Composition for improving heart 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

Composition for improving cardiac function

[0001] This patent application claims priority to Japanese Patent Application No. 2021-211106, the entire contents of which are incorporated herein by reference. The present disclosure relates to compositions for improving cardiac function.

[0002] Heart failure is defined as "a clinical syndrome characterized by some form of cardiac dysfunction, i.e., a breakdown in the metabolic mechanism of cardiac pumping due to organic and / or functional abnormalities in the heart, resulting in dyspnea, fatigue, and edema, and a corresponding decline in exercise tolerance." As the population ages, the incidence and mortality rates of heart failure are increasing.

[0003] Many cases of heart failure involve left ventricular dysfunction, and the American College of Cardiology Foundation and the Japanese Circulation Society guidelines classify heart failure according to left ventricular contractility. Heart failure is primarily classified into heart failure with reduced left ventricular ejection fraction (LVEF) (HFrEF) and heart failure with preserved LVEF (HFpEF). HFrEF is primarily characterized by systolic dysfunction, while HFpEF is primarily characterized by diastolic dysfunction. Drugs that improve cardiac contractility, so-called inotropes, are used to treat HFrEF; however, adverse side effects occur due to an increase in contractility alone. Meanwhile, no drugs are known to improve cardiac diastolic function, and effective treatments for HFpEF have yet been fully established. Therefore, the development of a means to improve cardiac diastolic function is desirable.

[0004] Certain 4-amino-naphthalene-1-sulfonic acid derivatives inhibit the ATPase activity of VCP (valosin-containing protein), the 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 4-amino-naphthalene-1-sulfonic acid derivatives suppress myocardial cell death in an ischemia-reperfusion model.

[0005] International Publication No. 2012 / 014994 Pamphlet International Publication No. 2012 / 043891 Pamphlet International Publication No. 2014 / 129495 Pamphlet International Publication No. 2015 / 129809 Pamphlet International Publication No. 2015 / 033981 Pamphlet International Publication No. 2019 / 131720 Pamphlet International Publication No. 2019 / 203176 Pamphlet International Publication No. 2020 / 027137 Pamphlet International Publication No. 2021 / 079983 Pamphlet

[0006] The purpose of the present disclosure is to provide new means for improving cardiac function.

[0007] The present inventors have found that compounds of formula (I) improve cardiac function in models of heart failure. Thus, in one aspect, the present disclosure provides compounds of formula (I): wherein 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-carboxy ester, and cyano; and m is an integer selected from 0 to 4, or an ester, oxide, prodrug, pharmaceutically acceptable salt, or solvate thereof, for improving cardiac function.

[0008] In certain aspects, the present disclosure provides a composition for treating heart failure comprising a compound of formula (I) or an ester, oxide, prodrug, pharmaceutically acceptable salt, or solvate thereof.

[0009] The present disclosure makes it possible to improve cardiac function and treat heart failure.

[0010] Figure 1 shows a schematic diagram of aortic coarctation (TAC) model. Figure 2 shows the experimental protocol for injecting KUS121 or 5% glucose (Tz) into a mouse model of acute heart failure induced by pressure overload. Figure 3 shows the heart weight to body weight ratio (left), lung weight to body weight ratio (center), and BNP mRNA levels (right) for sham-operated mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg) after TAC. Figure 4 shows the experimental protocol for injecting KUS121 or 5% glucose into a mouse model of cardiac hypertrophy induced by pressure overload. Figure 5 shows the heart weight (left) and the ratio of heart weight to body weight (right) for sham-operated mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg / day) after TAC. Figure 1 shows the results of quantification of 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. The end-diastolic interventricular septum diameter (IVSd) (left), left ventricular ejection fraction (LVEF) (center), and left ventricular mass (right) were assessed by echocardiography in sham-operated mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg / day) after TAC. The experimental protocol for injecting KUS121 or 5% glucose into a pressure-overload-induced heart failure model mouse is shown. Changes in left ventricular ejection fraction (LVEF) assessed by echocardiography are shown for sham-operated mice receiving 5% glucose, mice receiving 5% glucose after TAC, and mice receiving KUS121 (50 mg / kg / day) after TAC. Changes in left ventricular mass (upper left), left ventricular end-diastolic diameter (LVDd) (upper right), and interventricular septum diameter (IVSd) at end-diastole (lower right) are shown for sham-operated mice receiving 5% glucose, mice receiving 5% glucose after TAC, and mice receiving KUS121 (50 mg / kg / day) after TAC. Shown are heart weight (upper left), heart weight to body weight ratio (upper right), lung weight (lower left), and lung weight to body weight ratio (lower right) for sham-operated mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg / day) after TAC.Figure 1 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 2 shows the results of quantifying the area of ​​fibrosis in the hearts of mice administered 5% glucose after TAC and mice administered KUS121 (50 mg / kg / day) after TAC, after Masson's trichrome staining. Figure 3 shows the mRNA levels of Col1a1 and Postn in the hearts of sham-operated mice administered 5% glucose, mice administered 5% glucose after TAC, and mice administered KUS121 (50 mg / kg / day) after TAC. TAC surgery was performed on 8-week-old mice, and the changes in left ventricular ejection fraction (LVEF) (upper left), left ventricular end-diastolic diameter (LVDd) (upper right), and heart rate (HR) (lower) were evaluated by echocardiography 5 weeks after TAC surgery in mice at 8 weeks of age. The time course of left ventricular ejection fraction measured by echocardiography 5 weeks after surgery is shown (data up to 150 minutes after KUS121 injection (50 mg / kg)). The experimental protocol for KUS121 injection into a beagle dog model of heart failure using rapid ventricular pacing is shown. This figure shows left ventricular ejection fraction (EF) (showing EF by Teichholz method and modified-Simpson's method) and left ventricular fractional shortening measured by echocardiography 15 minutes after KUS121 injection at 40 mg / hr into a beagle dog model of heart failure induced by rapid ventricular pacing. This figure shows changes in heart rate (upper left), systolic blood pressure (upper right), and diastolic blood pressure (lower) following KUS121 injection in a beagle dog model of heart failure. This figure shows changes in left ventricular ejection fraction (LVEF) (upper left), mean pulmonary artery pressure (upper right), and pulmonary capillary wedge pressure (lower) following KUS121 injection in a beagle dog model of heart failure. This figure shows changes in left ventricular end-diastolic pressure (left) and adjusted dp / dt (right) following KUS121 injection in a beagle dog model of heart failure. FIG. 1 shows changes in heart rate (upper left), systolic blood pressure (upper right), cardiac output (middle left), mean pulmonary artery pressure (middle right), left ventricular end-diastolic pressure (lower left), and left ventricular dp / dt (lower right) following dobutamine infusion in a beagle dog model of heart failure.Representative PV loop shifts due to preload reduction by inferior vena cava occlusion are shown in a beagle dog model of heart failure at baseline (left) and during KUS121 infusion (40 mg / hr) (right). Changes from baseline in the end-systolic PV relationship (ESPVR) (left) and end-diastolic pressure-volume relationship (EDPVR) (right) obtained by PV loop shifts during KUS121 infusion (40 mg / hr) are shown in a beagle dog model of heart failure. Body weight (upper left), heart weight (upper right), heart weight / tibia length (lower left), and the ratio of heart weight to body weight (lower right) are shown for control mice administered 5% glucose, HFpEF model mice administered 5% glucose, and HFpEF model mice administered KUS121 (50 mg / kg). Figure 1 shows 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 2 shows changes in GLS (upper row), E / A (middle row), and E / E' (lower row) in control mice administered 5% glucose, HFpEF model mice administered 5% glucose, and HFpEF model mice administered KUS121 (50 mg / kg). Figure 3 shows changes in blood pressure (upper row) and heart rate (lower row) in control mice administered 5% glucose, HFpEF model mice administered 5% glucose, and HFpEF model mice administered KUS121 (50 mg / kg). Changes in running distance in a treadmill test were shown for control mice administered 5% glucose, HFpEF model mice administered 5% glucose, and HFpEF model mice administered KUS121 (50 mg / kg). Eight-week-old mice underwent TAC surgery, and changes in left ventricular ejection fraction (LVEF) assessed by echocardiography were shown for mice 5 weeks later, before and after injection of 5% glucose (left) or KUS187 (50 mg / kg) (right).

[0011] In this disclosure, when a numerical value is accompanied by the term "about," it is intended to encompass a range of ±10% of that value. For example, "about 20" is intended to include "18 to 22." A range of numerical values ​​includes all values ​​between and at the endpoints. "About" in reference to a range applies to both endpoints of the range. Thus, for example, "about 20 to 30" is intended to include "18 to 33."

[0012] Unless otherwise specified, terms used in this disclosure have the meanings commonly understood by those skilled in the art of organic chemistry, medicine, pharmacology, molecular biology, microbiology, etc. Below, definitions of some terms used in this disclosure are provided, but these definitions take precedence over common understandings in this disclosure.

[0013] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Alkyl refers to straight and branched chain hydrocarbyl groups such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and neopentyl.

[0014] The prefix "substituted" before a group means that one or more hydrogen atoms on the group have been replaced with the same or different specified substituent(s).

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

[0016] "Alkoxy" refers to the group -O-alkyl, where alkyl is defined in this disclosure. Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0017] "Aryl" means a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Aryl groups typically include phenyl and naphthyl. "Aryloxy" means the group -O-aryl, where aryl is defined herein, and includes, for example, phenoxy and naphthoxy.

[0018] "Cyano" refers to the group -CN. "Carboxyl" or "carboxy" refers to -COOH or its salts. "Carboxy ester" refers to the group -C(O)O-alkyl, where alkyl is defined in this disclosure. "Halo" refers to halogen, particularly fluoro, chloro, bromo, and iodo. "Hydroxy" refers to the group -OH.

[0019] Unless otherwise specified, the nomenclature for substituents not explicitly defined in this disclosure is based on naming the terminal portion of the functional group and then the adjacent functional group toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" means (aryl)-(alkyl)-O-C(O)-.

[0020] Depending on the substitution pattern, the compounds of formula (I) may exist as enantiomers or diastereomers. The compounds of formula (I) may be racemic or may be separated into stereoisomerically pure components by known methods. Some compounds may be tautomers.

[0021] "Ester" means an ester that is hydrolyzable in vivo and includes those that break down readily 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 alkanoic, alkenoic, cycloalkanoic, and alkanedioic acids, where each alkyl or alkenyl group has, for example, 6 or fewer carbon atoms. Specific examples of esters include formate, acetate, propionate, butyrate, acrylate, and ethylsuccinate. "Oxide" means that the nitrogen ring atom of a heteroaryl group is oxidized to form an N-oxide.

[0022] "Prodrug" means a prodrug of a compound that is, within the scope of sound medical judgment, suitable for use in contact with human or animal tissues without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio, and effective for the intended use. Prodrugs are compounds that are rapidly converted in vivo, for example by hydrolysis in the blood, to yield the parent compound of the above formula. A general description is 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 of which are incorporated 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 inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or organic carboxylic or sulfonic acids 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] Pharmaceutically acceptable salts may also be salts with conventional bases, for example alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts), or ammonium salts, especially sodium salts, derived from ammonia or organic amines (e.g. diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, methylpiperidine, L-arginine, creatine, choline, L-lysine, ethylenediamine, benzathine, ethanolamine, meglumine or tromethamine).

[0025] "Solvate" means a compound of formula (I) that, in the solid or liquid state, forms a complex by coordination with solvent molecules. Preferred solvates are hydrates.

[0026] Reference in this disclosure to "compounds of formula (I)" is intended to encompass esters, oxides, prodrugs, pharmaceutically acceptable salts and solvates thereof, unless the context is inappropriate.

[0027] In one embodiment, in formula (I), each Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, alkoxy, and CHO. In one embodiment, in formula (I), each Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, and alkoxy. In one embodiment, in formula (I), each Ra is independently selected from the group consisting of halo and alkyl. In one embodiment, in formula (I), there are two Ra, one is halo, and the other is alkyl. In one embodiment, in formula (I), each Ra is independently selected from the group consisting of alkyl, alkoxy, and CHO. In one embodiment, in formula (I), there are three Ra, one is alkyl, one is alkoxy, and one is CHO.

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

[0029]

[0030]

[0031] In one embodiment, a compound of the formula: or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof, preferably a sodium salt thereof, is used.

[0032] In one embodiment, a compound of the formula: or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof, preferably a sodium salt thereof, is used.

[0033] The properties and synthesis methods of the compounds of formula (I), in particular the above compounds, are described in detail in WO 2012 / 014994.

[0034] In the Examples described below, the compound of formula (I) attenuated compensatory cardiac hypertrophy in a pressure overload heart failure model mouse and reduced the deterioration of heart failure. 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 systolic and diastolic function. Furthermore, the compound of formula (I) improved left ventricular diastolic function and exercise tolerance in a heart failure with preserved LVEF (HFpEF) model.

[0035] Therefore, in certain embodiments, compounds of formula (I) can 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 annular motion velocity waveform. Right ventricular contractility can be assessed, for example, by tricuspid annular systolic excursion distance or right ventricular area change rate. Right ventricular diastolic function can be assessed, for example, by right ventricular inflow blood flow velocity waveform. Compounds of formula (I) can improve at least one of left ventricular contractility, left ventricular diastolic function, right ventricular contractility, and right ventricular diastolic function. In certain embodiments, compounds of formula (I) can improve cardiac function in patients with heart failure.

[0036] In another embodiment, the compounds of Formula (I) can be used to treat heart failure. The progression of heart failure stages is known, for example, through the heart failure staging system of the American College of Cardiology Foundation / American Heart Association (ACCF / AHA). In the present disclosure, heart failure includes Stage C, in which heart failure symptoms are present due to organic heart disease, and Stage B, in which cardiac remodeling occurs due to compensatory mechanisms but heart failure symptoms are not present. Stage C heart failure includes decompensated heart failure, in which hemodynamics is not compensated after the onset of organic heart disease, and compensated heart failure, in which hemodynamics is compensated. Compensatory mechanisms include cardiac remodeling such as cardiac hypertrophy and enlargement, and increased cardiac output due to activation of neurohumoral factors. Heart failure may or may not be accompanied by myocardial cell death. In some embodiments, heart failure is not accompanied by myocardial cell death.

[0037] Heart failure is classified based on left ventricular contractility into heart failure with reduced left ventricular ejection fraction (LVEF) (HFrEF), heart failure with preserved LVEF (HFpEF), and heart failure with mildly reduced LVEF (HFmrEF). While classification criteria may vary, for example, according to the 2021 JCS / JHFS Guideline Focus Update for the Management of Acute and Chronic Heart Failure, HFrEF is defined as LVEF less than 40%, HFpEF as 50% or greater, and HFmrEF as 40% to less than 50%. Heart failure can also be classified based on changes in LVEF over time into heart failure with improved LVEF (HFrecEF), heart failure with worsening LVEF (HFworEF), and heart failure with unchanged LVEF (HFuncEF).

[0038] In addition, in the past, acute heart failure was defined as "a condition in which the compensatory mechanism of cardiac pump function suddenly fails, causing an increase in ventricular end-diastolic pressure and insufficient perfusion to major organs, resulting in the sudden appearance or worsening of symptoms and signs," while chronic heart failure was defined as "a condition in which chronic cardiac pump failure leads to continued congestion in the pulmonary and / or systemic venous system and tissue hypoperfusion, interfering with daily life." Acute exacerbation of chronic heart failure is included in acute heart failure.

[0039] The causes of heart failure are not limited. 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, non-compaction, takotsubo cardiomyopathy, etc.), cardiotoxic substances (addictive substances such as alcohol, cocaine, amphetamines, anabolic steroids, heavy metals such as copper, iron, lead, cobalt, mercury, anticancer drugs (anthracyclines, etc.), immunosuppressants, antidepressants, antiarrhythmic drugs, NSAIDs, anesthetics, radiation damage, etc.), myocarditis (viral, bacterial, rickettsial infection, Chagas disease, etc.), immune diseases (rheumatoid arthritis, systemic lupus erythematosus, polymyositis, mixed connective tissue disease, etc.), pregnancy (peripartum cardiomyopathy including puerperal cardiomyopathy, etc.), infiltrative diseases (sarcoidosis, amyloidosis, hemochromatosis, malignant tumors, etc.) infiltration, etc.), endocrine disorders (hyperthyroidism, Cushing's disease, pheochromocytoma, adrenal insufficiency, growth hormone secretion abnormalities, etc.), metabolic disorders (diabetes, etc.), congenital enzyme abnormalities (Fabry disease, Pompe disease, Hurler syndrome, Hunter syndrome, etc.), muscle diseases (muscular dystrophy, laminopathies, etc.), high blood pressure, valvular disease, structural abnormalities of the heart (congenital valvular disease, atrial septal defect, ventricular septal defect, other congenital heart diseases, aortic valve, mitral valve heart failure), epicardial abnormalities (e.g., constrictive pericarditis, cardiac tamponade), endocardial abnormalities (e.g., eosinophilic endocardial disease, endocardial elastosis), high cardiac output heart failure (e.g., severe anemia, hyperthyroidism, Paget's disease, arteriovenous shunt, pregnancy, heart beriberi), volume expansion (e.g., renal failure, excessive fluid administration), tachyarrhythmia (e.g., atrial fibrillation, atrial tachycardia, ventricular tachycardia), bradyarrhythmia (e.g., sick sinus syndrome, atrioventricular block). In one embodiment, the cause of heart failure is not a cardiac disease accompanied by myocardial cell death. In one embodiment, the cause of heart failure is not myocardial infarction, hypertension, or dilated cardiomyopathy.

[0040] In this disclosure, "treating heart failure" or "treatment of heart failure" means slowing or halting the progression of heart failure and / or reducing, alleviating, ameliorating, or eliminating heart failure in a subject with heart failure.

[0041] The compounds of formula (I) can be administered to animals, typically mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.), particularly humans.

[0042] The method of administration of a compound of Formula (I) is not particularly limited, and can be via common administration routes such as oral administration, parenteral administration, injection, infusion, etc. Parenteral administration can be systemic administration or local administration, and includes, for example, intravenous administration, intraarterial administration, intradermal administration, subcutaneous administration, transdermal administration, intramuscular administration, intraperitoneal administration, or intranasal administration. In some embodiments, a compound of Formula (I) is administered intravenously to a subject. In some embodiments, a compound of Formula (I) is administered orally to a subject.

[0043] The compound of Formula (I) may be administered in a composition. The composition may be solid, liquid, or any intermediate form (e.g., semisolid). Various known formulations may be used depending on the characteristics of the subject, the method of administration, and the dosage. Oral dosage forms include granules, fine granules, powders, coated tablets, tablets, powders, capsules, microcapsules, chewable tablets, liquids, suspensions, emulsions, and the like. Injectable dosage forms include common pharmaceutical dosage forms such as intravenous injections, infusions, and formulations with extended release of active substances. Injectable dosage forms include aqueous and non-aqueous injection solutions and suspensions. Injectable dosage forms may be provided in sealed ampoules or vials, or as lyophilized products that require only the addition of a sterile liquid (e.g., water for injection) immediately before use. Injectable solutions or suspensions may be prepared from powders, granules, or tablets.

[0044] These dosage forms are prepared by conventional formulation methods. Furthermore, various pharmaceutically acceptable pharmaceutical substances can be blended as needed for the formulation. Pharmaceutical substances can be appropriately selected depending on the dosage form of the preparation, and examples include buffering agents, surfactants, stabilizers, preservatives, excipients, diluents, additives, disintegrants, binders, coating agents, lubricants, glidants, flavoring agents, sweeteners, solubilizers, antioxidants, bacteriostatic agents, isotonicity agents, suspending agents, thickeners, pigments, dyes, and fragrances.

[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 species, health condition, age, body weight, route of administration, dosage form, etc. of the animal to be administered so that an effective amount of the compound of Formula (I) is administered to the subject. The effective amount in a given situation can be easily determined by routine experimentation. For example, the compound of Formula (I) may be administered at a rate of about 0.001 to about 1000 mg / kg body weight / day, about 0.01 to about 200 mg / kg body weight / day, or about 0.1 to about 100 mg / kg body weight / day. Alternatively, the compound of Formula (I) may be continuously infused at a rate of about 0.1 to 1000 mg / hr, about 1 to 500 mg / hr, or about 5 to 100 mg / hr.

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

[0047] The compound of formula (I) can be used alone or in combination with one or more additional active ingredients. The term "combined use" of ingredients refers not only to the use of a dosage form containing all ingredients or the use of a combination of dosage forms containing each ingredient separately, but also to the simultaneous administration of each ingredient or the administration of any ingredient at a later time, as long as they are used to improve cardiac function or treat heart failure. Two or more additional active ingredients can also be used in combination. For example, a composition containing one or more additional active ingredients in addition to the compound of formula (I) can be used. Active ingredients suitable for combination use include therapeutic agents for heart failure, such as diuretics, mineralocorticoid receptor antagonists, cardiotonic agents, antiarrhythmic agents, and beta-blockers.

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

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

[0050] In some embodiments, a composition for treating heart failure is provided, comprising a compound of Formula (I). In some embodiments, a method for treating heart failure is provided, comprising administering to a subject an effective amount of a compound of Formula (I). In some embodiments, a compound of Formula (I) is provided for treating heart failure. In some embodiments, a use of a compound of Formula (I) for treating heart failure is provided. In some embodiments, a 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] Formula (I): [wherein 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-carboxy ester, and cyano, and m is an integer selected from 0 to 4, or an ester, oxide, prodrug, pharmaceutically acceptable salt, or solvate thereof for improving cardiac function. [2] The composition according to item 1, wherein the cardiac function is left ventricular diastolic function. [3] The composition according to item 1, wherein the cardiac function is left ventricular systolic function. [4] The composition according to item 1, wherein the cardiac function is left ventricular diastolic function and systolic function. [5] The composition according to any one of items 1 to 4, for improving cardiac function in a patient with heart failure.

[0052] [6] Formula (I): [wherein 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-carboxy ester, and cyano, and m is an integer selected from 0 to 4, or an ester, oxide, prodrug, pharmaceutically acceptable salt, or solvate thereof for treating heart failure. [7] The composition according to item 5 or 6, wherein the heart failure is heart failure with reduced left ventricular ejection fraction (LVEF) (HFrEF). [8] The composition according to item 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 item 8, wherein the heart failure is HFpEF.

[10] The composition according to item 5 or 6, wherein the heart failure is heart failure with improved LVEF (HFrecEF), heart failure with worsened LVEF (HFworEF), or heart failure with unchanged LVEF (HFuncEF).

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

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

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

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

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

[16] The composition according to any one of items 5 to 15, wherein the cause of heart failure is ischemic heart disease, cardiomyopathy, a cardiotoxic substance, myocarditis, an immune disease, pregnancy, an infiltrative disease, an endocrine disease, a metabolic disease, a congenital enzyme abnormality, a muscle disease, hypertension, a valvular disease, a structural cardiac abnormality, an epicardial abnormality, an endocardial abnormality, high cardiac output heart failure, volume expansion, tachyarrhythmia, or bradyarrhythmia.

[17] The composition according to any one of items 5 to 16, wherein the cause of heart failure is not a cardiac disease accompanied by myocardial cell death.

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

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

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

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

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

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

[25] The composition according to any one of items 1 to 20 and 24, wherein there are three Ra, one is alkyl, one is alkoxy, and one is CHO.

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

[28] The composition according to any one of items 1 to 23, 26 and 27, comprising 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt.

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

[30] The composition according to any one of items 1 to 21, 24 to 26, and 29, comprising 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt.

[0054] All documents cited in this specification are incorporated herein by reference. The present invention will be described in more detail in the following examples, but the present invention is not limited to these examples. The above descriptions are all non-limiting, and the present invention is defined in the appended claims, and various modifications are possible within the scope of the technical idea thereof.

[0055] Example 1 Materials and Methods Compounds 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt (KUS121) and 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid sodium salt (KUS187), both prepared by the method described in WO 2012 / 014994, were used.

[0056] Experimental Animals: Institute of Cancer Research (ICR) mice were purchased from Charles River Laboratory. Mice were housed under specific pathogen-free conditions in a temperature-controlled room with a 14:10-h light / dark cycle at the Institute of Laboratory Animal Science, Graduate School of Medicine, Kyoto University. 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 Institutional Review Board.

[0057] Pressure-overload cardiac hypertrophy / heart failure model. Transaortic aortic constriction (TAC) was performed as described in the following publication [Date et al. (2002) The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in an in vivo murine pressure-overload model. J Am Coll Cardiol 39: 907-912]. Eight- to ten-week-old mice were intraperitoneally administered anesthesia (medetomidine 0.3 mg / kg, midazolam 4.0 mg / kg, butorphanol 5.0 mg / kg), and a proximal sternal incision was made to visualize the aorta. A 7-0 silk suture was placed around the aortic arch distal to the brachiocephalic trunk. The suture was then tightly tightened around a 26-gauge blunt needle placed adjacent to the aorta. The needle was then removed, and the chest and overlying skin were closed. Sham mice underwent the same procedure without ligating the aortic arch. After surgery, 0.3 mg / kg of atipamezole was administered subcutaneously to attenuate the effect of medetomidine. A schematic diagram of 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 isolated 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 was analyzed using Verso （商標）Using a cDNA Synthesis Kit (Thermo Fisher Scientific, AB1453A), reverse transcription was performed using a 3:1 (volume / volume) blend of random hexamer and oligo dT primers according to the manufacturer's protocol, and the resulting cDNA was analyzed by qRT-PCR. qRT-PCR measurements were performed using THUNDERBIRD SYBR qPCR Mix (TOYOBO) according to the manufacturer's instructions. Messenger RNA (mRNA) expression levels were normalized with housekeeping genes and analyzed using 2 －ΔΔＣｔ All analyses were performed using the StepOnePlus Real-Time PCR System and StepOne Software v2.3 (Applied Biosystems, Inc.).

[0060] Wheat germ agglutinin (WGA) staining and quantification. Paraffin-embedded ventricular short-axis sections were stained with FITC-conjugated lectin (Sigma, L4895). Images were taken using an Axio Observer 7 (Zeiss). Cardiomyocyte cross-sectional area measurements were performed 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 quantification: After fixation with 4% paraformaldehyde, the sections were dehydrated in 70% ethanol and embedded in paraffin. After deparaffinization, the nuclei were stained with hematoxylin and the cytoplasm with eosin. Images were taken with an Axio Observer 7 (Zeiss). The 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 quantification: After deparaffinization, sections were stained with hematoxylin for nuclei, Masson's solution for cytoplasm, and aniline blue for collagen fibers. After photographing with a microscope (BZ-9000, Keyence), the area stained with aniline blue was measured using ImageJ64 software (NIH).

[0063] Mouse echocardiogram: Vevo was used to analyze cardiac function at various time points after TAC surgery. （登録商標） A 2100 (VISUALSONICS) was used. Mice were anesthetized with 2.5% isoflurane. LV function was measured in M-mode in a parasternal short-axis view.

[0064] Pacing-induced heart failure model in beagle dogs. Ten- to twelve-month-old male beagle dogs (9.80-11.50 kg) were anesthetized with thiopental sodium (20 mg / kg, i.v.; 0.5 g for injection, Nipro ES Pharma Co., Ltd.). A tracheal cannula was inserted into the airway, and artificial ventilation was performed using an Acoma animal ventilator (PRO-45Va, Acoma Medical Industries Co., Ltd.). Anesthesia was maintained by inhaling a gas mixture (air:O2 = 3:0.2) and 1.0-2.5% isoflurane (isoflurane inhalation anesthetic solution "Pfizer," Mylan Pharmaceuticals Co., Ltd.) using an Acoma animal anesthesia machine (NS-5000A, Acoma Medical Industries Co., Ltd.). A constant depth of anesthesia was maintained. The right neck of the animals was incised, and an internal cardiac pacemaker (SIP-501, Star Medical Co., Ltd.) was implanted subcutaneously. Under X-ray fluoroscopy (BV Pulsera, Koninklijke Philips NV), a retractable screw-in lead (Tendrill STS J, St. Jude Medical Co., Ltd.) was inserted via the right jugular vein, with the tip lodged in the right ventricular wall. Pacing was initiated at 244-251 beats per minute on postoperative day 1. Animals whose ejection fraction (EF) had fallen to 30-50% four weeks after pacemaker activation were considered to be in a state of heart failure and were included for analysis.

[0065] Echocardiography was performed using a general-purpose ultrasound imaging diagnostic device (Vivid S6, GE Medical Systems). A sector probe (10 MHz) was placed on the chest in M-mode to measure left ventricular end-diastolic dimension (LVIDd), left ventricular end-systolic dimension (LVIDs), ejection fraction (EF), and left ventricular fractional shortening (%FS).

[0066] Canine cardiac catheterization: Dogs were anesthetized intravenously with secobarbital sodium [Ional Sodium (0.2%) for injection, Nichi-Iko Pharmaceutical Co., Ltd.] (14.5-22.3 mg / kg) and then subcutaneously administered 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 Industries 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. Respiration was controlled using a mixed gas (FiO2 = 0.3-1.0) with an Acoma animal anesthesia machine (NS-5000A, Acoma Medical Industries Co., Ltd.). Expiratory CO2 was monitored using an exhaled carbon dioxide monitor (OLG-2800, Nihon Kohden Corporation). ２ Partial pressure was monitored. The animal was fixed in a dorsal position, and the thighs and neck were shaved. Anesthesia was maintained by continuous intravenous infusion of secobarbital sodium (5 mg / kg / hr) via the cephalic vein using a Terufusion syringe pump (STC-523, Terumo Corporation). A Swan-Ganz catheter was inserted via the left femoral vein. A catheter for coronary angiography was inserted via 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 via the left internal jugular artery. An 8F occlusion balloon was inserted via the right femoral vein, and an occlusion test was performed. KUS121 was also administered via the left common jugular vein.

[0067] Statistical Analysis: Measurements were expressed as mean ± standard error of the mean (SEM). Other statistical comparisons were performed using unpaired Student's t-test (two groups, parametric), Mann-Whitney test (two groups, nonparametric), or one-way analysis of variance (ANOVA) with Sidak's post-hoc test (three or more groups), as described in the figure legends. A p value of less than 0.05 was considered statistically significant. Statistical analysis was performed using GraphPad Prism 6 (GraphPad Software, Inc.).

[0068] Results: Acute Phase Study in Heart Failure Model Mice. Pressure-overload cardiac hypertrophy / heart failure model mice were created by transaortic constriction (TAC). Immediately after TAC, 50 mg / kg of KUS121 was administered intraperitoneally. Sham-operated (sham) mice and control mice were administered 5% glucose. Mice were sacrificed 3 hours later, 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. Lung weight-to-body weight ratio and BNP mRNA levels increased in control mice, but were suppressed by KUS121 administration. There was no significant difference in heart weight-to-body weight ratio. These results indicate that KUS121 improves left ventricular load in acute heart failure model mice.

[0069] Examination of cardiac hypertrophy in a mouse model of heart failure. Pressure-overload cardiac hypertrophy / heart failure model mice were created by TAC. Immediately after TAC, 50 mg / kg of KUS121 was administered intraperitoneally daily for two weeks. Sham-operated (sham) and control mice were administered 5% glucose. Echocardiograms were obtained two weeks after TAC, and the mice were sacrificed. Body and heart weights were measured, and cardiac samples were collected. The experimental protocol is shown in Figure 4.

[0070] Heart weight and the ratio of heart weight to body weight are shown in Figure 5. Both increased in control mice but were suppressed by KUS121 administration. The boundaries of cardiomyocytes were clarified by WGA staining, 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] The mRNA levels of cardiac hypertrophy markers (BNP, ANF) and endoplasmic reticulum stress markers (Bip, CHOP, VCP) were measured in the heart by qRT-PCR. The mRNA levels of cardiac hypertrophy markers were elevated in control mice but decreased with KUS121 administration. There was no significant difference in the mRNA levels of endoplasmic reticulum stress markers.

[0072] The end-diastolic interventricular septum diameter (IVSd), left ventricular mass, and left ventricular ejection fraction (LVEF) evaluated by echocardiography are shown in Figure 7. The interventricular septum and left ventricle were hypertrophied in control mice, but both were improved by KUS121 administration. A decrease in the left ventricular ejection fraction was observed in control mice, but no significant improvement was observed by KUS121 administration.

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

[0074] Study of the heart failure stage in a mouse model of heart failure. Pressure-overload cardiac hypertrophy / heart failure model mice were created using TAC. Starting 5 weeks after TAC, 50 mg / kg of KUS121 was administered intraperitoneally daily for 3 weeks. Sham-operated (sham) mice and control mice were administered 5% glucose. Echocardiograms were obtained 5 and 8 weeks after TAC. At 8 weeks, the mice were sacrificed, and body, heart, and lung weights were measured, and cardiac samples were collected. The experimental protocol is shown in Figure 8.

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

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

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

[0078] The 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 was ameliorated by KUS121 administration.

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

[0080] These results indicate that KUS121 improves cardiac function and fibrosis in a mouse model of heart failure at the heart failure stage.

[0081] Examination of the acute effects of KUS121 in a mouse model of heart failure. Eight-week-old mice underwent TAC surgery, and 5 weeks later (13 weeks old), the 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 in left ventricular ejection fraction and left ventricular end-diastolic diameter were observed, suggesting that KUS121 improves cardiac function without significantly altering heart rate.

[0082] Eight-week-old mice underwent TAC surgery, and 5 weeks later (13 weeks of age), left ventricular pressure was measured by cardiac catheterization before and 10 minutes after KUS121 injection (50 mg / kg). 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. Thus, while HR remained unchanged, both left ventricular pressure and dp / dt increased. These results suggest that KUS121 has a cardiotonic effect. Furthermore, when the 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 (FIG. 16).

[0083] Study on a Medium-Sized Animal Heart Failure Model: 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 and after KUS121 administration at a 40 mg / hr continuous infusion. KUS121 administration demonstrated increases in both LVEF and %FS using the Teichholz and modified Simpson methods (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] A beagle dog model of heart failure was treated according to the experimental protocol in Figure 17 , except that dobutamine (Fuji Pharma Co., Ltd.) was used instead of KUS121 at the doses 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 beagle dog model of heart failure, preload was reduced by inferior vena cava occlusion at baseline and during KUS121 infusion (40 mg / hr), and pressure-volume relationship (PV loop) data were obtained. Representative PV loop shifts are shown in Figure 23. Changes from baseline in the end-systolic PV relationship and end-diastolic pressure-volume relationship obtained by PV loop shifts during KUS121 infusion are shown in Figure 24.

[0086] These results indicate that KUS121 administration reduced pulmonary artery pressure and pulmonary artery wedge pressure, and improved left ventricular systolic and diastolic function without changing heart rate or systolic blood pressure. Furthermore, acute blood sampling data showed that liver and renal function remained normal. Meanwhile, dobutamine, a conventional cardiac inotropic agent, improved left ventricular systolic function but also increased heart rate.

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

[0088] Next, we investigated the acute effects of KUS121 on HFpEF. KUS121 was administered intraperitoneally at 50 mg / kg to ICR mice fed a normal diet or a high-fat diet plus 0.5 g / L L-NAME for 5 weeks. Cardiac function was assessed by echocardiography before and 10 minutes after administration. Echocardiography revealed no difference in EF between the normal diet and high-fat diet plus L-NAME groups before 5% glucose (Tz) or KUS121 administration (Figure 26). 5% Tz administration did not alter EF in the control group or the high-fat diet plus L-NAME group (Figure 26, left, center). However, KUS121 administration improved EF in the high-fat diet plus L-NAME group (Figure 26, right). Previous reports have shown that the endogenous ATP supply is reduced in HFpEF using an MRS experimental system (J Am Coll Cardiol. 2009 Jul 28;54(5):402-9.), and therefore it was thought that KUS121 had an effect of improving contractile force.

[0089] Next, we examined cardiac diastolic function. Global longitudinal strain (GLS), E / A, and E / E' were evaluated. Even before KUS121 administration, mice in the high-fat diet + L-NAME group exhibited elevated GLS and E / A + E / E' values, indicating diastolic dysfunction, although the degree varied among individuals (Figure 27). Administration of 5% Tz did not alter GLS, E / A, or E / E' values ​​in the control group or the high-fat diet + L-NAME group (Figure 27, left, center). However, KUS121 administration improved GLS, E / A, and E / E' values ​​(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). Both systolic and diastolic blood pressure were high in the high-fat diet + L-NAME group (Figure 28, top). Administration of KUS121 resulted in a decrease in blood pressure (Figure 28, top) and a slight decrease in heart rate (Figure 28, bottom).

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

[0092] As a result, administration of KUS121 to the HFpEF model was found to have an effect of improving 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 five weeks later (13 weeks old), the left ventricular ejection fraction (LVEF) was assessed by echocardiography before and 10 minutes after injection of 5% glucose or KUS187 (50 mg / kg). The results are shown in Figure 30. An improvement in left ventricular ejection fraction was observed, suggesting that KUS187 improves cardiac function.

[0094] The present disclosure provides methods for improving cardiac function and treating heart failure, which are useful in the medical field.

Claims

1. Formula (I): 【Chemical 1】 [In the formula,[[]] 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-carboxylate and cyano,[[]] m is an integer selected from 0 to 4][[]] A composition for improving cardiac function, comprising a compound of the formula or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof.

2. The composition according to claim 1, wherein the cardiac function is the diastolic function of the left ventricle.

3. The composition according to claim 1, wherein the cardiac function is the diastolic and systolic functions of the left ventricle.

4. Formula (I): 【Chemical 2】 [In the formula,[[]] 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-carboxylate and cyano,[[]] m is an integer selected from 0 to 4][[]] A composition for the treatment of heart failure, comprising a compound of the formula or an ester, oxide, prodrug, pharmaceutically acceptable salt or solvate thereof.

5. The composition according to claim 4, wherein the heart failure is heart failure with preserved left ventricular ejection fraction (HFpEF).

6. The composition according to claim 4, wherein the heart failure is acute heart failure.

7. The composition according to claim 4, wherein the cause of the heart failure is not a heart disease accompanied by cardiomyocyte death.

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

9. The composition according to any one of claims 1 to 7, wherein each Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, and alkoxy.

10. The compound of formula (I) is 4-amino-3-(6-phenylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 4-amino-3-(6-p-tolylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 4-Amino-3-(6-m-tolylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 4-Amino-3-(6-o-tolylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 4-Amino-3-(6-biphenyl-2-ylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 3-[6-(2-Acetylphenyl)pyridin-3-ylazo]-4-aminonaphthalene-1-sulfonic acid; 3-[6-(3-Acetylphenyl)pyridin-3-ylazo]-4-aminonaphthalene-1-sulfonic acid; 3-[6-(4-Acetylphenyl)pyridin-3-ylazo]-4-aminonaphthalenesulfonic acid; 4-Amino-3-[6-(2,4-dichlorophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-trifluoromethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-trifluoromethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-chlorophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3-chlorophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-chlorophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-methoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-methoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-isopropoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-isopropoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-phenoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3-methoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2,3-dimethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2,5-dimethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3,5-dimethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3-trifluoromethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-{4-[5-(1-amino-4-sulfonaphthalen-2-ylazo)pyridin-2-yl]phenyl}-4-oxobutyric acid; 4-Amino-3-(6-biphenyl-3-ylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3-cyanophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-cyanophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3,5-bistrifluoromethylphenyl)pyridin-3-ylazo]naphthalenesulfonic acid; 4-Amino-3-[6-(4-benzoylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-propoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(5-fluoro-2-propoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-fluoro-6-propoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-fluoro-2-propoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(5-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-fluoro-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-butoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-hexyloxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-butylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-hydroxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-{6-[2-(6-hydroxyhexyloxy)phenyl]pyridin-3-ylazo}naphthalene-1-sulfonic acid; 4-{2-[5-(1-amino-4-sulfonaphthalen-2-ylazo)pyridin-2-yl]phenoxy}butyric acid; 4-Amino-3-{6-[2-(3-hydroxypropoxy)phenyl]pyridin-3-ylazo}naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-isobutoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(5-chloro-2-hydroxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-methylbiphenyl-2-yl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4'-chloro-4-methylbiphenyl-2-yl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4,3',5'-trimethylbiphenyl-2-yl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3'-chloro-4-methylbiphenyl-2-yl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2,6-dimethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3-formyl-2-isopropoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; and, 4-Amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; The composition according to any one of claims 1 to 7, selected from the group consisting of. Claim 11 The composition according to any one of claims 1 to 7, wherein the compound of formula (I) is 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid. Claim 12 The composition according to any one of claims 1 to 7, wherein the compound of formula (I) is 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid.

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