )
さらにフクヤマらによって化学合成されている公知の化
合物である〔テトラヘドロン57、P2O45−78(
1981))。The above gliotoxin has already been isolated by Weidling et al.
27, P1175 (1937))
Furthermore, there are known compounds chemically synthesized by Fukuyama et al. [tetrahedron 57, P2O45-78 (
1981)).
しかしながら、グリオトキシンが血小板凝集阻害作用を
有していることは、現在までまったく知られていなかっ
た。However, it has not been known until now that gliotoxin has an inhibitory effect on platelet aggregation.
その効果は、本発明者らによる血小板凝集を抑制する優
れた効果を有する物質の開発研究において、初めて見い
出されたものであり、したがって、本発明により、微量
で強い効果を有し、かつ投与量の選択により充分に臨床
応用の可能性を期待し得る優れた抗血小板凝集剤が提供
される口
以下、上記のグリオトキシンの薬理作用について、試験
例を示し、具体的に説明する。なお、試験に用いた該化
合物(グリオトキシン〕は、後述の実施例Iで単離・精
製して得られたものである。This effect was discovered for the first time by the present inventors in research and development of a substance that has an excellent effect of suppressing platelet aggregation. Therefore, the present invention allows for a substance that has a strong effect in a small amount and can be administered at a low dosage. An excellent anti-platelet aggregation agent which can be expected to have a good possibility of clinical application is provided by selection of the following.The pharmacological effects of the above-mentioned gliotoxin will be specifically explained by showing test examples. The compound (gliotoxin) used in the test was obtained by isolation and purification in Example I described below.
試験例1 抗血小板凝集作用
グリオトキシン溶液(目的投与量のグリ・オドキシンを
ジメチルスルホキシド(以下DMSOという)に溶かし
た溶液)0.04mをTCR系雄マクス(体重的4Of
、1群6頭〕の腹腔内に投与した。Test Example 1 Antiplatelet aggregation effect Gliotoxin solution (a solution in which the target dose of glyodoxin was dissolved in dimethyl sulfoxide (hereinafter referred to as DMSO))
, 6 animals per group].
120分後に、あらかじめ五8%クエン酸ナトリウム(
C6H5Na507・2H20; my 294 )
0.08d O入った注射筒でエーテル麻酔下にて該マ
ウス下大静脈より0.72−採血し、クエン陵面(3,
8%クエン酸ナトリウム水溶液を血液0.9容に対し、
0.1容加えたもの)をつくった。該クエン陵面n、B
−を遠心分離によって分離(600rpm 、 5分
間)し、上層液(以下A液という)を回収した。次に沈
渣をさらに遠心分離によって分離(3100rpm、1
0分間〕し、上層液(以下、B液という〕を回収した。After 120 minutes, add 58% sodium citrate (
C6H5Na507・2H20; my 294)
Blood was collected from the inferior vena cava of the mouse under ether anesthesia using a syringe containing 0.08 dO, and
8% sodium citrate aqueous solution to 0.9 volume of blood,
0.1 volume added). Said Kuen Lingmian n, B
- was separated by centrifugation (600 rpm, 5 minutes), and the upper layer liquid (hereinafter referred to as liquid A) was collected. The precipitate was then further separated by centrifugation (3100 rpm, 1
0 minutes], and the upper layer liquid (hereinafter referred to as liquid B) was collected.
A液とB液を混合し、多血小板血漿(以下PRPという
〕とした。さらに、PRPの一部を別の容器にとり残り
を遠心分離(3100rpm、 5’分間)し、上層を
回収し、これを乏血小板血漿(以下、PPPという)と
した。Solution A and solution B were mixed to obtain platelet-rich plasma (hereinafter referred to as PRP).Furthermore, a portion of the PRP was placed in a separate container, the remainder was centrifuged (3100 rpm, 5 minutes), and the upper layer was collected. was designated as platelet-poor plasma (hereinafter referred to as PPP).
(PRP 、 PPPの作製にあたっての詳細は、文献
「血小板の分子薬理−基礎と臨床、」日高弘義編講談社
サイエンティフィック、74−94頁に記載されている
方法を参照されたい、)
これにより、血小板凝集率(NKK )(EMATRA
CER二光バイオサイエンス社〕を用い、血小板凝集率
の0%、100%をそれぞれPRP、 ’PPPによっ
て測定した。さらに、PRPα20mにアデノシンニ燐
酸(以下ADPという)を終濃度5μMとなるように添
加してAJ)P凝集実験を行った。(For details on the production of PRP and PPP, please refer to the method described in the document "Molecular Pharmacology of Platelets - Basic and Clinical," edited by Hiroyoshi Hidaka, Kodansha Scientific, pp. 74-94.) , platelet aggregation rate (NKK) (EMATRA
0% and 100% of the platelet aggregation rate were measured by PRP and 'PPP, respectively. Furthermore, an AJ)P aggregation experiment was conducted by adding adenosine diphosphate (hereinafter referred to as ADP) to PRPα20m at a final concentration of 5 μM.
また、対照群としては、ICR系雄マウス(体重的40
9.1群6匹)にDMBOをQ、04−投与したものを
用いた。In addition, as a control group, ICR male mice (weight 40
9.1 group (6 animals) administered with DMBO Q,04- were used.
図!に示すよ5に最大凝集率をMとし、ADP凝集開始
からMまでの時間(分〕をtとし、ADP凝集開始から
2を後の血小板凝集残率(血小板未解離率〕をDとする
と結果は表1のように表わされる〇
表 1
1対照群69.B±5.562.2±5.52.10±
0.15 i68土0.72Hα25り1064.rJ
±5.350.0±&61゜57±α15父20±23
41[[CL5011%’/% 6&2±1.951.
8±2.71.63±Q、15 a75±α78IV
1.00111P/Kr 65.3±に949.2±′
5.91.68±α249.70±1.3にの表より対
照群に比較して、グリオトキシンを投与した場合の方が
明らかに最大凝集率を低下させかつ血小板凝集残率も著
しく低下している、すなわち、血小板凝集解離速度(M
−D )/を値でみられるように解離速度を著しく抑制
していることがわかる。figure! As shown in Figure 5, if the maximum aggregation rate is M, the time (minutes) from the start of ADP aggregation to M is t, and the remaining rate of platelet aggregation (undissociated platelet rate) after 2 from the start of ADP aggregation is D, the result is is expressed as in Table 1〇Table 1 1Control group 69.B±5.562.2±5.52.10±
0.15 i68 soil 0.72Hα25ri 1064. rJ
±5.350.0±&61゜57±α15 father 20±23
41[[CL5011%'/% 6&2±1.951.
8±2.71.63±Q, 15 a75±α78IV
1.00111P/Kr 65.3± to 949.2±'
From the table in 5.91.68±α249.70±1.3, compared to the control group, administration of gliotoxin clearly lowered the maximum aggregation rate and also significantly lowered the residual rate of platelet aggregation. That is, the platelet aggregation dissociation rate (M
-D)/, it can be seen that the dissociation rate is significantly suppressed.
従って、グリオトキシンは、生体内において生じた血小
板凝集塊の解離を促進し、顕著な血栓症予防効果を期待
できるものである。Therefore, gliotoxin promotes the dissociation of platelet aggregates generated in vivo, and can be expected to have a significant thrombosis preventive effect.
試験例2 グリオトキシンの毒性
ジョンソンら〔ジャーナル・オプ・アメリカンケミカル
・ソサイエテイ66.5(71(1944))によると
、グリオトキシンの致死量はウサギ(i、v、)で45
1’v/Kf、 マウス<1−p−)で5019/LI
、ラツ) (i、p・)で5U〜65q/Kfである。Test Example 2 Toxicity of Gliotoxin According to Johnson et al. [Journal of the American Chemical Society 66.5 (71 (1944)), the lethal dose of gliotoxin is 45% in rabbits (i, v,).
1'v/Kf, 5019/LI in mouse <1-p-)
, Ratu) (i, p.) is 5U to 65q/Kf.
ただし、この文献値(LDso)は、グリオトキシンを
水に懸濁させて投与した値である。However, this literature value (LDso) is a value obtained by suspending gliotoxin in water and administering it.
それに対して、前述の実験においては、グリオトキシン
が水に対して不溶性であることから、DMS Oに溶か
して行われた。In contrast, in the aforementioned experiments, gliotoxin was dissolved in DMSO since it is insoluble in water.
そこで、毒性についてもグリオトキシンJ)MSO溶液
としてICR系雄マウス(1群5匹〕の腹腔内ニ、51
19−グリオトキシン/麺の投与を行ったところ5匹す
べての生存(1週間)が確認された。Therefore, regarding toxicity, gliotoxin J) was administered intraperitoneally to ICR male mice (5 mice per group) as an MSO solution.
When 19-gliotoxin/noodles were administered, all five animals were confirmed to be alive (for one week).
これにより、グリオトキシンをジメチルスルホキシド溶
液に溶かした場合の毒性LD5Q値は5’Ilf/に9
以上であることが判明した。As a result, the toxicity LD5Q value when gliotoxin is dissolved in dimethyl sulfoxide solution is 5'Ilf/9.
It turns out that this is all.
本発明は、以上に述べたようなグリオトキシンに関する
新規な知見に基づき完成されたものであり、該グリオト
キシンを有効成分として含有する血小板凝集を抑制する
抗血小板凝集剤を提供するものである。The present invention has been completed based on the above-mentioned novel findings regarding gliotoxin, and provides an antiplatelet aggregation agent that suppresses platelet aggregation and contains the gliotoxin as an active ingredient.
本発明の抗血小板凝集剤の有効成分であるグリオトキシ
ンの製造については、格別の方法を用いる必要はなく、
公知の方法によって、微生物による産生によりまたは化
学合成により製造することができる〔例えばジャーナル
・オブ・アメリカン・ケミカル・ソサイエテイ65、p
2oosあるいはテトラヘドロン37、P2O45参照
〕。There is no need to use any special method for producing gliotoxin, which is the active ingredient of the antiplatelet aggregation agent of the present invention.
It can be produced by known methods, by microbial production or by chemical synthesis [e.g., Journal of American Chemical Society 65, p.
2oos or tetrahedron 37, see P2O45].
また、投与方法としては、経口投与、静脈注射等が考え
られるが経口投与の場合15〜20■/Kf、静脈注射
の場合0.05〜2.0η/KQが望ましい投与量であ
る。Possible administration methods include oral administration and intravenous injection, but the preferred dosage is 15 to 20 η/Kf for oral administration and 0.05 to 2.0 η/KQ for intravenous injection.
なお、投与するグリオトキシンは、純粋なものでなく、
培養p液からの粗精製物であっても投与量の選択により
、抗血小板凝集効果に何ら影響を与えるものではない。Please note that the gliotoxin administered is not pure;
Even if it is a crudely purified product from culture p fluid, it will not affect the anti-platelet aggregation effect in any way depending on the dosage selection.
従って本発明による抗血小板凝集剤は、単に血小板凝集
を抑制する作用が優れていることにとどまらず、投与量
の選択により、充分に臨床治療に用いられる可能性を有
する点で極めて有効なものである。以下、実施例を掲げ
て本発明を具体的に説明する。Therefore, the antiplatelet aggregation agent according to the present invention is not only excellent in its ability to inhibit platelet aggregation, but also extremely effective in that it has the potential to be used in clinical treatment by selecting the dosage. be. The present invention will be specifically described below with reference to Examples.
実施例 I
表2に示す組成(酵母エキス2?、NaN033 f1
KH2PO41,51%に2!(PO41,9f 、
FeSO4”7H20(]、CI 1 r。Example I Composition shown in Table 2 (yeast extract 2?, NaN033 f1
KH2PO41, 51% to 2! (PO41,9f,
FeSO4”7H20(], CI 1 r.
NaCL 0.2 ?、グルコース30 f 5Mg5
O4・7H20CL5t、精製水1t)の培地を3本の
600−の坂ロフラスコに均等に分注し、アスはルギル
ス・フミガタス・7レセニナスを7日間、27℃にて振
盪培養した。NaCL 0.2? , glucose 30 f 5Mg5
A medium containing 5 tons of O4.7H20CL and 1 t of purified water was equally dispensed into three 600-sized Sakaro flasks, and Rugilus fumigatus 7reseninus was cultured with shaking at 27° C. for 7 days.
表 2
培養後、該培養液をアスピレータ−を用いて吸引濾過し
、1500−の戸液を得た。該培養戸液1500−にリ
ン酸を添加し、pH3とした。該戸液に1500−の酢
酸エチルを添加し、分液ロートを用いて抽出する操作を
2回繰り返すことで約3000−の抽出液を得た。該抽
出液を硫酸ナトリウム(Na2804)で脱水し、核液
をエバポレーターによる減圧乾固によって764Wの抽
出物を得た。次に該抽出物30019をシリカゲルカラ
ム(Wakogel C−200)に吸着させ、ベンゼ
7ニ”C洗浄した後、ジクロルメタン150−で活性画
分ヲ溶出しエバポレーターを用いて、減圧濃縮を行い、
174M9の粗精製物を得た。該粗精製物をアセトニト
リル中で、再結晶法により精製し、高速液体クロマトグ
ラフィー(カラム: F’1nepaksilc−18
、溶媒;アセトニトリル:京間30ニア0)により、純
粋な活性物質を得た。Table 2 After culturing, the culture solution was suction-filtered using an aspirator to obtain a 1500-ml solution. Phosphoric acid was added to the 1500-ml culture solution to adjust the pH to 3. The operation of adding 1,500 ml of ethyl acetate to the liquid and extracting using a separating funnel was repeated twice to obtain an approximately 3,000 ml of extract. The extract was dehydrated with sodium sulfate (Na2804), and the core liquid was dried under reduced pressure using an evaporator to obtain a 764W extract. Next, the extract 30019 was adsorbed on a silica gel column (Wakogel C-200), washed with benzene 7"C, and the active fraction was eluted with 150% dichloromethane and concentrated under reduced pressure using an evaporator.
A crude product of 174M9 was obtained. The crude product was purified by recrystallization in acetonitrile, and subjected to high performance liquid chromatography (column: F'1nepaksilc-18).
, solvent; acetonitrile: Kyoma 30Nia 0) to obtain the pure active substance.
該活性物質がグリオトキシンであることは以下の方法に
よって確認された。It was confirmed that the active substance was gliotoxin by the following method.
該活性物質を質量分析計により、質量分析な行い、その
データをオンラインシステム(C工S)で検索した結果
、該当物質はグリオトキシン1件に限定された。なお、
質量分析データから、この物質の分子量は、326と決
定され、グリオトキシンのそれと一致した。The active substance was subjected to mass spectrometry using a mass spectrometer, and the data was searched on an online system (C Engineering S), and as a result, the relevant substance was limited to one substance, gliotoxin. In addition,
From mass spectrometry data, the molecular weight of this material was determined to be 326, consistent with that of gliotoxin.
本発明の抗血小板凝集剤において、上記のグリオトキシ
ンは、そのままで、もしくは、従来知られ、使用されて
いる添加物(賦形剤、分散剤等〕と共に、種々の列形の
製剤とすることができる。In the antiplatelet aggregation agent of the present invention, the above-mentioned gliotoxin may be prepared as it is or in various formulations together with conventionally known and used additives (excipients, dispersants, etc.). I can do it.
以下に本発明の抗血小板凝集剤の製剤例を示す0
(1)錠剤
グリオトキシン 10
エチルセルロース 50
結晶セルロース 80
カルボキシメチルセルロース 7ステアリン
酸マグネシウム 3Examples of formulations of the antiplatelet aggregation agent of the present invention are shown below.
【図面の簡単な説明】
図IはADP血小板凝集率をみるために血小板凝集計を
用いて経過時間による光透過率の変化を測定した結果を
示す図である。縦軸は光透過率(−)、横軸は経過時間
(分)が示されている。
特許出願人 株式会社 ヤ り ル ト 本社代理人
弁理士 南 孝 夫
第1図BRIEF DESCRIPTION OF THE DRAWINGS FIG. I is a diagram showing the results of measuring changes in light transmittance over time using a platelet aggregometer to determine the ADP platelet aggregation rate. The vertical axis shows the light transmittance (-), and the horizontal axis shows the elapsed time (minutes). Patent Applicant: Yaruto Co., Ltd. Head Office Agent: Patent Attorney Takao Minami Figure 1
Claims (1)
凝集剤。[Scope of Claims] An antiplatelet aggregation agent containing gliotoxin as an active ingredient represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11653885A JPS61277617A (en) | 1985-05-31 | 1985-05-31 | Inhibitor of blood platelet aggregation |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11653885A JPS61277617A (en) | 1985-05-31 | 1985-05-31 | Inhibitor of blood platelet aggregation |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS61277617A true JPS61277617A (en) | 1986-12-08 |
Family
ID=14689600
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP11653885A Pending JPS61277617A (en) | 1985-05-31 | 1985-05-31 | Inhibitor of blood platelet aggregation |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS61277617A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006066775A1 (en) * | 2004-12-23 | 2006-06-29 | Cell Therapeutics Europe S.R.L. | Use of diketodithiopiperazine antibiotics for the preparation of antiangiogenic pharmaceutical compositions |
WO2008112014A1 (en) * | 2006-10-05 | 2008-09-18 | Mayo Foundation For Medical Education And Research | Methods and compositions for treating cancer |
US7981878B2 (en) | 2005-06-21 | 2011-07-19 | Medizinische Universitat Wien | Tumor treatment with gliotoxin derivatives |
-
1985
- 1985-05-31 JP JP11653885A patent/JPS61277617A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006066775A1 (en) * | 2004-12-23 | 2006-06-29 | Cell Therapeutics Europe S.R.L. | Use of diketodithiopiperazine antibiotics for the preparation of antiangiogenic pharmaceutical compositions |
US7981878B2 (en) | 2005-06-21 | 2011-07-19 | Medizinische Universitat Wien | Tumor treatment with gliotoxin derivatives |
WO2008112014A1 (en) * | 2006-10-05 | 2008-09-18 | Mayo Foundation For Medical Education And Research | Methods and compositions for treating cancer |
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