JPH0820532A - Anti-pancreatitic agent - Google Patents
Anti-pancreatitic agentInfo
- Publication number
- JPH0820532A JPH0820532A JP15323794A JP15323794A JPH0820532A JP H0820532 A JPH0820532 A JP H0820532A JP 15323794 A JP15323794 A JP 15323794A JP 15323794 A JP15323794 A JP 15323794A JP H0820532 A JPH0820532 A JP H0820532A
- Authority
- JP
- Japan
- Prior art keywords
- group
- active ingredient
- salt
- acetimidoyl
- naphthyl
- 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.)
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- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、抗膵炎剤に関する。TECHNICAL FIELD The present invention relates to an anti-pancreatitis agent.
【０００２】[0002]
【０００３】抗膵炎剤としては、プロテア−ゼ阻害剤の
として、メシル酸カモスタット、メシル酸ナファモスタ
ット及びウリナスタチンが知られているが、作用・効果
の強さにおいて十分でない。また、十二指腸粘膜から分
泌され、膵外分泌を刺激するといわれているコレシスト
キニン（cholecystokinin；以下、ＣＣＫと略す。）拮
抗剤の開発が行われているが臨床での有用性は確立され
たものではなく、これらは十分な薬効が不明なことか
ら、新規化学構造をもつ有用な抗膵炎剤の開発がまたれ
るところである。As anti-pancreatitis agents, camostat mesylate, nafamostat mesylate and ulinastatin are known as protease inhibitors, but their actions and strengths are not sufficient. In addition, a cholecystokinin (hereinafter abbreviated as CCK) antagonist secreted by the duodenal mucosa and said to stimulate exocrine pancreas is being developed, but its clinical utility is not established. Nonetheless, since their sufficient drug efficacy is unknown, the development of useful anti-pancreatitis agents having a new chemical structure is being overtaken.
【０００４】[0004]
【発明が解決しようとする課題】副作用の少ない抗膵炎
剤であって、効力の強い新規化学構造を有する抗膵炎剤
を提供することである。SUMMARY OF THE INVENTION It is an object of the present invention to provide an anti-pancreatitis agent having few side effects and having a novel chemical structure with high potency.
【課題を解決するための手段】そこで、本発明者らは、
新たな抗膵炎剤を見いだすべく、鋭意研究を重ねた結
果、抗血液凝固作用を示す薬剤として知られている式
（１）で示される化合物群に優れた抗すい炎作用のある
ことを見いだし、発明を完成させた。Means for Solving the Problems Accordingly, the present inventors have:
As a result of intensive studies to find a new anti-pancreatitis agent, they found that the compound group represented by the formula (1), which is known as an agent having anticoagulant activity, has an excellent antipancreatic effect, Completed the invention.
【０００５】本発明は、次ぎの（１）から（１１）に関
する。 （１）本発明は、次の一般式（１）で表される芳香族ア
ミジン誘導体又はその塩を有効成分とする抗膵炎剤に関
する。The present invention relates to the following (1) to (11). (1) The present invention relates to an anti-pancreatitis agent containing an aromatic amidine derivative represented by the following general formula (1) or a salt thereof as an active ingredient.
【化４】 （式中の置換基の定義は次のとおりである。Ｒ１は水素
原子又はアルコキシル基を意味する。Ｒ２は水素原子、
アルキル基、アルコキシル基、カルボキシル基、アルコ
キシカルボニル基、カルボキシアルキル基、又はアルコ
キシカルボニルアルキル基を意味する。Ｒ３は水素原
子、カルボキシル基、アルコキシカルボニル基、カルボ
キシアルキル基、アルコキシカルボニルアルキル基、カ
ルボキシアルコキシル基、又はアルコキシカルボニルア
ルコキシル基を意味する。Ｒ４は水素原子、水酸基、ア
ルキル基、又はアルコキシル基を意味する。ｎは０乃至
４の整数を意味する。Ａは炭素数１乃至４のアルキレン
基を意味し、これは１個又は２個以上のヒドロキシアル
キル基、カルボキシル基、アルコキシカルボニル基、カ
ルボキシアルキル基、又はアルコキシカルボニルアルキ
ル基が置換していてもよい。Ｘは単結合、酸素原子、硫
黄原子、又はカルボニル基を意味する。Ｙは５若しくは
６員環の飽和若しくは不飽和環状炭化水素基、５若しく
は６員環の飽和若しくは不飽和複素環基、アミノ基、又
はアミノアルキル基、を意味し、これらはそれぞれが置
換基を有することがある。[Chemical 4] (The definition of the substituent in the formula is as follows. R 1 represents a hydrogen atom or an alkoxyl group. R 2 represents a hydrogen atom,
It means an alkyl group, an alkoxyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, or an alkoxycarbonylalkyl group. R 3 represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxyl group, or an alkoxycarbonylalkoxyl group. R 4 represents a hydrogen atom, a hydroxyl group, an alkyl group, or an alkoxyl group. n means an integer of 0 to 4. A represents an alkylene group having 1 to 4 carbon atoms, which may be substituted with one or more hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups, or alkoxycarbonylalkyl groups. . X means a single bond, an oxygen atom, a sulfur atom, or a carbonyl group. Y represents a 5- or 6-membered saturated or unsaturated cyclic hydrocarbon group, a 5- or 6-membered saturated or unsaturated heterocyclic group, an amino group, or an aminoalkyl group, each of which is a substituent. I may have.
【化５】 で表される基は、インドリル基、インドリニル基、ベン
ゾフラニル基、ベンゾチエニル基、ベンズオキサゾリル
基、ベンズイミダゾリル基、ベンゾチアゾリル基、ナフ
チル基、テトラヒドロナフチル基、インデニル基、又は
インダニル基、を意味する。）で表される化合物又はそ
の塩を有効成分とする抗膵炎剤。また、（２）本発明
は、一般式（１）中、Embedded image The group represented by means an indolyl group, an indolinyl group, a benzofuranyl group, a benzothienyl group, a benzoxazolyl group, a benzimidazolyl group, a benzothiazolyl group, a naphthyl group, a tetrahydronaphthyl group, an indenyl group, or an indanyl group. . ) An anti-pancreatitis agent comprising a compound represented by the formula (4) or a salt thereof as an active ingredient. Further, (2) the present invention provides the compound represented by the general formula (1):
【化６】 で表される基が、ナフチル、ベンゾチエニル、又はイン
ドリル基である請求項１記載の化合物又はその塩を有効
成分とする抗膵炎剤に関する。また、本発明は、Ｙが、
置換基を有していてもよい飽和若しくは不飽和の５若し
くは６員環の複素環基又は置換基を有していてもよい飽
和若しくは不飽和の５若しくは６員環の環状炭化水素基
である請求項１記載の抗膵炎剤：Ｙが、アセトイミドイ
ル基を有する５若しくは６員環の複素環基又はアセトイ
ミドイル基を有する５若しくは６員環の環状炭化水素基
である請求項３記載の抗膵炎剤：飽和若しくは不飽和の
５若しくは６員環の複素環基が、ヘテロ原子として１若
しくは２個の窒素原子、又は／及び、１若しくは２個の
酸素原子を含む請求項４記載の抗膵炎剤に関する。ま
た、本発明は、（２Ｓ）−２−［４−［［（３Ｓ）−１
−アセトイミドイル−３−ピロリジニル］オキシ］フェ
ニル］−３−（７−アミジノ−２−ナフチル）プロピオ
ン酸又はその塩を有効成分とする抗膵炎剤：２−［４−
［（１−アセトイル−３−ピロリジニル）オキシ］フェ
ニル］−３−（７−アミジノ−２−ナフチル）プロピオ
ン酸又はその塩を有効成分とする抗膵炎剤：（＋）−２
−［４−［［（３Ｓ）−１−アセトイミドイル−３−ピ
ロリジニル］オキシ］フェニル］−３−（７−アミジノ
−２−ナフチル）プロピオン酸又はその塩を有効成分と
する抗膵炎剤：（２Ｒ）−２−［４−［［（３Ｒ）−１
−アセトイミドイル−３−ピロリジニル］オキシ］フェ
ニル］−３−（７−アミジノ−２−ナフチル）プロピオ
ン酸又はその塩を有効成分とする抗膵炎剤：２−［４−
［（１−アセトイミドイル−２−ピロリジニル）メトキ
シ］フェニル］−３−（５−アミジノベンゾ［ｂ］チエ
ン−２−イル）プロピオン酸又はその塩を有効成分とす
る抗膵炎剤：（＋）−２−［４−［［（２Ｓ）−１−ア
セトイミドイル−２−ピロリジニル］メトキシ］フェニ
ル］−３−（５−アミジノベンゾ［ｂ］チエン−２−イ
ル）プロピオン酸又はその塩を有効成分とする抗膵炎
剤：２−［４−［（１−アセトイミドイル−４−ピペリ
ジニル）オキシ］フェニル］−３−（７−アミジノ−２
−ナフチル）プロピオン酸又はその塩を有効成分とする
抗膵炎剤：（＋）−２−［４−［（１−アセトイミドイ
ル−４−ピペリジニル）オキシ］フェニル］−３−（７
−アミジノ−２−ナフチル）プロピオン酸又はその塩を
有効成分とする抗膵炎剤に関する。[Chemical 6] A group represented by is a naphthyl, benzothienyl, or indolyl group, and relates to an anti-pancreatitis agent comprising the compound or a salt thereof as an active ingredient. Further, in the present invention, Y is
It is a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent or a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent. The anti-pancreatitis agent according to claim 1, wherein Y is a 5- or 6-membered heterocyclic group having an acetimidoyl group or a 5- or 6-membered cyclic hydrocarbon group having an acetimidoyl group. 5. The anti-pancreatitis agent according to claim 4, wherein the saturated or unsaturated 5- or 6-membered heterocyclic group contains 1 or 2 nitrogen atoms as heteroatoms, and / or 1 or 2 oxygen atoms. It relates to an anti-pancreatitis agent. The present invention also provides (2S) -2- [4-[[(3S) -1.
-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof as an active ingredient: anti-pancreatitis agent: 2- [4-
An anti-pancreatitis agent containing [(1-acetoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof as an active ingredient: (+)-2
An anti-pancreatitis agent containing-[4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof as an active ingredient: (2R) -2- [4-[[(3R) -1
-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof as an active ingredient: anti-pancreatitis agent: 2- [4-
Anti-pancreatitis agent containing [(1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid or a salt thereof as an active ingredient: (+) 2- [4-[[(2S) -1-acetimidoyl-2-pyrrolidinyl] methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid or a salt thereof is effective Anti-pancreatitis agent as a component: 2- [4-[(1-acetimidoyl-4-piperidinyl) oxy] phenyl] -3- (7-amidino-2
-Naphthyl) propionic acid or a salt thereof as an active ingredient: an anti-pancreatitis agent: (+)-2- [4-[(1-acetimidoyl-4-piperidinyl) oxy] phenyl] -3- (7
-Amidino-2-naphthyl) propionic acid or a salt thereof as an active ingredient.
【００１２】ここで、上記（１）から（１２）に記載し
た本発明の抗膵炎剤に含まれる有効成分とする化合物
は、それぞれに記載した、化合物そのもの、それらの
塩、水和物若しくはそれらの組合せを含むものとする。Here, the compounds as the active ingredient contained in the anti-pancreatitis agent of the present invention described in the above (1) to (12) are the compounds themselves, their salts, hydrates or the same. The combination of
【００１３】式（１）で示される本発明の抗膵炎剤に係
る化合物の製造方法は、特開平５−２０８９４６号及び
特願平第５−１７５６３６号に記載の製造方法により得
ることができる。The method for producing the compound relating to the anti-pancreatitis agent of the present invention represented by the formula (1) can be obtained by the production methods described in JP-A-5-208946 and Japanese Patent Application No. 5-175636.
【００１４】かくして得られた芳香族アミジン誘導体
（１）及びその塩は、特異的かつ優れた抗膵炎作用を有
し、膵炎の治療薬として有用である。この化合物（１）
は、経口投与でも効果を発揮するため、経口、非経口投
与のいずれの投与経路によっても有効性を得ることがで
きる。化合物（１）の投与量は、経口投与或は非経口投
与においても、患者の症状、年齢、体重、膵炎の症状の
程度等により適宜、増減することができる。一般的には
経口投与の場合、成人一人当たり５〜１０００ｍｇ／
日、好ましくは１０〜５００ｍｇ／日が適当である。投
与剤形としては錠剤、カプセル剤、散剤、顆粒剤等、を
挙げることができる。これらは、通常の賦形剤、滑沢
剤、結合剤等の添加剤と共に、公知の製剤技術により製
造することができる。また、非経口投与の場合成人一人
当たり、０．１〜１００ｍｇ／日、好ましくは０．５〜
３０ｍｇ／日を皮下投与、皮内投与、静脈内投与、点滴
静脈内投与、坐薬等による直腸内投与等により適用する
ことができる。The aromatic amidine derivative (1) and its salt thus obtained have a specific and excellent anti-pancreatitis action and are useful as a therapeutic drug for pancreatitis. This compound (1)
Since it exhibits its effect even when it is orally administered, the efficacy can be obtained by any of the administration routes of oral and parenteral administration. The dose of the compound (1) can be appropriately increased or decreased depending on the patient's condition, age, body weight, degree of pancreatitis, etc. even in oral or parenteral administration. Generally, in the case of oral administration, 5-1000 mg / adult per adult
A day, preferably 10-500 mg / day is suitable. Examples of the dosage form include tablets, capsules, powders, granules and the like. These can be produced by known formulation techniques together with usual excipients, lubricants, additives such as binders and the like. In the case of parenteral administration, 0.1 to 100 mg / day, preferably 0.5 to 0.5, per adult
30 mg / day can be applied by subcutaneous administration, intradermal administration, intravenous administration, intravenous drip administration, rectal administration by suppository, etc.
【００１５】[0015]
【発明の効果】本発明の化合物は優れた抗膵炎作用を示
す。この作用は、抗プロテア−ゼ作用に基づくものと考
えられる。この作用は、セルレイン（ｃａｅｒｕｌｅｉ
ｎ）投与動物における膵炎モデルにおいて、経口投与に
より治療効果が認められる。The compound of the present invention exhibits excellent anti-pancreatitis action. This action is considered to be based on the antiprotease action. This action is called caerulei.
n) In the pancreatitis model in the treated animal, a therapeutic effect is observed by oral administration.
【００１６】[0016]
実施例 １ （１） 実験に用いたラットは、Ｓｌｃ：ＳＤ系ラット
（体重１５０ 〜１９０ｇ、６週齢、雄）をエスエルシ
−より購入し、１週間の訓化後に実験に用いた。実験に
用いたこれらのラットは、湿度２３±２℃、相対湿度５
５±１５％、照明午前８時から午後８時までの一定環境
下に飼育した。ラットに膵炎モデルをつくるために、神
経ペプチド（消化管ペプチド）であるＣＣＫの分泌促進
のためトリプシン分泌亢進をもたらし、膵臓等に炎症に
至らしめるとされているセルレイン（caerulein；シグ
マ社製）を用いた。セルレインを０．２５％ＢＳＡ（牛
血清アルブミン）含有生理食塩水に溶解し、ラットの背
部皮下に、１０μｇ／２ｍｇ／ｋｇを１時間毎に４回に
分けて投与した。初回投与の２及び４時間後に尾静脈よ
り、６時間後の屠殺時には腹大静脈より採血した。屠殺
後、膵臓を摘出して、重量を測定すると共に、一部の組
織を鏡検用標本として採取した。血液は遠心後、血清を
採取し、総蛋白量、アミラ−ゼ、及びリパ−ゼ活性を測
定した。有効性試験に用いた抗膵炎作用をもつ検体は、
請求項４に示す、（２Ｓ）−２−［４−［［（３Ｓ）−
１−アセトイミドイル−３−ピロジニル］オキシ］フェ
ニル」−３−（７−アミジノ−２−ナフチル）プロピオ
ン酸（以下、この化合物を化合物Ａと称する。）を用い
た。無処理動物を正常対照群とし、セルレインのみ投与
した動物を病態対照群とし、セルレイン投与後、化合物
Ａ投与動物を、検体治療群とし、それらの膵炎治療効果
を比較した。病理組織学的検査については、採取した膵
臓は直ちに、１０％ホルマリンで固定し、包埋薄切後、
ヘマトキシリン・エオシン染色を施し、光学顕微鏡によ
り観察した。病理所見は各病変毎に、−（変化なし）、
±（極微小変化）、＋（微小変化）、＋＋（中程度変
化）の４段階で表した。Example 1 (1) As the rat used in the experiment, Slc: SD strain rat (body weight 150 to 190 g, 6 weeks old, male) was purchased from SLC, and used for the experiment after 1 week of training. These rats used in the experiment had a humidity of 23 ± 2 ° C. and a relative humidity of 5
The animals were bred under a constant environment of 5 ± 15% and lighting from 8 am to 8 pm. In order to create a pancreatitis model in rats, caerulein (caerulein; manufactured by Sigma), which is said to induce trypsin secretion to promote secretion of CCK which is a neuropeptide (gastrointestinal peptide) and causes inflammation in pancreas etc. Using. Cerulein was dissolved in physiological saline containing 0.25% BSA (bovine serum albumin), and 10 μg / 2 mg / kg was subcutaneously administered to the back of the rat in 4 divided doses every hour. Blood was collected from the tail vein 2 and 4 hours after the first administration, and from the abdominal vena cava at the time of sacrifice 6 hours later. After the sacrifice, the pancreas was removed, the weight was measured, and a part of the tissue was collected as a specimen for microscopic examination. Blood was centrifuged and serum was collected to measure total protein amount, amylase, and lipase activity. The samples with anti-pancreatitis effect used in the efficacy test are
(2S) -2- [4-[[(3S)-
1-acetimidoyl-3-pyridinyl] oxy] phenyl "-3- (7-amidino-2-naphthyl) propionic acid (hereinafter, this compound is referred to as compound A) was used. The untreated animals were used as the normal control group, the animals administered with cerulein alone were used as the pathological condition control group, and the animals treated with Compound A after administration of cerulein were used as the specimen treatment group, and their therapeutic effects on pancreatitis were compared. Regarding histopathological examination, the collected pancreas was immediately fixed with 10% formalin, and after embedding thin section,
The cells were stained with hematoxylin / eosin and observed with an optical microscope. The pathological findings were − (no change) for each lesion,
It was expressed in four stages: ± (very small change), + (small change), and ++ (medium change).
【００１７】（２） 正常対照動物（ラット）に対し、
セルレイン投与した病態対照動物（ラット）では明かに
膵臓重量の増加が認められた。この障害ラットに化合物
Ａを３０ｍｇ／ｋｇ、１００ｍｇ／ｋｇ 又は３００ｍ
ｇ／ｋｇ を各々投与した。正常対照動物の膵臓の相対
重量が０．３７（％）であり、セルレイン投与病態動物
の膵臓相対重量が０．７６（％）であるとき、本発明に
かかる化合物Ａの３０ｍｇ／ｋｇを投与した動物では膵
臓相対重量が０．６２（％）（３６％）であり、１００
ｍｇ／ｋｇ 投与した動物では膵臓・相対重量が ０．
４９（％）（４９％）であり、また、３００ｍｇ／ｋｇ
を投与した動物では膵臓・相対重量が０．３８％（９７
％）であった。これらの投与量においては、ほぼ用量依
存的に膵臓重量の増加抑制が有意に認められた。(2) For a normal control animal (rat),
An increase in pancreas weight was clearly observed in the disease control animals (rats) administered with cerulein. Compound A was added to this injured rat at 30 mg / kg, 100 mg / kg or 300 m
g / kg was administered each. When the relative weight of the pancreas of the normal control animal was 0.37 (%) and the relative weight of the pancreas of the pathological animal treated with cerulein was 0.76 (%), 30 mg / kg of the compound A according to the present invention was administered. In animals, the relative pancreas weight was 0.62 (%) (36%),
In animals dosed with mg / kg, the pancreas and relative weight are 0.
49 (%) (49%) and also 300 mg / kg
Pancreatic relative weight of 0.38% (97
%)Met. At these doses, the increase in pancreatic weight was significantly suppressed in a dose-dependent manner.
【００１８】（３）病理組織学的検討 病態対照群では腺房細胞内空胞形成および間質性浮腫が
顕著であり、間質性細胞浸潤、トモ−ゲン顆粒の減少お
よび間質性出血も認められた。このような病態動物に化
合物Ａを投与すると３０ｍｇ／ｋｇより浮腫の減少傾向
及び明かな細胞浸潤の軽減が観察された。更に、１００
ｍｇ／ｋｇ投与より腺房細胞内空胞形成の抑制およびチ
モ−ゲン顆粒の減少の抑制傾向が観察された（表２−１
及び２−２）。(3) Histopathological Examination In the pathological control group, vacuolar formation in acinar cells and interstitial edema were remarkable, and interstitial cell infiltration, reduction of tomogen granules and interstitial hemorrhage were also observed. Admitted. When compound A was administered to such pathological animals, a decrease tendency of edema and a clear decrease of cell infiltration were observed from 30 mg / kg. Furthermore, 100
From the administration of mg / kg, a tendency to suppress vacuolar formation in acinar cells and a decrease in zymogen granules was observed (Table 2-1).
And 2-2).
【００１９】[0019]
【表１】 [Table 1]
【００２０】[0020]
【表２】 [Table 2]
【００２１】[0021]
【表３】 [Table 3]
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 31/40 31/415 31/42 31/425 31/445 // Ｃ０７Ｄ 207/12 211/46 263/56 277/64 333/58 333/64 333/68 409/12 ２１１ Continuation of the front page (51) Int.Cl. 6 Identification number Reference number within the agency FI Technical indication location A61K 31/40 31/415 31/42 31/425 31/445 // C07D 207/12 211/46 263/56 277/64 333/58 333/64 333/68 409/12 211
Claims (13)
ジン誘導体又はその塩を有効成分とする抗膵炎剤 【化１】 （式中の置換基の定義は次のとおりである。Ｒ１は水素
原子又はアルコキシル基を意味する。Ｒ２は水素原子、 アルキル基、 アルコキシル基、 カルボキシル基、 アルコキシカルボニル基、 カルボキシアルキル基、又はアルコキシカルボニルアル
キル基を意味する。Ｒ３は水素原子、 カルボキシル基、 アルコキシカルボニル基、 カルボキシアルキル基、 アルコキシカルボニルアルキル基、 カルボキシアルコキシル基、又はアルコキシカルボニル
アルコキシル基を意味する。Ｒ４は水素原子、 水酸基、 アルキル基、又はアルコキシル基を意味する。ｎは０乃
至４の整数を意味する。Ａは炭素数１乃至４のアルキレ
ン基を意味し、これは１個又は２個以上のヒドロキシア
ルキル基、 カルボキシル基、 アルコキシカルボニル基、 カルボキシアルキル基、又はアルコキシカルボニルアル
キル基が置換していてもよい。Ｘは単結合、 酸素原子、 硫黄原子、又はカルボニル基を意味する。Ｙは５若しく
は６員環の飽和若しくは不飽和環状炭化水素基、 ５若しくは６員環の飽和若しくは不飽和複素環基、 アミノ基、又はアミノアルキル基、を意味し、 これらはそれぞれが置換基を有することがある。 【化２】 で表される基は、 インドリル基、 インドリニル基、 ベンゾフラニル基、 ベンゾチエニル基、 ベンズオキサゾリル基、 ベンズイミダゾリル基、 ベンゾチアゾリル基、 ナフチル基、 テトラヒドロナフチル基、 インデニル基、又はインダニル基、を意味する。）1. An anti-pancreatitis agent comprising an aromatic amidine derivative represented by the following general formula (1) or a salt thereof as an active ingredient: (The definition of the substituent in the formula is as follows. R 1 represents a hydrogen atom or an alkoxyl group. R 2 represents a hydrogen atom, an alkyl group, an alkoxyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, R 3 represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxyl group, or an alkoxycarbonylalkoxyl group, and R 4 represents a hydrogen atom, It means a hydroxyl group, an alkyl group, or an alkoxyl group, n means an integer of 0 to 4, A means an alkylene group having 1 to 4 carbon atoms, and this means one or more hydroxyalkyl groups, Carboxyl group, alkoxycarbonyl group, carboxy Syalkyl group or alkoxycarbonylalkyl group may be substituted, X represents a single bond, oxygen atom, sulfur atom, or carbonyl group, and Y represents a 5- or 6-membered saturated or unsaturated cyclic hydrocarbon group. , A 5- or 6-membered saturated or unsaturated heterocyclic group, an amino group, or an aminoalkyl group, each of which may have a substituent. The group represented by means an indolyl group, an indolinyl group, a benzofuranyl group, a benzothienyl group, a benzoxazolyl group, a benzimidazolyl group, a benzothiazolyl group, a naphthyl group, a tetrahydronaphthyl group, an indenyl group, or an indanyl group. . )
インドリル基である請求項１記載のアミジン誘導体又は
その塩を有効成分とする抗膵炎剤2. In the general formula (1), The group represented by is a naphthyl group, a benzothienyl group, or an indolyl group, and an antipancreatitis agent containing the amidine derivative or a salt thereof as an active ingredient.
しくは不飽和の５若しくは６員環の複素環基又は置換基
を有していてもよい飽和若しくは不飽和の５若しくは６
員環の環状炭化水素基である請求項１記載の抗膵炎剤3. Y is a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, or saturated or unsaturated 5 or 6 which may have a substituent.
The anti-pancreatitis agent according to claim 1, which is a cyclic hydrocarbon group having a member ring.
しくは６員環の複素環基又はアセトイミドイル基を有す
る５若しくは６員環の環状炭化水素基である請求項３記
載の抗膵炎剤4. The anti-pancreatitis agent according to claim 3, wherein Y is a 5- or 6-membered heterocyclic group having an acetimidoyl group or a 5- or 6-membered cyclic hydrocarbon group having an acetimidoyl group.
の複素環基が、ヘテロ原子として１若しくは２個の窒素
原子、又は／及び、１若しくは２個の酸素原子を含む請
求項４記載の抗膵炎剤5. The saturated or unsaturated 5- or 6-membered heterocyclic group contains 1 or 2 nitrogen atoms as hetero atoms, and / or 1 or 2 oxygen atoms. Anti-pancreatitis
−アセトイミドイル−３−ピロリジニル］オキシ］フェ
ニル］−３−（７−アミジノ−２−ナフチル）プロピオ
ン酸又はその塩を有効成分とする抗膵炎剤6. (2S) -2- [4-[[(3S) -1
-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof as an active ingredient
３−ピロリジニル）オキシ］フェニル］−３−（７−ア
ミジノ−２−ナフチル）プロピオン酸又はその塩を有効
成分とする抗膵炎剤7. 2- [4-[(1-acetimidoyl-
Anti-pancreatitis agent containing 3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof as an active ingredient
アセトイミドイル−３−ピロリジニル］オキシ］フェニ
ル］−３−（７−アミジノ−２−ナフチル）プロピオン
酸又はその塩を有効成分とする抗膵炎剤8. (+)-2- [4-[[(3S) -1-
Anti-pancreatitis agent containing acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof as an active ingredient
−アセトイミドイル−３−ピロリジニル］オキシ］フェ
ニル］−３−（７−アミジノ−２−ナフチル）プロピオ
ン酸又はその塩を有効成分とする抗膵炎剤9. (2R) -2- [4-[[(3R) -1
-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof as an active ingredient
−２−ピロリジニル）メトキシ］フェニル］−３−（５
−アミジノベンゾ［ｂ］チエン−２−イル）プロピオン
酸又はその塩を有効成分とする抗膵炎剤10. 2- [4-[(1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5
-Antipancreatitis agent containing amidinobenzo [b] thien-2-yl) propionic acid or a salt thereof as an active ingredient
−アセトイミドイル−２−ピロリジニル］メトキシ］フ
ェニル］−３−（５−アミジノベンゾ［ｂ］チエン−２
−イル）プロピオン酸又はその塩を有効成分とする抗膵
炎剤11. (+)-2- [4-[[(2S) -1)
-Acetimidoyl-2-pyrrolidinyl] methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2
-Yl) an anti-pancreatitis agent containing propionic acid or a salt thereof as an active ingredient
−４−ピペリジニル）オキシ］フェニル］−３−（７−
アミジノ−２−ナフチル）プロピオン酸又はその塩を有
効成分とする抗膵炎剤12. 2- [4-[(1-acetimidoyl-4-piperidinyl) oxy] phenyl] -3- (7-
Anti-pancreatitis agent containing amidino-2-naphthyl) propionic acid or a salt thereof as an active ingredient
ミドイル−４−ピペリジニル）オキシ］フェニル］−３
−（７−アミジノ−２−ナフチル）プロピオン酸又はそ
の塩を有効成分とする抗膵炎剤13. (+)-2- [4-[(1-acetimidoyl-4-piperidinyl) oxy] phenyl] -3
-An anti-pancreatitis agent containing (7-amidino-2-naphthyl) propionic acid or a salt thereof as an active ingredient
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15323794A JPH0820532A (en) | 1994-07-05 | 1994-07-05 | Anti-pancreatitic agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15323794A JPH0820532A (en) | 1994-07-05 | 1994-07-05 | Anti-pancreatitic agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0820532A true JPH0820532A (en) | 1996-01-23 |
Family
ID=15558059
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15323794A Pending JPH0820532A (en) | 1994-07-05 | 1994-07-05 | Anti-pancreatitic agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0820532A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000073270A1 (en) * | 1999-05-31 | 2000-12-07 | Daiichi Pharmaceutical Co., Ltd. | Remedies for periodontal diseases |
| US6562828B1 (en) | 1998-04-10 | 2003-05-13 | Japan Tobacco Inc. | Amidine compounds |
| KR100469028B1 (en) * | 1996-05-31 | 2005-07-07 | 주식회사 씨앤드씨신약연구소 | Aromatic amidine derivatives useful as selective thrombin inhibitors |
| US7834037B2 (en) | 2005-11-04 | 2010-11-16 | Amira Pharmaceuticals, Inc. | 5-lipoxygenase-activating protein (FLAP) inhibitors |
| US7977359B2 (en) | 2005-11-04 | 2011-07-12 | Amira Pharmaceuticals, Inc. | 5-lipdxygenase-activating protein (FLAP) inhibitors |
| CN102225903A (en) * | 2011-04-21 | 2011-10-26 | 田伏洲 | Amidino guanido substituted aromatic heterocyclic copmound and synthesis and use thereof |
| US8399666B2 (en) | 2005-11-04 | 2013-03-19 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
| US8546431B2 (en) | 2008-10-01 | 2013-10-01 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
| US8697730B2 (en) | 2007-10-26 | 2014-04-15 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase activating protein (FLAP) inhibitor |
| US8772495B2 (en) | 2008-05-23 | 2014-07-08 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein inhibitor |
-
1994
- 1994-07-05 JP JP15323794A patent/JPH0820532A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100469028B1 (en) * | 1996-05-31 | 2005-07-07 | 주식회사 씨앤드씨신약연구소 | Aromatic amidine derivatives useful as selective thrombin inhibitors |
| US6562828B1 (en) | 1998-04-10 | 2003-05-13 | Japan Tobacco Inc. | Amidine compounds |
| WO2000073270A1 (en) * | 1999-05-31 | 2000-12-07 | Daiichi Pharmaceutical Co., Ltd. | Remedies for periodontal diseases |
| US7834037B2 (en) | 2005-11-04 | 2010-11-16 | Amira Pharmaceuticals, Inc. | 5-lipoxygenase-activating protein (FLAP) inhibitors |
| US7977359B2 (en) | 2005-11-04 | 2011-07-12 | Amira Pharmaceuticals, Inc. | 5-lipdxygenase-activating protein (FLAP) inhibitors |
| US8399666B2 (en) | 2005-11-04 | 2013-03-19 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
| US8710081B2 (en) | 2005-11-04 | 2014-04-29 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
| US8841295B2 (en) | 2005-11-04 | 2014-09-23 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
| US8697730B2 (en) | 2007-10-26 | 2014-04-15 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase activating protein (FLAP) inhibitor |
| US8772495B2 (en) | 2008-05-23 | 2014-07-08 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein inhibitor |
| US8546431B2 (en) | 2008-10-01 | 2013-10-01 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
| CN102225903A (en) * | 2011-04-21 | 2011-10-26 | 田伏洲 | Amidino guanido substituted aromatic heterocyclic copmound and synthesis and use thereof |
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