JPS59104317A

JPS59104317A - Agent for preventing ishemic cardiopathy containing aminobenzoic acid derivative as an active ingredient

Info

Publication number: JPS59104317A
Application number: JP21214382A
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:An agent for preventing ishemic cardiopathy is obtained by using 0.01-100wt% of a compound of formula (R is glycoside) or its salt such as p-aminobenzoic acid-N-L-arabinoside as an active ingredient and mixing it with diluents such as extender, binder humectant or disintegrator. It is effective to coronary ateriosclerosis, acute or chronic myocardiac infarction, stable and unstable stenocardia, arrhythmia, cardiac insufficiency and so on. The drug is orally administered 0.1-1,000mg/kg/day, parenterally 0.01-200mg/kg/day once to 4 times in portions a day. Since the compound has no antibiotic activity, there is no anxiety of disturbing intestional flora. Further, it exerts no influence on mutagenecity, cellular and humoral immunities, thus being a very safe drug.

Description

[Detailed description of the invention]

本発明は一般式（Ｉ）（式中、ＩＲはグリコシドを示づ）で表わされるアミノ安息香酸誘導体又は医薬上許容しく
ｑるイの塩を有効成分とする抗虚血性心疾患剤に係る。従来、制癌剤として合成化合物や抗生物質などが用いら
れてきたが、これらは殺癌効果（、上りぐれていても正
常細胞に５作用するためｍ　ｆ（が強く、副作用を呈す
る欠点があった。そこで最近では宿主の免疫能を４１め
ることにＪ、り制癌効果を発揮りる種々の起諒の多糖体
が注目されるようになった。本発明者等はり（パに１！Ｉ了菌山来多糖Ｊ、りなる制
癌剤を間発し４会に提供しＣいるが、この制靜Ｉ剤の構
造並びに活性の？ｔｌｌ究中に上記　般式（１）で示さ
れる化合物に顕著な抗虚血性心疾患作用を児出し、本発
明を完成したものＣ゛ある。上記一般式（］）Ｔ：示される化合物（双子−１゛′水
物質″ど略称りる）は閤Ｑｊ　’、＞構造でありながら
、極めＣ低ンぢ・１〈１であり［］つ抗抗菌性がないの
The present invention relates to an antiischemic heart disease agent containing as an active ingredient an aminobenzoic acid derivative represented by the general formula (I) (wherein IR represents a glycoside) or a pharmaceutically acceptable salt thereof. Conventionally, synthetic compounds and antibiotics have been used as anticancer agents, but these have the disadvantage of having a strong m f (mf) effect and causing side effects, even if they have an excellent carcinogenic effect (5), because they act on normal cells. Therefore, recently, polysaccharides of various origins have attracted attention as they exhibit anti-cancer effects by enhancing the host's immune function. Ryobacterium Yamaki Polysaccharide J provides an intermittent anticancer drug to the 4th society, but during the investigation of the structure and activity of this anticancer drug, it was found that the compound represented by the above general formula (1) is remarkable. There is a compound C that has an anti-ischemic heart disease effect and has completed the present invention. ＞Despite its structure, it has an extremely low C and has no antibacterial properties.

【゛腸内菌叢撹乱などの心配がなく、長期投！うが可能
である。また変異原性や細胞性及び体液性免疫にも影響
を！ｊえり゛、したがって付印な人に苅り−る催奇形刊
やアレルニ１゛−反応などの危険もなく、極め−Ｃ安全
な薬剤である。加えて、本物質はいずれも冠血流６１増
加（’１ＩＩＪ　４イＪ　シ”Ｃおり、抗虚血刊心疾患
剤どして石川Ｃある。本物質の１ミノ基の位置は１）−１ＩＩ＋−１０−と３
秤類あり、イれぞれ活性に多少のｊ〃いがみられること
もあるが、本質的にはい４゛れｂ有用である。本物τ１は塩の形態であってもＪ、く、イの場合医薬十
へ′Ｆ容し得る塩であればいずれも包含される。アルミニウム金属塩が含まれる。通常はＮａ、Ｋ。Ｍｇ、Ｃａ　、Δ１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」シトを形成する糖−（あれぼ
Ｊ、い。糖としては、例えばアラビノース。キシロース、刀ラクトース、グルコース、マンノース、
ラムノース等を含む。糖はＤ又はＬ体もしくはα−１ツ
マ−１β−アノマーの形またはアノマーの混合物の形で
あってもよい。したがって本物質もα又はβもしくはこ
れらの混合アノマー〇あることが出来る。本物質の製法は上記のごとく例示される。アミノ安息香酸４．５へ５ｇ、糖（１−−アラビノース
、Ｄ−キシ上１−ス、Ｄ−グル−１−ス、ｌ）−カラク
１ヘース、１−−ラムノースまたは［）−＝ｚンノース
）！ｉ−，ｆｌｉｇ、Ｊｕ化７’　ン’［：　ニウム０
．１・−０，Ｊｌ　ヲ９４？−・１００％」−タノール
また（３１純メタノール４０〜５０１１１　ｌ　（１）
連流下にＣ加熱１ｉｉ合μしめる。室温またｔＪ冷所放
置後しばら＜　Ｌ　’Ｕ結品の析出Ｊるものは反応液を
濾過し、結晶を水、ノフルー１−ル、」−−フルなとで
パ十分に洗浄後、メタノール水またはエタノール水より
再結晶刀る。カル小１シルエ１ｔの水素をＪハ３．Ｉ　Ｃ置換・Ｊる
には周知の方法にｔｙ−拠りろとＪ、い。すなわち、一
般式（Ｊ）で示される本物Ｙ１をアル」−ル水系溶媒に
溶解し無９４　Ｊ２Ｒを加えＣ置換覆る。以上の製法にＪ、す１７らｆｚＩこ本物質の物用１化学
的Ｗ　ｔ！Ｊを上記表１に示づ。また赤外線吸収スペク
ｌ−ルを第１へ・２４図に示づ。なお、表ＩＩこお（ノ
イ）フ）新方法は次の通りで゛ある。（１）　ａｌ！　　　魚　柳本微ｍ融点測定装置を用（
八で測定した。（２）元素分析　柳本ＣＩ−Ｉ　Ｎ−１−ダー１ｖｌ　
Ｉ　２昌１こより測定した。（３）ＵＶ　　　　目立１川−’　Ｓ　−３Ｔ型自記分
光）式度削により、−１−１はアルニ］−ル −水系、−Ｎａは水を溶媒として測定した。（／Ｉ）ＩＲ日本分光［）３−７（１１Ｇ型（こｊ、す
Ｋ　［３ｒ法Ｃ測定した。尚、図１ｒＩｉ番号は表１の
試料ＮＯ，と一致りる。次に本物質のｍ勧学的特性を承り。１）急性Δｉ性Ｉ　ＣＲＪ　Ｃｌ系ンウスを用い−Ｃ腹腔内及び強制経
口投与による急性毒性を調べた。本物質は腹腔両投／ｊ
ＣはＩＵＪ中食塩水に、経［１投与？’　ｌ；ｉ蒸溜水
に溶解し、これを汗ｑ・１筒まｌこは胃ゾンフ１゛を用
いて所定の吊に調整しｃＩｊえた。投！ｊ後中毒症状の観察を続り、７日〜目まＣ゛の経詩
的死Ｉ−率から１．　ｌ）５．　Ｉ＋ｒｉを求めた。、
４Ｌ　ｒｉ例、夕り白側と７）解Ｒ１１シて所う１（を
胃た。１−Ｄ、、値Ｃよリッチフィールド・ウィル」ク
ソン（１，１ｔｃｂｆｉｃｌｄ　−ｗ　ｒ　＋　ｃｏｘ
ｏｎ　）図ｉｌｌ　ｆｌ’ｘ法ニＪ：　リ求メ７；、：
。Ｔｉｉ　果＋、ｔ　ｂ　２に示１゜いヂれら腹１１・
Ｐ内、経１」を間ゎりＬ−ｏ　ｙｏＩＩＣ＋は６ｇ／Ｋ
ｑ以」−Ｃ゛、さらに１０種類中６種類の化合物、すな
わら？１′数１ス十がしＤ５０値で１０＋１／Ｋｑ以七
と極めて安全・１」の高い薬剤Ｃ・あるといえる。２）抗菌話ｉ（１本物質を蒸溜水に溶解しく２倍希釈系ＩＩＩをイ′（成
し、この摺釈液を９　Ｆ５４！ｉ＋の加温溶解した寒天
＋１３地に混和し、ぺ１〜り冊に注いひ平板どした１、
Ｊ８地にはバーｌ−インヒタ１−ジ］ン寒天（細菌）及
び１ノブＩコー寒天（負菌）を用い、前Ｊ８養した試験
菌を４抹ｊと後軸細菌は３γ゛Ｃｌ２Ｏ〜２４１＋　ｒ
、真菌は２５℃、３・〜７０間ぞれぞれ培養し−（／、
１台のイｊ無を調べＩこ。被検菌とじＣは次の各菌種を使用した。緑膿口１　　（１’　Ｓ（！１ＩｄＯＩｎｏｌｌａｓ　
　　１ｌｏｒｌｌｊｌ！１１０ｓａ　　　ｌ　　Ａ　Ｍ
１！１１４）大腸菌（１’ｓｃｌ＋ｃｒｉｃｌ＋ｉａ　　ｃｏｌｉ　
　Ｉ　ｒ−０１２７３／ｌ）黄色１トウ球Ｇｌ　（Ｓ　
Ｌｉ１ｐＨｙｌｏｃｏｃｃｕｓ　　２１ｕｒ（！ＵＳ２
（＋ＵＰ）枯７，１菌（旦ａｃｉｌｌｕｓ　　５ｕｂｔｉｌｉｓ　
　ｌ　ＡＭ　　１０６９）パン酵母（Ｓ　ａｃｃｌ＋ａ
ｒｏｍｙｃｃｓ　　ｃｅｒｅｖｉｓｉａｅ１ΔＭ　　４
２０７）カンシタ酵７ＳＪ　（Ｃａｎｄｉｄａ　　ａｌｂｉｃ旧
１ｓ　　Δ王００７５２）白ｇ菌　（Ｔ　　ｒｉｃｈｏｐｌ＋ｙｔｏｎ　　　　ｍ
ｅｎｔ　　ｇｒｏｐｈｙｔｅｓＩＦＯ６１２４）黒かび（Ａ　ｓｐｃｒｇ　ｉ　ｌ　ｌｕｓ　　旧ｇｅｒ
　　Ｉ　Ａ　ｆｖｌ　　３ｏｏ１　）その結果、本物質
はいり゛れの菌に対しても１ｍ＋＋／ｍｌの濃度で生育
明止を示さなかった。３）変六原１′！１；Ｌす’　ＲＱＣａｓＳａｙによる検問を行なった。す
なわら、用換修復欠１０株（１３ａｃｉｌｌｕｓ　　　
５ｕｂｔｉｌｉｓ　　Ｍ４５）ど紺換修復保持株（Ｂ−
１ｓｕｂｔｉｌｉｓ　　ｌ−１１７）の２株を［３−Ｉ
Ｉ寒人ＬしｊＪｔ！ｌ（陶工４−ス１０す、ボリベゾト
ン１０ｇ　、　Ｎａ　Ｃ１５（］、寒天１５ｇ、蒸溜水
１０００１１１１、＋１　＋−１７、Ｏ）上に出発点が
ひいに接触しないように画線した。本物質を滅菌水に溶
解し、その０．０５１を直径８ｍｍの円形濾紙に吸収さ
せた後、直Ｊうに画線の開始点をおおうようにｉｉ？Ｉ
置し、３７℃で−晩］１３養しＣ生育ＩＵＪｌ域の長さ
を測定した。陰ｆ’ｌ幻照としてカッマイシン、陽性ス
・１照としてマイ１−マイシンＣを用いた３゜次に復帰変ｂ１〆試験をＳａｌｍｏｎｃｌｌａ　ｔｙｌ
ｌ＋ｉＩｎｕｒｉｕｍ−１−△５）８ど−ＩＡＨ）０（
いり゛れｂヒスＪジン要求性）を用い（行なった。０．
！ｉｍＭビデＡ　ン−０，！ｉ　ｍｆｖｌヒスデシン溶
液１．・川０１°Ｙを加えた軟穿入？ｌｋ（ＮａＣ１１
３ｇ、　穿入６す、　蒸イ留水１０００１１１　ｌ　）
　　　２ｍ　ｌ　Ｍ　ｉ＞ｊ液（１，１ｎ１１、共８ｋ
　（１，１ｍ　ｌを加えＣよ＜　ｆＩｆｉ合し、最小寒
天ｊ８地上に千層した。３１°ＣＦ　２　Ｅ１間Ｊ８養
し１り帰変異−１１，１’−−−数を泪故しＩこ。陽性
対照どしてノリルノラマイド（ＡＩ　　２）を使用した
。１１０ｃａｓｓ詩のＩＶ＋宋を表３、復帰変５“シ試験
の結果を表４にイれぞれノ＋−ｉＪ’、ｌ又ｅｃ−ａｓ
ｓａｙにおいては本物質は変）！原１（［を１−″チｉ
間度まＣ゛示さないか、特にｐ−アミノ安息香酸ツ１〜
リウム誘導体が−４ぐれ（いＩこ。また１９帰変ｒ＜試
験Ｃ′は本物質による変周発生率は高濃度をｆ’ｌ用さ
けた場合でも無添加対照と比較しく何ら変化はみられず
、安全・門の高い薬剤で゛あることが証明された。４）遅延型皮肉ｊ叉応本物質の細胞・１ノ１免役への影響を知るためにｌ　Ｃ
１’＜−Ｊ　Ｃｌ−ンウスを用いＣヒツジ赤血球を抗Ｉ
にｊどづる足踵反応（ｒ’　００１１１ａｄ　ｌ’Ｑａ
ｃＬ！０１１）　（＝行な−）た。ヒツジ赤血球’ｃ　１４埋食塩水に１０％量懸ｊ蜀ｕし
め、この液０．２ｍｌをＬ〔：静脈Ｊ、り注入しＣ１次
感作を行ない、さらに７０　Ｉｎにヒツジ赤血球の４（
）％Ｗ懸濁液０．０５ｍ１を犀随に注目Ｊ　して２次感
作を行ないマ）Ｉ日足鯨厚の測定をｆｌ’Ｊ　’（Ｌ：
・）だ。本物質（Ｊ、１次感ｆｉ。日を中心（ご２５０ｍｇ／　Ｋ　リを腹腔内へ連［二１
５回投６し　）こ　。 −ｔ　ノＩ＋’＋　宋、本物ｖ′ｉ投ｔｊ　（ｉｒ（１
）犀ｒｌＱ　Ｊｃｊ（Ｄ増加は対（（（（（非役’−ｊ
）Ｊ！Ｉ’と比較しＣ何ら石８差【よ認めなかっＩＪ。５）抗体片生能本物質の体液１？１免投への影響を知るために、ＩＣＲ
−Ｊ　Ｃｌ−マウス１．ｌ対し、ヒツジ赤血球の１０％
母懸濁液０．２ｍｌを尾静脈Ｊ、すε）−人して感作し
、感作後７日日に採血して赤血球凝集反応により抗体産
ど］−能を測定した。なお本物質は感作Ｌ１を中心（ご
しｌ’　　２５０ｍす、−’　Ｋ　ｇを連日５回腹腔内
へ投！ｊした。結果は、本物質投与君Ｙと対照群の凝集価に何ら有怠差
（Ｊみられなかった。次に４＼物貨の薬理学的特性を述べる。１）冠面わ１≧昂増加作用各７ｉｒ３匹のＪ［：’４゛じ−グル人を用いて心肺標
本を作製した。冠血流０は右心房より冠状静脈側に仲人
したＭｏｒａｗｉｔｙのカニユーレにより電磁流量１ｉ
１（スタＩツムＳ　Ｉ）　　２２０２）を用いＣ記録し
た。本物質は４埋良塩水に溶Ｍ後、１ｏｏｍｇ／　Ｋ　
（］を上人静脈Ｊ、り注入した。結果は表５に示り−如
く、投り前平均面流荀←二対りる投与後平均血流用の増
加パーセン１−４・・表わした。試験に供した化合物はリベて冠血流吊増加作用がみられ
たが、’４１ｓに　１〕−ｊ′ミノ′！、どＱ青酸Ｊ１
〜リウム−Ｎ−１つ一マンノシド、　　１１−ノアミノ
安に都古酸ノｌ〜リウム−Ｎ−１）−ノ１＼ノシドおよ
び１）−アミン安息香酸ノ１〜リウノ、Ｎ−１〕−キシ
ロシドが冠血流ｉ１増加率ででれてれ１司、２％、　４
９．４％おＪ、び３８．３％を示しづぐれた効果を示Ｊ
点が注目された。表　５　　本物質の冠血流ｍ増加作用法に本物質の製剤化についＣ述べる、。本物質は抗虚血・１／１心疾患剤として使用り−る場合
、疾患の（・ｐ類及びｔｌｊ状に応じ−Ｃ薬効を１１１
るのに都合の−こい形状Ｃ′使使用さ、イしＣ単独ま／
ごは製薬−に６′［容し１！する昂釈剤及び他の桑剤ど
の混合物どして使用できる。本物質は経１−１的よＩこは非経口的に適用される。したがって経１」的４１、たは）［経Ｌ［」的に投１ｊ
Ｊるための形態を任意にとり（ｉＩる、。本物質は投某中（キン形（゛提供づることがＣ′きる。右効桑ωのイｊ効成分が含有され、その形態とじＣは散
剤、顆粒、錠剤、糖衣錠、カプセル、座薬、懸濁剤、液
剤、乳剤、）７ンブル、注射８になどの形態をとり得る
。、イ６釈剤とし又固体、液体、半固体、あるいは摂取
し１ｑるカゾレルでもＪ、く、例えは次のものがあけら
れるｏ　１Ｊ”！＞わら、賦形剤、増量剤、結合剤、湿
潤化剤、１イ１１解剤、表面活性剤、滑ｉｔ（剤、分散
剤、紡％＋剤、占ｒ１、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種以上を混合して
使用し得る。本発明の抗１ｊＲ血↑１心疾患剤は既知のいかなる力演
でｂ製造しくｑる。本発明におい−で用いられる組成物
中の粘性成分は一般に０２０１から　１００ＷＥ％含ま
れる。本発明の抗Ｉお°血性心疾患剤は人間及び動物に軽口的
または非経し］的に投〜されるか経口投与がりｒましい
。経口段重ノラは舌下役！ｊを包含する。非経口的投与
は注射、例えば皮ＩＣ１筋肉、静脈？１剣、点滴４１ど
ｂ含む。本発明の抗ｌＪ６血性心疾患剤は冠動脈硬化、急１！Ｉ
又は慢性心筋梗塞、安定又は不安定狭心症、不整脈、心
不全等の開型に有効である。本発明の抗罰血性心疾患剤の投与用は動物か人間かにＪ
、す、また年齢、個人差、病状などに影響されるので場
合にＪ、つ（は下記９（１間外Ｃハを投’ｊ　８Ｉる場
合も生り゛るか、一般に人間を対象どＪる場合、本物質
の経口投！ｊ量は体千月（ｇ　、１１−．１当り０．１
へ１０１００Ｏ、好ましくは　１〜５００…ｑ、非経１
」段重与ｍは同じく、ｏ、ｏｉ　＝−２００ｍ（１、好
ましくは０．１〜１００　ｍ　ｇを１回・・−４回に分
（ノ℃投４　”４る。以下、本発明物Ｙ″（の製剤化例並びに製ｊ告例を示し
本発明をよりみＹ細に説明する。製剤化例１本物質（ｐ　ツノミノ安息占酸ノ１〜リウ１１　Ｎ−Ｌ
−７ラピノシド）１０部重質酸化ングネシ・ツム　　　　　　　　１ｊ）部乳　
　糖　　　　　　　　　　　　　　　　　　　　　　　
　　７５部を均一に混合しく粉末または細粒状として散
剤とづる。またこの１１り剤をカブレル容器に入れ−Ｃ
カブレル剤どした。製剤化例２本物質（Ｏ−アミノ安息香酸）−１〜リウムーＮ−１つ
一キシロシド）４５部澱　　粉　　　　　　　　　　　　　　　　　　　　　
　　　　　＋　ｂ　ｉ’ｉｌｉ乳　　糖　　　　　　　
　　　　　　　　　　　　　　　　　　１６部結晶ヒル
［」−ス　　　　　　　　　　　２１部ポリビニルアル
コール　　　　　　　　　３部水　　　　　　　　　　
　　　　　　　　　　　　　　　　　　　　　３０部を
均一に混合ｉｆλ和後、破砕造粒しＣ乾燥、篩別後顆粒
どりる。製剤化例３製剤化例２にＪｊＬ）る０−アミノ安息市醇ソ１〜リウ
ムーＮ−Ｄ　−−−ＦシロシトのかわりにＯ−アミノ安
息香酸ノー１ヘリウム−Ｎ−Ｄ−クルコシ１〜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／１部を加え−Ｃ圧縮成形し−Ｃ直径
１０１１１ｍの錠剤と７る。製剤化例４本物質（０−アミノ安息香酸す］・リウムーＮ−１−−
−ラムノシト）９４部ポリビールアル１−ル　　　　　　　　　（１部水　　
　　　　　　　　　　　　　　　　　　　　　　　　　
　　　　３部部を用い−Ｃ製剤化例２と同様の１ｊ法Ｃ
顆４１′ｆ剤どりる。得られた顆粒の９０部に結晶セルロース１０部を加えて
圧縮成形し−Ｃ直径８　Ｉｌｌ　ｎｌの錠剤とし、これ
にシロップげラチン、沈降性１井酸）Ｊルシウムを加え
（糖衣錠とりる。。製剤化例５本物′ｉ′１（１）　　ノ′ミノ安息香酸ノー１〜リウ
八　Ｎ−１）−ガラク１−シト）０．６部非イオン系界面８！＋１１１剤　　　　　　　２．４部
生理食塩水　　　　　　　　　　　　９７部を加温混合
後滅菌しＵ　２：１射剤と覆る。１羨！！！Ｌ１　　　＋）−アミン安息香酸−Ｎ−１−
−−アラヒｐ−シ′ミノ安息香酸４．Ｇ！＋　、１−−
−−アシピノ−１部５ｇ、ｊ篇化アンしニウム０．５ｇ
を９４％エチルアルｌ−ル４０ｍ１中でｊ至流下、加熱
縮合Ｊる。反応液を冷蔵庫に放置りるど、結晶の析出を
みる。反応液を口過し、結晶を一丁一テルで洗い、５０
％メヂルアル］−ルから数回再結を繰り返して、無色ｒ
Ｉ状の結晶を１′１だ１．収率４５．８％であった。このＪ、うにしＣ得られた。ｐ−アミノ安息香酸−Ｎ−
Ｌ−−アラじノシドを５１算量のＮａ０ｉｌを含む１％
水溶液に徐々に溶解し、不溶物を口過し、白液を減）−
１−濃縮し、大過剰のアＬ７＋−ンを加え、脱水後、乾
燥して無色の結晶を得た。収率１００％、全収率４５．
８％Ｃあった。ｊ７ンスラール酸２，３ｑ　、　ｌ−アラヒノース２．
５９、塩化アンモニウム０　、２　ｇをメチルアルニ１
−ル３ｆＩＩＩＩ　Ｉ　ＩＩＩ　ｒ　Ｅ流１・、加熱縮
合りる。反応後、室温放買づると、結晶の析出をみる３゜反応液
を１１過して１１７６れる結晶を、水、メブルアルコー
ル、十−アルで洗い、無口１１状Ｊ、たは（１：（状の
結晶をｔｇた。収率６１．３％であった。このよう（こし−Ｃ１ツられた、アンスラニル酸−Ｎ−
１−７ラビ／　シ（”’ａ−ｒｌｔＨｊ！ノＮａ　Ｏ１
１ヲ含ｉＤ　１％水溶液に徐々にｉ８解し、不溶物を口
過し、１」液を減ＪＴ濃縮し、大過剰のアｔｅｌ・ンを
加え、ｌｌ１Ｊ水後乾燥しＣ無色の結晶を１”ｊｌ、二
。収；Ｉ′１００％、全敗率６１．３％であった。１〕−アミノ安息香酸２，３（１、Ｄ　−ｔシ１１−ス
２．５ｑ　、塩化）７ン１−１−シム０．０５（ｌを］
−プルアル−１−ル２５■１中Ｃ′運流下、加熱縮合り
る。反応中に結晶の析出があるが、溶媒を追加し、加熱を続
（）Ｃ反応を終る。冷所に数置した接、反応液を１過し
たのち、結晶を、水、稲メヂルアル」−ル、おＪ、び生
立のエーテル（−洗い、９４％土デルアルコールから再
結晶して、無色剣状の結晶を得た。収率７３．７％−Ｃ
あった。このＪ、うにし−’Ｃ４Ｒられた、ｐ−アミノ安息香酸
〜Ｎ　−Ｌ）　−１−シ［Ｊシトを語算吊のＮａ０ｌ−
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ＩＩ′１１縮し、大過剰のアＬ！１〜ンを加え
、脱水後、乾燥して無口の結晶を得た。収率１ｏＯ％、
−１−ｏｔａｌ収率７３．７％Ｃあった。アンスラニル酸２．３Ｑ　、　［）−キシ［１−ス２．
５ｇ、塩化アン−しニラｌ＼（１，２ｇをエチルアルコ
ール３！Ｊｌ中Ｃ′還流上、加熱１Ｒ１合りる。反応後、減圧上に約１／′２に濃縮し、゛至°温に放［
腎りると結晶の１１１出をみる。反応液を１１過したの
ら、結晶を、水、メチルアル−１−ル、１−−−アルで
洗い、」−プル１ル１−ルＪ、す？１１結晶して、無色
＄１状の結晶を得た。収率７４．６％であった。このようにしｌ　ｉニア６１１だ、アンスラニルＭＱ　
−、Ｎ−１〕−キシ［ｌシトロＭ’ｊ”Ｊ　ｌ？ＩのＮ
ａＯ＋−１をａむ１％水溶液に徐々に溶解し・、不溶物
を口過し、１−１液を減圧濃縮し、大過剰の１Ｌ＋・ン
を加え、１１；２水後乾燥して無口の結晶をＩＦＩｋ、
’　、、収率１００％、１ｏｔａｌ収率７ｆｉ、４％Ｃ
あっ／ｊ　。ｐ−ｊ′ミノ安愈市酸ｊＩｇ、Ｄ−グルー」−ス〔；、
４す、ｌｉ化アンを二「シム（１、！ｉりを９４％−１
ニブール〕７ルニｌ−ル５　ｆｌ　Ｉｎ　ｌ中Ｃ運流士
、加熱縮合りる。反応後、減Ｉ［下に約１／３に濃縮し、冷所に敢＠りる
と液全体がゲル状に膠化した。少Ｕの水を加え、再び加
温し−Ｃ溶解した後、冷蔵外に放置刀るど結晶の析出を
みる。反応液を１」過し、結晶を、水、稀メゾルアルニｌ−ル
、おＪ、び生爪のエーテルで洗い、５０％メヂルアル丁
１−ルから（１ｊ結晶して、無色２１状Ｊ４）結晶を得
た。。収率３３．７％Ｃ゛あった。このＪ、うにし−（’　（３７られた、ｌ］−アミノ安
息香酸−Ｎ−１）−−グルー］シトを計算量のＮａ　Ｏ
Ｈを自む１％水溶液に徐々に溶解し、不溶物を］１過し
、Ｅ−１液を減圧濃縮し、大過剰のアセトンを加え、ｎ
；１水後、乾燥しＣ無色の結晶を得た。収率１００％、
Ｔｏｔａｌ収１３３３．７％であった。アンスラニル酸４．６（１、Ｄ−グルニ■−ス６．Ｏｇ
、塩化アン−しニウム０．５ｇを９５％エヂルアル」−
ル／ｌ０１１１＋中に還流下、加だ！縮合フる。反応後、減汁°士に約　１／３に濃縮し、冷蔵１１１１
に一模放直づるど結＋’ｉｌ’＋の４；１出をみる。反
応液を［１過し、結晶を、水、タブルアルー１−ル、Ｉ
−−−フルＣ洗い、メチルアルコールから５〕度書結晶
し無色６，１状の結晶をＩＨｙた。収１７４．（ｉ％Ｃ
あった。このよう（こしく得られｌ（、アシスラニル酸−ＮＬ）
　−−り）Ｌｒ　Ｊ　７１’　ヲｉ＊Ｉ　節；５０）Ｎ
　ａ　０１−１　ヲＣ７Ｑ　１％水溶液に徐々に溶解し
、不溶物を［口過し、■液を減圧濃縮し、大過剰のアレ
１ヘンを加え、１１；３水後乾燥しＣ無色の結晶をｊ′
１ｋ。収率１００％、ｌ０ｔａｌｌ１７率４．６％Ｃ′
あっｋ。ｐ−アミノ安息香酸　１，５ｇ、＋つ一刀うク１ヘース
２ｇ、塩化）′ンｔニウｌ、　＋１．１（Ｉを９４％ニ
ブルアル１−ル３０１ｎ　ｌ　＋４Ｔ　−Ｃ還流下、加
熱縮合Ｊる。反応後、減Ｉ」濃縮し、冷所にｂ”ｌ直重ると、結晶の
析出をみる。反応液を口過し、結晶を水、稀メヂルアル
コール、および少量の土−アルて洗い、タブルアルー１
−ルから再結晶し＋１無色釦状の結晶を１りだ。収＄４
８．１％であった。このＪ、うにして得られた、　ｐ−）′ミノ安！社香醇
−Ｎ　−１）−−カラクトシトを８１算ωのＮａＯＨを
含む１％水溶液に徐々に溶解し、不溶物を１）過し、日
溜を減圧濃縮し、大過剰のアＬ−１〜ンを加え、脱水後
、乾燥して無色の結晶を得た。収率１００％、丁ｏｔａ
ｌ収率１８．１％であつｌこ。ノ７ンスラニル酸２．４ｇ、［）−ガラクトース３．０
ｇ、塩化アンモニウムｏ、２ｇを９５％エチルアルコー
ル３０ｍ１中に還流下、加熱縮合りる。反応後、減月−十に約　１７／２に淵む１ｊシ、室温に
／Ｉり買りると結晶の析出をみる３１反応液を１−１過
し、結晶を、水、メヂルアルニ１−ル、」ニーアルｃ′
？’Ａ、い、９５％エヂルアルーＪ−ルＪ、り再結晶し
て無色１１状の結晶を１：１ｋ。収率Ｈｉ、４９（、ｔ
・あった。このＪ、うにし７：１！ＩＩうれた、アンスラールｎＤ
　　Ｎ−１〕−刀シク［・シトを−Ｒ−７１のＮａ０１
ｉを含む１％水溶液に徐々に溶解し゛、不溶物を］１過
し、１１液を減圧）１川ｆｉｉｉ　Ｌノ、大過剰のｊノ
Ｌ？Ｉ−ンを加え、１１；（ホ後乾燥しＣ無色の結晶を
１■１ｋ。収率１００％、１−Ｏｔａｌ収率１６．４％
Ｃ゛あ−〕ｌご。ｐ　−ｊ７ミノ安息占酸３す、１−　ラムノース４ｇ、
塩化アンし一ウｌ＼（１、１！＋を９４％上デルアルー
１−ル中に遠流冷２ＪＩ　１・、加熱縮合する。。）又応後、室温（こｂ’ｄ　ｉｒ’ｉ”りると、結晶の
ｌｉ出をみる。反応液をＬ１過し、結晶を水、稀メチル）フルコールで
洗った後、５０％メチルアルコールＪ、り再結晶しＣ無
色１１状の結晶を杓る。収率３０．９％であった。このよ−）にして得られた、ｐ−アミノ安息香酸−Ｎ　
１−ンムノシドをＳ１紳司のＮａＯ＋１を含む１％水溶
液に徐々に溶解し、不溶物を口過し、Ｌ１液を減圧ｌｌ
ｉ！縮し、大過剰のアセトンを加え、脱水後、乾燥しＣ
無色の結晶を得た。収率１００％、１０１ａｌ収率３０
，９％テあツタ。ノノンスノール酎２，３ｐ　、　Ｉ−−ラムノース２，
８Ｑ、塩化アンモニウム（１，２ｑをメチルアルコール
２５ｍ１中に還流下、加熱縮合りる。反応後、室温に放置すると結晶の析出をみる。反応液をＬ】過し、結晶を、水、メチルアルコールで洗
った後、５０％メヂルアルー１−ルＪ、すｔり結晶して
無色ぐ１状の６１４品を１ツる。収率〇、８％（゛あっ
た。このＪ、うにし−（ｉＵられた、アンスンール酸−Ｎ−
し一うムノシ１〜を泪（１吊のＮ　ａ　ＯＬｌを含む１
％水溶液に徐々に溶解し、不溶物を１］過し、１．１液
４減１＋　ｉｆｆ柑１し、大過剰のノ′セトンを加え、
ＩＩ））水１ν乾燥し−Ｃ無色の結晶を得た３、収率１
００％、＋−ｏｔａ＋収率９．８収率９市８び塩化アントニウム０．２ｇを十チルアルー１−ル１０
ｍ　ｌ　”Ｉ　ＣｉＷ流１１．ｌ（約’Ｉ　ＩＩ．’ｉ
間加熱しＣｌ１ｉ合反応を行わμる。反応後、／．１成
物を室温に敢直しＣ結晶を析出さｌる１，ついで、この
結晶を分別しく水、積土チルノフルー１−ルおＪ、び歩
行）のよ−フルＣＡ浄した後、５０％メチル１ル］−ル
を用いてｒＴｊ結晶さＶＣ．ｐ−アミノ宥恕１５酸　Ｎ
　　＋）−マンノシドの無色針状の結晶を得た。収率５
６．１％であった。上述のようにして得られたｐ−アミノ安息香酸−Ｎ−Ｄ
−−マンノシドの水和物を口筒用のＮａ０ｌ−１を含む
１％水溶液に溶解した液に徐々に加えて溶解後、減圧濃
縮し、これに過剰のニ［チルアルコールを加えて沈澱を
生成さける。この沈澱を採取し、脱水後、乾燥づるど無
色の結晶が寄られる。この結晶を、さらに、水５部、ア
セ１〜ン１部からなる水溶液を用い゛”Ｉ’］　Ｉ＋！
ｉ晶さ「て　Ｉ〕−アミノ安息香酸す［〜リウムーＮ−
１）−マンノシドのｄＱ！、色の結晶を得た。収率９５
％、１Ｏｔａｌ収率５３．３％であった。ｍ−アミノ安息香酸２ｇ、Ｄ−マンノース３ｇ、塩化ア
ンモニウム０．２（ｌをエチルアルコール１０■１中に
還流下、９５〜９６℃潟浴中にて加熱縮合づる。反無色
ｉｉ状の結晶を得た。収率５６．１％であった。 −トｊボのＪ、゛）にして１ｑられた　Ｄ−アミノ安息
香酸−Ｎ　［）−マンノシドの水和物を５１算用のＮ　
ａ　Ｏ　Ｈをａむ１％水溶液に溶解した液に徐々に加え
（溶ｗ（後、減圧濃縮し、これに過剰の二「チルノフル
ゴ」−ルを加え一Ｃ沈澱を生成させる。この沈澱を採取
し、１Ｂ２水後、乾燥づると無色の結晶が１ｑられる。この結晶を、さらに、水５部、アセトン１部ｈｌ　Ｉう
なる水溶液を用いＣ再結晶さけ一Ｕ　ｐ−アミノ安１；
．’．　ｆｒ　Ｍ〕１〜リウム−Ｎ−Ｄ−マンノシドの
無色の１１′１品を４Ｈｉた。収率９５％、Ｔｏｔａｌ
収率５３．３％Ｃ・あった。 ■ーアミノ安息香酸２ｇ、Ｄ−マンノース３ｇ、塩化ア
シ七ーウム０。２ｇをエチルアルコール１０…１中に連
流−ト、９ｊＩ〜９６℃渇浴中にて加熱縮合する。反応
生成物を加イ易後しばらくしＣ厚い結晶洩をｉｌｒ　ｔ
ｌ．ｆさせる。反応液を１１過してｉＩ′ｉられる結晶を、／Ｉ＜、メ
チルアル１ールＣ光分洗つｌこ後、メｆールアルーＪ−
ルより再結晶しＵ　１ｔｉｉ色１：１払の１，１４品を
冑だ。収！ｔ′３　：ｉ　、　（１％であった。このＪ、うにしてＨＨｉられｔ＝　ｍ　　アミノ安息香
酸−Ｎ−１〕　　マンノシドを旧穀帛のＮａ（−）ＩＩ
を６Ｇ　４％水溶液中に徐／Ｚに浴ｒ１７シ、不溶物か
（（〕れ（Ｊ１１過し、１１液４減汀ｉ：１ｆｆｉ　１
ｔｉｉ　シ、大過剰の土りノールを加え、脱水後乾燥し
く無色の結晶を１！１ｋ。収率１０（）％、Ｔｏｔａｌ
収，−ｔ＋．　３　、’！　９Ｇ　（あった。[゛No worries about intestinal flora disturbance, long-term use! It is possible. It also affects mutagenicity and cellular and humoral immunity! Therefore, there is no risk of teratogenicity or allergy reactions when administered to people with the drug, making it an extremely safe drug. In addition, this substance increases coronary blood flow by 61% ('1IIJ4IJC'C), and Ishikawa C is known as an anti-ischemic heart disease agent. 1II+-10- and 3
There are different types of scales, and although there may be some differences in activity, they are essentially all useful. Even if the genuine product τ1 is in the form of a salt, any salt that can be used as a pharmaceutical drug is included. Contains aluminum metal salts. Usually Na, K. Mg, Ca, Δ1, etc. are preferable, and Na is particularly preferable. The sugar moiety of this substance is a sugar that forms a glycoside. Examples of sugar include arabinose, xylose, lactose, glucose, mannose,
Contains rhamnose etc. The sugar may be in the D or L form or in the form of the α-1-1β-anomer or in the form of a mixture of anomers. Therefore, the present substance can also be α or β or a mixed anomer thereof. The method for producing this substance is exemplified as above. Aminobenzoic acid 4.5 to 5 g, sugar (1--arabinose, D-xy-1-se, D-gluc-1-se, l)-karak 1-hose, 1--rhamnose or [)-=z-nose )! i-,flig, Ju7'n'[: nium0
．． 1・-0, Jl wo94? -・100%''-tanol (31 pure methanol 40~50111 l (1)
C. Heat 1ii μm under continuous flow. If precipitation of crystals occurs at room temperature or after leaving in a cold place for a while, filter the reaction solution, wash the crystals thoroughly with water, 1-fluid, and methanol water. Or recrystallize from ethanol water. Calculate 1 ton of hydrogen into J 3. I recommend that you rely on well-known methods for IC substitution. That is, the real product Y1 represented by the general formula (J) is dissolved in an aqueous alkaline solvent, and 94 J2R is added to cover the C substitution. J, S17, fzI for the above manufacturing method 1 chemical W t! J is shown in Table 1 above. The infrared absorption spectrum is shown in Figure 1 and Figure 24. The new method shown in Table II is as follows. (1) Al! Fish Using Yanagimoto fine m melting point measuring device (
Measured at 8. (2) Elemental analysis Yanagimoto CI-I N-1-der 1vl
I Measured from 2sho 1. (3) UV: -1-1 was measured using an alni]-water system, and -Na was measured using water as a solvent, using a UV method. (/I) IR Japan Spectroscopy [) 3-7 (11G type (Kj, SK) [Measured by 3r method C. The number in Figure 1rIi matches the sample NO in Table 1. Next, the number of this substance 1) Acute toxicity was investigated by intraperitoneal and forced oral administration of -C using acute Δi CRJ Cl system.This substance was administered by both intraperitoneal injections/j
C is for IUJ saline, orally [1 administration? Dissolved in distilled water, 1 tube of sweat was added, and adjusted to a predetermined concentration using 1 tube of gastric tissue. Throw! We continued to observe the symptoms of poisoning after 7 days, and from the 7th day to the 7th day, the rate of death was 1. l)5. I+ri was calculated. ,
4L ri example, evening white side and 7) solution R11 then 1 (stomach. 1 - D,, value C, Litchfield Will' cox (1,1tcbficld -wr + cox
on ) Figure ill fl'x method ni J: Request 7;,:
. Tii fruit +, t b 2 shows 1゜ Ijirera belly 11・
L-o yoIIC+ is 6g/K between P and meridian 1.
q - C゛, and 6 out of 10 compounds, that is? It can be said that it is an extremely safe drug with a D50 value of 10+1/Kq or more. 2) Antibacterial story i (1) To dissolve this substance in distilled water, make a 2-fold dilution series III (1), mix this diluted liquid with 9 F54! 1. Pour it into a book and put it on a flat plate.
Bar l-inhita l-di]n agar (bacteria) and l-Ko agar (negative bacteria) were used for the J8 background, and 4 test bacteria cultured in the front J8 and 3γ゛Cl2O~241+ for the rear axis bacteria were used. r
, fungi were cultured at 25°C for 3 to 70 days.
I checked the absence of one car. The following bacterial species were used as the test bacteria Toji C. aeruginosa 1 (1'S(!1IdOInollas
1lorlljl! 110sa l A M
1!114) Escherichia coli (1'scl+cricl+ia coli
I r-01273/l) Yellow 1 tow bulb Gl (S
Li1pHylococcus 21ur (!US2
(+UP) Acillus 5ubtilis
l AM 1069) Baker's yeast (S accl+a
romyccs cerevisiae1ΔM 4
207) Candida yeast 7SJ (Candida albic former 1s Δ King 00752) White g bacteria (Trichopl+yton m
ent grophytesIFO6124) Black mold (A spcrg i l lus old ger
IA fvl 3oo1) As a result, this substance did not inhibit the growth of any of the bacteria at a concentration of 1 m++/ml. 3) Henrokuhara 1′! 1 ;L'S' RQCasSay investigation was conducted. In other words, 10 strains lacking replacement repair (13acillus
5ubtilis M45) dark blue repair carrying strain (B-
1 subtilis l-117) were added to [3-I
I cold person L shijJt! Stretches were made on 1 (Potter 4-10, 10 g of boribbezoton, Na C15 (), 15 g of agar, 10001111 of distilled water, +1 +-17, O) so that the starting point did not touch the surface.The material was sterilized. After dissolving 0.051 in water and absorbing it on a circular filter paper with a diameter of 8 mm, spread it directly over the starting point of the image line.ii?I
The seedlings were incubated at 37° C. overnight for 13 hours, and the length of the C growth IUJl region was measured. Next, a reversion b1 test was carried out on Salmonclla tyl.
l+iInurium-1-△5)8d-IAH)0(
0.
! imM video A n-0,! i mfvl hisdecine solution 1.・Soft penetration with river 01°Y? lk(NaC11
3g, 6 liters of water, 1000111 liters of distilled water)
2ml M i>j liquid (1, 1n11, both 8k
(Add 1.1 ml and combine with C < fIfi, and form a 1,000-layer layer on the ground of minimum agar j8. Incubate J8 between 31°C CF 2 E1 and record the number of recursive mutations -11,1'---I Norylnoramide (AI 2) was used as a positive control. Table 3 shows the IV+Song test for 110 cass poems, and Table 4 shows the results of the return test for IV+-iJ', l and ec, respectively. -as
In say, this substance is strange)! Hara 1 ([wo1-″chii
Do not show C, especially p-aminobenzoic acid.
In addition, the 19-return r<Test C' shows that the rate of oscillation caused by this substance shows no change compared to the non-additive control even when high concentrations of f'l are avoided. It has been proven that it is a highly safe and highly safe drug. 4) In order to understand the effects of the substance on delayed sarcasm and immune function on cells and 1-1 immune system.
1'<-J C sheep red blood cells were treated with anti-I using
nij dozuru heel reaction (r' 00111ad l'Qa
cL! 011) (=rowa-)ta. 14 Sheep red blood cells were diluted with 10% volume in saline, and 0.2 ml of this solution was injected into a vein for primary sensitization.
) 0.05ml of %W suspension was applied to the rhinoceros for secondary sensitization.
·)is. This substance (250 mg/K) should be administered intraperitoneally on a daily basis [21
5 innings, 6 pitches). -t ノI+'+ Song, real v'i throwtj (ir(1
) SairlQ Jcj(D increase is pair(((((non-role'-j
)J! Compared to I', there is a difference of 8 stones in C [IJ does not accept it. 5) Antibody activity In order to understand the effect of this substance on body fluid 1-1 immunity, ICR
-J Cl- Mouse 1. l vs. 10% of sheep red blood cells
The mice were sensitized by injecting 0.2 ml of the mother suspension into the tail vein, blood was collected on the 7th day after sensitization, and antibody production was measured by hemagglutination. This substance was administered intraperitoneally to the sensitized L1 (250 ml, -' Kg) 5 times daily.The results showed that there was no difference in the agglutination titer between the group administered with this substance and the control group. Lazyness (J was not observed. Next, the pharmacological properties of the 4\ substance will be described. 1) Crown surface 1 ≧ agitation increasing effect. A heart-lung specimen was prepared. Coronary blood flow was 0, and an electromagnetic flow rate of 1 i was used with Morawity's cannula placed on the coronary vein side from the right atrium.
1 (Stat Izum S I) 2202). This substance has a concentration of 1 oomg/K after dissolving in 4 Umira salt water.
() was injected into the Jonin vein. The results are shown in Table 5. The increase in mean blood flow after administration compared to the mean surface flow before injection ← 2 was expressed as 1-4%. The compound tested had an effect of increasing coronary blood flow, but in '41s 1]-j'mino'!, DoQ cyanide J1
〜Rium-N-11-Mannoside, 11-Noaminoanni Tsuko acid Nori~Rium-N-1)-No1\noside and 1)-Aminebenzoic acid No1-Ryuno, N-1]-xyloside The increase rate of coronary blood flow i1 is 1, 2%, 4
9.4% and 38.3%, showing excellent effectiveness.
The point was noticed. In Table 5, the method of action of this substance to increase coronary blood flow m describes the formulation of this substance. When this substance is used as an anti-ischemic and 1/1 heart disease agent, it has a 111-111
It is convenient to use a small-shaped C', and a single C is used.
The rice is pharmaceutical - 6' [1 container! Mixtures of stimulants and other stimulants can be used. The substance is applied either orally or parenterally. Therefore, the sutra 1" is 41, or) [the sutra L[" is 1j
This substance can be provided in any form (iI). This substance can be provided in a certain form (C'). It can take the form of powders, granules, tablets, dragees, capsules, suppositories, suspensions, solutions, emulsions, tablets, injections, solids, liquids, semisolids, or ingestibles. For example, the following items can be found in cazorel: straw, excipients, fillers, binders, wetting agents, 1-11 dissolving agents, surfactants, lubricants. (agents, dispersants, spinning percentage agents, diluent r1, preservatives, solubilizing agents, solvents, etc.) Furthermore, one or more of these may be used in combination. Anti-1JR blood of the present invention↑ The anti-heart disease agent of the present invention can be manufactured using any known method.The viscous component in the composition used in the present invention generally contains 0.2 to 100%.The anti-heart disease agent of the present invention It is administered to humans and animals either lightly or parenterally, or is preferably administered orally. Oral administration includes sublingual administration. Parenteral administration includes injection, e.g. Muscles, veins, including 1 sword, and 41 drips.The anti-IJ6 blood heart disease agent of the present invention is effective against coronary artery sclerosis, acute 1!I
It is also effective for open types such as chronic myocardial infarction, stable or unstable angina, arrhythmia, and heart failure. The anti-blood heart disease agent of the present invention can be administered to animals or humans.
In addition, since it is affected by age, individual differences, medical conditions, etc., there may be cases where the following 9(1) is used. When administered orally, the amount of this substance is 0.1 per thousand months (g, 11-.1).
to 10,100O, preferably 1 to 500...q, non-linear 1
'' stage weight m is the same, o, oi = -200 m (1, preferably 0.1 to 100 mg, divided into 1...-4 times (°C dose 4''4).Hereinafter, the present invention will be described. The present invention will be explained in detail by showing examples of formulations and reports of ``Y''. Formulation Example 1 This substance (p)
-7 rapinoside) 10 parts heavy oxidized Ngnesi tum 1j) part milk
sugar
Mix 75 parts uniformly and make a powder or fine granules to prepare a powder. Also, put this 11 medicine in a cabrel container -C
What happened to Kabrel drug? Formulation Example 2 This substance (O-aminobenzoic acid)-1 to lium-N-1 xyloside) 45 parts starch
+ b i'ili lactose
16 parts crystalline leech 21 parts polyvinyl alcohol 3 parts water
After uniformly mixing 30 parts of the mixture, crush and granulate it, dry it, and sieve it to remove the granules. Formulation Example 3 In place of O-Aminobenzoic acid No. 1 Helium-N-D-Curkoshi 1- in place of O-Aminobenzoic acid No. Granules were made in the same manner using the granules, 1 part of calcium stearate was added to 96 parts of the granules, and the mixture was compression molded to form tablets with a diameter of 10111 m. Formulation Example 4 This substance (0-aminobenzoic acid) Lium-N-1--
- rhamnocyto) 94 parts polyviral 1-l (1 part water

1j method C similar to -C formulation example 2 using 3 parts
Take the condyle 41'f medicine. 10 parts of crystalline cellulose are added to 90 parts of the obtained granules and compressed to form tablets with a diameter of 8 Ill nl, to which syrup geratin and precipitated 1-I acid lucium are added (take sugar-coated tablets). Formulation Example 5 Genuine 'i'1 (1) No'minobenzoic acid No1-Ryuhachi N-1)-Galac1-Cyto) 0.6 parts Nonionic interface 8! Mix 2.4 parts of +111 agent and 97 parts of physiological saline, sterilize and cover with U 2:1 injection. 1 I'm jealous! ! ! L1 +)-aminebenzoic acid-N-1-
--Arahi p-cyminobenzoic acid4. G! +, 1--
--Acipino-1 part 5g, J-formed unshinium 0.5g
was heated and condensed in 40 ml of 94% ethyl alcohol under a stream of water. Leave the reaction solution in the refrigerator and observe the precipitation of crystals. Pass the reaction solution through the mouth, wash the crystals one by one with 50 ml of
%Medial]-repeated recombination several times to form a colorless r
I-shaped crystal is 1'11. The yield was 45.8%. This J, sea urchin C was obtained. p-Aminobenzoic acid-N-
1% L--aradinoside containing 51 calc. of Na0il
Gradually dissolve in aqueous solution, pass insoluble matter, reduce white liquor)
1-Concentrate, add a large excess of Al7+-one, dehydrate, and dry to obtain colorless crystals. Yield 100%, total yield 45.
There was 8% C. j7 thralic acid 2,3q, l-arahynose 2.
59, 0.2 g of ammonium chloride to 1 methylaluminum
-ru 3fIII I III r E stream 1. Condensation is carried out by heating. After the reaction, let it sit at room temperature to see if crystals precipitate. Pass the reaction mixture for 3 degrees and wash the resulting crystals with water, meblu alcohol, and ten-alcohol. The yield was 61.3%.
1-7 Rabbi/ shi(”'a-rltHj!ノNa O1
Gradually dissolve i8 in a 1% aqueous solution containing 1, filter out the insoluble matter, reduce and concentrate the 1' solution, add a large excess of atel, add 1,1 J water, and dry to obtain C colorless crystals. 1"jl, 2. Yield: I'100%, total failure rate 61.3%. 1]-Aminobenzoic acid 2,3 (1, D-t series 2.5q, chloride) 7 1-1-shim 0.05 (l)
-Plual-1-Al 25-1 Heat condensation under C' flow. Although crystals precipitate during the reaction, add a solvent and continue heating ()C to terminate the reaction. After leaving the reaction solution in a cool place for several minutes, the crystals were washed with water, rice alcohol, and fresh ether, and then recrystallized from 94% sodium chloride alcohol. Colorless sword-shaped crystals were obtained. Yield 73.7% -C
there were. This J, sea urchin-'C4R, p-aminobenzoic acid~N-L) -1-[J site, Na0l-
Gradually dissolve in a 1% aqueous solution containing 1, pass through the mouth to remove insoluble matter,
1 liquid was reduced by II'11, and there was a large excess of aL! After dehydration and drying, dry crystals were obtained. Yield 1oO%,
-1-otal yield was 73.7%C. Anthranilic acid 2.3Q, [)-xy[1-su2.
5 g of ammonium chloride l\ (1.2 g) was heated to 1R1 in 3 Jl of ethyl alcohol under C' reflux. After the reaction, it was concentrated to about 1/2 under reduced pressure and brought to a temperature of released to [
When I go to the kidneys, I see 111 crystals coming out. After filtering the reaction solution, the crystals were washed with water, methylal-1-al, and 1--al. 11 crystals were obtained to obtain colorless $1-shaped crystals. The yield was 74.6%. In this way, I'm near 611, Anthranil MQ.
-, N-1]-xy[lcitroM'j"J l?I's N
Gradually dissolve aO + -1 in a 1% aqueous solution containing a The crystal of IFIk,
',, yield 100%, 1otal yield 7fi, 4%C
Ah/j. p-j'minoasuichi acid jIg, D-glue''-su [;,
4, li conversion to 2 "sim (1, !i to 94% - 1
Nibour] 7 Runil l-ru 5 Fl In l C flow operator, heated and condensed. After the reaction, the solution was concentrated to about 1/3 of the original volume, and when placed in a cold place, the entire solution became gel-like. After adding a small amount of water and heating again to dissolve the -C, leave it outside the refrigerator to observe the precipitation of crystals. The reaction solution was filtered for 1 hour, and the crystals were washed with water, diluted mesolyl alcohol, and ether of fresh nails. Obtained. . The yield was 33.7%C. This J, sea urchin-(' (37d, l]-aminobenzoic acid-N-1)--glue) was added with a calculated amount of NaO
Gradually dissolve H in a 1% aqueous solution, filter the insoluble matter, concentrate solution E-1 under reduced pressure, add a large excess of acetone, and
; After 1 water, it was dried to obtain C colorless crystals. Yield 100%,
The total yield was 1333.7%. Anthranilic acid 4.6 (1, D-glunic acid 6.0g
, 0.5 g of ammonium chloride was added to 95% edial.
Le/l0111+ under reflux, add! Condensation. After the reaction, concentrate to about 1/3 in a juice reducer and refrigerate.
I saw a 4;1 result of Ikkou Naozurudo + 'il' +. The reaction solution was filtered [1], and the crystals were mixed with water, tabular alcohol,
---The product was washed with full C and crystallized from methyl alcohol at 5 degrees to obtain colorless 6,1 crystals. Yield: 174. (i%C
there were. In this way, it was obtained (, acysranilic acid-NL)
--ri)Lr J 71' woi*I clause;50)N
a 01-1 Gradually dissolve in a 1% aqueous solution of C7Q, filter to remove insoluble materials, 2) Concentrate the solution under reduced pressure, add a large excess of Aleben, and dry after 11:3 water to form C colorless crystals. j′
1k. Yield 100%, l0tall17 rate 4.6%C'
Ah k. 1.5 g of p-aminobenzoic acid, 2 g of chloride, 1.1 g of p-aminobenzoic acid, 1.1 g of p-aminobenzoic acid, 1.1 g of p-aminobenzoic acid, 1.1 g of p-aminobenzoic acid, 1.5 g of p-aminobenzoic acid, 1.1 g of p-aminobenzoic acid, 1.5 g of p-aminobenzoic acid, 1.5 g of p-aminobenzoic acid, 1.1 g of p-aminobenzoic acid, 1.1 g of p-aminobenzoic acid, 1.1 g of p-aminobenzoic acid, 1.5 g of p-aminobenzoic acid, 1.5 g of p-aminobenzoic acid, 2 g of chloride, +1.1 (1. After the reaction, concentrate the mixture and place it in a cool place to see the precipitation of crystals. Pass the reaction solution through the mouth, and mix the crystals with water, diluted alcohol, and a small amount of earth-alcohol. Wash, table alue 1
Recrystallize from -1 colorless button-shaped crystal. Income $4
It was 8.1%. This J, obtained by sea urination, p-)' minoyasu! Calactocyto-N-1)--Calactocyto was gradually dissolved in a 1% aqueous solution containing NaOH of 81 ω, filtered to remove insoluble matter, and the daily distillate was concentrated under reduced pressure. After dehydration and drying, colorless crystals were obtained. Yield 100%, clove
The yield was 18.1%. 2.4g of non-7thranilic acid, [)-galactose 3.0
g and 2 g of ammonium chloride were condensed under reflux in 30 ml of 95% ethyl alcohol. After the reaction, the temperature decreases to about 17/2 in 10 months, and then the mixture is brought to room temperature, where crystals precipitate. le,”neal c′
? 'A, 95% edil-all-J-le-J, recrystallized to give colorless 11-shaped crystals at 1:1k. Yield Hi, 49(,t
·there were. This J, sea urchin 7:1! II: Ansral nD
N-1]-Katana Shiku[・Sitowo-R-71's Na01
Gradually dissolve it in a 1% aqueous solution containing i, filter the insoluble matter, and reduce the pressure of the liquid in step 1). 11; After drying, 1k of colorless crystals were obtained. Yield: 100%, 1-Otal yield: 16.4%
C゛ah-　lgo. p-j7 minobenzoic acid 3s, 1-rhamnose 4g,
Ammonium chloride (1,1!+) is heated and condensed in a 94% upper aluminum chloride solution with cold current at room temperature. The reaction solution was filtered through L1, and the crystals were washed with water and dilute methyl alcohol, then recrystallized with 50% methyl alcohol. The yield was 30.9%.
1-munoside was gradually dissolved in a 1% aqueous solution of S1 containing NaO + 1, the insoluble material was sifted, and the L1 liquid was removed under reduced pressure.
i! After shrinking, add a large excess of acetone, dehydrate, and dry.
Colorless crystals were obtained. Yield 100%, 101al yield 30
, 9% Te Atsuta. Nononsunol chu2, 3p, I--rhamnose 2,
8Q, ammonium chloride (1,2q) is heated and condensed in 25 ml of methyl alcohol under reflux. After the reaction, if it is left at room temperature, precipitation of crystals will be observed. After washing it with Ansunuric acid-N-
Shiichi Munoshi 1 ~ Tears (1 including 1 hanging Na OLl)
% aqueous solution, filter out insoluble matter, reduce 1.1 liquid by 4 to 1 + 1, add a large excess of no'cetone,
II)) Dry 1ν of water to obtain -C colorless crystals 3, yield 1
00%, +-ota + yield 9.8 yield 9 city 8 and 0.2 g of anthonium chloride to 1-10
m l ”I CiW style 11.l (approximately 'I II.'i
The mixture was heated for a while to carry out the Cl1i reaction. After reaction, /. 1. The product was cooled to room temperature to precipitate C crystals. 1.Then, the crystals were thoroughly washed with water, silt, and chlorine, and then diluted with 50% methyl. rTj crystal using VC. p-aminoacid 15 acid N
+)-Mannoside colorless needle-like crystals were obtained. Yield 5
It was 6.1%. p-Aminobenzoic acid-N-D obtained as described above
-- Gradually add the hydrate of mannoside to a 1% aqueous solution containing Na0l-1 for the mouthpiece, dissolve it, concentrate under reduced pressure, and add excess nityl alcohol to form a precipitate. Shout out. After collecting this precipitate and dehydrating it, colorless crystals are collected as it dries. These crystals were further treated with an aqueous solution consisting of 5 parts of water and 1 part of acetone.
i crystals 'te I]-aminobenzoic acid [~lium-N-
1)-dQ of mannoside! , obtained colored crystals. Yield 95
%, 1 Otal yield was 53.3%. 2 g of m-aminobenzoic acid, 3 g of D-mannose, and 0.2 (l) of ammonium chloride were heated and condensed in 10 parts of ethyl alcohol under reflux in a lagoon bath at 95-96°C. The yield was 56.1%. - The hydrate of D-aminobenzoic acid-N[)-mannoside, which was converted to 1q by J,
Gradually add a OH to a 1% aqueous solution of a and concentrate under reduced pressure, and add an excess of dichlorofluorol to this to form a 1C precipitate. Collect this precipitate. Then, after drying with 1B2 water, 1q of colorless crystals are obtained.The crystals are further recrystallized using an aqueous solution of 5 parts of water and 1 part of acetone.
．． '． fr M] 1 ~ Colorless 11'1 product of lium-N-D-mannoside was 4Hi. Yield 95%, Total
The yield was 53.3%C. (2) - 2 g of aminobenzoic acid, 3 g of D-mannose, and 0.2 g of acetium chloride are continuously poured into 10...1 ethyl alcohol and condensed by heating at 9jI to 96 DEG C. in a dry bath. After adding the reaction product, thick crystals leak out for a while.
l. f. After filtering the reaction solution for 11 minutes and washing the crystals with /I<, methylalyl C light,
I recrystallized the 1.14th item of U 1tii color 1:1 payment from the helmet. Revenue! t'3: i, (1%. This J was then HHied and t=m aminobenzoic acid-N-1) Mannoside was converted into Na(-)II of the old grain.
6G in 4% aqueous solution/Z bath r17, insoluble matter (() (J11 filtration, 11 liquid 4 reduction i:1ffi 1
tii Add a large excess of earthenol, and after dehydration, 1.1k of dry colorless crystals were obtained. Yield 10()%, Total
Collection, -t+. 3,'! 9G (There was.

[Brief explanation of the drawing]

添附図面の第′１図乃〒第２４図は、表１に示りＮｏ．
１乃〒２４の各化合物の赤外線吸収スベク１−ル特許庁
長官若杉和夫殿１．事件の表示　　　■１イ和５フイ１特γ［願第２１
２１４３号２、発明の名称　　　アミノ安息香酸誘尋体
を有効成分とづる抗＋ＪＢ面性心疾患剤３、補正をηる者事イ′１どの関係　　ｑれ′１出願人名　称　　　　（ＮＯ）呉羽化学工業株式会社４、代　
埋　人　　　東京都新宿区新宿１丁目１番１４号　山１
月ビル通り補充りる。（内容に変更なし）Figures '1 to 24 of the attached drawings are shown in Table 1 and are No. 1 to 24.
Infrared absorption spectrum of each compound of 1 to 24 Kazuo Wakasugi, Commissioner of the Japan Patent Office 1. Display of the incident ■1 iwa 5 fei 1 special gamma [Gan No. 21
No. 2143 No. 2, Title of the invention Anti-JB heart disease agent containing aminobenzoic acid derivative as an active ingredient 3, Matters concerning amendment A'1 Relationship Q'1 Name of applicant Name (NO) Kureha Chemical Co., Ltd. Kogyo Co., Ltd. 4th generation
Buried Yama 1, 1-1-14 Shinjuku, Shinjuku-ku, Tokyo
Moon building street replenishment. (No change in content)

Claims

[Scope of Claims] <1) At least one of the aminoanyl derivatives or pharmaceutically acceptable salts of the general formula (1) (in which 1 represents glycoside) Contains 61 kinds of active ingredients1
Anti-ischemic + heart disease agent. <2) I< is selected from the group consisting of arahynoside, -1: cilloside, gulni J cyto, galactoside, rhamnocyto, and mannoside; 4. The anti-ischemic disease agent according to claim 1, characterized in that it is an anti-ischemic disease agent. (3) The anti-ischemic heart disease agent according to claim 1, wherein the pharmaceutically acceptable salt of Br is a 1-lium salt.