JPS63208520A - Blood platelet agglutination inhibitor containing pyrazine derivative - Google Patents
Blood platelet agglutination inhibitor containing pyrazine derivativeInfo
- Publication number
- JPS63208520A JPS63208520A JP4155087A JP4155087A JPS63208520A JP S63208520 A JPS63208520 A JP S63208520A JP 4155087 A JP4155087 A JP 4155087A JP 4155087 A JP4155087 A JP 4155087A JP S63208520 A JPS63208520 A JP S63208520A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- blood platelet
- pyrazine derivative
- expressed
- platelet agglutination
- 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
- 150000003216 pyrazines Chemical class 0.000 title claims abstract description 22
- 229940127218 antiplatelet drug Drugs 0.000 title claims abstract description 9
- 210000001772 blood platelet Anatomy 0.000 title abstract 3
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims description 7
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims description 7
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 4
- 102000008186 Collagen Human genes 0.000 abstract description 3
- 108010035532 Collagen Proteins 0.000 abstract description 3
- 229940114079 arachidonic acid Drugs 0.000 abstract description 3
- 235000021342 arachidonic acid Nutrition 0.000 abstract description 3
- 229920001436 collagen Polymers 0.000 abstract description 3
- 239000000546 pharmaceutical excipient Substances 0.000 abstract description 3
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 abstract description 3
- YLBCZNNGPOPTGM-UHFFFAOYSA-N 2-chloro-3,5-diphenylpyrazine Chemical compound ClC1=NC=C(C=2C=CC=CC=2)N=C1C1=CC=CC=C1 YLBCZNNGPOPTGM-UHFFFAOYSA-N 0.000 abstract description 2
- FYIHUZXWJJAIJW-UHFFFAOYSA-N 2-methyl-3,5-diphenylpyrazine Chemical compound CC1=NC=C(C=2C=CC=CC=2)N=C1C1=CC=CC=C1 FYIHUZXWJJAIJW-UHFFFAOYSA-N 0.000 abstract description 2
- 229920000858 Cyclodextrin Polymers 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 239000002775 capsule Substances 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 239000003937 drug carrier Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 229910052763 palladium Inorganic materials 0.000 abstract description 2
- 239000000843 powder Substances 0.000 abstract description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000725 suspension Substances 0.000 abstract description 2
- 239000006188 syrup Substances 0.000 abstract description 2
- 235000020357 syrup Nutrition 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 abstract description 2
- 206010008111 Cerebral haemorrhage Diseases 0.000 abstract 1
- 206010061216 Infarction Diseases 0.000 abstract 1
- 230000004520 agglutination Effects 0.000 abstract 1
- 230000000747 cardiac effect Effects 0.000 abstract 1
- 206010008118 cerebral infarction Diseases 0.000 abstract 1
- 208000026106 cerebrovascular disease Diseases 0.000 abstract 1
- 238000007796 conventional method Methods 0.000 abstract 1
- 230000007574 infarction Effects 0.000 abstract 1
- 230000000302 ischemic effect Effects 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- 230000000087 stabilizing effect Effects 0.000 abstract 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000003146 anticoagulant agent Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 230000000702 anti-platelet effect Effects 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010008132 Cerebral thrombosis Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
１０発明の背景
技術分野
本発明はピラジン誘導体を含有する血小板凝集抑制剤に
関する。DETAILED DESCRIPTION OF THE INVENTION 10. Background Technical Field of the Invention The present invention relates to a platelet aggregation inhibitor containing a pyrazine derivative.
本発明のピラジン誘導体は強力な血小板凝集抑制作用を
有するので、血小板凝集に起因する疾患即ち血栓症等の
予防に有効である。Since the pyrazine derivatives of the present invention have a strong platelet aggregation inhibiting effect, they are effective in preventing diseases caused by platelet aggregation, such as thrombosis.
先行技術
抗血小板凝集作用を有する物質は種々知られているが１
作用が弱いものであり、より改善された薬剤の出現が望
まれている。また、心筋梗塞や脳血栓といった血栓症は
、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抗血栓症剤の出現が望まれている
。PRIOR ART Various substances having antiplatelet aggregation effects are known, but 1
The effect is weak, and it is hoped that an improved drug will emerge. In addition, thromboses such as myocardial infarction and cerebral thrombosis have become a large proportion of adult diseases in recent years.
It is desired that an antithrombotic agent that effectively prevents this phenomenon be developed.
従来種々のピラジン誘導体が知られており、ペテロサイ
クルズ第２２巻、第２３１７頁（１９８４年）には３，
５−ジフェニル−２−メチルピラジンが記載されている
。しかしながらこれらのピラジン誘導体が抗血小板凝集
抑制作用を有することはこれまで知られていない。Various pyrazine derivatives have been known so far, and 3,
5-diphenyl-2-methylpyrazine is described. However, it has not been known so far that these pyrazine derivatives have an anti-platelet aggregation inhibitory effect.
■０発明の目的
本発明者等はピラジン誘導体を合成し、それらの薬理活
性を鋭意研究した結果、特定のピラジン誘導体が優れた
血小板凝集抑制作用を有することを見い出し、本発明を
完成させた。(1) Purpose of the Invention The present inventors synthesized pyrazine derivatives and, as a result of intensive research on their pharmacological activities, discovered that a specific pyrazine derivative has an excellent platelet aggregation inhibiting effect, and completed the present invention.
したがって本発明は有効成分としてピラジン誘導体を含
有する血小板凝集抑制剤を提供することを目的とする。Therefore, an object of the present invention is to provide a platelet aggregation inhibitor containing a pyrazine derivative as an active ingredient.
かかる目的を達成するため本発明は下記の構成を有する
。In order to achieve this object, the present invention has the following configuration.
式（１） を有するピラジン誘導体を含有する血小板凝集抑制剤。Formula (1) A platelet aggregation inhibitor containing a pyrazine derivative having
■０発明の詳細な説明
本発明によれば前記式（１）で示されるピラジン誘導体
を含有する血小板凝集抑制剤が提供される。(1) Detailed Description of the Invention According to the present invention, a platelet aggregation inhibitor containing a pyrazine derivative represented by the above formula (1) is provided.
ピラジン誘導体（１）は式（ＩＩ）
で示される２−クロロ−３，５−ジフェニルピラジンを
不活性有機溶媒（例えばジオキサン）中、零価のパラジ
ウム錯体を共存させてトリメチルアルミニウムと２０〜
１２０℃で加熱することにより製造される。Pyrazine derivative (1) is prepared by combining 2-chloro-3,5-diphenylpyrazine represented by formula (II) with trimethylaluminum in an inert organic solvent (e.g. dioxane) in the coexistence of a zero-valent palladium complex.
Manufactured by heating at 120°C.
本発明のピラジン誘導体（１）は、血小板の凝集を阻害
する作用を有するので、血小板凝集抑制剤として脳血栓
等の予防に有効に使用される。投与量は一般に成人１日
量約３０〜６００ｍｇであり、必要により１〜３回に分
けて投与するのがよい、投与方法は投与に適した任意の
形態をとることができ、特に経口投与が望ましいが、静
注も可能である。Since the pyrazine derivative (1) of the present invention has an action of inhibiting platelet aggregation, it can be effectively used as a platelet aggregation inhibitor to prevent cerebral thrombosis and the like. The dosage is generally about 30 to 600 mg per day for adults, preferably divided into 1 to 3 doses if necessary.The administration method can be any form suitable for administration, especially oral administration. Although preferred, intravenous administration is also possible.
本発明の化合物は単独また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炭酸
カルシウム、リン酸カルシウム、でんぷん、しょ糖、乳
糖、タルク、ステアリン酸マグネシウム等があげられる
６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 of the present invention may be formulated into tablets, powders, capsules, or granules either alone or mixed with pharmaceutical carriers or excipients in a conventional manner. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc, magnesium stearate, etc. 6 In addition to the solid formulations mentioned above, the compounds of the present invention may be prepared in oily suspensions,
It can also be made into a liquid preparation such as syrup.
本発明の化合物をサイクロデキストリンで包接し安定化
することもできる。The compound of the present invention can also be stabilized by inclusion with cyclodextrin.
次に製造例および薬理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 by showing production examples and pharmacological test examples.
製造例
アルゴン気流下２−クロロ−３，５−ジフェニルピラジ
ン（１，５９６ｇ）とテトラキス（トリフェニルホスフ
ィン）パラジウム（３４８ｍｇ）に無水ジオキサン（２
０ｍｆｌ）を加え、ついで１５％トリメチルアルミニウ
ムのｎ−ヘキサン溶液（２ｍΩ）を室温下、少量ずつ加
えた後、２時間加熱還流する０反応後、水を加え塩化メ
チレンで抽出し、該塩化メチレン層を芒硝で乾燥し、次
いで溶媒を留去後、シリカゲルカラムクロマトグラフィ
ーに付す、ｎ−ヘキサン−塩化メチレン（１０：１）溶
出区分をとり、溶媒を留去し、残留物をｎ−ヘキサンよ
り再結晶することにより、３゜５−ジフェニル−２メチ
ルピラジン（１，４０ｇ）を得た。このものの物理化学
的データは下記式（１）の構造を支持する。Production Example Anhydrous dioxane (2.5%
After adding 15% trimethylaluminum in n-hexane (2 mΩ) little by little at room temperature, the mixture was heated under reflux for 2 hours. After the reaction, water was added and extracted with methylene chloride to extract the methylene chloride layer. was dried with Glauber's salt, then the solvent was distilled off, and the fraction was subjected to silica gel column chromatography.The fraction eluted with n-hexane-methylene chloride (10:1) was taken, the solvent was distilled off, and the residue was re-evaporated with n-hexane. By crystallization, 3°5-diphenyl-2methylpyrazine (1.40 g) was obtained. The physicochemical data of this product support the structure of the following formula (1).
融点 ９０．５〜９１．５℃
元素分析値 Ｃ１？ Ｈｌ−Ｎ ２に対する計算値：Ｃ
，８２，９０％：Ｈ，５，７３％Ｎ、１１．３７％
実測値：Ｃ，８３，０４％；Ｈ，５，７６％Ｎ、１１．
３８％
ＭＡＳＳ （ｍ／ｅ）： ２４６ （分子イオンピーク
）
’Ｈ−ＮＭＲ（ＣＤＣＱ、） δ （ｐｐｍ）：２゜
６０ （３Ｈ，ｓ）、７．２７〜７．７０ （８Ｈ。Melting point 90.5-91.5℃ Elemental analysis value C1? Calculated value for Hl-N2: C
, 82,90%: H, 5,73% N, 11.37% Actual value: C, 83,04%; H, 5,76% N, 11.
38% MASS (m/e): 246 (molecular ion peak) 'H-NMR (CDCQ,) δ (ppm): 2°60 (3H, s), 7.27-7.70 (8H.
ｍ）、７．８７〜８．０７ （２Ｈ，ｍ）、８．７７
（ＬＨ，ｅ）
薬理試験例 １
血小板凝集抑制作用
３．８％クエン酸ナトリウム溶液（１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
血液を遠心分離し、血小板に富む血漿（ＰＲＰニアＸ１
０’個／μＱを得る。 該ＰＲＰ２６８μ党をキュベツ
トに入れ、３７℃恒温槽で２分間加温し、試験するピラ
ジン誘導体のエタノール溶液２μ意を加え３分間インキ
ュベツトした後、血小板の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を加え血小板凝集をボー
ン（Ｂ ｏ ｒ ｎ）の比濁法〔たとえばジャーナル・
オブ・フィジオロジー（Ｊ、Ｐｈｙｓｉ。m), 7.87-8.07 (2H, m), 8.77
(LH, e) Pharmacological test example 1 Platelet aggregation inhibitory effect 9 volumes of blood are collected from the rabbit carotid artery using a syringe containing 3.8% sodium citrate solution (1 volume). The blood was centrifuged and platelet-rich plasma (PRP Nia
Obtain 0' pieces/μQ. The PRP268 μg was placed in a cuvette, heated for 2 minutes in a 37°C constant temperature bath, 2 μl of an ethanol solution of the pyrazine derivative to be tested was added, and incubated for 3 minutes. platelet aggregation using Born's nephelometric method [for example, Journal
of Physiology (J, Physi.
１、第１６８巻、第１７８頁、１９６８年発行）に記載
されている〕で測定した。アラキドン酸（５０マイクロ
モル）またはコラーゲン（１０μｇ／ｍＱ）によって惹
起される血小板凝集に対する５０％抑制温度を表１に示
す。アセチルサリチル酸を比較例として用いた。1, Vol. 168, p. 178, published in 1968)]. The 50% inhibition temperatures for platelet aggregation induced by arachidonic acid (50 micromol) or collagen (10 μg/mQ) are shown in Table 1. Acetylsalicylic acid was used as a comparative example.
表１に示す如く本発明のピラジン誘導体は顕著な抗血小
板凝集活性を示した。As shown in Table 1, the pyrazine derivatives of the present invention exhibited significant antiplatelet aggregation activity.
尚１表中５０％阻害濃度とは本発明に係るピラジン誘導
体を導入しない場合の血小板の凝集能を１００％とした
場合、該ピラジン誘導体の導入により前記血小板の凝集
能を５０％まで抑制する為に要したピラジン誘導体溶液
濃度を意味する。In addition, the 50% inhibitory concentration in Table 1 means that the aggregation ability of platelets is suppressed to 50% by introducing the pyrazine derivative according to the present invention, assuming that the aggregation ability of platelets without introducing the pyrazine derivative according to the present invention is 100%. means the pyrazine derivative solution concentration required for
表１． 抗血小板凝集活性
急性毒性
ＩＣＲ系雄性マウス（５週令）を用いて、経口投与によ
る急性毒性試験を行った０本発明のピラジン誘導体のＬ
Ｄ０値は３００ｍｇ／ｋｇ以上であり、高い安全性が確
認された。Table 1. Anti-platelet aggregation activity Acute toxicity An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks old).
The D0 value was 300 mg/kg or more, confirming high safety.
■０発明の効果
本発明によればピラジン誘導体を含有する血小板凝集抑
制剤が提供される。(1) Effects of the Invention According to the present invention, a platelet aggregation inhibitor containing a pyrazine derivative is provided.
本発明の上記化合物は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作用を顕著に抑制するの
で、血小板凝集に起因する疾患、特に心筋梗塞、脳出血
後の虚血性発作、脳梗塞等血小板凝集の関与する血栓症
の予防剤として使用することができる。The above-mentioned compounds of the present invention significantly inhibit platelet aggregation induced by arachidonic acid or collagen. It can be used as a prophylactic agent for thrombosis.
（外２名）(2 others)
Claims (1)
。[Claims] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A platelet aggregation inhibitor containing a pyrazine derivative represented by (I).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4155087A JPS63208520A (en) | 1987-02-26 | 1987-02-26 | Blood platelet agglutination inhibitor containing pyrazine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4155087A JPS63208520A (en) | 1987-02-26 | 1987-02-26 | Blood platelet agglutination inhibitor containing pyrazine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63208520A true JPS63208520A (en) | 1988-08-30 |
| JPH0575728B2 JPH0575728B2 (en) | 1993-10-21 |
Family
ID=12611534
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4155087A Granted JPS63208520A (en) | 1987-02-26 | 1987-02-26 | Blood platelet agglutination inhibitor containing pyrazine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63208520A (en) |
Cited By (8)
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|---|---|---|---|---|
| JP2013526540A (en) * | 2010-05-12 | 2013-06-24 | バーテックス ファーマシューティカルズ インコーポレイテッド | Compounds useful as ATR kinase inhibitors |
| US9365557B2 (en) | 2008-12-19 | 2016-06-14 | Vertex Pharmaceuticals Incorporated | Substituted pyrazin-2-amines as inhibitors of ATR kinase |
| US9630956B2 (en) | 2010-05-12 | 2017-04-25 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
| US9791456B2 (en) | 2012-10-04 | 2017-10-17 | Vertex Pharmaceuticals Incorporated | Method for measuring ATR inhibition mediated increases in DNA damage |
| US9862709B2 (en) | 2011-09-30 | 2018-01-09 | Vertex Pharmaceuticals Incorporated | Processes for making compounds useful as inhibitors of ATR kinase |
| US10478430B2 (en) | 2012-04-05 | 2019-11-19 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase and combination therapies thereof |
| US10813929B2 (en) | 2011-09-30 | 2020-10-27 | Vertex Pharmaceuticals Incorporated | Treating cancer with ATR inhibitors |
| US11464774B2 (en) | 2015-09-30 | 2022-10-11 | Vertex Pharmaceuticals Incorporated | Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors |
-
1987
- 1987-02-26 JP JP4155087A patent/JPS63208520A/en active Granted
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10479784B2 (en) | 2008-12-19 | 2019-11-19 | Vertex Pharmaceuticals Incorporated | Substituted pyrazin-2-amines as inhibitors of ATR kinase |
| US9365557B2 (en) | 2008-12-19 | 2016-06-14 | Vertex Pharmaceuticals Incorporated | Substituted pyrazin-2-amines as inhibitors of ATR kinase |
| US9701674B2 (en) | 2008-12-19 | 2017-07-11 | Vertex Pharmaceuticals Incorporated | Substituted pyrazines as ATR kinase inhibitors |
| US10961232B2 (en) | 2008-12-19 | 2021-03-30 | Vertex Pharmaceuticals Incorporated | Substituted pyrazines as ATR kinase inhibitors |
| US9334244B2 (en) | 2010-05-12 | 2016-05-10 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
| US9630956B2 (en) | 2010-05-12 | 2017-04-25 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
| JP2013526540A (en) * | 2010-05-12 | 2013-06-24 | バーテックス ファーマシューティカルズ インコーポレイテッド | Compounds useful as ATR kinase inhibitors |
| US9862709B2 (en) | 2011-09-30 | 2018-01-09 | Vertex Pharmaceuticals Incorporated | Processes for making compounds useful as inhibitors of ATR kinase |
| US10208027B2 (en) | 2011-09-30 | 2019-02-19 | Vertex Pharmaceuticals Incorporated | Processes for preparing ATR inhibitors |
| US10813929B2 (en) | 2011-09-30 | 2020-10-27 | Vertex Pharmaceuticals Incorporated | Treating cancer with ATR inhibitors |
| US10822331B2 (en) | 2011-09-30 | 2020-11-03 | Vertex Pharmaceuticals Incorporated | Processes for preparing ATR inhibitors |
| US10478430B2 (en) | 2012-04-05 | 2019-11-19 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase and combination therapies thereof |
| US11110086B2 (en) | 2012-04-05 | 2021-09-07 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase and combination therapies thereof |
| US9791456B2 (en) | 2012-10-04 | 2017-10-17 | Vertex Pharmaceuticals Incorporated | Method for measuring ATR inhibition mediated increases in DNA damage |
| US11464774B2 (en) | 2015-09-30 | 2022-10-11 | Vertex Pharmaceuticals Incorporated | Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0575728B2 (en) | 1993-10-21 |
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