JPH0536435B2 - - Google Patents
Info
- Publication number
- JPH0536435B2 JPH0536435B2 JP28619887A JP28619887A JPH0536435B2 JP H0536435 B2 JPH0536435 B2 JP H0536435B2 JP 28619887 A JP28619887 A JP 28619887A JP 28619887 A JP28619887 A JP 28619887A JP H0536435 B2 JPH0536435 B2 JP H0536435B2
- Authority
- JP
- Japan
- Prior art keywords
- platelet aggregation
- present
- pyrazine derivative
- pyrazine
- derivative
- 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
- 150000003216 pyrazines Chemical class 0.000 claims description 26
- 229940127218 antiplatelet drug Drugs 0.000 claims description 7
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 7
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims description 6
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- 239000013078 crystal Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
- 235000021342 arachidonic acid Nutrition 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 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
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 2
- 238000000921 elemental analysis Methods 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
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- PTZIVVDMBCVSMR-UHFFFAOYSA-N 2,3-diphenylpyrazine Chemical compound C1=CC=CC=C1C1=NC=CN=C1C1=CC=CC=C1 PTZIVVDMBCVSMR-UHFFFAOYSA-N 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
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 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
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 239000004480 active ingredient Substances 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
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 239000002775 capsule Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- -1 ethoxy, propoxy, isopropoxy, isobutoxy Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 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 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 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
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
〔産業上の利用分野〕
本発明は新規なピラジン誘導体およびこれを含
有する血小板凝集抑制剤に関する。
本発明のピラジン誘導体は強力の血小板凝集抑
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。また、一般に
シクロオキシゲナーゼ阻害作用を有する化合物
は、抗炎症作用を有することが知られており、本
発明のピラジン誘導体は上記阻害作用を有するの
で、抗炎症剤としての使用も期待される。
〔従来の技術および発明が解決しようとする問題
点〕
抗血小板凝集作用を有する物質は種々知られて
いるが、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
血栓といつた血栓症は、近年成人病の中で大きな
割合を占めるに至つており、これを有効に予防す
る抗血栓症剤の出現が強く望まれている。
従来種々のピラジン誘導体が知られており、例
えばシヤーナル・オブ・ヘテロサイクリツク・ケ
ミストリー、21巻、第103〜106頁には２，３−ジ
フエニ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。
本発明者等は多くの新規な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。
従つて、本発明は血小板凝集抑制剤として有用
な新規なピラジン誘導体を提供することを目的と
する。
さらに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。
〔問題点を解決するための手段〕
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。
１ 一般式（）又は（）
（式中Ｘは水素原子、ハロゲン原子、低級アル
キル基、低級アルコキシ基、シアノ基を示す。）
で表されるピラジン誘導体。
２ 前記一般式（）又は（）で表されるピラ
ジン誘導体を含有する血小板凝集抑制剤。
本発明によれば前記式（）又は（）を有す
る新規なピラジン誘導体が提供される。
前記式（）、（）においてＸは水素原子、ハ
ロゲン原子（例えば塩素、臭素、弗素原子）、低
級アルキル基（例えば、メチル、エチル、プロピ
ル、イソプロピル、ブチル、イソブチル）、低級
アルキル基（例えばメトキシ、エトキシ、プロポ
キシ、イソプロポキシ、イソブトキシ）、シアノ
基を示す。
ピラジン誘導体（）は式
（式中Ｘは前述したものと同一意義を有する）を
有するベンジル誘導体と１，２−ジアミノサイク
ロヘキサン（）を適当な有機溶楳（例えばエタ
ノール）中で加熱後、硫黄とともに100〜180℃で
加熱することによつて製造される。
一方、ピラジン誘導体（）は上記式（）
と、０−フエニレンジアミン（）を適当な有機
溶楳（例えばエタノール）中で加熱することによ
り製造される。
本発明のピラジン誘導体（）、（）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。さらに本発明のピラジン誘導体（）、（）
は抗炎症剤としても使用されうる。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。
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、しよ糖、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、シロツ
プのような液剤とすることもできる。
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。
次に実施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。
実施例 １
アニシル（2.70ｇ、10ｍＭ）、１，２−ジアミ
ノサイクロヘキサン（1.14ｇ、10ｍＭ）のエタノ
ール（40ml）溶液を２時間加熱還流。冷却後、少
量の黄色針状結晶（アニシル）が析出。この結晶
を吸引濾過し、濾取。濾液を減圧留去。得られた
残渣にイオウ（0.64ｇ）を加え、150℃で30分間
加熱。冷却後、反応残渣を中圧シリカゲルカラム
クロマトグラフイー*（カラム：Kieselgel60、
230〜400メツシユ、メルク社製、20mm×200mm、
溶媒塩化メチレン）に付すと、２，３−ビス（ｐ
−メトキシフエニル）−５，６，７，８−テトラ
ヒドロキノキサリン1.24ｇ（36％）を得た。融点
189〜190℃（黄色プリズム晶、アセトニトリルよ
り再結晶）。本品の物性データは下記式（）の
構造を支持する。
＊UVILOG ALPC−100（応用分光機器株式会
社）
元素分析値：（C22H22N2O2）
計算値：Ｃ、76.27；Ｈ、6.40；Ｎ、8.09
実測値：Ｃ、75.99；Ｈ、6.38；Ｎ、8.13
MASS（ｍ／ｚ）：346（分子イオンピーク）1
H−NMR（CDCl3）δ（ppm）：1.95（4H、ｍ）
3.00（4H、ｍ）、3.77（6H、Ｓ）6.78（4H、ｄ、
Ｊ＝９Hz）、7.35（4H、ｄ、Ｊ＝９Hz）、
実施例 ２
アニシル（10.8ｇ、40ｍＭ）、０−フエニレン
ジアミン（5.32ｇ、40ｍＭ）のメタノール溶液を
10時間加熱還流。冷却後、析出した結晶を濾取。
該結晶をメタノールより再結晶し、無色針状晶と
して２−３−ビス（ｐ−メトキシフエニル）キノ
キサリンを11.0ｇ（80％）得た。融点151〜153℃
本品の物性データは下記式（）の構造を支持す
る。
元素分析値：（C22H16N2O2）
計算値：Ｃ、77.17；Ｈ、5.30；Ｎ、8.18
実施値：Ｃ、77.03；Ｈ、5.31；Ｎ、8.16
MASS（ｍ／ｚ）：342（分子イオンピーク）1
H−NMR（CDCl3）δ（ppm）：3.78（6H、ｓ）、
6.83（4H、ｄ、Ｊ＝９Hz）、7.67（2H、dd、Ｊ＝
６Hz、Ｊ＝３Hz）、8.08（2H、dd、Ｊ＝６Hz、
Ｊ＝３Hz）
薬理試験例
〔血小板凝集抑制作用〕
ウサギ頚動脈より1/10容3.8％クエン酸ナトリ
ウム採血後、該血液を遠心分離し、血小板に富む
血漿（PRP：５×105個／μ）を得る。
該PRP200μ及び生食25μをキユベツトに入
れ、アグリゴメーターにセツトし37℃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
1.25μを加え３分間インキユベートした後、血
小板の凝集惹起剤であるアラキドン酸溶液あるい
はカラーゲン溶液を加え血小板凝集をアグリゴメ
ーター〔ヘマトレーサー：二光バイオサイエン
ス(株)〕で測定した。アラキドン酸（80μM）また
はコラーゲン（15μｇ／ml）によつて惹起される
血小板凝集に対する50％抑制濃度を表１に示す。
アセチルサリチル酸を比較例として用いた。
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見出した。また、表１に示
さない本発明に係るピラジン誘導体も同様な活性
を示すことが確認された。尚、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。
[Industrial Field of Application] The present invention relates to a novel pyrazine derivative and a platelet aggregation inhibitor containing the same. 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. Furthermore, compounds having a cyclooxygenase inhibitory effect are generally known to have an anti-inflammatory effect, and since the pyrazine derivative of the present invention has the above-mentioned inhibitory effect, it is also expected to be used as an anti-inflammatory agent. [Prior Art and Problems to be Solved by the Invention] Various substances having antiplatelet aggregation effects are known, but their effects are weak, and there is a desire for a more improved drug. In addition, thrombosis such as myocardial infarction and cerebral thrombosis has recently become a large proportion of adult diseases, and there is a strong desire for an antithrombotic agent to effectively prevent this. Various pyrazine derivatives are conventionally known, and for example, 2,3-diphenylpyrazine is described in Journal of Heterocyclic Chemistry, Vol. 21, pp. 103-106. However, it has not been known so far that these pyrazine derivatives have an inhibitory effect on platelet aggregation. The present inventors have synthesized many novel pyrazine derivatives, and as a result of intensive research on their pharmacological activities, they have discovered that a specific pyrazine derivative has an excellent platelet aggregation inhibiting effect, and have completed the present invention. Therefore, an object of the present invention is to provide a novel pyrazine derivative useful as a platelet aggregation inhibitor. A further object of the present invention is to provide a platelet aggregation inhibitor containing a pyrazine derivative as an active ingredient. [Means for Solving the Problems] In order to achieve the above object, the present invention has the following configuration. 1 General formula () or () (In the formula, X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a cyano group.)
Pyrazine derivative represented by 2. A platelet aggregation inhibitor containing a pyrazine derivative represented by the general formula () or (). According to the present invention, a novel pyrazine derivative having the above formula () or () is provided. In the above formulas () and (), , ethoxy, propoxy, isopropoxy, isobutoxy), and cyano group. Pyrazine derivative () has the formula A benzyl derivative having the formula (wherein X has the same meaning as described above) and 1,2-diaminocyclohexane () are heated in a suitable organic solution (e.g. ethanol) and then heated with sulfur at 100 to 180°C. Manufactured by heating. On the other hand, the pyrazine derivative () has the above formula ()
and 0-phenylenediamine () in a suitable organic solvent (for example, ethanol). Since the pyrazine derivatives () and () of the present invention have the effect of inhibiting platelet aggregation, they are effectively used as platelet aggregation inhibitors to prevent cerebral thrombosis and the like. Furthermore, the pyrazine derivatives (), () of the present invention
can also be used as an anti-inflammatory agent. The dosage is generally about 30 to 600 mg per day for adults, and if necessary,
It is best to administer in ~3 doses. The method of administration can take any form suitable for administration, with oral administration being particularly preferred, although intravenous injection is also possible. 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, and the like. In addition to the solid formulations mentioned above, the compounds of the present invention can also be formulated into liquid formulations such as oily suspensions and syrups. The compound of the present invention can also be stabilized by inclusion with cyclodextrin. Next, the present invention will be explained in more detail with reference to Examples and pharmacological test examples. Example 1 A solution of anisyl (2.70g, 10mM) and 1,2-diaminocyclohexane (1.14g, 10mM) in ethanol (40ml) was heated under reflux for 2 hours. After cooling, a small amount of yellow needle crystals (anisyl) precipitated. The crystals were collected by suction filtration. The filtrate was distilled off under reduced pressure. Sulfur (0.64g) was added to the resulting residue and heated at 150℃ for 30 minutes. After cooling, the reaction residue was subjected to medium pressure silica gel column chromatography * (column: Kieselgel60,
230-400 mesh, manufactured by Merck, 20mm x 200mm,
When applied to the solvent methylene chloride), 2,3-bis(p
1.24 g (36%) of -methoxyphenyl)-5,6,7,8-tetrahydroquinoxaline was obtained. melting point
189-190℃ (yellow prism crystal, recrystallized from acetonitrile). The physical property data of this product supports the structure of the following formula (). *UVILOG ALPC-100 (Applied Spectroscopic Instruments Co., Ltd.) Elemental analysis value: (C 22 H 22 N 2 O 2 ) Calculated value: C, 76.27; H, 6.40; N, 8.09 Actual value: C, 75.99; H, 6.38 ;N, 8.13 MASS (m/z): 346 (molecular ion peak) 1 H-NMR (CDCl 3 ) δ (ppm): 1.95 (4H, m)
3.00 (4H, m), 3.77 (6H, S) 6.78 (4H, d,
J=9Hz), 7.35 (4H, d, J=9Hz), Example 2 A methanol solution of anisyl (10.8g, 40mM) and 0-phenylenediamine (5.32g, 40mM)
Heat under reflux for 10 hours. After cooling, filter the precipitated crystals.
The crystals were recrystallized from methanol to obtain 11.0 g (80%) of 2-3-bis(p-methoxyphenyl)quinoxaline as colorless needle-like crystals. Melting point 151-153℃
The physical property data of this product supports the structure of the following formula (). Elemental analysis value: (C 22 H 16 N 2 O 2 ) Calculated value: C, 77.17; H, 5.30; N, 8.18 Actual value: C, 77.03; H, 5.31; N, 8.16 MASS (m/z): 342 (Molecular ion peak) 1 H-NMR (CDCl 3 ) δ (ppm): 3.78 (6H, s),
6.83 (4H, d, J = 9Hz), 7.67 (2H, dd, J =
6Hz, J=3Hz), 8.08(2H, dd, J=6Hz,
J=3Hz) Pharmacological test example [Platelet aggregation inhibitory effect] After collecting 1/10 volume of 3.8% sodium citrate blood from a rabbit carotid artery, the blood is centrifuged to obtain platelet-rich plasma (PRP: 5 x 10 5 cells/μ). Put 200μ of the PRP and 25μ of saline into a cuvette, set it on an aggregometer, and heat it at 37°C for 2 minutes to prepare an ethanol solution of the pyrazine derivative to be tested.
After adding 1.25μ and incubating for 3 minutes, an arachidonic acid solution or a colorgen solution, which is an agent for inducing platelet aggregation, was added, and platelet aggregation was measured using an aggregometer (Hematotracer: Niko Bioscience Co., Ltd.). The 50% inhibitory concentrations for platelet aggregation induced by arachidonic acid (80 μM) or collagen (15 μg/ml) are shown in Table 1.
Acetylsalicylic acid was used as a comparative example. As shown in Table 1, the pyrazine derivatives of the present invention were found to have significant antiplatelet aggregation activity. Furthermore, it was confirmed that pyrazine derivatives according to the present invention not shown in Table 1 also exhibited similar activity. In addition, the 50% inhibitory concentration in the table means that when the platelet aggregation ability without introducing the pyrazine derivative according to the present invention is taken as 100%, the platelet aggregation ability is increased by 50% by introducing the pyrazine derivative.
It means the pyrazine derivative solution concentration required to suppress the concentration to %.
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つた。本発明のピラジ
ン誘導体のLD50値はいずれも300mg／Kg以上であ
り、高い安全性が加人された。
〔発明の効果〕
本発明によれば新規なピラジン誘導体及びこれ
を含有する血小板凝集抑制剤が提供される。
本発明の上記化合物はアラキドン酸あるいはコ
ラーゲンによつて誘起される血小板凝集作用を顕
著に制御するので、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。
An acute toxicity test by oral administration was conducted using ICR male mice (5 weeks old). The LD 50 values of the pyrazine derivatives of the present invention were all 300 mg/Kg or more, indicating high safety. [Effects of the Invention] According to the present invention, a novel pyrazine derivative and a platelet aggregation inhibitor containing the same are provided. The above compounds of the present invention significantly control the platelet aggregation effect induced by arachidonic acid or collagen, so that diseases caused by platelet aggregation,
In particular, it can be used as a prophylactic agent for thrombosis involving platelet aggregation, such as myocardial infarction, ischemic attack after cerebral hemorrhage, and cerebral infarction.
Claims (1)
ル基、低級アルコキシ基、シアノ基を示す。）で
表されるピラジン誘導体。 ２ 一般式（）又は（） （式中Ｘは水素原子、ハロゲン原子、低級アルキ
ル基、低級アルコキシ基、シアノ基を示す。）で
表されるピラジン誘導体を含有する血小板凝集抑
制剤。[Claims] 1 General formula () or () A pyrazine derivative represented by (wherein X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a cyano group). 2 General formula () or () A platelet aggregation inhibitor containing a pyrazine derivative represented by (wherein X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a cyano group).
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62286198A JPH01128972A (en) | 1987-11-12 | 1987-11-12 | Pyrazine derivative and platelet aggregation suppressing agent containing said derivative |
| EP19880909824 EP0397859A4 (en) | 1987-11-12 | 1988-11-11 | Pyrazine derivatives and medicinal preparation containing same |
| PCT/JP1988/001141 WO1989004308A1 (en) | 1987-11-12 | 1988-11-11 | Pyrazine derivatives and medicinal preparation containing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62286198A JPH01128972A (en) | 1987-11-12 | 1987-11-12 | Pyrazine derivative and platelet aggregation suppressing agent containing said derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01128972A JPH01128972A (en) | 1989-05-22 |
| JPH0536435B2 true JPH0536435B2 (en) | 1993-05-31 |
Family
ID=17701231
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62286198A Granted JPH01128972A (en) | 1987-11-12 | 1987-11-12 | Pyrazine derivative and platelet aggregation suppressing agent containing said derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01128972A (en) |
-
1987
- 1987-11-12 JP JP62286198A patent/JPH01128972A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01128972A (en) | 1989-05-22 |
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