JPH0848664A - New guanidinobenzoic acid ester derivative - Google Patents
New guanidinobenzoic acid ester derivativeInfo
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- JPH0848664A JPH0848664A JP6204558A JP20455894A JPH0848664A JP H0848664 A JPH0848664 A JP H0848664A JP 6204558 A JP6204558 A JP 6204558A JP 20455894 A JP20455894 A JP 20455894A JP H0848664 A JPH0848664 A JP H0848664A
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、セリンプロテアーゼ阻
害作用を有する医薬品として有用な新規グアニジノ安息
香酸エステル誘導体に関するものである。FIELD OF THE INVENTION The present invention relates to a novel guanidinobenzoic acid ester derivative useful as a drug having serine protease inhibitory activity.
【０００２】[0002]
【従来の技術】生体内には種々のセリンプロテアーゼが
存在し、それらの酵素が何らかの要因により異常に活性
化されると、炎症、疼痛、アレルギー、血液異常、組織
破壊等の疾患を引き起こすと考えられている。従来、種
々のグアニジノ安息香酸誘導体が、セリンプロテアーゼ
であるトリプシン、プラスミン、トロンビン、エラスタ
ーゼ等の活性を阻害し、臨床に使用できることが知られ
ている。代表的なものとして、特開昭５１−１３８６４
２号公報、特開昭６２−１０３０５８号公報、特開昭６
２−１５５２５３号公報、特開昭６３−１６５３５７号
公報、特開平４−４６１４８号公報、特開平４−１５９
２６１号公報等に記載の化合物が知られている。しかし
ながら本発明のグアニジノ安息香酸エステル誘導体に関
しては全く開示されていない。BACKGROUND OF THE INVENTION Various serine proteases exist in the body, and it is considered that when these enzymes are abnormally activated by some factors, diseases such as inflammation, pain, allergies, blood abnormalities and tissue destruction are caused. Has been. It is conventionally known that various guanidinobenzoic acid derivatives inhibit the activities of serine proteases trypsin, plasmin, thrombin, elastase and the like and can be used clinically. As a typical example, JP-A-51-13864
No. 2, JP 62-103058 A, JP 6
2-155253, JP-A-63-165357, JP-A-4-46148, and JP-A-4-159.
The compounds described in Japanese Patent No. 261 and the like are known. However, nothing is disclosed regarding the guanidinobenzoic acid ester derivative of the present invention.
【０００３】[0003]
【発明が解決しようとする課題】そこで本発明は十分な
セリンプロテアーゼ阻害作用を有し、より副作用の少な
いセリンプロテアーゼ阻害剤の開発を目的とし、セリン
プロテアーゼにより仲介される種々の疾患に対して有用
な新規グアニジノ安息香酸エステル誘導体及び該化合物
を含有してなるセリンプロテアーゼ阻害剤を提供するこ
とにある。Therefore, the present invention aims to develop a serine protease inhibitor having a sufficient serine protease inhibitory action and less side effects, and is useful for various diseases mediated by serine protease. Another object of the present invention is to provide a novel guanidinobenzoate derivative and a serine protease inhibitor containing the compound.
【０００４】[0004]
【課題を解決するための手段】本発明のグアニジノ安息
香酸エステル誘導体は下記一般式（Ｉ）The guanidinobenzoic acid ester derivative of the present invention has the following general formula (I):
【化３】 ［式中、Ａは（ＣＨ2 ）n （式中、ｎは０〜５の整数を
示す）またはスチレン基を、Ｒ1 は水素原子、ハロゲン
原子、低級アルキル基を、Ｒ2 は−（ＣＨ2 ）m ＣＯＲ
3 （式中、ｍは２または３の整数を、Ｒ3 は２−チアゾ
リルアミノ基、（４，５−ジメチルチアゾール−２−イ
ル）アミノ基、３，５−ジクロロアニリノ基、２−ピリ
ダジルアミノ基、（５−メチルイソキサゾール−３−イ
ル）アミノ基、ピペリジノ基、２−メトキシカルボニル
アニリノ基を示す）、−（ＣＨ2）m ＣＯＯＲ4 （式
中、ｍは前記と同じ意味を、Ｒ4 は水素原子、低級アル
キル基、置換または無置換ベンジル基を示す）、−ＮＨ
（ＣＨ2 ）n ＣＯＲ3 （式中、ｎは１〜５の整数を、Ｒ
3 は前記と同じ意味を示す）、−ＮＨ（ＣＨ2 ）n ＣＯ
ＯＲ4 （式中、ｎ及びＲ4 前記と同じ意味を示す）、−
ＮＨＣＨ−（−Ｒ5 ）−ＣＯＯＲ4 （式中、Ｒ4 は前記
と同じ意味を、Ｒ5 は置換または無置換ベンジル基、メ
トキシカルボニルメチル基を示す）、−ＮＨ−Ｃ6 Ｈ4
−（ＣＨ2 ）pＣＯＯＲ4 （式中、ｐは０または１の整
数を、Ｒ4 は前記と同じ意味を示す）］で表されるグア
ニジノ安息香酸エステル誘導体及びその塩類。に関する
ものである。[Chemical 3] [In the formula, A is (CH 2 ) n (wherein n is an integer of 0 to 5) or a styrene group, R 1 is a hydrogen atom, a halogen atom, a lower alkyl group, and R 2 is-(CH 2 ) m COR
3 (In the formula, m is an integer of 2 or 3, R 3 is 2-thiazolylamino group, (4,5-dimethylthiazol-2-yl) amino group, 3,5-dichloroanilino group, 2-pyridazylamino group , (5-methylisoxazole-3-yl) amino group, piperidino group, 2-methoxy shows a carbonyl anilino group), - (CH 2) m COOR 4 ( wherein, m is as defined above, R 4 represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted benzyl group), —NH
(CH 2 ) n COR 3 (In the formula, n is an integer of 1 to 5;
3 has the same meaning as above), - NH (CH 2) n CO
OR 4 (in the formula, n and R 4 represent the same meaning as described above), −
NHCH - (- R 5) -COOR 4 ( wherein the same meaning as R 4 is the, R 5 represents a substituted or unsubstituted benzyl group, a methoxycarbonylmethyl group), - NH-C 6 H 4
-(CH 2 ) p COOR 4 (in the formula, p represents an integer of 0 or 1, and R 4 has the same meaning as described above)], and a guanidinobenzoic acid ester derivative and salts thereof. It is about.
【０００５】上記一般式（Ｉ）について具体的に説明す
る。ハロゲン原子とは、フッ素、塩素、臭素、ヨウ素
を、低級アルキル基とは、メチル、エチル、ｎ−プロピ
ル、ｉｓｏ−プロピル、ｎ−ブチル、ｉｓｏ−ブチル、
ｔｅｒｔ−ブチル、ｎ−ペンチル、ｎ−ヘキシル、等の
炭素数１〜６のアルキル基を、置換ベンジル基の置換基
とは、ハロゲン原子、ニトロ基、低級アルキル基、ヒド
ロキシ基、メトキシ、エトキシ、プロポキシ、ｉｓｏ−
プロポキシ、ｎ−ブトキシ、ｉｓｏ−ブトキシ、ｔｅｒ
ｔ−ブトキシ等の炭素数２〜６の低級アルコキシ基を意
味する。またその塩類は、塩酸、硫酸、硝酸、リン酸等
の無機酸塩及び、酢酸、マレイン酸、シュウ酸、フマル
酸、コハク酸、マロン酸、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等の有機酸塩である
が、これらに限定されるものではない。The above general formula (I) will be specifically described. The halogen atom is fluorine, chlorine, bromine, iodine, and the lower alkyl group is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
The substituent of the substituted benzyl group is an alkyl group having 1 to 6 carbon atoms such as tert-butyl, n-pentyl, n-hexyl and the like, and the substituent of the substituted benzyl group is a halogen atom, a nitro group, a lower alkyl group, a hydroxy group, methoxy, ethoxy, Propoxy, iso-
Propoxy, n-butoxy, iso-butoxy, ter
It means a lower alkoxy group having 2 to 6 carbon atoms such as t-butoxy. In addition, salts thereof include inorganic acid salts such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and acetic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, malonic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like. Organic acid salts, but are not limited to these.
【０００６】一般式（Ｉ）で示される化合物を医薬とし
て用いる場合、そのままもしくは公知の賦形剤と共に、
錠剤、カプセル剤、散剤、細粒剤、坐剤、注射剤、軟膏
剤、ゲル剤、クリーム剤、リザーバー型貼付剤、エアゾ
ール剤等の適宜の剤形として、通常全身的あるいは局所
的に、経口または非経口的に安定に投与することができ
る。投与量は、投与対象の症状、年齢、性別等に応じて
適宜決定されるが通常成人に対して経口投与する場合、
化合物（Ｉ）またはその塩類を１回量１０〜５００ｍｇ
程度１日約１〜数回程度投与することが好ましい。When the compound represented by the general formula (I) is used as a medicine, as it is or together with a known excipient,
Oral systemically or systemically as appropriate dosage forms such as tablets, capsules, powders, fine granules, suppositories, injections, ointments, gels, creams, reservoir patches, aerosols, etc. Alternatively, it can be stably administered parenterally. The dose is appropriately determined according to the symptoms, age, sex, etc. of the administration subject, but when orally administered to an adult,
Compound (I) or a salt thereof in a single dose of 10 to 500 mg
It is preferable to administer about 1 to several times a day.
【０００７】次に本発明化合物の製造法について述べ
る。本発明の化合物は以下に記載する方法によって収率
よく得ることができるが、本発明の範囲はこれらに限定
されるものではない。 製造法 １Next, a method for producing the compound of the present invention will be described. The compound of the present invention can be obtained in good yield by the method described below, but the scope of the present invention is not limited thereto. Manufacturing method 1
【化４】 （式中、Ａ、Ｒ1 及びＲ2 は前記と同じ意味を示す。） 一般式（ＩＩ）で表される化合物と一般式（ＩＩＩ）で
表される化合物を適当な溶媒中、縮合剤の存在下で反応
させることにより、一般式（Ｉ）で表される化合物を得
ることができる。ここで反応溶媒としては、例えばピリ
ジン、ジメチルホルムアミド、クロロホルム、ジクロロ
メタン、四塩化炭素、ベンゼン、トルエン、ジエチルエ
ーテル、ジオキサン、テトラヒドロフラン、酢酸エチ
ル、ジメチルスルホキシド等の反応に関与しない溶媒で
あれば特に限定されない。縮合剤としては、例えばジシ
クロヘキシルカルボジイミド、１−（３−ジメチルアミ
ノプロピル）−３−エチルカルボジイミド、ジフェニル
ホスホリルアジド、Ｎ，Ｎ’−カルボジイミダゾール等
を用いることができるが、これらに限定されるものでは
ない。[Chemical 4] (In the formula, A, R 1 and R 2 have the same meanings as described above.) The compound represented by the general formula (II) and the compound represented by the general formula (III) are treated with a condensing agent in a suitable solvent. By reacting in the presence, the compound represented by the general formula (I) can be obtained. Here, the reaction solvent is not particularly limited as long as it is a solvent that does not participate in the reaction, such as pyridine, dimethylformamide, chloroform, dichloromethane, carbon tetrachloride, benzene, toluene, diethyl ether, dioxane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, and the like. . As the condensing agent, for example, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, diphenylphosphoryl azide, N, N′-carbodiimidazole and the like can be used, but the condensing agent is not limited thereto. is not.
【０００８】製造法 ２Manufacturing method 2
【化５】 （式中、Ａ、Ｒ1 及びＲ2 は前記と同じ意味を示し、Ｈ
ａｌはハロゲン原子を意味する。） 一般式（ＩＶ）で表される化合物と一般式（ＩＩＩ）で
表される化合物を無溶媒または適当な溶媒中、塩基触媒
の存在下で反応させることにより、一般式（Ｉ）で表さ
れる化合物を得ることができる。ここで反応溶媒として
は、例えばクロロホルム、ジクロロメタン、四塩化炭
素、テトラヒドロフラン、ジオキサン、ジメチルホルム
アミド、ジメチルスルホキシド等の反応に関与しない溶
媒であれば特に限定されない。また塩基触媒しては、ピ
リジン、トリエチルアミン、トリ−ｎ−プロピルアミ
ン、Ｎ−メチルモルホリン等を用いることができるが、
これらに限定されるものではない。前記製造法で用いた
一般式（ＩＩ）、（ＩＩＩ）、（ＩＶ）で示される化合
物は、公知の反応の組み合わせによって製造することが
できる。Embedded image (In the formula, A, R 1 and R 2 have the same meanings as described above, and H
al means a halogen atom. ) A compound represented by the general formula (I) is obtained by reacting a compound represented by the general formula (IV) with a compound represented by the general formula (III) in the absence of a solvent or a suitable solvent in the presence of a base catalyst. Can be obtained. Here, the reaction solvent is not particularly limited as long as it is a solvent that does not participate in the reaction, such as chloroform, dichloromethane, carbon tetrachloride, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide. As the base catalyst, pyridine, triethylamine, tri-n-propylamine, N-methylmorpholine and the like can be used,
It is not limited to these. The compounds represented by the general formulas (II), (III) and (IV) used in the above production method can be produced by a known combination of reactions.
【０００９】[0009]
【実施例】以下に実施例を示し、本発明を更に詳細に説
明する。ただし、本発明はこれら実施例に限定されるも
のではない。The present invention will be described in more detail with reference to the following examples. However, the present invention is not limited to these examples.
【００１０】実施例 １ ４−グアニジノ安息香酸塩酸塩（１．０８ｇ）のピリジ
ン（２０ｍｌ）溶液にジシクロヘキシルカルボジイミド
（以下ＤＣＣと略、１．０３ｇ）を−１５℃で加え、２
０分間攪拌した後、Ｎ−（２−チアゾリル）−４−ヒド
ロキシベンズアミド（１．１０ｇ）を加え、０℃で一夜
攪拌させた。反応終了後、不溶物をろ別し、ろ液に飽和
炭酸水素ナトリウム水を加え、生じた結晶をろ取、水お
よびアセトンで順次洗浄し、乾燥した。結晶をメタノー
ルに懸濁させ、メタンスルホン酸（０．５ｇ）を加え、
不溶物をろ別し、ろ液にアセトンを加え析出した結晶を
乾燥し、下記構造の化合物（１．３４ｇ）を得た。融点
は１４３〜１４８℃であった。 ＩＲ：３１５０，１７４０，１６８４，１５７４，１２
０９，１０６０ｃｍ-1 元素分析値（Ｃ18Ｈ15Ｎ 5Ｏ 3Ｓ・２ＣＨ 3ＳＯ 3Ｈ・２Ｈ 2Ｏとして） 計算値 Ｃ：３９．４０ Ｈ：４．４６ Ｎ：１１．４９ 実測値 Ｃ：３９．４８ Ｈ：４．２７ Ｎ：１１．４２Example 1 Pyridyl 4-guanidinobenzoic acid hydrochloride (1.08 g)
Solution (20 ml) in dicyclohexylcarbodiimide
(Hereinafter DCC, abbreviated as 1.03 g) is added at -15 ° C, and 2
After stirring for 0 minutes, N- (2-thiazolyl) -4-hydr
Add Roxybenzamide (1.10g) and stir at 0 ° C overnight.
Allowed to stir. After the reaction is complete, the insoluble matter is filtered off and the filtrate is saturated.
Aqueous sodium hydrogen carbonate solution was added, and the formed crystals were collected by filtration and washed with water.
And sequentially washed with acetone and dried. Methano crystals
Suspended in water, added methanesulfonic acid (0.5 g),
Insoluble matter was filtered off, acetone was added to the filtrate, and the precipitated crystals were collected.
It was dried to obtain a compound having the following structure (1.34 g). Melting point
Was 143-148 ° C. IR: 3150, 1740, 1684, 1574, 12
09,1060 cm-1 Elemental analysis value (C18HFifteenN 5 O 3S / 2CH 3SO 3H / 2H Calculated value C: 39.40 H: 4.46 N: 11.49 Actual value C: 39.48 H: 4.27 N: 11.42
【化６】 [Chemical 6]
【００１１】実施例 ２ ４−グアニジノ安息香酸塩酸塩（１．０４ｇ）のピリジ
ン（１５ｍｌ）−ジメチルホルムアミド（５ｍｌ）溶液
にＤＣＣ（０．９９ｇ）を−１５℃で加え、２０分間攪
拌した後、Ｎ−（２−チアゾリル）−３−（４−ヒドロ
キシベンゾイル）プロパナミド（１．３３ｇ）を加え、
０℃で一夜攪拌させた。反応終了後、不溶物をろ別し、
ろ液に飽和炭酸水素ナトリウム水を加え、生じた結晶を
ろ取、水およびアセトンで順次洗浄し、乾燥した。結晶
をエタノールに懸濁させ、メタンスルホン酸（０．５
ｇ）を加え、不溶物をろ別し、ろ液を４℃で一夜放置
し、析出した結晶を乾燥し、下記構造の化合物（０．３
５ｇ）を得た。融点は１８２〜１８６℃であった。 ＩＲ：３３８２，１７２３，１６８６，１５７６，１１
９３，１０４４ｃｍ-1 元素分析値（Ｃ21Ｈ19Ｎ5 Ｏ4 Ｓ・２ＣＨ3 ＳＯ3 Ｈ・１／２Ｈ2 Ｏとして） 計算値 Ｃ：４３．２５ Ｈ：４．４２ Ｎ：１０．９７ 実測値 Ｃ：４３．１９ Ｈ：４．４０ Ｎ：１０．８６Example 2 DCC (0.99 g) was added to a solution of 4-guanidinobenzoic acid hydrochloride (1.04 g) in pyridine (15 ml) -dimethylformamide (5 ml) at -15 ° C, and the mixture was stirred for 20 minutes. N- (2-thiazolyl) -3- (4-hydroxybenzoyl) propanamide (1.33 g) was added,
Let stir at 0 ° C. overnight. After the reaction is completed, the insoluble matter is filtered off,
Saturated aqueous sodium hydrogencarbonate was added to the filtrate, and the resulting crystals were collected by filtration, washed successively with water and acetone and dried. The crystals were suspended in ethanol, and methanesulfonic acid (0.5
g) was added, the insoluble matter was filtered off, the filtrate was left overnight at 4 ° C., the precipitated crystals were dried, and the compound of the following structure (0.3
5 g) was obtained. The melting point was 182-186 ° C. IR: 3382, 1723, 1686, 1576, 11
93,1044 cm -1 Elemental analysis value (as C 21 H 19 N 5 O 4 S.2CH 3 SO 3 H.1 / 2H 2 O) Calculated value C: 43.25 H: 4.42 N: 10.97 Actual measurement Value C: 43.19 H: 4.40 N: 10.86
【化７】 [Chemical 7]
【００１２】実施例 ３ ４−グアニジノ安息香酸メタンスルホン酸塩（２．７５
ｇ）のピリジン（５０ｍｌ）溶液にＤＣＣ（２．０６
ｇ）を−１５℃で加え、２０分間攪拌した後、３−（４
−ヒドロキシベンゾイル）プロピオン酸４−ニトロベン
ジル（３．２９ｇ）を加え、０℃で一夜攪拌させた。反
応終了後、不溶物をろ別し、ろ液に飽和炭酸水素ナトリ
ウム水を加えて生じた結晶をろ取、水およびアセトンで
順次洗浄し、乾燥した。結晶をメタノールに懸濁させ、
メタンスルホン酸（１．０ｇ）を加え、不溶物をろ別し
た後、ろ液を減圧濃縮した。濃縮物をシリカゲルクロマ
トグラフィー（クロロホルム：メタノール＝５：１）で
精製し、下記構造の化合物（１．６ｇ）を得た。融点は
７８〜８２℃であった。 ＩＲ：３３７０，１７４０，１６８６，１６０３，１２
０９，１１６６ｃｍ-1 元素分析値（Ｃ25Ｈ22Ｎ4 Ｏ7 ・ＣＨ3 ＳＯ3 Ｈ・１／２Ｈ2 Ｏとして） 計算値 Ｃ：５２．４３ Ｈ：４．５７ Ｎ：９．４１ 実測値 Ｃ：５２．３０ Ｈ：４．６８ Ｎ：９．２８Example 3 4-guanidinobenzoic acid methanesulfonate (2.75)
g) in pyridine (50 ml) in DCC (2.06
g) was added at -15 ° C and stirred for 20 minutes, and then 3- (4
4-Nitrobenzyl (hydroxybenzoyl) propionate (3.29 g) was added, and the mixture was stirred at 0 ° C. overnight. After completion of the reaction, the insoluble matter was filtered off, saturated aqueous sodium hydrogencarbonate was added to the filtrate, and the resulting crystals were collected by filtration, washed successively with water and acetone, and dried. Suspend the crystals in methanol,
Methanesulfonic acid (1.0 g) was added, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel chromatography (chloroform: methanol = 5: 1) to obtain a compound (1.6 g) having the following structure. The melting point was 78-82 ° C. IR: 3370, 1740, 1686, 1603, 12
09,1166 cm -1 Elemental analysis value (as C 25 H 22 N 4 O 7 .CH 3 SO 3 H.1 / 2H 2 O) Calculated value C: 52.43 H: 4.57 N: 9.41 Measured value C: 52.30 H: 4.68 N: 9.28
【化８】 Embedded image
【００１３】実施例 ４ 実施例３で合成した４−〔３−（４−ニトロベンジルオ
キシカルボニル）プロパノイル〕フェニル−４−グアニ
ジノベンゾエート炭酸塩（３．９ｇ）を酢酸（７０ｍ
ｌ）、メタノール（５０ｍｌ）及び水（３０ｍｌ）の混
合溶液に、５％−Ｐｄ／Ｃ（０．４ｇ）を加え、常圧下
にて３時間水素添加を行った。反応終了後、不溶物をろ
別し、ろ液にアセトンを加え、生じた結晶をろ取、乾燥
した。結晶をジメチルホルムアミド−アセトン溶液に懸
濁し、メタンスルホン酸（１．０ｇ）を加え、不溶物を
ろ別し、ろ液にエーテルを加え、析出した結晶を乾燥
し、下記構造の化合物（０．４５ｇ）を得た。融点は２
１２〜２１４℃であった。 ＩＲ：３１６８，１７３８，１７０９，１６７３，１５
７６，１１９９ｃｍ-1 元素分析値（Ｃ18Ｈ17Ｎ3 Ｏ5 ・ＣＨ3 ＳＯ3 Ｈとして） 計算値 Ｃ：５０．５５ Ｈ：４．６９ Ｎ：９．３１ 実測値 Ｃ：５０．４１ Ｈ：４．６４ Ｎ：９．３６Example 4 4- [3- (4-nitrobenzyloxycarbonyl) propanoyl] phenyl-4-guanidinobenzoate carbonate (3.9 g) synthesized in Example 3 was mixed with acetic acid (70 m).
5% -Pd / C (0.4 g) was added to a mixed solution of 1), methanol (50 ml) and water (30 ml), and hydrogenation was carried out under normal pressure for 3 hours. After completion of the reaction, the insoluble matter was filtered off, acetone was added to the filtrate, and the generated crystals were collected by filtration and dried. The crystals were suspended in a dimethylformamide-acetone solution, methanesulfonic acid (1.0 g) was added, the insoluble matter was filtered off, ether was added to the filtrate, and the precipitated crystals were dried to give a compound of the following structure (0. 45 g) was obtained. Melting point is 2
It was 12-214 degreeC. IR: 3168, 1738, 1709, 1673, 15
76,1199 cm −1 Elemental analysis value (as C 18 H 17 N 3 O 5 .CH 3 SO 3 H) Calculated value C: 50.55 H: 4.69 N: 9.31 Measured value C: 50.41 H : 4.64 N: 9.36
【化９】 [Chemical 9]
【００１４】実施例５〜３０ 実施例１〜４の方法に準じて表１〜表３の本発明化合物
を合成した。融点はメタンスルホン酸塩での結果を示
す。Examples 5 to 30 The compounds of the present invention shown in Tables 1 to 3 were synthesized according to the methods of Examples 1 to 4. Melting points indicate results with methanesulfonate.
【００１５】[0015]
【表１】 [Table 1]
【００１６】[0016]
【表２】 [Table 2]
【００１７】[0017]
【表３】 [Table 3]
【００１８】以下に、本発明化合物がセリンプロテアー
ゼ阻害活性作用を示すことを立証するためにカリクレイ
ン及びプラスミン阻害活性作用についての実験方法及び
その結果について示す。In order to prove that the compound of the present invention exhibits serine protease inhibitory activity, the experimental method and the result of kallikrein and plasmin inhibitory activity are shown below.
【００１９】カリクレイン阻害活性作用についての実験 ヒトプラズマカリクレイン及びＨ−Ｄ−Ｐｒｏ−Ｐｈｅ
−Ａｒｇ−ｐ−ニトロアニリドを用いて行った。すなわ
ち、０．０５Ｍトリス−塩酸緩衝液（ｐＨ ７．８）で
種々の検体及び酵素液を作成し、これらの反応混液を３
７℃で４分間インキュベートした。１５％酢酸を加えて
反応を停止し４０５ｎｍで吸光度を測定した。試験結果
は、５０％阻害濃度（ＩＣ50）で表した。 Experiment on Kallikrein Inhibitory Activity Human plasma kallikrein and HD-Pro-Phe
-Arg-p-nitroanilide. That is, various specimens and enzyme solutions were prepared with 0.05 M Tris-hydrochloric acid buffer solution (pH 7.8), and the reaction mixture solution was mixed with 3
Incubated at 7 ° C for 4 minutes. The reaction was stopped by adding 15% acetic acid, and the absorbance was measured at 405 nm. The test results were expressed as 50% inhibitory concentration (IC 50 ).
【００２０】プラスミン阻害活性作用についての実験 ヒトプラスミン及びＨ−Ｄ−Ｖａｌ−Ｌｅｕ−Ｌｙｓ−
ｐ−ニトロアニリドを用いて行った。すなわち、０．０
５Ｍトリス−塩酸緩衝液（１１０ｍＭ ＮａＣｌを含
む、ｐＨ ７．４）で種々の検体及び酵素液を作成し、
これらの反応混液を３７℃で４分間インキュベートし
た。１５％酢酸を加えて反応を停止し４０５ｎｍで吸光
度を測定した。試験結果は、ＩＣ50で表した。 Experiment on plasmin inhibitory activity Human plasmin and HD-Val-Leu-Lys-
Performed with p-nitroanilide. That is, 0.0
Various samples and enzyme solutions were prepared with 5 M Tris-hydrochloric acid buffer solution (containing 110 mM NaCl, pH 7.4),
These reaction mixtures were incubated at 37 ° C for 4 minutes. The reaction was stopped by adding 15% acetic acid, and the absorbance was measured at 405 nm. The test results are expressed as IC 50 .
【００２１】結果 阻害活性（ＩＣ50）の結果を以下の表４に示す。 Results The results of the inhibitory activity (IC 50 ) are shown in Table 4 below.
【表４】 [Table 4]
【００２２】[0022]
【発明の効果】本発明の化合物〔１〕は優れたセリンプ
ロテアーゼ阻害活性作用を有する。従って、セリンプロ
テアーゼにより仲介される出血性疾患、血栓、膵炎等の
種々の疾患に対する治療剤として、または予防剤として
の使用が期待でき、有用な医薬を提供することができ
る。The compound [1] of the present invention has an excellent serine protease inhibitory activity. Therefore, it can be expected to be used as a therapeutic agent or a preventive agent for various diseases such as hemorrhagic diseases mediated by serine protease, thrombosis, pancreatitis, etc., and a useful medicine can be provided.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/50 Ｃ０７Ｃ 309/04 7419−4Ｈ Ｃ０７Ｄ 237/08 261/14 277/44 295/18 Ｚ (72)発明者 藤本 典行 佐賀県鳥栖市田代大官町408番地 久光製 薬株式会社内 (72)発明者 武田 和久 佐賀県鳥栖市田代大官町408番地 久光製 薬株式会社内─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical display location A61K 31/50 C07C 309/04 7419-4H C07D 237/08 261/14 277/44 295/18 Z (72) Inventor Noriyuki Fujimoto 408 Tashiro Daikancho, Tosu City, Saga Prefecture, Hisamitsu Pharmaceutical Co., Ltd. (72) Inventor, Kazuhisa Takeda 408, Tashiro Daikanmachi, Tosu City, Saga Prefecture
Claims (2)
示す）またはスチレン基を、Ｒ1 は水素原子、ハロゲン
原子、低級アルキル基を、Ｒ2 は−（ＣＨ2 ）m ＣＯＲ
3 （式中、ｍは２または３の整数を、Ｒ3 は２−チアゾ
リルアミノ基、（４，５−ジメチルチアゾール−２−イ
ル）アミノ基、３，５−ジクロロアニリノ基、２−ピリ
ダジルアミノ基、（５−メチルイソキサゾール−３−イ
ル）アミノ基、ピペリジノ基、２−メトキシカルボニル
アニリノ基を示す）、−（ＣＨ2）m ＣＯＯＲ4 （式
中、ｍは前記と同じ意味を、Ｒ4 は水素原子、低級アル
キル基、置換または無置換ベンジル基を示す）、−ＮＨ
（ＣＨ2 ）n ＣＯＲ3 （式中、ｎは１〜５の整数を、Ｒ
3 は前記と同じ意味を示す）、−ＮＨ（ＣＨ2 ）n ＣＯ
ＯＲ4 （式中、ｎ及びＲ4 前記と同じ意味を示す）、−
ＮＨＣＨ−（−Ｒ5 ）−ＣＯＯＲ4 （式中、Ｒ4 は前記
と同じ意味を、Ｒ5 は置換または無置換ベンジル基、メ
トキシカルボニルメチル基を示す）、−ＮＨ−Ｃ6 Ｈ4
−（ＣＨ2 ）pＣＯＯＲ4 （式中、ｐは０または１の整
数を、Ｒ4 は前記と同じ意味を示す）］で表されるグア
ニジノ安息香酸エステル誘導体及びその塩類。1. A compound of the general formula (I) [In the formula, A is (CH 2 ) n (wherein n is an integer of 0 to 5) or a styrene group, R 1 is a hydrogen atom, a halogen atom, a lower alkyl group, and R 2 is-(CH 2 ) m COR
3 (In the formula, m is an integer of 2 or 3, R 3 is 2-thiazolylamino group, (4,5-dimethylthiazol-2-yl) amino group, 3,5-dichloroanilino group, 2-pyridazylamino group , (5-methylisoxazole-3-yl) amino group, piperidino group, 2-methoxy shows a carbonyl anilino group), - (CH 2) m COOR 4 ( wherein, m is as defined above, R 4 represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted benzyl group), —NH
(CH 2 ) n COR 3 (In the formula, n is an integer of 1 to 5;
3 has the same meaning as above), - NH (CH 2) n CO
OR 4 (in the formula, n and R 4 represent the same meaning as described above), −
NHCH - (- R 5) -COOR 4 ( wherein the same meaning as R 4 is the, R 5 represents a substituted or unsubstituted benzyl group, a methoxycarbonylmethyl group), - NH-C 6 H 4
-(CH 2 ) p COOR 4 (in the formula, p represents an integer of 0 or 1, and R 4 has the same meaning as described above)], and a guanidinobenzoic acid ester derivative and salts thereof.
示す）またはスチレン基を、Ｒ1 は水素原子、ハロゲン
原子、低級アルキル基を、Ｒ2 は−（ＣＨ2 ）m ＣＯＲ
3 （式中、ｍは２または３の整数を、Ｒ3 は２−チアゾ
リルアミノ基、（４，５−ジメチルチアゾール−２−イ
ル）アミノ基、３，５−ジクロロアニリノ基、２−ピリ
ダジルアミノ基、（５−メチルイソキサゾール−３−イ
ル）アミノ基、ピペリジノ基、２−メトキシカルボニル
アニリノ基を示す）、−（ＣＨ2）m ＣＯＯＲ4 （式
中、ｍは前記と同じ意味を、Ｒ4 は水素原子、低級アル
キル基、置換または無置換ベンジル基を示す）、−ＮＨ
（ＣＨ2 ）n ＣＯＲ3 （式中、ｎは１〜５の整数を、Ｒ
3 は前記と同じ意味を示す）、−ＮＨ（ＣＨ2 ）n ＣＯ
ＯＲ4 （式中、ｎ及びＲ4 前記と同じ意味を示す）、−
ＮＨＣＨ−（−Ｒ5 ）−ＣＯＯＲ4 （式中、Ｒ4 は前記
と同じ意味を、Ｒ5 は置換または無置換ベンジル基、メ
トキシカルボニルメチル基を示す）、−ＮＨ−Ｃ6 Ｈ4
−（ＣＨ2 ）pＣＯＯＲ4 （式中、ｐは０または１の整
数を、Ｒ4 は前記と同じ意味を示す）］で表されるグア
ニジノ安息香酸エステル誘導体及びその塩類を有効成分
として含有するセリンプロテアーゼ阻害剤。2. A compound represented by the general formula (I): [In the formula, A is (CH 2 ) n (wherein n is an integer of 0 to 5) or a styrene group, R 1 is a hydrogen atom, a halogen atom, a lower alkyl group, and R 2 is-(CH 2 ) m COR
3 (In the formula, m is an integer of 2 or 3, R 3 is 2-thiazolylamino group, (4,5-dimethylthiazol-2-yl) amino group, 3,5-dichloroanilino group, 2-pyridazylamino group , (5-methylisoxazole-3-yl) amino group, piperidino group, 2-methoxy shows a carbonyl anilino group), - (CH 2) m COOR 4 ( wherein, m is as defined above, R 4 represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted benzyl group), —NH
(CH 2 ) n COR 3 (In the formula, n is an integer of 1 to 5;
3 has the same meaning as above), - NH (CH 2) n CO
OR 4 (in the formula, n and R 4 represent the same meaning as described above), −
NHCH - (- R 5) -COOR 4 ( wherein the same meaning as R 4 is the, R 5 represents a substituted or unsubstituted benzyl group, a methoxycarbonylmethyl group), - NH-C 6 H 4
-(CH 2 ) p COOR 4 (in the formula, p represents an integer of 0 or 1 and R 4 has the same meaning as described above)] and contains a guanidinobenzoate derivative and salts thereof as an active ingredient. Serine protease inhibitor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6204558A JPH0848664A (en) | 1994-08-05 | 1994-08-05 | New guanidinobenzoic acid ester derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6204558A JPH0848664A (en) | 1994-08-05 | 1994-08-05 | New guanidinobenzoic acid ester derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0848664A true JPH0848664A (en) | 1996-02-20 |
Family
ID=16492474
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6204558A Pending JPH0848664A (en) | 1994-08-05 | 1994-08-05 | New guanidinobenzoic acid ester derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0848664A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008508188A (en) * | 2004-07-27 | 2008-03-21 | アステラス製薬株式会社 | Thiazole derivatives having VAP-1 inhibitor activity |
| JP2010229141A (en) * | 2010-05-19 | 2010-10-14 | Sumitomo Chemical Co Ltd | Method for producing camostat hydrochloride |
| US20100286267A1 (en) * | 2008-01-15 | 2010-11-11 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| WO2013039187A1 (en) | 2011-09-15 | 2013-03-21 | アステラス製薬株式会社 | Guanidinobenzoic acid compound |
| WO2014142219A1 (en) | 2013-03-13 | 2014-09-18 | アステラス製薬株式会社 | Guanidinobenzoic acid ester compound |
| US9969705B2 (en) | 2014-02-13 | 2018-05-15 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compound |
| US10023544B2 (en) | 2014-02-13 | 2018-07-17 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
-
1994
- 1994-08-05 JP JP6204558A patent/JPH0848664A/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008508188A (en) * | 2004-07-27 | 2008-03-21 | アステラス製薬株式会社 | Thiazole derivatives having VAP-1 inhibitor activity |
| US20100286267A1 (en) * | 2008-01-15 | 2010-11-11 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| US8481595B2 (en) * | 2008-01-15 | 2013-07-09 | Wellstat Therapeutics Corporation | Compounds for the treatment of metabolic disorders |
| JP2010229141A (en) * | 2010-05-19 | 2010-10-14 | Sumitomo Chemical Co Ltd | Method for producing camostat hydrochloride |
| US9199927B2 (en) | 2011-09-15 | 2015-12-01 | Astellas Pharma Inc. | Guanidinobenzoic acid compound |
| WO2013039187A1 (en) | 2011-09-15 | 2013-03-21 | アステラス製薬株式会社 | Guanidinobenzoic acid compound |
| KR20140061515A (en) | 2011-09-15 | 2014-05-21 | 아스텔라스세이야쿠 가부시키가이샤 | Guanidinobenzoic acid compound |
| WO2014142219A1 (en) | 2013-03-13 | 2014-09-18 | アステラス製薬株式会社 | Guanidinobenzoic acid ester compound |
| KR20150130392A (en) | 2013-03-13 | 2015-11-23 | 아스텔라스세이야쿠 가부시키가이샤 | Guanidinobenzoic acid ester compound |
| US9969709B2 (en) | 2013-03-13 | 2018-05-15 | Takeda Pharmaceutical Company Limited | Guanidinobenzoic acid ester compound |
| CN105051008B (en) * | 2013-03-13 | 2018-05-29 | 武田药品工业株式会社 | Guanidinobenzoic acid ester compounds |
| US9969705B2 (en) | 2014-02-13 | 2018-05-15 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compound |
| US10023544B2 (en) | 2014-02-13 | 2018-07-17 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
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