Treatment or prevention of chronic heart failure

Abstract

One of the purposes of the present invention is to provide treatment or prevention of chronic heart failure. A pharmaceutical composition for treatment or prevention of chronic heart failure is provided, which contains a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof; and a method for treatment or prevention of chronic heart failure, characterized in that a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof is administered.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for treating or preventing chronic heart failure, which contains a SGLT (Na + -glucose cotransporter) 1 or a pharmaceutically acceptable salt thereof; and a method for treating or preventing chronic heart failure, characterized in that a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof is administered. Background Art

[0002] Heart failure is defined as a cardiac dysfunction, i.e., organic and / or functional abnormalities in the heart that lead to failure of the compensatory mechanism of cardiac pumping function, resulting in dyspnea, fatigue and / or edema, and a clinical syndrome accompanied by decreased exercise tolerance, one of the characteristics of which is the confirmation of an increase in left ventricular end-diastolic pressure. Chronic heart failure is a condition that these conditions persist over time.

[0003] In chronic heart failure, fatigue during movement, coughing, edema, and accompanying weight gain are observed. Chronic heart failure is classified into heart failure with reduced left ventricular ejection fraction (hereinafter referred to as "HFrEF" (heart failure with reduced ejection fraction)) and heart failure with preserved left ventricular ejection fraction (hereinafter referred to as "HFpEF" (heart failure with preserved ejection fraction)) based on left ventricular ejection fraction.

[0004] HFrEF is considered to be mainly caused by impaired left ventricular contractility, and is characterized by left ventricular enlargement in most cases. Enlargement here refers to an increase in the inner diameter or cavity of the heart. In HFrEF, the shortening rate of the left ventricular inner diameter is reduced.

[0005] Although standard treatment for HFrEF has been established, none of the drugs can solve the common safety issues of these drugs, such as hemodynamic side effects such as hypotension and bradycardia, and hyperkalemia and decreased renal function. Furthermore, it is still a disease with a poor prognosis.

[0006] On the other hand, HFpEF is considered to be mainly caused by impaired left ventricular diastolic function, and is characterized by left ventricular hypertrophy being observed in many cases. Here, hypertrophy refers to a state in which the wall thickness of the heart increases.

[0007] As therapeutic drugs for HFpEF, although diuretics and neurohumoral factor inhibitors are used to relieve congestion and background diseases, respectively, there is no drug that improves life prognosis.

[0008] Prior art literature

[0009] Patent Literature

[0010] Patent Document 1: International Publication No. 2013 / 031922

[0011] Patent Document 2: International Publication No. 2019 / 168096

[0012] Patent document 3: International Publication No. 2019 / 194207. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The results show that the left ventricular end-diastolic pressure in the vehicle group of rats with heart failure after myocardial infarction was significantly increased compared with the sham operation group, and the compound of Example 1 (referred to as "Compound 1" in this specification) showed a lower value of left ventricular end-diastolic pressure in rats with heart failure after myocardial infarction compared with the vehicle. †† in the figure indicates p<0.01 compared with the sham operation group.

[0014] Figure 2 The results show that the left ventricular ejection fraction of rats with heart failure after myocardial infarction was significantly decreased in the vehicle group compared with the sham operation group, and the left ventricular ejection fraction of rats with heart failure after myocardial infarction was significantly increased in the compound 1 (increased) group compared with the vehicle group, and the left ventricular ejection fraction of compound 1 (3 mg / kg) was higher than that of the vehicle group. †† in the figure indicates p<0.01 relative to the sham operation group, and * indicates p<0.05 relative to the vehicle group of rats with heart failure after myocardial infarction.

[0015] Figure 3 The results show that the left ventricular end-diastolic pressure of the vehicle group of hypertensive heart failure rats was significantly increased compared with the normal control group, and the left ventricular end-diastolic pressure of the compound 1 in the hypertensive heart failure rats was significantly reduced compared with the vehicle group. †† in the figure indicates p<0.01 relative to the normal control group, and * and ** indicate p<0.05 and p<0.01 relative to the vehicle group of hypertensive heart failure rats.

[0016] Figure 4 The results show that the end-diastolic pressure-volume relationship (hereinafter referred to as "EDPVR") β significantly increased in the medium group of hypertensive heart failure rats compared with the normal control group, and that EDPVRβ significantly decreased in the compound 1 (increased) group compared with the medium group in the hypertensive heart failure rats, and that EDPVRβ showed a lower value in the compound 1 (3 mg / kg) group compared with the medium group. † in the figure indicates p < 0.05 relative to the normal control group, and * indicates p < 0.05 relative to the medium group of the hypertensive heart failure rats.

[0017] Figure 5 It was shown that no change was confirmed in left ventricular ejection fraction in any group.

[0018] Figure 6The results show that the systolic blood pressure of the vehicle group of rats with hypertensive heart failure was significantly increased compared with the normal control group. †† in the figure indicates p<0.01 compared with the normal control group.

[0019] Figure 7 It was shown that in rats with hypertensive heart failure, compound 1 had no effect on urine volume compared with the vehicle. DETAILED DESCRIPTION

[0020] A plurality of specific embodiments are exemplified below.

[0021] [Item 1]

[0022] A pharmaceutical composition for treating or preventing chronic heart failure, comprising a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof.

[0023] [Item 2]

[0024] A pharmaceutical composition for treating or preventing chronic heart failure, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof:

[0025] [Chemistry 1]

[0026]

[0027] [Wherein,

[0028] R 1 is hydrogen or a halogen,

[0029] R 2 C 1-6 Alkyl or halogenated C 1-6 alkyl,

[0030] R 3 for

[0031] (1)C 1-6 alkyl,

[0032] (2) Halogenated C 1-6 alkyl,

[0033] (3) R 3A Substituted pyridyl, or

[0034] (4) Optional R 3B substituted pyrazinyl, pyrimidinyl or pyridazinyl,

[0035] R 3A is cyano, halogen or halogenated C 1-3 alkyl,

[0036] R 3B Halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C1-3 Alkoxy or -N(R 4 )(R 5 ),

[0037] R 4 and R 5 are independently hydrogen or C 1-3 alkyl].

[0038] [Item 3]

[0039] The pharmaceutical composition according to item 1 or 2, wherein the SGLT1 inhibiting compound or the compound of formula [I] or a pharmaceutically acceptable salt thereof is a compound of any one of formulas [II] to [V] or a pharmaceutically acceptable salt thereof:

[0040] [Chemistry 2]

[0041] .

[0042] [Item 4]

[0043] The pharmaceutical composition according to any one of items 1 to 3, wherein the SGLT1 inhibiting compound or the compound of formula [I] or a pharmaceutically acceptable salt thereof is a compound of formula [II] or a pharmaceutically acceptable salt thereof:

[0044] [Chemistry 3]

[0045]

[0046] [Item 5]

[0047] The pharmaceutical composition according to any one of items 1 to 4, wherein the chronic heart failure is HFrEF.

[0048] [Item 6]

[0049] The pharmaceutical composition according to any one of items 1 to 4, wherein the chronic heart failure is HFpEF.

[0050] [Item 7]

[0051] A method for treating or preventing chronic heart failure, characterized in that a therapeutically effective amount of a compound that inhibits SGLT1 or a compound of formula [I] as described in item 2 or a pharmaceutically acceptable salt thereof is administered to a subject.

[0052] [Item 8]

[0053] A compound that inhibits SGLT1 or a compound of formula [I] as described in item 2 or a pharmaceutically acceptable salt thereof, which is used for treating or preventing chronic heart failure.

[0054] [Item 9]

[0055] Use of a compound that inhibits SGLT1 or a compound of formula [I] as described in item 2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing chronic heart failure.

[0056] The following is part of the structure:

[0057] [Chemistry 4]

[0058]

[0059] The double wavy lines indicate the bonding sites of the structure.

[0060] The "halogen" includes, for example, fluorine, chlorine, bromine and iodine.

[0061] “C 1-3 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 3 carbon atoms. 1-3 The term "alkyl" includes methyl, ethyl, n-propyl and isopropyl.

[0062] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 The term "alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and n-hexyl.

[0063] "Halogenated C 1-3 "Alkyl" refers to the above "C" substituted by 1 to 5 halogens independently selected from the above "halogen" 1-3 Alkyl." "Halo C 1-3 The term "alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl and 3,3,3-trifluoropropyl.

[0064] "Fluorine C 1-3 "Alkyl" refers to the above "C 1-3 Alkyl". "Fluoro C 1-3 The term "alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 1,1-difluoropropyl and 3,3,3-trifluoropropyl.

[0065] "Halogenated C 1-6 "Alkyl" refers to the above "C" substituted by 1 to 5 halogens independently selected from the above "halogen" 1-6 Alkyl." "Halo C 1-6The term "alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl and 6,6,6-trifluorohexyl.

[0066] "Fluorine C 1-6 "Alkyl" refers to the above "C 1-6 Alkyl". "Fluoro C 1-6 The term "alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl and 6,6,6-trifluorohexyl.

[0067] “C 1-3 "Alkoxy" refers to the above-mentioned "C 1-3 Alkyl" is a group bonded to an oxygen atom. 1-3 The term "alkoxy" includes methoxy, ethoxy, n-propoxy and isopropoxy.

[0068] "Pyridyl" refers to any of the following formulae.

[0069] [Chemistry 5]

[0070]

[0071] "Pyrazinyl" refers to the following formula.

[0072] [Chemistry 6]

[0073]

[0074] "Pyrimidinyl" refers to any of the following formulae.

[0075] [Chemistry 7]

[0076]

[0077] "Pyridazinyl" refers to any of the following formulae.

[0078] [Chemistry 8]

[0079]

[0080] "Substitution" includes any chemically acceptable substitution. For example, "replacement by R 3A "Substituted pyridyl" refers to any one of the following formulae.

[0081] [Chemistry 9]

[0082]

[0083] Each substituent of the compound of formula [I] includes the specific embodiments exemplified below for each substituent, and embodiments obtained by combining the specific embodiments of each substituent are also included in the compound of formula [I].

[0084] In a certain way, R 1 In another embodiment, R 1 For fluorine.

[0085] In a certain way, R 2 C 1-6 Alkyl or fluorine C 1-6 In another embodiment, R 2 C 1-6 In another embodiment, R 2 Fluorine C 1-3 alkyl.

[0086] In a certain way, R 3 for

[0087] (1) Halogenated C 1-6 alkyl,

[0088] (2) R 3A Substituted pyridyl, or

[0089] (3) Optional R 3B Substituted pyrazinyl or pyrimidinyl.

[0090] In another way, R 3 Selected from halogenated C 1-6 Alkyl groups and formulas [H1] to [H14].

[0091] In yet another embodiment, R 3 Halogenated C 1-6 Alkyl, formula [H2] or [H8].

[0092] [Chemistry 10]

[0093]

[0094] In a certain way, R 3A is halogen or halogenated C 1-3 In another embodiment, R 3A is fluorine or fluorine C 1-3 alkyl.

[0095] In a certain way, R 3B is halogen or halogenated C 1-3 In another embodiment, R 3B Fluorine C1-3 alkyl.

[0096] In a certain way, R 4 and R 5 Each independently is C 1-3 alkyl.

[0097] In one embodiment, the compound of formula [I] is a compound of formula [II] or [III]:

[0098] [Chemistry 11]

[0099]

[0100] In another embodiment, the compound of formula [I] is a compound of formula [II]. In yet another embodiment, the compound of formula [I] is a monohydrate of a compound of formula [III], that is, a compound of formula [VI]:

[0101] [Chemistry 12]

[0102] .

[0103] The pharmaceutically acceptable salts in this specification may be any salts as long as they are known in the art and are not accompanied by excessive toxicity. Specifically, salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases may be mentioned. Various forms of pharmaceutically acceptable salts are well known in the art, for example, as described in the following references:

[0104] (a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977),

[0105] (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002),

[0106] (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007).

[0107] The compound of formula [I] can be reacted with an inorganic acid, an organic acid, an inorganic base or an organic base according to a method known per se to obtain a pharmaceutically acceptable salt thereof.

[0108] Examples of the salt with an inorganic acid include a salt with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid. Preferably, a salt with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid or hydrobromic acid is used.

[0109] Examples of the salt with an organic acid include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, dehydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylarsanilic acid, hexylresorcinol, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid. The salts of the present invention include salts of oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theocyanic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid or glutamic acid. Preferred examples include salts of oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 2-hydroxy-1-ethanesulfonic acid.

[0110] Examples of the salt with an inorganic base include a salt with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth or ammonium, and preferably a salt with sodium, potassium, calcium, magnesium or zinc.

[0111] Examples of the salt with an organic base include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine or lysine. Preferably, salts with tris(hydroxymethyl)methylamine, N-methylglucamine or lysine are mentioned.

[0112] The compound or pharmaceutically acceptable salt thereof that inhibits SGLT1 (hereinafter also referred to as "SGLT1 inhibitor") can be any substance as long as it inhibits SGLT1, and can be a low molecular weight compound, nucleic acid, polypeptide, protein, antibody, vaccine, etc. The SGLT1 inhibitory activity can be measured by a method known to those skilled in the art, for example, according to the evaluation method described in any one of Patent Documents 1 to 3, based on the labeled substance ( 14 The intracellular uptake of C-AMG was calculated.

[0113] In one embodiment, the SGLT1 inhibitor is a compound of formula [I] or a pharmaceutically acceptable salt thereof:

[0114] [Chemistry 13]

[0115]

[0116] [In the formula, each symbol has the same meaning as above].

[0117] The compounds included in formula [I] can be produced by methods known to those skilled in the art, for example, by any of the methods described in Patent Documents 1 to 3. In addition, the SGLT1 inhibitory activity of the compounds included in formula [I] has been confirmed by these documents.

[0118] In this specification, SGLT1 inhibitors can be used in combination with other agents, such as compounds that inhibit SGLT2 or their pharmaceutically acceptable salts (hereinafter also referred to as "SGLT2 inhibitors") to treat and / or prevent chronic heart failure. SGLT2 inhibitors can be any substance as long as they are substances that inhibit SGLT2, and can be low molecular weight compounds, nucleic acids, polypeptides, proteins, antibodies, vaccines, etc. In a certain embodiment, SGLT2 inhibitors are substances that have the function of increasing the excretion of sugar in urine by inhibiting the reuptake of glucose from urine, thereby being able to lower blood sugar levels.

[0119] SGLT1 inhibitors (e.g., compounds of formula [I] or pharmaceutically acceptable salts thereof) and SGLT2 inhibitors sometimes exist in the form of solvates. Solvates refer to molecules coordinated with solvents on compounds of formula [I] or pharmaceutically acceptable salts thereof, for example. Solvates may be pharmaceutically acceptable solvates, and examples thereof include hydrates, ethanolates, and dimethyl sulfoxides of compounds of formula [I] or pharmaceutically acceptable salts thereof. Specifically, examples include hemihydrates, monohydrates, dihydrates, or monoethanolates of compounds of formula [I], or monohydrates of sodium salts of compounds of formula [I] or 2 / 3 ethanolates of dihydrochlorides. These solvates can be obtained by known methods. For example, compounds of formula [III] may exist in the form of monohydrates, as shown in formula [VI].

[0120] [Chemistry 14]

[0121]

[0122] The compound of formula [I] may be isotopically ( 2 H. 3 H. 14 C. 35 S, etc.) mark.

[0123] The compound of formula [I] or its pharmaceutically acceptable salt is preferably a substantially purified compound of formula [I] or its pharmaceutically acceptable salt. More preferably, the compound of formula [I] or its pharmaceutically acceptable salt is purified to a purity of 80% or more.

[0124] Inhibiting SGLT1 means inhibiting the function of SGLT1 so that its activity disappears or weakens. Preferably, human SGLT1 is inhibited. The inhibition of the function of SGLT1 or the disappearance or weakening of its activity is preferably performed in human clinical applications. In a certain embodiment, by inhibiting SGLT1, the rise in left ventricular end-diastolic pressure is inhibited, and / or the left ventricular ejection fraction is increased, thereby improving HFrEF and having a preventive or therapeutic effect on chronic heart failure. In another embodiment, by inhibiting SGLT1, the left ventricular end-diastolic pressure is reduced, and / or EDPVRβ is reduced, thereby improving HFpEF and having a preventive or therapeutic effect on chronic heart failure. SGLT1 inhibitors can improve either or both of HFrEF and HFpEF.

[0125] Inhibition of SGLT2 means inhibiting the function of SGLT2 so that its activity disappears or weakens. Preferably, human SGLT2 is inhibited. The inhibition of the function of SGLT2 or the disappearance or weakening of its activity is preferably performed in clinical applications in humans.

[0126] In this specification, SGLT2 inhibitors include, for example, glycoside compounds or salts thereof or solvates thereof. Here, glycoside compounds refer to compounds in which sugar or sugar derivatives are bonded to aglycone moieties via glycosidic bonds (e.g., C-glycosidic bonds or O-glycosidic bonds), and sugar or sugar derivatives have the following structure.

[0127] [Chemistry 15]

[0128]

[0129] [In the formula, Y is O or S, and the glycosidic bond is formed with the carbon atom at position 1]

[0130] The SGLT2 inhibitors in this specification include, for example, the following substances. It should be noted that, for convenience, conventional names are used throughout this specification.

[0131] [Table 1]

[0132] .

[0133] [Table 2]

[0134] .

[0135] In one embodiment, an SGLT1 inhibitor can be administered to a subject in combination with an SGLT2 inhibitor for the treatment and / or prevention of chronic heart failure.

[0136] In another embodiment, there is provided a medicament for treating or preventing chronic heart failure containing an SGLT1 inhibitor, wherein the SGLT1 inhibitor and an SGLT2 inhibitor are used in combination.

[0137] In still another embodiment, there is provided a medicament for treating or preventing chronic heart failure containing an SGLT2 inhibitor, wherein the medicament is used in combination with an SGLT1 inhibitor and an SGLT2 inhibitor.

[0138] In still another embodiment, there is provided a medicament for treating or preventing chronic heart failure containing an SGLT1 inhibitor, wherein the medicament is administered to a subject currently receiving treatment with an SGLT2 inhibitor.

[0139] In still another embodiment, there is provided a medicament for treating or preventing chronic heart failure containing an SGLT2 inhibitor, characterized in that the medicament is administered to a subject currently receiving treatment with an SGLT1 inhibitor.

[0140] In this specification, combined use refers to giving, for example, SGLT1 inhibitors and SGLT2 inhibitors to an object in any order. Each medicament has different mechanisms of action, so by using in combination, it is possible to achieve additive or synergistic treatment or preventive effects. In another mode, combined use is by using medicaments with different mechanisms of action, compared with the situation of giving a kind of medicament alone, the dosage of each medicament can be reduced, and the intrinsic side effects of each medicament can be alleviated. Here, as side effects, for example, hypoglycemia, weight gain, dehydration, polyuria, frequent urination, etc. can be cited. In a certain mode, SGLT1 inhibitors and SGLT2 inhibitors can be given to an object simultaneously, continuously or at a certain interval (for example, within 30 minutes, within 1 hour, within 2 hours, within 4 hours), together or respectively in any order. A kind of medicament, when it is given to an object, can be given during the period when the active ingredient contained in another medicament initially given exists in the body of the object with effective amount in treatment. In another mode, SGLT1 inhibitor and SGLT2 inhibitor can be given to the object as a single mixture obtained by combining these medicaments. The administration ratio and the combination ratio of these medicaments can be appropriately selected according to the administration object, administration route, object disease, symptom, severity of the disease and their combination. For example, when the object is given to a person, relative to 1 weight portion of SGLT1 inhibitor, 0.01 weight portion to 1000 weight portions of SGLT2 inhibitor can be used.

[0141] In one embodiment, the combined use of an SGLT1 inhibitor and an SGLT2 inhibitor includes the combined use of a compound of formula [I] or a pharmaceutically acceptable salt thereof and a glycoside compound or a salt thereof or a solvate thereof.

[0142] In another embodiment, the combined use of an SGLT1 inhibitor and an SGLT2 inhibitor includes the combined use of a compound of formula [II] or a pharmaceutically acceptable salt thereof and a glycoside compound or a salt thereof or a solvate thereof.

[0143] In one embodiment, the combination of an SGLT1 inhibitor and an SGLT2 inhibitor includes, for example

[0144] The compound of formula [I] or its pharmaceutically acceptable salt and dapagliflozin,

[0145] A compound of formula [I] or a pharmaceutically acceptable salt thereof and empagliflozin,

[0146] A compound of formula [I] or a pharmaceutically acceptable salt thereof and togliflozin,

[0147] The compound of formula [I] or its pharmaceutically acceptable salt and empagliflozin,

[0148] A compound of formula [I] or a pharmaceutically acceptable salt thereof and canagliflozin, and

[0149] A compound of formula [I] or a pharmaceutically acceptable salt thereof and rupagliflozin

[0150] Use in combination.

[0151] In another embodiment, the combination of an SGLT1 inhibitor and an SGLT2 inhibitor comprises

[0152] The compound of formula [II] or its pharmaceutically acceptable salt and dapagliflozin,

[0153] A compound of formula [II] or a pharmaceutically acceptable salt thereof and empagliflozin,

[0154] A compound of formula [II] or a pharmaceutically acceptable salt thereof and togliflozin,

[0155] The compound of formula [II] or its pharmaceutically acceptable salt and empagliflozin,

[0156] A compound of formula [II] or a pharmaceutically acceptable salt thereof and canagliflozin, and

[0157] A compound of formula [II] or a pharmaceutically acceptable salt thereof and rupagliflozin

[0158] Use in combination.

[0159] In the present specification, the combined use refers to the combined use of the compound of formula [I] or its pharmaceutically acceptable salt and dapagliflozin.

[0160] In the present specification, the combined use refers to the combined use of the compound of formula [I] or its pharmaceutically acceptable salt and empagliflozin.

[0161] In the present specification, the combined use refers to the combined use of the compound of formula [II] or its pharmaceutically acceptable salt and dapagliflozin.

[0162] In the present specification, the combined use refers to the combined use of the compound of formula [II] or its pharmaceutically acceptable salt and empagliflozin.

[0163] In this specification, a drug refers to an SGLT1 inhibitor or an SGLT2 inhibitor. Administration of a drug to a subject receiving treatment based on another drug refers to a mode of combined use, including, for example, administering a drug to a subject while the active ingredient contained in the other drug administered first is present in the subject's body in a therapeutically effective amount.

[0164] The effective amount of the SGLT1 inhibitor in this specification can be appropriately changed according to the subject, route of administration, target disease, symptom, severity of the disease, and their combination. In the case of oral administration to a person (body weight 60kg), as the lower limit of the effective amount for treatment, for example, about 0.01mg, about 0.1mg, about 0.5mg, about 1mg, about 10mg, about 20mg or about 50mg can be enumerated, and as the upper limit of the effective amount for treatment, for example, about 1mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg, about 200mg, about 500mg or about 1000mg can be enumerated.

[0165] In the present specification, the SGLT1 inhibitor and the pharmaceutical composition may be administered once, twice, three times or more per day, respectively.

[0166] In this specification, treatment refers to improvement of symptoms, prevention of aggravation, maintenance of remission, and prevention of recurrence. For example, treatment of chronic heart failure refers to recovery and improvement of cardiac function, specifically, reduction of left ventricular end-diastolic pressure, increase of left ventricular ejection fraction, and reduction of EDPVR (end-diastolic pressure-volume relationship) β.

[0167] The term "prevention" as used herein includes suppressing the onset of symptoms. For example, prevention of chronic heart failure includes maintaining cardiac function, specifically, suppressing the increase in left ventricular end-diastolic pressure, maintaining left ventricular ejection fraction, and maintaining systolic blood pressure.

[0168] "Chronic heart failure" in this specification is sometimes also referred to as congestive heart failure, including HFrEF and HFpEF. "HFrEF" is sometimes also referred to as systolic heart failure, systolic heart failure, or systolic heart failure, including, for example, heart failure after myocardial infarction. "HFpEF" is sometimes also referred to as diastolic heart failure, diastolic heart failure, or diastolic heart failure, including, for example, hypertensive heart failure.

[0169] In this specification, "HFrEF" is defined as heart failure with reduced left ventricular ejection fraction, and more specifically, is defined as heart failure with a left ventricular ejection fraction of less than 45%. In one embodiment, HFrEF includes heart failure with a left ventricular ejection fraction of less than 40%. In another embodiment, HFrEF includes heart failure with a left ventricular ejection fraction of less than 35%.

[0170] In one embodiment, HFrEF includes HFrEF caused by coronary artery disease. Examples of coronary artery disease include ischemic heart disease, specifically angina pectoris and myocardial infarction. Angina pectoris is a disease caused by narrowing of the coronary arteries due to arteriosclerosis, etc., and excessive absorption of glucose in the blood may be a cause. Myocardial infarction is a disease caused by blockage of the coronary arteries, and excessive absorption of glucose in myocardial cells may be a cause.

[0171] In this specification, "HFpEF" is defined as heart failure with preserved left ventricular ejection fraction, and more specifically, is defined as heart failure with a left ventricular ejection fraction of 45% or more. In one embodiment, HFpEF includes heart failure with a left ventricular ejection fraction of 50% or more.

[0172] In one embodiment, HFpEF includes HFpEF caused by hypertension.

[0173] The left ventricular ejection fraction is the amount of blood pumped out by the heart during each heartbeat (pump volume) divided by the left ventricular end-diastolic volume during diastole.

[0174] The left ventricular ejection fraction can be obtained using, for example, an ultrasound diagnostic device.

[0175] EDPVR represents the relationship between end-diastolic volume and end-diastolic pressure, and the relationship can be approximated by an exponential curve. The higher the value of EDPVRβ, which is the slope of the curve, the harder the heart is and the harder it is to relax. In other words, EDPVRβ is one of the indicators of left ventricular diastolic capacity. For example, when EDPVRβ is greater than 0.015, the left ventricular diastolic capacity is reduced.

[0176] EDPVR can be obtained using, for example, a pressure-volume measurement catheter system.

[0177] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing chronic heart failure, comprising an SGLT1 inhibitor.

[0178] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing chronic heart failure caused by coronary artery disease or hypertension, which contains an SGLT1 inhibitor. In another embodiment, the present invention is a pharmaceutical composition for treating or preventing chronic heart failure caused by angina pectoris, myocardial infarction or hypertension, which contains an SGLT1 inhibitor.

[0179] In one embodiment, the present invention is a pharmaceutical composition for reducing left ventricular end-diastolic pressure in an individual whose left ventricular end-diastolic pressure is higher than the normal range, comprising an SGLT1 inhibitor. In one embodiment, the normal range of left ventricular end-diastolic pressure is 4 to 8 mmHg.

[0180] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF, comprising an SGLT1 inhibitor.

[0181] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF caused by coronary artery disease, comprising an SGLT1 inhibitor. In another embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF caused by angina pectoris or myocardial infarction, comprising an SGLT1 inhibitor.

[0182] In one embodiment, the present invention is a pharmaceutical composition for increasing left ventricular ejection fraction in an individual whose left ventricular ejection fraction is decreased to less than 45%, comprising an SGLT1 inhibitor.

[0183] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFpEF, comprising an SGLT1 inhibitor.

[0184] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFpEF caused by hypertension, comprising an SGLT1 inhibitor.

[0185] In one embodiment, the present invention is a pharmaceutical composition for reducing EDPVR (end-diastolic pressure-volume relationship) β in an individual with high EDPVR (end-diastolic pressure-volume relationship) β, the pharmaceutical composition comprising an SGLT1 inhibitor.

[0186] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing chronic heart failure, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0187] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing chronic heart failure caused by coronary artery disease or hypertension, which contains a compound of formula [I] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is a pharmaceutical composition for treating or preventing chronic heart failure caused by angina pectoris, myocardial infarction or hypertension, which contains a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0188] In one embodiment, the present invention is a pharmaceutical composition for reducing left ventricular end-diastolic pressure in an individual whose left ventricular end-diastolic pressure is higher than the normal range, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0189] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0190] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF caused by coronary artery disease, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF caused by angina pectoris or myocardial infarction, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0191] In one embodiment, the present invention is a pharmaceutical composition for increasing left ventricular ejection fraction in an individual whose left ventricular ejection fraction is decreased to less than 35%, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0192] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFpEF, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0193] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFpEF caused by hypertension, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0194] In one embodiment, the present invention is a pharmaceutical composition for reducing EDPVR (end-diastolic pressure-volume relationship) β in an individual having an EDPVR (end-diastolic pressure-volume relationship) β greater than 0.015, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0195] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing chronic heart failure, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0196] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing chronic heart failure caused by coronary artery disease or hypertension, which contains a compound of formula [II] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is a pharmaceutical composition for treating or preventing chronic heart failure caused by angina pectoris, myocardial infarction or hypertension, which contains a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0197] In one embodiment, the present invention is a pharmaceutical composition for reducing left ventricular end-diastolic pressure in an individual whose left ventricular end-diastolic pressure is higher than the normal range, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0198] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0199] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF caused by coronary artery disease, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF caused by angina pectoris or myocardial infarction, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0200] In one embodiment, the present invention is a pharmaceutical composition for increasing left ventricular ejection fraction in an individual whose left ventricular ejection fraction is decreased to less than 35%, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0201] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFpEF, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0202] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFpEF caused by hypertension, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0203] In one embodiment, the present invention is a pharmaceutical composition for reducing EDPVR (end-diastolic pressure-volume relationship) β in an individual having an EDPVR (end-diastolic pressure-volume relationship) β greater than 0.015, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0204] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing chronic heart failure, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0205] In one embodiment, the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure caused by coronary artery disease or hypertension, which contains an SGLT1 inhibitor and an SGLT2 inhibitor. In another embodiment, the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure caused by angina pectoris, myocardial infarction or hypertension, which contains an SGLT1 inhibitor and an SGLT2 inhibitor.

[0206] In one embodiment, the present invention is a pharmaceutical composition for reducing left ventricular end-diastolic pressure in an individual whose left ventricular end-diastolic pressure is higher than a normal range, the pharmaceutical composition comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0207] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0208] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF caused by coronary artery disease, comprising an SGLT1 inhibitor and an SGLT2 inhibitor. In another embodiment, the present invention is a pharmaceutical composition for treating or preventing HFrEF caused by angina pectoris or myocardial infarction, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0209] In one embodiment, the present invention is a pharmaceutical composition for increasing left ventricular ejection fraction in an individual whose left ventricular ejection fraction is decreased to less than 35%, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0210] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFpEF, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0211] In one embodiment, the present invention is a pharmaceutical composition for treating or preventing HFpEF caused by hypertension, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0212] In one embodiment, the present invention is a pharmaceutical composition for reducing EDPVR (end-diastolic pressure-volume relationship) β in an individual having an EDPVR (end-diastolic pressure-volume relationship) β exceeding 0.015, the pharmaceutical composition comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0213] The pharmaceutical composition in this specification can be manufactured by a method known in the technical field of pharmaceutical preparations, by appropriately mixing a therapeutically effective amount of an SGLT1 inhibitor with at least one or more pharmaceutically acceptable carriers and an SGLT2 inhibitor as required. The content of the SGLT1 inhibitor in the pharmaceutical composition varies depending on the dosage form, dosage, etc., and is, for example, 0.1 to 100% by weight of the entire composition.

[0214] The dosage form of the pharmaceutical composition in this specification includes oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions, and non-oral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0215] As pharmaceutically acceptable carriers, various organic or inorganic carrier substances commonly used as raw materials for preparations can be cited, and excipients, disintegrants, binders, fluidizers, lubricants, etc. in solid preparations, solvents, solubilizers, suspending agents, isotonic agents, buffers, pain-relieving agents, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, stabilizers, dispersants, plasticizers, pH adjusters, absorption accelerators, gelling agents, preservatives, fillers, solubilizers, solubilizers, suspending agents, etc. in semisolid preparations can be cited. Further, additives such as preservatives, antioxidants, colorants, sweeteners, etc. can be added as needed.

[0216] Examples of the excipient include lactose, saccharide, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic.

[0217] Examples of the disintegrant include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethyl starch sodium, cross-linked carboxymethylcellulose sodium, cross-linked povidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, and crystalline cellulose.

[0218] Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, crystalline cellulose, white sugar, dextrin, starch, gelatin, sodium carboxymethyl cellulose, and gum arabic.

[0219] Examples of the fluidizing agent include light anhydrous silicic acid and magnesium stearate.

[0220] Examples of the lubricant include magnesium stearate, calcium stearate, and talc.

[0221] Examples of the solvent include purified water, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, and olive oil.

[0222] Examples of the solubilizing agent include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate.

[0223] Examples of the suspending agent include benzalkonium chloride, carboxymethyl cellulose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, and glycerol monostearate.

[0224] Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, and D-mannitol.

[0225] Examples of the buffer include sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.

[0226] Examples of the pain-relieving agent include benzyl alcohol and the like.

[0227] Examples of the base include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyols, hydrocarbons (white vaseline, liquid paraffin, paraffin, etc.), hydrophilic vaseline, refined lanolin, water-absorbing ointment, water-added lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), synthetic polymers (carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, etc.), propylene glycol, polyethylene glycol (polyethylene glycol 200 to 600, etc.), and combinations of two or more thereof.

[0228] Examples of the preservative include ethyl p-hydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.

[0229] Examples of the antioxidant include sodium sulfite and ascorbic acid.

[0230] Examples of the coloring agent include food coloring (food red No. 2 or No. 3, food yellow No. 4 or No. 5, etc.), and β-carotene.

[0231] Examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, and aspartame.

[0232] The pharmaceutical composition in this specification can be administered orally or non-orally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to humans and mammals other than humans (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, monkeys, etc.). The dosage varies according to the subject, disease, symptoms, dosage form, route of administration, etc. For example, the dosage for oral administration to adult patients (weight 60 kg) is for the effective ingredient, which is usually about 0.01 mg to about 1 g per day. These amounts can be divided into one or more administrations. In a certain way, SGLT1 inhibitors can be formulated with other drugs as a separate pharmaceutical composition and used in combination, or they can be administered to the subject in any order and time interval by different administration routes. In another way, the dosage of each drug used in combination can be reduced compared to the case of administering each drug alone, and the dosage for oral administration to adult patients (weight 60 kg) can be about 0.01 mg to 1000 mg per day.

[0233] In a certain mode, SGLT1 inhibitor can be provided in the form of a kit (administration, treatment and / or prevention kit, etc.), a package (package, etc.) and a pharmaceutical group (and / or container), which together contain an SGLT1 inhibitor, an appropriate SGLT2 inhibitor, and a record of whether it can be used or should be used for treatment and / or prevention. Such a kit, package and pharmaceutical group can have one or more containers filled with an SGLT1 inhibitor, an appropriate SGLT2 inhibitor, and / or other agents or drugs (or ingredients). As examples of such a kit, package and pharmaceutical group, commercial kits, commercial packages and commercial pharmaceutical groups suitable for the treatment and / or prevention of target diseases can be cited. As the records contained in such a kit, package and pharmaceutical group, precautions or accompanying documents in the form indicated by the government agency for the manufacture, use or sale of controlled drugs or biological products can be cited, which are precautions or accompanying documents indicating the permission of the government agency involved in the manufacture, use or sale of products related to administration to people. The above-mentioned kits, packages and drug sets may include packaged products, and may also include structures constructed for appropriate administration steps (steps), and may also include structures constructed in a manner that can achieve more preferred medical treatment and / or prevention, such as treatment and / or prevention of the target disease. Example

[0234] The compounds of Examples 1 to 40 (hereinafter referred to as Compounds 1 to 40) were obtained according to the production methods described in Patent Documents 2 and 3. The physical property values ​​and SGLT1 inhibitory activity data of each compound are as described in these documents.

[0235] [Table 3-1]

[0236]

[0237] [Table 3-2]

[0238]

[0239] [Table 3-3]

[0240]

[0241] [Table 3-4]

[0242]

[0243] [Table 3-5]

[0244]

[0245] [Table 3-6]

[0246]

[0247] [Table 3-7]

[0248]

[0249] [Table 3-8]

[0250] .

[0251] [Test Example 1]

[0252] Evaluation of cardiac function in rats with heart failure after myocardial infarction

[0253] Male SD rats (8 weeks old, Japan SLC Co., Ltd.) were anesthetized with pentobarbital, and the chest was opened under artificial respirator management, and the left anterior descending coronary artery was permanently ligated to make rats with heart failure after myocardial infarction. A sham operation group with the same chest opening and only heart exposure was set. Two weeks after myocardial infarction, the heart failure rat group after myocardial infarction was orally administered with a medium (0.5% methylcellulose solution) or compound 1 (3 mg / kg group or gradual increase group) once a day. The gradual increase group started from 3 mg / kg, increased to 6 mg / kg after 2 weeks, and increased to 8 mg / kg after further 2 weeks, and then administered at 8 mg / kg. In the sham operation group, the medium was orally administered once a day. After 8 weeks of administration, the left ventricular ejection fraction was measured using an ultrasonic diagnostic device (Aplio 300, Toshiba Medical Systems Co., Ltd.), and the left ventricular end-diastolic pressure was measured by inserting a catheter-tipped micromanometer (Model SPR-320, Millar Inc.) from the left carotid artery into the left ventricle. Statistical analysis Aspin-Welch t test was performed between the sham operation medium administration group and the post-myocardial infarction heart failure rat medium administration group. Steel's multi-group test was performed on the test of compound 1 relative to the medium of post-myocardial infarction heart failure rats. The significance level was set at 5% on both sides. As a result, the left ventricular ejection fraction was reduced and the left ventricular end-diastolic pressure was increased in the post-myocardial infarction heart failure rat medium administration group compared with the sham operation medium administration group, so the onset of HFrEF could be confirmed. In post-myocardial infarction heart failure rats, compound 1 increased the left ventricular ejection fraction and inhibited the increase in left ventricular end-diastolic pressure, thereby improving HFrEF. The results are shown in Figure 1 and 2 .

[0254] By Test Example 1, it was confirmed that Compound 1 has an HFrEF improvement effect. By the same method as in Test Example 1, the HFrEF improvement effect of Compounds 2 to 40 can be confirmed. By the same method as in Test Example 1, the HFrEF improvement effect of using Compounds 1 to 40 (e.g., Compound 1) in combination with an SGLT2 inhibitor (e.g., dapagliflozin) can be confirmed.

[0255] [Test Example 2]

[0256] Evaluation of cardiac function in rats with hypertensive heart failure

[0257] Male DIS / Eis (Dahl-Iwai S) rats (Dahl rats) (7 weeks old, Japan SLC Co., Ltd.) were fed with a high-salt diet (MF 8% sodium chloride feed, Oriental Yeast Industry Co., Ltd.) to produce hypertensive heart failure rats. The normal control was fed with a normal diet (CRF-1 solid, Oriental Yeast Industry Co., Ltd.). After 3 weeks, after the onset of the morbidity (hypertension or cardiac hypertrophy) was confirmed, the hypertensive heart failure rat group was orally administered with a medium (0.5% methylcellulose solution) or compound 1 (3 mg / kg group or gradual increase group) once a day. The gradual increase group started at 3 mg / kg, increased to 6 mg / kg after 1 week, and further increased to 8 mg / kg in stages after 1 week, and then administered at 8 mg / kg. In the normal control group, the medium was orally administered once a day. After 5 weeks of administration, the systolic blood pressure was measured using an ultrasonic diagnostic device (Aplio 300, Toshiba Medical Systems Co., Ltd.) and a non-blood-observing automatic blood pressure measuring device (BP-98A, Softron Co., Ltd.). After 6 weeks of administration, an ADVantage PV catheter (Model FTH-1918B-E318, Transonic Scisense Inc.) was inserted into the left ventricle from the apex of the heart to measure the left ventricular end-diastolic pressure. Furthermore, EDPVRβ was calculated from the pressure-volume relationship using transient inferior vena cava occlusion using ADVantage P-Vcatheter and Ultrasonic flow probe (Model 2.5PSB1459, Transonic Scisense Inc.). Statistical analysis Student test or Aspin-Welch t test was performed between the normal control medium-administered group and the medium-administered group of hypertensive heart failure rats. Dunnett's multi-group test was performed on the compound 1 relative to the medium of the hypertensive heart failure rats. The significance level was set at 5% on both sides. As a result, compared with the normal control group, the EDPVRβ and left ventricular end-diastolic pressure in the hypertensive heart failure rats increased, and no decrease in the left ventricular ejection fraction was confirmed, so the onset of HFpEF could be confirmed. Furthermore, in the hypertensive heart failure rats, compound 1 reduced EDPVRβ and left ventricular end-diastolic pressure and improved HFpEF. At this time, compared with the normal control group, the hypertensive heart failure rats confirmed an increase in systolic blood pressure and showed hypertension, but compound 1 had no effect on systolic blood pressure. In addition, compound 1 had no effect on urine volume in the hypertensive heart failure rats. The results are shown in Figure 3 , 4 , 5, 6 and 7.

[0258] By Test Example 2, it was confirmed that Compound 1 has an HFpEF improvement effect. By the same method as in Test Example 2, the HFpEF improvement effect of Compounds 2 to 40 can be confirmed. By the same method as in Test Example 2, the HFpEF improvement effect of using Compounds 1 to 40 (e.g., Compound 1) in combination with an SGLT2 inhibitor (e.g., dapagliflozin) can be confirmed.

[0259] [Preparation Example]

[0260] Examples of formulations of the compound of formula [I] include, but are not limited to, the following formulations.

[0261] Preparation Example 1 (Manufacture of capsules)

[0262] (1) Compound 1 30 mg

[0263] (2) Microcrystalline cellulose 10 mg

[0264] (3) Lactose 19 mg

[0265] (4) Magnesium stearate 1mg

[0266] Ingredients (1), (2), (3) and (4) are mixed and filled into gelatin capsules.

[0267] Preparation Example 2 (Manufacture of tablets)

[0268] (1) Compound 1 10 g

[0269] (2) Lactose 50g

[0270] (3) 15g corn starch

[0271] (4) Carboxymethylcellulose calcium 44g

[0272] (5) Magnesium stearate 1g

[0273] The total amount of ingredients (1), (2), and (3) and 30 g of ingredient (4) were mixed with water, vacuum dried, and then granulated. 14 g of ingredient (4) and 1 g of ingredient (5) were mixed with the granulated powder, and the mixture was compressed by a tablet press. In this way, 1000 tablets containing 10 mg of compound 1 per tablet were obtained.

[0274] Industrial Applicability

[0275] It is expected that a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof is useful for the treatment or prevention of chronic heart failure.

Claims

1. Use of a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing chronic heart failure, wherein: The SGLT1-inhibiting compound or a pharmaceutically acceptable salt thereof is a compound of any one of formulas [II] to [VI] or a pharmaceutically acceptable salt thereof: [Chemistry 1] 2. The use according to claim 1, wherein: The compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof is a compound of formula [II] or a pharmaceutically acceptable salt thereof: [Chemistry 2] 3. The use according to claim 1 or 2, wherein: Chronic heart failure is HFrEF.

4. The use according to claim 1 or 2, wherein: Chronic heart failure is HFpEF.

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