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Patent Application Titled "1,4-Benzothiazepine-1-Oxide Derivative and Pharmaceutical Composition Utilizing the Same" Published Online

June 8, 2014



By a News Reporter-Staff News Editor at Heart Disease Weekly -- According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors Kaneko, Noboru (Oyama-shi, JP); Takahashi, Mitsuru (Takatsuki-shi, JP), filed on December 24, 2013, was made available online on May 22, 2014 (see also Patents).

The assignee for this patent application is KANEKO; Noburo.

Reporters obtained the following quote from the background information supplied by the inventors: "The heart has a pumping mechanism consisting of periodic contraction and relaxation functions in the myocardium, which provides blood to the internal organs and tissues of the whole body through a process where the blood is constantly circulating and returning to the heart. This process is a constant, periodic action in which the myocardium is supplied the necessary oxygen and nutrition from coronary circulation of the right and left coronary arteries. In a normal functioning myocardium, the oxygen supply and consumption are maintained in the homeostatic state.

"When the myocardium is unable to contract and relax properly resulting in damage to the pumping function, congestion in the general organs and tissues is induced and heart failure occurs. During heart failure, activation of the sympathetic nervous system occurs, as well as increased levels of norepinephrine in the blood, leading to an increase in heart rate.

"Presently, there are drug treatments for heart failure such as .beta.-blockers that decrease heart rate, and lessen the contractility force, resulting in a decrease of oxygen consumption required from the myocardium. However, at high doses, .beta.-blockers increase the risk for heart failure and must be used or administered with caution.

"The myocardium contracts and relaxes regularly and periodically. This cardiac cycle is divided into two phases; systolic phase and diastolic phase. The systolic phase is from the mitral valve closure to the aortic valve closure and the diastolic phase is from the aortic valve closure to the mitral valve closure. Moreover, diastolic phase has 4 stages; isovolumic relaxation, rapid left ventricular filling, slow left ventricular filling, and atrial contraction. In the latter 3 stages among the 4 stages; rapid left ventricular filling, slow left ventricular filling, and atrial contraction, the ventricular myocardium expands more and blood inflow from atrium to ventricle occurs. The diastolic function of the ventricle has important significance on the cardiac function. When myocardial expansion is impaired, the blood inflow to the ventricle is hindered and then heart failure, especially heart failure due to diastolic dysfunction, occurs. Moreover, blood flows from the coronary artery into the myocardial tissues during diastolic phase, which is different from that of other organs. The diastolic blood flow is remarkably more from the left coronary artery than the right coronary artery. Therefore, the diastolic impairment of left ventricle induces disturbance of coronary flow into the left ventricular myocardial tissues, generates myocardial ischemia, and as a result aggravates heart failure due to diastolic dysfunction.

"Moreover, left ventricular diastolic impairment occurs in elderly people and in patients with hypertension and cardiac hypertrophy even without the presence of heart failure. Left ventricular diastolic impairments can easily be diagnosed using Doppler echocardiography. Some patients with left ventricular diastolic impairment complain of symptoms including fatigue, shortness of breath, chest discomfort and chest pain. During prolongation of left ventricular diastolic impairment, impairment of the cardiomyocytes and fibrosis in the myocardium eventually induce heart failure.

"To maintain normal functions of the heart, the appropriate amounts of oxygen and nutrients required are supplied to the myocardium through coronary perfusion by the left and right coronary arteries. The contraction and relaxation of the myocardium requires the oxygen and nutrients to function properly.

"The drugs used to dilate the coronary arteries leads to an increase of oxygen supply to the myocardium, thus reducing the risk of myocardial ischemia. Myocardial oxygen consumption is determined by the heart rate and cardiac contractility, and that drug decreases oxygen consumption by reducing heart rate and myocardial contractility, lowering the risk of myocardial ischemia. A drug capable of dilating the coronary artery combined with decreasing heart rate and contractility, is a treatment agent or a prophylactic agent for ischemic heart disease, such as angina pectoris and myocardial infarction.

"Heart failure is divided into systolic failure and diastolic failure. In systolic failure, the left ventricular minimum diastolic pressure and left ventricular diastolic pressure both increase, therefore the drug reinforcing the left ventricular diastolic function is comprised of an agent that leads to the improvement of systolic failure.

"Furthermore, a drug is a treatment agent for angina pectoris and myocardial infarction because it dilates the coronary artery and then enhances the oxygen supply to the myocardium. The consumption of oxygen from the myocardium is dependent upon the contractility force and heart rate. It is comprised of a drug that is a prophylactic agent for ischemic heart disease, such as angina pectoris and myocardial infarction. The .beta.-blocker is a treatment agent for angina pectoris and myocardial infarction, however, it does not have the effect to dilate the coronary arteries or increase left ventricular diastolic function.

"A drug, reinforcing the left ventricular diastolic function, decreasing heart rate, increasing reduction of contractility, combined with dilation of the coronary artery, is comprised of a treatment agent or a prophylactic agent for heart failure due to diastolic dysfunction.

"Moreover, the relaxant function in the heart is equally important as systolic function and diastolic function. Relaxation is the main component in the first stage among the four stages of the diastolic phase; the function of isovolumic relaxation, which is able to be estimated using the maximal negative first derivative of the left ventricular pressure (-dP/dt) and the disturbance of relaxant function is able to be detected in the left ventricular wall motion by using Doppler echocardiography.

"Heart failure is induced by numerous complexities such as myocardial systolic impairment, relaxation impairment, or diastolic impairment. Diastolic heart failure is generally formed with the complexities of diastolic impairment and relaxant impairment. Relaxant impairment is recognized in ischemic heart disease, atrial fibrillation, and ventricular arrhythmia and worsens severely, resulting in decreased cardiac contractility. The improvement of myocardial relaxant function is essential for the treatment of ischemic heart disease, atrial fibrillation, and ventricular arrhythmia. Relaxation impairment worsens severely and 'Rigor' occurs, not allowing relaxation. Deterioration of relaxation impairment leads to heart failure.

"Myocardial relaxation impairment is recognized in ischemic heart disease, hypertensive heart disease, heart failure, atrial fibrillation, and ventricular arrhythmia. There are still no drugs that allow a relaxant effect on the myocardium. Catecholamines such as epinephrine and norepinephrine (NE) stimulate to take the calcium uptake of the sarcoplasmic reticulum and promote myocardial relaxation. However, those substrates also increase heart rate and blood pressure, resulting in enhancement of myocardial oxygen consumption. It is difficult to use the treatment agents for the disease mentioned. The ideal drug is a myocardial relaxant which promotes myocardial relaxation without changing the heart rate. It is an agent that does not change heart rate and accelerates myocardial relaxation, and an agent which can improve ischemic heart disease, hypertensive heart disease, heart failure, atrial fibrillation, and ventricular arrhythmia, and cardiac function.

"Blood pressure is determined by cardiac output, peripheral blood resistance, circulation blood volume, and blood viscosity. Norepinephrine increases the peripheral vascular resistance and raises blood pressure. It is a treatment agent or a prophylactic agent used to decrease blood pressure for hypertension due to norepinephrine-loaded hypertension.

"Meanwhile, 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-- b enzothiazepine and derivatives thereof have been reported to have the effective compounds which inhibit myocardial necrosis including kinetic cell death (KD) and acute myocardial infarction without cardiac suppressive effects (Patent Documents 1 and 2). There have been many reports regarding its effectiveness on atrial fibrillation as well as its anticancer properties, for example, use for the treatment of atrial fibrillation (Patent Document 3), enhancement of anti-cancer agents for the treatment of cancer (Patent Document 4), use for the improvement or stabilization of the ryanodine receptor function, Ca.sup.2+ leak from the sarcoplasmic reticulum (Patent Document 5), muscle relaxation accelerator, treatment for left ventricular relaxation disturbance, treatment for angina pectoris, treatment for acute pulmonary emphysema, for improvement of microcirculation blood flow, for hypertension, for ventricular tachycardia and torsades de pointes (Patent Document 6)."

In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "Problems to be Solved by the Invention

"The present invention provides a novel pharmaceutical composition for treatment agent enhancing cardiac relaxation and improving myocardial relaxation impairment, and a therapeutic agent of relaxation of the vascular smooth muscle and hypertension by decreasing blood pressure. Moreover, it accelerates relaxation of skeletal muscle and uterine smooth muscle and provides a compound as a treatment agent or a prophylactic agent for muscle hypertonia and miscarriage.

"Furthermore, the present invention provides a novel compound that is useful as a treatment agent or a pharmaceutical compound containing the same for improving cardiac relaxation without changing heart rate.

"Means for Solving the Problems

"The present inventor has been researching several pharmacological effects of 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-- benzothiazepine and derivatives thereof. These compounds have been reported to have extremely significant pharmacological effects in the citations listed above. The present inventor urged more research and found that its sulfur (S)-oxide derivatives have similar effects as the basic free compound and specific pharmacological effects not found in the basic free compound.

"That is, the present invention provides a novel 1,4-benzothiazepine-1-oxide derivative represented by the following general formula [1]:

"##STR00002##

"(wherein, R is a hydrogen atom or a hydroxyl group.)

"and a pharmaceutically acceptable salt thereof.

"The present invention also provides a pharmaceutical composition comprising the 1,4-benzothiazepine-1-oxide derivative or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier.

"The present invention includes contents explained in detail below.

"(1) A 1,4-benzothiazepine-1-oxide derivative represented by the following general formula [I]:

"##STR00003##

"(wherein, R is a hydrogen atom or a hydroxyl group.)

"and a pharmaceutically acceptable salt thereof. (2) The 1,4-benzothiazepine-1-oxide derivative according to (1), wherein the pharmaceutically acceptable salt of 1,4-benzothiazepine-1-oxide-derivative in an oxalate. (3) A pharmaceutical composition comprising the 1,4-benzothiazepine-1-oxide derivative according to (1) or (2), or the pharmaceutically acceptable salt thereof and the pharmacologically acceptable carrier. (4) The pharmaceutical composition according to (3), wherein the pharmaceutical composition is a treatment agent or a prophylactic agent for cardiac disease and hypertension. (5) The pharmaceutical composition according to (4), wherein the cardiac disease includes cardiac failure, angina pectoris or myocardial infarction. (6) The pharmaceutical composition according to (5), wherein cardiac failure includes left ventricular diastolic impairment or cardiac relaxation impairment. (7) The pharmaceutical composition according to (4), wherein the hypertension is due to the effect of decreasing blood pressure during high blood pressure. (8) The pharmaceutical composition according to (3), wherein the pharmaceutical composition is a treatment agent or a prophylactic agent for myocardial relaxation impairments due to complications of ischemic heart disease, hypertension cardiac disease, heart failure, atrial fibrillation, and ventricular arrhythmia, by promoting acceleration of myocardial relaxation without changing heart rate. (9) A pharmaceutical composition according to any one of (3) to (8), wherein the 1,4-benzothiazepine-1-oxide derivative or a pharmaceutically acceptable salt thereof is generated in vivo by administering a 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof represented by the following formula [II]:

"##STR00004##

"(wherein, R is a hydrogen atom or a hydroxyl group.)

"to a subject as a maternal compound of the 1,4-benzothiazepine derivative represented by the following formula [I]. (10) A method of producing a 1,4-benzothiazepine-1-oxide derivative represented by the following general formula [I]:

"##STR00005##

"(wherein, R is a hydrogen atom or a hydroxyl group.)

"and a pharmaceutically acceptable salt thereof comprising a step by oxidizing a 1,4-benzothiazepine derivative represented by the following formula[II]:

"##STR00006##

"(wherein, R is a hydrogen atom or a hydroxyl group.).

"(11) A method of producing a 1,4-benzothiazepine derivative according to (10), wherein the oxidation carries out in the presence of peracid as a oxidation agent. (12) A use of a 1,4-benzothiazepine-1-oxide derivative or a pharmaceutically acceptable salt thereof represented by the general formula [I] described above to produce a treatment agent or a prophylactic agent for cardiac disease or hypertension. (13) A use of a 1,4-benzothiazepine-1-oxide derivative or a pharmaceutically acceptable salt thereof represented by the general formula [I] described above to produce a treatment agent or a prophylactic agent for cardiac failure due to myocardial relaxation impairment. (14) A use according to (12) or (13), wherein a 1,4-benzothiazepine-1-oxide derivative or a pharmaceutically acceptable salt thereof represented by the general formula [I] described above, is generated in vivo by administering a 1,4-benzothiazepine derivative or a pharmaceutically acceptable salt thereof represented by the general formula [II] described above. (15) A 1,4-benzothiazepine-1-oxide derivative or a pharmaceutically acceptable salt thereof represented by the general formula [I] described above to be used for a treatment agent or a prophylactic agent for cardiac disease or hypertension. (16) A 1,4-benzothiazepine-1-oxide derivative or a pharmaceutically acceptable salt thereof represented by the general formula [I] described above to be used for a treatment agent or a prophylactic agent for cardiac failure due to myocardial relaxation impairment. (17) A method of treatment of cardiac disease and hypertension by administrating an effective dose of a pharmaceutical composition comprising of a 1,4-benzothiazepine-1-oxide derivative or a pharmaceutically acceptable salt thereof represented by the general formula [I] described above to a patient with cardiac disease or hypertension. (18) A method of treatment of cardiac failure due to myocardial relaxation impairment by administrating an effective dose of a pharmaceutical composition comprising of a 1,4-benzothiazepine-1-oxide derivative or a pharmaceutically acceptable salt thereof represented by the general formula [I] to a patient with cardiac failure due to myocardial relaxation impairment.

"While the compound of the present invention represented by general formula [I] or a salt thereof is thought to be metabolized in vivo from the general formula [II] of the basic compound or a salt thereof, the present inventor has produced the compound of the general formula [I], discussed in detail the properties, and firstly found that the concerned compound represented by the general formula [I] possesses useful pharmacological effects.

"Moreover, the compound of the present invention represented by the general formula [I] or a salt thereof is different from the basic compound represented by the general formula [II] or a salt thereof, regulates the cardiac relaxant function without increasing the heart rate, and is considered to have different pharmacological effects compared to the basic compound represented by the general formula [II] or a salt thereof

"It is difficult even for the cardiologist to know how to treat diseases using .beta.-blockers because it reduces myocardial contractility and decreases heart rate. It is generally recommended to use treatment at low doses since administration at a high dose is dangerous. The Ca.sup.2+ antagonist dilates the coronary artery and rapidly decreases blood pressure and it is also generally recommended for treatment at low doses since administration at a high dose is dangerous. For safety concerns and requirements, mild agents are best used for dilatation of the coronary artery, suppressive effects on cardiac contraction, and decrease in heart rate.

"The present inventor has been found that the compound of the present invention represented by the general formula [I] or the salt thereof possesses the ability to increase left ventricular diastolic function, dilate the coronary artery, reduce myocardial contractility, mildly decrease heart rate, and is useful for cardiac failure, cardiac failure due to diastolic dysfunction, left ventricular diastolic impairment, angina pectoris, or myocardial infarction. Moreover, the compound of the present invention has been found to be useful as a treatment agent to improve the cardiac relaxant function without changing heart rate for ischemic heart disease, hypertensive heart disease, cardiac failure, atrial fibrillation, and ventricular arrhythmia.

"And, it has been found that the compound of the present invention represented by the general formula [I] or a salt thereof has the mild effect to improve myocardial diastolic function, dilate the coronary arteries, decrease heart rate and decrease cardiac contractility.

"The present inventor discovered that the compound of the present invention possesses useful effects for improvement of left ventricular diastolic function and inhibits norepinephrine-induced left ventricular diastolic impairment.

"The present invention provides the compound of the present invention as a useful agent to improve left ventricular diastolic function, cardiac failure and diastolic failure, wherein physical signs of an increase in left ventricular minimum diastolic pressure and left ventricular end-pressure are present.

"The present invention provides a useful agent of treatment and prevention wherein the compound of the present invention is administered to the elder person and patients with hypertension and cardiac hypertrophy, and for the improvement of left ventricular diastolic impairment in patients with physical signs of left ventricular diastolic impairment. In the present invention, the compound of the present invention is provided as a safe, useful agent to patients of angina pectoris with significant constriction of coronary artery and myocardial infarction. Moreover, the present invention is provided by the compound of the present invention as a useful treatment agent or a prophylactic agent to improve myocardial relaxation impairment combined with ischemic heart disease, hypertensive heart disease, cardiac failure, atrial fibrillation, and ventricular arrhythmia.

"Therefore, the present invention provides a novel compound which is useful, and a pharmaceutical compound containing these compounds of the present invention.

"Moreover, the compound of the present invention represented by the general formula [I] or a salt thereof is considered the basic compound represented by the general formula [II] or the metabolite of the salt in vivo. So, the pharmaceutical compound of the present invention is able to use the basic compound represented by the general formula [II] or a salt thereof as the pro-drug instead the present invention represented general formula [I] and the basic compound represented by the general formula [II].

"Effects of the Invention

"The compound of the present invention itself possesses the effects to improve myocardial diastolic function, to mildly dilate the coronary artery, decrease heart rate, and increase the oxygen supply by decreasing myocardial oxygen consumption. Therefore, the present invention provides a novel pharmaceutical compound that is useful as a treatment agent and a prophylactic agent in a safe and desirable manner for the elder person and patients with hypertension and cardiac hypertrophy, patients of cardiac failure due to diastolic failure, angina pectoris and myocardial infarction, and for those who have bad prognoses and are conventionally difficult to treat.

"In addition, the compound of the present invention possesses the ability to improve cardiac relaxation without changing heart rate and is useful for myocardial relaxant impairment. The compound of the present invention is useful as a treatment agent or a prophylactic agent for hypertension. Moreover, the compound of the present invention is useful as a treatment agent or a prophylactic agent for improving myocardial relaxation impairment combined with ischemic heart disease, hypertensive heart disease, cardiac failure, atrial fibrillation, and ventricular arrhythmia.

"The present pharmaceutical compound may be administered through oral, sublingual, transdermal patch, and intravenous methods, or infused into the coronary artery to eliminate spasms after inducing it diagnostically, and as well as treatment and prevention of coronary spasms.

"Moreover, the compound of the present invention is able to allow lower dosages of .beta.-blockers and Ca.sup.2+ antagonists for treatment or prevention of angina pectoris, especially myocardial ischemia on angina pectoris, and for treatment or prevention against cardiac failure, especially cardiac failure due to diastolic failure.

BRIEF DESCRIPTION OF THE DRAWINGS

"FIG. 1 is a graph showing a comparison of change in heart rate (beats/min) before and after administration of the compounds of the present invention [III], and its basic compound of general formula [II] (R.dbd.H).

"FIG. 2 is a graph showing a comparison of change in left ventricular pressure (mmHg) before and after administration of the compounds of the present invention [III], and its basic compound of general formula [II] (R.dbd.H).

"FIG. 3 is a graph showing a comparison of change in cardiac diastolic relaxation function (mmHg/sec) before and after administration of the compounds of the present invention [III], and its basic compound of general formula [II] (R.dbd.H).

"FIG. 4 is a graph showing the comparison of change in left ventricular pressure before and after administration of the present invention [III] on norepinephrine-induced hypertension."

For more information, see this patent application: Kaneko, Noboru; Takahashi, Mitsuru. 1,4-Benzothiazepine-1-Oxide Derivative and Pharmaceutical Composition Utilizing the Same. Filed December 24, 2013 and posted May 22, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1991&p=40&f=G&l=50&d=PG01&S1=20140515.PD.&OS=PD/20140515&RS=PD/20140515

Keywords for this news article include: Drugs, Gases, Patents, Therapy, Arteries, Elements, Hydrogen, Angiology, Cardiology, Chalcogens, Heart Rate, Myocardium, Heart Attack, Hemodynamics, Hypertension, Pharmacology, Vasopressors, Blood Vessels, Ethanolamines, Heart Disease, Heart Failure, Amino Alcohols, Blood Pressure, Catecholamines, Norepinephrine.

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Source: Heart Disease Weekly


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