JP2010195759A - 1,4-benzothiazepine derivative, preparation method thereof and application thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel 1,4-benzothiazepine derivative or a pharmacologically acceptable salt thereof which is useful for treating or preventing heart failure, angina pectoris or myocardial infarction. <P>SOLUTION: The 1,4-benzothiazepine derivative represented by formula [I] (wherein R<SB>1</SB>is a hydrogen atom or hydroxyl group) or a pharmacologically acceptable salt thereof is provided. The novel 1,4-benzothiazepine derivative or a pharmacologically acceptable salt thereof moderately enhances coronary dilation, increases oxygen supply to cardiac muscle, decreases oxygen consumption by the cardiac muscle and is thus effective as an agent for treating or preventing heart failure, angina pectoris or myocardial infarction. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

The present invention relates to a novel 1,4-benzothiazepine derivative having a coronary vasodilatory action and a heart rate reducing action or a pharmaceutically acceptable salt thereof for mammals including humans. A novel drug that is useful as a drug and improves or eliminates myocardial ischemia and myocardial injury by increasing the oxygen supply to the myocardium by dilating the coronary artery in ischemic heart diseases such as angina pectoris and myocardial infarction The present invention relates to a 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof.
The present invention also relates to a novel 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof having a function of dilating coronary arteries to mammals including humans, for treating heart failure or myocardial ischemia or The present invention relates to a novel 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof effective for prevention.
Furthermore, the present invention relates to a novel 1,4-benzothiazepine derivative useful for the treatment or prevention of angina pectoris due to exertion (labor angina) or angina pectoris due to coronary spasm (coronary spasm angina) or a pharmacology thereof Relating to chemically acceptable salts.
Furthermore, the present invention relates to a novel 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof having a function of dilating coronary arteries and a function of reducing myocardial oxygen consumption. The present invention relates to a therapeutic or prophylactic agent for myocardial infarction, comprising thiazepine or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention also relates to a method for producing a novel 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof, particularly a 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof.

  The heart repeats contraction and relaxation of the myocardium periodically, sends blood to tissues and organs throughout the body, and functions as a pump that circulates blood. In order for the myocardium to contract and relax, it is necessary to supply oxygen and nutrients to the myocardium. Supply of oxygen and nutrients to the myocardium is performed by the left and right coronary arteries. The myocardium is supplied with oxygen and nutrients through the left and right coronary arteries, and consumes this oxygen and nutrients to contract and relax. In healthy people, oxygen supply to the myocardium and oxygen consumption in the myocardium are in equilibrium.

  Myocardial oxygen consumption depends on myocardial contractility and heart rate. Myocardial oxygen consumption increases as myocardial contractility and heart rate increase, and myocardial oxygen consumption decreases as these decrease. . In general, since the myocardial oxygen consumption is proportional to the product of the heart rate and the average blood pressure (double product), an increase in heart rate and an increase in blood pressure increase the myocardial oxygen consumption. During intense exercise, myocardial oxygen consumption is 3-4 times normal and myocardial oxygen supply is correspondingly 3-4 times. For example, myocardial oxygen consumption increases due to daily work such as bathing and cleaning, mental excitement, sympathetic nervous state, fever, and the like.

  If the amount of oxygen supply to the myocardium is insufficient relative to the amount of oxygen consumed by the myocardium, the balance between the two is lost, resulting in myocardial ischemia. The weight of the heart is usually around 280-310 grams for an adult, and a man has a heavier heart than a woman. Myocardial hypertrophy occurs in the left ventricle in hypertension and aortic stenosis, and in the right ventricle in pulmonary hypertension. In idiopathic hypertrophic cardiomyopathy, the cause of which is unknown, myocardial hypertrophy occurs in both ventricles. In these diseases, myocardial oxygen consumption is increased due to cardiac hypertrophy. Blood pressure rises due to daily work such as bathing and cleaning, mental excitement, sympathetic nervous state, fever, etc. As heart rate increases, myocardial oxygen consumption further increases. In such a case, the oxygen consumption of the myocardium increases more than the oxygen supply to the myocardium, the balance of myocardial oxygen consumption with the oxygen supply to the myocardium is lost, and the myocardium falls into ischemia. Causes myocardial damage in patients with heart failure or angina or myocardial infarction. For heart failure and myocardial injury that occurred in this way, a drug that has the function of expanding the coronary arteries and the function of reducing myocardial oxygen consumption is said to be a therapeutic or preventive drug for heart failure, angina pectoris or myocardial infarction. ing.

Conventionally, for patients with heart failure, angina pectoris or myocardial infarction, agents that dilate coronary vessels, agents that reduce myocardial contractility, agents that reduce heart rate, such as β-blockers and Ca ²⁺ antagonists ( Diltiazem, verapamil) are used for the treatment. However, in the use of these drugs, for example, the use of β-blockers reduces myocardial contractility and reduces myocardial oxygen consumption, but overdose can lead to heart failure and reverse coronary vessels. This is a problem because it causes the myocardial ischemia to worsen. Also, the use of an excessive amount of β-blocker is a problem because it causes a sudden drop in blood pressure and concomitantly increases myocardial oxygen consumption due to a reflexive increase in heart rate. Furthermore, the use of Ca ²⁺ antagonists such as diltiazem and verapamil also has the effect of reducing myocardial contractility, but if overdose, the risk of reducing cardiac contractility and causing heart failure is the same as β-blockers. In addition, rapid administration dilates peripheral blood vessels, lowers blood pressure, and increases heart rate due to reflex sympathetic excitation. This increase in heart rate increases myocardial oxygen consumption. As a result, myocardial ischemia is caused.

  Also, when there is a significant stenosis of 75% or more in the coronary artery, the coronary blood flow is reduced and the myocardial oxygen supply is reduced. When a person with such significant stenosis exercises, the heart rate and blood pressure increase, the myocardial oxygen consumption increases, the balance of myocardial oxygen consumption with the oxygen supply to the myocardium is disrupted, I have ischemia. This is why labor angina occurs. In addition, even when spasm occurs in the coronary artery and the coronary blood flow rate decreases, the oxygen supply amount to the myocardium decreases and angina pectoris occurs. This is why coronary spasm angina occurs. In the case of such coronary spasm angina, a drug having a function of expanding the coronary arteries and a function of reducing myocardial oxygen consumption can be used as a therapeutic or prophylactic for these angina.

  When there is a significant stenosis in the coronary artery, for example, when there is an old myocardial infarction, heart failure is caused by myocardial ischemia. A drug having the function of expanding the coronary artery and the function of reducing the oxygen consumption of the myocardium reduces the work of the myocardium, and therefore can be used as a therapeutic or preventive drug for heart failure.

By the way, the use of β-blockers and Ca ²⁺ antagonists, which are agents that dilate coronary vessels, reduce myocardial contractility, and reduce heart rate, is difficult even for cardiologists, and is generally low. It is recommended to use from a dose, and high doses are considered dangerous. For this reason, a drug having a vasodilatory action, a cardiac contraction inhibitory action, and a heartbeat lowering action is required from the viewpoint of safety.
An object of the present invention is to provide a drug with a mild action that dilates coronary blood vessels, reduces myocardial contractility, and reduces heart rate.

〔式中、Ｒは水素原子又は水酸基を表わす。〕で示される新規な１，４−ベンゾチアゼピン誘導体又はその薬学的に許容される塩（以下、本発明の化合物という）を提供し、本発明の化合物が、冠動脈を拡張させる作用、心筋への酸素供給量を増加させ、心筋拡張機能を増強させる作用を合わせ持つものであり、何れの作用も穏やかであることを発見した。
本発明は、本発明の化合物を、心不全を改善する薬剤として提供するものである。
また、本発明は、本発明の化合物を、高血圧や大動脈弁狭窄症における左室肥大、特発性肥大型心筋症、肺高血圧に伴う右室の肥大などの心筋の酸素消費量が多い患者や、冠動脈に有意の狭窄または冠攣縮を起こす狭心症、特に、狭心症患者の心筋虚血を治療又は予防する薬剤として提供するものであり、さらに、本発明は、本発明の化合物を、冠動脈に有意の狭窄があり心不全を起こす虚血性心不全患者に対して、安全な望ましい治療薬または予防薬として提供するものである。
さらに、本発明は、本発明の化合物の４−｛３−［４−（４−ヒドロキシベンジル）ピペリジン−１−イル］プロピオニル｝−７−メトキシ−２，３，４，５−テトラヒドロ−１，４−ベンゾチアゼピン又はその薬学的に許容される塩の製造方法を提供するものであり、さらにまた、本発明は、本発明の化合物の４−｛３−［４−（２，４−ジヒドロキシベンジル）ピペリジン−１−イル］プロピオニル｝−７−メトキシ−２，３，４，５−テトラヒドロ−１，４−ベンゾチアゼピン又はその薬学的に許容される塩の製造方法を提供するものである。The inventors have the following general formula [I]

[Wherein, R represents a hydrogen atom or a hydroxyl group. And a pharmaceutically acceptable salt thereof (hereinafter referred to as a compound of the present invention), wherein the compound of the present invention has a function of dilating a coronary artery, to the myocardium. It has been found that both the action of increasing the amount of oxygen supply and enhancing the function of expanding myocardium are mild.
The present invention provides the compound of the present invention as a drug for improving heart failure.
Further, the present invention is a compound of the present invention, a patient with high myocardial oxygen consumption such as left ventricular hypertrophy in hypertension or aortic stenosis, idiopathic hypertrophic cardiomyopathy, hypertrophy of the right ventricle associated with pulmonary hypertension, The present invention provides an agent for treating or preventing angina pectoris causing significant stenosis or coronary spasm in the coronary artery, particularly myocardial ischemia in a patient with angina, and the present invention further provides a compound of the present invention as a coronary artery. It is provided as a safe and desirable therapeutic or prophylactic agent for patients with ischemic heart failure who have significant stenosis and cause heart failure.
Furthermore, the present invention relates to 4- {3- [4- (4-hydroxybenzyl) piperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1, a compound of the present invention. The present invention provides a process for producing 4-benzothiazepine or a pharmaceutically acceptable salt thereof, and further, the present invention provides 4- {3- [4- (2,4-dihydroxy) of the compound of the present invention. (Benzyl) piperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine or a pharmaceutically acceptable salt thereof .

〔式中、Ｒは水素原子又は水酸基を表わす。〕で示される１，４−ベンゾチアゼピン誘導体又はその薬学的に許容される塩にある。The present invention relates to a compound of the present invention, that is, the following general formula [I]

[Wherein, R represents a hydrogen atom or a hydroxyl group. Or a pharmaceutically acceptable salt thereof.

で示される４−｛３−［４−（４−ヒドロキシベンジル）ピペリジン−１−イル］プロピオニル｝−７−メトキシ−２，３，４，５−テトラヒドロ−１，４−ベンゾチアゼピン又はその薬学的に許容される塩（以下、本発明の化合物〔ＩＩ〕という）とすることができる。In addition, the compound of the present invention has the following formula [II]

4- {3- [4- (4-hydroxybenzyl) piperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine represented by the formula: Salt (hereinafter referred to as compound [II] of the present invention).

で示される４−｛３−［４−（２，４−ジヒドロキシベンジル）ピペリジン−１−イル］プロピオニル｝−７−メトキシ−２，３，４，５−テトラヒドロ−１，４−ベンゾチアゼピン又はその薬学的に許容される塩（以下、本発明の化合物〔ＩＩＩ〕という）とすることができる。Furthermore, the compound of the present invention has the following formula [III]

4- {3- [4- (2,4-dihydroxybenzyl) piperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine or The pharmaceutically acceptable salt thereof (hereinafter referred to as the compound [III] of the present invention).

  In addition, the present invention lies in a therapeutic or prophylactic agent for heart failure, angina pectoris or myocardial infarction characterized by containing one or more of the compounds of the present invention as an active ingredient. And a compound for treating or preventing heart failure, angina pectoris or myocardial infarction, comprising one or more compounds among the compounds [III] of the present invention as active ingredients.

で示される化合物の４−｛３−［４−ベンジルピペリジン−１−イル］プロピオニル｝−７−メトキシ−２，３，４，５−テトラヒドロ−１，４−ベンゾチアゼピン（以下、化合物〔ＩＶ〕という）をラット又はイヌに投与し、化合物ＩＶが投与されたラット又はイヌの代謝産物から本発明の化合物〔ＩＩ〕を分離することを特徴とする本発明の化合物〔ＩＩ〕の４−｛３−［４−（４−ヒドロキシベンジル）ピペリジン−１−イル］プロピオニル｝−７−メトキシ−２，３，４，５−テトラヒドロ−１，４−ベンゾチアゼピン又はその薬学的に許容される塩の製造方法にある。さらに加えて、本発明は、化合物〔ＩＶ〕の４−［３−（４−ベンジルピペリジン−１−イル〕プロピオニル］−７−メトキシ−２，３，４，５−テトラヒドロ−１，４−ベンゾチアゼピンが投与されたラット又はイヌの代謝産物から、本発明の化合物〔ＩＩＩ〕を分離することを特徴とする本発明の化合物〔ＩＩＩ〕の４−｛３−［４−（２，４−ジヒドロキシベンジル）ピペリジン−１−イル］プロピオニル｝−７−メトキシ−２，３，４，５−テトラヒドロ−１，４−ベンゾチアゼピン又はその薬学的に許容される塩の製造方法にある。Furthermore, the present invention provides the following formula [IV]

4- {3- [4-benzylpiperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (hereinafter referred to as compound [IV The compound [II] of the present invention is separated from the metabolite of the rat or dog administered with the compound IV. 3- [4- (4-Hydroxybenzyl) piperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine or a pharmaceutically acceptable salt thereof It is in the manufacturing method. In addition, the present invention relates to 4- [3- (4-benzylpiperidin-1-yl] propionyl] -7-methoxy-2,3,4,5-tetrahydro-1,4-benzoate of compound [IV]. The compound [III] of the present invention is isolated from the metabolite of a rat or dog administered with thiazepine, and the compound [III] of the present invention is isolated from 4- {3- [4- (2,4- Dihydroxybenzyl) piperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine or a pharmaceutically acceptable salt thereof.

The present invention has the property that the compound of the present invention has the effect of gently dilating the coronary artery, the property of slowly reducing the heart rate, and the property of increasing the oxygen supply to the myocardium and reducing the oxygen consumption of the myocardium. Oxygen consumption of the myocardium, such as hypertrophy of the left ventricle in hypertension and aortic stenosis, idiopathic hypertrophic cardiomyopathy, and hypertrophy of the right ventricle associated with pulmonary hypertension, which were previously considered difficult to treat and prevent Drugs that treat or prevent myocardial ischemia in patients with high volume and coronary arteries, especially myocardial ischemia in patients with angina, and ischemic that causes significant stenosis in coronary arteries and heart failure It can be a safe and desirable therapeutic or prophylactic for heart failure patients.
The compound of the present invention, particularly the compound [II] or [III] of the present invention can be administered orally, sublingually, pasted, or intravenously in combination with other drugs, either alone or as a mixture thereof. Although it can be injected into the coronary artery, it can be used to release the spasm after inducing coronary spasm diagnostically, to prevent and treat coronary spasm during the examination.
Furthermore, beta blockade to treat or prevent myocardial ischemia in angina, especially angina, or to provide a safe and desirable treatment or prevention for heart failure, especially ischemic heart failure. by combination with drugs and Ca ²⁺ antagonists can reduce the amount of β-blockers or Ca ²⁺ antagonists.

〔式中、Ｒは水素原子又は水酸基を表わす。〕で示される１，４−ベンゾチアゼピン誘導体又はその薬学的に許容される塩で示される１，４−ベンゾチアゼピン誘導体又はその薬学的に許容される塩を提供するものである。
前記本発明の化合物の一種以上、特に、本発明の化合物〔ＩＩ〕の４−｛３−［４−（４−ヒドロキシベンジル）ピペリジン−１−イル］プロピオニル｝−７−メトキシ−２，３，４，５−テトラヒドロ−１，４−ベンゾチアゼピン若しくはその薬学的に許容しうる塩、又はこれら、本発明の、前記一般式〔Ｉ〕で示される１，４−ベンゾチアゼピン誘導体若しくはその薬学的に許容しうる塩の一種以上を有効成分として含有する狭心症、心筋梗塞の治療または予防する薬剤、さらに、心不全に対して安全で望ましい治療薬又は予防薬とすることができる。The present invention relates to a compound of the present invention, that is, the following general formula [I]

[Wherein, R represents a hydrogen atom or a hydroxyl group. The 1,4-benzothiazepine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.
One or more of the compounds of the present invention, particularly 4- {3- [4- (4-hydroxybenzyl) piperidin-1-yl] propionyl} -7-methoxy-2,3, of the compound [II] of the present invention. 4,5-tetrahydro-1,4-benzothiazepine or a pharmaceutically acceptable salt thereof, or a 1,4-benzothiazepine derivative of the present invention represented by the above general formula [I] or a pharmacology thereof Which can be used as a therapeutic agent or an agent for treating or preventing angina pectoris and myocardial infarction, which contain one or more kinds of salts that are acceptable as an active ingredient, and a safe or desirable therapeutic agent or preventive agent for heart failure.

  Since the compound of the present invention has a basic nitrogen atom, an acid addition salt is formed at this position, and the acid addition salt should be pharmaceutically acceptable. The pharmaceutically acceptable salt of the 1,4-benzothiazepine derivative represented by the general formula [I] is also within the scope of the present invention. Examples of the pharmaceutically acceptable salt in the compound of the present invention include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate; oxalate, acetate , Propionate, succinate, glycolate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonic acid There are organic acid addition salts such as salts or ascorbates; amino acid addition salts such as aspartate or glutamate. However, it is not limited to these. In some cases, it may be a hydrate or hydrate.

The compound of the present invention represented by the above formula [II] or [III] can be administered orally, sublingually, affixed, or intravenously, but is injected into the coronary artery to diagnostically induce coronary spasm. Used for release, prevention of coronary spasm during examination, and treatment.
Furthermore, such a treatment or prevention, by combination with β-blockers and Ca ²⁺ antagonists can reduce the amount of β-blockers or Ca ²⁺ antagonists.

で示される化合物の４−｛３−［４−ベンジルピペリジン−１−イル］プロピオニル｝−７−メトキシ−２，３，４，５−テトラヒドロ−１，４−ベンゾチアゼピン（以下、化合物ＩＶという）を投与し、得られた尿及び糞に、水を加えてホモジネートし、その上清を、逆相カラムを使用する高速液体クロマトグラフィーにより成分分離した。本発明の化合物〔ＩＩ〕の保持時間は３０〜３５分であり、分離された成分は、マススペクトロメトリーにより、質量荷電比（ｍ／Ｚ）は４４１であった。
本発明の化合物〔ＩＩＩ〕の４−｛３−［４−（２，４−ジヒドロキシベンジル）ピペリジン−１−イル］プロピオニル｝−７−メトキシ−２，３，４，５−テトラヒドロ−１，４−ベンゾチアゼピン又はその薬学的に許容される塩は、ラット又はイヌに前記化合物〔ＩＶ〕で示される化合物を投与し、得られた尿及び糞に、水を加えてホモジネートし、その上清を、本発明の化合物〔ＩＩ〕と同じ手法で、逆相カラムを使用する高速液体クロマトグラフィーにより成分分離した。本発明の化合物〔ＩＩＩ〕の保持時間は２８〜３２分であり、分離された成分は、マススペクトロメトリーにより、分子量は、質量荷電比（ｍ／Ｚ）は４５７であった。4- {3- [4- (4-hydroxybenzyl) piperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1,4-benzo of the compound [II] of the present invention Thiazepine or a pharmaceutically acceptable salt thereof is administered to the following formula [IV] in rats or dogs.

4- {3- [4-benzylpiperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (hereinafter referred to as Compound IV) ) And the resulting urine and feces were homogenized by adding water, and the supernatant was separated into components by high performance liquid chromatography using a reverse phase column. The retention time of the compound [II] of the present invention was 30 to 35 minutes, and the separated component had a mass to charge ratio (m / Z) of 441 by mass spectrometry.
4- {3- [4- (2,4-dihydroxybenzyl) piperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1,4 of the compound [III] of the present invention -Benzothiazepine or a pharmaceutically acceptable salt thereof is obtained by administering a compound represented by the above compound [IV] to a rat or dog, adding water to the obtained urine and feces, and homogenizing the supernatant. Were separated by high performance liquid chromatography using a reverse phase column in the same manner as in the compound [II] of the present invention. The retention time of the compound [III] of the present invention was 28 to 32 minutes, and the separated component was measured by mass spectrometry. The molecular weight and the mass to charge ratio (m / Z) were 457.

Hereinafter, the present invention will be described more specifically with reference to an example of the present invention. However, the present invention is not limited to the examples and description herein.
Example 1

Test pig heart for coronary vasodilatory effect of compound [II] or [III] of the present invention was purchased and used without discrimination between males and females. Immerse the extracted heart in Krebs-Henseleit solution saturated with 95% oxygen (O ₂ ) and 2,5% carbon dioxide (CO ₂ ) and ice-cooled in advance. The anterior descending coronary artery with a diameter of 2.5-3 mm was removed. Store in the refrigerator overnight in the same nutrient solution and make the 3 mm wide strip of endothelium strip (open ring) the next day, at a temperature of 37 ° C., 95% oxygen (O ₂ ) and 5% carbon dioxide (CO ₂ ) It was suspended in 10 ml of an organ bath filled with Krebs-Henseleit solution saturated with ice and cooled. One was fixed and the other was connected to an isometric transducer (T7-8-240, T7-30-240 Orientec), and the change in tension was recorded with a tension amplifier. After stabilizing for 120 minutes under a load of 1.5 g, KCl (40 mM) was administered, and when contraction reached a maximum, washing out was performed, and this washing was performed four times at 15-minute intervals. After stable KCl contraction is obtained, KCl (30 mM) dissolved in physiological saline (saline) is added to obtain continuous contraction, and then the compound of the present invention dissolved in dimethyl sulfoxide (DSMO) [ II] or [III] was administered cumulatively from 0.01 to 100 μM.
Test results: In the control, the relaxation effect of the coronary arteries was 0%. However, the compound [II] or [III] of the present invention showed an action of relaxing the porcine isolated coronary artery in a concentration-dependent manner. The concentration of the compound [II] or [III] of the present invention (EC 50%) for relaxing the maximum contraction of the coronary artery by 50% was 7.7 μM and 15 μM, assuming the previous value as 100%.
Example 2

Test for reducing contractile ability of compound [II] or [III] of the present invention SLCartley, male guinea pig (900-1200 g) was used. After bruising the head, the carotid artery was severed and exsanguinated, and the chest was opened and the heart was removed. The right atrium was dissected from the ventricle and a right atrial specimen was prepared. This is an organ bath filled with Krebs-Henseleit solution at 31 ° C. under aeration of gas containing 95% oxygen (O ₂ ) and 5% carbon dioxide (CO ₂ ). Suspended in 20 ml, one was fixed and connected to an isometric transducer (TB-651-T: Nihon Kohden). The right atrial specimen was evaluated for drug action using spontaneous contraction as an index. The tension was recorded on a recorder (RECTIGRAPH-8K NEC Sanei) via a tension amplifier (EF601G). After stabilization for 60-90 minutes under a load of 0.5-1.0 g, 0.01-100 μM of the compound [II] or [III] of the present invention dissolved in dimethyl sulfoxide (DSMO) is cumulatively administered. did. A Krebs-Henseleit solution containing no test substance was used as a control. The concentration (IC50 value) that suppresses the maximum contraction by 50% was determined with the pre-dose value being 100%.
Test result: In the control group, the suppression of spontaneous contraction was 9%. The compound [II] or [III] of the present invention exhibited an effect of suppressing the magnitude of spontaneous contraction of the guinea pig right atrium in a concentration-dependent manner. The concentration (IC50) of the compound [II] or [III] of the present invention that suppresses 50% of the maximum value of the contraction amplitude of the previous value was 20 μM and 24 μM, respectively.
Example 3

Test for the heart rate lowering action of the compound [II] or [III] of the present invention The SLC Hartley system, male guinea pig (900-1200 g) was used. After bruising the head, the carotid artery was severed and exsanguinated, and the chest was opened and the heart was removed. The right atrium was dissected from the ventricle and a right atrial specimen was prepared. This is an organ bath filled with Krebs-Henseleit solution under aeration of gas containing 31 ° C., 95% oxygen (O ₂ ) and 5% carbon dioxide (CO ₂ ). The one was fixed and the other was connected to an isometric transducer (TB-651-T: Nihon Kohden). For the right atrial specimen, the number of beats due to spontaneous contraction was recorded on a recorder (RECTIGRAPH-8K NEC Sanei). 0.01-100 μM of the compound [II] or [III] of the present invention dissolved in dimethyl sulfoxide (DSMO) was examined cumulatively.
Detection result: In the control group, the heart rate of the right atrium could not be suppressed. The compound represented by the compound [II] or [III] of the present invention showed an action of suppressing the heart rate per minute of the guinea pig right atrium in a concentration-dependent manner. The concentration of the compound [II] or [III] of the present invention which suppresses the maximum shrinkage by 50% with the previous value as 100% was 8.1 μM and 23 μM.

  From the above three Examples, it was revealed that the compound [II] or [III] of the present invention has an action of expanding coronary blood vessels, an action of reducing cardiac contraction, and an action of suppressing heart rate.

  The compound represented by the formula [I] of the present invention is characterized by having both a decrease in myocardial oxygen consumption and a coronary vasodilatory action. Therefore, it is useful as a therapeutic or preventive for heart failure. It also increases myocardial oxygen supply by dilating coronary blood vessels and reduces myocardial oxygen consumption, thereby reducing myocardial ischemia and is useful as a therapeutic or preventive for angina or myocardial infarction.

Claims (10)

The following general formula [I]

[Wherein, R represents a hydrogen atom or a hydroxyl group. ] 1,4-benzothiazepine derivative | guide_body or its pharmaceutically acceptable salt shown by these.   The 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1 is 4- {3- [4- (4-hydroxybenzyl) piperidin-1-yl] propionyl} -7-. The 1,4-benzothiazepine derivative according to claim 1, which is methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine or a pharmaceutically acceptable salt thereof. Its pharmaceutically acceptable salt.   The 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1 is 4- {3- [4- (2,4-dihydroxybenzyl) piperidin-1-yl] propionyl}-. The 1,4-benzothiazepine according to claim 1, which is 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine or a pharmaceutically acceptable salt thereof. A derivative or a pharmaceutically acceptable salt thereof.   A therapeutic or prophylactic agent for heart failure comprising the 1,4-benzothiazepine derivative or the pharmaceutically acceptable salt thereof according to claim 1, 2 or 3 as an active ingredient.   A therapeutic or prophylactic agent for angina pectoris, comprising the 1,4-benzothiazepine derivative or the pharmaceutically acceptable salt thereof according to claim 1, 2, or 3 as an active ingredient.   A therapeutic or prophylactic agent for myocardial infarction comprising the 1,4-benzothiazepine derivative or the pharmaceutically acceptable salt thereof according to claim 1, 2 or 3 as an active ingredient. A mammalian metabolite of 4- [3- (4-benzylpiperidin-1-yl) propionyl] -7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine is used as the mammal. Of the following general formula [I], characterized in that it is separated from the excreta of

[Wherein, R represents a hydrogen atom or a hydroxyl group. ] The manufacturing method of the 1, 4- benzothiazepine derivative shown by this, or its pharmacologically acceptable salt. 4- [3- (4-Benzylpiperidin-1-yl) propionyl] -7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine was administered to rats or dogs, and after a certain time The excreta excreted is mixed with water, and an organic solvent is added to the mixture to dissolve it. The mixture is purified and concentrated, and the organic solvent and water are added to the concentrate. [I]

[Wherein, R represents a hydrogen atom or a hydroxyl group. ] The manufacturing method of the 1, 4- benzothiazepine derivative shown by this, or its pharmacologically acceptable salt.   9. The method for producing a 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein the 1,4-benzothiazepine derivative separated by liquid chromatography is 4- {3 8. [4- (4-Hydroxybenzyl) piperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine Or a method for producing the 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof according to 8.   9. The method for producing a 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein the 1,4-benzothiazepine derivative separated by liquid chromatography is 4- {3 -[4- (2,4-dihydroxybenzyl) piperidin-1-yl] propionyl} -7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine Item 9. A method for producing a 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof according to Item 7 or 8.