JPH04128233A

JPH04128233A - Platelet agglutination-inhibiting composition

Info

Publication number: JPH04128233A
Application number: JP2243729A
Authority: JP
Inventors: Akio Odawara; 小田原　昭男; Sakae Murata; 栄村田; Yasuhiko Sasaki; 靖彦佐々木
Original assignee: Tanabe Seiyaku Co Ltd
Current assignee: Tanabe Pharma Corp
Priority date: 1990-09-17
Filing date: 1990-09-17
Publication date: 1992-04-28
Anticipated expiration: 2010-02-01
Also published as: JPH078799B2

Abstract

PURPOSE:To provide a platelet agglutination-inhibiting composition containing a 1,5-benzothiazepine derivative and acetylsalicylic acid, exhibiting a remarkable synergistic activity and giving a high effect in a low dose. CONSTITUTION:The composition contains (A) a compound of the formula (R<1> is lower alkyl; R<2> is H, lower alkanoyl; R<3>, R<4> are lower alkyl; X is halogen) or a salt thereof, e.g. (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5)-one.maleate and (B) acetylsalicylic acid or a salt thereof in an A/B weight ratio of 1/0.3 to 1/40, preferably 1/1 to 1/10. The daily dose of the composition is preferably 10-30mg of A and 30-100mg of B within the range of the above-mentioned ratio.

Description

【発明の詳細な説明】（産業上の利用分野）本発明は、下記−数式の１．５−ベンゾチアゼピン誘導
体とアセチルサリチル酸を併用することにより、これら
化合物の単独投与に比べて、血小板凝集抑制作用がより
高められた医薬組成物に関する。Detailed Description of the Invention (Industrial Application Field) The present invention provides a method for improving platelet aggregation by using a 1,5-benzothiazepine derivative of the following formula in combination with acetylsalicylic acid, compared to single administration of these compounds. The present invention relates to a pharmaceutical composition with enhanced suppressive action.

（従来の技術及び発明が解決しようとする課題）本発明
における下記−数式（１）の１．５−ベンゾチアゼピン
誘導体は、例えば特公昭６３−１３９９４号公報に、降
圧作用、阻血拡張作用、血小板凝集抑制作用などを示す
化合物として知られている。(Prior Art and Problems to be Solved by the Invention) The 1,5-benzothiazepine derivative of the following formula (1) in the present invention is disclosed in Japanese Patent Publication No. 13994/1983, for example, as having antihypertensive action, ischemic dilation action, It is known as a compound that exhibits platelet aggregation inhibitory effects.

一方、アセチルサリチル酸は血小板凝集抑制作用がある
が、胃腸等に対し副作用があるため、その投与量を低く
おさえることが治療上要望されている。On the other hand, acetylsalicylic acid has an effect of inhibiting platelet aggregation, but it has side effects on the gastrointestinal tract and the like, so there is a therapeutic need to keep its dosage low.

（課題を解決するための手段）本発明は、上記の目的のために、下記１．５−ベンゾチ
アゼピン誘導体とアセチルサリチル酸を併用することに
より、相乗的に血小板凝集抑制作用が増強することを見
い出した。(Means for Solving the Problems) For the above-mentioned purpose, the present invention proposes that the platelet aggregation inhibiting effect is synergistically enhanced by using the following 1,5-benzothiazepine derivative and acetylsalicylic acid together. I found it.

すなわち、本発明は、一般式（式中、Ｒ１は低級アルキル基を表し、Ｒ３は水素原子
又は低級アルカノイル基を表し、Ｒ３及びＲ４は同−又
は異なり、低級アルキル基を表し、Ｘはハロゲン原子を
表す）で示される１、５−ベンゾチアゼピン誘導体又はその塩
と、アセチルサリチル酸又はその塩とを含有する血小板
凝集抑制組成物である。That is, the present invention is based on the general formula (wherein R1 represents a lower alkyl group, R3 represents a hydrogen atom or a lower alkanoyl group, R3 and R4 are the same or different and represent a lower alkyl group, and X is a halogen atom) This is a platelet aggregation inhibiting composition containing a 1,5-benzothiazepine derivative or a salt thereof represented by the following formula and acetylsalicylic acid or a salt thereof.

本発明において、式（１）の１，５−ベンゾチアゼピン
誘導体は、Ｒ’がメチル、エチル、プロピル、ブチルの
ような低級アルキル基、とくにメチルであり、Ｒ８が水
素原子又はアセチル、プロピオニル、ブチリルのような
低級アルカノイル基、とくにアセチルであり、Ｒ３及び
Ｒ４は同−又は異なり、メチル、エチル、プロピル、ブ
チルのような低級アルキル基であり、とくにＮ（Ｒ”１
（Ｒ４）は、ジメチルアミノであり、Ｘはクロル、ブロ
ム、フルオロのようなハロゲン原子、と（にクロルであ
る。また式（Ｉ）の化合物は、ベンゾチアゼピン骨格の
２位及び３位に不斉炭素原子を有するため、２種の立体
異性体（シス、トランス異性）又は４種の光学異性Ｃ（
＋）−シス、（−）−シス、（＋）−トランス、（−）
−トランス異性）が存在するが、本発明はこれら異性体
又はその混合物をも包含するものであるが、とくに（＋
）−シス異性体が好ましい、また、式（Ｉ）の化合物の
塩としては、薬学的に許容しつる酸付加塩、例えば塩酸
塩、臭化水素酸塩、硫酸塩、リン酸塩のような無機酸塩
、又はシュウ酸塩、酢酸、マレイン酸塩、フマル酸塩、
メタンスルホン酸塩のような有機酸塩があげられる。In the present invention, the 1,5-benzothiazepine derivative of formula (1) is such that R' is a lower alkyl group such as methyl, ethyl, propyl, or butyl, particularly methyl, and R8 is a hydrogen atom or acetyl, propionyl, Lower alkanoyl groups such as butyryl, especially acetyl, R3 and R4 being the same or different, lower alkyl groups such as methyl, ethyl, propyl, butyl, especially N(R"1
(R4) is dimethylamino, and X is a halogen atom such as chlor, bromo, or fluoro, and Because it has an asymmetric carbon atom, it has two types of stereoisomers (cis, trans isomerism) or four types of optical isomers C (
+)-cis, (-)-cis, (+)-trans, (-)
Although the present invention also includes these isomers or mixtures thereof, in particular (+
)-cis isomer is preferred; salts of compounds of formula (I) include pharmaceutically acceptable acid addition salts such as hydrochlorides, hydrobromides, sulfates, phosphates; Inorganic acid salts, or oxalates, acetic acids, maleates, fumarates,
Examples include organic acid salts such as methanesulfonate.

アセチルサリチル酸は、ナトリウム塩であってもよい。Acetylsalicylic acid may be a sodium salt.

これら両薬剤の配合比率は、１．５−ベンゾチアゼピン
誘導体［Ｉ］　１重量部に対し、アセチルサリチル酸を
０．３〜４０重量部、とりわけ１−１０重量部とするの
が好ましい、また、−日当りの投与量は、前記の配合比
率の範囲内で、１．５−ベンゾチアゼピン誘導体［Ｉ］
が５〜６０＋ａｇ、とりわけ１０〜３０ｍｇであり、ア
セチルサリチル酸が２０〜２００ｓ＋ｇ、とりわけ３０
〜１００ｍｇであるのが好ましい。The mixing ratio of these two drugs is preferably 0.3 to 40 parts by weight, particularly 1 to 10 parts by weight of acetylsalicylic acid per 1 part by weight of the 1.5-benzothiazepine derivative [I]. - The daily dose of 1,5-benzothiazepine derivative [I] is within the range of the above-mentioned mixing ratio.
is 5 to 60+ag, especially 10 to 30 mg, and acetylsalicylic acid is 20 to 200 s+g, especially 30
~100 mg is preferred.

本発明の組成物は、経口的又は非経口的に好適な製剤で
あり、経口剤としては錠剤又はカプセルとして、適当な
賦形剤、例えばデン粉、ラクトース、クルコース、リン
酸カルシウム、ステアリン酸を含有することができる。The composition of the present invention is a formulation suitable for oral or parenteral administration, and for oral administration, it is in the form of tablets or capsules containing suitable excipients such as starch, lactose, glucose, calcium phosphate, stearic acid. be able to.

所望により追加の香料及び／又は甘味剤を含むことがで
きる。注射剤として、適当な安定剤、可溶化剤又は緩衝
剤を含む水を用いることができる。Additional flavoring and/or sweetening agents can be included if desired. For injections, water containing appropriate stabilizers, solubilizers or buffers can be used.

（実験例）　血小板凝集抑制作用（方法）ヒトより採取した血液９容を、３．８％（ｗ／ｖｌクエ
ン酸三ナトリウム水溶液１容と混和し、該混合物を遠心
分１１４こより血小板懸濁血漿（ＰＲＰ）を調製した。(Experimental example) Platelet aggregation inhibitory effect (method) Nine volumes of blood collected from a human were mixed with one volume of a 3.8% (w/vl) trisodium citrate aqueous solution, and the mixture was centrifuged at 114 to obtain platelet-suspended plasma. (PRP) was prepared.

残存血液をさらに遠心分離して血小板除去血漿（ＰＰＰ
）を調製した。ＰＲＰをＰＰＰで希釈してＰＲＰの血小
板数を４ＸＩＯ’／ｙａｒｎ”に調整した。ＰＲＰ１７
５＃ｌと下記検体化合物溶液（Ａ）２５ＩＩＩ＋生理食
塩水２５ＩＩ！。The remaining blood is further centrifuged to obtain platelet-free plasma (PPP).
) was prepared. The platelet count of PRP was adjusted to 4XIO'/yarn'' by diluting PRP with PPP. PRP17
5#l and the following sample compound solution (A) 25III + physiological saline 25II! .

（Ｂ）２５ｄ＋生理食塩水２５ｄ、（Ｃ）２５ｄ＋生理
食塩水２５１１！、（Ａ）２５１１！＋　（Ｃ）２５μ
又は（Ｂ）２５ｐＪ＋　（Ｃ）２５ＩＡＩと（Ｄ混合物
を、３７℃で２分間撹拌後、コ、ラーゲン溶液［ビオキ
ミカ・工・ビオフィジ力・アクタ、、１８６巻、２５４
頁（１９６９年）１２５Ｎを加えて血小板凝集を起こさ
せた。血小板凝集能はボーンの方法［ネイチャー、１９
４巻、９２７頁（１９６２年）］により測定し、検体の
血小板凝集抑制作用を求めた。(B) 25d + 25d of physiological saline, (C) 25d + 2511 of physiological saline! , (A)2511! + (C) 25μ
Or (B) 25pJ+ (C) 25IAI and (D) After stirring the mixture at 37°C for 2 minutes, add the co-Lagen solution [Biochimica, Kogyo, Biophysics, Acta, Vol.
(1969) 125N was added to induce platelet aggregation. Platelet aggregation ability was measured using the Bourne method [Nature, 19
4, p. 927 (1962)] to determine the platelet aggregation inhibitory effect of the sample.

なお、生理食塩水５０μのみを加えたものを、非投薬対
照とした。Note that a sample to which only 50μ of physiological saline was added was used as a non-medication control.

（検体化合物）（Ａ）　　　（＋）−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−クロロー２．３−ジヒドロ−１，５−ベ
ンゾチアゼピン−４（５Ｈ）−オン・マレイン酸塩（Ｒ
’　、Ｒ”、Ｒ’　＝ＣＨ，、Ｒ”＝ＣＨ，Ｃｏ、ｘ＝
ＣＩ２）（Ｂ）　　　（＋）−シス−２−（４−メトキ
シフェニル）−３−ヒドロキシ−５−（２−（ジメチル
アミノ）エチル］−８−クロロー２．３−ジヒドロ−１
，５−ベンゾチアゼピン−４（５Ｈ）−オン（Ｒ’　、
　Ｒ’、　Ｒ’　＝ＣＨｍ、Ｒ’＝Ｈ１ｘ＝ｃＩ２）（Ｃ）　　アセチルサリチル酸（結果）（発明の効果）(Test compound) (A) (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)
ethyl]-8-chloro2,3-dihydro-1,5-benzothiazepine-4(5H)-one maleate (R
' , R", R' = CH, , R" = CH, Co, x =
CI2) (B) (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-(2-(dimethylamino)ethyl]-8-chloro2,3-dihydro-1
,5-benzothiazepin-4(5H)-one (R',
R', R' = CHm, R' = H1x = cI2) (C) Acetylsalicylic acid (result) (effect of the invention)

Claims

[Claims]

(1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents a lower alkyl group, R^2 represents a hydrogen atom or a lower alkanoyl group, R^3 and R ^4
are the same or different, represent a lower alkyl group, and X represents a halogen atom) A platelet aggregation inhibiting composition containing a 1,5-benzothiazepine derivative or a salt thereof, and acetylsalicylic acid or a salt thereof.

(2) The platelet aggregation inhibiting composition according to claim 1, wherein R^1 is a methyl group, R^2 is a hydrogen atom or an acetyl group, R^3 and R^4 are a methyl group, and X is a chlorine atom.

(3) The platelet aggregation inhibiting composition according to claim 1 or 2, wherein the 1,5-benzothiazepine derivative is a (+)-cis form.