JPS6087265A - Alpha-linoleic acid derivative and blood platelet coagulation inhibitor containing the same - Google Patents
Alpha-linoleic acid derivative and blood platelet coagulation inhibitor containing the sameInfo
- Publication number
- JPS6087265A JPS6087265A JP19559883A JP19559883A JPS6087265A JP S6087265 A JPS6087265 A JP S6087265A JP 19559883 A JP19559883 A JP 19559883A JP 19559883 A JP19559883 A JP 19559883A JP S6087265 A JPS6087265 A JP S6087265A
- Authority
- JP
- Japan
- Prior art keywords
- alpha
- acid
- linoleic acid
- lylunic
- blood platelet
- 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
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
ｌ 発明の背景
技術分野
本発明はα−リルン酸誘導体、特にα
−リルン酸ピリドキサミンアミドおよびそれを用いた血
小板凝集阻止剤に関するものである。本発明によって提
供されるα−リルン酸ピリドキサξンアミドは新規化合
物であって、強力な血小板凝集阻止作用を有することが
見出された。DETAILED DESCRIPTION OF THE INVENTION 1. BACKGROUND OF THE INVENTION Technical Field The present invention relates to α-lylunic acid derivatives, particularly α-lylunic acid pyridoxamine amide, and platelet aggregation inhibitors using the same. The α-lylunic acid pyridoxan amide provided by the present invention is a new compound and has been found to have a strong platelet aggregation inhibiting effect.
従って血小板凝集に起因する疾患、即ち血栓症の予防に
有効である。Therefore, it is effective in preventing diseases caused by platelet aggregation, that is, thrombosis.
α−リルン酸は亜麻仁油等の植物油に
含まれている必須脂肪酸であ抄、栄養学的にみても重要
な化合物である。ピリドキサミンはビタミンＢ６の前駆
体である。α-Lilunic acid is an essential fatty acid contained in vegetable oils such as flaxseed oil, and is an important compound from a nutritional standpoint. Pyridoxamine is a precursor of vitamin B6.
本発明者はα−リルン酸ピリドキサミ
ンアミ′ドを合成し、α−リルン酸ピリドキサミンアミ
ドがα−リルン酸にくらべ優れた血小板凝集抑制作用を
有することを見出し、本発明を完成するに至った。The present inventors synthesized α-lylunic acid pyridoxamine amide, discovered that α-lylunic acid pyridoxamine amide has a superior platelet aggregation inhibiting effect compared to α-lylunic acid, and completed the present invention. reached.
■ 発明の目的
本発明は血小板凝集阻止作用を有するα−リルン酸ピリ
ドキサミンアミドおよびそれ症は、近年成人病の中で大
きな割合を占めるに至っており、これを有効に予防する
薬剤の出現が強く望まれている。■ Purpose of the Invention The present invention aims to develop α-lylunic acid pyridoxamine amide, which has an inhibitory effect on platelet aggregation, and the disease, which has recently become a large proportion of adult diseases, and the emergence of a drug that can effectively prevent this disease. Highly desired.
■ 発明の詳細な説明
本発明の目的は以下の各項に示す構成によって達成され
る。■Detailed Description of the Invention The objects of the present invention are achieved by the configurations shown in the following sections.
（１） α−リルン酸ピリドキサミンアミドであるα−
−リルン誘導体。(1) α- which is α-lylunic acid pyridoxamine amide
- Rirun derivatives.
（２） α−リルン酸ピリドキサミンアミドを用いた血
小板凝集阻止剤。(2) Platelet aggregation inhibitor using α-lylunic acid pyridoxamine amide.
本発明のα−リルン酸ピリドキサミンアミドは、その反
応性誘導体とピリドキサミンとを反応させることにより
製造される。The α-lylunic acid pyridoxamine amide of the present invention is produced by reacting its reactive derivative with pyridoxamine.
α−リルン酸の反応性誘導体としてはα−リルン酸チア
ゾリジンチオンアミドを挙げることが出来る。As a reactive derivative of α-lylunic acid, α-lylunic acid thiazolidine thionamide can be mentioned.
本発明のα−リルン酸ピリドキサミンアミドは血栓症予
防剤として使用され、投与量は成人１日１５０〜２００
０ｍ９であり、必要により１〜３回に分けて投与する。The α-lylunic acid pyridoxamine amide of the present invention is used as a thrombosis preventive agent, and the dosage is 150 to 200 per day for adults.
0 m9, administered in 1 to 3 doses if necessary.
投与方法は経口投与が望ましいが、静注も可能である。Oral administration is preferable, but intravenous injection is also possible.
本発明の化合ｖｌＪは通常の方法で製剤担体あるいは賦
形剤と混合され、錠剤、散剤、カプセル剤、顆粒剤に製
剤化される。担体あるいは賦形剤の例としては炭酸カル
シウム、リン酸カルシウム、でんぷん９Ｍ糖、乳糖、タ
ルク、ステアリン酸マグネシウム等があげられる。本発
明の化合物は、上記の固形剤の他に油性懸濁剤、シロッ
プのような液剤とすることもできる。The compound vlJ of the present invention is mixed with pharmaceutical carriers or excipients in a conventional manner and formulated into tablets, powders, capsules, and granules. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch 9M sugar, lactose, talc, magnesium stearate, and the like. In addition to the above-mentioned solid formulations, the compounds of the present invention can also be formulated into liquid formulations such as oily suspensions and syrups.
次に実施例および試験例を示して本発明をさらに具体的
に説明する。Next, the present invention will be explained in more detail with reference to Examples and Test Examples.
実施例
アルゴン雰囲気下ピリドキサミンニ塩酸塩１５２ｍ９（
０，６３ｍｍｏｌ ）を乾燥テトラヒドロフラン（ＴＨ
Ｆ）（６ｍ）に溶解した溶液に、トリエチルアミン０．
７６ｍ（５，４６ｍ ｍｏｌ ） 、α−リルン酸ケチ
アゾリジンチオンアミド２４１Ｑ０．６３ｍｍｏｌ）を
乾で３倍量に希釈後、酢酸エチルで３回抽出操作を行な
い、有機層を水洗した。有機溶液を無水硫酸ナトリウム
で乾燥後、溶媒を減圧留去し抽出残前２９４． ｑを母
た。これをシリカゲルカラムクロマトグラフィーに付シ
、クロロホルム拳メタノール（１９：１）溶出画分より
α−リルン酸ピリドキサミンアミド２３６ｗ１９（０，
５５１ｍｍｏｌ）を得た。Example Pyridoxamine dihydrochloride 152m9 (under argon atmosphere)
0.63 mmol) in dry tetrahydrofuran (TH
F) (6m) was added with 0.0% triethylamine.
After dry diluting 76m (5.46 mmol) and α-lylunic acid quethiazolidine thionamide 241Q 0.63 mmol to three times the amount, extraction was performed three times with ethyl acetate, and the organic layer was washed with water. After drying the organic solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to leave an extraction residue of 294. Mother of q. This was subjected to silica gel column chromatography, and the fraction eluted with chloroform and methanol (19:1) was extracted with α-lylunic acid pyridoxamine amide 236w19 (0,
551 mmol) was obtained.
このものの分光学的データを以下に記す。The spectroscopic data of this product are described below.
３１３０、１６４０．１５２０１１４４５゜１３６０、
１２７５．１２３０．１０８０゜９９０、８９０
’Ｈ−Ｍ（ＣＤＧＩ ５ ）δ： ７．５５（ＩＨｌ
ｂｓ）ｐ６．８９ （１ｆ−Ｌ ｂ ｔ Ｊ＝６．６Ｈ
ｚ ）１５．３５（６Ｈ，ｍ）、 ４．６３ （，２Ｈ
，Ｓ）。3130, 1640.152011445°1360,
1275.1230.1080°990,890'HM(CDGI5)δ: 7.55(IHL
bs) p6.89 (1f-L b t J=6.6H
z ) 15.35 (6H, m), 4.63 (,2H
,S).
４．４１（２Ｈ，ｄ Ｊ＝６．６Ｈｚ）。4.41 (2H, dJ=6.6Hz).
ｊ、８０ （４Ｈ，ｂ ｔ、 Ｊ＝５．４Ｈｚ）。j, 80 (4H, bt, J=5.4Hz).
２．４６（３Ｈ，Ｓ）、 ２．１９〜１．９８（ｕｎｒ
ｅｓｏｌｕｂｌｅ ６Ｈ）。2.46 (3H, S), 2.19-1.98 (unr
6H).
１．５６ （２Ｈ，ｍ ） ＋
１．２６ （８Ｈ，ｂ ｓ ）ｓ
ｏ、９７（３Ｈ，ｔ Ｊ＝７．６Ｈｚ）試験例
血小板凝集抑制作用
３．８％クエン酸ナトリウム溶液（ｌ容）を入れた注射
器を用いてウサギ頚動脈より９容の血液を採取する。該
血液より遠心分離し、血小板に富む血漿（ＰＲＰ ：
５０万個／μｔ）を得る。1.56 (2H, m ) + 1.26 (8H, b s ) so, 97 (3H, t J=7.6Hz) Test example Platelet aggregation inhibitory effect 3.8% sodium citrate solution (l volume) Collect 9 volumes of blood from the rabbit carotid artery using a syringe containing . The blood is centrifuged and platelet-rich plasma (PRP:
500,000 pieces/μt).
該ＰＲＰｚ５０Ｐｔをキュベツトに入れ、３７℃恒温槽
で２分間加温し、検体の溶液（１，４Ｘ１０−２Ｍエタ
ノール溶液をトリス緩衝等張食塩水溶液−生理食塩水（
’ｌ：３ ）で希釈）２０μｔを加えて３分間インキユ
ベートシた後、凝集惹起剤であるアラキドン酸溶液ある
いはコラーゲン溶液ｌＯμｔ を加え、血小板凝集を測
定した。アラキドン酸（７０μｈ）によって誘起される
血小板凝集に対するα−リルン酸の５０％抑制濃度（Ｉ
Ｃ，ｏ）が１．２ＸＩＯ−’Ｍであるのに対シ、α−リ
ルン酸ピリドキサミンアミドのＩＣ５ｏは４．４Ｘ１０
−５Ｍであった。The PRPz50Pt was placed in a cuvette, heated for 2 minutes in a 37°C constant temperature bath, and the sample solution (1,4X10-2M ethanol solution was mixed with Tris-buffered isotonic saline solution-physiological saline solution).
After adding 20 .mu.t of diluted with 1:3) and incubating for 3 minutes, 10 .mu.t of a solution of arachidonic acid or a collagen solution, which is an aggregation-inducing agent, was added to measure platelet aggregation. 50% inhibitory concentration (I
C, o) is 1.2XIO-'M, whereas IC5o of α-lylunic acid pyridoxamine amide is 4.4X10
-5M.
尚に、同条件下のアスピリンのＩＣ５ｏｔｒｉ：。Furthermore, the IC5otri of aspirin under the same conditions:
５．２ＸＩＯＭであった。It was 5.2XIOM.
コラーゲン（１５μｆ／ｍ’）によって誘起される血小
板凝集に対するα−リルン酸のＩＣ，ｏｒｉ９．４ Ｘ
１０−’ Ｍであり、α−リルン酸ピリドキサミンア
シドＵ ２．４ Ｘ １０−’Ｍであった。IC of α-lylunic acid on platelet aggregation induced by collagen (15 μf/m′), ori9.4
10-'M, and α-lylunic acid pyridoxamine acid U2.4 x 10-'M.
α−リルン酸ピリドキサミンアミドの急性毒性について
マウス（雄）を用いて、経口投与により調べた結果、Ｌ
Ｄ５ｏは１ノ／に２を越え、高い安全性が示さ扛た。The acute toxicity of α-lylunic acid pyridoxamine amide was investigated by oral administration using male mice.
D5o exceeded 2 to 1/2, indicating high safety.
１ｖ 発明の作用効果
本発明によれは血栓症予防効果を有するα−リルン酸ピ
リドキサミンアミドが提供される。1v Effects of the Invention The present invention provides α-lylunic acid pyridoxamine amide having a thrombosis preventive effect.
本発明の上記化合物ハ、アラキドン酸あるいはコラーゲ
ンによって誘起される血小板凝集を顕著に抑制するので
、心筋硬塞、脳血栓等の血小板凝集の関与する血栓に起
因する種々の血栓症の予防剤として使用することができ
る。Since the above compound of the present invention significantly inhibits platelet aggregation induced by arachidonic acid or collagen, it can be used as a prophylactic agent for various thromboses caused by thrombosis involving platelet aggregation, such as myocardial infarction and cerebral thrombosis. be able to.
特許出願人 テルモ株式会社Patent applicant Terumo Corporation
Claims (1)
−リルン酸誘導体 （粉 α−リルン酸ピリドキサミンアミドを用いた血小
板凝集阻止剤(1) α-lylunic acid pyridoxamine 7′amide
- Platelet aggregation inhibitor using lylunic acid derivative (powder α-lylunic acid pyridoxamine amide)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19559883A JPS6087265A (en) | 1983-10-19 | 1983-10-19 | Alpha-linoleic acid derivative and blood platelet coagulation inhibitor containing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19559883A JPS6087265A (en) | 1983-10-19 | 1983-10-19 | Alpha-linoleic acid derivative and blood platelet coagulation inhibitor containing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6087265A true JPS6087265A (en) | 1985-05-16 |
| JPS632547B2 JPS632547B2 (en) | 1988-01-19 |
Family
ID=16343809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19559883A Granted JPS6087265A (en) | 1983-10-19 | 1983-10-19 | Alpha-linoleic acid derivative and blood platelet coagulation inhibitor containing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6087265A (en) |
-
1983
- 1983-10-19 JP JP19559883A patent/JPS6087265A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS632547B2 (en) | 1988-01-19 |
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