CN1972936A - Muscle relaxation accelerator and therapeutic agent for muscular tissue diseases such as muscle relaxation failure - Google Patents
Muscle relaxation accelerator and therapeutic agent for muscular tissue diseases such as muscle relaxation failure Download PDFInfo
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- CN1972936A CN1972936A CN 200580013602 CN200580013602A CN1972936A CN 1972936 A CN1972936 A CN 1972936A CN 200580013602 CN200580013602 CN 200580013602 CN 200580013602 A CN200580013602 A CN 200580013602A CN 1972936 A CN1972936 A CN 1972936A
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Abstract
A drug which can be used as a muscle relaxation accelerator, therapeutic agent for left ventricular diastolic dysfunction, therapeutic agent for angina pectoris, therapeutic agent for acute pulmonary edema, blood ameliorant for microcirculation system, therapeutic and preventive agent for hypertension, and therapeutic and preventive agent for ventricular tachycardia and Torsade de pointes. The drug is characterized by containing as an active ingredient either a 1,4-benzothiazepine derivative represented by the general formula [I]: [I] [wherein R<1> represents hydrogen or C1-3 alkoxy; R<2> represents hydrogen, C1-3 alkoxy, phenyl (provided that the phenyl may be substituted by one to three substituents selected from the group consisting of hydroxy and C1-3 alkoxys), or a group represented by the formula [II] or [III] (wherein R<3> represents C1-3 acyl); X represents -CO- or -CH2-; and n is 1 or 2] or a pharmaceutically acceptable salt of the derivative.
Description
Technical field
The present invention relates to have and promote muscle tissue, the i.e. compound of the function of myocardium, unstriated muscle and skeletal muscle relaxation, be particularly related to compound with the function that promotes that cardiac muscular tissue is lax, relate more specifically to have can give the myocardial relaxation deficiency, be the depleted patient of myocardial relaxation, promote the lax of cardiac muscular tissue, eliminate the compound of the effect of the lax depletion of cardiac muscular tissue.
The invention still further relates to myocardial relaxation obstacle relative disease, i.e. the curative of myocardial relaxation obstacle relative disease or prophylactic agent, this medicine contain the compound that tool promotes the function that cardiac muscular tissue is lax.The invention further relates to the improving blood flow medicine of microcirculqtory system, this medicine contains the compound that tool promotes the function that cardiac muscular tissue is lax; Relate to cardiac hypertrophy, aortic stenosis, particularly severe aortic stenosis, aortic incompetence, anginal curative or prophylactic agent again; The curative or the prophylactic agent that further relate to the tachycardia arrhythmias such as multiform ventricular tachycardia that for example are called as ventricular tachycardia or torsades de pointes ventricular tachycardia (Torsades de pointes) again.The invention still further relates to two Room diastole depletion, the curative or the prophylactic agent of myocardium obstacle relative diseases such as left ventricle diastole depletion, acute and chronic pulmonary congestion, acute lung edema, myocardium of left ventricle obstacle, described medicine contain the compound that tool promotes the function that cardiac muscular tissue is lax.The present invention relates to heart failure therapy medicine or prophylactic agent again, and this medicine contains the compound that tool promotes the function that cardiac muscular tissue is lax.In addition, the present invention relates to the curative or the prophylactic agent of acute lung edema again, and this medicine contains the compound that tool promotes the function that muscle tissue is lax.The invention still further relates to anginal curative of capillary blood vessel or prophylactic agent in stenocardia, the particularly cardiac muscle, this medicine contains the compound that tool promotes the function that muscle tissue is lax.The present invention relates to the hypertension therapeutic medicine again, and this medicine contains the compound that tool promotes the function that muscle tissue is lax, also relates to the hypertensive curative of bringing out property of youngster's naphthol amine.The ARR curative or the prophylactic agent that take place when the invention still further relates in myocardial cell calcium overload, this medicine contains the compound that tool promotes the function that muscle tissue is lax, also relates to curative or prophylactic agent that same catecholamine when calcium overload brings out arrhythmia.
Background technology
For example heart failure is considered to fall ill based on myocardium meat contractile function depletion at present, and therefore, curative in heart failure uses strengthens the medicine that myocardium meat shrinks.Promptly, the curative of described heart failure has: (1) foxglove (digoxin, digoxigenin, digilanogen C), (2) youngster's naphthol amine (Dopamine HCL, dobutamine, denopamine etc.), (3) phosphodiesterase inhibitor (PDE III Depressant, amrinone, milrinone, vesnarinone etc.), (4) calcium sensitizer (pimobendan) etc., wherein, medicine shown in above-mentioned (1)-(3) all promotes myocardium meat to shrink by increasing intracellular calcium, the medicine calcium sensitizer of above-mentioned (4) is to improve myocardium meat to shrink adjusting albumen---the calcium ion susceptibility of TnC, promotes myocardium meat to shrink.
Except that above-mentioned, it is the treatment of diseases or the prophylactic agent of pathogenic factor that the somebody has proposed with Muscle contraction, relaxing skill dysfunction, and this medicine is with by improving the Ryanodine function of receptors and/or stablizing to bring into play and suppress sarcoplasmic reticulum and discharge the compound of Ca ionic effect as effective constituent (spy of Japan opens the 2003-95977 communique).
But recently, in the case of heart failure, though find have a lot of patients to keep the contraction function of left ventricle, but heart failure has taken place, its quantity accounts for 40% of heart failure patient, and is difficult to the prognosis bona in this case.In above-mentioned heart failure patient, do not see left ventricular enlargement, among these patients, left ventricle diastole function becomes reason in heart failure, is referred to as diastole depletion.
Muscle has cardiac muscle, skeletal muscle and unstriated muscle, the contraction of these muscle and relax performance possess the internal organ of muscle or tissue or organ dysfunction aspect be integral.The contraction of muscle needed very macro-energy when blood was won out, therefore for these Muscle contraction and lax relevant treatment, the material that improves Muscle contraction was studied in the past, the medicine that improves Muscle contraction for example is example with the heart disease, it can be above-mentioned heart failure therapy medicine, with vascular disease is in the example, then is the medicine that strengthens vasoconstriction, improves blood pressure.In contrast, for example also have β-blocking agent etc. by weakening the medicine that cardiac contractile force reduces the zmount of oxygen consumption of muscle tissue, the anginal curative of fatigue is made in this medicinal application.
The torsades de pointes ventricular tachycardia is the specific type of multiform ventricular tachycardia, how in QT prolongation syndrome patient, to take place, be that generation QRS axle changes continuously, the QRS waveform is the periodically variable irregular pulse that axle reverses with the baseline, naturally stop mostly, but demonstration repeatability, sometimes cause and faint outbreak or transfer ventricular fibrillation to, may cause life danger.Antipsychotic drugs such as some kinds by anti-arrhythmic of torsades de pointes ventricular tachycardia, antihistaminic, chlorpromazine cause.Also can cause unusually by ionogen such as hypomagnesemia or hypokalemias.In the anti-arrhythmic that is given during the known treatment irregular pulse, the amiodarone of Quinidine, disopyramide, procainamide, Propafenone, cibenzoline and the above-mentioned classification III class of IA class, Nifekalant or the like cause the torsades de pointes ventricular tachycardia in the classification of the anti-arrhythmic of Vaughan Williams.These anti-arrhythmics have the effect that QT is prolonged on electrocardiogram(ECG, in experiment, by the non-ammonium of the chlorine of the above-mentioned III of being categorized as class (Network ロ Off ワ イ リ ウ system) the torsades de pointes ventricular tachycardia is expressed.
For example, because the heart failure that diastole depletion causes is different on the genesis mechanism of heart failure with the depleted heart failure that causes of contraction in the past, the heart failure that depleted heart failure that causes of contraction and diastole depletion cause has very big difference.Therefore, the depleted heart failure that causes of contraction is different with the methods of treatment of the heart failure that diastole depletion causes itself, someone proposes when the diastole of treatment left ventricle is depleted, use the curative of acute phase or the curative of chronic phase, but they are all incomplete, for example recent findings: influential to Muscle contraction as β-blocking agent that heart failure drugs uses, not talkative perfect, people wish to occur improving myocardial relaxation specific medicament, be the medicine of the heart failure that causes of diastole depletion.
The object of the present invention is to provide and in heart failure in the past, account for 40% myocardial relaxation depletion, be the specific treatment medicine of the heart failure that causes of diastole depletion.
But owing to the disease that can not promote the meat muscle relaxation to cause is a lot, these diseases can be by promoting of flaccid muscles the improvement, but problem is as why not making of flaccid muscles to Muscle contraction with exerting an influence.For example, heart shrinks repeatedly and relaxes, and with the form work of pump, crown perfusion mainly is to carry out at relaxation period, and is of flaccid muscles easy, also makes coronary circulation become easy.Therefore, patient for cardiac hypertrophy, particularly severe aortic stenosis or aorta pass incompetence, the coronary circulation generation obstacle of diastole, then cause stenocardia, but as why not Muscle contraction is exerted an influence and promote simultaneously of flaccid muscles, remove the coronary circulation obstacle of diastole, this is a problem.In addition, for hypertensive heart disease, idiopathic hypertrophy type myocardosis, valvular heart disease and the elderly's etc. cardiac hypertrophy or since aging cause follow the myocardial relaxation obstacle, in electrocardiogram(ECG, show the low myocardium obstacle of ST, for these diseases, as why not Muscle contraction being promoted myocardial relaxation with exerting an influence, thereby these diseases are treated or prevented, and this also is a problem.In the peripheral vessel, by making smooth muscle loosening make vasorelaxation, relax the rapid rising of blood pressure, also prevent the rapid decline of pressure by this adjusting power, therefore promote the lax medicine of muscle tissue to can be used as the hypertensive curative of bringing out property of catecholamine, but as why not Muscle contraction being promoted the lax of vascular smooth muscle with exerting an influence, this also is a problem.And, in ventricular tachycardia, the diastole of ventricle is short, and obstacle appears in crown perfusion, but as why not Muscle contraction is promoted myocardial relaxation with exerting an influence and to the treatment of tachycardia arrhythmia, the particularly ventricular tachycardia of lacking diastole, this is again a problem.When giving anti-arrhythmic and expressing the torsades de pointes ventricular tachycardia, present present situation is that the Plasma Concentration that can only wait for antiarrhythmics reduces, and can't prevent the sudden death that takes place etc. therebetween, and this is again a problem.
J.Biochem.131,739-743 points out in (2002): in the cardiac muscular tissue, Actin muscle and myosin are contractile proteins, when not having proteinic troponin and tropomyosin, this contractile protein-Actin muscle and myosin always are in state of activation, and muscle tissue is in contraction schedule.Under this state, even add tropomyosin, the contraction schedule of this muscle tissue can not change yet.But, add the Ca receptor protein---during troponin, the contractile response of muscle tissue can be by the control of the Ca concentration in the muscle tissue.The protein troponin is the protein complex with Troponin I, TnC and three kinds of compositions of TnT, wherein, Troponin I is the contraction arrestin of muscle tissue, and TnC is a calcium ion-binding protein, and TnT is and tropomyosin bonded protein.TnC combines with calcium ion, and then Troponin I is cancelled the restraining effect of muscle tissue, i.e. derepression, and the mutual slippage of myosin and Actin muscle, muscle tissue shrinks.Therefore, in order to promote the lax of muscle tissue, problem is how to make the Muscle contraction arrestin---Troponin I strengthens the combined function of Actin muscle-myosin mixture.
Myosin is the primary structure protein of muscle, in skeletal muscle, account for sarcostyle gross protein 60%, contain two myoglobulin heavy chains and four myosin light chains.The function of myosin is controlled by myosin light chain, and myosin light chain has and the effect of Muscle contraction protein Actin muscle bonded, is undertaking the critical function of Muscle contraction.Therefore, the keying action of myosin light chain and Actin muscle is changed, this is an important problem.
Summary of the invention
The object of the present invention is to provide muscle relaxation to promote medicine, this medicine is by promoting muscle relaxation, improving muscle relaxation obstacle etc., coronary circulation is become easily, and treatment or prevention stenocardia, hypertensive heart disease, idiopathic hypertrophy type myocardosis, valvular heart disease and the elderly's etc. that cause because of coronary circulation diastole obstacle in cardiac hypertrophy, particularly severe aortic stenosis, the aortic incompetence cardiac hypertrophy or aging cause thus follows the myocardial relaxation obstacle, show low myocardium obstacle or the ventricular tachycardia of ST in electrocardiogram(ECG.The present invention also aims to provide torsades de pointes ventricular tachycardia curative or the prophylactic agent that to treat or to prevent the torsades de pointes ventricular tachycardia.
The inventor found through experiments: 1 shown in the general formula [1], 4 benzothiazepine derivatives or its pharmacologically acceptable salt are (hereinafter referred to as above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt) be the compound of Actin muscle-tropomyosin mixture bonded increased functionality of making Muscle contraction arrestin matter Troponin I and muscle tissue, combined function by Muscle contraction arrestin matter Troponin I and this Actin muscle-tropomyosin mixture strengthens, can make Troponin I suppress the increased functionality of Muscle contraction, promote of flaccid muscles.And the inventor also finds: above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt further strengthen the co-precipitation of myosin light chain and Actin muscle-tropomyosin mixture.
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2For hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein, phenyl can be selected from hydroxyl or carbonatoms be that the substituting group of the lower alkoxy of 1-3 replaces) by 1-3,
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
The present invention is based on above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt have to Muscle contraction have no effect and promote muscle, be that the understanding of the lax function of muscle tissue forms, a kind of curative is provided, this curative relevant with in the past Muscle contraction, for example heart failure therapy medicine is different fully, be the curative that promotes that myocardial relaxation is relevant, this curative can be had no effect to myocardium meat contraction under the state of calcium overload and be promoted effectively of flaccid muscles.The present invention also provides left ventricle diastole obstacle to improve medicine, this left ventricle diastole obstacle improves medicine for example can be shunk the ground of having no effect, eliminate left ventricle diastole obstacle at short notice myocardium meat, carry out the treatment of left ventricle diastole obstacle, particularly also effective under the state of calcium overload in cardiac muscle.The inventor shrinks myocardium meat based on above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt and has no effect and promote the blood flow flow of lax, the microcirculation improvement system of cardiac muscle, has invented the improving blood flow medicine of microcirculqtory system thus.The present invention also finds: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt are had no effect to myocardium meat contraction as the medicine of effective constituent and are promoted myocardial relaxation, eliminate the myocardial relaxation obstacle, thereby invented the anginal curative of capillary blood vessel in angina pectoris treatment medicine, the particularly cardiac muscle.The inventor is again based on above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt shrink myocardium meat has no effect and promotes myocardial relaxation, eliminates myocardium obstacle, has invented the treatment of diseases medicines such as heart failure, hypertensive heart disease, valvular heart disease and hypertrophic cardiomyopathy that cause for the myocardial relaxation obstacle thus.
In addition, the inventor can shrink myocardium meat based on above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt again and have no effect and promote myocardial relaxation, eliminates the myocardial relaxation obstacle rapidly, has invented the acute heart failure curative thus.The inventor can promote myocardial relaxation based on above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt again, makes peripheral vessel lax easily, has invented the hypertension therapeutic medicine thus.The inventor finds that also above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt not only have prolongation by the effect of Q ripple to the length of T ripple, also has the effect of prevention and treatment torsades de pointes ventricular tachycardia.
The object of the present invention is to provide in short period of time or required time Muscle contraction had no effect and promote of flaccid muscles, eliminate the muscle relaxation obstacle, to treatment of diseases medicine and prophylactic agent, also provide the curative and the prophylactic agent of the torsades de pointes ventricular tachycardia of ventricular arrhythmia simultaneously from the lax obstacle of the muscle tissue of cardiac muscle, skeletal muscle and unstriated muscle.
That is, the present invention relates to the loose promotion medicine of flesh, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt, i.e. general formula [1]
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
Or
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-(carbonyl) or-CH
2-(methylene radical), n represents 1 or 2] shown in above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt as effective constituent; The invention still further relates to the loose promotion medicine of flesh, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt be as effective constituent, has the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making; The present invention provides left ventricle diastole treating dysfunction medicine again, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt as effective constituent; The invention still further relates to left ventricle diastole treating dysfunction medicine, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt be as effective constituent, has the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making; The invention still further relates to curative in heart failure, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt as effective constituent; The present invention relates to curative in heart failure again, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt be as effective constituent, has the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making; The present invention relates to the curative of acute lung edema again, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt as effective constituent; The invention still further relates to the curative of acute lung edema, it is characterized in that: contain 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt be as effective constituent, has the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making; In addition the invention still further relates to microcirculqtory system improving blood flow medicine, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt as effective constituent; Relate to microcirculqtory system improving blood flow medicine in addition, it is characterized in that: contain 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt be as effective constituent, has the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making; The present invention relates to anginal curative again, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt as effective constituent; The invention still further relates to anginal curative, it is characterized in that: contain 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt be as effective constituent, has the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making; Except that above-mentioned, the invention still further relates to the medicine that improves of myocardium obstacle, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt as effective constituent; In addition, the invention still further relates to the medicine that improves of myocardium obstacle, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt be as effective constituent, has the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making; The invention still further relates to the hypertension therapeutic medicine, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt as effective constituent; The present invention relates to the hypertension therapeutic medicine again, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt be as effective constituent, has the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making; The present invention relates to the curative of ventricular tachycardia again, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt as effective constituent; The invention still further relates to the curative of ventricular tachycardia, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt be as effective constituent, and this compound has the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making; And the invention still further relates to the curative and the prophylactic agent of torsades de pointes ventricular tachycardia, it is characterized in that: contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt as effective constituent.
Among the present invention, above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt can be made 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2,3,4,5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.Among the present invention, be cardiac muscle, particularly myocardium of left ventricle, skeletal muscle or unstriated muscle as the treatment of muscle relaxant or the muscle of object of prevention.
Among the present invention, contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt, that is, and general formula [1]
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2The lower alkoxy of expression hydrogen, carbonatoms 1-3, phenyl (wherein, phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-(carbonyl) or-CH
2-(methylene radical), n represents 1 or 2]
Shown by 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt have as the medicine of effective constituent has no effect and can promote cardiac muscle Muscle contraction, the effect that skeletal muscle and unstriated muscle etc. are of flaccid muscles, therefore after administration, in short period of time or specified time, can shrink myocardium meat and have no effect and make myocardial relaxation, the left ventricle of diastole heart easily for example, can also improve the coronary circulation of cardiac muscle, therefore blood flow in the particularly myocardium microcirculqtory system can provide the curative of left ventricle diastole obstacles such as left ventricle diastole depletion and the coronary circulation of cardiac muscle to improve medicine, particularly myocardium microcirculation improves medicine.And, crown perfusion mainly is that the relaxation period at heart carries out, therefore myocardium meat is shunk and have no effect, and easily make myocardial relaxation, can improve the blood flow in the coronary circulation like this, therefore contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt and can be used as anginal curative and prophylactic agent as the medicine of effective constituent.
In addition, among the present invention, contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt and have as the medicine of effective constituent Muscle contraction is had no effect, but muscle such as cardiac muscle, skeletal muscle and unstriated muscle lax had promoter action, therefore after administration.In short period of time or desired time, can have no effect and make cardiac muscle, skeletal muscle and smooth muscle loosening Muscle contraction, for example can improve because the interior microvascular blood flow of the cardiac muscle of following cardiac hypertrophy that hypertension causes, microvascular blood flow in the cardiac muscle in myocardium obstacle in idiopathic hypertrophy type myocardosis and the aortic stenosis and the elderly's etc. the myocardial relaxation obstacle be can also improve, treatment of diseases medicine and prophylactic agent therefore can be made based on the myocardial relaxation obstacle; And, can also make based on the heart failure of myocardial relaxation obstacle, for example curative and the prophylactic agent of acute or chronic pulmonary congestion DHF.Of the present inventionly contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt have the muscle relaxation promoter action that Muscle contraction is had no effect as the medicine of effective constituent, after administration, in short period of time or desired time, can make smooth muscle loosening rapidly to Muscle contraction with having no effect, the lax of peripheral vessel become easily, can make the hypertension therapeutic medicine.Of the present inventionly contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt have the muscle relaxation promoter action that Muscle contraction is had no effect as the medicine of effective constituent, after administration, in short period of time or desired time, can for example promote myocardial relaxation to Muscle contraction with having no effect, make the easy diastole of ventricle, the curative that can be used as the short arrhythmia that takes place frequently, particularly ventricular tachycardia of diastole plays a role.Contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt have the muscle relaxation promoter action that Muscle contraction is had no effect as the medicine of effective constituent, for example when myocardial ischemia, after administration, in short period of time or desired time, can treat or prevent for the irregular pulse that causes owing to calcium overload in the myocardial cell, youngster's naphthol amine brings out the effect of the curative or the prophylactic agent of arrhythmia in the time of can also bringing into play the calcium overload in the myocardial cell.Contain above-mentioned 1, bring out the torsades de pointes ventricular tachycardia of expression when 4 benzothiazepine derivatives or its pharmacologically acceptable salt can be suppressed at disease treatment such as irregular pulse as the medicine of effective constituent, can be difficult in the past treatment, prevent and treat by drug-induced torsades de pointes ventricular tachycardia.
As mentioned above, contain above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt and Muscle contraction is had no effect, can play a role for a lot of treatment of diseases or the prevention of following the muscle relaxation obstacle as the medicine of effective constituent, extremely useful in treatment, social effect is big.
Description of drawings
Fig. 1 is following in the condition that gives methoxamedrine, for the rabbit of embodiment A with the 50 μ g/kg/ minutes non-ammoniums of persistent intravenous injection chlorine, and this persistent intravenous injection begins electrocardiogram(ECG after 23 minutes during with 0.2mg/kg/ minute persistent intravenous injection present embodiment compound, laterally represents the time.In the electrocardiogram(ECG of this Fig. 1, do not find the waveform of ventricular arrhythmia with symbol 1 expression.
Fig. 2 is giving under the condition of methoxamedrine, and persistent intravenous injection begins the electrocardiogram(ECG of the about 25 minutes 18-24 in back between second during with the 50 μ g/kg/ minutes non-ammoniums of persistent intravenous injection chlorine to the rabbit of Comparative examples A, laterally represents the time.In the electrocardiogram(ECG of this Fig. 2, the moment that gives behind the non-ammonium of chlorine 25 minutes and 19 seconds represents that with the arrow of symbol 2 the torsades de pointes ventricular tachycardia waveform that occurs in the electrocardiogram(ECG is represented with symbol 3.
Fig. 3 is giving under the condition of methoxamedrine, and persistent intravenous injection begins electrocardiogram(ECG between the back about 25 minutes 41 seconds-48 seconds during with the 50 μ g/kg/ minutes non-ammoniums of persistent intravenous injection chlorine to the rabbit of Comparative examples A, laterally represents the time.The waveform of the torsades de pointes ventricular tachycardia that occurs in the electrocardiogram(ECG of this Fig. 3 represents with symbol 3, and in the electrocardiogram(ECG, the moment after torsades de pointes ventricular tachycardia waveform occurs during through 25 seconds is represented with the arrow of symbol 4.
Fig. 4 is giving under the condition of methoxamedrine, and persistent intravenous injection begins electrocardiogram(ECG between the back about 22 minutes 26 seconds-22 minutes 33 seconds during with the 50 μ g/kg/ minutes non-ammoniums of persistent intravenous injection chlorine to the rabbit of Comparative examples A, laterally represents the time.In the electrocardiogram(ECG of this Fig. 4, the moment when giving behind the non-ammonium of chlorine 22 minutes and 30 seconds represents that with the arrow of symbol 5 shape of the torsades de pointes ventricular tachycardia ripple of Fa Shenging is with symbol 3 expressions afterwards.
Fig. 5 is giving under the condition of methoxamedrine, and persistent intravenous injection begins electrocardiogram(ECG between the back about 23 minutes 16 seconds-23 minutes 23 seconds during with the 50 μ g/kg/ minutes non-ammoniums of persistent intravenous injection chlorine to the rabbit of Comparative examples A, laterally represents the time.In the electrocardiogram(ECG of this Fig. 5, the moment after the waveform of torsades de pointes ventricular tachycardia 3 occurs during through 49 seconds is represented with the arrow of symbol 6.
The best mode that carries out an invention
Among the present invention, about above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt, its rerum natura and preparation method are recorded in Japan and specially permit in No. 703408 communique, are known materials.Above-mentioned Japan speciallys permit in No. 703408 communique and puts down in writing: above-mentioned 1; 4 benzothiazepine derivatives are (1) 4-[3-(4-benzyl piepridine-1-yl) propionyls]-7-methoxyl group-2; 3; 4; 5-tetrahydrochysene-1; the 4-benzothiazepine [promptly; 4-[3-[1-(4-benzyl) piperidyl] propionyl]-7-methoxyl group-2; 3; 4; 5-tetrahydrochysene-1; 4-benzothiazepine]; (2) 4-[3-[1-(4-benzyl) piperidyl] propionyl]-2-(4-p-methoxy-phenyl)-7-methoxyl group-2,3,4; 5-tetrahydrochysene-1; the 4-benzothiazepine; (3) 4-[1-(4-benzyl) piperidyl] ethanoyl]-7-methoxyl group-2-(4-p-methoxy-phenyl)-2,3,4; 5-tetrahydrochysene-1; the 4-benzothiazepine; (4) 4-[3-[1-(4-benzyl) piperidyl] propyl group]-7-methoxyl group-2,3,4; 5-tetrahydrochysene-1; the 4-benzothiazepine; (5) 4-[3-[1-(4-benzyl) piperidyl] propyl group]-2-(4-p-methoxy-phenyl)-7-methoxyl group-2,3,4; 5-tetrahydrochysene-1; 4-benzothiazepine and (6) 4-[3-[1-(4-benzyl) piperidyl] propionyl]-2-methoxyl group-2,3,4; 5-tetrahydrochysene-1, the 4-benzothiazepine.These compounds have the muscle relaxation promoter action at least, in this specification sheets, with the 4-[3-in these compounds (4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4,5-tetrahydrochysene-1,4-benzothiazepine (hereinafter referred to as this compound) describes for example.
Among the present invention, above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt comprise these 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt, have Muscle contraction is had no effect and to promote the effect of muscle relaxation.Among the present invention, the medicine that contains above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt in short period of time or desired time, is had no effect to Muscle contraction after administration, is to make the muscle relaxation of cardiac muscle, skeletal muscle and smooth muscle loosening promote medicine easily.In addition, contain above-mentioned 1, the medicine of 4 benzothiazepine derivatives or its pharmacologically acceptable salt is after administration, in short period of time or desired time, Muscle contraction is had no effect, be left ventricle diastole obstacle, heart failure, acute lung edema, stenocardia or hypertensive curative and/or the prophylactic agent that promotes muscle relaxation, or the improving blood flow medicine of microcirculqtory system and/or myocardium obstacle improve medicine.Contain above-mentioned 1, the medicine of 4 benzothiazepine derivatives or its pharmacologically acceptable salt is after the administration, in short period of time or desired time, myocardium meat contraction is had no effect, promote myocardial relaxation, when myocardial ischemia owing to the myocardial cell in the ARR curative that produces of calcium overload, still be the ARR curative that brings out by catecholamine, for example suprarenin under the state of calcium overload when myocardial ischemia, in the myocardial cell.
In the muscle tissue, myosin and Actin muscle are respectively Muscle contraction albumen, and when not having troponin and tropomyosin, myosin and Actin muscle always are in state of activation, and muscle tissue is in contraction schedule.Even the muscle tissue to this state applies tropomyosin, the contraction schedule of this muscle tissue can not change yet, but adds Ca receptor protein troponin, and then the contraction of muscle tissue is subjected to Ca in the muscle tissue
++Ionic concn control.Here, troponin is the mixture of Troponin I, TnC and three kinds of subunits of TnT.In this subunit, Troponin I is that the contraction of muscle tissue suppresses composition, and TnC is Ca
++Ionic bond composition, TnT are that the contraction of muscle tissue suppresses in the composition and tropomyosin bonded composition, and troponin complex and Actin muscle and tropomyosin are got in touch.TnC and Ca
++Ionic bond then can break away from the Muscle contraction restraining effect of Troponin I, causes the contraction of muscle tissue by Actin muscle and myosin.
In the past, the mixture that will contain Actin muscle-tropomyosin mixture and TnC-I mixture passes through 100 down at 25 ℃, the super centrifugal force of 000 * g was handled 120 minutes, the throw out that generates is analyzed, by from above-mentioned throw out, detecting Actin muscle-tropomyosin mixture and TnC-I mixture, can confirm that the interior Actin muscle-tropomyosin of TnC-I mixture and muscle tissue combines.For example, the mixture that will contain Actin muscle-tropomyosin mixture and TnC-I mixture is in the presence of calcium sequestrant EGTA, promptly, do not exist under the state of calcium ion, handle by super centrifugal force, Actin muscle-tropomyosin mixture and TnC-I mixture combination, coprecipitation, can pass through the SDS-gel electrophoresis, from above-mentioned throw out, detect Troponin I, can confirm that thus this throw out is the mixture that Actin muscle-tropomyosin mixture and TnC-I mixture form.Like this, Actin muscle-tropomyosin mixture and TnC-I mixture form mixture and when precipitating, TnC-I combines with Actin muscle-tropomyosin mixture, and Troponin I is brought into play the flesh restraining effect in Actin muscle-tropomyosin mixture.
But, when not having calcium sequestrant EGTA, that is, exist under the state of calcium ion, even handle by the coprecipitation method of super centrifugal force, Troponin I or TnC-I mixture can not form throw out with Actin muscle-tropomyosin mixture yet.Like this, when Troponin I or TnC-I mixture does not form throw out with Actin muscle-tropomyosin mixture, be equivalent to not exist in Actin muscle-tropomyosin mixture the bonded situation of Troponin I or TnC-I, the demonstration Troponin I can not brought into play the flesh restraining effect in Actin muscle-tropomyosin mixture.
The inventor is adding above-mentioned 1 with containing, the mixture of the Actin muscle of 4 benzothiazepine derivatives or its pharmacologically acceptable salt-tropomyosin mixture and troponin passes through 100 down at 25 ℃, when the super centrifugal force of 000 * g is handled 120 minutes, discovery can with the interpolation concentration dependency of above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt obtain Troponin I and Actin muscle-tropomyosin mixture bonded throw out.Hence one can see that: the existence of above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt strengthens the bonding force of Troponin I and Actin muscle-tropomyosin mixture, and Troponin I is combined with Actin muscle-tropomyosin mixture, forms precipitation.This demonstration: above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt act on the Troponin I that suppresses Muscle contraction, improve this effect, have the effect that promotes that muscle tissue is lax.
Now, to contain usually the β-blocking agent that uses as the heart failure therapy medicine Proprasylyte, Actin muscle-tropomyosin mixture and troponin mixture 25 ℃, by 100, the super centrifugal force of 000 * g was handled 120 minutes, also can not form Actin muscle-tropomyosin mixture and Troponin I bonded throw out.This demonstration: above-mentioned β-blocking agent Proprasylyte and above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt have different effects for the mixture that contains Actin muscle-tropomyosin mixture and troponin, show that above-mentioned β-blocking agent Proprasylyte is not a picture above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt are such, and troponin and Actin muscle-tropomyosin mixture bonding force is strengthened.
Above-mentioned Japan speciallys permit in No. 2703408 and shows: above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt have the effect of kinetics inhibition necrocytosis (KD), can be used as anti-treatment of myocardial infarction medicine, particularly treatment of Acute Myocardial Infarction and prophylactic agent or myocardial necrosis Depressant.Give the preparation method and the various determination data of above-mentioned 1,4 benzothiazepine derivatives or its pharmacologically acceptable salt.Above-mentioned 1,4 benzothiazepine derivatives have basic nitrogen atom, therefore on this position, can form acid salt, the acid that forms acid salt is pharmaceutically acceptable acid, described pharmacologically acceptable salt for example has hydrochloride, vitriol or other inorganic acid salt, and Citrate trianion, maleate, fumarate, benzoate, succinate, acetate, tartrate or other organic acid salt.
Use among the present invention above-mentioned 1, when 4 benzothiazepine derivatives or its pharmacologically acceptable salt for example promote that as myocardial relaxation medicine uses, its dosage can be according to the degree of the kind of compound, disease, patient's body weight or route of administration etc. and different, be not particularly limited, usually the adult is 0.1mg-1000mg (mean body weight 60kg) every day, preferred 50mg-200mg is with about 1-3 time oral or non-oral (for example intravenous injection) administration every day.Formulation during administration for example has powder, granule, tablet, capsule and injection etc.When forming above-mentioned formulation, can use normally used preparations carrier, vehicle or thinner, form according to ordinary method.
As above-mentioned 1,4 benzothiazepine derivatives that uses among the present invention, for example to 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2,3,4,5-tetrahydrochysene-1,4-benzothiazepine (hereinafter referred to as this compound) describes.
When the medicine that contains this compound was the ampulla of injection, a hydrochloride that uses this compound used isotonic agent and pH value conditioning agent to be prepared as effective constituent.In this case, can use the D-Sorbitol Powder, can use citric acid and sodium hydroxide as pH value conditioning agent as isotonic agent.An example of this situation is: a hydrochloride of 1000mg D-Sorbitol Powder and 10mg citric acid and this compound of 40mg is dissolved in the water for injection, in a hydrochloride solution of this compound that dissolving obtains, add sodium hydroxide solution and citric acid, the pH value of solution is adjusted to 3.2-3.3, the water for injection that adds surplus while stirring, dissolving, the solution that this dissolving is obtained filters, and seals in the ampoule of the 20mL that packs into, is put into sterilization preparation in the autoclave.An example of its proportional quantity is 0.2% compound, 5%D-Sorbitol Powder, 0.5% citric acid and 0.5% sodium hydroxide.
This compound for example can suppress the expression of the torsades de pointes ventricular tachycardia that brings out owing to medicines such as giving anti-arrhythmic, can be effectively as the prophylactic agent and the curative of torsades de pointes ventricular tachycardia.By giving this compound, can make owing to causing that medicine that QT prolongs or the torsades de pointes ventricular tachycardia that takes place unusually owing to ionogen stop.Usually, by eliminating the reason that the torsades de pointes ventricular tachycardia takes place, it can disappear, and therefore when giving this compound the torsades de pointes ventricular tachycardia is stopped, preferably eliminating occurrence cause when giving this compound.For example when use causes the anti-arrhythmic treatment irregular pulse that QT prolongs, this compound and anti-arrhythmic are united use, then can not cause the torsades de pointes ventricular tachycardia and carry out ARR treatment.Like this, this compound and anti-arrhythmic are united when using, this compound for example can administration before the anti-arrhythmic administration, perhaps with anti-arrhythmic administration, perhaps administration after the anti-arrhythmic administration simultaneously.Under any circumstance can not cause the torsades de pointes ventricular tachycardia and carry out ARR treatment.When after the anti-arrhythmic administration, giving this compound, after giving anti-arrhythmic, afterwards or when confirming the torsades de pointes ventricular tachycardia takes place give this compound at the appointed time, also can suppress the torsades de pointes ventricular tachycardia.As mentioned above, this compound has prevention or treats ARR effect, therefore give this compound and can suppress the generation of torsades de pointes ventricular tachycardia, also can eliminate the occurrence cause of torsades de pointes ventricular tachycardia on the other hand, the torsades de pointes ventricular tachycardia is stopped, carrying out ARR treatment simultaneously.Among the present invention, in the prevention of carrying out the torsades de pointes ventricular tachycardia and treatment, total dosage of this compound is preferably 1mg-4mg/kg, can suitably increase and decrease according to symptom.That medication has is oral, intramuscular, intravenous injection etc., and intravenous injection can be seen curative effect as early as possible, and is therefore preferred.
Embodiment
Below, as embodiments of the invention, experimental example is described, but the present invention is not subjected to any qualification of following example and explanation.
Experimental example 1
In this example, the pharmacologically acceptable salt of above-mentioned 1,4 benzothiazepine derivatives uses a hydrochloride of this compound; be 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2,3,4; 5-tetrahydrochysene-1, a hydrochloride (hereinafter referred to as this compound) of 4-benzothiazepine.Use 8 week ages, body weight be the wistar male rat of 300-330g.Anesthesia is undertaken by injection 1000mg/kg urethanum and 80mg/kg Chloralosane under the peritonaeum, breathes to be general breathing.In this example, this compound dissolution of 100mg in 1mL dimethyl sulfoxide (DMSO) (DMSO), is prepared the DMSO solution of this compound, this solution is preserved down at 4 ℃.The injection rate of norepinephrine is 40 μ g/kg/ minutes, and its preparation method is that the 1mg norepinephrine is dissolved in the 41 μ L distilled water, makes the noradrenaline cellulose solution.
At first, right external jugular vein (the quiet Veins of Cervical outside the right side) to above-mentioned rat inserts the intubate that is used for continuing the injection calcium chloride water or contains the norepinephrine aqueous solution of calcium chloride, inserts micro-tip catheter (manufacturing of Millar company, SPC-320) by right common carotid artery to left ventricle equally.Further, injected by reagent thing solution by the right femoral vein insertion equally and use intubate.
Lead the acquisition electrocardiogram(ECG first, and, electrocardiogram(ECG, left ventricular pressure are recorded in the Personal Computer simultaneously through A/D converter.Every 1 minute, as left ventricular end-diastolic pressure, measured for 20 cardiac cycle with the pressure consistent with Electrocardiographic R ripple, ask its mean value, survey periodic left ventricle terminal pressure with this as this.Blood pressure, the rhythm of the heart, electrocardiogram(ECG to above-mentioned rat are monitored 15 minutes, when they are stablized, with per minute 16.6 μ L (being converted into calcium chloride is 9.0mg/kg/ minute), to inject by right external jugular vein according to 5% glucose solution that the body weight of rat has been regulated the calcium chloride of calcium chloride concentration, with this as preparation.
Then, begin to inject the norepinephrine aqueous solution that contains calcium chloride by right external jugular vein immediately, wherein calcium chloride is usage and the capacity that does not change above-mentioned calcium chloride water, norepinephrine is to inject with 40 μ g/kg/ minutes, after the beginning, contain the norepinephrine aqueous solution of calcium chloride by this, continue to inject calcium chloride and norepinephrine.The norepinephrine aqueous solution that contains calcium chloride by this right external jugular vein of beginning injected (intravenous injection) calcium chloride and norepinephrine after 5 minutes, continue to inject calcium chloride and norepinephrine by right external jugular vein by the norepinephrine aqueous solution that contains calcium chloride on one side, on one side in contrast, body weight is that the 1st rat of 300g is only injected the physiological saline that the 0.2mL contrast is subjected to the reagent thing from right femoral vein with 30 seconds time, with this in contrast 1. in addition, with above-mentioned contrast 1 similarly, for equally in contrast, body weight is the 2nd rat of 310g, inject (intravenous injection) calcium chloride and norepinephrine 5 minute after by right external jugular vein by the norepinephrine aqueous solution that contains calcium chloride in beginning, continue to inject calcium chloride and norepinephrine by right external jugular vein by the norepinephrine aqueous solution that contains calcium chloride on one side, similarly only injected from right femoral vein on one side and contrast solvent---the 1%DMSO aqueous solution that is subjected to the reagent thing with 30 seconds, with this in contrast 2.Further, with above-mentioned contrast 1 and 2 similarly, body weight for embodiment 1 is the 3rd rat of 310g, inject (intravenous injection) calcium chloride and norepinephrine 5 minute after by right external jugular vein by the norepinephrine aqueous solution that contains calcium chloride in beginning, continue to inject calcium chloride and norepinephrine by the norepinephrine aqueous solution that contains calcium chloride by right external jugular vein on one side, be subjected to the reagent thing Yi Bian similarly contained 0.3mg/kg from right femoral vein injection 0.2ml with 30 seconds---the 1%DMSO aqueous solution of this compound.With above-mentioned contrast 1-3 similarly, to embodiment 2, body weight is the 4th rat of 330g, inject (intravenous injection) calcium chloride and norepinephrine 5 minute after by right external jugular vein by the norepinephrine aqueous solution that contains calcium chloride in beginning, continue to inject calcium chloride and norepinephrine by the norepinephrine aqueous solution that contains calcium chloride by right external jugular vein on one side, be subjected to the reagent thing Yi Bian similarly contained 0.3mg/kg by right femoral vein injection 0.2mL with 30 second time---the 1%DMSO aqueous solution of this compound of this compound.In this example, still continue to inject calcium chloride and norepinephrine by the norepinephrine aqueous solution that contains calcium chloride after the reagent thing by right external jugular vein with injecting above-mentioned being subjected in 30 seconds.In this example, for contrast 1 and contrast 2, with injecting above-mentioned being subjected to after the reagent thing in 30 seconds, replenished by the reagent thing with the dilution of 1/10 concentration that is subjected to the reagent thing that will inject in 10 μ L/ minutes and inject, the time is to begin certainly in injection is subjected to behind the reagent thing during 15 minutes.In this example, for embodiment 1, injected the 1%DMSO aqueous solution that 0.2mL contains above-mentioned this compound that is subjected to the reagent thing of 0.3mg/kg with 30 seconds after, again replenish injecting the 1%DMSO aqueous solution of above-mentioned compound in 0.02mg/kg/ minute, the time be from begin to inject be subjected to the reagent thing after to 15 minutes during in.But, for embodiment 2, just injected the above-mentioned reagent thing that is subjected to 30 seconds, be not subjected to the additional injection of reagent thing.For each rat, left ventricular end-diastolic pressure is every 1 minute, as left ventricular end-diastolic pressure, measures for 20 cardiac cycle with the pressure consistent with Electrocardiographic R ripple, is obtained by its mean value.Injection is subjected to the reagent thing to begin to finish after 15 minutes experiment.As shown in table 1 below in this experiment every 5 minutes result.
Table 1
| Elapsed time | Left ventricular end-diastolic pressure (unit: mmHg) | |||
| Contrast 1 (physiological saline) | Contrast 2 (solvents) | Embodiment 1 (this compound) | Embodiment 2 (this compound) | |
| Preceding 30 minutes (begin to give CaCl 2Preceding 5 minutes) | 7.7 | 7.6 | 7.5 | 8.4 |
| Preceding 25 minutes (begin to give CaCl 2After immediately) | 7.5 | 7.6 | 7.5 | 8.6 |
| Preceding 20 minutes (begin to give CaCl 2Back 5 minutes) | 8.4 | 8.2 | 7.9 | 8.8 |
| Preceding 15 minutes (begin to give CaCl 2Back 1O minute) | 7.5 | 7.8 | 8.6 | 9.2 |
| Preceding 10 minutes (begin to give CaCl 2Back 15 minutes) | 8.5 | 8.4 | 8.5 | 9.0 |
| Preceding 5 minutes (before the beginning intravenous injection norepinephrine) | 8.6 | 8.6 | 8.6 | 9.3 |
| 0 minute (the beginning intravenous injection is subjected to before the reagent thing) | 7.8 | 8.8 | 8.9 | 9.6 |
| 5 minutes (the beginning intravenous injection was subjected to the reagent thing after 5 minutes) | 11.9 | 10.1 | 10.6 | 13.8 |
| 10 minutes (the beginning intravenous injection was subjected to the reagent thing after 10 minutes) | 30.4 | 37.5 | 12.5 | 16.4 |
| 15 minutes (the beginning intravenous injection was subjected to the reagent thing after 15 minutes) | 47.3 | 49.4 | 11.8 | 15.3 |
(annotating 1) " preceding 30 minutes " ... before " preceding " of " preceding 5 minutes " is meant that beginning to give (injection) is subjected to the reagent thing
The expression beginning intravenous injection of (annotating 2) " 0 minute "-" 15 minutes " is subjected to 0 minute-15 minutes time behind the reagent thing.
Expression is subjected to the reagent thing in the parenthesis on (annotating 3) contrast 1, contrast 2, embodiment 1 and embodiment 2 hurdles.Expression is subjected in the parenthesis of reagent thing, and this compound is represented with this compound.
This example carries out under 20-25 ℃ room temperature.In this example, after injecting calcium chloride before begin the intravenous injection norepinephrine, about left ventricular end-diastolic pressure, in the contrast 1 is 7.7-8.6mmHg, in the contrast 2 is 7.6-8.6mmHg, is 7.5-8.6mmHg among the embodiment 1, is 8.4-9.3mmHg among the embodiment 2, inject behind the calcium chloride to beginning before the intravenous injection norepinephrine, left ventricular end-diastolic pressure is almost as broad as long with contrast 1 and 2 in embodiment 1 and 2.But, beginning intravenous injection norepinephrine left ventricular end-diastolic pressure that (the beginning intravenous injection was subjected to the reagent thing after 10 minutes) (began intravenous injection and be subjected to the reagent thing after 15 minutes) after 20 minutes after 15 minutes rises to 30.4-47.3mmHg in contrast 1, in contrast 2, rise to 37.5-49.4mmHg, the depleted morbidity of visible left ventricle diastole.In contrast, in embodiment 1, beginning intravenous injection norepinephrine is (the beginning intravenous injection was subjected to the reagent thing after 10 minutes) after 15 minutes, left ventricular end-diastolic pressure rises to 12.5mmHg, but (begin intravenous injection norepinephrine 20 minute after) as this compound that is subjected to the reagent thing after 15 minutes in beginning intravenous injection (beginning administration), left ventricular end-diastolic pressure drops to 11.8mmHg.The left ventricular end-diastolic pressure of this embodiment 1 is compared with 2 left ventricular end-diastolic pressure with the contrast of synchronization 1, is 1/2 or following low value, shows by intravenous injection to be unlikely to cause left ventricle diastole depletion as this compound that is subjected to the reagent thing.In addition, in embodiment 2, beginning intravenous injection norepinephrine is (the beginning intravenous injection was subjected to the reagent thing after 10 minutes) after 15 minutes, left ventricular end-diastolic pressure rises to 16.4mmHg, but (begin intravenous injection norepinephrine 20 minute after) as this compound that is subjected to the reagent thing after 15 minutes in beginning intravenous injection (beginning administration), left ventricular end-diastolic pressure drops to 15.3mmHg.The left ventricular end-diastolic pressure of this embodiment 2 is compared with 2 left ventricular end-diastolic pressure with the contrast of synchronization 1, is 1/2 or following low value, shows by this compound of intravenous injection, is unlikely to cause left ventricle diastole depletion.
Result by above embodiment 1 and 2 sees, by being subjected to the additional intravenous injection of reagent thing, become easily by the detection of reagent thing, can measure the reduction of left ventricular end-diastolic pressure.Result by this experimental example sees, we can say the curative or the prophylactic agent that can effectively be used as left ventricle diastole depletion as this compound that is subjected to the reagent thing.
Experimental example 2
This compound is to the influence of blood pressure
In this experiment, use 8 ages in week, body weight is 310 and the wistar male rat of 330g.Anesthesia is undertaken by injection 1000mg/kg urethanum and 80mg/kg Chloralosane under the peritonaeum, breathes to be general breathing.In this experimental example, this compound dissolution of 100mg in 1mL dimethyl sulfoxide (DMSO) (DMSO), is prepared the DMSO solution of this compound, this solution is preserved under 4 ℃ temperature.In addition, the 1mg norepinephrine is dissolved in the 41 μ L distilled water, makes the noradrenaline cellulose solution.
This example and above-mentioned experimental example 1 are same, carry out under 20-25 ℃ room temperature.This example is also same with above-mentioned experimental example 1, the intubate of continue injecting calcium chloride water or containing the norepinephrine aqueous solution of calcium chloride is inserted into the right external jugular vein of above-mentioned rat, inserts micro-tip catheter (millar company makes, SPC-320) to aorta by right common carotid artery (right Gross Cervical Move Veins).
Lead the acquisition electrocardiogram(ECG by first, systolic blood pressure, diastolic blood pressure are recorded in the Personal Computer via A/D converter.Blood pressure, the rhythm of the heart and electrocardiogram(ECG to above-mentioned rat are monitored 15 minutes, when they are stablized, as preparation, will inject 25 minutes by right external jugular vein with per minute 16.6 μ L (being converted into calcium chloride is 9.0mg/kg/ minute) according to calcium chloride 5% glucose solution that the body weight of rat has been regulated calcium chloride concentration.
Then begin to inject the above-mentioned norepinephrine aqueous solution that contains calcium chloride immediately, wherein calcium chloride does not change the usage and the capacity of above-mentioned calcium chloride water, and norepinephrine injected with 40 μ g/kg/ minutes.Behind the intravenous injection norepinephrine 5 minutes, continue to inject calcium chloride and norepinephrine by the above-mentioned norepinephrine aqueous solution that contains calcium chloride on one side, be that the 1st rat of 310g was only injected the solvent that 0.2mL is subjected to the reagent thing with 30 second time by right femoral vein on one side in contrast body weight---DMSO concentration is 1% the aqueous solution, with this in contrast 3.For contrast 3, inject above-mentioned be subjected to the reagent thing after, appended with 10 μ L/ minutes and to inject the solvent that is subjected to the reagent thing---the concentration of DMSO is 1% the aqueous solution, and the time is subjected to reagent thing to 15 minute for the beginning intravenous injection.With contrast 3 similarly, by the above-mentioned norepinephrine aqueous solution intravenous injection norepinephrine of calcium chloride that contains after 5 minutes, continue to inject above-mentioned calcium chloride and norepinephrine by the above-mentioned norepinephrine aqueous solution that contains calcium chloride on one side, be the 2nd rat of 330g is contained this compound of 0.3mg/kg by right femoral vein injection 0.2mL with 30 seconds time 1%DMSO solution on one side to the body weight of embodiment 3, then, inject the 1%DMSO solution that contained this compound of 0.02mg/kg in 14 minutes to append in 0.02mg/kg/ minute.For each rat, measured its systolic blood pressure (mmHg) and diastolic blood pressure (mmHg) every 2 minutes, measure 20 cycles, systolic blood pressure and being determined at of diastolic blood pressure that should carry out every 2 minutes continued to carry out 14 minutes after the beginning intravenous injection is subjected to the reagent thing.By following formula, obtain mean blood pressure by systolic blood pressure (mmHg) and the diastolic blood pressure (mmHg) measured.
Mean blood pressure=[(systolic blood pressure+diastolic blood pressure) * 1/21 (formula)
Its result is as shown in table 2.
Table 2
| Elapsed time | Mean blood pressure (mmHg) | |
| Contrast 3 (solvents) | Embodiment 3 (this compound) | |
| 110 | 110 | 122 |
| Preceding 5 minutes (before the beginning intravenous injection norepinephrine) | 121 | 125 |
| 0 minute (the beginning intravenous injection is subjected to before the reagent thing) | 135 | 136 |
| 2 minutes (the beginning intravenous injection was subjected to the reagent thing after 2 minutes) | 147 | 149 |
| 4 minutes (the beginning intravenous injection was subjected to the reagent thing after 4 minutes) | 160 | 162 |
| 6 minutes (the beginning intravenous injection was subjected to the reagent thing after 6 minutes) | 160 | 141 |
| 8 minutes (the beginning intravenous injection was subjected to the reagent thing after 8 minutes) | 160 | 139 |
| 10 minutes (the beginning intravenous injection was subjected to the reagent thing after 10 minutes) | 161 | 135 |
| 12 minutes (the beginning intravenous injection was subjected to the reagent thing after 12 minutes) | 158 | 136 |
| 14 minutes (the beginning intravenous injection was subjected to the reagent thing after 14 minutes) | 160 | 134 |
(annotating 1) " preceding 30 minutes " ... before " preceding " of " preceding 5 minutes " is meant that the beginning intravenous injection is subjected to the reagent thing
The expression beginning intravenous injection of (annotating 2) " 0 minute "-" 14 minutes " is subjected to 0 minute-14 minutes time behind the reagent thing.
Expression is subjected to the reagent thing in the parenthesis on (annotating 3) contrast 3 and embodiment 3 hurdles.Expression is subjected in the parenthesis of reagent thing, and this compound is represented with this compound.
In this experimental example, beginning intravenous injection norepinephrine (injection) after 4 minutes, for contrast 3, mean blood pressure slightly rises to 160mmHg, but under the situation of present embodiment 3 of this compound that given (injection), behind the beginning intravenous injection norepinephrine 4 minutes the time, mean blood pressure reaches 162mmHg, reduces afterwards, behind beginning intravenous injection norepinephrine 10-14 minute the time, pressure value is between the 136-134mmHg, and mean blood pressure reduces as can be known.This result shows: this compound can be used as hypertensive curative.
Experimental example 3
Study of the influence of this compound by the tissue Doppler method to left ventricular wall diastole ability
In this experimental example, use 9 ages in week, body weight is 310 and the wistar male rat of 320g.Anesthesia is undertaken by injection 1000mg/kg urethanum and 80mg/kg Chloralosane under the peritonaeum, breathes to be general breathing.In this experimental example, this compound dissolution of 100mg in 1mL dimethyl sulfoxide (DMSO) (DMSO), is prepared the DMSO solution of this compound, this solution is preserved under 4 ℃ temperature.In addition, the 1mg norepinephrine is dissolved in the 41 μ L distilled water, makes the noradrenaline cellulose solution.
This example and above-mentioned experimental example 1 are same, carry out under 20-25 ℃ room temperature.This example is also same with above-mentioned experimental example 1, the intubate of continue injecting calcium chloride water or containing the norepinephrine aqueous solution of calcium chloride is inserted into the right external jugular vein of above-mentioned rat, similarly inserts micro-tip catheter (millar company makes, SPC-320) to aorta by right common carotid artery.
Lead the acquisition electrocardiogram(ECG by first, blood pressure, the rhythm of the heart and electrocardiogram(ECG to above-mentioned rat are monitored 15 minutes, when they are stablized, as preparation, injected 25 minutes by right external jugular vein with per minute 16.6 μ L (calcium: 9.0mg/kg/ minute) being dissolved in the calcium chloride water that is prepared from 5% glucose solution.
Then begin immediately to inject (intravenous injection) above-mentioned norepinephrine aqueous solution that contains calcium chloride from right external jugular vein, wherein calcium chloride does not change its usage and capacity, and norepinephrine injected with 40 μ g/kg/ minutes.Also continue to inject calcium chloride and norepinephrine after the beginning by the above-mentioned norepinephrine aqueous solution that contains calcium chloride.By this norepinephrine aqueous solution intravenous injection norepinephrine that contains calcium chloride after 5 minutes, continue to inject calcium chloride and norepinephrine by the above-mentioned norepinephrine aqueous solution that contains calcium chloride on one side, be that the 1st rat of 310g was only injected the solvent that 0.2mL is subjected to the reagent thing with 30 second time by right femoral vein on one side in contrast body weight---DMSO concentration is 1% the aqueous solution, with this in contrast 4.Then, with contrast 4 similarly, by this norepinephrine aqueous solution intravenous injection norepinephrine that contains calcium chloride after 5 minutes, continue to inject calcium chloride and norepinephrine by the above-mentioned norepinephrine aqueous solution that contains calcium chloride on one side, body weight to present embodiment 3 is the 2nd rat of 320g and contrast 4 was similarly contained this compound of 0.3mg/kg by right femoral vein injection 0.2mL with 30 second time 1%DMSO solution on one side, then, injected 20 minutes to append in 0.02mg/kg/ minute.Adopt the ultrasonic wave tissue Doppler method, each rat is checked the left ventricular wall diastolic function.The diagnostic ultrasound equipment (Toshiba Powervision SSA-380APSK-70LT) that diagnostic ultrasound equipment uses Toshiba Corporation to make is checked with the ultrasonic wave of 10MHz.For each rat, at first anterior part of chest is shaved hair, aim at apex of the heart position with ultrasound probe (エ コ one Block ロ one Block), scanning apex of the heart position long axis of left ventricle layer, place the sampling container (サ Application プ Le Port リ ユ one system) of pulse Doppler at the base portion of PM cusp, measure the left ventricular wall wall speed [Ea ripple (m/ second)] of diastole, with this as left ventricular wall diastole ability.In this experimental example, left ventricular wall diastole ability with the norepinephrine intravenous injection of obtaining by the tissue Doppler method after before left ventricular wall wall diastole speed and the same intravenous injection norepinephrine of obtaining with the tissue Doppler method of (give back) left ventricular wall (being normal left ventricular wall) wall velocity ratio diastole of (giving preceding) represent.Its result as shown in the following Table 3.
Table 3
| Elapsed time | The wall velocity ratio of left ventricular wall diastole | |
| Contrast 4 (solvents) | Embodiment 4 (this compound) | |
| Preceding 5 minutes (before the beginning intravenous injection norepinephrine) | 1.00 | 1.00 |
| 0 minute (the beginning intravenous injection is subjected to before the reagent thing) | 1.00 | 1.00 |
| 5 minutes (the beginning intravenous injection was subjected to the reagent thing after 5 minutes) | 0.85 | 1.02 |
| 10 minutes (the beginning intravenous injection was subjected to the reagent thing after 10 minutes) | 0.75 | 1.04 |
| 15 minutes (the beginning intravenous injection was subjected to the reagent thing after 15 minutes) | 0.70 | 1.00 |
| 20 minutes (the beginning intravenous injection was subjected to the reagent thing after 20 minutes) | 0.60 | 1.00 |
| 25 minutes (the beginning intravenous injection was subjected to the reagent thing after 25 minutes) | 0.55 | 0.94 |
| 30 minutes (the beginning intravenous injection was subjected to the reagent thing after 30 minutes) | 0.51 | 0.95 |
Before " preceding " of (annotating 1) " preceding 5 minutes " is meant that beginning injection is subjected to the reagent thing
The expression beginning intravenous injection of (annotating 2) " 0 minute "-" 30 minutes " is subjected to 0 minute-30 minutes time behind the reagent thing.
Expression is subjected to the reagent thing in the parenthesis on (annotating 3) contrast 4 and embodiment 4 hurdles.Expression is subjected in the parenthesis of reagent thing, and this compound is represented with this compound.
In this experimental example, behind the beginning intravenous injection norepinephrine 5 minutes the time, the wall speed of the left ventricle in the contrast 4 is reduced to 0.85 with the velocity ratio of the wall speed (Ea ripple) of normal left ventricular wall, 30 minutes the time, the wall speed (Ea ripple) of the left ventricular wall in the contrast 4 is reduced to 0.51 with the velocity ratio of the wall speed (Ea ripple) of normal left ventricular wall behind the beginning intravenous injection norepinephrine.In contrast, under the situation of present embodiment 3,30 minutes the time, the wall speed of left ventricular wall (Ea ripple) is 0.95 with the velocity ratio of the wall speed (Ea ripple) of normal left ventricle, does not almost see variation behind the beginning intravenous injection norepinephrine.The wall speed of left ventricular wall is represented the speed of unit time ventricular wall motion, and this then represents the slow movement of ventricle wall than little.This result shows, this compound can be used as the curative or the prophylactic agent of the heart failure that left ventricle diastole obstacle causes.
Experimental example 4
Measure the reagent of the associativity of Troponin I and Actin muscle-tropomyosin mixture
Actin muscle (from pig muscle), tropomyosin (from the chicken gizzard) and troponin (from pig myocardium) use the product of being bought by シ ダ マ ア Le De リ Star チ company, other if no special instructions, reagent all available from the pure medicine of light Co., Ltd..
Contain 60 mM KCl, 20mM MOPS (3-morpholino propanesulfonic acid), 2mMMgCl to 500 μ L
2, 0.05 μ g pepstatin A, 15mM 2 mercapto ethanol reaction solution in add 4.2 μ g Actin muscles, 2.1 μ g tropomyosin and 14 μ g troponins, make the sample of 500 μ L.With this sample under 25 ℃ of temperature, with the centrifugal force of 2,000 * g centrifugal 10 minutes, disgorging, with this supernatant respectively dispensing in the new a plurality of test tubes that contain 10mM EGTA, respectively as being examined sample.
In this experimental example, the tested sample of the 1st test tube does not contain this compound, that is, be that this compound concentrations is the reaction solution of 0mol, and the tested sample of the 2nd test tube is that this compound concentrations is 10
-4The reaction solution of mol, the tested sample of the 3rd test tube are that this compound concentrations is 10
-5The reaction solution of mol, the tested sample of the 4th test tube are that this compound concentrations is 10
-6The reaction solution of mol, the tested sample of the 5th test tube are that this compound concentrations is 10
-7The reaction solution of mol.For each tested sample, reaction is 120 minutes under 25 ℃ temperature, applies the centrifugal force of 100,000 * g under 25 ℃ temperature respectively, carry out 120 minutes centrifugal, remove supernatant.In isolating throw out, add reaction solution quietly, throw out is suspended.Suction strainer is removed once more, and washing precipitate is as tested throw out.
In each tested throw out of cleaning, add the sample buffer that is used for polyacrylamide gel electrophoresis (SDS-PAGE), thorough mixing, tested throw out is suspended, with this throw out go up at gel (PAG ミ ニ " first " 10/20), with the 40mA electrophoresis about 1 hour, behind the electrophoresis, carry out silver with silver-colored transfection reagent [2D-silver transfection reagent " first " (Daiichi Pure Chemicals Co., Ltd.'s manufacturing)] and dye, clean after drying with distilled water.The precipitation capacity of each protein band that the silver that is obtained by this gel electrophoresis is dyed by photodensitometer is quantitative.By the aminoacid sequence of peptide as can be known: quantitative precipitates protein is a Troponin I in the protein band.The following analysis of the aminoacid sequence of the peptide of gel electrophoresis protein band: after functional quality analyrical reagent (with the silver-colored transfection reagent of mass analysis of the pure medicine of light Co., Ltd. manufacturing) dyes, cut the protein band of gel electrophoresis, use highly effective liquid phase chromatographic device [(MAGIC2002) Michrom BioResources company (U.S.) makes] that the segment peptide is analyzed.This analytical results shows: the aminoacid sequence of the peptide of protein band is IDAAEEEKYDMEIK, is accredited as Troponin I.
The precipitation capacity of the 2nd to the 5th tested sedimentary Troponin I is by obtaining with the 1st ratio of precipitation capacity of Troponin I that does not contain the tested throw out (concentration is 0mol) of this compound.
Comparative example
As comparing the compound of research with this compound, use β-blocking agent Proprasylyte as heart failure drugs, according to the method identical the associativity of Troponin I, Actin muscle-tropomyosin is measured with experimental example 4.
That is, contain 60mM KCl, 20mM MOPS (3mol morpholino propanesulfonic acid), 2mM MgCl to 500 μ L
2, 0.05 μ g pepstatin A, 15mM 2 mercapto ethanol reaction solution in add 4.2 μ g Actin muscles, 2.1 μ g tropomyosin and 14 μ g Troponin Is, make the sample of 500 μ L.With this sample under 25 ℃ of temperature, with the centrifugal force of 2,000 * g centrifugal 10 minutes, disgorging, with its supernatant respectively dispensing in the new a plurality of test tubes that contain 10mM EGTA, respectively as being examined sample.
In the comparative example, the 1st comparison sample that compares test tube is that the concentration of Proprasylyte is the reaction solution of 0mol, and the 2nd comparison sample that compares test tube is that the concentration of Proprasylyte is 10
-4The reaction solution of mol, the 3rd comparison sample that compares test tube are that the concentration of Proprasylyte is 10
-5The reaction solution of mol, the 4th comparison sample that compares test tube are that the concentration of Proprasylyte is 10
-6The reaction solution of mol, the 5th comparison sample that compares test tube are that the concentration of Proprasylyte is 10
-7The reaction solution of mol.For each tested sample, reaction is 120 minutes under 25 ℃ temperature, applies the centrifugal force of 100,000 * g under 25 ℃ temperature respectively, carry out 120 minutes centrifugal, remove supernatant.In isolating throw out, add reaction solution quietly, throw out is suspended.Suction strainer is removed once more, washing precipitate, throw out as a comparison.
In each tested throw out of cleaning, add the sample buffer that is used for polyacrylamide gel electrophoresis (SDS-PAGE), thorough mixing, the comparison throw out is suspended, with this throw out go up at gel (PAG ミ ニ " first " 10/20), with the 40mA electrophoresis about 1 hour, behind the electrophoresis, carry out silver with silver-colored transfection reagent [2D-silver transfection reagent " first " (Daiichi Pure Chemicals Co., Ltd.'s manufacturing)] and dye, clean after drying with distilled water.The precipitation capacity of each protein band that the silver that is obtained by this gel electrophoresis is dyed by photodensitometer is quantitative.
The precipitation capacity of the 2nd to the 5th more sedimentary Troponin I is by obtaining with the ratio of the precipitation capacity of the Troponin I of the comparison throw out that does not contain Proprasylyte (Proprasylyte concentration is 0mol).
The precipitation capacity of the comparison throw out Troponin I when using Proprasylyte in the precipitation capacity of the tested throw out Troponin I when experimental example 4 is used this compound and the comparative example compares research, and the result is as shown in table 4 below.
Table 4
| Embodiment 5 | Comparative example | ||
| This compound concentrations (mole) | The precipitation capacity of Troponin I | The concentration of Proprasylyte (mole) | The precipitation capacity of Troponin I |
| 0 | 1.0 | 0 | 1.0 |
| 10 -7 | 1.2 | 10 -7 | 0.9 |
| 10 -6 | 1.8 | 10 -6 | 1.1 |
| 10 -5 | 2.2 | 10 -5 | 0.9 |
| 10 -4 | 2.8 | 10 -4 | 1.1 |
In (notes) table 4, this compound is expressed as this compound.
Provided the precipitation capacity of the Troponin I under each concentration of Proprasylyte in the precipitation capacity of the Troponin I under each concentration of this compound one hydrochloride among the embodiment 5 and the comparative example in the table 4.Among the embodiment 5 of table 4, when using this compound, the precipitation capacity of Troponin I along with this compound concentrations (mol) by 10
-7Increase to 10
-4, its precipitation capacity also increases to 2.8 by 1.2.But, in comparative example, use under the situation of Proprasylyte, even the concentration of Proprasylyte is by 10
-7Increase to 10
-4, the precipitation capacity of Troponin I is between the 0.9-1.1, does not almost change.Seen in the embodiment 5 of table 4, the increase of the Troponin I precipitation capacity that this compound causes is to increase from Troponin I and Actin muscle-tropomyosin mixture bonded.This means that this compound increases the binding capacity of Troponin I and Actin muscle-tropomyosin mixture, carry out muscle relaxation, show that thus this compound promotes muscle relaxation by Troponin I by Troponin I.
Experimental example 5
In this experimental example, study of the effect of this compound to the precipitation capacity of myosin light chain contained in the experimental sample troponin that uses in the experimental example 4.
In this experimental example, the method for example 4 forms tested throw out by experiment.
In this experimental example,
(1) the tested sample in the experimental example 4 is made simultaneously not calcium ions (Ca
++) and this compound, according to example 4 preparation tested throw outs (experiment numbers 1).
(2) will be made calcium ion (Ca by sample in the experimental example 4
++) concentration (mol) is 10
-5, this compound concentration (mol) is 0, according to example 4 preparation tested throw outs (experiment numbers 2).
(3) make the tested sample in the experimental example 4 make calcium ion (Ca
++) concentration (mol) is 0, this compound concentration (mol) is 10
-3, according to example 4 preparation tested throw outs (experiment numbers 3).
(4) make the tested sample in the experimental example 4 make calcium ion (Ca
++) concentration (mol) is 10
-5, this compound concentration (mol) is 0, according to example 4 preparation tested throw outs (experiment numbers 4).
The sample buffer that in the tested throw out of above-mentioned each that obtains, adds polyacrylamide gel electrophoresis (SDS-PAGE) usefulness, thorough mixing suspends tested throw out, with this suspension go up at gel (PAG ミ ニ " first " 10/20), with the 40mA electrophoresis about 1 hour.Behind the electrophoresis, carry out silver with silver-colored transfection reagent [2D-silver transfection reagent " first " (Daiichi Pure Chemicals Co., Ltd.'s manufacturing)] and dye, clean after drying with distilled water.The precipitation capacity of each protein band that the silver that is obtained by this gel electrophoresis is dyed by photodensitometer is quantitative.By the aminoacid sequence of peptide as can be known: quantitative precipitates protein is a myosin light chain in the protein band.The following analysis of the aminoacid sequence of the peptide of gel electrophoresis protein band: after functional quality analyrical reagent (with the silver-colored transfection reagent of mass analysis of the pure medicine of light Co., Ltd. manufacturing) dyes, cut the protein band of gel electrophoresis, use highly effective liquid phase chromatographic device [(MAGIC2002) Michrom BioResources company (U.S.) makes] that the fragment peptide is analyzed.This analytical results shows: the aminoacid sequence of the peptide of protein band is HVLATLGEK and ITLSQVGDVLR, is accredited as myosin light chain.
The precipitation capacity of experiment numbers 1-4 gained as shown in the following Table 5.
Table 5
| Experiment numbers | Ca ++Concentration (mole) | This compound concentration (mole) | The precipitation capacity of myosin light chain |
| 1 | 0 | 0 | 1.0 |
| 2 | 10 -5 | 0 | 0.6 |
| 3 | 0 | 10 -3 | 1.5 |
| 4 | 10 -5 | 10 -3 | 1.4 |
The precipitation capacity of (notes) myosin light chain is to be 1.0 with the precipitation capacity in the experiment numbers 1, with its ratio value representation.
In (notes) table 5, this compound is expressed as this compound.
In this experimental example, about the precipitation capacity of myosin light chain, with calcium ion (Ca
++) concentration is 10
-5Tested throw out during mol (M) (experiment numbers 2 and 4) is compared, the precipitation capacity of myosin light chain increases in the tested throw out when not having calcium ion (experiment numbers 1 and 3) (relaxed state), in addition, precipitation capacity about myosin light chain, tested throw out (experiment numbers 1 and 2) when not having this compound is compared, with 10
-3The precipitation capacity of the myosin light chain in the tested throw out when there is this compound in the concentration of mol (experiment numbers 3 and 4) increases.And, compare with the situation that has calcium ion, have 10
-3The precipitation capacity of the myosin light chain in the tested throw out during this compound of mol concentration (experiment numbers 3 and 4) is many slightly, but is almost same amount.This shows that the existence of this compound increases the precipitation capacity of myosin light chain, when calcium ion concn is 0mol and calcium ion concn be 10
-5Identical during mol.Therefore, this shows that having or not of this compound and calcium ion is irrelevant, can strengthen muscle lax.
Experimental example 6
Mensuration to the associativity of Troponin I and Actin muscle-tropomyosin mixture
Preparation adds the solution that contains 0.4 μ g Troponin I [preparation of CALBIOCHEM company], 0.54 μ g TnC (preparation of abcam company) gained in 23 μ L distilled water in 4 test tubes, with 100, behind 000 * g centrifugal 1 hour (HITACHI himac 120FC), get 20 μ L supernatants, 4 ℃ of preservations.Then, in other 4 test tubes, in 99.4 μ L distilled water, add MgCl as the KCl aqueous solution of 50 μ L 600mM concentration of reaction solution, the MOPS of 50 μ L 200mM concentration (3-morpholino propanesulfonic acid, the Tongrentang make) aqueous solution, 50 μ L 20mM concentration
2The aqueous solution, the 2-sulfydryl methyl alcohol (preparation of SIGMA company) of the pepstatin A of 5 μ L 10mg/mL concentration (preparation of SIGMA company), 50 μ L 150mM concentration.Add the Actin muscle [preparation of SIGMA company] of 3.2 μ L 1mg/mL concentration, the tropomyosin (preparation of SIGMA company) of 2.4 μ L 1mg/mL concentration again, mix, then 25 ℃, with separating centrifuge (HITACHI himac CF7D2) centrifugal 5 minutes with the centrifugal force of 2000 * g.Its supernatant is transferred to respectively in 4 new test tubes, added ATP (5 '-Triphosaden) solution of 50 μ L 50mM concentration again, while stirring 25 ℃ of incubations 30 minutes.
Then, 100,000 * g supernatant of pre-prepd Troponin I of 20 μ L and TnC is joined in each test tube, again at 25 ℃ of incubations 30 minutes while stirring.Then, only add 50 μ L distilled water or add final concentration and be adjusted to 10
-7, 10
-6, 10
-5This compound of test solution of M is while stirring 25 ℃ of incubations 30 minutes.
Then, with Ca
2+Solution and EGTA solution mix, and add 50 μ L final concentrations and are adjusted to 10
-6The solution of M, making final total liquid measure is the every pipes of 500 μ L/.With this solution 25 ℃ of interrupted stirrings, incubation 60 minutes, then at 25 ℃ trade(brand)name), centrifugal 120 minutes by whizzer (HITACHI himac 120FC: with 100,000 * g.
After centrifugal, remove supernatant, add the above-mentioned reaction solution of 1mL quietly and (remove Ca
2+And medicine), throw out is not suspended, suction strainer is removed once more, should operate and repeat twice again, with washing of precipitate three times altogether.
Remove washed solution fully, the sample buffer that in throw out, adds 20 μ L polyacrylamide gel electrophoresis (SDS-PAGE) usefulness, thorough mixing, throw out is suspended, 95 ℃ of heat treated 5 minutes, be injected into then in PAG ミ ニ " first " 10/20 gel (preparation of first pharmaceutical chemicals), electrophoresis is about 1 hour in 40mA.Behind the electrophoresis, carry out silver with 2D-silver transfection reagent II " first " (the first pharmaceutical chemicals manufacturing) and dye, use the distilled water wash after drying.Use scanner [EPSON ES-8500 (trade(brand)name)] scanning then, analyze by analysis software ImageJ (trade(brand)name).
Its result is as shown in table 6 below.
Table 6
The precipitation capacity of Troponin I
Test tube numbering condition ratio
1 Ca10
-6This compound of M (-) 1.0
2 Ca10
-6This compound of M (10
-7M) 1.4
3 Ca10
-6This compound of M (10
-6M) 3.4
4 Ca10
-6This compound of M (10
-5M) 5.4
In this experimental example, make that calcium concn is 10 in the test tube
-6M and when not containing this compound, the amount of setting Troponin I is 1.0 o'clock, with 10
-7, 10
-6, 10
-5The co-precipitation amount that this compound of M concentration obtains is respectively 1.4,3.4,5.4, shows that the precipitation capacity of Troponin I and this compound concentrations dependency ground increase.In this experimental example, Actin muscle is from the skeletal muscle of pig, and molecular weight is 43 kilodaltons, is prepared by SIGMA company.Tropomyosin is from the gizzard of chicken, and molecular weight is 36 kilodaltons, is prepared by SIGMA company.Troponin I is from people's cardiac muscle, and molecular weight is 24 kilodaltons, is prepared by CALBIOCHEM company.TnC is from people's cardiac muscle recombinant chou, and molecular weight is 18 kilodaltons, is prepared by ascam company.They separate by the poly-propionic acid amide gel electrophoresis of SDS-, can discern each band clearly.
In this experimental example, use and to contain 0.1-1.2 μ g and will condense the isolating Troponin I of composition and 0.2-1.6 μ g TnC, also contain the mixing solutions of the solution of the tropomyosin solution of Actin muscle solution, 2.4 μ L0.5-3mg/mL concentration of 3.2 μ L0.5-3mg/mL concentration and 4-6mMATP by ultracentrifuge method.This mixing solutions for example is prepared into total amount 500 μ L before reaction, so these medicines can use with the concentration in the concentration range of this preparation.
Experimental example 7
The mensuration of the associativity of Troponin I and Actin muscle-tropomyosin mixture
Preparation adds the solution that contains 0.4 μ g Troponin I [preparation of CALBIOCHEM company], 0.54 μ g TnC (preparation of abcam company) gained in 23 μ L distilled water in 4 test tubes, by whizzer (HITACHI himac 120FC) with 100, behind centrifugal 1 hour of the centrifugal force of 000 * g, get 20 μ L supernatants, 4 ℃ of preservations.Then, the MgCl that in other 4 test tubes, in 99.4 μ L distilled water, adds 50 μ L 600mM KCl solution as reaction solution, 50 μ L 200mM MOPS (N-morpholino propanesulfonic acid, Tongrentang make), 50 μ L 20mM concentration
2, pepstatin A (preparation of the SIGMA company) solution of 5 μ L 10mg/mL concentration, 2 mercapto ethanol (preparation of the SIGMA company) solution of 50 μ L 150mM concentration.Add the Actin muscle (preparation of SIGMA company) of 3.2 μ L 1mg/mL concentration, the tropomyosin (preparation of SIGMA company) of 2.4 μ L 1mg/mL concentration afterwards again, mix, then 25 ℃, with whizzer (HITACHI himac CF7D2) centrifugal 5 minutes with the centrifugal force of 2000 * g.Its supernatant is transferred to respectively in 4 new test tubes, added the ATP solution of 50 μ L 50mM concentration again, while stirring 25 ℃ of incubations 30 minutes.Then, pre-prepd Troponin I of 20 μ L and TnC are joined in each test tube with the centrifugal isolate supernatant that obtains of the centrifugal force of 100,000 * g, again at 25 ℃ of incubations 30 minutes while stirring.Then, be adjusted to 10 with final concentration
-5This compound of M joins 50 μ L in each test tube respectively as test solution, while stirring 25 ℃ of incubations 30 minutes.
Then, with Ca
2+Solution and EGTA solution mix, and add the final calcium ion concn of 50 μ L and are adjusted to 10
-8, 10
-7, 10
-6With 10
-5The solution of M, making final total liquid measure is every pipe 500 μ L.With this solution 25 ℃ of interrupted stirrings, incubation 60 minutes, then at 25 ℃ by whizzer (HITACHI himac 120FC), centrifugal 120 minutes with 100,000 * g.After centrifugal, remove supernatant, add the above-mentioned reaction solution of 1mL quietly and (remove Ca
2+And medicine), throw out is not suspended, suction strainer is removed once more, should operate and repeat twice again, with washing of precipitate 3 times altogether.
Remove washing soln fully, the sample buffer that in throw out, adds 20 μ L polyacrylamide gel electrophoresis (SDS-PAGE) usefulness, thorough mixing, throw out is suspended, 95 ℃ of heat treated 5 minutes, be injected into then in PAG ミ ニ " first " 10/20 gel (preparation of first pharmaceutical chemicals), electrophoresis is about 1 hour in 40mA.Behind the electrophoresis, carry out silver with 2D-silver transfection reagent II " first " (the first pharmaceutical chemicals manufacturing) and dye, use the distilled water wash after drying.Use scanner [EPSONES-8500 (trade(brand)name)] scanning then, ImageJ analyzes by analysis software, obtains the precipitation capacity of Troponin I.Its result is as shown in table 7 below.
Table 7
The precipitation capacity of Troponin I
Test tube numbering condition ratio
1 Ca10
-8This compound of M (10
-5M) 1.0
2 Ca10
-7This compound of M (10
-5M) 0.94
3 Ca10
-6This compound of M (10
-5M) 0.81
4 Ca10
-5This compound of M (10
-5M) 0.78
In this experimental example, this compound concentration is 10 in the setting test tube
-5M, calcium concn are 10
-8The amount of sedimentary Troponin I is 1.0 under the M, then along with calcium concn 10
-7, 10
-6, 10
-5The raising successively of M, precipitation capacity is respectively 0.94,0.81,0.78, reduces successively.This demonstration: calcium concn is low, and then the Troponin I precipitation capacity is many, that is, in this experimental example, the precipitation capacity of the Troponin I that this compound causes is subjected to the influence of calcium concn.
Experimental example 8
This compound is to the inhibition of the torsades de pointes ventricular tachycardia that brought out by the non-ammonium of chlorine
In this experimental example, use 4 white rabbits of body weight as 2.8kg-3.2kg.Anesthesia to each rabbit is to carry out with the intravenous anesthesia of 5mg/kg brietal sodium.In addition, under the artificial respiration of trachea cannula, each rabbit is inserted the intubate that is used to inject this compound and experimental drug thing to its right external jugular vein, insert the micro-tip catheter (manufacturing of Millar company, SPC-320) that is used to measure blood pressure by right common carotid artery.
This compound dissolution of 100mg in 1mL dimethyl sulfoxide (DMSO) (DMSO), is prepared this compound solution, this solution is preserved under 4 ℃ of temperature.
Each rabbit is led the acquisition electrocardiogram(ECG second, in addition, electrocardiogram(ECG and blood pressure are recorded in the Personal Computer simultaneously via A/D converter.In this experimental example, in electrocardiogram(ECG,, then be judged as the torsades de pointes ventricular tachycardia if the waveform of multiform ventricular tachycardia is continuous more than 6.In this experimental example,, be from giving behind the non-ammonium of chlorine in 30 minutes, by the expression number of times of detecting ECG torsades de pointes ventricular tachycardia for the torsades de pointes ventricular tachycardia.In this experimental example, α stimulating drug methoxamedrine causes the torsades de pointes ventricular tachycardia easily, thereby uses this medicine.In this experimental example, the non-ammonium of this compound, methoxamedrine and chlorine mixes with physiological saline and gives.
In this experimental example, it is the 1st rabbit of 3.0kg that embodiment A is to use body weight, and it is the 2nd rabbit of 3.1kg that Embodiment B is to use body weight.Comparative examples A is used 3rd rabbit of body weight as 2.8kg, and comparative example B uses 4th rabbit of body weight as 3.1kg.
In this experimental example, at first give methoxamedrine, after 10 minutes, began to give chlorine non-ammonium with 50 μ g/kg/ minutes with 15 μ g/kg/ minutes rabbits to embodiment A and B.The non-ammonium of chlorine be to begin to give the back to continue 20 minutes.For the rabbit of routine A and B, when beginning to give the non-ammonium of this chlorine, begin to give this compound with 0.2mg/kg/ minute intravenously.For the rabbit of embodiment A and B, this compound be to give to continue 10 minutes again after the non-ammonium of chlorine finishes.Observe by the electrocardiogram(ECG of the rabbit of embodiment A and B being expressed the torsades de pointes ventricular tachycardia, the torsades de pointes ventricular tachycardia takes place after give the non-ammonium of chlorine and finish again through 10 minutes, that is, last till to give behind the non-ammonium of chlorine 30 minutes.Continue to have given this compound during this, therefore above-mentioned Electrocardiographic observation is carried out during giving this compound.
In this experimental example, do not give this compound for the rabbit of Comparative examples A and B, in addition the rabbit with embodiment A and B carries out equally.That is, for the rabbit of Comparative examples A and comparative example B, give methoxamedrine with 15 μ g/kg/ minutes, beginning gave chlorine non-ammonium with 50 μ g/kg/ minutes after 10 minutes.The non-ammonium of chlorine be after beginning, to continue to give in 20 minutes.In this experimental example,, observe to express the electrocardiogram(ECG of torsades de pointes ventricular tachycardia for the rabbit of Comparative examples A and B, the torsades de pointes ventricular tachycardia be after giving the non-ammonium of chlorine and finishing again through 10 minutes, that is, last till to give behind the non-ammonium of chlorine 30 minutes.
With reference to Fig. 1-5, Electrocardiographic observations is described.
About the rabbit of embodiment A and B, giving under the condition of methoxamedrine beginning with 50 μ g/kg/ minutes non-ammoniums of persistent intravenous injection chlorine with 0.2mg/kg/ minute this compound of persistent intravenous injection, the electrocardiogram(ECG that begins during back 30 minutes is observed.But as shown in Figure 1, in the electrocardiogram(ECG of this embodiment A and B rabbit was observed, electrocardiogram(ECG was a waveform 1 of not seeing ventricular arrhythmia, after 23 minutes, did not see the expression of torsades de pointes ventricular tachycardia at the beginning persistent intravenous injection yet.Even the beginning persistent intravenous injection is not seen the expression of torsades de pointes ventricular tachycardia after 30 minutes yet yet.This expression: this compound has suppressed the generation of torsades de pointes ventricular tachycardia fully.
For the rabbit of Comparative examples A, giving under the condition of methoxamedrine beginning with the 50 μ g/kg/ minutes non-ammoniums of persistent intravenous injection chlorine, the electrocardiogram(ECG that begins during back 30 minutes is observed.As shown in Figure 2, in the electrocardiogram(ECG of the rabbit of Comparative examples A is observed,, can confirm that the waveform 3 of torsades de pointes ventricular tachycardia is expressed giving the non-ammonium of chlorine in the time of 25 minutes 19 seconds (arrow 2 represented the moment).As shown in Figure 3, the waveform 3 of the torsades de pointes ventricular tachycardia of this expression stops through 25 seconds (moment shown in the arrow 4) after expression, takes place repeatedly afterwards (being outside Fig. 3 scope, not shown).
For the rabbit of comparative example B, giving under the condition of methoxamedrine beginning with the 50 μ g/kg/ minutes non-ammoniums of persistent intravenous injection chlorine, the electrocardiogram(ECG that begins during back 30 minutes is observed.As shown in Figure 4, during the electrocardiogram(ECG of the rabbit of comparative example B observed, after giving the non-ammonium of chlorine 22 minutes 30 seconds the time (shown in the arrow 5 constantly), the waveform 3 of visible torsades de pointes ventricular tachycardia was expressed.As shown in Figure 5, the waveform 3 of the torsades de pointes ventricular tachycardia of this expression stops in back 49 seconds of expression (moment shown in the arrow 6), but afterwards (outside Fig. 5 scope, not shown) takes place repeatedly.These electrocardiogram(ECG observationss are as shown in table 8.
Table 8
Rabbit numbering experiment medicine torsades de pointes chamber property is aroused in interest
The occurrence number of overrunning
Non-ammonium+the methoxamedrine of experimental example A chlorine+this compound 0 time
Non-ammonium+the methoxamedrine of experimental example B chlorine+this compound 0 time
Non-ammonium+the methoxamedrine of embodiment A chlorine 9 times
Non-ammonium+the methoxamedrine of Embodiment B chlorine 4 times
Among Comparative examples A and the B,, all caused the torsades de pointes ventricular tachycardia, but when giving the non-ammonium of chlorine, given all not cause the torsades de pointes ventricular tachycardia in the embodiment A and B of this compound by giving chlorine non-ammonium.This shows: this compound has suppressed to give the generation of the torsades de pointes ventricular tachycardia that still continues behind the non-ammonium of chlorine fully.In this experimental example, the torsades de pointes ventricular tachycardia is that drug-induced property or ionogen are when unusual, by removing the occurrence cause of torsades de pointes ventricular tachycardia, the torsades de pointes ventricular tachycardia can disappear, in this case, when giving this compound, eliminate the occurrence cause of torsades de pointes ventricular tachycardia.The giving of this compound also has the effect that does not cause the torsades de pointes ventricular tachycardia and irregular pulse is stopped, therefore suppress the generation of torsades de pointes ventricular tachycardia, remove the occurrence cause of torsades de pointes ventricular tachycardia simultaneously, can be attended by the ARR treatment of torsades de pointes ventricular tachycardia.
Past, for experimental checking torsades de pointes ventricular tachycardia, usually use the non-ammonium of chlorine, therefore also used the non-ammonium of chlorine in this experimental example as the medicine that brings out the torsades de pointes ventricular tachycardia, also can use medicine third pyridine, Quinidine, procainamide or the Propafenone with the effect of moderate inhibition sodium channel of IA class in the treating irregular heart pulse medicine classification of being advocated by VaughanWilliams, the ARR curative that the Nifekalant of III class or amiodarone etc. cause multipole to postpone in this classification replaces the non-ammonium of chlorine in addition.
Experimental example 9
This compound is to the influence of blood pressure
Study of the influence of this compound according to the method identical to blood pressure with experimental example 2.In this experimental example, reference examples and embodiment 6-9 give the 20mg/kg Thiopental Sodium with the single intravenously respectively and implement anesthesia, and endotracheal intubation is breathed and used Spirophore (TypeAR1 Na リ シ ゲ manufacturing).In this experimental example, use the pharmacologically acceptable salts of this compound as above-mentioned 1,4 benzothiazepine derivatives.
In this experimental example, use the white rabbit of 5 body weight as 2.7kg-2.9kg.The rabbit body weight that contrasts the reference examples 1 of liquid is 2.8kg, and the rabbit body weight that gives the embodiment 6 of 0.04mg/kg/ minute this compound is 2.7kg, and the rabbit body weight that gives the embodiment 7 of 0.04mg/kg/ minute this compound equally is 2.7 kg.The rabbit body weight that gives the embodiment 8 of 0.4mg/kg/ minute this compound is 2.9kg, and the rabbit body weight that gives the embodiment 9 of 0.4mg/kg/ minute this compound is 2.8kg.
Give the 20mg/kg Thiopental Sodium to each rabbit single intravenously and implement anesthesia, endotracheal intubation is breathed and is used Spirophore (TypeAR1 Na リ シ ゲ manufacturing).Inject 90mg/kg/20 minute α glucochloral by ear vein then.This compound dissolution of 100mg in 1mL dimethyl sulfoxide (DMSO) (DMSO), is prepared the DMSO solution of this compound, this solution is preserved under 4 ℃ of temperature.
In this experimental example, the intubate that will be used to inject this compound and experimental drug thing is inserted into right external jugular vein, inserts the micro-tip catheter that measures blood pressure (Millar company makes, SPC-320) by right common carotid artery.Lead by second and to obtain electrocardiogram(ECG,, when treating that they stablize, pass through A/D converter, electrocardiogram(ECG and systolic blood pressure, the diastolic blood pressure of each rabbit is recorded in the Personal Computer blood pressure, heart rate, the electrocardiogram(ECG monitoring of rabbit 10 minutes.Contrast in the reference examples of liquid, 5% glucose solution that contains 0.1%DMSO with 0.1mL/ minute speed is liquid in contrast, gives 10 minutes.In the embodiment 6 and 7 that gives this compound, inject 5% D/W that contains this compound with 0.1mL/ minute speed, this moment, the injection rate of this compound was 0.04mg/kg/ minute.Among the embodiment 8 and 9, inject 5% D/W that contains this compound with 0.1mL/ minute speed, this moment, the injection rate of this compound was 0.4mg/kg/ minute.
Each rabbit for reference examples and embodiment, before giving test solution, give 5 minutes and 10 minutes after, measure systolic blood pressure (mmHg) and the diastolic blood pressure (mmHg) of 5 cardiac cycle, by following formula, obtain mean blood pressure (mmHg) by systolic blood pressure (mmHg) and the diastolic blood pressure (mmHg) measured.
Mean blood pressure (mmHg)=[(systolic blood pressure+diastolic blood pressure) * 1/2] (formula)
Experimental result as shown in the following Table 9.
Table 9
This compound administered dose (mg/kg/ minute) is to the influence of mean blood pressure (mmHg)
| Administered dose | 0 | 0.04 | 0.04 | 0.4 | 0.4 |
| (during mensuration) | Reference examples | Embodiment 6 | Embodiment 7 | Embodiment 8 | Embodiment 9 |
| Before giving | 78.3 (100％) | 85.6 (100％) | 87.7 (100％) | 74.7 (100％) | 97.7 (100％) |
| After 5 minutes | 75.4 (96.3％) | 79.5 (92.9％) | 82.0 (93.5％) | 35.7 (48.2％) | 64.5 (66.0％) |
| After 10 minutes | 78.7 (100.5％) | 85.9 (100.4％) | 93.4 (106.5％) | 41.7 (56.4％) | 46.3 (47.4％) |
Be 100% to contrast the mean blood pressure that is subjected to before the reagent thing respectively, the mean blood pressure of reference examples after 10 minutes is 100.5%, contrasts to be subjected to almost not change before and after the reagent thing.
With the mean blood pressure that gives before this compound is 100%, in the embodiment 6 that gave with 0.04mg/kg/ minute, is 100.4% after 10 minutes then, and embodiment 7 is 106.5%, and is identical with the normal control example, and mean blood pressure does not almost change.In with the embodiment that gave this compound in 0.4mg/kg/ minute, to be 100% before giving, then among the embodiment 8,, be to be 56.4% after 48.2%, 10 minute after 5 minutes with respect to the mean blood pressure before giving, with give before compare, reduce by 40% or more than.In the embodiment 9 that gave this compound in 0.4mg/kg/ minute, with respect to the mean blood pressure before giving, be to be 47.4% after 66.0%, 10 minute after 5 minutes, with give before compare reduce by 50% or more than.This expression: the effect that this compound brings high blood pressure down with having the concentration dependency can be used as hypertensive curative.
Experimental example 10
This compound is to the influence of heart rate and Electrocardiographic PQ interval (by the conduction of velocity of atrium to the stimulus-transmitting system system of ventricle)
In this experimental example, use a hydrochloride 4-[3-(4-benzyl piepridine-1-yl) propionyl of this compound]-7-methoxyl group-2,3; 4; 5-tetrahydrochysene-1, a hydrochloride (hereinafter referred to as this compound) of 4-benzothiazepine is as the pharmacologically acceptable salt of above-mentioned 1,4 benzothiazepine derivatives.
In this experimental example, use the white rabbits of 5 body weight as 2.7kg-2.9 kg.The rabbit body weight that contrasts the reference examples 1 of liquid is 2.8kg, and the rabbit body weight that gives the embodiment 10 of 0.04mg/kg/ minute this compound is 2.7kg, and the rabbit body weight that gives the embodiment 11 of 0.04mg/kg/ minute this compound equally is 2.7kg.The rabbit body weight that gives the embodiment 12 of 0.4mg/kg/ minute this compound is 2.9kg, and the rabbit body weight that gives the embodiment 13 of 0.4mg/kg/ minute this compound is 2.8kg.
Give the 20mg/kg Thiopental Sodium to each rabbit single intravenously and implement anesthesia, endotracheal intubation is breathed and is used Spirophore (TypeAR1 Na リ シ ゲ manufacturing).Inject 90mg/kg/20 minute α glucochloral by ear vein then.This compound dissolution of 100mg in 1mL dimethyl sulfoxide (DMSO) (DMSO), is prepared the DMSO solution of this compound, this solution is preserved under 4 ℃ of temperature.
In this experimental example, the intubate that will be used to inject this compound and experimental drug thing is inserted into right external jugular vein, inserts the micro-tip catheter that measures blood pressure (Millar company makes, SPC-320) by right common carotid artery.Lead by second and to obtain electrocardiogram(ECG,, when treating that they stablize, pass through A/D converter, electrocardiogram(ECG and systolic blood pressure, the diastolic blood pressure of each rabbit is recorded in the Personal Computer blood pressure, heart rate, the electrocardiogram(ECG monitoring of rabbit 10 minutes.Contrast in the reference examples of liquid, 5% glucose solution that contains 0.1%DMSO with 0.1mL/ minute speed is liquid in contrast, gives 10 minutes.In the embodiment 10 and 11 that gives this compound, inject 5% D/W that contains this compound with 0.1mL/ minute speed, this moment, the injection rate of this compound was 0.04mg/kg/ minute.Give among the embodiment 12 and 13 of this compound, inject 5% D/W that contains this compound with 0.1mL/ minute speed, this moment, the injection rate of this compound was 0.4mg/kg/ minute.
For each rabbit of reference examples, embodiment, before giving test solution, give after 5 minutes, 10 minutes to measure heart rate and PQ interval.The PQ interval is that the expression electricity irritation is by the conduction of velocity of atrium to ventricle by the beginning to the time the beginning of Q ripple of P ripple.To give before the test solution is 100%, carries out record with the ratio of this value.
Measurement of Heart Rate result is as shown in table 10 below.
Table 10
This compound administered dose (mg/kg/ minute) to heart rate/minute influence
| Administered dose | 0 | 0.04 | 0.04 | 0.4 | 0.4 |
| (during mensuration) | Reference examples | Embodiment 10 | Embodiment 11 | Embodiment 12 | Embodiment 13 |
| Before giving | 334 | 297 | 286 | 372 | 327 |
| (100％) | (100％) | (100％) | (100％) | (100％) | |
| After 5 minutes | 332 | 289 | 283 | 350 | 311 |
| (99.4％) | (97.3％) | (99.0％) | (94.1％) | (95.1％) | |
| After 10 minutes | 328 | 286 | 281 | 157 | 98 |
| (98.2％) | (96.3％) | (98.3％) | (42.2％) | (30.0％) |
Be 100% to contrast the heart rate that is subjected to before the reagent thing respectively, with after heart rate compare, in the reference examples that does not give, the heart rate that begins to measure after 10 minutes is 98.2%, contrast be subjected to before the reagent thing after almost not variation.
When giving this compound, being 100% with the heart rate before giving, in the embodiment 10 that gave this compound in 0.04mg/kg/ minute, is 96.3% after 10 minutes, same, among the embodiment 11 is 98.3%, identical with the normal control example, and heart rate does not almost change.In the embodiment 12 and 13 that gave this compound in 0.4mg/kg/ minute, to give before this compound is 100%, among the embodiment 12, is 94.1% after 5 minutes, be 42.2% after 10 minutes, with give before compare, reduce by 55% or more than, in the embodiment 13 that gave this compound in 0.4mg/kg/ minute, be 95.1% after 5 minutes, be 30.0% after 10 minutes, with give before compare, reduced by 70%.
This compound of table 11 administered dose (mg/kg/ minute) and PQ interval (millisecond)
| Administered dose | 0 | 0.04 | 0.04 | 0.4 | 0.4 |
| (during mensuration) | Reference examples | Embodiment 10 | Embodiment 11 | Embodiment 12 | Embodiment 13 |
| Before giving | 64 | 71 | 64 | 69 | 68 |
| (100％) | (100％) | (100％) | (100％) | (100％) | |
| After 5 minutes | 65 | 73 | 66 | 92 | 82 |
| (101.6％) | (102.8％) | (103.1％) | (133.3％) | (120.6％) | |
| After 10 minutes | 64 | 74 | 68 | 107 | 103 |
| (100％) | (104.2％) | (106.3％) | (155.1％) | (151.5％) |
To contrast the PQ interval that is subjected to before the reagent thing is 100%, and the PQ interval after relatively, the PQ interval of the reference examples that does not give after 10 minutes is 100%, does not change before and after contrasting tested medicine.The PQ interval that gives before this compound is 100%, with the PQ interval of the embodiment 10 that gave this compound in 0.04mg/kg/ minute be 104.2% at 10 minutes, the PQ interval of embodiment 11 is 106.3%, and is same with reference examples, the PQ interval, almost do not change.In the embodiment 12 and 13 that gave this compound in 0.4mg/kg/ minute, to be 100% before giving, after being 133.3%, 10 minute after 5 minutes, be 155.1% among the embodiment 12, with give before compare, increase more than 50%.Is 151.5% with the embodiment 13 that gave this compound in 0.4mg/kg/ minute after being 120.6%, 10 minute after 5 minutes, with give before compare, increase more than 50%.This result shows: this compound has concentration dependency ground and increases the PQ effect of interval, can be used for sinus tachycardia or supraventricular tachycardia (going up Shi Frequency Veins).
Experimental example 11
About the experimental example of this compound for myocardial relaxation prevention of disorder effect
This experimental example is the giving 20 minutes calcium, give in the experiment of calcium solution and noradrenaline cellulose solution then of experimental example 1, gives this compound before 5 minutes giving the noradrenaline cellulose solution, observes left ventricle diastole prevention of disorder effect.
In this experimental example, use the pharmacologically acceptable salt of this compound as above-mentioned 1,4 benzothiazepine derivatives.
Use 8 week ages, body weight be the wistar male rat of 310-320g.Anesthesia is injected 1000mg/kg urethanum and 80mg/kg Chloralosane down by peritonaeum and is carried out.Breathing is a tracheostomize, and endotracheal intubation uses Spirophore (SN-480-7, the シ of Co., Ltd. Na ノ makes institute).In this experimental example, this compound dissolution of 100mg in 1mL dimethyl sulfoxide (DMSO) (DMSO), is prepared the DMSO solution of this compound, this solution is preserved under 4 ℃ temperature.The injection rate of norepinephrine is 40 μ g/kg/ minutes, the 1mg norepinephrine is dissolved in the 41 μ L distilled water preparation noradrenaline cellulose solution.
At first, insert the intubate that the norepinephrine aqueous solution that continues to inject calcium chloride water or contain calcium chloride is used to the right external jugular vein of above-mentioned rat, insert micro-tip catheter (manufacturing of Millar company, SPC-320) by right common carotid artery to left ventricle equally, measure the left ventricle dilatation end of term and press.Similarly insert again and be subjected to reagent thing solution injection intubate by right femoral vein.
Lead the acquisition electrocardiogram(ECG first, and, electrocardiogram(ECG, left ventricular pressure are recorded in the Personal Computer simultaneously through A/D converter.Each 5 minutes, as left ventricular end-diastolic pressure, measured for 20 cardiac cycle with the pressure consistent with Electrocardiographic R ripple, ask its mean value, survey the periodic left ventricle end of term with this as this and press.Blood pressure, the rhythm of the heart, electrocardiogram(ECG to above-mentioned rat are monitored 15 minutes, when they are stablized, with per minute 16.6 μ L (being converted into calcium chloride is 12.0mg/kg/ minute), to inject 20 minutes by right external jugular vein according to 5% glucose solution that the body weight of rat has been regulated the calcium chloride of calcium chloride concentration, with this as preparation.
Then, begin to inject the norepinephrine aqueous solution that contains calcium chloride by right external jugular vein immediately, wherein calcium chloride is usage and the capacity that does not change above-mentioned calcium chloride water, norepinephrine is to inject with 40 μ g/kg/ minutes, after the beginning, continue to inject calcium chloride and norepinephrine by this norepinephrine aqueous solution that contains calcium chloride.Beginning to inject this norepinephrine aqueous solution (intravenous injection) norepinephrine that contains calcium chloride before 5 minutes from right external jugular vein, on one side continue to inject calcium chloride by right external jugular vein, on one side with time of 30 seconds conduct is not given this compound reference examples, body weight is that the rat of 310g is only injected the solvent that 0.2mL is subjected to the reagent thing from right femoral vein---the 1%DMSO aqueous solution.
Same with above-mentioned reference examples, in the body weight to embodiment 14 is before the rat of 320g is injected the norepinephrine aqueous solution contain calcium chloride 5 minutes, on one side continue to inject the norepinephrine aqueous solution that contains calcium chloride by right external jugular vein, with 30 second time similarly from right femoral vein injection 0.2mL contain the 1%DMSO aqueous solution of 0.3mg/kg on one side.
In this example,, with injecting above-mentioned being subjected to after the reagent thing in 30 seconds, be that the dilution of 1/10 concentration is subjected to the reagent thing with the reagent thing dilution that is subjected to of appending that injection will inject in 10 μ L/ minutes for reference examples, the time be after beginning injection to be subjected to the reagent thing to 15 minutes during in.In this example, for the embodiment 14 that has given this compound, injected the 1%DMSO aqueous solution that 0.2mL contains above-mentioned this compound that is subjected to the reagent thing of 0.3mg/kg with 30 seconds after, again appending the 1%DMSO aqueous solution that injects above-mentioned compound in 0.02mg/kg/ minute, the time be from begin to inject be subjected to the reagent thing after to 15 minutes during in.In this experimental example, being subjected to the reagent thing all is to be dissolved in 5% glucose solution.For each rat, left ventricular end-diastolic pressure is every 5 minutes, as left ventricular end-diastolic pressure, measures for 20 cardiac cycle with the pressure consistent with Electrocardiographic R ripple, is obtained by its mean value.Injection is subjected to the reagent thing to begin to finish after 15 minutes experiment.
Adopt the ultrasonic wave tissue Doppler method, each rat is checked the left ventricular wall diastolic function.The diagnostic ultrasound equipment (ToshibaPowervision SSA-380APSK-70LT) that diagnostic ultrasound equipment uses Toshiba Corporation to make is checked with the ultrasonic wave of 10MHz.For each rat, at first anterior part of chest is shaved hair, aim at apex of the heart position with ultrasound probe, scanning apex of the heart position long axis of left ventricle layer, place the sampling container of pulse Doppler at the base portion of PM cusp, measure the left ventricular wall wall speed [Ea ripple (m/ second)] of diastole, with this as left ventricular wall diastole ability.It is as shown in the table for the result to be subjected to the speed [Ea ripple (m/ second)] of left ventricular end-diastolic pressure and the myocardium of left ventricle wall of preceding 5 minutes reference examples of reagent thing and embodiment 14.In this experimental example, left ventricular wall diastole ability with the norepinephrine intravenous injection of obtaining by the tissue Doppler method after before left ventricular wall wall diastole speed and the same intravenous injection norepinephrine of obtaining with the tissue Doppler method of (give back) left ventricular wall (being normal left ventricular wall) wall velocity ratio diastole of (giving preceding) represent.Its result as shown in the following Table 12.
Table 12
| Elapsed time | Left ventricular end-diastolic pressure | |
| Reference examples | Embodiment 14 | |
| Give (to begin to give CaCl in preceding 25 minutes 2Preceding 5 minutes) | 7.4 | 7.2 |
| Give (to begin to give CaCl in preceding 20 minutes 2After immediately) | 7.6 | 7.7 |
| Give (to begin to give CaCl in preceding 10 minutes 2Back 10 minutes) | 8.2 | 7.9 |
| (begin to give CaCl before giving 2Back 20 minutes) | 8.0 | 8.1 |
| Give back 5 minutes (the beginning intravenous injection was subjected to the reagent thing after 5 minutes) | ||
| (before the beginning intravenous injection norepinephrine) | 8.2 | 8.0 |
| Give back 10 minutes (the beginning intravenous injection was subjected to the reagent thing after 10 minutes) | ||
| (beginning intravenous injection norepinephrine is after 5 minutes | 28.8 | 14.5 |
| Give back 15 minutes (the beginning intravenous injection was subjected to the reagent thing after 15 minutes) | ||
| (beginning intravenous injection norepinephrine is after 10 minutes | 46.4 | 18.3 |
The left ventricular end-diastolic pressure that reference examples gives before the calcium chloride is 7.4mmHg, and being subjected to reagent thing left ventricular end-diastolic pressure before is 8.0mmHg.In this reference examples, beginning intravenous injection norepinephrine was 28.8mmHg after 5 minutes, and beginning intravenous injection suprarenin rose to 46.4mmHg after 10 minutes.
Can see that from embodiment 14 left ventricular end-diastolic pressure before giving calcium chloride is 7.2mmHg, injection is subjected to be 8.1mmHg before the reagent thing.Give norepinephrine and be 14.5mmHg after 5 minutes, give norepinephrine and be 18.3mmHg after 10 minutes, compare, obviously suppressed the rising of left ventricular end-diastolic pressure when giving this compound as can be known with reference examples.Hence one can see that: even gave this compound contain the noradrenaline cellulose solution of calcium chloride in injection before, also can suppress the rising of left ventricular end-diastolic pressure, improve the diastole obstacle.
Experimental example 12
This compound is for the influence of microcirculqtory system in the cardiac muscle
Study of the influence of this compound to microcirculqtory system in the cardiac muscle.
In this example, the pharmacologically acceptable salt of above-mentioned 1,4 benzothiazepine derivatives uses a hydrochloride of this compound; be 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2,3,4; one hydrochloride (hereinafter referred to as this compound) of 5-tetrahydrochysene-1,4 benzothiazepine.
Use 48 week age, body weight be the wistar male rat of 300-310g.Anesthesia is undertaken by injection 1000mg/kg urethanum and 80 mg/kg Chloralosanes under the peritonaeum, and breathing is a tracheostomize, and endotracheal intubation uses Spirophore (Ha one バ one De).In this example, this compound dissolution of 100mg in 1mL dimethyl sulfoxide (DMSO) (DMSO), is prepared the DMSO solution of this compound, this solution is preserved under 4 ℃ of temperature.The injection rate of norepinephrine is 30 μ g/kg/ minutes, and its preparation method is that the 1mg norepinephrine is dissolved in the 41 μ L distilled water, makes the noradrenaline cellulose solution.
At first, the intubate that will be used for continuing the injection calcium chloride water or contain the norepinephrine aqueous solution of calcium chloride is inserted into the right external jugular vein of above-mentioned rat, similarly 2F polyethylene intubate is inserted in the left ventricle by right common carotid artery, is used to inject microsphere.Insert by right femoral vein equally and be subjected to reagent thing solution injection intubate.
Lead the acquisition electrocardiogram(ECG first,, electrocardiogram(ECG, left ventricular pressure are recorded in the Personal Computer simultaneously via A/D converter.Blood pressure, the rhythm of the heart, electrocardiogram(ECG to above-mentioned rat are monitored 15 minutes, when they are stablized, with per minute 16.6 μ L (being converted into calcium chloride is 12mg/kg/ minute), to inject 20 minutes by right external jugular vein according to 5% glucose solution that the body weight of rat has been regulated the calcium chloride of calcium chloride concentration, with this as preparation.Then, begin to inject the norepinephrine aqueous solution that contains calcium chloride by right external jugular vein equally, wherein calcium chloride is usage and the capacity that does not change above-mentioned calcium chloride water, norepinephrine is to inject with 30 μ g/kg/ minutes, after the beginning, contain the norepinephrine aqueous solution of calcium chloride by this, continue to inject calcium chloride and norepinephrine.Began to inject 5 minutes before by this norepinephrine aqueous solution that contains calcium chloride, continue to inject calcium chloride by right external jugular vein, to the rat (body weight 310g) of the reference examples A that do not give this compound with do not give the rat (body weight 300g) of the reference examples B of this compound, contain 5% glucose solution of the 0.1%DMSO aqueous solution by right femoral vein.In addition, to the rat (body weight 300g) of the embodiment 15 that given this compound and the rat (body weight 300g) of embodiment 16, contain preceding 5 minutes of the norepinephrine aqueous solution of calcium chloride beginning to inject (intravenous injection) by right external jugular vein, continue on one side to continue to inject calcium chloride by right external jugular vein, give on one side to be dissolved in 0.33mg/kg/ minute this compound 3 minutes in 5% glucose, give 25 minutes with 0.01mg/kg/ minute lasting intravenously then.Injection speed is: the speed with 0.5mL/3 minute gave in initial 3 minutes, was 0.05mL/3 minute speed afterwards.
Be determined at the twice cardiac muscular tissue volume of blood flow of the norepinephrine aqueous solution after 20 minutes that begins to give before the calcium chloride 5 minutes and begin to contain calcium chloride by the microsphere method.Via the polyethylene intubate that is retained in the left ventricle, use syringe pump (model KDS230) with 0.6mL/ minute speed with injecting microsphere [for the first time: (Yellow DYE-TRAK) VII+, for the second time: (Persimmon DYE-TRAK) VII+ (being the manufacturing of ト リ ト Application テ Network ノ ロ ジ one company)] in 50 seconds, inject about 200,000/every rat altogether.On the other hand, obtain with reference to blood via the intubate that is retained in the femoral artery.That is,, use syringe pump (model KDS230) by injecting before the microsphere 10 seconds to 75 second, with 0.84mL/ minute speed suction, blood sampling.After measuring end, extract left ventricle, measure left ventricular mass.Dissolve left ventricle and, extract contained pigment, use dual beam spectrophotometer (150-20, Hitachi Co., Ltd) to measure the absorbancy of pigment with reference to blood.Neutralize with reference to the microsphere computation organization volume of blood flow in the blood by the tissue of being measured.
Being calculated as follows of regional blood flow carried out.
Qm=(Am * Qr)/the Ar formula
In the formula, Qm represents the volume of blood flow (mL/ minute/myocardium g) of sample, and Qr represents that with reference to the blood rate of recovery (mL/ minute) Am represents the absorbancy of the microsphere part in the 1g tissue, and Ar represents the absorbancy with reference to the whole microspheres in the blood.
Gained cardiac muscular tissue volume of blood flow as shown in the following Table 13.
Table 13
| Embodiment | Cardiac muscular tissue's volume of blood flow (unit: ml/ minute/g) with than (%) | |
| Begin to give CaCl 25 minutes before | Begin to contain CaCl 2Norepinephrine after 20 minutes | |
| Reference examples A (solvent) reference examples B (solvent) | 5.5(100％) 5.1(100％) | 2.2(41％) 2.9(57％) |
| Embodiment 15 (this compound) embodiment 16 (these compounds) | 4.6(100％) 4.3(100％) | 3.2(70％) 4.2(98％) |
In the reference examples, be 100% to begin the giving preceding 5 minutes cardiac muscular tissue's volume of blood flow of calcium chloride, the cardiac muscular tissue volume of blood flow of norepinephrine after 20 minutes that begins to contain calcium chloride is 41% in reference examples A, is 57% in reference examples B.Give among the embodiment of this compound, the cardiac muscular tissue's volume of blood flow that began to give before the calcium chloride 5 minutes is 100%, the cardiac muscular tissue volume of blood flow of norepinephrine after 20 minutes that then begins to contain calcium chloride is 70% in embodiment 15, is 98% in embodiment 16.Hence one can see that: do not give this compound, have only in the reference examples of solvent, cardiac muscular tissue's volume of blood flow is 41%, 57%, descends, and in contrast, gives the reduction that this compound can suppress cardiac muscular tissue's volume of blood flow.
Usually, when causing the diastole obstacle, cardiac muscular tissue's volume of blood flow reduces by 50% approximately, and in contrast, by giving this compound, the reduction of this volume of blood flow can be controlled at below 30%.Hence one can see that: the blood flow that flows to cardiac muscular tissue mainly is to flow in the diastole of heart, so this compound improves the diastole obstacle of cardiac muscle, the volume of blood flow of increase cardiac muscular tissue, the microcirculqtory system obstacle of improvement cardiac muscle.
Industrial applicability
Contain above-mentioned 1,4 benzothiazepine derivatives or its officinal salt have the relexation of the muscle such as cardiac muscle, skeletal muscle and smooth muscle as the medicine of active ingredient, for example give after this medicine, within short time or desired time, can shrink myocardium meat and have no effect and lax cardiac muscle, thus, for example can improve the blood flow in myocardium coronary circulation, particularly the Myocardial Microcirculation system, can treat the angina pectoris that cardiomegaly, particularly severe aortic stenosis or aortic incompetence cause for this reason. For example, promote myocardial relaxation by giving this medicine, can also treat and preventing hypertension heart disease, idiopathic hypertrophy type cardiomyopathy and reduce the myocardium obstacle etc. of expression with Electrocardiographic ST. For example by giving this medicine, promote myocardial relaxation, also can treat and prevent the myocardial relaxation depletion such as LV Diastolic depletion. This medicine for example can be treated the acute pulmonary edema from the LV Diastolic obstacle that is difficult to cure, peripheral vessel can also relax, the curative that also can be used for the short arrhythmia that takes place frequently, particularly Ventricular Tachycardia of diastole as hypertension, the particularly hypertensive medicine of bringing out property of youngster's naphthol amine, and this medicine. This medicine also can provide preventive medicine and the curative because of the drug-induced torsades de pointes Ventricular Tachycardia that occurs that in the past not yet occurred, and this is for perfect message of patient Lai Shuoshi.
As mentioned above, contain above-mentioned Isosorbide-5-Nitrae benzothiazepine derivatives or its officinal salt and can bring into play new effect in treatment and the prevention of a lot of diseases as the medicine of active ingredient, extremely useful in treatment, can bring very large effect for society, application industrially is large.
Claims (36)
1. the loose promotion medicine of flesh is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
2. the loose promotion medicine of flesh is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2],
Have the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making.
3. claim 1 or 2 the loose promotion medicine of flesh, it is characterized in that: 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt are 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4,5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.
4. claim 1 or 2 the loose promotion medicine of flesh, it is characterized in that: muscle is skeletal muscle.
5. claim 1 or 2 the loose promotion medicine of flesh, it is characterized in that: muscle is unstriated muscle.
6. claim 1 or 2 the loose promotion medicine of flesh, it is characterized in that: muscle is cardiac muscle.
7. claim 1 or 2 the loose promotion medicine of flesh, it is characterized in that: muscle is myocardium of left ventricle.
8. left ventricle diastole treating dysfunction medicine is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
9. left ventricle diastole treating dysfunction medicine is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2],
Have the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making.
10. claim 8 or 9 left ventricle diastole treating dysfunction medicine; it is characterized in that: 1 shown in the general formula [1]; 4 benzothiazepine derivatives or its pharmacologically acceptable salt are 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4; 5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.
11. curative in heart failure is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
12. curative in heart failure is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2],
Have the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making.
13. the curative of the heart failure of claim 11 or 12 is characterized in that: 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt are 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4,5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.
14. the curative of acute lung edema is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
15. the curative of acute lung edema is characterized in that: the curative of acute lung edema is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2],
Have the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making.
16. the curative of the acute lung edema of claim 14 or 15; it is characterized in that: 1 shown in the general formula [1]; 4 benzothiazepine derivatives or its pharmacologically acceptable salt are 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4; 5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.
17. the improving blood flow medicine of microcirculqtory system is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
18. the improving blood flow medicine of microcirculqtory system is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2],
Have the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making.
19. the improving blood flow medicine of the microcirculqtory system of claim 17 or 18; it is characterized in that: 1 shown in the general formula [1]; 4 benzothiazepine derivatives or its pharmacologically acceptable salt are 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4; 5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.
20. anginal curative is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
21. anginal curative is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2],
Have the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making.
22. the anginal curative of claim 21 or 22 is characterized in that: 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt are 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4,5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.
23. myocardium obstacle improves medicine, it is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
24. myocardium obstacle improves medicine, it is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2],
Have the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making.
25. the myocardium obstacle of claim 24 or 25 improves medicine, it is characterized in that: 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt are 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4,5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.
26. the hypertension therapeutic medicine is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
27. the hypertension therapeutic medicine is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
Or
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2],
This compound has the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making.
28. the hypertension therapeutic medicine of claim 27 is characterized in that: 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt are 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4,5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.
29. the curative of ventricular tachycardia is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
30. the curative of ventricular tachycardia is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2],
Have the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making.
31. the curative of the ventricular tachycardia of claim 29 or 30; it is characterized in that: 1 shown in the general formula [1]; 4 benzothiazepine derivatives or its pharmacologically acceptable salt are 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4; 5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.
32. the curative of supraventricular tachycardia is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
33. the curative of supraventricular tachycardia is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2],
Have the Muscle contraction arrestin Troponin I that is present in the muscle and the associativity enhanced effect of Actin muscle-tropomyosin mixture of making.
34. the curative of the supraventricular tachycardia of claim 32 or 33; it is characterized in that: 1 shown in the general formula [1]; 4 benzothiazepine derivatives or its pharmacologically acceptable salt are 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4; 5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.
35. the curative of torsades de pointes ventricular tachycardia or prophylactic agent is characterized in that: contain 1,4 benzothiazepine derivatives shown in the general formula [1] or its pharmacologically acceptable salt as effective constituent:
[in the formula, R
1Expression hydrogen or carbonatoms are the lower alkoxy of 1-3, R
2Expression hydrogen, carbonatoms be 1-3 lower alkoxy, phenyl (wherein phenyl can be replaced by 1-3 substituting group that is selected from the lower alkoxy of hydroxyl or carbonatoms 1-3),
(wherein, R
3Acyl group for carbonatoms 1-3), X represent-CO-or-CH
2-, n represents 1 or 2].
36. the curative and the prophylactic agent of the torsades de pointes ventricular tachycardia of claim 35; it is characterized in that: 1 shown in the general formula [1]; 4 benzothiazepine derivatives or its pharmacologically acceptable salt are 4-[3-(4-benzyl piepridine-1-yl) propionyl]-7-methoxyl group-2; 3; 4; 5-tetrahydrochysene-1,4-benzothiazepine or its pharmacologically acceptable salt.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP134899/2004 | 2004-04-28 | ||
| JP2004134899 | 2004-04-28 | ||
| JP237533/2004 | 2004-08-17 | ||
| JP141792/2005 | 2005-04-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1972936A true CN1972936A (en) | 2007-05-30 |
| CN100554267C CN100554267C (en) | 2009-10-28 |
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|---|---|---|---|
| CNB200580013602XA Expired - Fee Related CN100554267C (en) | 2004-04-28 | 2005-04-28 | Muscle relaxation promotes the curative of muscle tissue relative diseases such as medicine and muscle relaxation depletion |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100554267C (en) |
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2005
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