Composition for improving cardiac function

Abstract

The present disclosure provides a composition that is for improving a heart function and that contains a compound represented by formula (I), or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof. Also provided is a composition that is for treating heart failure and that contains a compound represented by formula (I), or an ester, oxide, pharmaceutically acceptable salt or solvate thereof.

Description

Technical Field

[0001] This patent application claims priority from Japanese Patent Application No. 2021-211106, and the entire content thereof is incorporated herein by reference in its entirety. The present disclosure relates to a composition for improving cardiac function.

Background Art

[0002] Heart failure is defined as "a clinical syndrome in which some form of cardiac dysfunction, that is, organic and / or functional abnormalities occur in the heart, resulting in the breakdown of the metabolic mechanism of the cardiac pumping function, accompanied by the appearance of dyspnea, fatigue, and edema, and a decrease in exercise tolerance." With the aging of the population, the morbidity of heart failure and the mortality rate due to heart failure are increasing.

[0003] Left ventricular dysfunction is involved in many cases of heart failure, and in the guidelines of the American Heart Association Foundation and the Japanese Circulation Society, heart failure is classified according to left ventricular systolic function. Heart failure is mainly classified into heart failure with reduced left ventricular ejection fraction (HFrEF) and heart failure with preserved left ventricular ejection fraction (HFpEF). HFrEF is mainly characterized by systolic dysfunction, and HFpEF is mainly characterized by diastolic dysfunction. For the treatment of HFrEF, drugs that improve the systolic function of the heart, so-called cardiotonic drugs, are used, but harmful side effects occur due to only the increase in systolic function. On the other hand, drugs that improve the diastolic function of the heart are not known, and effective treatments for HFpEF have not been fully established. Therefore, the development of means to improve the diastolic function of the heart is desired.

[0004] Certain 4-amino-naphthalene-1-sulfonic acid derivatives inhibit the ATPase activity of VCP (valosin-containing protein), which is a major intracellular ATPase, and are expected to have therapeutic and / or preventive effects against various diseases (Patent Documents 1 to 9). Patent Document 7 discloses that a 4-amino-naphthalene-1-sulfonic acid derivative suppresses cardiomyocyte death in an ischemia-reperfusion model. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2012 / 014994 Pamphlet [Patent Document 2] International Publication No. 2012 / 043891 Pamphlet [Patent Document 3] International Publication No. 2014 / 129495 Pamphlet [Patent Document 4] International Publication No. 2015 / 129809 Brochure [Patent Document 5] International Publication No. 2015 / 033981 brochure [Patent Document 6] International Publication No. 2019 / 131720 brochure [Patent Document 7] International Publication Brochure No. 2019 / 203176 [Patent Document 8] International Publication No. 2020 / 027137 Brochure [Patent Document 9] International Publication No. 2021 / 079983 Brochure [Overview of the project] [Problems that the invention aims to solve]

[0006] The purpose of this disclosure is to provide a novel means for improving cardiac function. [Means for solving the problem]

[0007] The inventors have found that the compound of formula (I) improves cardiac function in a heart failure model. Therefore, in some embodiments, this disclosure relates to formula (I): [ka] [During the ceremony, Ra is selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, aryl, halo- or alkyl-substituted aryl, alkoxy, hydroxy- or carboxy-substituted alkoxy, aryloxy, halo- or alkyl-substituted aryloxy, CHO, C(O)-alkyl, C(O)-aryl, C(O)-alkyl-carboxyl, C(O)-alkylene-carboxyester, and cyano. m is an integer selected from 0 to 4. The present invention provides compositions for improving cardiac function, comprising compounds thereof or their esters, oxides, prodrugs, pharmaceutically acceptable salts, or solvates.

[0008] In some embodiments, the present disclosure provides compositions for treating heart failure comprising a compound of formula (I) or its esters, oxides, prodrugs, pharmaceutically acceptable salts, or solvates. [Effects of the Invention]

[0009] This disclosure will enable the improvement of cardiac function and the treatment of heart failure. [Brief explanation of the drawing]

[0010] [Figure 1] A schematic diagram of the aortic coarctation (TAC) model is shown. [Figure 2] This document describes an experimental protocol for injecting KUS121 or 5% glucose (Tz) into a mouse model of acute heart failure induced by pressure overload. [Figure 3] The left image shows the ratio of heart weight to body weight (left), the ratio of lung weight to body weight (center), and the mRNA level of BNP (right) in sham surgery mice administered 5% glucose, mice administered 5% glucose after transcatheter arterial chemotherapy (TAC), and mice administered KUS121 (50 mg / kg) after TAC. [Figure 4] This document describes an experimental protocol for injecting KUS121 or 5% glucose into a pressure-induced cardiac hypertrophy model mouse. [Figure 5]Shows the heart weight (left) and the ratio of heart weight to body weight (right) of sham-operated mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg / day) after TAC. [Figure 6] Shows the results of quantifying the cross-sectional area of cardiomyocytes in sham-operated mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg / day) after TAC. [Figure 7] Shows the end-diastolic diameter of the ventricular septum (IVSd) (left), left ventricular ejection fraction (LVEF) (center), and left ventricular weight (right) evaluated by echocardiogram in sham-operated mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg / day) after TAC. [Figure 8] Shows the experimental protocol of injecting KUS121 or 5% glucose into heart failure model mice by pressure overload. [Figure 9] Shows the change in left ventricular ejection fraction (LVEF) evaluated by echocardiogram in sham-operated mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg / day) after TAC. [Figure 10] Shows the changes in left ventricular weight (upper left), left ventricular end-diastolic diameter (LVDd) (upper right), and end-diastolic ventricular septum diameter (IVSd) (lower) evaluated by echocardiogram in sham-operated mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg / day) after TAC. [Figure 11] Shows the heart weight (upper left), ratio of heart weight to body weight (upper right), lung weight (lower left), and ratio of lung weight to body weight (lower right) in sham-operated mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg / day) after TAC. [Figure 12]The results of quantifying the cross-sectional area of ​​cardiomyocytes in sham-surgery mice administered 5% glucose, mice administered 5% glucose after transcatheter arterial chemotherapy (TAC), and mice administered KUS121 (50 mg / kg / day) after TAC are shown. [Figure 13] The results of quantifying the fibrotic area by Masson trichrome staining of the hearts of mice administered 5% glucose after TAC and mice administered KUS121 (50 mg / kg / day) after TAC are shown. [Figure 14] This shows the mRNA levels of Col1a1 and Postn in the hearts of sham-surgery mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg / day) after TAC. [Figure 15] This study shows the changes in left ventricular ejection fraction (LVEF) (upper left), left ventricular end-diastolic diameter (LVDd) (upper right), and heart rate (HR) (lower panel) as evaluated by echocardiography before and after KUS121 injection (50 mg / kg) in 8-week-old mice that underwent TAC surgery. [Figure 16] This shows the time course of left ventricular ejection fraction as measured by echocardiography 5 weeks post-surgery in mice that underwent TAC surgery at 8 weeks of age (data up to 150 minutes after KUS121 injection (50 mg / kg)). [Figure 17] This document presents an experimental protocol for injecting KUS121 into a beagle dog model of heart failure induced by rapid ventricular pacing. [Figure 18] This shows the left ventricular ejection fraction (EF) (EF shown by Teichholz method and Modified-Simpson's method) and left ventricular diameter shortening in beagle dogs, a model of heart failure induced by rapid ventricular pacing, 15 minutes after infusion of KUS at 40 mg / hr. [Figure 19] This shows the changes in heart rate (top left), systolic blood pressure (top right), and diastolic blood pressure (bottom) in a heart failure model beagle dog after KUS121 infusion. [Figure 20]This shows the changes in left ventricular ejection fraction (LVEF) (upper left), mean pulmonary artery pressure (upper right), and pulmonary capillary wedge pressure (lower panel) in a heart failure model beagle dog after KUS121 infusion. [Figure 21] This shows the changes in left ventricular end-diastolic pressure (left) and adjusted dp / dt (right) after KUS121 infusion in a heart failure model beagle dog. [Figure 22] The graph shows the changes in heart rate (top left), systolic blood pressure (top right), cardiac output (middle left), mean pulmonary artery pressure (middle right), left ventricular end-diastolic pressure (bottom left), and left ventricular dp / dt (bottom right) in a heart failure model beagle dog after dobutamine infusion. [Figure 23] This image shows typical PV loop shifts in a heart failure model beagle dog due to reduced preload caused by inferior vena cava occlusion, at baseline (left) and during KUS121 infusion (40 mg / hr) (right). [Figure 24] This image shows the changes from baseline in the end-systolic PV relationship (ESPVR) (left) and end-diastolic pressure-volume relationship (EDPVR) (right), obtained by PV loop shift during KUS121 infusion (40 mg / hr) in beagle dogs with heart failure. [Figure 25] The images show body weight (top left), heart weight (top right), heart weight / tibia length (bottom left), and heart weight as a percentage of body weight (bottom right) for control mice administered 5% glucose, HFpEF model mice administered 5% glucose, and HFpEF model mice administered KUS121 (50 mg / kg). [Figure 26] This shows the changes in left ventricular ejection fraction (LVEF) in control mice administered 5% glucose, HFpEF model mice administered 5% glucose, and HFpEF model mice administered KUS121 (50 mg / kg). [Figure 27] The changes in GLS (top panel), E / A (middle panel), and E / E' (bottom panel) in control mice administered 5% glucose, HFpEF model mice administered 5% glucose, and HFpEF model mice administered KUS121 (50 mg / kg) are shown. [Figure 28]The changes in blood pressure (top panel) and heart rate (bottom panel) in control mice administered 5% glucose, HFpEF model mice administered 5% glucose, and HFpEF model mice administered KUS121 (50 mg / kg) are shown. [Figure 29] This shows the changes in treadmill distance covered in control mice administered 5% glucose, HFpEF model mice administered 5% glucose, and HFpEF model mice administered KUS121 (50 mg / kg). [Figure 30] This image shows the change in left ventricular ejection fraction (LVEF), as evaluated by echocardiography, before and after 5 weeks of treatment with 5% glucose (left) or KUS187 injection (50 mg / kg) (right) in mice that underwent TAC surgery at 8 weeks of age. [Modes for carrying out the invention]

[0011] In this disclosure, when a number is accompanied by the term "approximately," it is intended to include a range of ±10% of that value. For example, "approximately 20" includes "18 to 22." A range of numbers includes all numbers between the two endpoints and the numbers at both endpoints. The "approximately" in relation to a range applies to both endpoints of that range. Therefore, for example, "approximately 20 to 30" includes "18 to 33."

[0012] Unless otherwise specified, terms used in this disclosure have the meanings generally understood by those skilled in the art in the fields of organic chemistry, medicine, pharmacy, molecular biology, microbiology, etc. Some definitions of terms used in this disclosure are given below, but these definitions take precedence over general understandings in this disclosure.

[0013] "Alkyl" means a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Alkyl means, for example, linear and branched hydrocarbyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and neopentyl.

[0014] The prefix "substituted" for a group means that one or more hydrogen atoms of that group are substituted by the same or different specified substituents.

[0015] "Alkylene" refers to a divalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Alkylene groups include branched and linear hydrocarbyl groups.

[0016] "Alkoxy" means an -O-alkyl group (where alkyl is as defined in this disclosure). Alkoxy means, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0017] "Aryl" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having one ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). Aryl groups typically include phenyl and naphthyl. "Aryloxy" means an -O-aryl group (where aryl is as defined in this disclosure), and includes, for example, phenoxy and naphthoxy.

[0018] "Cyano" means the base of -CN. "Carboxyl" or "carboxy" means -COOH or a salt thereof. "Carboxyester" means a -C(O)O-alkyl group (where alkyl is as defined in this disclosure). "Halo" refers to halogens, especially fluoro, chloro, bromo, and iodine. "Hydroxy" refers to the -OH group.

[0019] Unless otherwise specified, substituents not explicitly defined in this disclosure are nominated by naming the terminal portion of the functional group, followed by the functional groups adjacent to the bond site. For example, the substituent "arylalkyloxycarbonyl" means (aryl)-(alkyl)-OC(O)-.

[0020] Depending on the substitution pattern, the compound of formula (I) may exist as an enantiomer or a diastereomer. The compound of formula (I) may be a racemate or may be obtained by separating the stereoisomerically pure components using known methods. Certain compounds may be tautomers.

[0021] "Ester" refers to an ester that can be hydrolyzed in vivo, including those that are readily broken down in the human body to release the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanes, alkenes, cycloalkanoates, and alkanedioates (where each alkyl or alkenyl group has, for example, six or fewer carbon atoms). Specific examples of esters include formate esters, acetate esters, propionate esters, butyrate esters, acrylic esters, and ethyl succinate esters. "Oxide" refers to a substance in which the nitrogen ring atom of a heteroaryl group is oxidized to form an N-oxide.

[0022] A “prodrug” refers to a compound that is suitable for use in contact with human or animal tissue without excessive toxicity, irritation, or allergic reactions, within the bounds of reasonable medical judgment, has a reasonable benefit-to-risk ratio, and is effective for its intended use. A prodrug is a compound that is rapidly converted in vivo, for example, by hydrolysis in the blood, to yield the parent compound of the above formula. General descriptions are found in T. Higuchi and V. Stella, Pro drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 (both cited herein by reference).

[0023] A "pharmaceutically acceptable salt" may be a salt of the compound of formula (I) with an inorganic or organic acid. Preferred salts are salts with an inorganic acid, such as hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid, or salts with an organic carboxylic acid or sulfonic acid, such as acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, or naphthalenedisulfonic acid.

[0024] Furthermore, pharmaceutically acceptable salts may be salts with conventional bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), or ammonium salts, particularly sodium salts, derived from ammonia or organic amines (e.g., diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, methylpiperidine, L-arginine, creatine, choline, L-lysine, ethylenediamine, benzathine, ethanolamine, meglumine, or tromethamine).

[0025] A "solvate" refers to a compound of formula (I) that forms a complex with solvent molecules through coordination in a solid or liquid state. A preferred solvate is a hydrate.

[0026] Where the “compound of formula (I)” is referred to in this disclosure, it is intended to include its esters, oxides, prodrugs, pharmaceutically acceptable salts, and solvates, unless otherwise appropriate in the context.

[0027] In one embodiment, in formula (I), Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halosubstituted alkyl, alkoxy, and CHO. In one embodiment, in formula (I), Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halosubstituted alkyl, and alkoxy. In one embodiment, in formula (I), Ra is independently selected from the group consisting of halo and alkyl. In one embodiment, formula (I) contains two Ra elements, one being a halo and the other an alkyl group. In one embodiment, in formula (I), Ra is independently selected from the group consisting of alkyl, alkoxy, and CHO. In one embodiment, formula (I) contains three Ra elements: one alkyl, one alkoxy, and one CHO.

[0028] In one embodiment, the compound of formula (I) is selected from the compounds in Table 1 below: [Table 1-1]

[0029] [Table 1-2]

[0030] [Table 1-3]

[0031] In one embodiment, the following formula [ka] Use 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid, represented by , or its ester, oxide, prodrug, pharmaceutically acceptable salt or solvate, preferably a sodium salt.

[0032] In one embodiment, the following formula [ka] 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid, represented as , or its ester, oxide, prodrug, pharmaceutically acceptable salt or solvate, preferably a sodium salt, is used.

[0033] The compounds of formula (I), in particular the properties and synthesis methods of the above compounds, are described in detail in International Publication No. 2012 / 014994 (Patent Document 1).

[0034] In the examples described later, the compound of formula (I) mitigated compensatory cardiac hypertrophy and reduced the worsening of heart failure in a pressure overload heart failure model mouse. Furthermore, in a tachycardia-induced heart failure model in beagle dogs, the compound of formula (I) reduced left ventricular end-diastolic pressure and improved left ventricular contractility and diastolic function. In addition, the compound of formula (I) improved left ventricular diastolic function and exercise tolerance in a heart failure model with preserved left ventricular ejection fraction (HFpEF).

[0035] Therefore, in some embodiments, the compound of formula (I) may be used to improve cardiac function. Cardiac function includes cardiac contractility and diastolic function. Cardiac function may be assessed by any method known in the art, typically non-invasively by echocardiography. Left ventricular contractility can be assessed, for example, by left ventricular ejection fraction. Left ventricular diastolic function can be assessed, for example, by mitral valve orifice blood flow velocity waveform and mitral valve annular motion velocity waveform. Right ventricular contractility can be assessed, for example, by tricuspid annular systolic displacement or right ventricular area change rate. Right ventricular diastolic function can be assessed, for example, by right ventricular inflow blood flow velocity waveform. The compound of formula (I) may improve at least one of left ventricular contractility, left ventricular diastolic function, right ventricular contractility, and right ventricular diastolic function. In some embodiments, the compound of formula (I) may improve cardiac function in patients with heart failure.

[0036] In another embodiment, the compound of formula (I) may be used to treat heart failure. Regarding the progression of heart failure, for example, the American College of Cardiology Foundation / American Heart Association (ACCF / AHA) heart failure staging classification is known. In this disclosure, heart failure includes cases where heart failure symptoms develop due to organic heart disease (Stage C), and cases where cardiac remodeling occurs due to compensatory mechanisms but heart failure symptoms do not develop (Stage B). Stage C heart failure includes decompensated heart failure, where hemodynamics are not compensated after the onset of organic heart disease, and compensated heart failure, where circulation is compensated. Compensatory mechanisms include cardiac remodeling such as cardiac hypertrophy and cardiomegaly, and increased cardiac output due to activation of neurohumoral factors. Heart failure may or may not involve cardiomyocyte death. In one embodiment, heart failure does not involve cardiomyocyte death.

[0037] Heart failure is classified into three types based on left ventricular systolic function: heart failure with reduced left ventricular ejection fraction (HFrEF), heart failure with preserved LVEF (HFpEF), and heart failure with mildly reduced LVEF (HFmrEF). While classification criteria can vary, for example, according to the 2021 JCS / JHFS Guideline Focus Update for Acute and Chronic Heart Failure, HFrEF is defined as an LVEF of less than 40%, HFpEF as 50% or more, and HFmrEF as 40% to less than 50%. Furthermore, heart failure can also be classified into heart failure with improved LVEF (HFrecEF), heart failure with worsening LVEF (HFworEF), and heart failure with no change in LVEF (HFuncEF) based on changes in LVEF over time.

[0038] Furthermore, traditionally, acute heart failure was defined as "a condition in which the compensatory mechanisms of cardiac pump function rapidly fail, leading to an increase in ventricular end-diastolic pressure and insufficient perfusion to major organs, and resulting in the acute appearance or worsening of symptoms and signs," while chronic heart failure was defined as "a condition in which chronic cardiac pump dysfunction leads to persistent congestion of the lungs and / or systemic venous system and hypoperfusion of tissues, interfering with daily life." Acute exacerbations of chronic heart failure are included in acute heart failure.

[0039] The causes of heart failure are not limited to one another. For example, ischemic heart disease (ischemic cardiomyopathy, stunning, hibernation, microcirculatory disorders, etc.), cardiomyopathy (including genetic abnormalities; hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, noncompaction, takotsubo cardiomyopathy, etc.), cardiotoxic substances (addictive substances such as alcohol, cocaine, amphetamines, and anabolic steroids, heavy metals such as copper, iron, lead, cobalt, and mercury, and anticancer drugs (anthracyclines) Drugs such as phosphorus, immunosuppressants, antidepressants, antiarrhythmics, NSAIDs, anesthetics, radiation damage, etc., myocarditis (viral, bacterial, rickettsial infections, Chagas disease, etc.), immune disorders (rheumatoid arthritis, systemic lupus erythematosus, polymyositis, mixed connective tissue disease, etc.), pregnancy (peripartum cardiomyopathy including postpartum cardiomyopathy, etc.), invasive diseases (sarcoidosis, amyloidosis, hemochromatosis, malignant tumors) Infiltration, etc.), endocrine disorders (hyperthyroidism, Cushing's disease, pheochromocytoma, adrenal insufficiency, growth hormone secretion disorders, etc.), metabolic disorders (diabetes, etc.), congenital enzyme disorders (Fabry disease, Pompe disease, Hurler syndrome, Hunter syndrome, etc.), muscle diseases (muscular dystrophy, laminopathy, etc.), hypertension, valvular heart disease, cardiac structural abnormalities (congenital valvular heart disease, atrial septal defect, ventricular septal defect, other congenital heart diseases, aortic valve, mitral valve) Causes of heart failure include diseases, abnormalities of the pericardium (such as constrictive pericarditis and cardiac tamponade), abnormalities of the endocardium (such as eosinophilic endocardial disease and endocardial elastic fibrosis), high cardiac output heart failure (such as severe anemia, hyperthyroidism, Paget's disease, arteriovenous shunt, pregnancy, and beriberi heart disease), increased fluid volume (such as renal failure and fluid overload), tachyarrhythmias (such as atrial fibrillation, atrial tachycardia, and ventricular tachycardia), and bradyarrhythmias (such as sick sinus syndrome and atrioventricular block). In some embodiments, the cause of heart failure is not a heart disease involving cardiomyocyte death. In some embodiments, the cause of heart failure is not myocardial infarction, hypertension, or dilated cardiomyopathy.

[0040] In this disclosure, “treating heart failure” or “treating heart failure” means delaying or halting the progression of heart failure in a subject having heart failure, and / or reducing, alleviating, improving or eliminating heart failure.

[0041] The target animals for administration of the compound of formula (I) are animals, typically mammals (e.g., humans, mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, etc.), and especially humans.

[0042] The method of administering the compound of formula (I) is not particularly limited and can be via common routes of administration such as oral administration, parenteral administration, injection, or intravenous infusion. Parenteral administration may be systemic or local, and examples include intravenous administration, intra-arterial administration, intradermal administration, subcutaneous administration, transdermal administration, intramuscular administration, intraperitoneal administration, or intranasal administration. In one embodiment, the compound of formula (I) is administered intravenously. In another embodiment, the compound of formula (I) is administered orally.

[0043] The compound of formula (I) may be administered as part of a composition. The composition may be a solid, a liquid, or any form in between (e.g., semi-solid), and may take various known formulation forms depending on the characteristics of the target, the method of administration, and the dosage. Oral dosage forms include granules, fine granules, powders, coated tablets, tablets, powders, capsules, microcapsules, chewable tablets, solutions, suspensions, and emulsions. For injectable administration, general pharmaceutical dosage forms such as those for intravenous injection, intravenous infusion, and formulations that extend the release of the active substance can be used. Dosage forms for intravenous injection or intravenous infusion include aqueous and non-aqueous injection solutions and injection suspensions. Injectable dosage forms may be provided in sealed ampoules or vials, or as lyophilized products that only require the addition of sterile liquid (e.g., sterile water for injection) immediately before use. Injectable solutions or suspensions may be prepared from powders, granules, or tablets.

[0044] These dosage forms are manufactured by formulation using conventional methods. Furthermore, various pharmaceutically acceptable formulation substances may be added as needed for the formulation. The formulation substances can be appropriately selected depending on the dosage form of the formulation, but examples include buffering agents, surfactants, stabilizers, preservatives, excipients, diluents, additives, disintegrants, binders, coatings, lubricants, viscosities, flavoring agents, sweeteners, solubilizers, antioxidants, bacteriostatic agents, isotonic agents, suspending agents, thickeners, pigments, dyes, fragrances, etc.

[0045] The dosage and frequency of administration of the compound of formula (I) can be appropriately determined by those skilled in the art, depending on the animal species, health status, age, weight, route of administration, and form of administration, so that an effective amount of the compound of formula (I) is administered to the target. An effective dose in a given situation can be easily determined by routine experiments. For example, the compound of formula (I) can be administered at a rate of approximately 0.001 to approximately 1000 mg / kg body weight / day, approximately 0.01 to approximately 200 mg / kg body weight / day, or approximately 0.1 to approximately 100 mg / kg body weight / day. Alternatively, for example, the compound of formula (I) can be continuously infused at a rate of approximately 0.1 to 1000 mg / hr, approximately 1 to 500 mg / hr, or approximately 5 to 100 mg / hr.

[0046] The compound of formula (I) may be administered as a single dose, multiple doses, or as a continuous dose. When administered multiple times, for example, it may be administered once to several times a day, for example, once, twice, or three times a day, on consecutive days or every few days, for example, every 1, 2, 3, or 7 days. The duration of administration is not limited, and administration may be continued, for example, until cardiac function improves. A drug-free period may be provided.

[0047] The compound of formula (I) can be used alone or in combination with one or more additional active ingredients. “Combined use” of the ingredients means not only the use of a dosage form containing all the ingredients and the use of combinations of dosage forms containing each ingredient separately, but also the administration of each ingredient simultaneously or with a delay between each ingredient, insofar as they are used to improve cardiac function or treat heart failure. It is also possible to use two or more additional active ingredients in combination. For example, a composition containing one or more additional active ingredients in addition to the compound of formula (I) may be used. Suitable active ingredients for combination use include those used to treat heart failure, such as diuretics, mineralocorticoid receptor antagonists, inotropic agents, antiarrhythmics, and beta-blockers.

[0048] In addition to administering the compound of formula (I), non-pharmacological treatments may also be implemented. Suitable treatments include, for example, cardiac resynchronization therapy and implantable cardioverter-defibrillator (ICD) therapy.

[0049] In one embodiment, a composition for improving cardiac function is provided, comprising a compound of formula (I). In one embodiment, a method is provided for improving cardiac function, which includes administering an effective amount of a compound of formula (I) to a subject. In one embodiment, a compound of formula (I) for improving cardiac function is provided. In one embodiment, the use of a compound of formula (I) for improving cardiac function is provided. In one embodiment, the use of a compound of formula (I) in the manufacture of a composition for improving cardiac function is provided.

[0050] In one embodiment, a composition for treating heart failure is provided, comprising a compound of formula (I). In one embodiment, a method for treating heart failure is provided, comprising administering an effective amount of a compound of formula (I) to a subject. In one embodiment, a compound of formula (I) for treating heart failure is provided. In one embodiment, the use of a compound of formula (I) for treating heart failure is provided. In one embodiment, the use of a compound of formula (I) in the manufacture of a composition for treating heart failure is provided.

[0051] For example, the following embodiments are provided. [1] Equation (I): [ka] [During the ceremony, Ra is selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, aryl, halo- or alkyl-substituted aryl, alkoxy, hydroxy- or carboxy-substituted alkoxy, aryloxy, halo- or alkyl-substituted aryloxy, CHO, C(O)-alkyl, C(O)-aryl, C(O)-alkyl-carboxyl, C(O)-alkylene-carboxyester, and cyano. m is an integer selected from 0 to 4. A composition for improving cardiac function comprising the compound or its ester, oxide, prodrug, pharmaceutically acceptable salt or solvate. [2] The composition according to paragraph 1, wherein the cardiac function is the diastolic function of the left ventricle. [3] The composition according to paragraph 1, wherein the cardiac function is the contractile function of the left ventricle. [4] The composition according to paragraph 1, wherein the cardiac function is the diastolic and systolic function of the left ventricle. [5] A composition according to any one of paragraphs 1 to 4 for improving cardiac function in patients with heart failure.

[0052] [6] Equation (I): [ka] [During the ceremony, Ra is selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, aryl, halo- or alkyl-substituted aryl, alkoxy, hydroxy- or carboxy-substituted alkoxy, aryloxy, halo- or alkyl-substituted aryloxy, CHO, C(O)-alkyl, C(O)-aryl, C(O)-alkyl-carboxyl, C(O)-alkylene-carboxyester, and cyano. m is an integer selected from 0 to 4. A composition for treating heart failure comprising the compound or its ester, oxide, prodrug, pharmaceutically acceptable salt or solvate. [7] The composition according to paragraph 5 or 6, wherein the heart failure is heart failure with reduced left ventricular ejection fraction (HFrEF). [8] The composition according to paragraph 5 or 6, wherein the heart failure is heart failure with preserved LVEF (HFpEF) or heart failure with mildly reduced LVEF (HFmrEF). [9] The composition according to paragraph 8, wherein the heart failure is HFpEF.

[10] The composition according to paragraph 5 or 6, wherein the heart failure is heart failure with improved LVEF (HFrecEF), heart failure with worsened LVEF (HFworEF), or heart failure with no change in LVEF (HFuncEF).

[11] The composition according to any one of paragraphs 5 to 10, wherein the heart failure is acute heart failure.

[12] The composition according to any one of paragraphs 5 to 11, wherein the heart failure is an acute exacerbation of chronic heart failure.

[13] The composition according to any one of paragraphs 5 to 10, wherein the heart failure is chronic heart failure.

[14] The composition according to any one of paragraphs 5 to 10, wherein the heart failure is compensated heart failure.

[15] A composition according to any one of paragraphs 5 to 14, wherein the heart failure is not accompanied by cardiomyocyte death.

[16] A composition according to any one of paragraphs 5 to 15, wherein the cause of heart failure is ischemic heart disease, cardiomyopathy, cardiotoxic substances, myocarditis, immune disorders, pregnancy, infiltrative diseases, endocrine disorders, metabolic disorders, congenital enzyme abnormalities, muscle diseases, hypertension, valvular heart disease, cardiac structural abnormalities, epicardial abnormalities, endocardial abnormalities, high cardiac output heart failure, fluid volume increase, tachyarrhythmia or bradyarrhythmia.

[17] A composition according to any one of paragraphs 5 to 16, wherein the cause of heart failure is not a heart disease involving cardiomyocyte death.

[18] A composition according to any one of paragraphs 5 to 17, wherein the cause of heart failure is a cardiotoxic substance, myocarditis, an immune disorder, pregnancy, an infiltrative disease, an endocrine disorder, a metabolic disorder, a congenital enzyme disorder, a muscle disorder, a valvular heart disorder, a cardiac structural disorder, an epicardial disorder, an endocardial disorder, a high cardiac output heart failure, fluid volume increase, a tachyarrhythmia or a bradyarrhythmia.

[19] A composition according to any one of paragraphs 5 to 18, wherein the cause of heart failure is not myocardial infarction, hypertension, or dilated cardiomyopathy.

[0053]

[20] The composition according to any one of claims 1 to 19, wherein Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halosubstituted alkyl, alkoxy, and CHO.

[21] The composition according to any one of claims 1 to 20, wherein Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halosubstituted alkyl and alkoxy.

[22] The composition according to any one of claims 1 to 21, wherein Ra is independently selected from the group consisting of halo and alkyl.

[23] The composition according to any one of the items 1 to 22, wherein there are two Ra groups, one of which is a halo and the other is an alkyl group.

[24] The composition according to any one of the items 1 to 20, wherein Ra is independently selected from the group consisting of alkyl, alkoxy, and CHO.

[25] A composition according to any one of the claims 1 to 20 and 24, wherein there are three Ra groups, one of which is alkyl, one of which is alkoxy, and one of which is CHO.

[26] A composition according to any one of the items 1 to 19, wherein the compound of formula (I) is selected from the compounds listed in Table 1.

[27] The composition according to any one of the claims 1 to 23 and 26, wherein the compound of formula (I) is 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid.

[28] A composition according to any one of the following paragraphs, 1 to 23, 26, and 27, comprising 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonate sodium salt.

[29] The composition according to any of the paragraphs 1 to 21 and 24 to 26, wherein the compound of formula (I) is 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid.

[30] A composition according to any of the following paragraphs, 1 to 21, 24 to 26, and 29, comprising 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonate sodium salt.

[0054] All references cited herein are included as part of this specification upon proper attribution. The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Furthermore, the above description is non-limiting, and the present invention is defined in the appended claims, and various modifications are possible without departing from the technical spirit thereof. [Examples]

[0055] Example 1 Materials and methods compound We used 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonate sodium salt (KUS121) and 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonate sodium salt (KUS187), prepared by the method described in International Publication No. 2012 / 014994.

[0056] Laboratory animals The Institute of Cancer Research (ICR) mice were purchased from the Charles River Laboratory. The mice were housed at the Institute for Experimental Animal Science, Graduate School of Medicine, Kyoto University, in a temperature-controlled room with a 14:10 light-dark cycle, free from specific pathogens. The Beagle dogs were purchased from Kitayama Labes Co., Ltd. and housed at the Shiga Research Institute of Nissei Bayliss Co., Ltd. This study was approved by the Kyoto University Ethics Review Board.

[0057] Pressure-induced cardiac hypertrophy / heart failure model Aortic constriction (TAC) was performed using the method described in the following paper: [Date, et al. (2002) The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in in vivo murine pressure-overload model. J Am Coll Cardiol 39: 907-912]. Anesthetics (medetomidine 0.3 mg / kg, midazolam 4.0 mg / kg, butorphanol 5.0 mg / kg) were administered intraperitoneally to 8-10 week old mice, and the proximal part of the sternum was dissected to visualize the aorta. 7-0 silk sutures were placed around the aortic arch distal to the brachiocephalic artery. The sutures were tightly secured around a 26-gauge blunt needle positioned adjacent to the aorta. The needle was then removed, and the chest and the skin above it were closed. A similar procedure was performed on Siamese mice without ligation of the aortic arch. After the surgery, 0.3 mg / kg of atipamezole was administered subcutaneously to reduce the effect of medetomidine. A schematic diagram of the TAC is shown in Figure 1.

[0058] RNA extraction Tissue samples were homogenized in 1 mL of TriPure reagent (Sigma-Aldrich) using a Polytron homogenizer, and total RNA was extracted according to the manufacturer's protocol. Total RNA from cells was also separated using 1 mL of TriPure reagent. The quantity and quality of total RNA were measured using a NanoDrop™2000 spectrophotometer (Thermo Scientific).

[0059] Quantitative real-time PCR Total RNA is Verso (商標) Using the cDNA Synthesis Kit (Thermo Fisher Scientific, AB1453A), cDNA was reverse transcribed according to the manufacturer's protocol using a 3:1 (volume / volume) blend primer of random hexamers and oligo-dT, and the resulting cDNA was analyzed by qRT-PCR. qRT-PCR measurements were performed using the THUNDERBIRD SYBR qPCR Mix (TOYOBO) as instructed by the manufacturer. Messenger RNA (mRNA) expression levels were corrected for housekeeping genes. -ΔΔCt The calculations were performed according to the standard method. All analyses were conducted using the StepOnePlus real-time PCR system and StepOne Software v2.3 (Applied Biosystems, Inc).

[0060] Wheat germ aglutinin (WGA) staining and its quantification Short-axis sections of paraffin-embedded ventricles were stained with FITC-binding lectin (Sigma, L4895). Images were acquired using Axio Observer 7 (Zeiss). Cardiac cell cross-sectional area was measured using ImageJ64 software (NIH). Approximately 150-200 cells were measured per heart, and the average value was used for analysis.

[0061] Hematoxylin-eosin (HE) staining and its quantification After fixation with 4% paraformaldehyde, the tissue was dehydrated with 70% ethanol and embedded in paraffin. After deparaffinization of the sections, the nuclei were stained with hematoxylin solution and the cytoplasm with eosin solution. Images were taken with Axio Observer 7 (Zeiss). Cross-sectional area of ​​cardiomyocytes was measured using ImageJ64 software (NIH). Approximately 150-200 cells were measured per heart, and the average value was used for analysis.

[0062] Masson's trichrome staining and its quantification Similarly to the above, after deparaffinizing the sections, the nuclei were stained with hematoxylin, the cytoplasm with Masson's solution, and the collagen fibers with aniline blue. After imaging with a microscope (BZ-9000, Keyence), the aniline blue-stained areas were measured using ImageJ64 software (NIH).

[0063] Mouse echocardiogram For the analysis of cardiac function, Vevo was used at each point in time after TAC surgery. (登録商標) A 2100 (VISUALSONICS) was used. Mouse examinations were performed under 2.5% isoflurane inhalation anesthesia. LV function was measured in M-mode on a parasternal short-axis view.

[0064] A model of pacing-induced heart failure in Beagle dogs Male Beagle dogs aged 10-12 months (9.80-11.50 kg) were given general anesthesia induced with thiopental sodium (20 mg / kg, iv: Labonal injection 0.5 g, Nipro ES Pharma Co., Ltd.), then intubated with a tracheal cannula and artificial respiration was performed using an Acoma animal ventilator (PRO-45Va, Acoma Medical Industry Co., Ltd.). Anesthesia was maintained by inhaling a mixed gas (Air:O2=3:0.2) and 1.0-2.5% isoflurane (Isoflurane inhalation anesthetic solution "Pfizer", Mylan Pharmaceutical Co., Ltd.) using an Acoma animal anesthesia machine (NS-5000A, Acoma Medical Industry Co., Ltd.), thereby maintaining a constant depth of anesthesia. An incision was made in the right side of the animal's neck, and an internal cardiac pacemaker for animals (SIP-501, Star Medical Co., Ltd.) was implanted subcutaneously. Under the guidance of an X-ray fluoroscopy system (BV Pulsera, Koninklijke Philips NV), a retractable screw-in lead (Tendrill STS J, St. Jude Medical Co., Ltd.) was inserted through the right jugular vein, with its tip positioned in the right ventricular wall. Pacing was initiated at 244-251 beats / min on postoperative day 1. Animals whose ejection fraction (EF) decreased to 30-50% four weeks after pacemaker activation were considered to be in a state of heart failure, and were selected for analysis.

[0065] Canine ultrasound examination Echocardiography was performed using a general-purpose ultrasound imaging system (Vivid S6, GE Medical Systems). A sector probe (10 MHz) was placed on the chest, and left ventricular end-diastolic diameter (LVIDd), left ventricular end-systolic diameter (LVIDs), ejection fraction (EF), and left ventricular diameter shortening percentage (%FS) were measured in M ​​mode.

[0066] Canine cardiac catheterization Dogs were anesthetized intravenously with secobarbital sodium [Ional sodium for injection (0.2), Nichi-Iko Pharmaceutical Co., Ltd.] (14.5-22.3 mg / kg), followed by subcutaneous administration of meloxicam (Metacam 0.5% injection, Boehringer Ingelheim Animal Health Japan Co., Ltd.) at 0.2 mg / kg. A tracheal catheter was intubated into the airway and connected to an Acoma animal ventilator (PRO-45Va, Acoma Medical Industry Co., Ltd.). The ventilator was set to a respiratory rate of 14-18 strokes / min and a tidal volume of 10-20 mL / kg / stroke, and respiration was managed using a mixed gas (FiO2=0.3-1.0) via an Acoma animal anesthesia machine (NS-5000A, Acoma Medical Industry Co., Ltd.). Exhaled CO2 partial pressure was monitored using an exhaled carbon dioxide monitor (OLG-2800, Nihon Kohden Corporation). The animals were fixed in a dorsal position and the hair on their thighs and necks was shaved. Secobarbital sodium (5 mg / kg / hr) was continuously infused intravenously into the cephalic vein using a Terfusion syringe pump (STC-523, Terumo Corporation) to maintain anesthesia. A Swan-Ganz catheter was inserted into the left femoral vein. A catheter for coronary angiography was inserted into the left femoral artery. A 5F sheath for arterial blood sampling was placed in the right femoral artery. A catheter for PV-loop analysis was inserted into the left internal artery. An occlusion test was performed by inserting an 8F occlusion balloon into the right femoral vein. KUS121 was also administered via the left common jugular vein.

[0067] statistical analysis Measurement values ​​are shown as mean ± standard error of the mean (SEM). For other statistical comparisons, as described in the figure caption, one-way analysis of variance (ANOVA) (3 or more groups) was used with either an unpaired Student's t-test (2 groups, parametric), a Mann-Whitney test (2 groups, nonparametric), or Sidak's post-hoc test. A p-value less than 0.05 was considered statistically significant. Statistical analysis was performed using GraphPad Prism 6 (GraphPad Software, Inc).

[0068] result Investigation of the acute phase in a mouse model of heart failure Pressure-loaded cardiac hypertrophy / heart failure model mice were created by transaortic constriction (TAC), and 50 mg / kg of KUS121 was administered intraperitoneally immediately after TAC. Sham (Siamese) mice and control mice were administered 5% glucose. After 3 hours, the mice were sacrificed, and body weight, heart weight, lung weight, and BNP mRNA levels were measured. The experimental protocol is shown in Figure 2, and the results are shown in Figure 3. The ratio of lung weight to body weight and BNP mRNA levels increased in control mice, but were suppressed by KUS121 administration. There was no significant difference in the ratio of heart weight to body weight. These results indicate that KUS121 improves left ventricular load in acute heart failure model mice.

[0069] Examination of the cardiac hypertrophy phase in heart failure model mice. Pressure-induced cardiac hypertrophy / heart failure model mice were created using TAC, and 50 mg / kg of KUS121 was administered intraperitoneally daily for two weeks immediately after TAC. Sham (Siamese) mice and control mice were administered 5% glucose. Echocardiography was obtained two weeks after TAC, the mice were sacrificed, body weight and heart weight were measured, and cardiac samples were taken. The experimental protocol is shown in Figure 4.

[0070] Figure 5 shows the heart weight and the ratio of heart weight to body weight. Both increased in control mice but were suppressed by KUS121 administration. WGA staining was used to clarify the boundaries of cardiomyocytes, and the cross-sectional area of ​​cardiomyocytes was measured. The results are shown in Figure 6. The cross-sectional area of ​​cardiomyocytes increased in control mice but was suppressed by KUS121 administration.

[0071] mRNA levels of cardiac hypertrophy markers (BNP, ANF) and endoplasmic reticulum stress markers (Bip, CHOP, VCP) were measured by qRT-PCR. mRNA levels of cardiac hypertrophy markers were elevated in control mice but decreased with KUS121 administration. There were no significant differences in mRNA levels of endoplasmic reticulum stress markers.

[0072] Figure 7 shows the end-diastolic interventricular septal diameter (IVSd), left ventricular mass, and left ventricular ejection fraction (LVEF) as evaluated by echocardiography. While the interventricular septum and left ventricle were enlarged in control mice, both improved with KUS121 administration. Although a decrease in left ventricular ejection fraction was observed in control mice, no significant improvement was seen with KUS121 administration.

[0073] These results indicate that KUS121 suppresses cardiac hypertrophy in a mouse model of heart failure during the cardiac hypertrophy phase.

[0074] Examination of the heart failure phase in heart failure model mice Pressure-induced cardiac hypertrophy / heart failure model mice were created using TAC, and 50 mg / kg of KUS121 was administered intraperitoneally daily for 3 weeks starting 5 weeks after TAC. Sham (Siamese) mice and control mice were administered 5% glucose. Echocardiograms were obtained 5 and 8 weeks after TAC, and mice were sacrificed at 8 weeks. Body weight, heart weight, and lung weight were measured, and cardiac samples were taken. The experimental protocol is shown in Figure 8.

[0075] Left ventricular ejection fraction (LVEF) as assessed by echocardiography is shown in Figure 9, and left ventricular mass, left ventricular end-diastolic diameter (LVDd), and end-diastolic interventricular septal diameter (IVSd) are shown in Figure 10. Left ventricular systolic dysfunction was suggested in control mice, but it improved with KUS121 administration.

[0076] Figure 11 shows heart weight, the ratio of heart weight to body weight, lung weight, and the ratio of lung weight to body weight. All of these were increased in control mice, suggesting cardiac hypertrophy and pulmonary congestion. The increase in heart weight was suppressed by KUS121 administration. Figure 12 shows the cross-sectional area of ​​cardiomyocytes. Cardiomyocytes were hypertrophied in control mice, but this was improved by KUS121 administration.

[0077] mRNA levels of cardiac hypertrophy markers (ANF, BNP) and endoplasmic reticulum stress markers (VCP, CHOP, Bip) were measured by qRT-PCR. VCP mRNA levels increased with KUS121 administration, but there were no significant differences in mRNA levels of the other markers.

[0078] Mouse hearts were stained with Masson's trichrome, and the fibrotic area was quantified. The results are shown in Figure 13. Fibrosis of cardiac tissue was observed in control mice, but this was improved by KUS121 administration.

[0079] The mRNA levels of cardiac fibrosis markers (Col1a1 and Postn) were measured by qRT-PCR. The results are shown in Figure 14. While the mRNA levels of Col1a1 and Postn were elevated in control mice, they decreased after KUS121 administration.

[0080] These results demonstrate that KUS121 improves cardiac function and fibrosis in a mouse model of heart failure during the heart failure phase.

[0081] Investigation of the acute effects of KUS121 in a mouse model of heart failure. Eight-week-old mice underwent TAC surgery, and five weeks later (13 weeks old), left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDd), and heart rate (HR) were evaluated by echocardiography before and 10 minutes after KUS121 injection (50 mg / kg). The results are shown in Figure 15. Improvements were observed in left ventricular ejection fraction and left ventricular end-diastolic diameter, suggesting that KUS121 improves cardiac function without significantly altering heart rate.

[0082] Eight-week-old mice underwent TAC surgery, and left ventricular pressure was measured by cardiac catheterization before and 10 minutes after KUS121 injection (50 mg / kg) in mice 5 weeks later (13 weeks old). Before KUS121 administration, left ventricular pressure was 46.6 mmHg, but increased to 128.9 mmHg 10 minutes after KUS121 administration. Furthermore, Max / min dp / dt also changed from 1295.5 / -621.4 mmHg / s to 3972.8 / -1311.1 mmHg / s. In other words, the heart rate (HR) remained unchanged, while left ventricular pressure and dp / dt increased. These results suggest that KUS121 has a cardiotonic effect. Furthermore, when left ventricular ejection fraction was measured over time, it was 37% before KUS121 administration, increased to 67% 5 minutes after KUS121 administration, and returned to the original level in about 2 hours (Figure 16).

[0083] Studies in heart failure models of medium-sized animals A beagle dog model of heart failure was created using rapid ventricular pacing. The experimental protocol for KUS121 infusion is shown in Figure 17. Cardiac function was evaluated by echocardiography before KUS121 administration and after continuous infusion of 40 mg / hr. Both LVEF and %FS, measured by the Teichholz method and modified Simpson method, increased after KUS121 administration (Figure 18). Changes in heart rate, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, mean pulmonary artery pressure, pulmonary capillary wedge pressure, left ventricular end-diastolic pressure, and adjusted dp / dt are shown in Figures 19-21.

[0084] Heart failure model beagle dogs were treated according to the experimental protocol in Figure 17, except that dobutamine (Fuji Pharmaceutical Co., Ltd.) was used instead of KUS121 at the dose shown in Figure 22, and cardiac function was evaluated. Changes in heart rate, systolic blood pressure, cardiac output, mean pulmonary artery pressure, left ventricular end-diastolic pressure, and left ventricular dp / dt are shown in Figure 22.

[0085] In a heart failure model beagle dog, preload was reduced by inferior vena cava occlusion at baseline and during KUS121 infusion (40 mg / hr), and pressure-volume relationship (PV loop) data was obtained. A typical PV loop shift is shown in Figure 23. The changes from baseline in the end-systolic PV relationship and end-diastolic pressure-volume relationship obtained from the PV loop shift during KUS121 infusion are shown in Figure 24.

[0086] These results indicate that KUS121 administration did not alter heart rate or systolic blood pressure, but decreased pulmonary artery pressure and pulmonary artery wedge pressure, and improved left ventricular systolic and diastolic function. Furthermore, acute-phase blood test data showed that liver and kidney function remained normal. On the other hand, dobutamine, a conventionally used inotropic agent, improved left ventricular systolic function but also increased heart rate.

[0087] Example 2 HFpEF model mice were created by administering a high-fat diet and L-NG-nitroarginine methyl ester (L-NAME), and the effect of KUS121 on HFpEF was investigated. ICR mice were administered either a normal diet with ultrapure water or a high-fat diet with 0.5 g / L of L-NAME for 5 weeks. As expected, the high-fat diet + 0.5 g / L L-NAME group showed a significant increase in body weight and heart weight (Figure 25).

[0088] Next, we examined the acute effects of KUS121 on HFpEF. ICR mice, which had been fed either a normal diet or a high-fat diet + L-NAME 0.5 g / L for 5 weeks, were intraperitoneally administered KUS121 at 50 mg / kg, and cardiac function was evaluated by echocardiography before administration and 10 minutes after administration. Echocardiography showed no difference in EF between the normal diet group and the high-fat diet + L-NAME group before administration of 5% glucose (Tz) or KUS121 (Figure 26). With 5% Tz administration, there was no change in EF in the control group and the high-fat diet + L-NAME group (Figure 26 left, center), but EF improved in the high-fat diet + L-NAME group after KUS121 administration (Figure 26 right). Previous studies using MRS have shown that endogenous ATP supply is reduced in HFpEF (J Am Coll Cardiol. 2009 Jul 28;54(5):402-9.), so it was thought that KUS121 had a contractile force-improving effect.

[0089] Next, we examined diastolic function. Cardiac diastolic function was evaluated using global longitudinal strain (GLS), E / A, and E / E'. Before KUS121 administration, mice in the high-fat diet + L-NAME group showed elevated GLS, E / A, and E / E' values, and diastolic dysfunction was observed, although the degree varied among individuals (Figure 27). With 5% Tz administration, there were no changes in GLS, E / A, and E / E' in the control group and the high-fat diet + L-NAME group (Figure 27 left, center). However, upon administration of KUS121, improvements in GLS, E / A, and E / E' values ​​were observed (Figure 27 right), demonstrating the acute effect of KUS121 on diastolic dysfunction.

[0090] Next, blood pressure and heart rate were compared before and after KUS121 administration (Figure 28). Blood pressure was elevated in both systolic and diastolic levels in the high-fat diet + L-NAME group (Figure 28, upper panel). Administration of KUS121 resulted in a decrease in blood pressure (Figure 28, upper panel) and a slight decrease in heart rate (Figure 28, lower panel).

[0091] Furthermore, a treadmill test (TMT) was performed to assess exercise tolerance. Before KUS121 administration, the high-fat diet + L-NAME group showed a decrease in running distance. Exercise tolerance improved after KUS121 administration (Figure 29).

[0092] As a result, administration of KUS121 to the HFpEF model showed improvements in diastolic function and exercise tolerance.

[0093] Example 3 Acute effects of KUS187 in a mouse model of heart failure Eight-week-old mice underwent TAC surgery, and left ventricular ejection fraction (LVEF) was evaluated by echocardiography before and 10 minutes after injection of 5% glucose or KUS187 (50 mg / kg) in mice 5 weeks later (13 weeks old). The results are shown in Figure 30. Improvement in left ventricular ejection fraction was observed, suggesting that KUS187 improves cardiac function. [Industrial applicability]

[0094] This disclosure provides methods for improving cardiac function and for treating heart failure, and is useful in the field of medicine.

Claims

1. Equation (I): 【Chemistry 1】 [During the ceremony, Ra is selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, aryl, halo or alkyl-substituted aryl, alkoxy, hydroxy or carboxy-substituted alkoxy, aryloxy, halo or alkyl-substituted aryloxy, CHO, C(O)-alkyl, C(O)-aryl, C(O)-alkyl-carboxyl, C(O)-alkylene-carboxyester, and cyano. m is an integer selected from 0 to 4. A composition for improving left ventricular diastolic function, comprising a compound or a pharmaceutically acceptable salt or solvate thereof.

2. The composition according to claim 1 for improving the diastolic and systolic functions of the left ventricle.

3. Equation (I): 【Chemistry 2】 [During the ceremony, Ra is selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, aryl, halo or alkyl-substituted aryl, alkoxy, hydroxy or carboxy-substituted alkoxy, aryloxy, halo or alkyl-substituted aryloxy, CHO, C(O)-alkyl, C(O)-aryl, C(O)-alkyl-carboxyl, C(O)-alkylene-carboxyester, and cyano. m is an integer selected from 0 to 4. A composition for the treatment of heart failure, comprising a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the cause of heart failure is not myocardial infarction.

4. Formula (I): 【Transformation 3】 [During the ceremony, Ra is selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, aryl, halo or alkyl-substituted aryl, alkoxy, hydroxy or carboxy-substituted alkoxy, aryloxy, halo or alkyl-substituted aryloxy, CHO, C(O)-alkyl, C(O)-aryl, C(O)-alkyl-carboxyl, C(O)-alkylene-carboxyester, and cyano. m is an integer selected from 0 to 4. A composition comprising the compound or a pharmaceutically acceptable salt or solvate thereof, for the treatment of heart failure with preserved left ventricular ejection fraction (HFpEF).

5. The composition according to claim 3, wherein the heart failure is acute heart failure.

6. Formula (I): 【Chemistry 4】 [During the ceremony, Ra is selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, aryl, halo or alkyl-substituted aryl, alkoxy, hydroxy or carboxy-substituted alkoxy, aryloxy, halo or alkyl-substituted aryloxy, CHO, C(O)-alkyl, C(O)-aryl, C(O)-alkyl-carboxyl, C(O)-alkylene-carboxyester, and cyano. m is an integer selected from 0 to 4. A composition for the treatment of heart failure comprising a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the cause of heart failure is not a heart disease involving cardiomyocyte death.

7. The composition according to any one of claims 1 to 6, wherein Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halosubstituted alkyl, alkoxy, and CHO.

8. The composition according to any one of claims 1 to 6, wherein Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halosubstituted alkyl, and alkoxy.

9. The compound of formula (I) 4-amino-3-(6-phenylpyridine-3-ylazo)naphthalene-1-sulfonic acid; 4-amino-3-(6-p-tolylpyridine-3-ylazo)naphthalene-1-sulfonic acid; 4-amino-3-(6-m-tolylpyridine-3-ylazo)naphthalene-1-sulfonic acid; 4-amino-3-(6-o-tolylpyridine-3-ylazo)naphthalene-1-sulfonic acid; 4-amino-3-(6-biphenyl-2-ylpyridine-3-ylazo)naphthalene-1-sulfonic acid; 3-[6-(2-acetylphenyl)pyridine-3-ylazo]-4-aminonaphthalene-1-sulfonic acid; 3-[6-(3-acetylphenyl)pyridine-3-ylazo]-4-aminonaphthalene-1-sulfonic acid; 3-[6-(4-acetylphenyl)pyridine-3-ylazo]-4-aminonaphthalenesulfonic acid; 4-amino-3-[6-(2,4-dichlorophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-trifluoromethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4-trifluoromethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-chlorophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(3-chlorophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4-chlorophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-methoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4-methoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-isopropoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4-isopropoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-phenoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(3-methoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2,3-dimethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2,5-dimethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(3,5-dimethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(3-trifluoromethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-{4-[5-(1-amino-4-sulfonaphthalene-2-ylazo)pyridine-2-yl]phenyl}-4-oxobutyric acid; 4-amino-3-(6-biphenyl-3-ylpyridine-3-ylazo)naphthalene-1-sulfonic acid; 4-amino-3-[6-(3-cyanophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4-cyanophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(3,5-bistrifluoromethylphenyl)pyridine-3-ylazo]naphthalenesulfonic acid; 4-amino-3-[6-(4-benzoylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-propoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(5-fluoro-2-propoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-fluoro-6-propoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4-fluoro-2-propoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(5-fluoro-2-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-fluoro-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-butoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-hexyloxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4-butylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-hydroxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-{6-[2-(6-hydroxyhexyloxy)phenyl]pyridine-3-ylazo}naphthalene-1-sulfonic acid; 4-{2-[5-(1-amino-4-sulfonaphthalene-2-ylazo)pyridine-2-yl]phenoxy}butyric acid; 4-amino-3-{6-[2-(3-hydroxypropoxy)phenyl]pyridine-3-ylazo}naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-isobutoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(5-chloro-2-hydroxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4-methylbiphenyl-2-yl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4'-chloro-4-methylbiphenyl-2-yl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4,3',5'-trimethylbiphenyl-2-yl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(3'-chloro-4-methylbiphenyl-2-yl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2,6-dimethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(3-formyl-2-isopropoxy-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; And, 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid; A composition according to any one of claims 1 to 6, selected from the group consisting of the following.

10. The composition according to any one of claims 1 to 6, wherein the compound of formula (I) is 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid.

11. The composition according to any one of claims 1 to 6, wherein the compound of formula (I) is 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid.

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