Treatment or prevention methods for chronic heart failure

Abstract

One purpose of the present invention is to treat or prevent chronic heart failure. Provided are: a pharmaceutical composition for treating or preventing chronic heart failure, said composition comprising a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof; and a treatment or prevention method for chronic heart failure, said method being characterized by comprising administering a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for treating or preventing chronic heart failure containing a compound that inhibits SGLT (sodium + -glucose cotransporter) 1 or a pharmaceutically acceptable salt thereof, and a method for treating or preventing chronic heart failure, characterized by administering a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof.

Background Art

[0002] Heart failure is defined as a clinical syndrome in which some form of cardiac dysfunction, that is, organic and / or functional abnormalities occur in the heart, resulting in the breakdown of the compensatory mechanism of the heart pump function, accompanied by the appearance of dyspnea, fatigue, and / or edema, and a decrease in exercise tolerance. One of the characteristics is an increase in left ventricular end-diastolic pressure. Chronic continuation of these states is chronic heart failure.

[0003] In chronic heart failure, fatigue during exercise, cough, swelling, and associated weight gain are observed. Chronic heart failure is classified based on the left ventricular ejection fraction into heart failure with a reduced left ventricular ejection fraction (hereinafter referred to as "HFrEF" (heart failure with reduced ejection fraction)) and heart failure with a preserved left ventricular ejection fraction (hereinafter referred to as "HFpEF" (heart failure with preserved ejection fraction)).

[0004] In HFrEF, left ventricular systolic dysfunction is considered the main cause, and left ventricular enlargement is observed in many cases, which is one of the characteristics. Here, enlargement means an increase in the inner diameter or lumen of the heart. In HFrEF, the left ventricular internal diameter shortening rate is decreased. Although the standard treatment for HFrEF has been established, none of the drugs have solved the problems related to hemodynamic side effects such as hypotension and bradycardia, and safety issues common to these drugs such as hyperkalemia and renal function decline. Furthermore, it is still a disease with a poor prognosis.

[0005] On the one hand, HFpEF is considered to be mainly caused by left ventricular diastolic dysfunction, and one of the characteristics is that left ventricular hypertrophy is observed in many cases. Here, hypertrophy refers to the state where the wall thickness of the heart is increased. As therapeutic agents for HFpEF, although diuretics and neurohumoral factor inhibitors are used to relieve congestion and underlying diseases respectively, there is no drug that can improve the prognosis of life.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Brief Explanation of Drawings

[0007] [Figure 1] Figure 1 shows that the left ventricular end-diastolic pressure of the heart failure rat medium group after myocardial infarction was significantly increased compared with the sham operation group, and the compound of Example 1 (hereinafter referred to as "Compound 1" in this specification) showed a lower value of left ventricular end-diastolic pressure compared with the medium in the heart failure rats after myocardial infarction. †† in the figure indicates p < 0.01 for the sham operation group. [Figure 2] Figure 2 shows that the left ventricular ejection fraction of the heart failure rat medium group after myocardial infarction was significantly decreased compared with the sham operation group, and Compound 1 (increasing gradually) significantly increased the left ventricular ejection fraction compared with the medium in the heart failure rats after myocardial infarction, and Compound 1 (3 mg / kg) showed a higher value of left ventricular ejection fraction compared with the medium. †† in the figure indicates p < 0.01 for the sham operation group, and * indicates p < 0.05 for the heart failure rat medium group after myocardial infarction. [Figure 3]Figure 3 shows that the media group in hypertensive heart failure rats significantly increased left ventricular end-diastolic pressure compared to the normal control group, and compound 1 significantly decreased left ventricular end-diastolic pressure compared to the media group in hypertensive heart failure rats. †† 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 media group in hypertensive heart failure rats. [Figure 4] Figure 4 shows that the media group of hypertensive heart failure rats significantly increased the end-diastolic pressure-volume relationship (EDPVR) β compared to the normal control group, compound 1 (gradual increase) significantly decreased EDPVRβ compared to the media group in hypertensive heart failure rats, and compound 1 (3 mg / kg) showed a lower EDPVRβ compared to the media group. In the figure, † indicates p<0.05 compared to the normal control group, and * indicates p<0.05 compared to the media group of hypertensive heart failure rats. [Figure 5] Figure 5 shows that no change in left ventricular ejection fraction was observed in any of the groups. [Figure 6] Figure 6 shows that the hypertensive heart failure rat group significantly increased systolic blood pressure compared to the normal control group. †† in the figure indicates p<0.01 compared to the normal control group. [Figure 7] Figure 7 shows that compound 1 did not affect urine output compared to the medium in rats with hypertensive heart failure. [Modes for carrying out the invention]

[0008] Some specific examples are given below. [Section 1] A pharmaceutical composition for the treatment or prevention of chronic heart failure containing a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof.

[0009] [Section 2] Formula [I]: [ka] [In the formula, R 1 is hydrogen or halogen, R 2 is C 1-6 alkyl or halo C 1-6 alkyl, R 3 is (1) C 1-6 alkyl, (2) halo C 1-6 alkyl, (3) R 3A substituted pyridyl, or (4) R 3B substituted, pyrazinyl, pyrimidinyl or pyridazinyl, R 3A is cyano, halogen or halo C 1-3 alkyl, R 3B is halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy or -N(R 4 )(R 5 ) and R 4 and R 5 are each independently hydrogen or C 1-3 alkyl) A pharmaceutical composition for the treatment or prevention of chronic heart failure, containing a compound of or a pharmaceutically acceptable salt thereof.

[0010] [Item 3] A compound that inhibits SGLT1, or a compound of formula [I] or a pharmaceutically acceptable salt thereof is any of formulas [II] to [V]: [Chemical formula] <00,00162>The pharmaceutical composition according to Item 1 or 2, which is a compound of or a pharmaceutically acceptable salt thereof.

[0011] [Item 4] A compound that inhibits SGLT1, or a compound of formula [I] or a pharmaceutically acceptable salt thereof is formula [II]: [Chemical formula] A pharmaceutical composition according to any one of claims 1 to 3, which is a compound or a pharmaceutically acceptable salt thereof.

[0012] [Section 5] A pharmaceutical composition according to any one of claims 1 to 4, wherein the chronic heart failure is HFrEF.

[0013] [Section 6] A pharmaceutical composition according to any one of items 1 to 4, wherein the chronic heart failure is HFpEF.

[0014] [Section 7] A method for treating or preventing chronic heart failure, characterized by administering a therapeutically effective amount of a compound that inhibits SGLT1 or a compound of formula [I] described in item 2 or a pharmaceutically acceptable salt thereof to the target.

[0015] [Section 8] A compound that inhibits SGLT1 or a compound of formula [I] as described in item 2, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of chronic heart failure.

[0016] [Section 9] Use of SGLT1 inhibitory compounds or compounds of formula [I] as described in item 2 or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment or prevention of chronic heart failure.

[0017] The following in the substructure: [ka] The double wavy line indicates the joint site of the structure.

[0018] "Halogens" include, for example, fluorine, chlorine, bromine, and iodine.

[0019] "C 1-3 "Alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms. 1-3The term "alkyl" includes methyl, ethyl, n-propyl, and isopropyl.

[0020] "C 1-6 "Alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 "Alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl.

[0021] "HaroC 1-3 "Alkyl" refers to the above "C" which is substituted with 1 to 5 halogens independently selected from the above "halogen" group. 1-3 It means "alkyl". 1-3 "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.

[0022] "Fluoroc 1-3 "Alkyl" refers to the above "C" which is substituted with one to five fluorine atoms. 1-3 It means "alkyl". 1-3 "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.

[0023] "HaroC 1-6 "Alkyl" refers to the above "C" which is substituted with 1 to 5 halogens independently selected from the above "halogen" group. 1-6 It means "alkyl". 1-6"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.

[0024] "Fluoroc 1-6 "Alkyl" refers to the above "C" which is substituted with one to five fluorine atoms. 1-6 It means "alkyl". 1-6 "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.

[0025] "C 1-3 "Alkoxy" refers to the above "C 1-3 "Alkyl" refers to a group bonded to an oxygen atom. 1-3 "Alkoxy" includes methoxy, ethoxy, n-propoxy, and isopropoxy.

[0026] "Pyridyl" means one of the following: [ka]

[0027] "Pyrazinyl" means the following formula: [ka]

[0028] "Pyrimidinyl" means any of the following: [ka]

[0029] "Pyridazinyl" means any of the following: [ka]

[0030] "Substitution" includes any chemically acceptable substitution. For example, "R 3A "Pyridyl substituted with " means any of the following formulas: [ka]

[0031] Each substituent of the compound of formula [I] includes the specific embodiments exemplified below, and combinations of these specific embodiments of substituents are also included in the compound of formula [I].

[0032] In one embodiment, R 1 is a halogen. In another embodiment, R 1 It is fluorine.

[0033] In one embodiment, R 2 is C 1-6 Alkyl or fluoroC 1-6 It is alkyl. In another embodiment, R 2 is C 1-6 It is alkyl. In yet another embodiment, R 2 FluoroC 1-3 It is alkyl.

[0034] In one embodiment, R 3 teeth (1) Hello C 1-6 Alkyl, (2)R 3A Pyridyl substituted with, or (3)R3B It is a pyrazinyl or pyrimidinyl which may be substituted with. In another embodiment, R 3 is Hello C 1-6 Selected from the group consisting of alkyl and formulas [H1] to [H14]. In yet another embodiment, R 3 is Hello C 1-6 It is an alkyl group, of the formula [H2] or [H8]. [ka]

[0035] In one embodiment, R 3A This is a halogen or halo C 1-3 It is alkyl. In another embodiment, R 3A is fluorine or fluorocarbon 1-3 It is alkyl.

[0036] In one embodiment, R 3B This is a halogen or halo C 1-3 It is alkyl. In another embodiment, R 3B Fluoroc 1-3 It is alkyl.

[0037] In one embodiment, R 4 and R 5 Each is independent of C 1-3 It is alkyl.

[0038] In one aspect, the compound of formula [I] is a compound of formula [II] or [III]: [ka] It is a compound of [I]. In another embodiment, the compound of formula [I] is the compound of formula [II]. In yet another embodiment, the compound of formula [I] is the monohydrate of the compound of formula [III], i.e., formula [VI]: [ka] It is a compound of [the compound].

[0039] In this specification, a pharmaceutically acceptable salt is any salt known in the art that does not impose excessive toxicity. Specifically, this includes salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, pp. 1-19 (1977), (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). By reacting the compound of formula [I] with an inorganic acid, an organic acid, an inorganic base, or an organic base according to methods known to the present day, pharmaceutically acceptable salts thereof can be obtained.

[0040] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, or sulfuric acid. Preferably, salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, or hydrobromic acid are used. Examples of salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetate, ethane-1,2-disulfonic acid, dodecyl sulfate, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylarsanilic acid, hexylresorcinic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, Examples include salts with malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitrate, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid. Preferably, salts with 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 are used.

[0041] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium. Preferably, salts with sodium, potassium, calcium, magnesium, or zinc are used. Examples of salts with organic bases include salts with arecoline, betaine, choline, cremisole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine. Preferably, salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine are used.

[0042] A compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof (hereinafter also referred to as "SGLT1 inhibitor") can be any substance that inhibits SGLT1, such as a small molecule compound, nucleic acid, polypeptide, protein, antibody, vaccine, etc. SGLT1 inhibitory activity can be measured by methods known to those skilled in the art, for example, according to the evaluation method described in any of Patent Documents 1 to 3, the labeled product of α-methyl-D-glucopyranoside transported by SGLT1 ( 14 It can be calculated based on the amount of intracellular uptake of C-AMG.

[0043] In one aspect, SGLT1 inhibitors are expressed by formula [I]: [ka] [In the formula, each symbol has the same meaning as above.] It is a compound or a pharmaceutically acceptable salt thereof. 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. Furthermore, the SGLT1 inhibitory activity of compounds included in formula [I] has been confirmed in these documents.

[0044] In this specification, SGLT1 inhibitors may be used in combination with other agents, such as compounds that inhibit SGLT2 or pharmaceutically acceptable salts thereof (hereinafter also referred to as "SGLT2 inhibitors"), to treat and / or prevent chronic heart failure. An SGLT2 inhibitor can be any substance that inhibits SGLT2, such as a small molecule compound, nucleic acid, polypeptide, protein, antibody, vaccine, etc. In one embodiment, an SGLT2 inhibitor is a substance that can lower blood glucose levels by inhibiting glucose reuptake from urine and thereby increasing urinary excretion of sugar.

[0045] SGLT1 inhibitors (e.g., compounds of formula [I] or pharmaceutically acceptable salts thereof) and SGLT2 inhibitors may exist as solvates. A solvate is a compound of formula [I] or a pharmaceutically acceptable salt thereof to which a solvent molecule is coordinated. The solvate may be any pharmaceutically acceptable solvate, such as the hydrate, ethanol, and dimethyl sulfoxide dihydrate of the compound of formula [I] or a pharmaceutically acceptable salt thereof. Specifically, examples include the hemihydrate, monohydrate, dihydrate, or monoethanolate of the compound of formula [I], or the monohydrate or 2 / 3 ethanolate of the sodium salt or dihydrochloride of the compound of formula [I]. These solvates can be obtained by known methods. For example, the compound of formula [III] may exist as a monohydrate, as shown in formula [VI] below. [ka]

[0046] The compound of formula [I] contains isotopic elements ( 2 H, 3 H, 14 C, 35 It may also be marked with S, etc.

[0047] The compound of formula [I] or a pharmaceutically acceptable salt thereof is preferably substantially purified. More preferably, the compound of formula [I] or a pharmaceutically acceptable salt thereof is purified to a purity of 80% or higher.

[0048] Inhibiting SGLT1 means inhibiting the function of SGLT1, thereby eliminating or reducing its activity. Preferably, this involves inhibiting human SGLT1. Inhibition of SGLT1 function or elimination or reduction of its activity is preferably performed in a clinically appropriate setting in humans. In one embodiment, inhibiting SGLT1 can suppress the increase in left ventricular end-diastolic pressure and / or increase left ventricular ejection fraction, thereby improving HFrEF and potentially providing a preventive or therapeutic effect on chronic heart failure. In another embodiment, inhibiting SGLT1 can decrease left ventricular end-diastolic pressure and / or decrease EDPVRβ, thereby improving HFpEF and potentially providing a preventive or therapeutic effect on chronic heart failure. SGLT1 inhibitors can improve either or both HFrEF and HFpEF.

[0049] Inhibiting SGLT2 means inhibiting the function of SGLT2, thereby eliminating or reducing its activity. Preferably, this involves inhibiting human SGLT2. Inhibition of SGLT2 function or elimination or reduction of its activity is preferably performed in a clinically appropriate manner in humans.

[0050] In this specification, SGLT2 inhibitors include, for example, glycoside compounds, salts thereof, or solvates thereof. Here, a glycoside compound is a compound in which a sugar or sugar derivative is linked to an aglycone moiety by a glycosidic bond (e.g., a C-glycosidic bond or an O-glycosidic bond), wherein the sugar or sugar derivative has the following structure. [ka] [In the formula, Y is either O or S, and a glycosidic bond is formed with the carbon atom at position 1.]

[0051] In this specification, SGLT2 inhibitors include, for example, the following. For convenience, common names will be used throughout this specification. [Table 1] [Table 2] TIFF0007866935000018.tif95150

[0052] In one embodiment, SGLT1 inhibitors may be used in combination with SGLT2 inhibitors to treat and / or prevent chronic heart failure.

[0053] In another embodiment, a pharmaceutical product for the treatment or prevention of chronic heart failure containing an SGLT1 inhibitor is provided, characterized by the combined use of an SGLT1 inhibitor and an SGLT2 inhibitor.

[0054] In yet another embodiment, a pharmaceutical product for the treatment or prevention of chronic heart failure is provided, characterized by the combined use of an SGLT1 inhibitor and an SGLT2 inhibitor, and containing an SGLT2 inhibitor.

[0055] In yet another embodiment, a pharmaceutical product for the treatment or prevention of chronic heart failure is provided, which contains an SGLT1 inhibitor and is administered to a subject receiving treatment with an SGLT2 inhibitor.

[0056] In yet another embodiment, a pharmaceutical product for the treatment or prevention of chronic heart failure is provided, which contains an SGLT2 inhibitor and is administered to a subject receiving treatment with an SGLT1 inhibitor.

[0057] In this specification, "combination therapy" means, for example, administering SGLT1 inhibitors and SGLT2 inhibitors to a subject in any order. Since each drug has a different mechanism of action, combination therapy may produce additive or synergistic therapeutic or preventive effects. In one embodiment, combination therapy, by using multiple drugs with different mechanisms of action, may allow for a reduction in the dosage of each drug compared to administering a single drug alone, and may reduce the side effects specific to each drug. Here, side effects include, for example, hypoglycemia, weight gain, dehydration, polyuria, and frequent urination. In one embodiment, SGLT1 inhibitors and SGLT2 inhibitors may be administered to a subject simultaneously, consecutively, or at regular intervals (e.g., within 30 minutes, within 1 hour, within 2 hours, or within 4 hours), together or separately, in any order. One drug can be administered to the subject while the active ingredient of the other drug administered first is present in the subject's body in a therapeutically effective amount. In another embodiment, SGLT1 inhibitors and SGLT2 inhibitors may be administered to the subject as a single combination drug comprising these drugs. The dosage ratio and mixing ratio of these drugs may be appropriately selected depending on the target population, route of administration, target disease, symptoms, severity of the disease, and combinations thereof. For example, when the target population is human, 0.01 to 1000 parts by weight of SGLT2 inhibitor can be used for every 1 part by weight of SGLT1 inhibitor.

[0058] In one embodiment, the combination of an SGLT1 inhibitor and an SGLT2 inhibitor includes the combination of a compound of formula [I] or a pharmaceutically acceptable salt thereof with a glycoside compound or a salt thereof or a solvate thereof.

[0059] In another embodiment, the combination of an SGLT1 inhibitor and an SGLT2 inhibitor includes the combination of a compound of formula [II] or a pharmaceutically acceptable salt thereof with a glycoside compound or a salt thereof or a solvate thereof.

[0060] In one embodiment, the combined use of SGLT1 inhibitors and SGLT2 inhibitors may include, for example, Compound [I] or a pharmaceutically acceptable salt thereof and dapagliflozin, Compound [I] or a pharmaceutically acceptable salt thereof and ipragliflozin, Compound [I] or a pharmaceutically acceptable salt thereof and tofogliflozin, Compound [I] or a pharmaceutically acceptable salt thereof and empagliflozin, Compounds of formula [I] or pharmaceutically acceptable salts thereof and canagliflozin, Compound of formula [I] or a pharmaceutically acceptable salt thereof and luseogliflozin This includes the combined use of the two methods.

[0061] In another embodiment, the combination of SGLT1 inhibitors and SGLT2 inhibitors includes: The compound of formula [II] or a pharmaceutically acceptable salt thereof and dapagliflozin, Compound of formula [II] or a pharmaceutically acceptable salt thereof and ipragliflozin, Compound of formula [II] or a pharmaceutically acceptable salt thereof and tofogliflozin, Compound of formula [II] or a pharmaceutically acceptable salt thereof and empagliflozin, Compounds of formula [II] or pharmaceutically acceptable salts thereof and canagliflozin, Compound of formula [II] or a pharmaceutically acceptable salt thereof and luseogliflozin This includes the combined use of the two methods.

[0062] In this specification, "combination" includes the combination of a compound of formula [I] or a pharmaceutically acceptable salt thereof with dapagliflozin.

[0063] In this specification, "combination" includes the combination of a compound of formula [I] or a pharmaceutically acceptable salt thereof with empagliflozin.

[0064] In this specification, "combination" includes the combination of a compound of formula [II] or a pharmaceutically acceptable salt thereof with dapagliflozin.

[0065] In this specification, "combination" includes the combination of a compound of formula [II] or a pharmaceutically acceptable salt thereof with empagliflozin.

[0066] In this specification, "drug" means an SGLT1 inhibitor or an SGLT2 inhibitor. Administering one drug to a subject receiving treatment with another drug is a form of combination therapy that includes, for example, administering one drug to a subject while the active ingredient of the previously administered drug is present in the subject's body in a therapeutically effective amount.

[0067] In this specification, the therapeutically effective dose of an SGLT1 inhibitor may be appropriately changed depending on the target patient, route of administration, target disease, symptoms, severity of the disease, and combinations thereof. When administered orally to a human (60 kg body weight), the lower limit of the therapeutically effective dose may be, for example, about 0.01 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, or about 50 mg per day, and the upper limit of the therapeutically effective dose may be, for example, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, or about 1000 mg per day.

[0068] In this specification, the number of times SGLT1 inhibitors and pharmaceutical compositions are administered may be once, twice, three times, or more times per day, respectively.

[0069] In this specification, “treatment” includes improvement of symptoms, prevention of worsening, maintenance of remission, and prevention of relapse. For example, treatment of chronic heart failure includes recovery and improvement of cardiac function, specifically, a decrease in left ventricular end-diastolic pressure, an increase in left ventricular ejection fraction, and a decrease in EDPVR (end-diastolic pressure-volume relationship)β.

[0070] In this specification, “prevention” includes suppressing the onset of symptoms. For example, prevention of chronic heart failure includes maintaining cardiac function, specifically suppressing the rise in left ventricular end-diastolic pressure, maintaining left ventricular ejection fraction, and maintaining systolic blood pressure.

[0071] In this specification, “chronic heart failure” is often also called congestive heart failure and consists of HFrEF and HFpEF. “HFrEF” is often also called systolic heart failure, systolic heart failure, or systolic heart failure and includes, for example, post-myocardial infarction heart failure. “HFpEF” is often also called diastolic heart failure, diastolic heart failure, or diastolic heart failure and includes, for example, hypertensive heart failure.

[0072] In this specification, “HFrEF” is defined as heart failure with a reduced left ventricular ejection fraction, more specifically, 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%. In one embodiment, HFrEF includes HFrEF caused by coronary artery disease. Coronary artery disease includes, for example, ischemic heart disease, specifically angina pectoris and myocardial infarction. Angina pectoris is a disease caused by narrowing of the coronary arteries due to arteriosclerosis, and excessive absorption of glucose into the blood may be one contributing factor. Myocardial infarction is a disease caused by blockage of the coronary arteries, and excessive absorption of glucose into cardiomyocytes may be one contributing factor.

[0073] In this specification, “HFpEF” is defined as heart failure with preserved left ventricular ejection fraction, more specifically, as heart failure with a left ventricular ejection fraction of 45% or greater. In some embodiments, HFpEF includes heart failure with a left ventricular ejection fraction of 50% or greater. In one aspect, HFpEF includes HFpEF caused by hypertension.

[0074] Left ventricular ejection fraction is the value obtained by dividing the amount of blood the heart pumps out with each heartbeat (cardiac output) by the left ventricular end-diastolic volume when the heart is expanded. Left ventricular ejection fraction can be obtained, for example, using an ultrasound diagnostic device.

[0075] EDPVR shows the relationship between end-diastolic volume and end-diastolic pressure, and this relationship can be approximated by an exponential curve. The slope of this curve, EDPVRβ, indicates that the higher the value, the more rigid the heart is and the less able it is to expand. In other words, EDPVRβ is one indicator of left ventricular diastolic capacity. For example, if EDPVRβ exceeds 0.015, it indicates a state of reduced left ventricular diastolic capacity. EDPVR can be obtained, for example, using a pressure-volume measurement catheter system.

[0076] In one embodiment, the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure containing an SGLT1 inhibitor.

[0077] In one embodiment, the present invention is a pharmaceutical composition containing an SGLT1 inhibitor for the treatment or prevention of chronic heart failure caused by coronary artery disease or hypertension. In another embodiment, the present invention is a pharmaceutical composition containing an SGLT1 inhibitor for the treatment or prevention of chronic heart failure caused by angina pectoris, myocardial infarction, or hypertension.

[0078] In one embodiment, the present invention is a pharmaceutical composition containing an SGLT1 inhibitor for lowering left ventricular end-diastolic pressure in individuals whose left ventricular end-diastolic pressure is higher than the normal range. In one embodiment, the normal range for left ventricular end-diastolic pressure is 4 to 8 mmHg.

[0079] In one embodiment, the present invention is a pharmaceutical composition for the treatment or prevention of HFrEF containing an SGLT1 inhibitor.

[0080] In one embodiment, the present invention is a pharmaceutical composition containing an SGLT1 inhibitor for the treatment or prevention of HFrEF caused by coronary artery disease. In another embodiment, the present invention is a pharmaceutical composition containing an SGLT1 inhibitor for the treatment or prevention of HFrEF caused by angina pectoris or myocardial infarction.

[0081] In one embodiment, the present invention is a pharmaceutical composition containing an SGLT1 inhibitor for increasing the left ventricular ejection fraction in individuals whose left ventricular ejection fraction has decreased to less than 45%.

[0082] In one embodiment, the present invention is a pharmaceutical composition for the treatment or prevention of HFpEF containing an SGLT1 inhibitor.

[0083] In one embodiment, the present invention is a pharmaceutical composition containing an SGLT1 inhibitor for the treatment or prevention of hypertension-induced HFpEF.

[0084] In one embodiment, the present invention is a pharmaceutical composition containing an SGLT1 inhibitor for reducing EDPVR (end-diastolic pressure-volume relationship) β in individuals with high EDPVR β.

[0085] In one embodiment, the present invention relates to a pharmaceutical composition for the treatment or prevention of chronic heart failure, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0086] In one aspect, the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure caused by coronary artery disease or hypertension, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof. In another aspect, the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure caused by angina pectoris, myocardial infarction or hypertension, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0087] In one embodiment, the present invention is a pharmaceutical composition for reducing left ventricular end-diastolic pressure in individuals whose left ventricular end-diastolic pressure is higher than the normal range, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0088] In one aspect, the present invention relates to a pharmaceutical composition for the treatment or prevention of HFrEF containing a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0089] In one aspect, the present invention is a pharmaceutical composition for the treatment or prevention of HFrEF caused by coronary artery disease, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof. In another aspect, the present invention is a pharmaceutical composition for the treatment or prevention of HFrEF caused by angina pectoris or myocardial infarction, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0090] In one embodiment, the present invention is a pharmaceutical composition for increasing the left ventricular ejection fraction in an individual whose left ventricular ejection fraction has decreased to less than 35%, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0091] In one embodiment, the present invention relates to a pharmaceutical composition for the treatment or prevention of HFpEF containing a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0092] In one embodiment, the present invention relates to a pharmaceutical composition for the treatment or prevention of hypertension-induced HFpEF, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0093] In one embodiment, the present invention is a pharmaceutical composition for reducing EDPVR (end-diastolic pressure-volume relationship) β in individuals whose EDPVR β is greater than 0.015, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0094] In one embodiment, the present invention relates to a pharmaceutical composition for the treatment or prevention of chronic heart failure, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0095] In one aspect, the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure caused by coronary artery disease or hypertension, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof. In another aspect, the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure caused by angina pectoris, myocardial infarction or hypertension, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0096] In one embodiment, the present invention is a pharmaceutical composition for reducing left ventricular end-diastolic pressure in individuals whose left ventricular end-diastolic pressure is higher than the normal range, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0097] In one aspect, the present invention relates to a pharmaceutical composition for the treatment or prevention of HFrEF containing a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0098] In one aspect, the present invention is a pharmaceutical composition for the treatment or prevention of HFrEF caused by coronary artery disease, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof. In another aspect, the present invention is a pharmaceutical composition for the treatment or prevention of HFrEF caused by angina pectoris or myocardial infarction, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0099] In one embodiment, the present invention relates to a pharmaceutical composition for increasing the left ventricular ejection fraction in an individual whose left ventricular ejection fraction has decreased to less than 35%, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0100] In one embodiment, the present invention relates to a pharmaceutical composition for the treatment or prevention of HFpEF containing a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0101] In one embodiment, the present invention relates to a pharmaceutical composition for the treatment or prevention of hypertension-induced HFpEF, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0102] In one embodiment, the present invention is a pharmaceutical composition for reducing EDPVR (end-diastolic pressure-volume relationship) β in individuals whose EDPVR β is greater than 0.015, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof.

[0103] In one embodiment, the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0104] 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, comprising 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, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0105] In one embodiment, the present invention is a pharmaceutical composition containing an SGLT1 inhibitor and an SGLT2 inhibitor for lowering left ventricular end-diastolic pressure in individuals whose left ventricular end-diastolic pressure is higher than the normal range.

[0106] In one embodiment, the present invention is a pharmaceutical composition for the treatment or prevention of HFrEF containing an SGLT1 inhibitor and an SGLT2 inhibitor.

[0107] In one embodiment, the present invention is a pharmaceutical composition for the treatment or prevention of 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 the treatment or prevention of HFrEF caused by angina pectoris or myocardial infarction, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0108] In one embodiment, the present invention is a pharmaceutical composition containing an SGLT1 inhibitor and an SGLT2 inhibitor for increasing the left ventricular ejection fraction in individuals whose left ventricular ejection fraction has decreased to less than 35%.

[0109] In one embodiment, the present invention is a pharmaceutical composition for the treatment or prevention of HFpEF containing an SGLT1 inhibitor and an SGLT2 inhibitor.

[0110] In one embodiment, the present invention is a pharmaceutical composition for the treatment or prevention of hypertension-induced HFpEF, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0111] In one embodiment, the present invention is a pharmaceutical composition containing an SGLT1 inhibitor and an SGLT2 inhibitor for reducing EDPVR (end-diastolic pressure-volume relationship) β in individuals whose EDPVR β is higher than 0.015.

[0112] The pharmaceutical compositions described herein may be prepared by mixing a therapeutically effective amount of an SGLT1 inhibitor with at least one pharmaceutically acceptable carrier, and optionally an SGLT2 inhibitor, according to methods known in the art of pharmaceutical formulations. The content of the SGLT1 inhibitor in the pharmaceutical composition varies depending on the dosage form, dose, etc., but is, for example, 0.1 to 100% by weight of the total composition.

[0113] In this specification, the dosage forms of pharmaceutical compositions include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0114] Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, disintegrants, binders, fluidizers, lubricants, etc. in solid formulations; solvents, solubilizers, suspending agents, isotonic agents, buffers, analgesics, etc. in liquid formulations; and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solvents, solubilizers, suspending agents, etc. in semi-solid formulations. Furthermore, additives such as preservatives, antioxidants, colorants, and sweeteners may be added as needed.

[0115] Excipients include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of disintegrants include carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, and crystalline cellulose. Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic. Examples of fluidizing agents include light anhydrous silicic acid and magnesium stearate. Examples of lubricants include magnesium stearate, calcium stearate, and talc. Examples of solvents include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil. Examples of solubilizers include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate. Examples of suspending agents include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, and glyceryl monostearate. Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, and D-mannitol. Examples of buffering agents include sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate. Examples of pain-relieving agents include benzyl alcohol. Examples of bases 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, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, refined lanolin, absorbent ointment, hydrated lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogol (macrogol 200-600, etc.), and combinations of two or more of these. Examples of preservatives include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid. Examples of antioxidants include sodium sulfite and ascorbic acid. Examples of coloring agents include food colorings (such as Food Red No. 2 or 3, Food Yellow No. 4 or 5, etc.) and beta-carotene. Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, and aspartame.

[0116] In this specification, pharmaceutical compositions can be administered orally or parenterally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to humans and non-human mammals (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, monkeys, etc.). The dosage varies depending on the target, disease, symptoms, dosage form, route of administration, etc., but for example, when administered orally to an adult patient (weighing 60 kg), the dosage of the active ingredient is usually in the range of about 0.01 mg to about 1 g per day. These amounts can be administered in one to several divided doses. In one embodiment, the SGLT1 inhibitor may be formulated in separate pharmaceutical compositions with other drugs and administered in combination, and may be administered to the target in any order and time interval via different routes of administration. In another embodiment, the dosage of each drug when administered in combination may be lower than when each drug is administered alone, and the dosage when administered orally to an adult patient (weighing 60 kg) may be in the range of about 0.01 mg to 1000 mg per day.

[0117] In one embodiment, an SGLT1 inhibitor may be provided in the form of a kit (such as an administration, treatment, and / or prevention kit), package (such as a packaging), and drug set (and / or container), which may include, as appropriate, an SGLT2 inhibitor and a statement indicating that it may or should be used for treatment and / or prevention. Such a kit, package, and drug set may comprise one or more containers filled with the SGLT1 inhibitor and, as appropriate, an SGLT2 inhibitor and / or other drugs or substances (or components). Examples of such kits, packages, and drug sets include commercial kits, commercial packages, and commercial drug sets appropriately directed for the treatment and / or prevention of a target disease. The statements included in such kits, packages, and drug sets may include warnings or package inserts in the form directed by a government agency that regulates the manufacture, use, or sale of a pharmaceutical or biological product, indicating the approval of such government agency for the manufacture, use, or sale of the product in relation to human administration. The above-mentioned kits, packages, and drug sets may also include packaged products, structures configured for appropriate administration steps, and structures configured to achieve more favorable medical treatment and / or prevention, including treatment and / or prevention of the target disease. [Examples]

[0118] Compounds 1 to 40 (hereinafter referred to as Compounds 1 to 40) were obtained according to the manufacturing methods described in Patent Documents 2 and 3. The physical properties and SGLT1 inhibitory activity data for each compound are as described in those documents.

[0119] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8]

[0120] [Test Example 1] Evaluation of cardiac function in rats with post-myocardial infarction heart failure Male SD rats (8 weeks old, SLC Japan Co., Ltd.) were anesthetized with pentobarbital, and under mechanical ventilation, thoracotomy was performed and the left anterior descending coronary artery was permanently ligated to create rats with post-myocardial infarction and heart failure. A sham surgery group was also established, in which thoracotomy was performed but only the heart was exposed. Two weeks after the creation of myocardial infarction, the post-myocardial infarction and heart failure rat group was orally administered either the medium (0.5% methylcellulose solution) or compound 1 (3 mg / kg group or dose escalation group) once daily. The dose escalation group started at 3 mg / kg, increased to 6 mg / kg after two weeks, and then to 8 mg / kg after another two weeks, and continued to be administered at 8 mg / kg thereafter. The sham surgery group was orally administered the medium once daily. Eight weeks after administration, left ventricular ejection fraction was measured using an ultrasound diagnostic device (Aplio 300, Toshiba Medical Systems Corporation), and left ventricular end-diastolic pressure was measured by inserting a catheter-tipped micromanometer (Model SPR-320, Millar Inc.) into the left ventricle via the left carotid artery. Statistical analysis was performed using the Aspin-Welch t-test between the sham surgical medium administration group and the post-myocardial infarction heart failure rat medium administration group. Steel's multi-group test was used to test compound 1 against the medium in post-myocardial infarction heart failure rats. The significance level was set at a two-sided 5%. As a result, the post-myocardial infarction heart failure rat medium administration group showed decreased left ventricular ejection fraction and increased left ventricular end-diastolic pressure compared to the sham surgical medium administration group, confirming the development of HFrEF. In post-myocardial infarction heart failure rats, compound 1 increased left ventricular ejection fraction and suppressed the increase in left ventricular end-diastolic pressure, thus improving HFrEF. The results are shown in Figures 1 and 2.

[0121] Test Example 1 confirmed that compound 1 has an HFrEF-improving effect. The HFrEF-improving effects of compounds 2 to 40 can be confirmed using the same method as in Test Example 1. The HFrEF-improving effect of combining compounds 1 to 40 (e.g., compound 1) with an SGLT2 inhibitor (e.g., dapagliflozin) can be confirmed using the same method as in Test Example 1.

[0122] [Test Example 2] Evaluation of cardiac function in hypertensive heart failure rats Male DIS / Eis (Dahl-Iwai S) rats (Dahl rats) (7 weeks old, Nippon SLC Co., Ltd.) were fed a high-salt diet (MF 8% sodium chloride prepared feed, Oriental Yeast Co., Ltd.) to induce hypertensive heart failure in rats. Normal controls were fed a standard diet (CRF-1 solid type, Oriental Yeast Co., Ltd.). After 3 weeks, once the onset of disease (hypertension or cardiac hypertrophy) was confirmed, the hypertensive heart failure rat group was orally administered either a medium (0.5% methylcellulose solution) or compound 1 (3 mg / kg group or dose-escalation group) once daily. The dose-escalation group started at 3 mg / kg, increased to 6 mg / kg after 1 week, and then gradually increased to 8 mg / kg after another week, and continued at 8 mg / kg thereafter. The normal control group was orally administered the medium once daily. Five weeks after administration, left ventricular ejection fraction was measured using an ultrasound diagnostic device (Aplio 300, Toshiba Medical Systems Corporation), and systolic blood pressure was measured using a non-invasive automated blood pressure monitor (BP-98A, Softlon Co., Ltd.). Six weeks after administration, left ventricular end-diastolic pressure was measured by inserting an ADVantage PV catheter (Model FTH-1918B-E318, Transonic Scisense Inc.) into the left ventricle from the apex. Furthermore, EDPVRβ was calculated from the pressure-volume relationship due to transient inferior vena cava occlusion using an ADVantage PV catheter and an Ultrasonic flow probe (Model 2.5PSB1459, Transonic Scisense Inc.). For statistical analysis, Student's test or Aspin-Welch t test was performed between the normal control group and the hypertensive heart failure rat group. Dunnett's multi-group test was used to test for compound 1 against the media in hypertensive heart failure rats. The significance level was set at a two-sided 5%. As a result, hypertensive heart failure rats showed elevated EDPVRβ and left ventricular end-diastolic pressure compared to the normal control group, and no decrease in left ventricular ejection fraction was observed, confirming the development of HFpEF. Furthermore, in hypertensive heart failure rats, compound 1 decreased EDPVRβ and left ventricular end-diastolic pressure, improving HFpEF.At this time, hypertensive heart failure rats showed increased systolic blood pressure compared to the normal control group, but compound 1 did not affect systolic blood pressure. Furthermore, compound 1 did not affect urine output in hypertensive heart failure rats. The results are shown in Figures 3, 4, 5, 6, and 7.

[0123] Test Example 2 confirmed that compound 1 has an HFpEF-improving effect. The HFpEF-improving effects of compounds 2 to 40 can be confirmed using the same method as in Test Example 2. The HFpEF-improving effect of combining compounds 1 to 40 (e.g., compound 1) with an SGLT2 inhibitor (e.g., dapagliflozin) can be confirmed using the same method as in Test Example 2.

[0124] [Examples of formulations] Examples of formulations of the compound of formula [I] include, but are not limited to, the following formulations. Formulation Example 1 (Capsule Manufacturing) (1)Compound 1 30mg (2) Microcrystalline cellulose 10 mg (3) Lactose 19mg (4) Magnesium stearate 1 mg Mix ingredients (1), (2), (3), and (4) and fill them into gelatin capsules.

[0125] Formulation Example 2 (Tablet Manufacturing) (1) Compound 1 10g (2) Lactose 50g (3) Corn starch 15g (4) Carmellose calcium 44g (5) Magnesium stearate 1g The entire amounts of components (1), (2), and (3) and 30 g of component (4) are kneaded with water, vacuum-dried, and then granulated. 14 g of component (4) and 1 g of component (5) are mixed into this granulated powder and compressed into tablets using a tablet press. In this way, 1000 tablets are obtained, each containing 10 mg of compound 1. [Industrial applicability]

[0126] Compounds that inhibit SGLT1, or pharmaceutically acceptable salts thereof, are expected to be useful in the treatment or prevention of chronic heart failure.

Claims

1. Formula [II]: 【Chemistry 1】 A pharmaceutical composition for the treatment or prevention of chronic heart failure containing a compound that inhibits SGLT1, which is a compound of the same, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the chronic heart failure is heart failure with reduced left ventricular ejection fraction (HFrEF).

3. The pharmaceutical composition according to claim 1, wherein the chronic heart failure is heart failure with preserved left ventricular ejection fraction (HFpEF).

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