JPH0366628A - Gastrointestinal motility activator - Google Patents
Gastrointestinal motility activatorInfo
- Publication number
- JPH0366628A JPH0366628A JP20255689A JP20255689A JPH0366628A JP H0366628 A JPH0366628 A JP H0366628A JP 20255689 A JP20255689 A JP 20255689A JP 20255689 A JP20255689 A JP 20255689A JP H0366628 A JPH0366628 A JP H0366628A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- active ingredient
- gastrointestinal motility
- methyl
- amino
- 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.)
- Granted
Links
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
【発明の詳細な説明】 ［産業上の利用分野］ 本発明は、新規な消化管運動賦活剤に関する。[Detailed description of the invention] [Industrial application field] The present invention relates to a novel gastrointestinal motility activator.
［発明の背景］
食欲不振、悪心、嘔吐、腹部膨満感、上腹部不快感、胸
やけ、などの消化器系不定愁訴症状の一因として、消化
管運動機能の低下が挙げられる。[Background of the Invention] Decline in gastrointestinal motor function is one of the causes of indeterminate gastrointestinal symptoms such as anorexia, nausea, vomiting, abdominal distension, upper abdominal discomfort, and heartburn.
従って、これらの症状を除くために、胃や腸などの運動
を亢進する消化管運動賦活作用を有する薬剤を投与する
ことが有効であると考えられる。Therefore, in order to eliminate these symptoms, it is considered effective to administer a drug that has a gastrointestinal motility activating effect that enhances the motility of the stomach, intestines, etc.
消化管運動賦活作用を有する薬剤として、例えば、−数
名メトクロプラミド、−数名ドンベリドン、特開平１−
９３５６８号公報に記載のアミド化合物などが知られて
いるが、薬効、安全性などの点において必ずしも十分満
足し得るものとは言えない。Examples of drugs having a gastrointestinal motility activation effect include metoclopramide, dombelidone, and JP-A-1-
Although amide compounds such as those described in Japanese Patent No. 93568 are known, they are not necessarily fully satisfactory in terms of medicinal efficacy, safety, and the like.
本発明者らは、消化管の運動機作について鋭意研究した
結果、グルタミン酸拮抗剤であって、且つグルタミン酸
受容体の活性物質であるＮ−メチル−Ｄ−アスパラギン
酸の神経興奮作用を選択的に抑制し得る拮抗様式の物質
が、優れた消化管運動賦活作用を有することを見出し本
発明を完成した。As a result of extensive research into the motor mechanisms of the gastrointestinal tract, the present inventors have discovered that the neuroexcitatory effects of N-methyl-D-aspartate, which is a glutamate antagonist and an active substance of glutamate receptors, can be selectively inhibited. The present invention was completed by discovering that a substance that can be suppressed in an antagonistic manner has an excellent effect of activating gastrointestinal motility.
グルタミン酸受容体の機能に関与する物質については種
々の検討がなされているが、これらの物質が消化管運動
に対して作用を及ぼすことは全く知られていない。Although various studies have been conducted on substances involved in the function of glutamate receptors, it is completely unknown that these substances have an effect on gastrointestinal motility.
［問題点を解決するための手段］
本発明は、グルタミン酸拮抗剤であって且つＮ−メチル
−Ｄ−アスパラギン酸による神経興奮作用を選択的に抑
制し得る物質を有効成分として含有することを特徴とす
る消化管運動賦活剤である。[Means for Solving the Problems] The present invention is characterized in that it contains as an active ingredient a substance that is a glutamate antagonist and can selectively suppress the nerve excitatory effect caused by N-methyl-D-aspartic acid. It is a gastrointestinal motility activator.
本発明における有効成分は、グルタミン酸拮抗剤であっ
て、且つ、Ｎ−メチル−〇−アスパラギン酸による神経
興奮作用を選択的に抑制し得る物質である。（Ｒ，Ｌ、
Ｊｏｈｎｓｏｎら、Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉ−
ｃｉｎａｌ Ｃｈｅａ＋１ｓｔｒｙ、 １９８８． ｖ
ｏｌ、３１． Ｎｏ、１１．ｐ、２０５７−２０６６及
び、Ｊ、ＣＪａｔｋｉｎｓ、Ｎｅｕｒｏｔｏｘ’８８：
Ｍｏ１ｅｃｕｌａｒＢａｓｉｓ ｏｆ Ｄｒｕｇ ＆
Ｐｅ５ｔｉｃｉｄｅ Ａｃｔｉｏｎ、 ｐ、４４５−
４５９参照）。本発明における有効成分はこのような性
質を有するものであればよいが、特に好ましい物質の例
としては、
３−（（±）−２−カルボキシピペラジン−４−イル）
−プロピル−１−ホスホン酸、ＤＬ−２−アミノ−７−
ホスホノヘプタン酸、ＤＬ−２−アミノ−５−ホスホノ
ペンタン酸、Ｄ−α−アミノアジピン酸、
２−（２−クロロフェニル）−２−（メチルアミノ）シ
クロヘキサノン、
（±）−１０，１１−ジヒドロ−５−メチル−５Ｈ−ジ
ベンゾ［ａ、ｄ］シクロヘプテン−５゜１０−イミン、
及び、
ｃｉｓ−４−ホスホノメチル−２−ピペリジンカルボン
酸を挙げることができる。The active ingredient in the present invention is a glutamate antagonist and a substance capable of selectively suppressing the neuroexcitatory effect of N-methyl-〇-aspartic acid. (R,L,
Johnson et al., Journal of Medi-
cinal Chea+1stry, 1988. v
ol, 31. No, 11. p, 2057-2066 and J, C Jatkins, Neurotox'88:
Molecular Basis of Drug &
Pe5ticide Action, p, 445-
459). The active ingredient in the present invention may be any substance having such properties, but particularly preferred examples include 3-((±)-2-carboxypiperazin-4-yl)
-Propyl-1-phosphonic acid, DL-2-amino-7-
Phosphonoheptanoic acid, DL-2-amino-5-phosphonopentanoic acid, D-α-aminoadipic acid, 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone, (±)-10,11- dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5°10-imine,
and cis-4-phosphonomethyl-2-piperidinecarboxylic acid.
本発明における有効成分は、遊離体の形であってもよく
、また、その薬理学的に許容され得る塩であってもよい
。このような塩としては、無機酸（例、塩酸、硫酸、燐
酸、）又は有機酸（例、酢酸、プロピオン酸、クエン酸
、酒石酸、リンゴ酸、シュウ酸、メタンスルホン酸）等
の塩のような酸付加塩や、ナトリウム塩、カリウム塩、
トリエチルアミン塩等のような塩基性塩が挙げられる。The active ingredient in the present invention may be in the form of a free form or a pharmacologically acceptable salt thereof. Such salts include salts of inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, etc.) or organic acids (e.g., acetic acid, propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, methanesulfonic acid), etc. acid addition salts, sodium salts, potassium salts,
Basic salts such as triethylamine salts and the like can be mentioned.
本発明における有効成分は公知の物質であり、それ自体
公知の方法により製造したり入手することができる。例
えば、３−（（±）−２−カルボキシピペラジン−４−
イル）−プロピル−１−ホスホン酸はヨーロッパ特許出
願第１５９８８９号公報、ＤＬ−２−アミノ−７−ホス
ホノヘプタン酸は特開昭５８−１３１９５８号公報、（
±）−１０，１１−ジヒドロ−５−メチル−５Ｈ−ジベ
ンゾ［ａ、ｄｌシクロヘプテン−５，１０−イミンは特
開昭５４−６３１００号公報、そして、２（２−クロロ
フェニル）−２−（メチルアミノ）シクロヘキサノンは
米国特許第３２５４１２４号明細書等に記載の方法によ
り得られる。しかしながら、これらの物質が消化管運動
賦活作用を有することについては知られていない。The active ingredient in the present invention is a known substance and can be produced or obtained by a method known per se. For example, 3-((±)-2-carboxypiperazine-4-
yl)-propyl-1-phosphonic acid is disclosed in European Patent Application No. 159889, and DL-2-amino-7-phosphonoheptanoic acid is disclosed in JP-A-58-131958, (
±)-10,11-dihydro-5-methyl-5H-dibenzo[a,dl cyclohepten-5,10-imine is disclosed in JP-A-54-63100, and 2(2-chlorophenyl)-2-(methyl Amino)cyclohexanone can be obtained by the method described in US Pat. No. 3,254,124 and the like. However, it is not known that these substances have a gastrointestinal motility activating effect.
本発明における有効成分が優れた消化管運動賦活作用を
有することを下記の実験により示す。The following experiment shows that the active ingredient of the present invention has an excellent effect of activating gastrointestinal motility.
［実験方法］
Ｗ ｉ ｓ ｔ ａ ｒ系雄性ラットを２４時間絶食し
、ウレタン（１，２ｇ／ｋｇ、ｓ、ｃ、）で麻酔した。[Experimental Method] Wistar male rats were fasted for 24 hours and anesthetized with urethane (1.2 g/kg, s, c,).
腹部を正中線に沿って切開して胃を露出させ、前胃に小
孔を開け、小バルーンを挿入した。An abdominal incision was made along the midline to expose the stomach, a small hole was made in the forestomach, and a small balloon was inserted.
バルーンに５０ｍＨ２Ｏの圧負荷をかけ、１５Ｎ３０分
間放置したのち、胃の自発運動をバルーンの内圧変化と
して圧トランジューサーを介して測定した。After applying a pressure load of 50 mH2O to the balloon and leaving it for 30 minutes under 15N, spontaneous movement of the stomach was measured as a change in the internal pressure of the balloon via a pressure transducer.
薬物（上記有効成分）は、生理食塩液に溶解し、ＮａＯ
ＨでｐＨを７に調整したのち、大腿静脈より投与した。The drug (the above active ingredient) is dissolved in physiological saline and NaO
After adjusting the pH to 7 with H, it was administered through the femoral vein.
［実験成Ｍ］
本発明の有効成分は、いずれも低用量で胃の自発運動を
増強させた。胃の自発運動を増強させるための最小有効
量は、下記第１表に示す通りであった。[Experimental Preparation M] The active ingredients of the present invention all enhanced the spontaneous movement of the stomach at low doses. The minimum effective doses for enhancing gastric locomotor activity were as shown in Table 1 below.
第 １
表
有効成分
最小有効量（ｍｇ／ｋｇ、 ｉ、ｖ、）０ 、２５
０
０ 、０１
０ 、５
Ａ：３−（（±）−２−カルボキシピペラジン−４−イ
ル）−プロピル−１−ホスホン酸Ｂ：ＤＬ−２−アミノ
−７−ホスホノヘプタン酸Ｃ： （±）−１０，１１−
ジヒドロ−５−メチル−５Ｈ−ジベンゾ［ａ、ｄ］シク
ロヘプテン−５，１０−イミン
Ｄ ： ２− （２−クロロフェニル）−２−（メチル
アミノ）シクロヘキサノン
本発明の有効成分である前記物質は、優れた消化管運動
賦活作用を有しており、食欲不振、悪心、嘔吐、腹部膨
満感、上腹部不快感、胸やけ、などの消化器系不定愁訴
症状に対して優れた効能を有する。Table 1 Minimum effective amount of active ingredient (mg/kg, i, v,) 0, 25 0 0, 01 0, 5 A: 3-((±)-2-carboxypiperazin-4-yl)-propyl-1 -Phosphonic acid B: DL-2-amino-7-phosphonoheptanoic acid C: (±)-10,11-
Dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine D: 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone The above substance which is the active ingredient of the present invention is excellent. It has a gastrointestinal motility activating effect, and is highly effective against indeterminate digestive symptoms such as anorexia, nausea, vomiting, abdominal bloating, upper abdominal discomfort, and heartburn.
また、本発明の有効成分は、その効果の持続性が優れて
おり、投与に伴う副作用が少ない。Furthermore, the active ingredient of the present invention has excellent long-lasting effects and fewer side effects associated with administration.
本発明の有効成分は、遊離体又はその塩として投与でき
る。その投与量は、それらの何れであっても、遊離体の
量として、経口投与で一般に０．５ｍｇ〜５００ｍｇ／
日の範囲の量が適当である。本発明の有効成分は、経口
的にも非経口的（例、静脈内又は皮下注射、経鼻投与、
直腸投与）にも投与される。The active ingredient of the present invention can be administered as a free form or a salt thereof. The dosage for any of them is generally 0.5 mg to 500 mg/orally as the amount of free form.
A daily range of amounts is appropriate. The active ingredient of the present invention can be administered orally or parenterally (e.g., intravenous or subcutaneous injection, nasal administration,
Rectal administration) is also administered.
剤型としては、例えば、注射剤、型剤、散剤、点鼻剤、
丸剤、錠剤、シロップ剤等であってよく、それ自体公知
の賦形剤、崩壊剤、結合剤、滑沢剤、コーティング剤、
基材、その他などと共に製剤できる。Examples of dosage forms include injections, molds, powders, nasal sprays,
It may be a pill, tablet, syrup, etc., and may contain excipients, disintegrants, binders, lubricants, coating agents, etc. known per se.
It can be formulated together with base materials and others.
以下に実施例を示す。Examples are shown below.
［実施例１］ 製剤例（錠剤） １錠（２１０ｍｇ）中に下記成分を含有する。[Example 1] Formulation example (tablet) One tablet (210mg) contains the following ingredients.
活性成分 ４０ｍｇラクトース
１０３ ｍ ｇでんぷん
５０ｒｎｇステアリン酸マグネシウム
２ｍｇヒドロキシプロピルセルロース １５ｍｇ［
実施例２］
製剤例（カプセル剤）
ゼラチン硬カプセル１球中に下記成分（３３０ｍｇ）を
含有する。Active ingredient 40mg lactose
103 mg starch
50rng magnesium stearate
2mg Hydroxypropyl cellulose 15mg [
Example 2 Formulation Example (Capsule) One hard gelatin capsule contains the following ingredients (330 mg).
活性成分 ２０ｍｇラクトース
２００ｍｇでんぷん
７０ｍｇポリビニルピロリドン
５ｍｇ結晶セルロース ３５ｍｇ［実施
例３］
製剤例（顆粒）
顆粒１ｇ中に下記成分を含有する。Active ingredient 20mg lactose
200mg starch
70mg polyvinylpyrrolidone
5mg crystalline cellulose 35mg [Example 3] Formulation example (granules) The following ingredients are contained in 1 g of granules.
活性成分 １００ｍｇラクトース
４５０ｍｇトウモロコシデンプン
４００ｍｇヒドロキシプロピルセルロース
０ｍｇActive ingredient 100mg lactose
450mg corn starch
400mg Hydroxypropyl cellulose 0mg
Claims (1)
アスパラギン酸による神経興奮作用を選択的に抑制し得
る物質を有効成分として含有することを特徴とする消化
管運動賦活剤。 ２、該物質が、３−（（±）−２−カルボキシピペラジ
ン−４−イル）−プロピル−１−ホスホン酸、ＤＬ−２
−アミノ−７−ホスホノヘプタン酸、ＤＬ−２−アミノ
−５−ホスホノペンタン酸、Ｄ−α−アミノアジピン酸
、２−（２−クロロフェニル）−２−（メチルアミノ）
シクロヘキサノン、（±）−１０，１１−ジヒドロ−５
−メチル−５Ｈ−ジベンゾ［ａ、ｄ］シクロヘプテン−
５，１０−イミン、及びｃｉｓ−４−ホスホノメチル−
２−ピペリジンカルボン酸、からなる群から選択された
化合物であることを特徴とする請求項第１項記載の消化
管運動賦活剤。[Claims] 1. A glutamate antagonist and N-methyl-D-
A gastrointestinal motility activator characterized by containing as an active ingredient a substance capable of selectively suppressing the nerve excitation effect caused by aspartic acid. 2. The substance is 3-((±)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, DL-2
-Amino-7-phosphonoheptanoic acid, DL-2-amino-5-phosphonopentanoic acid, D-α-aminoadipic acid, 2-(2-chlorophenyl)-2-(methylamino)
Cyclohexanone, (±)-10,11-dihydro-5
-Methyl-5H-dibenzo[a,d]cycloheptene-
5,10-imine, and cis-4-phosphonomethyl-
2. The gastrointestinal motility activator according to claim 1, which is a compound selected from the group consisting of 2-piperidinecarboxylic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20255689A JP2826843B2 (en) | 1989-08-03 | 1989-08-03 | Gastrointestinal motility enhancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20255689A JP2826843B2 (en) | 1989-08-03 | 1989-08-03 | Gastrointestinal motility enhancer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0366628A true JPH0366628A (en) | 1991-03-22 |
| JP2826843B2 JP2826843B2 (en) | 1998-11-18 |
Family
ID=16459457
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20255689A Expired - Lifetime JP2826843B2 (en) | 1989-08-03 | 1989-08-03 | Gastrointestinal motility enhancer |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2826843B2 (en) |
-
1989
- 1989-08-03 JP JP20255689A patent/JP2826843B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2826843B2 (en) | 1998-11-18 |
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