JPS59104318A

JPS59104318A - Antithrombotic agent containing aminobenzoic acid derivative as an active ingredient

Info

Publication number: JPS59104318A
Application number: JP21214482A
Authority: JP
Inventors: Masanori Ubusawa; 生沢　政則; Fumio Hirose; 広瀬　文夫; Takami Fujii; 藤井　孝美; Kenichi Matsunaga; 謙一松永; Minoru Ohara; 稔大原; Takao Ando; 安藤　隆雄; Chikao Yoshikumi; 吉汲　親雄
Original assignee: Kureha Corp
Current assignee: Kureha Corp
Priority date: 1982-12-03
Filing date: 1982-12-03
Publication date: 1984-06-16

Abstract

PURPOSE:The titled drug that contains an aminobenzoic acid derivative or its salt as an active ingredient, thus permitting long-term administration, because of its low toxicity. CONSTITUTION:The objective antithrombotic agent is obtained by using 0.01- 100wt% of at least one of the compounds of the formula (R is glycoside) or their salts such as p-aminobenzoic acid-N-L-arabinoside and mixing it with diluents such as extender, binder, humectant, disintegrator and so on. It is effective to not only thrombosis in arteries and veins but also thrombopathy, improvement in thrmoboses accompanied by artificial membranes, renal transplantation, artificial dialysis. Further it is effective to nephrectopathy such as glomerulonephritis. The drug is orally administered 0.1-1,000mg/kg/day, parenterally 0.01-200mg/day. Further, since the compound of the formula has no antibacterial activity, there is no anxiety of disturbing intestinal flora and it exerts no influence on mutagenecity, cellular and humoral immunities, thus it is a very safe drug.

Description

[Detailed description of the invention]

本発明（３ト一般式（ＩＩ　）（式中、［＜はグリコシドを示づ）で表わされるアミノ安息沓酸誘導体又は医薬上６′Ｆ容
し得る（の塩を有効成分とづる抗血栓剤に係る。従来、制癌剤どして合成化合物や抗生物質７＝どが用い
られてきたが、これらは殺癌効果はＪぐれていても正常
細胞にも作用するため毒性が強く、副作用をヱする欠点
があった。そこで最近では宿主の免疫能を高めることに
より制ブ１θ効果を発揮りる種々の起源の多糖体が注目
されるようになった。ホ発明者簀はＴＪ　Ｃに担子α１山来多糖Ｊ、すなと）
制癌剤を間介し社会The present invention (3) An antithrombotic agent containing as an active ingredient an aminobenzoic acid derivative represented by the general formula (II) (where [< indicates a glycoside) or a salt of the pharmaceutically acceptable 6'F Conventionally, synthetic compounds and antibiotics have been used as anticancer drugs, but although these drugs may have poor cancer-killing effects, they are highly toxic and have side effects because they also act on normal cells. Therefore, recently, polysaccharides of various origins that exert anti-1θ effects by enhancing the immune capacity of the host have attracted attention. Kipolysaccharide J, Sunato)
Society through anticancer drugs

【こ提供しているが、この制ｈ−１
・）剤の構造並びに活１（１のｆσ１究中に上記一般式
（］）で示される化合物に顕と２．−抗血栓作用を見出
し、本発明を完成しＩこムの４ある。」二記一般式（Ｉ）ｒ小される化合物（以下、″本物貿
″と略称りる）は簡単な構造り゛ありながら、１へめで
低バｒ　’ｌノ１．−Ｐあり丁１つ抗菌縮性がないの０
腸内菌最攪乱などの心配がなく、長期投′〕がｉｉＪ能
Ｃ′ある。よＩご変異原ＩＩ＋や細胞性及び体液・１ノ
１免疫にも影響を′ｊえ４”、したかっ−Ｃ健康な人に
対りる１１ｒ白形ｔ’ｌ　ｌ゛）ｉ’レル１−反応など
の危険も’、ｃ＜、極めて安全な桑剤Ｃ゛ある１、加え
Ｃ、本物質はいり゛れｂ面小板凝集目１１１−作用、面
栓塞栓死抑制作用を石しており、抗血栓１１１剤とし゛
（石川である。本物質の１ミノ基の（ｉ／首は１〕−１ｍ−１０−と３
（Φ類あり、ぞれ−とれ活ｔ７１に多少の違いかみられ
ることもあるが、本質的にはいり゛れｂ石川−Ｃある。。本物質は塩の形態であっても」、く、その揚合区薬１−
Ｗ１容しくｑる塩であればいす“れも包含される。その中にはアルカリ金属塩、アルカリ土類金属塩、アル
ミニウム金属塩が含まれる。通常はＮａ、Ｋ。Ｍｉｌｌ　、　Ｃａ　、△１などが好ましく、特にＮａ
が好ましい。本物質の糖部分は、グリコシドを形成づる糖Ｃあればよ
い。糖どしては、例えはアラビノース。キシロース、刀゛ラクトース、グルニｌ−ス、マンノー
ス、ラムノース等を含む。糖（より又は１一体もしくは
α−ｊ２ノンー１β−アノンーの形または〕′ツマーの
ｉＲ合物の形であってもよい。したがって本物質もα又
はβｂ＋、＜はこれらの混合アンマーＣあることが出来
る。本物質の製法は下記のごとく例示される。アミン安息青酸４．５〜５ｇ、糖（［−−アラビノース
、Ｄ−１ニジ］］−ス、１）−グルニ］−ス、１）−ノ
ｊラクト−ス、１−−ラムノースまたはＤ−マンノース
）５〜ＧＨ）、塩化アンしニラ７１０．１へ・（１、５
（］を９！１へ・１００％」タノール３１、た【よ純メ
タノール４０〜５０ｎｌｌＯ）還流下にＣ加熱９１１１
含μしめる。室温または冷所敢四後しばら＜　Ｉ、−（
結晶の析出りるものは反応液を濾過し、ｔ１１品を水、
アル７」−ル、■−ｊルなどで１−分に洗汀１後、メタ
ノール水またはエタノール水Ｊ、り再結晶りる、。７Ｊル小−１シル基の水素を塩基Ｃ゛置換るには周知の
方法に１へ（拠するとＪ、い。すなわら、一般式（［）
で示される本物質をノフル」−ル水系溶媒に溶解し無（
幾塩を加え−Ｃ買換する。以−Ｌの製法にＪ、す１“１られた本物質の物理化学的
特性を下記表１に承り。また赤外線吸ｌｌｌ！スペク１
〜ルを第一１・＝、２４図に小す１．４＞お、表１にお
りる分析方法は次の通りＣ゛ある。（１）融　　点　柳本微量融点測定装置を川（１て一測
定した。（２）元素分析　柳本Ｃｆ−Ｉ　Ｎ　Ｊ−ター間−１２
型（こＪ、り測定した。（３）ＵＶ　　　　目立［−Ｐ　Ｓ　−３−１型自記分
光光度Ｇ１により、−１１はアルニ］−）レー水系、−
Ｎａは水を溶媒としで一測定した。（／１）ＩＩ又　　　Ｌ１本分光［）３−７０１Ｇ型（
こよりＫＢｒ法で測定した。尚、図ｉ１′ｉｉ番号は表
１の砥石ＮＯ，と一致Ｊる。次に本物質の７７７　！Ｉ＆ノ学的特ｆ１を示４゜１）
急性汚性ＩＣｌ２−Ｊ　Ｃｌ−系ンウスを用いて腹１１・）“内
及び強制経［」投与による急性パｉ性を調べた。本物質
は腹腔両投！ｊＣは生理食塩水に、経口投与Ｃは蒸溜水
に溶解し、これを注射筒または胃ゾンデを用い−Ｃ所定
の罪に調整しくｌ）えた。投与後中洟症状の観祭を続（Ｊ、７０口まＣ゛の経時的
死亡率から１−１〕５ｏ値を求めた。生存例、Ｉｌ、　
ＩｌＸ例とも解剖しＣ所見を得た。ｍｌ）５ｏ値はリッ
プフィールド・ウィル１クソン（Ｌ　ｉｔｃＭｉｅｌｄ
　−Ｗ　ｉ　１ｃｏｘｏｎ　）図ｉ’ｉｌ’　Ｇ″１法
により求めた。結果は表２に示す。いヂ４′ｌ、　ＯＩ
＋！、ｉｌ　ＩＩ’！’内、経１−１を間ゎ！／’　Ｉ
−Ｄ　　値０は６０／　Ｋ　！Ｊ以トく、さらに１０種類中６秤類の
化合物、−ｉＪなわら半数以−［が１−１〕　　値で１
０す／にり０以１−ど極め（安全性の高い薬剤であるといえる。２　）　抗ｒ！、＋　２；’ａ　ｌｉ本動物質蒸溜水に溶解して２倍希釈系列を作成し、この
希釈液を９〕１８聞の加温溶解した（１！天ｊ８地に混
和し、べ１へり曲（Ｊ汀いＣ甲板とした。Ｊ（ｒ、地に
はバー１ヘインヒ１−ジョ穿入人（細菌）及びリブ１」
−寒天（真菌）を用い、前Ｊｒ１養した試験菌を塗抹接
種後細菌Ｌｉ３７℃、２０−２４１＋ｒ、真菌ｔＪ２５
°Ｃ，３３〜７［１間それぞれ培養しＣ牛γ■の有無を
調べｌこ。被検菌としては次の各菌種を使用した。緑膿菌　（１）ｓＯｕｄｏｍｏｎａｓ　　ａｅｒｕ（Ｉ
ｉｎｏｓａ　　　ｌ　　Ａ　ｆｖ１１！＋１４）２（＋９１））ｌＡｆＶ＋　　４２０７）カンシタ酵ＰＪ　（Ｃａｌ’ｌｄ！ｄａ　　ａｌｌｌＩ
ＣａｌｌＳ　　△−ｒ　ＣＣ７５２）白？菌（ｌ　ｒｉｃｈｏｐｌ＋ｙｔｏｎ　　ｍｅ＋ｕ　
ｇｒｏｐｈｙｔｅｓ１ト０　６１２４）黒かび（△ｓｌ＋ｃｒｇｉｌｌｕｓ　　ｎｉｇｅｒ　　
ＩＡＭ　　３０（１１）その結果、本物質はいづ゛れの
菌に対し−Ｃも１ｍｕ／■１１の）農度Ｃ牛育閉止を示
さなかった。３）変異１ガ１１（１まり川＜６ｃｍａｓｓａｙによる検問を行なった。づな
わち、組換ｉｌｌ　復欠損株（Ｂａｃｉｌｌｕｓ　　５
ｕｂｔｉｌｉｓ　　Ｍ２Ｓ）ど組換１１工復保持株（旦
−、５ｕｂｔｉｌｉｓ　　１（１７）の２株を１３−　
ＩＩ寒大培地（肉１キス１０ｇ、ボリペゾ１ヘン１０ｇ
、Ｎａ　Ｃｌ　５（！、寒天１５す、蒸溜水１０００ｍ
　ｌ、ｐｌ−１７，０）上に出発点が互いに接触しない
ように画線した３１本物質を滅菌水に溶解し、その０．
０５１１１１を自任８　Ｉｌｌ　Ｉｌｌの円形濾紙に吸
収さけた後、直ちに画線の開始点をおおうＪ、うに静置
し、３７°ＣＣ゛−晩培養し一η牛Ｙ■田止域の長さを
測定した１、陰性対照とし−Ｃカナ！イシン、陽・ｔ！
１対照どじで一メイ１〜マイシンＣを用いｌこ。次に復帰変５１イ試験をＳ　ａｌｍｏｎｃｌｌａ　ｔｙ
ｌ＋Ｉ＋ｉ＋ｎｕｒｉｕｍ］Δ９８ど−［△ＨＩＯ（い
り゛れもヒスデシン要求性）を用いＣ１ｊなツ１．＝。０．５１ｎＭビチＡン−（１、５ｍ　Ｍヒスプシン溶液
１，１０１容を加えた軟寒天液＜ＮａＣｌｅｇ、寒天６
！Ｊ、蒸溜水１０００ｍ　ｌ　）　　２ｍ　ｌ　！ご菌
液０．１ｍ　ｌ、循液０　、１　ｍ　ｌを加えてＪ、く
混合し、ｆ−小穿入ｊ）１地−！（こ中層しｌこ３，３
７°Ｏｉ（２１」問ｊ？ｌ谷し復帰変異−」１１−一数
を４故した。陽性対照としＣフリルツノ：／　（＋’　
（Δ１２）を使用した。Ｒｃ　ｃ　−ａ　ｓ　ｓ　ａ　ｙの結果を表３、復帰変
異試験のれ１１果を表４にでれそ゛れ示り。１（ｅｃ費
１ｓｓａｙにＪ３いては本物ｖｔ　ハ変１’Ｊ　ｌｊｊ
’ｊ性’ｌ’　ｌ：’ＩＩ　ＩＩｊＪ　Ｉ！Ｊ　’Ｊ、
　’７１”　示すなイカ、４’１４ｑｐ−ｊ７ミノ安ｐ
、青酸）−１−リウム誘導体がりぐれていた。まＩこ復
帰変異試験（は本物質にＪ、る変異発生率は高温Ｉ長を
作用さけ７．：場合でも無添加対照と比較して何ら変化
はみられず、安全性の高い薬剤Ｃ′あることかｊ［明さ
れた。／Ｉ’）近延型皮内反応本物質の細胞性免役への影響を知るために１ＣＩ＜−Ｊ
　Ｃｌ−マウスを用い−Ｃヒツジ赤血Ｄｔｉを抗原とす
る屋踵反応（Ｆ　ｏｏｔ　ｐａｄ　ｒｅａｃｔｉｏｎ）
を１１なった。ヒツジ赤血球を牛］！ｌ！良牌１水に１０％ｍ懸濶ｌし
め、このｄを０　、２　ｍ　ｌをｌに静脈、ｊ、り２４
人しＣ１次感作を行ない、さらに７１（後にじツジ赤血
球の４０％ｉｉ　ｌ’ｐ濶＞１９０．０５ｍ１　ヲ５ｆ
ＦＩＪｆＭｉ１’１Ｊ−１シＴ　２　’（’Ａ感１’＋
＝　ヲ＜−Ｊなイ翌「１足Ｉｎ　、ｌ’、；’の測定を
ｔｊ　％・）だ。本物質は１次感イ′１の目を中心に　
２　り　０１１１す／にりを膜層１内へ連ｆ−ｌ　５回
投′うした。その結！、！４．Ａ物ｒ！ｌ　１ｊｔ−ｊノｎγのｔ側
７の増加は対照（非役４　）　７ｉｌ′と比較し−Ｃ何
らイ）恵方は認めなかつｌこ　。５ン抗体産生能本物質のイホａｆ１１免疫への影響を知るために、ｊＣ
Ｒ−Ｊ　（：：　ｌマウスに夕・１し、ヒツジ赤血球の
１０％Ｍ懸濁液０．２ｍｌを尾静脈より注入し−Ｃ感作
し、感作後７日１１に採血して赤血球凝集反応により抗
体産／：Ｌ能を測定した。なお本物質は感作［１を中心
にしＵ　２５０ｎｌ（１／　Ｋ　！Ｊを連日５回腹腔内
へ投′うしＩ、二〇結果は、本物質投与群と対照群の凝
集価に何ら有恵方はみられなかった。次に本物質の桑即学的特ｆ１をｊホべろ。１　）　＋１＋小板凝東抑制作川ヒ１へ新町静脈ｎ）＋よりＰ　Ｐ　Ｐ　（Ｐ　１ａｔｅ
ｌｃｔ　ｌ＜ｉｃｌ＋ｐｌａｓｌＩｌａ）を調製した。凝集剤どしく、△Ｄ　Ｐ（Ａ　ｄｃ＋＋ｏｓｉ＋＋ｅ　
ｃｌｉｐｌ＋ｏｓｐｌ＋ａｔｅ）　、　］ラーグン、ア
ラキドン酸を用い、凝集剤添加後の血小板）凝集の１α
合をｊ′グリゴメーターを用いて測定した。本物￥４は
５Ｏｎ＋ν１を凝集剤添加２分前【Ｊ添加した。結果は対照（本物質の代りに生理的Ｑ塩水を添加）の最
大凝集度に対する凝集抑制率で表わし表５に示した。試
験に供した化合物【よ１ぺで凝集抑制作用がみられ７ｊ
か、特にｐ−アミノ安息香酸ツートリウム−Ｎ−１〕−
７ンノシドが全Ｃの凝集剤に対しリ−ぐれた効果を示！
Ｊ＋ｔ７＋が注口される。表　５　　＊物質の血小板凝集抑制作用〈抑制率％）２
）血栓塞栓化に対りる抑制作用マウス＋、Ｚ本物ｉ：’ｌ　３００１１１ｉＪ　／　Ｋ
　ｇ’ｉ経ｒ−Ｉ　ＩＱ〜し３時間後に△１つ［〕又は
−〕Ｊラーゲン庖静脈注０１シ死亡を測定した１、ス・
］照どしく水物τ′１の代りに蒸溜水を経１」投すした
。結果を表０に示した。試験に供した化合物はりｌ＼Ｃ
クヒ已率を抑制したが、特に１）アミノ安ｊ、′、Ｂ市
酸）　ｉ−’Ｊウム　Ｎ−１）−ンンノシ１−がりくれ
た効果を示Ｕ　＋：ｔｉが注１−１される。表　６　　本物質の血栓塞栓化に対する抑制効果（死亡
率％）次に本物質の製剤化についＣ述べる。本物質は抗血栓剤としＣ使用覆る場合、疾患の種類及び
症状に応じＣ共動を冑るのに都合のよい形状で使用でさ
、イしで単独または製’ＩＥ　、１．　ａ’ｒ容し１ｑ
る希釈剤及び他の共剤どの混合物とし゛Ｃ使用て゛きる
。本物！ｔは軒Ｌ１的、１．Ｉこは非軽ＩＩ的に適用され
る１、したがっ（杆１−ｊ的まｌ（は非経［」的に投Ｉ
うＪるための形態を汀意にとり（７る。本物質は投某中位形（−提供づることができる。有効薬Ｉ８の有効成分が含有され、その形態とじＣは散
剤、顆粒、錠剤、な１１衣錠、カブＵル、座桑、懸澗剤
、液剤、乳剤、］７ンブル、注射液などの形態をどりＩ
Ｌする。希釈剤どじζ固体、液体、半固体、あるいは摂
取しく：ノるカゾレルでもよく、例えは次の１）のがあ
Ｕられる。ずなわち、賦形剤、増量剤、結合剤、湿潤化
剤、ｉｉｉ］解剤、表面活性剤、滑沢剤、分散剤、緩衝
剤、香石、保存料、溶解補助剤、溶剤などで・ある。さ
らにこれらの１種または１種以上を）ｄ合しＣ使用し得
る。本発明の抗血栓剤【よ既知のいかなる方法でも製造し得
る。本発明にａ３い−Ｃ用いられる組成物中の活性成分
は一般に０．０１から　１００ｗｔ％含まれる。本Ｒ明の抗血栓剤は人間及び動物に経「」的３したは非
経［１的に投！うされるが軽口後〜が好ましい。経口的投！うは馬上投与を包含覆る。非経Ｉ」的投勾は
注射、例え（よ座上、筋肉、静脈性ｑ・１、点滴なとも
含む。本発明の抗血栓剤は動・静脈の血栓症に対しＣのみなら
づ′、血小板機能異常症や、人工弁、腎移植、人１ニ透
析に伴なう血栓の改善等にイＪ効である。更に糸球体腎炎等の腎疾患に対しても有効である。本Ｒ明の抗血栓剤の投与量は動物か人間かにＪ、す、ま
た年齢、個人差、病状などに彩管されるので場合にＪ、
つ−Ｃ（。Ｌ１記範囲外ｍを投り刀る場合も生り′るが
、　般【ご人間を対τｌとり−る場合、本物質の軽ＩＩ
投！ｊ吊は体重Ｈ＜　ｇ、　Ｉ　Ｌｌ当り０．１へ、１
（ｔｏ。ｍｇ、々ｒましくＣよ　１−５００　Ｉｎす、非紅口的
投与ｍは同じく、Ｏ６旧〜２　（１（ｌ　ｍ　！＋、１
）ｆましくは０．１〜Ｈ１（１ｍｇを１回・〜４回に分
（Ｊ′Ｃ投Ｌｊづる。以下、本発明物Ｙ１４の製剤化例並びに”ＡＪ貴例を示
し本発明をＪ、り訂！Ｆｉｌｌ　Ｉこ説明する。製剤化例１本物質Ｃ＋＋−ｊ’ミノ安息香酸す１〜リウム−Ｎ−し
−アラビノシト）１０部重質酸化ングネシウム　　　　　　　　１５部乳　　糖
　　　　　　　　　　　　　　　　　　　　　　　　　
７５部を均　にｔｆＪ含しＣ粉末３；、Ｉこは細粒状と
じて散剤とづる。またこの１１（剤をカーｆ１．フル容
器に入れてカブレル剤どした。。製剤化例２本物″ｊ！１（０−アミノ安麿香酸〕１〜リウｌ＼−Ｎ
−１つ−４−シ［１シト）４５部澱　　粉　　　　　　　　　　　　　　　　　　　　　
　　　　１　ｂ　ｆＪＩ乳　　糖　　　　　　　　　　
　　　　　　　　　　　　　　　１６部結晶レしＩ−，
ｉ−ス　　　　　　　　　　　２’１部ポリビニルアル
コール　　　　　　　　　３部水　　　　　　　　　　
　　　　　　　　　　　　　　　　　　　　３０部を均
一に握合混和後、破砕造粒して乾燥、篩別後顆粒とダる
。製剤化例３製剤化例２に（１３（〕る〕Ｏ−アミノ安忠香すＬ−リ
ウム−Ｎ　−１，）−−−１ニシロシドのかわりにＯ−
アミン安息香酸ノー１〜リウム−Ｎ−θ−グルニ１シト
を用いて同様の方法で顆粒剤を作り、この顆粒剤９６部
にステアリン酸カルシウム／ｌ　ｉｎを加えて圧縮成形
して直径１０ｍｍの錠剤とする。製剤化例１本物質（＋１−７ミノ安息西酸Ｕ１−リウム−Ｎ−（−
−ラムノンド）９４部ポリヒールアル−」−ル　　　　　　　　　６部水　　
　　　　　　　　　　　　　　　　　　　　　　　　　
　　　３０部を用いで製剤化例２ど同様の方法で顆Ｋｉ
ｔ剤とづる。得られたλ：Ｃ目、７の９（ン部に結晶セル１」−ス１
０部を加えて圧縮成形し−Ｃ直仔８ｍ１０の錠剤どｂ、
これにシ１−１ツブゼラチン、沈＃−ｆ　Ｐ１炭酸カル
シウムを加えて糖へ錠とづる。すｊ化例５本物質（１１〕′ミノ安息占酸ノ１−リウム　Ｎ［〕−
ガプラク１〜シト０．６部非イＡン系稈面活１！Ｉ剤　　　　　　　２．４部住理
食塩水　　　　　　　　　　　　９７部を／Ｊｌ目１ｄ
混含後滅菌しく？１射剤と覆る。製造例１　　１１−、−、Ｉミノ安息香酸−Ｎ−Ｌ−ア
ラヒｐ−、７ミ／安息香＠　Ｌ６ｇ　、１．−７ラヒ／
−ス５ｇ１塩化アンＬニウム０，５（］を９４％エチル
アルコール４０ｍ１中ｒ：正流下、加熱縮合づる。反応
液を冷蔵沖に故買すると、結晶の析出をみる。反応液を
口過し、Ｍ品を土−アルで洗い、５０％メチルアルコー
ルから数回再結を繰り返して、無色剣状の結晶を得た。収率４５．８％であった。このＪ、うにしり１！１られた、ｐ−アミノ友息香酸−
Ｎ−１−−アラヒノシドをｌ　ｎ　ｍのＮａ０１−１を
含む１％水溶液に徐々に溶解し、不溶物をＬ１過し、０
液を減圧）層線し、大過剰のアレトンを加え、１１；）
水接、乾燥して無色の結晶を１Ｊた。収率１００％、全
敗率４５．８％であった。アンスジニル酸２，３！］　、　ｌ　　アラ上ノース２
．５Ｑ、塩化ノ７ンモ−ラム０，２（Ｊをメチルアル−
］−／し３０ｍ１中で正流−■・、加熱縮合りる。反応後、゛早温敢Ｌｊ／；づると、結晶の析１］１をみ
る。反応液を１］過しｌ冑られる結晶を、水、メチル）ノル
ニ］−ル、−１−ノルＣ洗い、無色Ｈ状まＩこｆ、ｉ　
Ｇｉ？　１人の結晶を（！）だ。１１ソ率Ｇ１．３％（
゛あ・）だ１゜このＪ、うにしで１１１られた、アシス
ジニル酸−Ｎ−１−−−／’ラビノシトをｊ’ｌｌ　’
７１　ｍのＮａＣｌ２をｆ）む１％水溶液に徐々に溶解
し、不溶物を「」過し、１」液を減１１−．　ｉｇ’ｌ
縮し、大過剰のノル１−ンを加え、脱水１ね乾燥しｕ（
（芭の結晶を１１また。収率１００％、全敗；参。６１　、　：ｉ％くあった。１］−ノ′ミノ宥１四Ｃ１ｊ酸２．３ｑ、Ｉ）−にシ１
−１−ス２、：〕リ　、１福化アン■−ラム　００５ｇ
を」−ラフレアル］−ル２！ｉＮ申Ｃ−還流下、＋３１
１熱縮含りる。反応中に結晶の析出があるが、溶媒を追加し、加熱を続
（Ｊで反応を終る。冷所に敢（６シｌこ後、反応）１夕
を１１過しＩこのち、”結晶を、水、稀メチルアルコー
ル、および少ωのエーテルで洗い、９４％上プルアル」
−ルから再結晶して、無色Ｈ状の結晶をＮだ、、　ｌｌ
’ｉ率７３．７％であった。このＪ、うにしく得られた、ｐ−７ミノ安息香醇−Ｎ　
Ｄ−Ｖシロシ１：を５１　”Ａ　（’ｊｉのＮ　ａ　Ｏ
ｌ−１を含む１％水溶液に徐々に溶解し、不溶物を口過
し、０液を減）十）１岩縮し、大過剰のアセ１〜ンをハ
１１え、１１）２水後、乾燥し″（無色の結晶を１ｑた
。収率１００％、１−ｏｌ、ａｌ収１．Ｂ３．７％Ｃ・
あツ１コ。アンスラニル酸２．３（］　、　］Ｄ−キシロース２．
５ｇ１ｎ化アンモニウム＜１　、２　ｇを１チルアルコ
ール３５ｍ１中Ｃｊ＝流１・、加だ１１１１合８Ｊる。反応後、減圧１′。：に約　１／２に濃縮し、′デ温に
放首りるど結晶の１１１出をみる。反応液を１−１過し
たのち、結晶を、水、メｆルアルニ１−ル、」−チルで
洗い、土デルアルー１−ルＪ、す７１ｊ結晶しＣ１無色
眉状の結晶を得た。収率７４．６％であった。このＪ、うにして１１１られた、アンスラニル酸−Ｎ−
Ｄ　−：ｌ二：／　Ｉ−Ｉ　シＩ”を１ｉｌｔｆｆｌｌ
（７）Ｎａ　Ｏ１ｌヲｎム’Ｉ％水溶ｄをに徐々に溶解
し、不溶物を口過し、［」液を減Ｉ丁淵縮し、大過剰の
アｔ？ｌ・ンを加え、Ｉ］ｔＪ水ＩＣ？と燥して７ＩＩ
Ｉ（！２の結晶を１１１ｋ。収率ｔｏｏ％、１Ｏｔａｌ
収率７６、１１％（−あった、。ｐ−ｊ′ミノ安１；’ｂｔ　？！ｉ酸ｊ）（１，１）−
グルニ］−ス６．４（）、ＪＩＶＩ化アシし一つム（）
、５りを９４％」ブルノ７ルニ】−ル５０…１中ＣｊＷ
流１・、加熱縮合する。反応後、減ｊ１１・に約１／３に濃縮し、冷所に放間づ
ると液全体がゲル状に膠化した。少量の水を加え、再ひ
加？：＋Ａ　シ’ｌ溶解した後、冷藏即に放置りるど結
晶の析出をみる。反応液を［１過し、結晶を、水、綿メチルアルコール、
および少量のニーアルで洗い、５０％メチルアル−コー
ルから再結晶して、無色＄１私の結晶をｌｉ’？　／ご
。収率゛３３．７％であった。このように（〕Ｃ得られた、　１）−アミノ安息香酸−
Ｎ−Ｌつ一タル」シトを訓算午のＮａ○１−（を含む１
％水溶液に徐々に溶解し、不溶物を口過し、［１液を減
Ｊｊ濶綿し、大過剰のアｔ　ｌ・ンを加え、脱水後、乾
燥し一４無色の結晶を得た、１収率１（）０％、Ｔ’ｏ
ｔａｌ収率３３．７％て゛あった。アンスラニル酸４．６（１、Ｑ−グ／Ｌ／］−ス（ｉ、
０（１。塩化アンし−ラム０．！＋りを９５％−［ブルノフルー
Ｉ−ル４　Ｏｍ　ｌ中に）７流ｌ・、力１世ｊ１綿合り
る。艮応１変、６表月１・に約　１／′３にｉ１′：縮し、
１１寵戊川１に一夜放置刀るど結晶の析出をみる。反１
＋ｉｘ＋液を１１過し、結晶を、水、メＪルノノルー１
−ル、−１−−ｊルＣ゛洗い、メ升ルフルー１−ルから
二度再結晶し無色１１状の結晶を１′−１ｋ１．収１４
．６％Ｃあった。このＪ、うにしく１１１られた、アンスラニルＭ−Ｎ−
１１）−−グル１シ１−をｉ１綽吊のＮａ０ｌｌを１）
む１％水溶液に徐ノンにｉＲ解し７、不溶物を［」過し
７．１）（１々を減月−淵縮し、大過剰のｊ’　Ｉ：　
ｈン合加え、１１（２水後乾燥しＣ〕）ｊｊ　（Ｑの結
晶Ａ１’＋　Ｉｙ。収＋１００％、１ｏｃａｌ収率４　
、　（ｉ　％　”Ｃあ）　ｌ；、　。Ｄ−ノアミノ安１１冒”ｉｎ’、２１，５！Ｊ　、Ｉ：
）−カン’、／　ｈ　　２２（１、塩化ノノン■−ウｌ
ｚ　０．１ｇを９４％−ＩＪルノフル−１−ル３　（ｌ
　ｍ　ｌ中（゛ｊ７流手、加熱縮合づ−る。反応後、減圧濃縮し、冷所に放「ｌづるど、結晶の析出
をみる。反応液を【」過し、結晶を水、（にメヂルアル
ーＪ−ル、および少量のエーテルＣ洗い、メブルアルニ
１−ルから再結晶し−Ｃ１無色ε１状の結晶を＜！７ｋ
。収率１８．１％であった。このＪ、うにｕＵ　ｔｈられた、ｐ−ノ′ミノ安息吉酸
−Ｎ　−１）−刀うクトシドを計算賞のＮａ○１−（を
ａむ１％水溶澱に徐々に溶解し、不溶物を［］過し、ｒ
ｊ液４減月−ｊ；）？綿し、大過剰のアレトンを加え、
１１）２水後、乾燥して無色の結晶を得た、１収率１０
０％、王ｏｔａｌ収イ、’１８．ｉ％で゛あった。アンスラニルＭ　２．４ｇ、　Ｄ−力ラフＩ・−ス３．
０！ｌ　Ｎ　Ｗ化アン七ニウム０．２ｑを９５％」ニヂ
ルアル−１−ル３０ｍ１中にｊ至論下、加熱縮合づる。反応後、減Ｉ「上に約１．／２にｊ層線し、室温に放同
りると結晶の析出をみる。反応液を１」過し、結晶を、
水、メブルノフル」−ル、１−−デルｃ−′洗い、９５
％エチルアルｌ−ルＪ、り再結晶しく　；ｌｊ　ＣＩ！
釧状の結晶を得た。収率１６．４％であった。このＪ、うにしＵＪ＃’；ｊ’うれた、ｊ７ンスラール
ＩＩＮ＝１つ一刀うク１〜シトを１ｌＲｆｆｉのＮａ０
Ｎを含む１％水溶液に徐々に溶Ｖｆｔ　Ｌ／、不溶物を
口過し、ｌ−，１液を減圧′ｆＡ縮し、大過剰の１１？
１−ンを加え、１１；１水後乾燥しＣ無色の結晶を１！
１ｋ。収率１００％、「ｏＬａｌ収率１６．４％であっ
ｌ、１゜１１−−アミン安息青酸３ｇ、１−−−ラムノース４ｇ
、塩化アンＬニウｌＸＯ，１りを９４％−Ｌチルアル」
−ル中に還流冷７．ｌＩ上、加熱紺Ｉ合りる。陵応後、室温に敢１ｆｉ７．するど、結晶の析出をＩノ
る。反応液を１−１過し、結晶を水、稀メブルアル」−ルで
洗った後、５０％メチルアルコールより再結晶して無色
σ１状の結晶を得る。収率３０．９％であった。このＪ、うにしく’　ｉ！７られた、１］−アミノ安息
香酸−Ｎ−１−ソｌ＼ノシドを４算■のＮａＯＨを含む
１％水溶液に徐／ンに溶解し、不溶物を口過し、）ニ１
液を減ＩｆＣ幅し、大過剰のアｌ？　ｌ−ンを加え、１
ｊ；（水接、乾燥して無色の結晶を得た。収率１００％
、Ｔ−ｏｊａｌ収率３０　、９　％であった。アンメラール酸２，３！７　、　Ｌ−ツムノース２８ｇ
、塩化ノノンし−・ツム０．２ｇをメヂルアル−」−ル
ー２！１ｍｌ中に還流下、加熱縮合する。反応後、室温に放置すると結晶の析出をみる。反応液を［」過し、結晶を、水、メブルアル」−ルで洗
った後、！＋（１％メチルアル」−ルＪ、り再結晶して
無色１１状の結晶を１（する。収率９．８％Ｃあった。このＪ、うにし−４得られた、ｊ７ンスラニル酸−Ｎ−
１−−−′／ｌ＼ノシｌ”　’ｔｅｌＩ＋Ｉ　’ｔ１　
！ＴｆのＮ　ａ　ＯＮ　’ａ含む１％水溶液に徐／Ｚに
溶解し、不屑物を１−１過し、１−目１夕を減月−澗ｉ
ｉｉ　シ、大過剰のアｌ〜ンを加え、ｎｔ２水後水煙乾
燥無色の結晶を１１１ｋ。収碍　ｉｏｏ％、］−ｏｔａ
ｌ収率９．８％であった。。１〕−アミノ安危１、ｉｌ！ｉ醋２す、１つ−マンノー
ス３ＱおＪ、び塩化アン［ニウム０，２ｇを１−ゾルア
ルニ１−ル１０口１１中Ｃ′運流トに（約１１１．’１
間加熱しく縮合反応４行わける１３反応後、〕１成物を
全’　ｆ：ｉａに故ｆ　Ｌ＋−（結晶を析出ざμる。つ
い（゛、この結晶を分別し〕で水、稀Ｊ−プルｊツルー
１−ル（１５Ｊ、び少ｎ１の土−アルＣ−洗浄した後、
５０％メ１ル＞フルー］−ルを用いて再結晶さけで、１
）−アミノ安Ｑ占ｆｌ！２−　Ｎ　　ｌ）−マンノシド
の無色１１状の６１７品を（ｑだ。収率５Ｇ、１％てあ
った。十）ホのＪ、うにしＣ得られた　１）−アミノ安＠香酸
−Ｎ−１）−２ンノシドの水和物をｔ【１のＮａ０１１
をａむ１％水溶液に溶解した液に徐々に加えＣ溶Ｍ後、
１賊ｈ−濃縮し、これに過剰の−［デルアル−１−ルを
加えて沈澱を生成さける。この沈澱を採取し、脱水後、
乾燥覆ると無色の結晶が（：１られる、１この結晶を、
さらに、水５部、アセ１−ン１部／ＪＩ　Ｉら％ろ水溶
液を用いて再結晶さけＣ］〕−アミノ安５ユ丙酸ノ１〜
リウム−Ｎ−Ｌ）−マンノシドのフハ（色の結晶を１１
１だ。収率９５％、１−Ｏｔａｌ収率５３．３％Ｃあっ
た。ｍ−アミノ安息香酸２（＋、１）−マンノース３ｇ、塩
化アン七ニウム０，２Ｑをエチルアルコール１０ｍｌ中
に還流下、９！＋−９ｆｉ℃湯浴中にＣ加熱縮合りる。反応〈ｊ酸物を加湿後しばら＜Ｌ（厚い結晶塊を＋Ｉｊ
　：ＬｉさＵる。反応液を１１過しｌ胃られる結晶を、水、メｙ−ル１ル
了１−ルＣ充づ）（先つ１．Ｌ後、メｆ−ルアル」−ル
Ｊ、り再結晶しく無色１１状の結晶を得た。収率３３．
（１％て′　あ　つ　１．、：ａこのＪ、うにしＣ１゛１られた川−アミノ安息香酸−Ｎ
−１つ一ンンノシトをｉ１鋒吊のＮａＣｌ２を含む１％
水溶液中に徐々（こｉＲ解し、不溶物があれば１−１過
し、［１液を減月ＣＩｉｉ　Ｌ、大過剰の一■−タノー
ルを加え、脱水後乾燥しＣ無色の結晶を冑ｌこ３．収率
１００％、１ｏｔａｌ収＋３３％Ｃあ−）Ｉご。[This is provided, but this system h-1
While investigating the structure and fσ1 of the drug, we discovered that the compound represented by the above general formula () has a significant antithrombotic effect, completed the present invention, and completed the present invention. The compound represented by the general formula (I) (hereinafter referred to as ``genuine trader'') has a simple structure, but has a low barrage in the first half. No antibacterial shrinkage properties
There is no need to worry about disturbance of intestinal bacteria, and long-term administration is possible. It also affects the mutagen II+, cellular and body fluids, and immunity. - There is no danger of reactions such as ', c<, extremely safe mulberry agent C'. , as an antithrombotic 111 agent (Ishikawa).
(There are Φ classes, and although there may be some differences in the activity t71 of each, essentially they are Ishikawa-C. Even if this substance is in the form of a salt, Yanggo Ward Medicine 1-
Salts with a W1 value of 1 are also included. These include alkali metal salts, alkaline earth metal salts, and aluminum metal salts. Usually Na, K, Mill, Ca, △1, etc. is preferable, especially Na
is preferred. The sugar moiety of this substance may be any sugar C that forms a glycoside. An example of sugar is arabinose. Contains xylose, lactose, glutinose, mannose, rhamnose, etc. It may be in the form of a saccharide (or monomer or α-j2non-1β-anone-or in the form of an iR compound of ]').Therefore, this substance may also be α or βb+, < is a mixture of these ammers. The method for producing this substance is exemplified as follows: 4.5 to 5 g of amine benzocyanic acid, sugar ([--arabinose, D-1 di]]-su, 1)-glunis]-su, 1)- (1,5
(] to 9!1・100%"tanol 31, then [very pure methanol 40-50nllO) C heating under reflux 9111
Contains μ. Store at room temperature or in a cool place for a while <I, -(
If crystals precipitate, filter the reaction solution, and add t11 product to water,
After washing for 1 minute with Al 7''-ol, ■-J, etc., recrystallize with methanol water or ethanol water. To replace the hydrogen of the small-1 silyl group with a base C, a well-known method is used to replace the hydrogen of the 7J silyl group with a base C (according to J, i.e., the general formula ([)
This substance shown by is dissolved in an aqueous solvent (noflu).
Add some salt and buy a new one. The physical and chemical properties of this substance, which were applied to the production method of I-L, are shown in Table 1 below.
The analytical methods listed in Table 1 are as follows. (1) Melting point Measured using Yanagimoto's micro melting point measuring device. (2) Elemental analysis Yanagimoto Cf-INJ-12
(3) UV visibility [-PS-3-1 type self-registered spectrophotometer G1, -11 is Alni] -) Ray water system, -
Na was measured using water as a solvent. (/1) II or L1 spectroscopy [) 3-701G type (
This was measured using the KBr method. Note that the numbers in Figure i1' and II correspond to the grindstone No. in Table 1. Next is 777 of this substance! 4゜1)
Acute ICl2-J Cl- system mice were used to examine acute impotence by intraperitoneal and forced oral administration. This substance is thrown into the peritoneal cavity! jC was dissolved in physiological saline, and oral administration C was dissolved in distilled water, and these were adjusted to the specified concentration using a syringe or a stomach tube. After administration, Nakasu symptoms were observed and the 5o value was determined from the mortality rate over time (J, 70 mouths).
Autopsy was performed for both cases of IlX and C findings were obtained. ml) 5o value is L itcMield
-W i 1coxon) Figure i'il'G''1 method.The results are shown in Table 2.Iji4'l, OI
+! ,il II'! 'Inside, between sutra 1-1! /'I
-D value 0 is 60/K! In addition to J, 6 out of 10 types of compounds, -iJ, more than half - [is 1-1] with a value of 1
0su/nori 0 1-Dogeki (It can be said that it is a highly safe drug. 2) Anti-r! , + 2;'a li This animal substance was dissolved in distilled water to create a 2-fold dilution series, and this diluted solution was dissolved by heating for 9 to 18 minutes. Song (J, C deck.
- Using agar (fungus), after smear inoculation with test bacteria previously cultured with Jr1, bacteria Li37℃, 20-241+r, fungal tJ25
Incubate at 33-7°C for 1 hour and check for the presence of C.gamma. The following bacterial species were used as test bacteria. Pseudomonas aeruginosa (1) sOudomonas aeru (I
Inosa l A fv11! +14) 2(+91)) lAfV+ 4207) Canshita yeast PJ (Cal'ld!da allllI
CallS △-r CC752) White? Bacteria (l richopl+yton me+u
grophytes1to0 6124) Black mold (△sl+crgillus niger
IAM 30 (11) As a result, this substance did not inhibit -C (1 mu/11) against any of the bacteria. 3) Inspection was conducted using mutation 1<6cmassay. In other words, recombinant ill redefective strain (Bacillus 5
ubtilis M2S) and a recombinant 11-carrying strain (dan-, 5 ubtilis 1 (17))
II agar medium (10 g of meat 1 kiss, 10 g of Boripezo 1 heng)
, Na Cl 5 (!, agar 15 s, distilled water 1000 m
1, pl-17,0), with 31 lines marked so that the starting points do not touch each other, are dissolved in sterile water, and the 0.
After absorbing 051111 on a circular filter paper of 8 Ill Ill, immediately cover the starting point of the streak, leave it to stand, and culture it at 37°C overnight. Measured 1, used as a negative control - C Kana! Ishin, Yang T!
Use 1 to 1 to 1 to 100% mycin C with 1 control. Next, perform the return change 51 test.
l+I+i+nurium] Δ98d-[ΔHIO (both require hisdecine) and C1j 1. =. Soft agar solution with 1,101 volumes of 0.51 nM Vithin A (1,5mM hispusin solution <NaCleg, agar 6
! J, distilled water 1000ml) 2ml! Add 0.1 ml of bacterial solution and 0.1 ml of circulating fluid, mix thoroughly, and make a small penetration. (This middle layer is 3,3
7°Oi (21" Question j?l Valley reversion mutation -" 11-1 number was 4 times. As a positive control, C frilled horn: / (+'
(Δ12) was used. The results of Rcc-assay are shown in Table 3, and the 11 results of the reverse mutation test are shown in Table 4. 1 (EC fee 1ssay is genuine vt Ha strange 1'J ljj
'j-sexuality'l'l:'II IIjJ I! J'J,
'71'Don't show it, squid, 4'14qp-j7 mino anp
, prussic acid)-1-lium derivatives were removed. In this case, no change was observed compared to the non-additive control, making it a highly safe drug C'. Is that true? [It has been clarified. /I') In order to know the effect of this substance on cellular immunity, 1CI<-J
Foot pad reaction using C sheep red blood Dti as an antigen using Cl mice
became 11. Cow red blood cells]! l! Add 10% m of a good tile to water, add this d to 0, add 2 ml to the vein, j, and 24
Human C primary sensitization was performed, and further 71 (40% of the red blood cells) II l'p > 190.05 m1
FIJfMi1'1J-1shiT2'('A feeling 1'+
= ヲ＜-J い Next day, measure ``1 foot In, l', ;' by tj %・).This substance is mainly used for the eyes of the primary sense
2. 0111su/nori was cast into the membrane layer 1 five times in succession. The conclusion! ,! 4. A thing r! The increase in 7 on the t side of l1jt-jnonnγ is compared to the control (non-role 4) 7il' -C no a) Eho is not accepted and l this. In order to understand the effect of this substance on Iho af11 immunity, jC
0.2 ml of a 10% M suspension of sheep red blood cells was injected into the R-J (:: l mouse) through the tail vein in the evening to sensitize it, and blood was collected on day 7 and 11 after sensitization to determine red blood cell agglutination. Antibody production/:L ability was measured by reaction.This substance was used to induce sensitization [250 nl (1/K! There was no difference in the agglutination value between the administration group and the control group.Next, let's look at the mulberry sokki chemical properties f1 of this substance. )+ from P P P (P 1ate
lctl<icl+plaslIla) was prepared. Flocculant, △D P(A dc++osi++e
1α of platelet aggregation after addition of aggregating agent using clipl + ospl + ate), ] ragne, arachidonic acid
The concentration was measured using a j'glygometer. The genuine product for ¥4 added 5On+v1 2 minutes before adding the coagulant. The results are shown in Table 5, expressed as the aggregation inhibition rate relative to the maximum aggregation degree of the control (physiological Q saline was added in place of the present substance). The compound used in the test showed an aggregation inhibiting effect in Yo1pe and 7j
or, especially, p-aminobenzoic acid tutolium-N-1]-
7-noside shows superior effect to total C flocculants!
J+t7+ is poured. Table 5 * Platelet aggregation inhibitory effect of substances (inhibition rate %) 2
) Suppressive effect on thromboembolization Mouse+, Z genuine i:'l 300111iJ/K
g'i meridian r-I IQ ~ 3 hours later △1 [] or -] J Ragen Intravenous Injection 01 Shi death was measured 1, S.
] Embarrassingly, I poured distilled water instead of water τ′1. The results are shown in Table 0. Compound beam used in the test
In particular, 1) amino acid (1) amino acid) i-'Jum N-1) -nnnnosi 1- showed a reduced effect on U+:ti. Ru. Table 6 Effect of this substance on suppressing thromboembolism (mortality rate %) Next, we will discuss the formulation of this substance. When this substance is used as an antithrombotic agent, it can be used in a form convenient for curing C synergism depending on the type and symptoms of the disease, and can be used alone or in the form of 1. a'r volume 1q
Any mixture of diluents and other co-agents can be used. Authentic! t is like eaves L1, 1. This is applied non-judgmentally, so (rod 1-j target is non-judicially applied).
The substance can be provided in certain intermediate forms (7) at will.The substance contains the active ingredient of the active drug (I8), and its forms (C) include powders, granules, and tablets. , 11 Coated tablets, capsules, lozenges, suspensions, solutions, emulsions,] 7 tablets, injections, etc.
L. The diluent may be solid, liquid, semi-solid, or ingestible; examples include the following 1). In other words, excipients, fillers, binders, wetting agents, iii) peptizers, surfactants, lubricants, dispersants, buffers, aromatic stones, preservatives, solubilizing agents, solvents, etc. ·be. Furthermore, one or more of these may be used in combination. The antithrombotic agent of the present invention can be produced by any known method. The active ingredient in the a3-C composition used in the present invention is generally comprised between 0.01 and 100% by weight. The antithrombotic agent of the present invention can be administered to humans and animals either orally or parenterally. It is preferable to use a lighter tone. Oral throw! This covers equine administration. Non-transferential injections include injections, such as supine, intramuscular, intravenous injections, and infusions. It is effective for improving platelet function abnormalities, artificial valves, kidney transplants, and blood clots associated with human dialysis.It is also effective for renal diseases such as glomerulonephritis. The dosage of antithrombotic agents varies depending on whether it is an animal or a human, as well as age, individual differences, medical conditions, etc.
-C(.Although it may occur when throwing a sword outside the range of L1, when dealing with humans, the light II
Throw! j hanging weight H < g, I to 0.1 per Ll, 1
(to. mg, almost C 1-500 Ins, non-red administration m is also O6 old ~ 2 (1(l m !+, 1
) f Preferably 0.1 to H1 (1 mg divided into 1 to 4 doses (J'C) , Revised! Fill I will explain.Formulation Example 1 This substance C++-j'minobenzoic acid (1-lium-N-shi-arabinosyto) 10 parts heavy magnesium oxide 15 parts lactose
75 parts of tfJ-containing C powder are pulverized into fine granules to prepare a powder. In addition, this 11 (agent) was placed in a car f1.full container and used as Kabrel's agent. Formulation example 2 Genuine "j!1 (0-aminoamaroic acid)
-1 piece -4-piece [1 piece] 45 parts starch
1 b fJI lactose
16 parts crystal resi I-,
i-su 2'1 part polyvinyl alcohol 3 parts water
After 30 parts are uniformly mixed and crushed, the mixture is crushed and granulated, dried, and sieved to form granules. Formulation Example 3 In Formulation Example 2, (13(〕ru)O-aminoanthukasuL-lium-N-1,)---1-instead of O-
Granules were prepared in the same manner using amine benzoic acid No. 1 to Lium-N-θ-glunic acid, and calcium stearate/l in was added to 96 parts of the granules and compression molded to form tablets with a diameter of 10 mm. do. Formulation Example 1 This substance (+1-7 minobenzoic acid U1-lium-N-(-
94 parts polyheal alcohol 6 parts water

Condyle Ki was prepared in the same manner as in Formulation Example 2 using 30 parts.
It's called T agent. Obtained λ: C-th, 7th 9 (crystal cell 1" - 1"
0 parts were added and compression molded to give 8 ml of 10 tablets.
To this, add Si1-1 tube gelatin and Precipitate #-f P1 calcium carbonate, and form a tablet into sugar. Synthesis Example 5 This substance (11)'minobenzoanolium N[]-
Gaprak 1 to Shito 0.6 part non-A type culm activity 1! I agent 2.4 parts Sumitomo saline 97 parts/Jl eye 1d
Should it be sterilized after mixing? Cover with 1 shot. Production Example 1 11-,-,I minobenzoic acid-N-L-arahi p-, 7mi/benzoic@L6g, 1. -7 Rahi/
5 g of ammonium chloride and 0.5 g of ammonium chloride are heated and condensed in 40 ml of 94% ethyl alcohol under normal flow. When the reaction solution is stored in a refrigerator, precipitation of crystals is observed. The reaction solution is passed through the mouth. , Product M was washed with earth-alcohol and re-crystallized several times from 50% methyl alcohol to obtain colorless sword-shaped crystals. The yield was 45.8%. This J, sea urchin 1!1 p-aminofriendzoic acid-
N-1--Arahinoside was gradually dissolved in a 1% aqueous solution containing 1 nm of Na01-1, the insoluble matter was filtered through L1, and 0
Strain the solution under reduced pressure, add a large excess of aretone, 11;)
Wet with water and dry to give 1 J of colorless crystals. The yield was 100% and the total failure rate was 45.8%. Ansudinylic acid 2,3! ] , l Ara Kami North 2
．． 5Q, 0.2 ammonium chloride (J is methyl alcohol)
]-/Condensation is carried out under normal flow in 30 ml by heating. After the reaction, see Analysis of Crystals 1] 1. The reaction solution was filtered and the crystals were washed with water and methyl)norni]-l-1-norC to form a colorless H-form.
Gi? One person's crystal (!). 11 So rate G1.3% (
゛A・) 1゜This J is 111 with sea urchin, acysudinylic acid-N-1---/'rabinocytoj'll'
Gradually dissolve 71 m of NaCl2 in a 1% aqueous solution containing f), filter out insoluble materials, and reduce 11-. ig'l
Shrink it, add a large excess of norone, dehydrate and dry.
(Crystals of 11 times a day. Yield: 100%, complete loss; Reference. 61, :i%.
-1-Su2, :] Ri, 1 Fuhua Ann■-Rum 005g
"-La Real]-Le 2! iN Mon C- under reflux, +31
1Includes heat shrinkage. During the reaction, crystals were precipitated, but the solvent was added and heating was continued. was washed with water, dilute methyl alcohol, and a small amount of ether, and washed with 94% pure ether.
-Recrystallize from the liquid to obtain colorless H-shaped crystals from N.
'i rate was 73.7%. This J, p-7 minobenzoin-N, obtained by sea urchins
D-V Shiroshi 1: 51 "A ('ji's Na O
Gradually dissolve in a 1% aqueous solution containing l-1, pass through the insoluble matter, reduce the liquid to 0)) 1) Shrink 1, remove a large excess of ace 1 to 11), 11) After 2 water , dried" (1 q of colorless crystals were obtained. Yield 100%, 1-ol, al yield 1.B3.7%C.
1 piece. Anthranilic acid 2.3(] , ]D-xylose 2.
5 g of ammonium nitride<1,2 g in 35 ml of 1 methyl alcohol, Cj=stream 1., add 1111 8J. After the reaction, the pressure was reduced to 1'. : It was concentrated to about 1/2 of its original volume, and 111 crystals were observed when it was released at a temperature of about 100 liters. After the reaction solution was filtered for 1-1 minutes, the crystals were washed with water, methanol, and chloride, and crystallized to give C1 colorless eyebrow-shaped crystals. The yield was 74.6%. This J, anthranilic acid-N-
D-:l2:/I-I 1iltffll
(7) Gradually dissolve the NaO11% aqueous solution in water, filter out the insoluble matter, and reduce the liquid to a large excess. Add l・n, I]tJ water IC? To dry 7II
I(!2 crystals were 111k. Yield too%, 1Otal
Yield 76, 11% (-.
Guruni]-su 6.4 (), JIVI conversion Ashishi Hitoshimu ()
, 5ri 94% "Brno 7 Runi] - Ru 50...1 CjW
Stream 1: Heat condensation. After the reaction, the solution was concentrated to about 1/3 by 11.degree. and left in a cool place for a while, and the entire solution became gelatinous. Add a small amount of water and add again? :+A After dissolving, leave it immediately in a cold oven and observe the precipitation of crystals. The reaction solution was filtered [1], and the crystals were washed with water, cotton methyl alcohol,
and a small amount of Neal, and recrystallized from 50% methyl alcohol to obtain colorless $1 crystals. /Go. The yield was 33.7%. In this way, (]C was obtained, 1) -Aminobenzoic acid-
Na○1-(including 1
% aqueous solution, filtered out the insoluble matter, [1 solution was reduced to 100 ml, added with a large excess of attenuate, dehydrated, and dried to obtain 14 colorless crystals. 1 yield 1()0%, T'o
The tal yield was 33.7%. Anthranilic acid 4.6(1,Q-g/L/]-su(i,
0 (1. Ammonium chloride - Rum 0.! + 95% - [in Brunoflour I-4 Oml) 7 liters, force 1 j 1 cotton. I1': reduced to about 1/'3 of the 1st month of the 6th month,
11. Rudo crystals were observed to precipitate on the Abe River 1 after being left overnight. anti-1
+ix+ liquid 11 filtration, crystals, water, 11 ml
1'-1k1. Collection 14
．． There was 6% C. This J, anthranil M-N-
11) -- Glue 1 Shi 1 - i1 Suspended Na0ll 1)
The mixture was slowly dissolved in iR in a 1% aqueous solution 7, and the insoluble matter was filtered out. 7.1)
Add 11 (2 water and dry C)jj (Crystals of Q A1' + Iy. Yield +100%, 1ocal yield 4
, (i % "Ca) l;, . D-noaminoan 11 deterioration"in', 21,5! J, I:
)-kan', / h 22 (1, nonone chloride - ul
z 0.1g to 94%-IJ Lunoflu-1-3 (l
After the reaction, concentrate under reduced pressure and leave in a cool place to observe the precipitation of crystals.Filter the reaction solution and dissolve the crystals in water, ( Washed with medyl alkyl and a small amount of ether C, and recrystallized from mebralnyl to give -C1 colorless ε1-like crystals <!7k
. The yield was 18.1%. This J, UU th, p-nominobenzoic acid-N-1)-touctoside was gradually dissolved in a 1% aqueous precipitate containing Na○1-(am), and the insoluble matter was passed [], r
J liquid 4 decreased month - j;)? Cotton, add a large excess of arethone,
11) After 2 water and drying, colorless crystals were obtained, 1 yield: 10
0%, Otal Collection, '18. It was i%. Anthranil M 2.4g, D-force rough I・-su 3.
0! 0.2 q of N W hydride was heated and condensed in 30 ml of 95% nitrogen hydride under extreme conditions. After the reaction, reduce the I layer to about 1./2 on the top, and let it cool to room temperature to see the precipitation of crystals.
Water, mebrunoflu'-le, 1-del c-' wash, 95
% ethylalyl J, recrystallize; lj CI!
A cylindrical crystal was obtained. The yield was 16.4%. This J, Sea Urchin UJ
Gradually dissolve Vft L/ in a 1% aqueous solution containing N, pass through the insoluble matter, condense the l-, 1 solution under reduced pressure, and make a large excess of 11?
Add 1-ton and dry after 11;1 water to give 1!C colorless crystals.
1k. Yield 100%, oLal yield 16.4%, 1°11-amine benzocyanic acid 3 g, 1--rhamnose 4 g
, ammonium chloride, 94%-L,
- Cool under reflux in the bottle7. On I, heating navy blue I fits. After the funeral, let it cool to room temperature. As a result, crystals begin to precipitate. The reaction solution was filtered 1-1, the crystals were washed with water and diluted alcohol, and then recrystallized from 50% methyl alcohol to obtain colorless σ1 crystals. The yield was 30.9%. This J, Unishiku' i! 7. 1]-Aminobenzoic acid-N-1-sol\noside was slowly dissolved in a 1% aqueous solution containing 4 parts of NaOH, the insoluble material was sifted,
If the liquid is reduced by IfC width, there is a large excess of Al? Add 1
j; (Wetted with water and dried to obtain colorless crystals. Yield 100%
, T-ojal yield was 30.9%. Ammelalic acid 2,3!7, L-tumnose 28g
, 0.2 g of nonone chloride was condensed under reflux in 2.1 ml of Medial Al-'-ru. After the reaction, if left at room temperature, crystals will precipitate. After filtering the reaction solution and washing the crystals with water and methanol,... +(1% methylalyl)-J was recrystallized to give colorless 11-shaped crystals (1).The yield was 9.8%C. N-
1---'/l\noshil'''telI+I't1
! Dissolve Tf in a 1% aqueous solution containing NaON'a slowly/Z, pass through 1-1 to remove waste, and remove 1-1 night.
ii Add a large excess of Al to 111k of nt2 water and dry colorless crystals. Collection ioo%,]-ota
The yield was 9.8%. . 1] - Amino Anki 1, il! Add 2 ml of mannose and 0.2 g of ammonium chloride to C' in 11 10 mouths of 1-solalniole (approximately 111.'1
After 13 reactions in which the condensation reaction 4 is carried out at high temperatures, the first product is separated from the total f:ia to precipitate crystals. -Pull J True 1-Rule (15J, less n1 soil-AlC-After washing,
1 without recrystallization using 50% mel>fleur.
) - Aminoyasu Q-sense fl! 617 colorless 11-form products of 2-Nl)-mannoside were obtained (q. Yield 5G, 1%. 10) E-J, sea urchin C were obtained. Na011 of t[1]
After gradually adding C to a solution of a in a 1% aqueous solution,
Concentrate the monomer and add excess -[deral-1-al] to avoid forming a precipitate. After collecting this precipitate and dehydrating it,
When dried and covered, colorless crystals appear (:1, 1This crystal,
Furthermore, recrystallize using 5 parts of water, 1 part of acetone/JI I et al.
lium-N-L)-mannoside fuha (color crystals 11
It's 1. The yield was 95%, and the 1-Otal yield was 53.3%C. 3 g of m-aminobenzoic acid 2(+,1)-mannose and 0,2Q am7nium chloride in 10 ml of ethyl alcohol under reflux, 9! Heat condensation of C in a +-9fi°C water bath. Reaction 〈j After humidifying the acid, for a while 〈L (thick crystal mass +Ij
:LisaUru. The reaction mixture was filtered for 11 liters, and the crystals obtained were recrystallized and colorless. 11-shaped crystals were obtained. Yield: 33.
(1% te'atsu 1., :a This J, sea urchin C1゛1 dehydrated river-aminobenzoic acid-N
- 1% containing NaCl2, suspended one by one
Gradually dissolve in the aqueous solution, if there are any insoluble materials, 1-1 filtration, reduce 1 solution, add a large excess of 1-tanol, dehydrate, dry and remove colorless crystals. 3. Yield: 100%, total yield + 33%Ca-)Igo.

[Brief explanation of the drawing]

添１１ｆ＝１図而のり１１図乃″（ゝ第２４図は、表１
に示ＪＮ（１，１乃〒２４の各化合物の赤外線吸収スペ
ク１−ル１寺ｒ１庁長官若杉和夫殿１．事イ′１の表示　　　昭和ｂ’７３［特ム′Ｉ願第
２１２１／１４号２、発明の名称　　　アミノ安息香酸
誘府体を有効成分とづる抗血（↑剤３、補正をＪる考事イ′１との関係　　ＱＸｉ　ｉｉＴ出願人名　称　　
　　（１１０）呉羽化学工業株式会社４、代　理　人　
　　東Ｊバ都ｉｉ宿１メ新宿１−１’１．１１番１４シ
ー３　１１１１１１ビル通り浦光りる。（内容に変更な
し）Attachment 11f = 1 Figure 11 (Figure 24 is Table 1)
Infrared absorption spectra of each compound of JN (1. No. 2, Title of the Invention: Anti-blood therapy containing aminobenzoic acid derivative as an active ingredient (↑ Agent 3, Relationship with Amendment J Consideration I'1) QXi iiT Applicant Name Name
(110) Kureha Chemical Industry Co., Ltd. 4, Agent
Higashi Jba To II Inn 1 Me Shinjuku 1-1'1.11 No. 14 Sea 3 111111 Building Street Ura Hikaru. (No change in content)

Claims

[Claims]

(1) J7 minoamino acid derivatives or medicinal compounds represented by the general formula (TI)
A small number of 61 types of antithrombotic agents with different active ingredients.

(2) R is arc to noside, -1 Shiroshi 1ko, Guru Jshi! -9 Tora Raku 1 Hesid, Nomunoside and Nunnoside J,
4'jj i? 16 Fl-ni'i The anti-blood-curing agent according to item 1.

(3) The anti-1f salt according to claim 1, characterized in that the salt containing a certain E is a [-rium salt].
i+ 4II agent.