JPH0720868B2 - Pharmaceutical composition - Google Patents
Pharmaceutical compositionInfo
- Publication number
- JPH0720868B2 JPH0720868B2 JP5622190A JP5622190A JPH0720868B2 JP H0720868 B2 JPH0720868 B2 JP H0720868B2 JP 5622190 A JP5622190 A JP 5622190A JP 5622190 A JP5622190 A JP 5622190A JP H0720868 B2 JPH0720868 B2 JP H0720868B2
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- chloro
- oxoimidazolidine
- derivative
- salt
- 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 - Lifetime
Links
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 (産業上の利用分野) 本発明は、血圧降下剤として有用な医薬組成物に関す
る。TECHNICAL FIELD The present invention relates to a pharmaceutical composition useful as an antihypertensive agent.
(従来技術) (+)−シス−2−(4−メトキシフェニル)−3−ア
セトキシ−5−〔2−(ジメチルアミノ)エチル〕−8
−クロロ−2,3−ジヒドロ−1,5−ベンゾチアゼビン−4
(5H)−オンが血圧降下剤として有用な化合物であるこ
とは知られている(特開昭61−103828)。(Prior Art) (+)-cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8
-Chloro-2,3-dihydro-1,5-benzothiazebin-4
It is known that (5H) -one is a compound useful as an antihypertensive agent (JP-A 61-103828).
また、(4S)−1−メチル−3−{(2S)−2−〔N−
((1S)−1−エトキシカルボニル−3−フェニルプロ
ピル)アミノ〕プロピオニル}−2−オキソイミダゾリ
ジン−4−カルボン酸が、アンジオテンシン変換酵素
(ACE)阻害作用を有し、血圧降下剤として有用な化合
物であることも知られている(特開昭60−13715)。In addition, (4S) -1-methyl-3-{(2S) -2- [N-
((1S) -1-Ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxoimidazolidine-4-carboxylic acid has angiotensin converting enzyme (ACE) inhibitory action and is useful as an antihypertensive agent It is also known to be a compound (JP-A-60-13715).
(発明の構成及び効果) 本発明は、(+)−シス−2−(4−メトキシフェニ
ル)−3−アセトキシ−5−〔2−(ジメチルアミノ)
エチル〕−8−クロロ−2,3−ジヒドロ−1,5−ベンゾチ
アゼピン−4(5H)−オン(以下、8−クロロ−ベンゾ
チアゼピン誘導体(I)と称する)又はその薬理的に許
容しうる塩と(4S)−1−メチル−3−{(2S)−2−
〔N−((1S)−1−エトキシカルボニル−3−フェニ
ルプロピル)アミノ〕プロピオニル}−2−オキソイミ
ダゾリジン−4−カルボン酸(以下、オキソイミダゾリ
ジン誘導体(II)と称する)又はその薬理的に許容しう
る塩とを含む医薬組成物である。(Structure and Effect of the Invention) The present invention provides (+)-cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino).
Ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one (hereinafter referred to as 8-chloro-benzothiazepine derivative (I)) or pharmacologically acceptable thereof Possible salt and (4S) -1-methyl-3-{(2S) -2-
[N-((1S) -1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxoimidazolidine-4-carboxylic acid (hereinafter referred to as oxoimidazolidine derivative (II)) or pharmacologically A pharmaceutical composition containing a salt acceptable for the following.
本発明の医薬組成物は、8−クロロ−ベンゾチアゼピン
誘導体(I)又はその塩と、オキソイミダゾリジン誘導
体(II)又はその塩とを配合したものであり、各活性成
分を各々単独で投与する場合に較べて、より強い血圧降
下作用を示すと共に作用持続性が優れているという利点
がある。The pharmaceutical composition of the present invention comprises an 8-chloro-benzothiazepine derivative (I) or a salt thereof and an oxoimidazolidine derivative (II) or a salt thereof, and each active ingredient is administered alone. In comparison with the case of the above, there is an advantage that it exhibits a stronger blood pressure lowering effect and is excellent in action duration.
8−クロロ−ベンゾチアゼピン誘導体(I)は、遊離化
合物もしくは塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、
過塩素酸塩、硫酸塩、リン酸塩、シュウ酸塩、マレイン
酸塩、フマル酸塩、酒石酸塩、メタンスルホン酸塩の如
きその薬理学的に許容しうる酸付加塩としても投与でき
る。The 8-chloro-benzothiazepine derivative (I) is a free compound or hydrochloride, hydrobromide, hydroiodide,
It can also be administered as its pharmaceutically acceptable acid addition salts such as perchlorates, sulphates, phosphates, oxalates, maleates, fumarates, tartrates and methanesulphonates.
オキソイミダゾリジン誘導体(II)は、遊離酸もしくは
塩酸塩、臭化水素酸塩、硫酸塩、リン酸塩、コハク酸
塩、マレイン酸塩、フマル酸塩、メタンスルホン酸塩、
リジン塩、オルニチン塩、ナトリウム塩、カリウム塩、
カルシウム塩、マグネシウム塩の如きその薬理的に許容
しうる塩の形でも投与できる。The oxoimidazolidine derivative (II) is a free acid or hydrochloride, hydrobromide, sulfate, phosphate, succinate, maleate, fumarate, methanesulfonate,
Lysine salt, ornithine salt, sodium salt, potassium salt,
It can also be administered in the form of its pharmacologically acceptable salts such as calcium salts and magnesium salts.
これらの両活性成分化合物の配合比率は、8−クロロ−
ベンゾチアゼピン誘導体(I)1に対し、オキソイミダ
ゾリジン誘導体(II)を10分の1乃至当量とするのが好
ましく、また、一日当たりの投与量は、前記の配合比率
の範囲内で8−クロロ−ベンゾチアゼピン誘導体(I)
が3〜300mg及びオキソイミダゾリジン誘導体(II)が
1〜100mgであるのが望ましい。The compounding ratio of these two active ingredient compounds is 8-chloro-
It is preferable to set the oxoimidazolidine derivative (II) to 1/10 to an equivalent amount relative to 1 of the benzothiazepine derivative (I), and the daily dose is within the range of the above compounding ratio. Chloro-benzothiazepine derivative (I)
Is 3 to 300 mg and the oxoimidazolidine derivative (II) is 1 to 100 mg.
本発明の医薬組成物は、経口的にも非経口的にも用いる
ことができ、また両活性成分は単一製剤中に含有させた
ものであってもよく、各活性成分を別々の製剤とし、両
製剤をユニットとしたものでもよい。The pharmaceutical composition of the present invention can be used orally or parenterally, and both active ingredients may be contained in a single preparation, and each active ingredient is prepared as a separate preparation. Alternatively, both formulations may be used as a unit.
経口投与する場合の剤型は、錠剤、散散、カプセル剤、
顆粒剤の如き固形剤であってもよく、溶液、懸濁液の如
き液剤であってもよく、経口投与に適した医薬担体と共
に医薬製剤として使用することができる。かかる医薬担
体としては、例えば結合剤(シロップ、アラビアゴム、
ゼラチン、ソルビット、トラガント、ポリビニルピロリ
ドンなど)、賦形剤(乳糖、砂糖、コーンスターチ、リ
ン酸カリウム、ソルビット、グリシンなど)、潤滑剤
(ステアリン酸マグネシウム、タルク、ポリエチレング
リコール、シリカなど)、崩壊剤(バレイショデンプン
など)及び湿潤剤(ラウリル硫酸ナトリウムなど)が挙
げられる。The dosage form for oral administration is tablets, dispersions, capsules,
It may be a solid preparation such as granules or a liquid preparation such as a solution or suspension, and can be used as a pharmaceutical preparation together with a pharmaceutical carrier suitable for oral administration. Examples of such pharmaceutical carriers include binders (syrup, gum arabic,
Gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit, glycine, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants ( Potato starch) and humectants (such as sodium lauryl sulfate).
一方、非経口的に投与する場合の剤型は、例えば注射用
蒸留水、生理的食塩水、ブドウ糖水溶液等を用いて注射
剤や点滴注射剤とするのが好ましい。On the other hand, the dosage form for parenteral administration is preferably an injection or drip injection using, for example, distilled water for injection, physiological saline, an aqueous glucose solution or the like.
実験例 <SHRに対する降圧作用> (方法) 一夜絶食させた自然発症高血圧症ラット(SHR)を1群
5匹とし、検体投与群には、下記検体化合物(A)及び
/又は(B)をイオン交換水に溶解して強制経口投与
(投与量:各検体とも1mg/kg)した。Experimental Example <Hypertensive action on SHR> (Method) One group of 5 spontaneously hypertensive rats (SHR) fasted overnight was used as a group, and the test compound administration group (A) and / or (B) below was used as an ion. It was dissolved in exchanged water and administered by oral gavage (dose: 1 mg / kg for each sample).
ラットの収縮期血圧を、テール プレステモグラフ法
〔ザ・ジャーナル・オブ・ラボラトリー・アンド・クリ
ニック・メディシン,78,957(1971)〕により、検体投
与前と投与後1、3及び6時間目に測定し、投与前に対
する血圧低下度合を求めた。The systolic blood pressure of the rat tail PlayStation model graph method [The Journal of Laboratory and Clinic Medicine, 78, 957 (1971)], the 1, 3 and at 6 hours after administration and before the specimen administration The blood pressure was measured and the degree of decrease in blood pressure before administration was determined.
検体化合物(A):8−クロロ−ベンゾチアゼピン誘導体
(I)のマレイン酸塩 検体化合物(B):オキソイミダゾリジン誘導体(II)
の塩酸塩 血圧降下作用の効果判定は、下記の基準に従って行っ
た。Analyte Compound (A): Maleic Acid Salt of 8-Chloro-benzothiazepine Derivative (I) Analyte Compound (B): Oxoimidazolidine Derivative (II)
The effect of the antihypertensive effect of the hydrochloride was determined according to the following criteria.
(結果) 結果は下記第1表の通りであり、検体(A)及び(B)
を併用した場合には、単独使用の場合に較べて、より強
い血圧降下作用を示すと共に作用持続性も優れているこ
とがわかる。 (Results) The results are shown in Table 1 below, and samples (A) and (B)
It can be seen that, when used in combination, the compound exhibits a stronger antihypertensive effect and is superior in duration of action, as compared with the case where it is used alone.
Claims (1)
ル)−3−アセトキシ−5−〔2−(ジメチルアミノ)
エチル〕−8−クロロ−2,3−ジヒドロ−1,5−ベンゾチ
アゼピン−4(5H)−オン又はその薬理的に許容しうる
塩と(4S)−1−メチル−3−{(2S)−2−〔N−
((1S)−1−エトキシカルボニル−3−フェニルプロ
ピル)アミノ〕プロピオニル}−2−オキソイミダゾリ
ジン−4−カルボン酸又はその薬理的に許容しうる塩と
を含む血圧降下用医薬組成物。1. (+)-cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino)
Ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one or a pharmaceutically acceptable salt thereof and (4S) -1-methyl-3-{(2S ) -2- [N-
A pharmaceutical composition for lowering blood pressure, which comprises ((1S) -1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxoimidazolidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5622190A JPH0720868B2 (en) | 1990-03-07 | 1990-03-07 | Pharmaceutical composition |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5622190A JPH0720868B2 (en) | 1990-03-07 | 1990-03-07 | Pharmaceutical composition |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH03258721A JPH03258721A (en) | 1991-11-19 |
JPH0720868B2 true JPH0720868B2 (en) | 1995-03-08 |
Family
ID=13021052
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP5622190A Expired - Lifetime JPH0720868B2 (en) | 1990-03-07 | 1990-03-07 | Pharmaceutical composition |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0720868B2 (en) |
-
1990
- 1990-03-07 JP JP5622190A patent/JPH0720868B2/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
JPH03258721A (en) | 1991-11-19 |
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