WO2021187548A1 - 慢性心不全の治療又は予防方法 - Google Patents

慢性心不全の治療又は予防方法 Download PDF

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WO2021187548A1
WO2021187548A1 PCT/JP2021/011003 JP2021011003W WO2021187548A1 WO 2021187548 A1 WO2021187548 A1 WO 2021187548A1 JP 2021011003 W JP2021011003 W JP 2021011003W WO 2021187548 A1 WO2021187548 A1 WO 2021187548A1
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compound
heart failure
pharmaceutically acceptable
acceptable salt
formula
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French (fr)
Japanese (ja)
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千尋 大熊
龍平 佐野
大介 冨本
由富 中根
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Japan Tobacco Inc
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Japan Tobacco Inc
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Priority to JP2022508425A priority Critical patent/JPWO2021187548A1/ja
Priority to AU2021237149A priority patent/AU2021237149A1/en
Priority to BR112022018396A priority patent/BR112022018396A2/pt
Priority to CN202180021810.3A priority patent/CN115209919B/zh
Priority to CA3175131A priority patent/CA3175131A1/en
Priority to EP21772065.5A priority patent/EP4122495A4/en
Application filed by Japan Tobacco Inc filed Critical Japan Tobacco Inc
Priority to MX2022011490A priority patent/MX2022011490A/es
Priority to KR1020227035794A priority patent/KR20220156574A/ko
Priority to US17/796,606 priority patent/US20230321044A1/en
Publication of WO2021187548A1 publication Critical patent/WO2021187548A1/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to a pharmaceutical composition for treating or preventing chronic heart failure containing a compound that inhibits SGLT (Na + -glucose cotransporter) 1 or a pharmaceutically acceptable salt thereof, and a compound that inhibits SGLT 1 or a pharmaceutical product thereof. It relates to a method for treating or preventing chronic heart failure, which comprises administering an acceptable salt.
  • Heart failure is the appearance of dyspnea, malaise and / or edema as a result of some cardiac dysfunction, ie, organic and / or functional abnormalities in the heart that disrupt the compensatory mechanism of cardiac pump function. It is defined as a clinical syndrome with decreased exercise tolerance and is characterized by an increase in left ventricular end-diastolic pressure. Chronic heart failure is the chronic continuation of these conditions.
  • Chronic heart failure is based on the left ventricular ejection fraction, and is heart failure in which the left ventricular ejection fraction is reduced (hereinafter referred to as “HFrEF” (heart failure with reduced ejection fraction)) and heart failure in which the left ventricular ejection fraction is maintained (hereinafter referred to as “HFrEF”).
  • HFrEF heart failure in which the left ventricular ejection fraction is reduced
  • HFrEF heart failure in which the left ventricular ejection fraction is maintained
  • HFpEF heart failure with pressed ejection fraction
  • HFrEF is considered to be mainly caused by left ventricular systolic dysfunction, and one of the characteristics is that left ventricular enlargement is observed in many cases.
  • enlargement means that the inner diameter and lumen of the heart become larger.
  • HFrEF the rate of shortening the left chamber diameter is reduced.
  • HFpEF is considered to be mainly caused by left ventricular diastolic dysfunction, and is characterized by left ventricular hypertrophy in many cases.
  • hypertrophy refers to a state in which the wall thickness of the heart is increased.
  • FIG. 1 shows that the post-myocardial infarction heart failure rat medium group significantly increased the left ventricular end-diastolic pressure as compared to the sham surgery group, and the compound of Example 1 in post-myocardial infarction heart failure rats (in the present specification, “Compound 1”. ”) Indicates that the left ventricular end-diastolic pressure was lower than that of the medium.
  • ⁇ in the figure indicates p ⁇ 0.01 for the sham surgery group.
  • FIG. 2 shows that the post-myocardial infarction heart failure rat medium group significantly reduced the left ventricular ejection fraction compared to the sham surgery group, and compound 1 (gradual increase) in post-myocardial infarction heart failure rats significantly reduced the left ventricular ejection fraction compared to the medium.
  • the ejection fraction was significantly increased, indicating that Compound 1 (3 mg / kg) showed a higher left ventricular ejection fraction compared to the vehicle.
  • ⁇ indicates p ⁇ 0.01 for the sham surgery group
  • * indicates p ⁇ 0.05 for the post-myocardial infarction heart failure rat medium group.
  • FIG. 3 shows that the hypertensive heart failure rat medium group significantly increased the left ventricular end diastolic pressure compared to the normal control group, and compound 1 significantly increased the left ventricular end diastolic pressure compared to the medium in hypertensive heart failure rats. Indicates that it has been reduced.
  • ⁇ indicates p ⁇ 0.01 with respect to the normal control group
  • * and ** indicate p ⁇ 0.05 and p ⁇ 0.01 with respect to the hypertensive heart failure rat medium group.
  • FIG. 4 shows that the hypertensive heart failure rat medium group significantly increased the end-diastolic pressure-volume relationship (referred to as “EDPVR” (end-diastolic pressure-volume relaxation ship) in the present specification) ⁇ as compared with the normal control group.
  • EDPVR end-diastolic pressure-volume relaxation ship
  • FIG. 6 shows that the hypertensive heart failure rat medium group significantly increased systolic blood pressure as compared to the normal control group.
  • ⁇ in the figure indicates p ⁇ 0.01 with respect to the normal control group.
  • FIG. 7 shows that in hypertensive heart failure rats, Compound 1 did not affect urine output as compared to the vehicle.
  • a pharmaceutical composition for treating or preventing chronic heart failure containing a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof.
  • 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) pyridyl substituted with R 3A , or (4) pyrazineyl, pyrimidinyl or pyridadinyl optionally substituted with R 3B.
  • R 3A is a 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 ).
  • R 4 and R 5 are independently hydrogen or C 1-3 alkyl
  • a pharmaceutical composition for treating or preventing chronic heart failure containing the compound of the above or a pharmaceutically acceptable salt thereof.
  • a compound that inhibits SGLT1, a compound of formula [I], or a pharmaceutically acceptable salt thereof is any of formulas [II] to [V]: Item 3.
  • a compound that inhibits SGLT1, a compound of formula [I], or a pharmaceutically acceptable salt thereof is of formula [II] :.
  • Item 3. The pharmaceutical composition according to any one of Items 1 to 3, which is a compound of the above or a pharmaceutically acceptable salt thereof.
  • Item 4 The pharmaceutical composition according to any one of Items 1 to 4, wherein the chronic heart failure is HFrEF.
  • Item 4 The pharmaceutical composition according to any one of Items 1 to 4, wherein the chronic heart failure is HFpEF.
  • a method for treating or preventing chronic heart failure which comprises administering to a subject a therapeutically effective amount of a compound that inhibits SGLT1, a compound of the formula [I] according to Item 2, or a pharmaceutically acceptable salt thereof.
  • [Item 8] A compound that inhibits SGLT1 or a compound of the formula [I] according to Item 2 or a pharmaceutically acceptable salt thereof for treating or preventing chronic heart failure.
  • the double wavy line indicates the binding site of the structure.
  • Halogen includes, for example, fluorine, chlorine, bromine, and iodine.
  • C 1-3 alkyl means a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms.
  • C 1-3 alkyl includes methyl, ethyl, n-propyl, and isopropyl.
  • C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
  • C 1-6 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl.
  • halo C 1-3 alkyl means the “C 1-3 alkyl” substituted with 1 to 5 halogens independently selected from the “halogen” group.
  • Halo C 1-3 alkyl includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2,2- Included are trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, and 3,3,3-trifluoropropyl.
  • fluoro C 1-3 alkyl means the above “C 1-3 alkyl” substituted with 1 to 5 fluorines.
  • FluoroC 1-3 alkyl includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, Includes 3-fluoropropyl, 1,1-difluoropropyl, and 3,3,3-trifluoropropyl.
  • halo C 1-6 alkyl means the “C 1-6 alkyl” substituted with 1 to 5 halogens independently selected from the “halogen” group.
  • Halo C 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 are included.
  • fluoro C 1-6 alkyl means the above “C 1-6 alkyl” substituted with 1 to 5 fluorines.
  • FluoroC 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-tri Includes fluorohexyl.
  • C 1-3 alkoxy means a group in which the above “C 1-3 alkyl” is bonded to an oxygen atom.
  • C 1-3 Alkoxy includes methoxy, ethoxy, n-propoxy, and isopropoxy.
  • substitution includes any chemically acceptable substitution.
  • pyridyl substituted with R 3A means any of the following formulas.
  • Each substituent of the compound of the formula [I] includes the specific embodiments exemplified below for each, and an embodiment in which the specific embodiments of each of these substituents are combined is also included in the compound of the formula [I].
  • R 1 is a halogen. In another embodiment, R 1 is fluorine.
  • R 2 is C 1-6 alkyl or fluoroalkyl C 1-6 alkyl. In another embodiment, R 2 is C 1-6 alkyl. In yet another embodiment, R 2 is fluoro C 1-3 alkyl.
  • R 3 is (1) halo C 1-6 alkyl, (2) Pyridyl substituted with R 3A , or (3) Pyrazineyl or pyrimidinyl optionally substituted with R 3B.
  • R 3 is selected from the group consisting of halo C 1-6 alkyl and formulas [H1] to [H14].
  • R 3 is halo C 1-6 alkyl, of formula [H2] or [H8].
  • R 3A is a halogen or halo C 1-3 alkyl. In another embodiment, R 3A is fluorine or fluoroC 1-3 alkyl.
  • R 3B is a halogen or halo C 1-3 alkyl. In another embodiment, R 3B is fluoroC 1-3 alkyl.
  • R 4 and R 5 are independently C 1-3 alkyl.
  • the compounds of formula [I] are of formula [II] or [III] :. It is a compound of.
  • the compound of formula [I] is a compound of formula [II].
  • the compound of formula [I] is a monohydrate of the compound of formula [III], i.e. formula [VI] :. It is a compound of.
  • the pharmaceutically acceptable salt may be any salt known in the art that is not excessively toxic. Specific examples thereof include a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, and a salt with an organic base.
  • Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the references below: (A) Berge et al., J. Mol. Pharm. Sci. , 66, p1-19 (1977), (B) Stahl et al., "Handbook of Physical Salt: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002), (C) Paulekhun et al., J. Mol. Med. Chem. , 50, p6665-6672 (2007).
  • a pharmaceutically acceptable salt thereof can be obtained by reacting the compound of the formula [I] with an inorganic acid, an organic acid, an inorganic base or an organic base according to a method known per se.
  • Examples of the salt with the inorganic acid include a salt with hydrofluoric acid, hydrochloride, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid.
  • Salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylene citrate, benzoic acid, benzene sulfonic acid, calcium edetate, gypsum acid, camphor-10-sulfonic acid, carbonic acid, citrus.
  • Acids edetic acid, ethane-1,2-disulfonic acid, dodecylsulfate, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylalarsanic acid, hexylresorcinic acid, hydroxy- Naftoeic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfate, methylnitrate, methylenebis (salicylic acid), galactalic acid, naphthalene-2-sulfone Acids, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid,
  • oxalic acid maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartrate acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid. , P-toluenesulfonic acid or salt with 2-hydroxy-1-ethanesulfonic acid.
  • Examples of the salt with an inorganic base include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth or ammonium. Preferred include salts with sodium, potassium, calcium, magnesium or zinc.
  • Examples of the salt with an organic base include salts with arecoline, betaine, choline, cremisol, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris (hydroxymethyl) methylamine, arginine or lysine. Preferred include salts with tris (hydroxymethyl) methylamine, N-methylglucamine or lysine.
  • the compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof may be any substance that inhibits SGLT1, such as a small molecule compound, a nucleic acid, a polypeptide, a protein, or an 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 of Patent Documents 1 to 3, the label of ⁇ -methyl-D-glucopyranoside transported by SGLT1. It can be calculated based on the intracellular uptake amount of 14 C-AMG).
  • the SGLT1 inhibitor is of formula [I] :.
  • each symbol is synonymous with the above] Compound or a pharmaceutically acceptable salt thereof.
  • the compound included in the formula [I] can be produced by a method known to those skilled in the art, and may be produced, for example, by any of the methods described in Patent Documents 1 to 3.
  • the SGLT1 inhibitory activity of the compounds included in the formula [I] has been confirmed by these documents.
  • SGLT1 inhibitors are 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 treat chronic heart failure. You may prevent it.
  • the SGLT2 inhibitor may be any substance that inhibits SGLT2, and may be a small molecule compound, a nucleic acid, a polypeptide, a protein, an antibody, a vaccine, or the like.
  • an SGLT2 inhibitor is a substance that has the ability to lower blood glucose levels by inhibiting the reuptake of glucose from urine and increasing the urinary excretion of sugar.
  • SGLT1 inhibitors eg, compounds of formula [I] or pharmaceutically acceptable salts thereof
  • SGLT2 inhibitors may be present as solvates.
  • the solvate is, for example, a compound of the formula [I] or a pharmaceutically acceptable salt thereof coordinated with a molecule of the solvent.
  • the solvate may be any pharmaceutically acceptable solvate, and examples thereof include a hydrate of a compound of formula [I] or a pharmaceutically acceptable salt thereof, an ethanol solvate, and a dimethyl sulfoxide solvate. .. Specifically, hemihydrate, monohydrate, dihydrate or monoethanol sum of the compound of formula [I], or monohydrate or dihydrochloride of the sodium salt of the compound of formula [I]. Examples include a 2/3 ethanol compound of salt.
  • These solvates can be obtained according to known methods.
  • the compound of formula [III] can exist as a monohydrate, as in the formula [VI] below.
  • the compound of formula [I] may be labeled with an isotope element (2 H, 3 H, 14 C, 35 S, etc.).
  • the compound of formula [I] or a pharmaceutically acceptable salt thereof is preferably a substantially purified compound of formula [I] or a pharmaceutically acceptable salt thereof. More preferably, it is a compound of formula [I] or a pharmaceutically acceptable salt thereof, which has been purified to a purity of 80% or more.
  • Inhibiting SGLT1 means inhibiting the function of SGLT1 and eliminating or diminishing its activity. Preferably, it inhibits human SGLT1. Inhibition or loss or attenuation of SGLT1 function is preferably performed in human clinical indications. In some embodiments, inhibition of SGLT1 suppresses an increase in left ventricular end-diastolic pressure and / or increases left ventricular ejection fraction, thereby improving HFrEF and providing a prophylactic or therapeutic effect on chronic heart failure. sell. In another embodiment, inhibition of SGLT1 may reduce left ventricular end-diastolic pressure and / or EDPVR ⁇ , thereby improving HFpEF and providing prophylactic or therapeutic effects on chronic heart failure. SGLT1 inhibitors can improve either or both of HFrEF and HFpEF.
  • Inhibiting SGLT2 means inhibiting the function of SGLT2 and eliminating or diminishing its activity. Preferably, it inhibits human SGLT2. Inhibition of SGLT2 function or loss or attenuation of activity is preferably carried out in human clinical indications.
  • SGLT2 inhibitors include, for example, glycoside compounds or salts thereof, or solvates thereof.
  • the glycoside compound is a compound in which a sugar or a sugar derivative has a glycosidic bond (for example, a C-glycoside bond or an O-glycoside bond) with an aglycone moiety, and the sugar or the sugar derivative has the following structure. .. [In the formula, Y is O or S, and the glycosidic bond is formed with the carbon atom at position 1]
  • SGLT2 inhibitors include, for example: For convenience, trivial names are used throughout this specification.
  • the SGLT1 inhibitor may be used for the treatment and / or prevention of chronic heart failure by administering to the subject in combination with the SGLT2 inhibitor.
  • a medicament for treating or preventing chronic heart failure containing an SGLT1 inhibitor which comprises using an SGLT1 inhibitor and an SGLT2 inhibitor in combination, is provided.
  • a medicament for treating or preventing chronic heart failure containing an SGLT2 inhibitor which comprises using an SGLT1 inhibitor and an SGLT2 inhibitor in combination, is provided.
  • a medicament for treating or preventing chronic heart failure containing an SGLT1 inhibitor comprises administering to a subject who is being treated with an SGLT2 inhibitor.
  • a medicament for treating or preventing chronic heart failure containing an SGLT2 inhibitor comprises administering to a subject who is being treated with an SGLT1 inhibitor.
  • the combined use means, for example, administration of an SGLT1 inhibitor and an SGLT2 inhibitor to a subject in an arbitrary order. Since each drug has a different mechanism of action, the combined use may exert an additive or synergistic therapeutic or preventive effect. In some embodiments, the combination may reduce the dose of each drug as compared to the case of administering one drug alone by using a plurality of drugs having different mechanisms of action, resulting in side effects specific to each drug. Can be reduced.
  • side effects for example, hypoglycemia, weight gain, dehydration, polyuria, pollakiuria and the like can be mentioned.
  • the SGLT1 inhibitor and the SGLT2 inhibitor are applied to the subject simultaneously, continuously or at regular intervals (eg, within 30 minutes, within 1 hour, within 2 hours, within 4 hours). They may be administered together or separately in any order.
  • One drug can be administered to a subject while the active ingredient contained in the first administered other drug is present in the subject's body in a therapeutically effective amount.
  • the SGLT1 inhibitor and the SGLT2 inhibitor may be administered to the subject as a single combination of these agents.
  • the administration ratio and combination ratio of these agents may be appropriately selected depending on the administration target, administration route, target disease, symptom, severity of disease, and combination thereof. For example, when the administration target is a human, 0.01 to 1000 parts by weight of the SGLT2 inhibitor can be used with respect to 1 part by weight of the SGLT1 inhibitor.
  • the combination of an SGLT1 inhibitor and an SGLT2 inhibitor includes a 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. ..
  • the combination of an SGLT1 inhibitor and an SGLT2 inhibitor includes a combination of a compound of formula [II] or a pharmaceutically acceptable salt thereof and a glycoside compound or a salt thereof or a solvate thereof. Is done.
  • the combined use of an SGLT1 inhibitor and an SGLT2 inhibitor may include, for example, A compound of formula [I] or a pharmaceutically acceptable salt thereof and dapagliflozin, Compounds of formula [I] or pharmaceutically acceptable salts thereof and ipragliflozin, A compound of formula [I] or a pharmaceutically acceptable salt thereof and tofogliflozin, A compound of formula [I] or a pharmaceutically acceptable salt thereof and empagliflozin, Includes a combination of a compound of formula [I] or a pharmaceutically acceptable salt thereof and canagliflozin, and a compound of formula [I] or a pharmaceutically acceptable salt thereof and luseogliflozin.
  • an SGLT1 inhibitor and an SGLT2 inhibitor A compound of formula [II] or a pharmaceutically acceptable salt thereof and dapagliflozin, Compounds of formula [II] or pharmaceutically acceptable salts thereof and ipragliflozin, A compound of formula [II] or a pharmaceutically acceptable salt thereof and tofogliflozin, A compound of formula [II] or a pharmaceutically acceptable salt thereof and empagliflozin, Includes a combination of a compound of formula [II] or a pharmaceutically acceptable salt thereof and canagliflozin, and a compound of formula [II] or a pharmaceutically acceptable salt thereof and luseogliflozin.
  • the concomitant use includes a concomitant use of a compound of formula [I] or a pharmaceutically acceptable salt thereof and dapagliflozin.
  • the concomitant use includes a concomitant use of a compound of formula [I] or a pharmaceutically acceptable salt thereof and empagliflozin.
  • the concomitant use includes a concomitant use of a compound of formula [II] or a pharmaceutically acceptable salt thereof and dapagliflozin.
  • the concomitant use includes a concomitant use of a compound of formula [II] or a pharmaceutically acceptable salt thereof and empagliflozin.
  • the agent means an SGLT1 inhibitor or an SGLT2 inhibitor.
  • Administering one drug to a subject being treated with another drug is an aspect of concomitant use, for example, when a drug is administered to a subject, it is effective contained in another drug previously administered. It involves administering the drug while the ingredient is present in the subject's body in a therapeutically effective amount.
  • the therapeutically effective amount of the SGLT1 inhibitor can be appropriately changed depending on the administration target, administration route, target disease, symptom, severity of disease, and a combination thereof.
  • the lower limit of the therapeutically effective amount is, for example, about 0.01 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg per day.
  • about 50 mg can be mentioned, and examples of the upper limit of the therapeutically effective amount include 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. ..
  • the number of administrations of the SGLT1 inhibitor and the pharmaceutical composition include once, twice, three times or more times a day, respectively.
  • 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) ⁇ . include.
  • prevention includes suppressing the onset of symptoms.
  • prevention of chronic heart failure includes maintenance of cardiac function, specifically suppression of elevation of left ventricular end-diastolic pressure, maintenance of left ejection fraction, and maintenance of systolic blood pressure.
  • Chronic heart failure as used herein is often referred to as congestive heart failure and consists of HFrEF and HFpEF.
  • HFrEF is also often referred to as systolic, systolic, or systolic heart failure, including, for example, post-myocardial infarction heart failure.
  • HFpEF is often referred to as diastolic heart failure, diastolic heart failure, or diastolic heart failure and includes, for example, hypertensive heart failure.
  • HFrEF is defined as heart failure with a reduced left-ventricular ejection fraction, and more specifically, heart failure with a left-ventricular ejection fraction of less than 45%.
  • HFrEF comprises heart failure with a left ventricular ejection fraction of less than 40%.
  • HFrEF includes heart failure with a left ventricular ejection fraction of less than 35%.
  • HFrEFs include HFrEFs caused by coronary artery disease. Examples of coronary artery disease include ischemic heart disease, specifically angina pectoris and myocardial infarction.
  • Angina is a disease caused by narrowing of the coronary arteries due to arteriosclerosis or the like, and for example, excessive absorption of glucose into the blood may be a factor.
  • Myocardial infarction is a disease caused by blockage of the coronary arteries, for example, excessive absorption of glucose into cardiomyocytes can contribute.
  • HFpEF is defined as heart failure with a left-ventricular ejection fraction, and more specifically, heart failure with a left-ventricular ejection fraction of 45% or more. In some embodiments, HFpEF comprises heart failure with a left ventricular ejection fraction of 50% or greater. In some embodiments, HFpEFs include HFpEFs caused by hypertension.
  • the left ventricular ejection fraction is the value obtained by dividing the amount of blood pumped by the heart for each heartbeat by the volume at the end of diastolic dilatation of the left ventricle when the heart expands.
  • the left ventricular ejection fraction can be obtained, for example, using an ultrasonic diagnostic apparatus.
  • EDPVR shows the relationship between the end-diastolic volume and the end-diastolic pressure, and the relationship can be approximated by an exponential curve.
  • the slope of the curve, EDPVR ⁇ indicates that the higher the value, the harder the heart is and the less likely it is to expand. That is, EDPVR ⁇ is one of the indexes of left ventricular diastolic capacity. For example, when EDPVR ⁇ exceeds 0.015, it means that the left ventricular diastolic capacity is reduced.
  • EDPVR can be obtained using, for example, a pressure volumetric catheter system.
  • the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure containing an SGLT1 inhibitor.
  • 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.
  • the invention is a pharmaceutical composition for treating or preventing chronic heart failure caused by angina, myocardial infarction or hypertension, which contains an SGLT1 inhibitor.
  • the present invention is a pharmaceutical composition containing an SGLT1 inhibitor for reducing left ventricular end diastolic pressure in an individual whose left ventricular end diastolic pressure is above the normal range.
  • the normal range of left ventricular end-diastolic pressure is 4-8 mmHg.
  • the present invention is a pharmaceutical composition for the treatment or prevention of HFrEF containing an SGLT1 inhibitor.
  • the present invention is a pharmaceutical composition for the treatment or prevention of HFrEF caused by coronary artery disease, which contains an SGLT1 inhibitor.
  • the present invention is a pharmaceutical composition for treating or preventing HFrEF caused by angina or myocardial infarction, which contains an SGLT1 inhibitor.
  • the present invention is a pharmaceutical composition containing an SGLT1 inhibitor for increasing the left-ventricular ejection fraction in an individual whose left-ventricular ejection fraction is reduced to less than 45%.
  • the present invention is a pharmaceutical composition for the treatment or prevention of HFpEF containing an SGLT1 inhibitor.
  • the present invention is a pharmaceutical composition for the treatment or prevention of HFpEF caused by hypertension, which contains an SGLT1 inhibitor.
  • the present invention is a pharmaceutical composition containing an SGLT1 inhibitor for reducing EDPVR (end-diastolic pressure-volume relationship) ⁇ in individuals with high EDPVR (end-diastolic pressure-volume relationship) ⁇ .
  • the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure containing a compound of formula [I] or a pharmaceutically acceptable salt thereof.
  • the present invention is a pharmaceutical composition for treating or preventing chronic heart failure caused by coronary artery disease or hypertension, which comprises a compound of formula [I] or a pharmaceutically acceptable salt thereof.
  • the invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure caused by angina, myocardial infarction or hypertension, which comprises a compound of formula [I] or a pharmaceutically acceptable salt thereof.
  • the present invention is a medicament for reducing left ventricular end diastolic pressure in an individual whose left ventricular end diastolic pressure is above the normal range, which contains a compound of formula [I] or a pharmaceutically acceptable salt thereof. It is a composition.
  • the present invention is a therapeutic or prophylactic pharmaceutical composition of HFrEF containing a compound of formula [I] or a pharmaceutically acceptable salt thereof.
  • the present invention is a pharmaceutical composition for the treatment or prevention of HFrEF caused by coronary artery disease, which comprises a compound of formula [I] or a pharmaceutically acceptable salt thereof.
  • the invention is a pharmaceutical composition for the treatment or prevention of HFrEF caused by angina or myocardial infarction, which comprises a compound of formula [I] or a pharmaceutically acceptable salt thereof.
  • the present invention increases the left ventricular ejection fraction in an individual containing a compound of formula [I] or a pharmaceutically acceptable salt thereof and having a left ventricular ejection fraction reduced to less than 35%.
  • the present invention is a therapeutic or prophylactic pharmaceutical composition of HFpEF containing a compound of formula [I] or a pharmaceutically acceptable salt thereof.
  • the present invention is a pharmaceutical composition for the treatment or prevention of HFpEF caused by hypertension, which comprises a compound of formula [I] or a pharmaceutically acceptable salt thereof.
  • the present invention comprises an EDPVR (end-of-expansion pressure volume) in an individual having an EDPVR (end-of-expansion pressure-volume relationship) ⁇ greater than 0.015, containing a compound of formula [I] or a pharmaceutically acceptable salt thereof. Relationship) A pharmaceutical composition for lowering ⁇ .
  • the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure containing a compound of formula [II] or a pharmaceutically acceptable salt thereof.
  • the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure caused by coronary artery disease or hypertension, which comprises a compound of formula [II] or a pharmaceutically acceptable salt thereof.
  • the invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure caused by angina, myocardial infarction or hypertension, which comprises a compound of formula [II] or a pharmaceutically acceptable salt thereof.
  • the present invention is a medicament for reducing left ventricular end-diastolic pressure in an individual whose left ventricular end-diastolic pressure is above the normal range, containing a compound of formula [II] or a pharmaceutically acceptable salt thereof. It is a composition.
  • the present invention is a therapeutic or prophylactic pharmaceutical composition of HFrEF containing a compound of formula [II] or a pharmaceutically acceptable salt thereof.
  • the present invention is a pharmaceutical composition for the treatment or prevention of HFrEF caused by coronary artery disease, which comprises a compound of formula [II] or a pharmaceutically acceptable salt thereof.
  • the invention is a pharmaceutical composition for the treatment or prevention of HFrEF caused by angina or myocardial infarction, which comprises a compound of formula [II] or a pharmaceutically acceptable salt thereof.
  • the present invention increases the left ventricular ejection fraction in an individual containing a compound of formula [II] or a pharmaceutically acceptable salt thereof and having a left ventricular ejection fraction reduced to less than 35%.
  • a pharmaceutical composition for is a pharmaceutical composition for.
  • the present invention is a therapeutic or prophylactic pharmaceutical composition of HFpEF containing a compound of formula [II] or a pharmaceutically acceptable salt thereof.
  • the present invention is a pharmaceutical composition for the treatment or prevention of HFpEF caused by hypertension, which comprises a compound of formula [II] or a pharmaceutically acceptable salt thereof.
  • the present invention comprises an EDPVR (end-of-expansion pressure volume) in an individual having an EDPVR (end-of-expansion pressure-volume relationship) ⁇ greater than 0.015, containing a compound of formula [II] or a pharmaceutically acceptable salt thereof. Relationship) A pharmaceutical composition for lowering ⁇ .
  • the present invention is a pharmaceutical composition for the treatment or prevention of chronic heart failure containing an SGLT1 inhibitor and an SGLT2 inhibitor.
  • the present invention is a pharmaceutical composition for treating or preventing chronic heart failure caused by coronary artery disease or hypertension, which comprises an SGLT1 inhibitor and an SGLT2 inhibitor.
  • the invention is a pharmaceutical composition for treating or preventing chronic heart failure caused by angina, myocardial infarction or hypertension, which comprises an SGLT1 inhibitor and an SGLT2 inhibitor.
  • the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an SGLT1 inhibitor and an SGLT2 inhibitor to reduce left ventricular end diastolic pressure in an individual whose left ventricular end diastolic pressure is above the normal range.
  • the present invention is a pharmaceutical composition for the treatment or prevention of HFrEF containing an SGLT1 inhibitor and an SGLT2 inhibitor.
  • the present invention is a pharmaceutical composition for treating or preventing HFrEF caused by coronary artery disease, which comprises an SGLT1 inhibitor and an SGLT2 inhibitor.
  • the invention is a pharmaceutical composition for the treatment or prevention of HFrEF caused by angina or myocardial infarction, which comprises an SGLT1 inhibitor and an SGLT2 inhibitor.
  • the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an SGLT1 inhibitor and an SGLT2 inhibitor to increase the left-ventricular ejection fraction in an individual having a left-ventricular ejection fraction reduced to less than 35%. ..
  • the present invention is a pharmaceutical composition for the treatment or prevention of HFpEF containing an SGLT1 inhibitor and an SGLT2 inhibitor.
  • the present invention is a pharmaceutical composition for the treatment or prevention of HFpEF caused by hypertension, which comprises an SGLT1 inhibitor and an SGLT2 inhibitor.
  • the present invention reduces EDPVR (end-of-expansion pressure-volume relationship) ⁇ in individuals with an EDPVR (end-of-expansion pressure-volume relationship) ⁇ greater than 0.015, containing SGLT1 and SGLT2 inhibitors. It is a pharmaceutical composition of.
  • the pharmaceutical composition in the present specification is used to inhibit a therapeutically effective amount of an SGLT1 inhibitor with at least one or more pharmaceutically acceptable carriers and the like, if necessary, according to a method known in the technical field of pharmaceutical preparations. It may be produced by appropriately mixing with an agent.
  • the content of the SGLT1 inhibitor in the pharmaceutical composition varies depending on the dosage form, dosage and the like, but is, for example, 0.1 to 100% by weight of the entire composition.
  • the dosage forms of the pharmaceutical compositions include oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions and suspensions, and external preparations, suppositories, injections and eye drops.
  • oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions and suspensions
  • external preparations such as suppositories, injections and eye drops.
  • parenteral preparations such as preparations, nasal preparations, and pulmonary preparations.
  • Examples of pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as preparation materials, and solvents in liquid preparations such as excipients, disintegrants, binders, fluidizers, and lubricants in solid preparations. , Dissolution aids, suspending agents, tonicity agents, buffers, soothing agents, etc., and bases, emulsifiers, wetting agents, stabilizers, stabilizers, dispersants, plastics, pH in semi-solid formulations. Examples thereof include modifiers, absorption promoters, gelling agents, preservatives, fillers, solubilizers, solubilizing agents, suspending agents and the like. Further, if necessary, additives such as preservatives, antioxidants, colorants, and sweeteners may be added.
  • Excipients include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and Arabia.
  • examples include rubber.
  • the disintegrant include carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low degree of substitution hydroxypropyl cellulose, hydroxypropyl methyl cellulose, crystalline cellulose and the like.
  • binder examples include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, sodium carmellose, and gum arabic.
  • fluidizing agent examples include light anhydrous silicic acid and magnesium stearate.
  • lubricant examples include magnesium stearate, calcium stearate, talc and the like.
  • solvent examples include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizing agent examples include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, glycerin monostearate and the like.
  • tonicity agent examples include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.
  • buffer examples include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like.
  • the pain-relieving agent examples include benzyl alcohol and the like.
  • Bases include water, animal and vegetable oils (olive oil, corn oil, lacquer oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and The esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white vaseline, liquid paraffin, paraffin, etc.), hydrophilic vaseline, purified lanolin, water-absorbing ointment, hydrous lanolin, hydrophilic ointment, starch, purulan, arabic gum, tragacanth gum , Gelatin, dextran, cellulose derivatives (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogol (macro)
  • Examples of the preservative include ethyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.
  • Examples of the antioxidant include sodium sulfite, ascorbic acid and the like.
  • Examples of the colorant include edible pigments (edible red No. 2 or 3, edible yellow No. 4 or 5, etc.), ⁇ -carotene and the like.
  • Examples of the sweetener include sodium saccharin, dipotassium glycyrrhizinate, aspartame and the like.
  • the pharmaceutical composition is oral or non-human to humans and non-human mammals (mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, cow, horse, sheep, monkey, etc.). It can be administered orally (topically, rectal, intravenously, intramuscularly, subcutaneously, etc.).
  • the dose varies depending on the administration target, disease, symptom, dosage form, administration route, etc., but for example, the dose when orally administered to an adult patient (body weight 60 kg) is usually about 0 per day for the active ingredient. It ranges from 0.01 mg to about 1 g. These amounts can be administered in 1 to several divided doses.
  • the SGLT1 inhibitor may be formulated in a pharmaceutical composition separate from the other agent and administered in combination, or may be administered to the subject in any order and at time intervals by different administration routes.
  • the dose of each drug in combination may be lower than when each drug is administered alone, and the dose when orally administered to an adult patient (body weight 60 kg) is per day. It may be in the range of about 0.01 mg to 1000 mg.
  • the SGLT1 inhibitor comprises a kit (administration, treatment and) comprising, as appropriate, an SGLT2 inhibitor and a statement stating that it can or should be used for treatment and / or prophylaxis. / Or may be provided in the form of a preventive kit, etc.), a package (packaging, etc.) and a drug set (and / or a container).
  • kits, packages and drug sets may include one or more containers filled with an SGLT1 inhibitor and, as appropriate, an SGLT2 inhibitor and / or other drug or drug (or ingredient). Examples of such kits, packages and drug sets include commercial kits, commercial packages and commercial drug sets specifically directed for the treatment and / or prevention of the disease of interest.
  • kits, packages and drug sets may also include packaged products and may include structures configured for the appropriate dosing step (step), treatment of the subject disease and / or Structures configured to achieve more preferred medical treatments and / or prophylaxis, including prophylaxis, may be included.
  • the vehicle (0.5% methylcellulose solution) or compound 1 (3 mg / kg group or gradual increase group) was orally administered to the post-myocardial infarction heart failure rat group once a day.
  • the escalating group started at 3 mg / kg, increased to 6 mg / kg after 2 weeks, further increased to 8 mg / kg after 2 weeks, and thereafter administered at 8 mg / kg.
  • the sham-surgery group was orally administered the vehicle once daily.
  • the ejection fraction of the left chamber was measured using an ultrasonic diagnostic device (Aplio 300, Toshiba Medical Systems Corporation), and a catheter-tipped micromanometer (Model SPR-320, Millar Inc.) was placed in the left chamber from the left carotid artery. The left ventricular end-diastolic pressure was measured.
  • Aspin-Welch's test was performed between the sham surgical medium-administered group and the post-myocardial infarction heart failure rat-administered group.
  • a multi-group assay of Steel was performed. The significance level was 5% on both sides.
  • the post-myocardial infarction heart failure rat medium-administered group had a lower left ventricular ejection fraction and an increased left ventricular end-diastolic pressure than the sham-surgical medium-administered group, and thus developed HFrEF.
  • Compound 1 improved HFrEF because it increased left ventricular ejection fraction and suppressed the increase in left ventricular end-diastolic pressure. The results are shown in FIGS. 1 and 2.
  • Test Example 1 it was confirmed that Compound 1 has an HFrEF improving effect.
  • the HFrEF improving effect of Compounds 2 to 40 can be confirmed by the same method as in Test Example 1.
  • the effect of improving HFrEF by the combined use of Compounds 1 to 40 (for example, Compound 1) and an SGLT2 inhibitor (for example, dapagliflozin) can be confirmed.
  • 1 vehicle (0.5% methylcellulose solution) or compound 1 (3 mg / kg group or gradual increase group) was added to the hypertensive heart failure rat group. It was orally administered once a day.
  • the escalating group started at 3 mg / kg, increased to 6 mg / kg after 1 week, gradually increased to 8 mg / kg after 1 week, and then administered at 8 mg / kg thereafter.
  • the normal control group was orally administered the vehicle once daily.
  • the hypertensive heart failure rats showed an increase in systolic blood pressure and exhibited hypertension as compared with the normal control group, but Compound 1 did not affect the systolic blood pressure. In addition, compound 1 did not affect urine output in hypertensive heart failure rats. The results are shown in FIGS. 3, 4, 5, 6 and 7.
  • Test Example 2 It was confirmed by Test Example 2 that Compound 1 had an HFpEF improving effect.
  • the HFpEF improving effect of Compounds 2 to 40 can be confirmed by the same method as in Test Example 2.
  • the HFpEF improving effect of the combined use of Compounds 1 to 40 for example, Compound 1
  • an SGLT2 inhibitor for example, dapagliflozin
  • Examples of pharmaceutical formulations of the compound of formula [I] include, but are not limited to, the following pharmaceutical formulations.
  • Pharmaceutical example 1 (manufacturing of capsule) (1) Compound 1 30 mg (2) Microcrystalline cellulose 10 mg (3) Lactose 19 mg (4) Magnesium stearate 1 mg Ingredients (1), (2), (3) and (4) are mixed and filled in gelatin capsules.
  • composition 2 (manufacturing of tablets) (1) Compound 1 10 g (2) Lactose 50g (3) Corn starch 15g (4) Carmellose calcium 44g (5) Magnesium stearate 1 g The total amount of the components (1), (2) and (3) and 30 g of the component (4) are kneaded with water, vacuum dried, and then granulated. 14 g of the component (4) and 1 g of the component (5) are mixed with the sizing powder and locked by a locking machine. In this way, 1000 tablets containing 10 mg of compound 1 per tablet are obtained.
  • a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof is expected to be useful for the treatment or prevention of chronic heart failure.

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WO2023210634A1 (ja) * 2022-04-28 2023-11-02 国立大学法人東海国立大学機構 拡張障害を伴う心不全の治療用医薬組成物
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