JPS6049185B2 - Guanidinobenzoic acid derivatives - Google Patents
Guanidinobenzoic acid derivativesInfo
- Publication number
- JPS6049185B2 JPS6049185B2 JP12867578A JP12867578A JPS6049185B2 JP S6049185 B2 JPS6049185 B2 JP S6049185B2 JP 12867578 A JP12867578 A JP 12867578A JP 12867578 A JP12867578 A JP 12867578A JP S6049185 B2 JPS6049185 B2 JP S6049185B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- guanidinobenzoyloxy
- methyl
- acid derivatives
- general formula
- 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
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
ソー゛゛（Ｇ、−−
（式中、Ｚはメチレン基、又はエチレン基を表わし、Ｒ
は低級アルキル基を表わす）で示されるクアニジノ安息
香酸誘導体又はその酸付加塩、並びにその製造方法に関
する。Detailed Description of the Invention So゛゛(G, -- (wherein, Z represents a methylene group or an ethylene group, and R
represents a lower alkyl group) or an acid addition salt thereof, and a method for producing the same.
一般式〔Ｉ〕に於てＲが表わす低級アルキル基の例とし
ては、直鎖又は分枝鎖の炭素数１ないし３のアルキル基
、すなわちメチル基、エチル基、ｎ−プロピル基及びイ
ソプロピル基があげられる。Examples of the lower alkyl group represented by R in general formula [I] include straight chain or branched alkyl groups having 1 to 3 carbon atoms, namely methyl group, ethyl group, n-propyl group and isopropyl group. can give.
本発明によれば前記一般式〔Ｉ〕で示されるグアニジノ
安息香酸誘導体は一般式〔■〕本発明は医薬として有用
な一般式〔Ｉ〕
ＨＺ−ＣＯＯＲＣＩ〕
一ンＣ−ＮＨ ＯＸ〔■〕
（式中、Ｘはハロゲン原子を表わす）
で示される化合物の酸付加塩と一般式〔■〕Ｈ Ｚ−Ｃ
ＯＯＲ〔■〕（式中、Ｚ及びＲは前記と同じ意味を表わ
す）で示される化合物を不活性溶媒中、脱ハロゲン化・
水素剤の存在下に−２０℃ないし室温で１〜５時間反応
させることにより製造することができる。According to the present invention, the guanidinobenzoic acid derivative represented by the general formula [I] has the general formula [■], which is useful as a pharmaceutical according to the present invention [I] HZ-COORCI] 1-C-NH OX [■] ( (wherein, X represents a halogen atom) and the acid addition salt of the compound represented by the general formula [■] H Z-C
A compound represented by OOR[■] (in the formula, Z and R have the same meanings as above) was dehalogenated and
It can be produced by reacting in the presence of a hydrogen agent at -20°C to room temperature for 1 to 5 hours.
上記の反応に用いることができる脱ハロゲン化水素剤と
しては、例えばトリエチルアミン、トリブチルアミン、
Ｎ，Ｎ−ジメチルアニリン、Ｎ−メチルピペリジン、ピ
リジン等の第三級アミンがあげられる。溶媒としては、
例えばベンゼン、トルエン、ジエチルエーテル、テトラ
ヒドロフラン、ジオキサン、アセトン、アセトニトリル
、ピリジン等、あるいはこれらの２種以上の混合溶媒が
あげられるがなかでもピリジンが溶媒としても又脱ハロ
ゲン化水素剤としても作用する点で好ましい。Examples of dehydrohalogenating agents that can be used in the above reaction include triethylamine, tributylamine,
Examples include tertiary amines such as N,N-dimethylaniline, N-methylpiperidine, and pyridine. As a solvent,
Examples include benzene, toluene, diethyl ether, tetrahydrofuran, dioxane, acetone, acetonitrile, pyridine, etc., or a mixture of two or more of these solvents, with pyridine acting as both a solvent and a dehydrohalogenating agent. It is preferable.
反応生成物は酸付加塩の形で生成するので、そのまま単
離してもよいし、あるいは、反応液又は反応溶媒を減圧
留去した残留物に炭素水素ナトリウム水溶液を加えて析
出する結晶を分取してもよい。Since the reaction product is produced in the form of an acid addition salt, it can be isolated as it is, or the reaction solution or reaction solvent can be distilled off under reduced pressure, and an aqueous sodium hydrogen carbonate solution can be added to the residue to separate the precipitated crystals. You may.
一般式〔１〕て示される化合物は必要により薬理学的に
許容され得る酸の酸付加塩にたやすく変換することがで
きる。The compound represented by the general formula [1] can be easily converted into an acid addition salt of a pharmacologically acceptable acid, if necessary.
このような酸としては例えば、塩酸、臭化水素酸、硝酸
、リン酸、硫酸等の無機酸、あるいはメタンスルホン酸
、ベンゼンスルホン酸、トルエンスルホン酸、クエン酸
等の有機酸があげられる。一般式〔旧で示される化合物
はｐ−グアニジーノ安息香酸から通常の方法で製造でき
る。Examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, and sulfuric acid, and organic acids such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and citric acid. The compound represented by the general formula [formula] can be produced from p-guanidinobenzoic acid by a conventional method.
例えばチオニルクロライドと加温することによりｐ−グ
アニジノベンゾイルクロライドの塩酸塩が得られ、これ
をこのま）次の反応に使用する。本発明によつて得られ
る化合物はトリプシンが！プラスミンを阻害する作用を
有しており、これらの阻害作用は極めて低い濃度で強く
現われた。For example, by heating with thionyl chloride, the hydrochloride of p-guanidinobenzoyl chloride is obtained, which is used directly in the next reaction. The compound obtained by the present invention is trypsin! It has the effect of inhibiting plasmin, and these inhibitory effects were strong at extremely low concentrations.
インビトロ（ＩｎｖｉｔｒＯ）でのトリプシン及びプラ
スミンの阻害作用をメチルｐ−（ｐ−グアニジノベンゾ
イルオキシ）フエニルアセタートについこて村松等の方
法〔トリプシンについてはザ●ジャーナル・オブ・バイ
オケミストリー（ＴｈｅＪＯｕｒｒｌａｌＯｆＢｌＯｃ
ｈｅｍｊｓｔｒｙ），？，２１４（１９６５）；プラス
ミンについては同誌，Ｍ，４Ｏ２（１９６４）参照〕を
用いて測定し、第一表に示すような結果を４得た。１３
ｒＣ１３紛間の反応でトリプシン０．謳ｙがｐ−トシル
アルギニンメチルエステルを水解する作用を５０％抑制
するメチルｐ−（ｐ−グアニジノベンゾイルオキシ）フ
エニルアセタートの濃度。The inhibitory effects of trypsin and plasmin in vitro (InvitrO) were investigated using methyl p-(p-guanidinobenzoyloxy)phenylacetate using the method of Muramatsu et al.
hemjstry),? , 214 (1965); for plasmin, see the same magazine, M, 4O2 (1964)], and the results shown in Table 1 were obtained. 13
Trypsin 0. The concentration of methyl p-(p-guanidinobenzoyloxy) phenyl acetate that inhibits by 50% the action of y to hydrolyze p-tosylarginine methyl ester.
２ ヒトオイグロプリン（１０倍希釈液）０．１ｍ１、
ストレプトキナーゼ（２００弾位／ｍｌ）０．１ｍ１、
フィブリノーゲン（４０％溶液）０．４ｍ１、緩衝液０
．３ｍ１及びメチルｐ−（ｐ−グアニジノベンゾイルオ
キシ）フエニルアセタートの溶液０．１１１ｔから成る
系で３７℃、３吟間反応させた場合のプラスミンを５０
％阻害するメチルｐ−（ｐ−グアニジノベンゾイルオキ
シ）フエニルアセタートの濃度。2 Human euglopurin (10 times diluted solution) 0.1ml,
Streptokinase (200 levels/ml) 0.1ml,
Fibrinogen (40% solution) 0.4ml, buffer 0
．． 3 ml of plasmin and 0.111 t of a solution of methyl p-(p-guanidinobenzoyloxy) phenyl acetate at 37°C for 3 minutes.
% inhibiting concentration of methyl p-(p-guanidinobenzoyloxy)phenylacetate.
このように一般式〔１〕で示されるグアニジノ安息香酸
誘導体又はその酸付加塩は蛋白分解酵素トリプシンやプ
ラスミンを強力に阻害する作用を有しているので、急性
膵炎等の治療用医薬として、あるいは抗プラスミン剤と
して出血性疾患等の治療用医薬として有用てある。Since the guanidinobenzoic acid derivative represented by the general formula [1] or its acid addition salt has the effect of strongly inhibiting proteolytic enzymes trypsin and plasmin, it can be used as a drug for treating acute pancreatitis, etc. As an anti-plasmin agent, it is useful as a medicine for treating bleeding disorders, etc.
本発明に含まれる一般式〔１〕で示されるグアニジノ安
息香酸誘導体としては、メチルｐ−（ｐーグアニジノベ
ンゾイルオキシ）フエニルアセタート、エチルｐ−（ｐ
−グアニジノベンゾイルオキシ）フエニルアセタート、
ｎ−プロピルｐ−（ｐ−グアニジノベンゾイルオキシ）
フエニルアセタート、イソプロピルｐ−（ｐ−グアニジ
ノベンゾイルオキシ）フエニルアセタート、メチル３−
〔ｐ−（ｐ−グアニジノベンゾイルオキシ）フェニル〕
プロビオナート、エチル３−〔ｐ−（ｐーグアニジノベ
ンゾイルオキシ）フェニル〕プロビオナートがあげられ
る。The guanidinobenzoic acid derivatives represented by the general formula [1] included in the present invention include methyl p-(p-guanidinobenzoyloxy)phenylacetate, ethyl p-(p-guanidinobenzoyloxy)phenylacetate, ethyl p-(p
-guanidinobenzoyloxy)phenylacetate,
n-propyl p-(p-guanidinobenzoyloxy)
Phenyl acetate, isopropyl p-(p-guanidinobenzoyloxy) phenyl acetate, methyl 3-
[p-(p-guanidinobenzoyloxy)phenyl]
Examples include probionate and ethyl 3-[p-(p-guanidinobenzoyloxy)phenyl]probionate.
以下実施例により本発明を詳述する。The present invention will be explained in detail with reference to Examples below.
実施例
メチルｐ−（ｐ−グアニジノベンゾイルオキシ）フエニ
ルアセタートメタンスルホン酸塩の製造ｐ−グアニジノ
安息香酸３．６０ｇにチオニルクロライド１５ｍＬを加
えて３吟間加熱攪拌した後、石油エーテルを加えて得ら
れた結晶を淵取し、石油エーテルで洗浄した。Example: Preparation of methyl p-(p-guanidinobenzoyloxy)phenylacetate methanesulfonate 15 mL of thionyl chloride was added to 3.60 g of p-guanidinobenzoic acid, heated and stirred for 3 minutes, and then petroleum ether was added. The obtained crystals were collected and washed with petroleum ether.
この結晶を、メチルｐ−ヒドロキシフエニルアセタート
３．３６ダをピリジン２７ｍＬに溶かした溶液に０゜Ｃ
で加え、その後２時間０′Ｃて攪拌した。The crystals were added to a solution of 3.36 das of methyl p-hydroxyphenylacetate dissolved in 27 mL of pyridine at 0°C.
and then stirred at 0'C for 2 hours.
この反応液に重炭酸ソーダの飽和水溶液を加え、析出し
て来た結晶をｐ取し、水、アセトンで洗浄し乾燥した。
ここで得られた結晶をメタノールに懸濁しメタンスルホ
ン酸を加えて酸性（ＰＨ３）にし、エーテルを加えた。
析出した結晶を枦取し、メタノールから再結晶して、標
題化合物２．８３Ｖを得た。融点：１４６〜１４８、ＣA saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the precipitated crystals were collected, washed with water and acetone, and dried.
The crystals obtained here were suspended in methanol, methanesulfonic acid was added to make the suspension acidic (pH 3), and ether was added.
The precipitated crystals were collected and recrystallized from methanol to obtain the title compound 2.83V. Melting point: 146-148, C
Claims (1)
はメチレン基、又はエチレン基を表わし、Ｒは低級アル
キル基を表わす）で示されるグアニジノ安息香酸導体又
は酸付加塩。[Claims] 1 General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, Z
represents a methylene group or an ethylene group, and R represents a lower alkyl group).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12867578A JPS6049185B2 (en) | 1978-10-20 | 1978-10-20 | Guanidinobenzoic acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12867578A JPS6049185B2 (en) | 1978-10-20 | 1978-10-20 | Guanidinobenzoic acid derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5555154A JPS5555154A (en) | 1980-04-22 |
| JPS6049185B2 true JPS6049185B2 (en) | 1985-10-31 |
Family
ID=14990656
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12867578A Expired JPS6049185B2 (en) | 1978-10-20 | 1978-10-20 | Guanidinobenzoic acid derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6049185B2 (en) |
-
1978
- 1978-10-20 JP JP12867578A patent/JPS6049185B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5555154A (en) | 1980-04-22 |
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