WO2020110346A1 - Therapeutic agent for nonobstructive hypertrophic cardiomyopathy - Google Patents

Therapeutic agent for nonobstructive hypertrophic cardiomyopathy Download PDF

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WO2020110346A1
WO2020110346A1 PCT/JP2019/018298 JP2019018298W WO2020110346A1 WO 2020110346 A1 WO2020110346 A1 WO 2020110346A1 JP 2019018298 W JP2019018298 W JP 2019018298W WO 2020110346 A1 WO2020110346 A1 WO 2020110346A1
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hypertrophic cardiomyopathy
carbon atoms
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compound represented
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PCT/JP2019/018298
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French (fr)
Japanese (ja)
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希臣 濱田
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希臣 濱田
株式会社テクノネットワーク四国
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/41641,3-Diazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to a therapeutic agent for non-obstructive hypertrophic cardiomyopathy.
  • Hypertrophic cardiomyopathy is the so-called intractable disease, which is the 58th target disease of the Research and Treatment Program for Specific Diseases. It is known that hypertrophic cardiomyopathy causes marked cardiac hypertrophy and left ventricular diastolic disorder (Non-Patent Document 1). Sudden death and death from heart failure are known to be the main causes of death in patients with hypertrophic cardiomyopathy.
  • Hypertrophic cardiomyopathy is classified into obstructive hypertrophic cardiomyopathy and non-obstructive hypertrophic cardiomyopathy (Non-patent Document 1).
  • Obstructive hypertrophic cardiomyopathy and non-obstructive hypertrophic cardiomyopathy differ in the structure of the ventricles during ventricular hypertrophy, and thus the mechanism by which symptoms occur.
  • the ventricular septum is enlarged, and the myocardium in the left ventricle becomes a physical barrier to blood flow. Therefore, an apex with high pressure and a cardiac base with low pressure are generated in the left ventricle. Therefore, it is considered that the pressure gradient between the two causes symptoms of obstructive hypertrophic cardiomyopathy.
  • non-obstructive hypertrophic cardiomyopathy unlike the case of obstructive hypertrophic cardiomyopathy, the myocardium in the left ventricle does not serve as a physical barrier to blood flow even if ventricular septal hypertrophy occurs. Therefore, in non-obstructive hypertrophic cardiomyopathy, the pressure gradient observed in obstructive hypertrophic cardiomyopathy does not occur. Therefore, it is believed that other mechanisms cause the symptoms of non-obstructive hypertrophic cardiomyopathy.
  • this invention aims at provision of the pharmaceutical for non-obstructive hypertrophic cardiomyopathy.
  • the pharmaceutical composition for non-obstructive hypertrophic cardiomyopathy (hereinafter, also referred to as “medicine”) of the present invention comprises a compound represented by the following formula (1) or a salt thereof:
  • R may be the same or different, and each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms
  • R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted Is an aralkyl group
  • the substituted aralkyl group has one aromatic ring residue selected from the group consisting of a fluorine atom
  • the myocardial hypertrophy that occurs in non-obstructive hypertrophic cardiomyopathy can be regressed by including the compound represented by the formula (1) or a salt thereof. That is, according to the present invention, since myocardial hypertrophy that occurs in non-obstructive hypertrophic cardiomyopathy can be regressed, it can be used for treatment of non-obstructive hypertrophic cardiomyopathy.
  • FIG. 1 is a diagram showing an electrocardiogram of a healthy person in Example 1.
  • FIG. 2 is a diagram showing an electrocardiogram before administration of cibenzoline to a patient with non-obstructive hypertrophic cardiomyopathy in Example 1.
  • FIG. 3 is a diagram showing an electrocardiogram of a patient with non-obstructive hypertrophic cardiomyopathy after administration of cibenzoline in Example 1.
  • FIG. 4 is a photograph showing an echocardiogram of a healthy person in Example 1.
  • FIG. 5 is a photograph showing an echocardiogram of a patient with non-obstructive hypertrophic cardiomyopathy before administration of cibenzoline in Example 1.
  • FIG. 1 is a diagram showing an electrocardiogram of a healthy person in Example 1.
  • FIG. 2 is a diagram showing an electrocardiogram before administration of cibenzoline to a patient with non-obstructive hypertrophic cardiomyopathy in Example 1.
  • FIG. 3 is a diagram showing an electrocardiogram of a patient
  • FIG. 6 is a photograph showing an echocardiogram of a patient with non-obstructive hypertrophic cardiomyopathy after administration of cibenzoline in Example 1.
  • FIG. 7 is a graph showing the results of all HNCM patients before and after administration of cibenzoline in Example 1.
  • FIG. 8 is a graph showing the results of all HNCM patients before and after administration of cibenzoline in Example 1.
  • the medicament for non-obstructive hypertrophic cardiomyopathy of the present invention contains the compound represented by the following formula (1) or a salt thereof, as described above:
  • R may be the same or different, and each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms
  • R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted Is an aralkyl group
  • the substituted aralkyl group has one aromatic ring residue selected from the group consisting of a fluorine atom, a chlorine atom
  • the medicament of the present invention is characterized by containing the compound represented by the above formula (1) or a salt thereof, and other configurations and conditions are not particularly limited. It is presumed that the drug of the present invention induces the regression of myocardial hypertrophy by the following mechanism.
  • the present invention is not limited to the following estimation.
  • the compound represented by the formula (1) or a salt thereof blocks the Na + channel in the cardiomyocyte membrane, thereby suppressing the inflow of Na + ions into the cardiomyocyte. As a result, the decrease of Na + ions in the cardiomyocytes occurs and the cardiomyocytes cannot be depolarized. Since the depolarization disorder is directly linked to the damage of cardiomyocytes, the Na + -Ca 2+ exchange system in the cardiomyocyte membrane is activated.
  • hypertrophic non-obstructive cardiomyopathy means, for example, hypertrophic cardiomyopathy without a left ventricular pressure difference.
  • the non-occlusive hypertrophic cardiomyopathy can be determined based on, for example, measurement of myocardial hypertrophy by electrocardiography, measurement of myocardial wall thickness by echocardiography, and diagnostic criteria for non-occlusive hypertrophic cardiomyopathy. An example of the determination method is shown below, but the HNCM determination is not limited to this. Specifically, first, the electrocardiogram of the subject is measured to determine whether or not cardiac hypertrophy has occurred, and the subject with cardiac hypertrophy is extracted as the first candidate for hypertrophic cardiomyopathy.
  • the thickness of the left ventricle in the first candidate group for hypertrophic cardiomyopathy is measured by echocardiography. It is known that in the left ventricle, the septal thickness of the ventricle and the posterior wall of the left ventricle generally reflect the degree of cardiac hypertrophy.
  • the second candidate for hypertrophic cardiomyopathy is extracted based on the obtained echocardiogram.
  • the first candidate for hypertrophic cardiomyopathy is a healthy person or a hypertensive patient (compensatory cardiac hypertrophy)
  • cardiac hypertrophy is almost uniform in any part of the left ventricle.
  • the thickened area is not constant.
  • the second candidate for hypertrophic cardiomyopathy is extracted from the first candidate for hypertrophic cardiomyopathy based on the above criteria.
  • the second candidate for hypertrophic cardiomyopathy if a part of the left ventricular myocardium has a myocardial hypertrophy of 15 mm or more based on the echocardiogram, it is extracted as the hypertrophic cardiomyopathy patient. Furthermore, it is measured whether there is a pressure gradient in the left ventricle of the hypertrophic cardiomyopathy patient. When there is no left ventricular pressure difference, the hypertrophic cardiomyopathy patient can be determined to be an HNCM patient. Even if it is determined by the electrocardiogram that cardiac hypertrophy occurs, if the subject suffers from a systemic system disease, the subject is not hypertrophic cardiomyopathy, but secondary cardiac hypertrophy. Can be determined.
  • treatment may mean any of the treatment of cardiac hypertrophy, improvement, suppression of symptom progression, and/or cessation of symptom progression. Therefore, the pharmaceutical agent of the present invention can be referred to as, for example, a therapeutic agent for HNCM, an improving agent, a progress inhibitor, and/or a progress stopping agent.
  • the drug of the present invention can relieve myocardial hypertrophy in patients with HNCM.
  • "regression of myocardial hypertrophy” means that the myocardial thickness at the site of myocardial hypertrophy is (significantly) reduced as compared with the absence of the above-mentioned pharmaceutical agent of the present invention (non-administration condition).
  • the thickness of the myocardium is, for example, the thickness of the interventricular septum.
  • the pharmaceutical composition of the present invention can reduce myocardial hypertrophy in patients with HNCM, it can suppress, for example, death from heart failure in patients with HNCM. Therefore, in the medicine of the present invention, “treatment” may be used to mean any of the suppression, prevention, and/or improvement of heart failure death associated with cardiac hypertrophy. Therefore, the medicament of the present invention can be referred to as, for example, a suppressive agent, preventive agent, and/or ameliorating agent for (failure) death of heart failure due to HNCM.
  • “suppression of death from heart failure” means that the probability of death from heart failure is (significantly) lower than that in the absence of the drug of the present invention (non-administration condition).
  • the compound represented by the above formula (1) has an asymmetric carbon atom. Therefore, the compound represented by the above formula (1) may exist as a racemate, an enantiomer of R and S thereof, or a mixture of R and S at any ratio.
  • the compound represented by the formula (1) may have two or more asymmetric centers. In this case, the compound represented by the formula (1) may include a diastereomer and a mixture thereof.
  • the compound of the present invention may include geometrical isomers such as cis and trans isomers.
  • R is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms, and preferably a hydrogen atom. ..
  • the two Rs may be the same or different, but are preferably the same.
  • the alkyl group having 1 to 5 carbon atoms is, for example, a linear, branched or cyclic saturated or unsaturated alkyl group having 1 to 5 carbon atoms.
  • Specific examples of the alkyl group having 1 to 5 carbon atoms include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n -Pentyl group, isopentyl group, sec-pentyl group, tert-pentyl group, neopentyl group and the like.
  • the alkyl group in the alkoxy group having 1 to 5 carbon atoms is, for example, a linear, branched, or cyclic saturated or unsaturated alkyl group having 1 to 5 carbon atoms.
  • Specific examples of the alkoxy group having 1 to 5 carbon atoms include methoxy group, ethoxy group, propyloxy group, butyloxy group, pentyloxy group and the like.
  • R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted It is an aralkyl group, and preferably a hydrogen atom.
  • the alkenyl group having 2 to 5 carbon atoms is, for example, a linear, branched or cyclic alkenyl group having 2 to 5 carbon atoms.
  • Specific examples of the alkenyl group having 2 to 5 carbon atoms include, for example, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group and 2-methylallyl group.
  • the alkynyl group having 2 to 5 carbon atoms is, for example, a linear, branched or cyclic alkynyl group having 2 to 5 carbon atoms.
  • Specific examples of the alkynyl group having 2 to 5 carbon atoms include, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group and 1-methyl-2. Examples thereof include a propynyl group, a 1-pentynyl group, a 2-pentynyl group, a 3-pentynyl group, a 4-pentynyl group and a 1-methyl-3-butynyl group.
  • alkyl group in the hydroxyalkyl group having 1 to 5 carbon atoms for example, the above description of the alkyl group having 1 to 5 carbon atoms can be applied.
  • the alkyl group in the unsubstituted or substituted aralkyl group is, for example, an alkyl group having 1 to 5 carbon atoms.
  • the alkyl group in the unsubstituted or substituted aralkyl group for example, the above description of the alkyl group having 1 to 5 carbon atoms can be referred to.
  • the unsubstituted aralkyl group include benzyl group (phenylmethyl group), phenethyl group (phenylethyl group), phenylpropyl group, phenylbutyl group, phenylpentyl group, and the like.
  • the substituted aralkyl group has one aromatic ring residue selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms. It is an aralkyl group substituted with a group.
  • the number of substitutions in the aromatic ring residue (phenyl group) is, for example, 1 to 5.
  • the substitution position in the aromatic ring residue is, for example, any one or more in the 2-position, 3-position, 4-position, 5-position, and 6-position.
  • R may be the same or different and each independently represents a hydrogen atom, a fluorine atom or a methyl group
  • R 1 represents a hydrogen atom, a methyl group or isopropyl. It is preferably a group, a propylene group, an n-butyl group, a hydroxyethyl group, a benzyl group, a p-methylbenzyl group, a phenethyl group, or a 3,4,5-trimethyloxybenzyl group.
  • the compound represented by the formula (1) can more effectively induce the regression of myocardial hypertrophy and can improve the cardiac function during left ventricular diastole, the compound represented by the following formula (2) is It is preferable to include.
  • the compound of the following formula (2) can also be referred to as, for example, cibenzoline, ciphenline, or 2-(2,2-diphenylcyclopropyl)-4,5-dihydro-1H-imidazole.
  • the compound of the following formula (2) is, for example, a compound registered under PubChem CID:2747, Cas registration number: 53267-01-9.
  • the compound represented by the above formula (1) may be, for example, an isomer.
  • the isomers include tautomers and stereoisomers.
  • Examples of the tautomers or stereoisomers include all theoretically possible tautomers or stereoisomers.
  • the configuration of each substituent is not particularly limited.
  • the compound represented by the formula (1) may be, for example, a hydrate or a solvate of the compound represented by the formula (1) or a salt thereof.
  • the salt of the compound represented by the formula (1) is not particularly limited and is, for example, a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt is not particularly limited, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, Aliphatic amine salts such as dichlorohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, etc., aralkylamine salts such as N,N-dibenzylethylenediamine; pyridine salt, picoline salt, quinoline salt, isoquinoline salt.
  • Heterocyclic aromatic amine salts such as; quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, tetrabutylammonium salt; arginine salt, lysine Amino acid salts such as salts, aspartates and glutamate; inorganic salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates, hydrogencarbonates and perchlorates; acetates, propionates, succinates Acid salt, glycolate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate, hydroxymaleate, pyruvate, phenylacetate, benzoate, Aliphatic or aromatic organic acids such as 4-aminobenzoate, anthranilate, 4-
  • the salt of the compound represented by the formula (1) is preferably succinate.
  • the succinate salt of the compound of formula (2) is, for example, a compound registered under Cas registration number: 100678-32-8.
  • the medicament of the present invention may be used, for example, in vivo or in vitro .
  • the medicine of the present invention may be composed of, for example, a plurality of components.
  • the medicament of the present invention can be referred to as a pharmaceutical composition, for example.
  • the subject of administration of the medicament of the present invention is not particularly limited.
  • the subject to be administered includes, for example, humans or non-human animals other than humans.
  • the non-human animals include mice, rats, rabbits, dogs, sheep, horses, cats, goats, monkeys, and guinea pigs.
  • the administration target includes, for example, cells, tissues, organs and the like, and the cells include, for example, cells collected from a living body, cultured cells and the like. Examples of the cells include cardiomyocytes.
  • administration conditions of the pharmaceutical agent of the present invention are not particularly limited, and, for example, the administration form, administration time, dose, etc. can be appropriately set according to the type of administration subject.
  • the dose of the medicament of the present invention is not particularly limited.
  • the medicament of the present invention when used in vivo, it can be appropriately determined depending on, for example, the type of subject to be administered, symptoms, age, administration method and the like.
  • the dose of the compound represented by the formula (1) per day is not particularly limited, and, for example, the blood concentration in the administration subject is 100 to 2000 ng/mL, Preferably, the dose can be set to 300 to 1500 ng/mL. With such a dose, the drug of the present invention can effectively suppress heart failure death in HNCM, for example.
  • the total dose of the compound represented by the above formula (1) is, for example, 50 to 500 mg, 100 to 400 mg, preferably 250 mg or more, about 300 mg. (Eg, 200 to 400 mg, 250 to 400 mg, etc.).
  • the pharmaceutical composition of the present invention can effectively prevent regression of myocardial hypertrophy and prevention or suppression of death from heart failure. ..
  • the number of administrations per day is, for example, 1 to 5 times, 1 to 3 times, preferably about 3 times (eg, 2 to 4 times).
  • the blood concentration in the administration subject becomes, for example, 300 to 1500 ng/mL.
  • the medicament of the present invention may be administered continuously or non-continuously.
  • the non-continuous administration can also be referred to as intermittent administration, for example.
  • the continuous administration is, for example, 1, 2, 3, or 4 weeks or more, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or 1, 2 or more. Administration for 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years or more, preferably 3 months or more.
  • the continuous administration means, for example, administration without administration of the drug of the present invention, that is, so-called withdrawal period.
  • the non-continuous administration for example, administration including a so-called drug holiday, in which the medicament of the present invention is not administered.
  • the administration intervals of the pharmaceutical agent of the present invention are preferably approximately equal intervals.
  • the drug of the present invention when administered three times, it is preferable that the drug is administered about every 8 hours (eg, 6 to 10 hours).
  • the amount of the compound represented by the formula (1) per day is, for example, 50, 100, 150, 200, 250, 300, 350, 400, or 450 mg, and is 1 day.
  • the number of times of administration is 1 to 5 times.
  • the content of the compound represented by the formula (1) in the medicine is not particularly limited and can be appropriately set, for example, according to the above-mentioned daily dose.
  • the administration form of the medicament of the present invention is not particularly limited.
  • the pharmaceutical agent of the present invention may be administered orally or parenterally.
  • the parenteral administration includes, for example, intravenous injection (intravenous administration), intramuscular injection (intramuscular administration), transdermal administration, subcutaneous administration, intradermal administration, enteral administration, rectal administration, vaginal administration, nasal administration, Examples include pulmonary administration, intraperitoneal administration, and local administration.
  • the dosage form of the medicament of the present invention is not particularly limited and can be appropriately determined depending on, for example, the above administration form.
  • Examples of the dosage form include liquid form and solid form.
  • Specific examples of the dosage form include modified release preparations (enteric-coated preparations, sustained-release preparations, etc.), capsules, oral liquid preparations (elixir preparations, suspensions, emulsions, aromatic water preparations, limonade preparations, etc.), syrup preparations.
  • injection preparations such as injections (implanted injections, continuous injections, infusions (drip preparations), freeze-dried injections, powder injections, filled syringes, cartridges, etc.); dialysis agents (Peritoneal dialysis agents, hemodialysis agents) and other dialysis preparations; Inhalants (inhalation aerosols, inhalation solutions, inhalation powders, etc.) and other bronchial and pulmonary preparations; Eye ointments, eye drops, etc.
  • injections such as injections (implanted injections, continuous injections, infusions (drip preparations), freeze-dried injections, powder injections, filled syringes, cartridges, etc.); dialysis agents (Peritoneal dialysis agents, hemodialysis agents) and other dialysis preparations; Inhalants (inhalation aerosols, inhalation solutions, inhalation powders, etc.) and other bronchial and pulmonary preparations; Eye ointments,
  • ear preparations such as ear drops
  • nasal preparations such as nasal drops (nasal drops, nasal powders etc.); rectal preparations such as suppositories, semi-solids for rectal and enema preparations
  • Vaginal suppositories vaginal preparations such as vaginal tablets
  • external liquids asake, liniments, lotions, etc.
  • creams gels
  • external solids external solids
  • sprays external aerosols, pumps
  • Spray agents etc., patches (tapes, poultices, etc.), ointments and other skin application agents; and the like.
  • examples of the dosage form include tablets, coated tablets, pills, fine granules, granules, powders, capsules, solutions, syrups, emulsions, suspensions and the like. Be done.
  • examples of the dosage form include injection preparations and infusion preparations.
  • examples of the dosage form include external preparations such as patches, coatings, ointments, creams and lotions.
  • the drug of the present invention may contain additives, for example, if necessary, and in this case, it can be referred to as a pharmaceutical composition.
  • the additive preferably comprises a pharmaceutically acceptable additive or a pharmaceutically acceptable carrier.
  • the additive is not particularly limited, and examples thereof include base materials, excipients, colorants, lubricants, binders, disintegrants, stabilizers, preservatives, and flavoring agents such as fragrances. ..
  • the compounding amount of the additive is not particularly limited as long as it does not hinder the function of the compound.
  • excipients examples include sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; corn starch, potato starch, ⁇ -starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; pullulan.
  • Organic excipients such as; light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, silicate derivatives such as magnesium aluminometasilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; calcium sulfate Inorganic excipients such as sulfates.
  • Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, and other stearic acid metal salts; talc; polyethylene glycol; silica; hydrogenated vegetable oil and the like.
  • Examples of the flavoring agents include cocoa powder, peppermint, aroma powder, peppermint oil, borneol, cinnamon powder and the like, sweeteners, acidulants and the like.
  • Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol and the like.
  • disintegrant examples include cellulose derivatives such as carboxymethyl cellulose and carboxymethyl cellulose calcium; chemically modified starch such as carboxymethyl starch, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone, and chemically modified celluloses.
  • stabilizer examples include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid. Sorbic acid and the like can be mentioned.
  • the compound represented by the above formula (1) or (2) may be a commercially available product or may be prepared in-house. In the latter case, the compound represented by the above formula (1) or (2) can be produced by a known method, for example, JP-A-49-93363 (US Pat. No. 3,903,104). Can be referred to and is incorporated as part of this specification.
  • myocardial hypertrophy that occurs in HNCM can be regressed. That is, according to the present invention, myocardial hypertrophy that occurs in HNCM can be regressed, and thus can be used for treatment of HNCM.
  • the medicament of the present invention may include, for example, a Na channel blocker, that is, a compound that inhibits Na channel, instead of or in addition to the compound represented by the formula (1) or a salt thereof.
  • a Na channel blocker include Group I antiarrhythmic drugs.
  • the group I antiarrhythmic drug include quinidine (for example, PubChemCID:5953), procainamide (for example, PubChemCID:4913), disopyramide (disopyramide, for example, PubChemCID:3114), and pyrmenol (for example, PubChem).
  • the method for treating non-obstructive hypertrophic cardiomyopathy of the present invention includes an administration step of administering the above-mentioned pharmaceutical for non-occlusive hypertrophic cardiomyopathy of the present invention to a patient.
  • the therapeutic method of the present invention is characterized by administering the pharmaceutical agent of the present invention, that is, the compound represented by the formula (1) or a salt thereof, and other steps and conditions are not particularly limited.
  • the description of the pharmaceutical agent of the present invention can be applied.
  • the treatment method of the present invention myocardial hypertrophy that occurs in non-obstructive hypertrophic cardiomyopathy can be regressed. Therefore, according to the treatment method of the present invention, non-obstructive hypertrophic cardiomyopathy can be treated. According to the therapeutic method of the present invention, it is possible to treat a patient with non-obstructive hypertrophic cardiomyopathy. Therefore, the therapeutic method of the present invention can be referred to as, for example, a method for treating non-obstructive hypertrophic cardiomyopathy.
  • the treatment method of the present invention includes, for example, an administration step of administering the drug, and specifically includes an administration step of administering the drug to a patient (administration subject).
  • the medicament may be administered in vitro or may be administered in vivo .
  • the administration subject and administration conditions of the medicament of the present invention for example, the explanation of the administration subject and administration conditions in the medicament of the present invention can be cited.
  • the present invention is a compound represented by the above formula (1) or a salt thereof, or use thereof for use in the treatment of non-obstructive hypertrophic cardiomyopathy. Further, the present invention is the use of the compound represented by the above formula (1) or a salt thereof for producing a medicament for treating non-obstructive hypertrophic cardiomyopathy.
  • the description of the medicine and the treatment method of the present invention can be incorporated.
  • Example 1 It was confirmed that the drug of the present invention causes cardiac hypertrophy in patients with HNCM.
  • HNCM patients 40 patients who are to be administered with cibenzoline (compound represented by the above formula (2)) have pressure in the left ventricle of the heart in patients diagnosed with hypertrophic cardiomyopathy. The patient was considered to have no difference. Diagnosis of hypertrophic cardiomyopathy was performed by echocardiography using an echocardiographic device (a SEQUOIA-512 (manufactured by Siemens Healthcare) or ProSound II SSD-6500SV (manufactured by Hitachi-Aloca)). The pressure gradient in the left ventricle was calculated by the following formula (A) by measuring the continuous wave Doppler velocity in the middle ventricle or the left ventricular ejection tract.
  • A The pressure gradient in the left ventricle was calculated by the following formula (A) by measuring the continuous wave Doppler velocity in the middle ventricle or the left ventricular ejection tract.
  • Cibenzoline was orally administered (internally) to a HNCM patient for 3 years or more. Oral administration of cibenzoline was 100 mg/dose 3 times/day. The dosing time was around 2:00 pm and 9:00 pm after breakfast. This controlled blood levels of cibenzoline in patients with HNCM to 300-1500 ng/mL. The average observation period of patients was 9.5 ⁇ 3.0 years.
  • the cardiac hypertrophy was evaluated using an echocardiogram and an electrocardiogram. Specifically, an echocardiogram was obtained from each patient using the ultrasonic diagnostic apparatus, and the left ventricular posterior wall thickness (LVPWT) and the interventricular septal thickness (IVST) were measured from the echocardiogram. Further, by using the electrocardiogram measuring device (Cardiofax G, manufactured by NIHON Kohden Corporation), an electrocardiogram is measured, Sokolow-Lyon index is an indicator of cardiac hypertrophy (SV1 (S wave of V 1 of the chest lead electrocardiogram) + RV5 (chest leads The R wave of V 5 on the electrocardiogram)) and the depth of the negative T wave (negative T wave depth) were measured.
  • LVPWT left ventricular posterior wall thickness
  • IVST interventricular septal thickness
  • the rate of change before and after administration of cibenzoline was calculated based on the following formula (B). Further, as a control, each measured value was similarly measured for 15 healthy persons.
  • R c (ba)/b ⁇ 100(%) (B)
  • R c rate of change b: measured value before administration of cibenzoline (at the start of administration, before treatment)
  • a measured value after final administration of cibenzoline (after treatment)
  • FS left ventricular diameter shortening rate
  • LVDd left ventricular end diastolic diameter (mm)
  • LVDs Left ventricular end systolic diameter (mm)
  • FIGS. 1 to 3 Results Representative examples of electrocardiogram before and after administration of cibenzoline in healthy subjects and patients are shown in FIGS. 1 to 3.
  • FIG. 1 shows the results of electrocardiogram of healthy subjects.
  • the first column shows a bipolar lead electrocardiogram (I, II or III)
  • the second column shows the unipolar lead electrocardiogram (aV R, aV L or aV F)
  • the third column Shows the chest lead electrocardiogram (V 1 , V 2 or V 3 )
  • the fourth column shows the chest lead electrocardiogram (V 4 , V 5 or V 6 ).
  • FIG. 2 shows the results of the electrocardiogram of the patient before administration of cibenzoline (March 18, 2013).
  • FIG. 3 shows the electrocardiographic results of the same patient as FIG. 2 after administration of cibenzoline (March 28, 2018).
  • bipolar lead electrocardiogram I, II or III
  • monopolar lead ECG aV R, aV L or aV F
  • right column chest-lead ECG (V 1, V 2 , V 3 , V 4 , V 5 or V 6 ) is shown.
  • the depth of the S wave at V 1 (SV1) was deeper and the height of the R wave at V 5 (RV5) was deeper than that of healthy subjects. Became higher.
  • the T wave at V 5 is a positive T wave showing an upward spike
  • the T wave at V 5 was a negative T wave showing a downward spike. From these, it was found that cardiac hypertrophy has progressed in patients with HNCM before administration of cibenzoline.
  • FIG. 1 in patients with HNCM before administration of cibenzoline.
  • FIGS. 4 to 6 show typical examples of echocardiograms before and after administration of cibenzoline in healthy subjects and HNCM patients.
  • FIG. 4 shows the result of an echocardiogram of a healthy person.
  • FIG. 5 shows the results of echocardiography of the patient before administration of cibenzoline (October 19, 2012).
  • FIG. 6 shows the results of echocardiography of the same patient as FIG. 5 after administration of cibenzoline (September 27, 2018).
  • (A) shows an echocardiogram of the left ventricle of the heart
  • (B) shows an echocardiogram by the M-mode method in a region where cardiac hypertrophy occurs.
  • ventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) were increased, and cardiac hypertrophy occurred. Further, both the left ventricular end diastolic diameter (LVDd) and the left ventricular end systolic diameter (LVDs) were narrowed. In contrast, as shown in FIGS. 5 and 6, in patients with HNCM after administration of cibenzoline, ventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) were decreased, and cardiac hypertrophy was regressed. .. In addition, the left ventricular end diastolic diameter (LVDd) and the left ventricular end systolic diameter (LVDs) were both increased.
  • FIGS. 7 and 8 are graphs showing the results of all cases of HNCM patients before and after administration of cibenzoline.
  • FIG. 7 shows the results of the left ventricular end diastolic diameter (LVDd)
  • (B) shows the results of the left ventricular end systolic diameter (LVDs)
  • (C) shows the left ventricular shortened diameter.
  • (LVFS) results are shown
  • (D) shows left atrial diameter (LAD) results.
  • LAD left atrial diameter
  • FIGS. 7 and 8 and Table 1 show the results of ventricular septal thickness (IVST), (B) shows the result of left ventricular posterior wall thickness (LVPWT), (C) shows the result of SV1+RV5, (D) shows the results of negative T-wave depth.
  • IVST ventricular septal thickness
  • LVPWT left ventricular posterior wall thickness
  • D shows the results of negative T-wave depth.
  • the left ventricular end diastolic diameter (LVDd) expanded by 7.7%, and there was no significant change in the left ventricular diameter shortening rate (LVFS).
  • the left atrium diameter (LAD) was reduced by 7.8%.
  • administration of the drug of the present invention causes regression of cardiac hypertrophy in non-obstructive hypertrophic cardiomyopathy. Further, it was found that administration of the drug of the present invention did not cause a decrease in cardiac function during left ventricular systole, and improved cardiac function during left ventricular diastole.
  • Example 2 It was confirmed that the drug of the present invention reduces the rate of heart failure death in patients with non-obstructive hypertrophic cardiomyopathy.
  • Example 1 All the causes of death of patients with HNCM in Example 1 were followed. As a result, none of the patients died of heart failure in all cases. On the other hand, it is known that 55% of patients with hypertrophic cardiomyopathy without apparent left heart dysfunction develop heart failure. Therefore, it was found that the drug of the present invention reduces the rate of heart failure death in patients with non-obstructive hypertrophic cardiomyopathy. Moreover, based on these results, it can be said that the drug of the present invention can suppress or prevent heart failure death in a patient with non-obstructive hypertrophic cardiomyopathy.
  • a medicament for non-obstructive hypertrophic cardiomyopathy which comprises a compound represented by the following formula (1) or a salt thereof:
  • R may be the same or different, and each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms
  • R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted Is an aralkyl group
  • the substituted aralkyl group has one aromatic ring residue selected from
  • R may be the same or different and each independently is a hydrogen atom, a fluorine atom, or a methyl group
  • R 1 is a hydrogen atom, a methyl group, an isopropyl group, a propylene group, an n-butyl group, a hydroxyethyl group, a benzyl group, a p-methylbenzyl group, a phenethyl group, or a 3,4,5-trimethyloxybenzyl group.
  • the drug for non-obstructive hypertrophic cardiomyopathy according to Appendix 1.
  • the compound represented by the formula (1) is the pharmaceutical composition for non-obstructive hypertrophic cardiomyopathy according to appendix 1 or 2, represented by the following formula (2).
  • (Appendix 4) 4.
  • (Appendix 5) 5.
  • Appendix 7 The pharmaceutical composition for non-obstructive hypertrophic cardiomyopathy according to any one of appendices 1 to 6, wherein the compound represented by the formula (1) is administered at 250 mg or more per day.
  • Appendix 8) 8. The nonobstructive hypertrophic cardiomyopathy according to any one of appendices 1 to 7, wherein the nonobstructive hypertrophic cardiomyopathy is a pharmaceutical for suppressing or preventing death of heart failure caused by nonobstructive hypertrophic cardiomyopathy. Medicine.
  • (Appendix 9) A medicament for regressing myocardial hypertrophy in non-obstructive hypertrophic cardiomyopathy, which comprises the pharmaceutical for non-occlusive hypertrophic cardiomyopathy according to any one of appendices 1 to 7.
  • (Appendix 10) A medicament for suppressing or preventing death of heart failure due to non-obstructive hypertrophic cardiomyopathy, which comprises the medicament for non-occlusive hypertrophic cardiomyopathy according to any one of appendices 1 to 7.
  • (Appendix 11) A method for treating non-obstructive hypertrophic cardiomyopathy, comprising the step of administering to the patient the pharmaceutical composition for non-occlusive hypertrophic cardiomyopathy according to any one of appendices 1 to 7.
  • (Appendix 12) A method for regressing myocardial hypertrophy in non-obstructive hypertrophic cardiomyopathy, comprising the step of administering to a patient the pharmaceutical for regressing myocardial hypertrophy in non-obstructive hypertrophic cardiomyopathy according to Appendix 9.
  • (Appendix 13) A method for suppressing or preventing death from heart failure due to non-obstructive hypertrophic cardiomyopathy, comprising an administration step of administering to a patient a pharmaceutical for suppressing or preventing death from heart failure due to non-obstructive hypertrophic cardiomyopathy. ..
  • (Appendix 14) A compound represented by the following formula (1) or a salt thereof for use in the treatment of non-obstructive hypertrophic cardiomyopathy.
  • R may be the same or different, and each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms
  • R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted Is an aralkyl group
  • the substituted aralkyl group has one aromatic ring residue selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms.
  • R may be the same or different and each independently is a hydrogen atom, a fluorine atom, or a methyl group
  • R 1 is a hydrogen atom, a methyl group, an isopropyl group, a propylene group, an n-butyl group, a hydroxyethyl group, a benzyl group, a p-methylbenzyl group, a phenethyl group, or a 3,4,5-trimethyloxybenzyl group.
  • the compound represented by the formula (1) is the compound or the salt thereof according to supplementary note 14 or 15, represented by the following formula (2).
  • the compound represented by the formula (1) is a compound or a salt thereof according to any one of supplementary notes 14 to 16, which is administered at substantially equal intervals.
  • (Appendix 20) The compound represented by the formula (1), or a salt thereof, according to any one of supplementary notes 14 to 19, which is administered in an amount of 250 mg or more per day.
  • (Appendix 21) The compound or salt thereof according to any one of appendices 14 to 20, for use in the regression of myocardial hypertrophy in non-obstructive hypertrophic cardiomyopathy.
  • (Appendix 22) The compound or a salt thereof according to any one of appendices 14 to 20, which is used for suppressing or preventing death of heart failure caused by non-obstructive hypertrophic cardiomyopathy.
  • myocardial hypertrophy that occurs in non-obstructive hypertrophic cardiomyopathy can be regressed by including the compound represented by the formula (1) or a salt thereof. That is, according to the present invention, since myocardial hypertrophy that occurs in non-obstructive hypertrophic cardiomyopathy can be regressed, it can be used for treatment of non-obstructive hypertrophic cardiomyopathy. Therefore, the present invention can be said to be extremely useful in the fields of medicine and the like.

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Abstract

Provided is a therapeutic agent for nonobstructive hypertrophic cardiomyopathy. This therapeutic agent for nonobstructive hypertrophic cardiomyopathy contains a compound represented by formula (1) or a salt thereof.

Description

非閉塞性肥大型心筋症治療薬Nonobstructive hypertrophic cardiomyopathy drug
 本発明は、非閉塞性肥大型心筋症治療薬に関する。 The present invention relates to a therapeutic agent for non-obstructive hypertrophic cardiomyopathy.
 肥大型心筋症は、特定疾患治療研究事業の58番目の対象疾患であり、いわゆる、難病である。肥大型心筋症では、著しい心肥大と左室拡張障害とを生じることが知られている(非特許文献1)。肥大型心筋症患者の主な死亡原因としては、突然死と心不全死とが知られている。 Hypertrophic cardiomyopathy is the so-called intractable disease, which is the 58th target disease of the Research and Treatment Program for Specific Diseases. It is known that hypertrophic cardiomyopathy causes marked cardiac hypertrophy and left ventricular diastolic disorder (Non-Patent Document 1). Sudden death and death from heart failure are known to be the main causes of death in patients with hypertrophic cardiomyopathy.
 肥大型心筋症は、閉塞性肥大型心筋症と非閉塞性肥大型心筋症とに分類される(非特許文献1)。閉塞性肥大型心筋症および非閉塞性肥大型心筋症は、心室肥大時の心室内の構造が異なり、これにより、症状が生じるメカニズムも異なる。具体的には、閉塞性肥大型心筋症の場合、心室中隔が肥大し、左室内の心筋が、血流に対する物理的な障壁となる。このため、左室内において、圧が高い心尖部と、圧が低い心基部とが生じる。したがって、両者の圧較差により、閉塞性肥大型心筋症の症状が生じると考えられている。また、この知見に基づき、米国では、肥厚した心筋(心室中隔)を外科的に除去することによる治療が行なわれ効果をあげている。また、欧州では、圧較差出現の原因となっている心筋(心室中隔)の削除を目的とし、前記心筋に血液を供給している冠動脈を閉塞し、心筋の細胞死を誘導する治療法が開発され、効果を上げている。 Hypertrophic cardiomyopathy is classified into obstructive hypertrophic cardiomyopathy and non-obstructive hypertrophic cardiomyopathy (Non-patent Document 1). Obstructive hypertrophic cardiomyopathy and non-obstructive hypertrophic cardiomyopathy differ in the structure of the ventricles during ventricular hypertrophy, and thus the mechanism by which symptoms occur. Specifically, in the case of obstructive hypertrophic cardiomyopathy, the ventricular septum is enlarged, and the myocardium in the left ventricle becomes a physical barrier to blood flow. Therefore, an apex with high pressure and a cardiac base with low pressure are generated in the left ventricle. Therefore, it is considered that the pressure gradient between the two causes symptoms of obstructive hypertrophic cardiomyopathy. Further, based on this finding, in the United States, treatment by surgically removing the thickened myocardium (ventricular septum) is performed, and it is effective. Further, in Europe, there is a therapeutic method for inducing myocardial cell death by occluding the coronary artery supplying blood to the myocardium for the purpose of removing the myocardium (ventricular septum) that causes the appearance of pressure gradient. Developed and effective.
 他方、非閉塞性肥大型心筋症の場合、閉塞性肥大型心筋症とは異なり、心室中隔の肥大が生じても、左室内の心筋が、血流に対する物理的な障壁にはならない。このため、非閉塞性肥大型心筋症では、閉塞性肥大型心筋症で観察される圧較差も生じない。したがって、他のメカニズムにより、非閉塞性肥大型心筋症の症状が生じていると考えられている。 On the other hand, in the case of non-obstructive hypertrophic cardiomyopathy, unlike the case of obstructive hypertrophic cardiomyopathy, the myocardium in the left ventricle does not serve as a physical barrier to blood flow even if ventricular septal hypertrophy occurs. Therefore, in non-obstructive hypertrophic cardiomyopathy, the pressure gradient observed in obstructive hypertrophic cardiomyopathy does not occur. Therefore, it is believed that other mechanisms cause the symptoms of non-obstructive hypertrophic cardiomyopathy.
 また、現状、非閉塞性肥大型心筋症に有効な治療薬は知られていない。そこで、本発明は、非閉塞性肥大型心筋症用医薬の提供を目的とする。 Also, at present, there is no known effective drug for non-obstructive hypertrophic cardiomyopathy. Then, this invention aims at provision of the pharmaceutical for non-obstructive hypertrophic cardiomyopathy.
 前記目的を達成するために、本発明の非閉塞性肥大型心筋症用医薬(以下、「医薬」ともいう)は、下記式(1)で表される化合物またはその塩を含む:
Figure JPOXMLDOC01-appb-C000005
前記式(1)において、
Rは、同じでも異なってもよく、それぞれ独立して、水素原子、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、または炭素数1~5のアルコキシ基であり、
は、水素原子、炭素数1~5のアルキル基、炭素数2~5のアルケニル基、炭素数2~5のアルキニル基、炭素数1~5のヒドロキシアルキル基、または、非置換もしくは置換アラルキル基であり、
前記置換アラルキル基は、その芳香環残基が、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、および炭素数1~5のアルコキシ基からなる群から選択された1種類の基により置換されたアラルキル基である。
In order to achieve the above-mentioned object, the pharmaceutical composition for non-obstructive hypertrophic cardiomyopathy (hereinafter, also referred to as “medicine”) of the present invention comprises a compound represented by the following formula (1) or a salt thereof:
Figure JPOXMLDOC01-appb-C000005
In the formula (1),
R may be the same or different, and each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms,
R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted Is an aralkyl group,
The substituted aralkyl group has one aromatic ring residue selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms. It is an aralkyl group substituted with a group.
 本発明によれば、前記式(1)で表される化合物またはその塩を含むことにより非閉塞性肥大型心筋症において生じる心筋の肥大を退縮させることができる。すなわち、本発明によれば、非閉塞性肥大型心筋症において生じている心筋肥大を退縮できることから、非閉塞性肥大型心筋症の治療に用いることができる。 According to the present invention, the myocardial hypertrophy that occurs in non-obstructive hypertrophic cardiomyopathy can be regressed by including the compound represented by the formula (1) or a salt thereof. That is, according to the present invention, since myocardial hypertrophy that occurs in non-obstructive hypertrophic cardiomyopathy can be regressed, it can be used for treatment of non-obstructive hypertrophic cardiomyopathy.
図1は、実施例1における健常者の心電図を示す図である。FIG. 1 is a diagram showing an electrocardiogram of a healthy person in Example 1. 図2は、実施例1における非閉塞性肥大型心筋症の患者のシベンゾリン投与前の心電図を示す図である。FIG. 2 is a diagram showing an electrocardiogram before administration of cibenzoline to a patient with non-obstructive hypertrophic cardiomyopathy in Example 1. 図3は、実施例1における非閉塞性肥大型心筋症の患者のシベンゾリン投与後の心電図を示す図である。FIG. 3 is a diagram showing an electrocardiogram of a patient with non-obstructive hypertrophic cardiomyopathy after administration of cibenzoline in Example 1. 図4は、実施例1における健常者の心エコー図を示す写真である。FIG. 4 is a photograph showing an echocardiogram of a healthy person in Example 1. 図5は、実施例1におけるシベンゾリン投与前の非閉塞性肥大型心筋症の患者の心エコー図を示す写真である。FIG. 5 is a photograph showing an echocardiogram of a patient with non-obstructive hypertrophic cardiomyopathy before administration of cibenzoline in Example 1. 図6は、実施例1におけるシベンゾリン投与後の非閉塞性肥大型心筋症の患者の心エコー図を示す写真である。FIG. 6 is a photograph showing an echocardiogram of a patient with non-obstructive hypertrophic cardiomyopathy after administration of cibenzoline in Example 1. 図7は、実施例1におけるシベンゾリンの投与前後のHNCMの患者の全例の結果を示すグラフである。FIG. 7 is a graph showing the results of all HNCM patients before and after administration of cibenzoline in Example 1. 図8は、実施例1におけるシベンゾリンの投与前後のHNCMの患者の全例の結果を示すグラフである。FIG. 8 is a graph showing the results of all HNCM patients before and after administration of cibenzoline in Example 1.
<非閉塞性肥大型心筋症用医薬>
 本発明の非閉塞性肥大型心筋症用医薬は、前述のように、下記式(1)で表される化合物またはその塩を含む:
Figure JPOXMLDOC01-appb-C000006
前記式(1)において、
Rは、同じでも異なってもよく、それぞれ独立して、水素原子、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、または炭素数1~5のアルコキシ基であり、
は、水素原子、炭素数1~5のアルキル基、炭素数2~5のアルケニル基、炭素数2~5のアルキニル基、炭素数1~5のヒドロキシアルキル基、または、非置換もしくは置換アラルキル基であり、
前記置換アラルキル基は、その芳香環残基が、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、および炭素数1~5のアルコキシ基からなる群から選択された1種類の基により置換されたアラルキル基である。
<Medication for non-obstructive hypertrophic cardiomyopathy>
The medicament for non-obstructive hypertrophic cardiomyopathy of the present invention contains the compound represented by the following formula (1) or a salt thereof, as described above:
Figure JPOXMLDOC01-appb-C000006
In the formula (1),
R may be the same or different, and each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms,
R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted Is an aralkyl group,
The substituted aralkyl group has one aromatic ring residue selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms. It is an aralkyl group substituted with a group.
 本発明の医薬は、前記式(1)で表される化合物またはその塩を含むことが特徴であって、その他の構成および条件は、特に制限されない。本発明の医薬は、下記メカニズムで、心筋肥大の退縮を誘導していると推定される。なお、本発明は、以下の推定に何ら制限されない。前記式(1)で表される化合物またはその塩は心筋細胞膜のNaチャネルを遮断することで、心筋細胞内へのNaイオンの流入を抑制する。この結果、前記心筋細胞内のNaイオンの低下が生じ、前記心筋細胞の脱分極ができなくなる。脱分極の障害は心筋細胞の損傷に直結するため、心筋細胞膜におけるNa-Ca2+交換系が活性化される。この交換系の活性化により、前記心筋細胞では、Naイオンの細胞内への流入、およびCa2+イオンの細胞外へのくみ出しが増加する。このため、心筋細胞内での脱分極が容易となり、心筋の収縮能が向上するため、心筋肥大が退縮すると推定される。したがって、前記式(1)で表される化合物により、心筋細胞膜においてNa-Ca2+交換系が活性化することで、細胞内のCa2+イオンの低下が生じ、非閉塞性肥大型心筋症の心肥大が退縮すると推定される。 The medicament of the present invention is characterized by containing the compound represented by the above formula (1) or a salt thereof, and other configurations and conditions are not particularly limited. It is presumed that the drug of the present invention induces the regression of myocardial hypertrophy by the following mechanism. The present invention is not limited to the following estimation. The compound represented by the formula (1) or a salt thereof blocks the Na + channel in the cardiomyocyte membrane, thereby suppressing the inflow of Na + ions into the cardiomyocyte. As a result, the decrease of Na + ions in the cardiomyocytes occurs and the cardiomyocytes cannot be depolarized. Since the depolarization disorder is directly linked to the damage of cardiomyocytes, the Na + -Ca 2+ exchange system in the cardiomyocyte membrane is activated. Activation of this exchange system increases the inflow of Na + ions into the cell and the extraction of Ca 2+ ions out of the cell in the cardiomyocytes. Therefore, depolarization within the cardiomyocytes is facilitated, and the myocardial contractility is improved, so it is presumed that myocardial hypertrophy regresses. Therefore, activation of the Na + -Ca 2+ exchange system in the cardiomyocyte membrane by the compound represented by the above formula (1) causes a decrease in intracellular Ca 2+ ions, which leads to non-occlusive hypertrophic cardiomyopathy. It is estimated that cardiac hypertrophy will regress.
 本発明において、「非閉塞性肥大型心筋症(hypertrophic non-obstructive cardiomyopathy:HNCM)」は、例えば、肥大型心筋症において、左室内圧較差を認めない疾患を意味する。前記非閉塞性肥大型心筋症は、例えば、心電図による心筋肥大の測定、心エコー図による心筋壁厚の測定および非閉塞性肥大型心筋症の診断基準に基づき、判定できる。以下に、判定方法の一例を示すが、HNCMの判定はこれに限定されない。具体的には、まず、対象者について、心電図を測定し、心肥大が生じているかを判定し、心肥大が生じている対象者を肥大型心筋症第1候補者として、抽出する。つぎに、心エコーにより、前記肥大型心筋症第1候補群における左室の厚みを測定する。なお、前記左室において、心室中隔厚と左室後壁厚は、一般的に心肥大の程度を反映することが知られている。つぎに、得られた心エコー図に基づき、肥大型心筋症第2候補者を抽出する。前記肥大型心筋症第1候補者が健常者または高血圧患者(代償性心肥大)の場合、心肥大は、左室のどの部位でもほぼ均一となる。他方、肥大型心筋症患者では、肥厚部位が一定ではない。そこで、前記肥大型心筋症第1候補者から、上記基準に基づき、前記肥大型心筋症第2候補者を抽出する。つぎに、前記肥大型心筋症第2候補者において、前記心エコー図に基づき、左室心筋の一部に15mm以上の心筋肥大がある場合、前記肥大型心筋症患者として抽出する。さらに、前記肥大型心筋症患者について、左室内圧較差が存在するかを測定する。そして、左室内圧較差が存在しない場合、前記肥大型心筋症患者をHNCM患者と判定できる。なお、前記心電図により、心肥大が生じていると判定されても、前記対象者が全身性系統疾患を罹患している場合、前記対象者は、肥大型心筋症ではなく、二次性心肥大と判定できる。 In the present invention, “hypertrophic non-obstructive cardiomyopathy (HNCM)” means, for example, hypertrophic cardiomyopathy without a left ventricular pressure difference. The non-occlusive hypertrophic cardiomyopathy can be determined based on, for example, measurement of myocardial hypertrophy by electrocardiography, measurement of myocardial wall thickness by echocardiography, and diagnostic criteria for non-occlusive hypertrophic cardiomyopathy. An example of the determination method is shown below, but the HNCM determination is not limited to this. Specifically, first, the electrocardiogram of the subject is measured to determine whether or not cardiac hypertrophy has occurred, and the subject with cardiac hypertrophy is extracted as the first candidate for hypertrophic cardiomyopathy. Next, the thickness of the left ventricle in the first candidate group for hypertrophic cardiomyopathy is measured by echocardiography. It is known that in the left ventricle, the septal thickness of the ventricle and the posterior wall of the left ventricle generally reflect the degree of cardiac hypertrophy. Next, the second candidate for hypertrophic cardiomyopathy is extracted based on the obtained echocardiogram. When the first candidate for hypertrophic cardiomyopathy is a healthy person or a hypertensive patient (compensatory cardiac hypertrophy), cardiac hypertrophy is almost uniform in any part of the left ventricle. On the other hand, in hypertrophic cardiomyopathy patients, the thickened area is not constant. Therefore, the second candidate for hypertrophic cardiomyopathy is extracted from the first candidate for hypertrophic cardiomyopathy based on the above criteria. Next, in the second candidate for hypertrophic cardiomyopathy, if a part of the left ventricular myocardium has a myocardial hypertrophy of 15 mm or more based on the echocardiogram, it is extracted as the hypertrophic cardiomyopathy patient. Furthermore, it is measured whether there is a pressure gradient in the left ventricle of the hypertrophic cardiomyopathy patient. When there is no left ventricular pressure difference, the hypertrophic cardiomyopathy patient can be determined to be an HNCM patient. Even if it is determined by the electrocardiogram that cardiac hypertrophy occurs, if the subject suffers from a systemic system disease, the subject is not hypertrophic cardiomyopathy, but secondary cardiac hypertrophy. Can be determined.
 本発明の医薬において、「治療」は、心肥大の治療、改善、症状の進展の抑制、および/または症状の進展の停止のいずれの意味で用いてもよい。このため、本発明の医薬は、例えば、HNCMの治療薬、改善薬、進展抑制薬および/または進展停止薬ということもできる。 In the medicine of the present invention, “treatment” may mean any of the treatment of cardiac hypertrophy, improvement, suppression of symptom progression, and/or cessation of symptom progression. Therefore, the pharmaceutical agent of the present invention can be referred to as, for example, a therapeutic agent for HNCM, an improving agent, a progress inhibitor, and/or a progress stopping agent.
 本発明の医薬は、前述のように、HNCMの患者における心筋肥大を退縮できる。本発明において、「心筋肥大の退縮」は、前記本発明の医薬の非存在下(非投与条件)と比較して、心筋肥大が生じている部位の心筋の厚みが(有意に)低下していることを意味する。前記心筋の厚みは、例えば、心室中隔の厚みである。 As described above, the drug of the present invention can relieve myocardial hypertrophy in patients with HNCM. In the present invention, "regression of myocardial hypertrophy" means that the myocardial thickness at the site of myocardial hypertrophy is (significantly) reduced as compared with the absence of the above-mentioned pharmaceutical agent of the present invention (non-administration condition). Means that The thickness of the myocardium is, for example, the thickness of the interventricular septum.
 本発明の医薬は、HNCMの患者における心筋肥大を退縮できるため、これにより、例えば、HNCMの患者における心不全死を抑制できる。このため、本発明の医薬において、「治療」は、心肥大に伴う、心不全死の抑制、予防、および/または改善のいずれの意味で用いてもよい。したがって、本発明の医薬は、例えば、HNCMによる(起因する)心不全死の抑制薬、予防薬、および/または改善薬ということもできる。 Since the pharmaceutical composition of the present invention can reduce myocardial hypertrophy in patients with HNCM, it can suppress, for example, death from heart failure in patients with HNCM. Therefore, in the medicine of the present invention, “treatment” may be used to mean any of the suppression, prevention, and/or improvement of heart failure death associated with cardiac hypertrophy. Therefore, the medicament of the present invention can be referred to as, for example, a suppressive agent, preventive agent, and/or ameliorating agent for (failure) death of heart failure due to HNCM.
 本発明において、「心不全死の抑制」は、前記本発明の医薬の非存在下(非投与条件)と比較して、心不全死の確率が(有意に)低下していることを意味する。 In the present invention, “suppression of death from heart failure” means that the probability of death from heart failure is (significantly) lower than that in the absence of the drug of the present invention (non-administration condition).
 以下、前記式(1)で表される化合物における各置換基について、例を挙げて説明する。各置換基の説明において、特に言及がない場合、他の置換基の説明における具体例を援用できる。また、以下の説明で特に言及がない場合、前記式(1)で表される化合物の説明は、例えば、前記式(1)で表される化合物の塩の説明に援用できる。 Hereinafter, each substituent in the compound represented by the formula (1) will be described with examples. In the description of each substituent, unless otherwise specified, specific examples in the description of other substituents can be used. Unless otherwise specified in the following description, the description of the compound represented by the formula (1) can be incorporated into the description of the salt of the compound represented by the formula (1).
 前記式(1)で表される化合物は、不斉炭素原子を有する。このため、前記式(1)で表される化合物は、例えば、ラセミ体、そのRおよびSのエナンチオマー、またはRおよびSの任意の割合の混合物として存在してもよい。前記式(1)で表される化合物は、2以上の不斉中心を有してもよい。この場合、前記式(1)で表される化合物は、ジアステレオマーおよびその混合物を含んでもよい。前記式(1)で表される化合物が分子中に2重結合を有する場合、本発明の化合物は、例えば、シスおよびトランス異性体の幾何異性体の形態を含んでもよい。 The compound represented by the above formula (1) has an asymmetric carbon atom. Therefore, the compound represented by the above formula (1) may exist as a racemate, an enantiomer of R and S thereof, or a mixture of R and S at any ratio. The compound represented by the formula (1) may have two or more asymmetric centers. In this case, the compound represented by the formula (1) may include a diastereomer and a mixture thereof. When the compound represented by the formula (1) has a double bond in the molecule, the compound of the present invention may include geometrical isomers such as cis and trans isomers.
 前記式(1)において、Rは、水素原子、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、または炭素数1~5のアルコキシ基であり、好ましくは、水素原子である。2つのRは、同じでもよいし、異なってもよいが、同じであることが好ましい。 In the above formula (1), R is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms, and preferably a hydrogen atom. .. The two Rs may be the same or different, but are preferably the same.
 前記炭素数1~5のアルキル基は、例えば、炭素数1~5の直鎖、分岐状、もしくは環状の飽和または不飽和アルキル基である。具体例として、前記炭素数1~5のアルキル基は、例えば、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基、n-ペンチル基、イソペンチル基、sec-ペンチル基、tert-ペンチル基、ネオペンチル基等があげられる。 The alkyl group having 1 to 5 carbon atoms is, for example, a linear, branched or cyclic saturated or unsaturated alkyl group having 1 to 5 carbon atoms. Specific examples of the alkyl group having 1 to 5 carbon atoms include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n -Pentyl group, isopentyl group, sec-pentyl group, tert-pentyl group, neopentyl group and the like.
 前記炭素数1~5のアルコキシ基におけるアルキル基は、例えば、炭素数1~5の直鎖、分岐状、もしくは環状の飽和または不飽和アルキル基である。具体例として、前記炭素数1~5のアルコキシ基は、例えば、メトキシ基、エトキシ基、プロピルオキシ基、ブチルオキシ基、ペンチルオキシ基等があげられる。 The alkyl group in the alkoxy group having 1 to 5 carbon atoms is, for example, a linear, branched, or cyclic saturated or unsaturated alkyl group having 1 to 5 carbon atoms. Specific examples of the alkoxy group having 1 to 5 carbon atoms include methoxy group, ethoxy group, propyloxy group, butyloxy group, pentyloxy group and the like.
 Rは、水素原子、炭素数1~5のアルキル基、炭素数2~5のアルケニル基、炭素数2~5のアルキニル基、炭素数1~5のヒドロキシアルキル基、または、非置換もしくは置換アラルキル基であり、好ましくは、水素原子である。 R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted It is an aralkyl group, and preferably a hydrogen atom.
 前記炭素数2~5のアルケニル基は、例えば、炭素数の2~5の直鎖、分岐状、もしくは環状のアルケニル基である。具体例として、前記炭素数2~5のアルケニル基は、例えば、ビニル基、アリル基、1-プロペニル基、イソプロペニル基、1-ブテニル基、2-ブテニル基、3-ブテニル基、2-メチルアリル基、1-ペンテニル基、2-ペンテニル基、3-ペンテニル基、4-ペンテニル基、2-メチル-2-ブテニル基等があげられる。 The alkenyl group having 2 to 5 carbon atoms is, for example, a linear, branched or cyclic alkenyl group having 2 to 5 carbon atoms. Specific examples of the alkenyl group having 2 to 5 carbon atoms include, for example, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group and 2-methylallyl group. Group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-methyl-2-butenyl group and the like.
 前記炭素数2~5のアルキニル基は、例えば、炭素数2~5の直鎖、分岐状、もしくは環状のアルキニル基である。具体例として、前記炭素数2~5のアルキニル基は、例えば、エチニル基、1-プロピニル基、2-プロピニル基、1-ブチニル基、2-ブチニル基、3-ブチニル基、1-メチル-2-プロピニル基、1-ペンチニル基、2-ペンチニル基、3-ペンチニル基、4-ペンチニル基、1-メチル-3-ブチニル基等があげられる。 The alkynyl group having 2 to 5 carbon atoms is, for example, a linear, branched or cyclic alkynyl group having 2 to 5 carbon atoms. Specific examples of the alkynyl group having 2 to 5 carbon atoms include, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group and 1-methyl-2. Examples thereof include a propynyl group, a 1-pentynyl group, a 2-pentynyl group, a 3-pentynyl group, a 4-pentynyl group and a 1-methyl-3-butynyl group.
 前記炭素数1~5のヒドロキシアルキル基におけるアルキル基は、例えば、前述の炭素数1~5のアルキル基の説明を援用できる。 For the alkyl group in the hydroxyalkyl group having 1 to 5 carbon atoms, for example, the above description of the alkyl group having 1 to 5 carbon atoms can be applied.
 前記非置換もしくは置換アラルキル基におけるアルキル基は、例えば、炭素数1~5のアルキル基である。前記非置換もしくは置換アラルキル基におけるアルキル基は、例えば、前述の炭素数1~5のアルキル基の説明を援用できる。前記非置換アラルキル基は、例えば、ベンジル基(フェニルメチル基)、フェネチル基(フェニルエチル基)、フェニルプロピル基、フェニルブチル基、フェニルペンチル基等があげられる。前記置換アラルキル基は、その芳香環残基が、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、および炭素数1~5のアルコキシ基からなる群から選択された1種類の基により置換されたアラルキル基である。前記芳香環残基(フェニル基)における置換数は、例えば、1~5である。また、前記芳香環残基における置換位置は、例えば、2位、3位、4位、5位、および6位におけるいずれか1つ以上である。 The alkyl group in the unsubstituted or substituted aralkyl group is, for example, an alkyl group having 1 to 5 carbon atoms. For the alkyl group in the unsubstituted or substituted aralkyl group, for example, the above description of the alkyl group having 1 to 5 carbon atoms can be referred to. Examples of the unsubstituted aralkyl group include benzyl group (phenylmethyl group), phenethyl group (phenylethyl group), phenylpropyl group, phenylbutyl group, phenylpentyl group, and the like. The substituted aralkyl group has one aromatic ring residue selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms. It is an aralkyl group substituted with a group. The number of substitutions in the aromatic ring residue (phenyl group) is, for example, 1 to 5. Further, the substitution position in the aromatic ring residue is, for example, any one or more in the 2-position, 3-position, 4-position, 5-position, and 6-position.
 前記式(1)で表される化合物において、Rは、同じでも異なってもよく、それぞれ独立して、水素原子、フッ素原子、またはメチル基であり、Rは、水素原子、メチル基、イソプロピル基、プロピレン基、n-ブチル基、ヒドロキシエチル基、ベンジル基、p-メチルベンジル基、フェネチル基、または3,4,5-トリメチルオキシベンジル基であることが好ましい。 In the compound represented by the formula (1), R may be the same or different and each independently represents a hydrogen atom, a fluorine atom or a methyl group, and R 1 represents a hydrogen atom, a methyl group or isopropyl. It is preferably a group, a propylene group, an n-butyl group, a hydroxyethyl group, a benzyl group, a p-methylbenzyl group, a phenethyl group, or a 3,4,5-trimethyloxybenzyl group.
 前記式(1)で表される化合物は、例えば、心筋肥大の退縮をより効果的に誘導でき、かつ左室拡張期の心機能を改善できることから、下記式(2)で表される化合物を含むことが好ましい。下記式(2)の化合物は、例えば、シベンゾリン、シフェンリン、または2-(2,2-diphenylcyclopropyl)-4,5-dihydro-1H-imidazoleということもできる。下記式(2)の化合物は、例えば、PubChem CID:2747、Cas登録番号:53267-01-9で登録されている化合物である。
Figure JPOXMLDOC01-appb-C000007
Since the compound represented by the formula (1) can more effectively induce the regression of myocardial hypertrophy and can improve the cardiac function during left ventricular diastole, the compound represented by the following formula (2) is It is preferable to include. The compound of the following formula (2) can also be referred to as, for example, cibenzoline, ciphenline, or 2-(2,2-diphenylcyclopropyl)-4,5-dihydro-1H-imidazole. The compound of the following formula (2) is, for example, a compound registered under PubChem CID:2747, Cas registration number: 53267-01-9.
Figure JPOXMLDOC01-appb-C000007
 前記式(1)で表される化合物は、例えば、異性体でもよい。前記異性体は、例えば、互変異性体または立体異性体があげられる。前記互変異性体または立体異性体は、例えば、理論上可能なすべての互変異性体もしくは立体異性体があげられる。また、本発明において、各置換基の立体配置は、特に制限されない。本発明の医薬において、前記式(1)で表される化合物は、例えば、前記式(1)で表される化合物またはその塩の水和物でもよいし、溶媒和物でもよい。 The compound represented by the above formula (1) may be, for example, an isomer. Examples of the isomers include tautomers and stereoisomers. Examples of the tautomers or stereoisomers include all theoretically possible tautomers or stereoisomers. Further, in the present invention, the configuration of each substituent is not particularly limited. In the medicine of the present invention, the compound represented by the formula (1) may be, for example, a hydrate or a solvate of the compound represented by the formula (1) or a salt thereof.
 本発明において、前記式(1)で表される化合物の塩は、特に制限されず、例えば、薬学的に許容される塩である。前記薬学的に許容される塩は、特に制限されず、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩;カルシウム塩、マグネシウム塩等のアルカリ土類金属塩;アンモニウム塩;トリメチルアミン塩、トリエチルアミン塩、ジクロヘキシルアミン塩、エタノールアミン塩、ジエタノールアミン塩、トリエタノールアミン塩、ブロカイン塩等の脂肪族アミン塩、N,N-ジベンジルエチレンジアミン等のアラルキルアミン塩;ピリジン塩、ピコリン塩、キノリン塩、イソキノリン塩等の複素環芳香族アミン塩;テトラメチルアンモニウム塩、テトラエチルアンモニウム塩、ベンジルトリメチルアンモニウム塩、ベンジルトリブチルアンモニウム塩、メチルトリオクチルアンモニウム塩、テトラブチルアンモニウム塩等の第4級アンモニウム塩;アルギニン塩、リジン塩、アスパラギン酸塩、グルタミン酸塩等のアミノ酸塩;塩酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩、炭酸水素塩、過塩素酸塩等の無機酸塩;酢酸塩、プロピオン酸塩、コハク酸塩、グリコール酸塩、乳酸塩、マレイン酸塩、フマール酸塩、酒石酸塩、リンゴ酸塩、クエン酸塩、アスコルビン酸塩、ヒドロキシマレイン酸塩、ピルビン酸塩、フェニル酢酸塩、安息香酸塩、4-アミノ安息香酸塩、アントラニル酸塩、4-ヒドロキシ安息香酸塩、サリチル酸塩、4-アミノサリチル酸塩、パモ酸塩、グルコン酸塩、ニコチン酸塩、等の脂肪族有機酸または芳香族有機酸塩、メタンスルホン酸塩、イセチオン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ハロベンゼンスルホン酸塩、p-トルエンスルホン酸塩、トルエンスルホン酸塩、ナフタレンスルホン酸塩、スルファニル酸塩、シクロヘキシルスルファミン酸塩等のスルホン酸塩等があげられる。本発明において、前記式(1)で表される化合物の塩は、コハク酸塩が好ましい。前記式(2)の化合物のコハク酸塩は、例えば、Cas登録番号:100678-32-8で登録されている化合物である。 In the present invention, the salt of the compound represented by the formula (1) is not particularly limited and is, for example, a pharmaceutically acceptable salt. The pharmaceutically acceptable salt is not particularly limited, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, Aliphatic amine salts such as dichlorohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, etc., aralkylamine salts such as N,N-dibenzylethylenediamine; pyridine salt, picoline salt, quinoline salt, isoquinoline salt. Heterocyclic aromatic amine salts such as; quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, tetrabutylammonium salt; arginine salt, lysine Amino acid salts such as salts, aspartates and glutamate; inorganic salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates, hydrogencarbonates and perchlorates; acetates, propionates, succinates Acid salt, glycolate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate, hydroxymaleate, pyruvate, phenylacetate, benzoate, Aliphatic or aromatic organic acids such as 4-aminobenzoate, anthranilate, 4-hydroxybenzoate, salicylate, 4-aminosalicylate, pamoate, gluconate, nicotinate, etc. Salt, methanesulfonate, isethionate, ethanesulfonate, benzenesulfonate, halobenzenesulfonate, p-toluenesulfonate, toluenesulfonate, naphthalenesulfonate, sulfanilate, cyclohexylsulfamine Examples thereof include sulfonates such as acid salts. In the present invention, the salt of the compound represented by the formula (1) is preferably succinate. The succinate salt of the compound of formula (2) is, for example, a compound registered under Cas registration number: 100678-32-8.
 本発明の医薬は、例えば、in vivoで使用してもよいし、in vitroで使用してもよい。本発明の医薬は、例えば、複数の成分から構成されてもよい。この場合、本発明の医薬は、例えば、医薬組成物ということもできる。 The medicament of the present invention may be used, for example, in vivo or in vitro . The medicine of the present invention may be composed of, for example, a plurality of components. In this case, the medicament of the present invention can be referred to as a pharmaceutical composition, for example.
 本発明の医薬の投与対象は、特に制限されない。本発明の医薬をin vivoで使用する場合、前記投与対象は、例えば、ヒト、またはヒトを除く非ヒト動物があげられる。前記非ヒト動物としては、例えば、マウス、ラット、ウサギ、イヌ、ヒツジ、ウマ、ネコ、ヤギ、サル、モルモット等があげられる。前記本発明の医薬をin vitroで使用する場合、前記投与対象は、例えば、細胞、組織、器官等があげられ、前記細胞は、例えば、生体から採取した細胞、培養細胞等があげられる。前記細胞は、例えば心筋細胞等があげられる。 The subject of administration of the medicament of the present invention is not particularly limited. When the pharmaceutical agent of the present invention is used in vivo , the subject to be administered includes, for example, humans or non-human animals other than humans. Examples of the non-human animals include mice, rats, rabbits, dogs, sheep, horses, cats, goats, monkeys, and guinea pigs. When the pharmaceutical agent of the present invention is used in vitro , the administration target includes, for example, cells, tissues, organs and the like, and the cells include, for example, cells collected from a living body, cultured cells and the like. Examples of the cells include cardiomyocytes.
 本発明の医薬の使用条件(投与条件)は、特に制限されず、例えば、投与対象の種類等に応じて、投与形態、投与時期、投与量等を適宜設定できる。 The use conditions (administration conditions) of the pharmaceutical agent of the present invention are not particularly limited, and, for example, the administration form, administration time, dose, etc. can be appropriately set according to the type of administration subject.
 本発明の医薬の投与量は、特に制限されない。本発明の医薬をin vivoで使用する場合、例えば、投与対象の種類、症状、年齢、投与方法等により適宜決定できる。具体例として、ヒトに投与する場合、1日あたりの前記式(1)で表される化合物の投与量は、特に制限されず、例えば、投与対象における血中濃度が、100~2000ng/mL、好ましくは、300~1500ng/mLとなる投与量に設定できる。このような投与量とすることにより、本発明の医薬は、例えば、HNCMにおける心不全死を効果的に抑制できる。ヒトに投与する場合、1日あたりの前記式(1)で表される化合物の投与量は、例えば、その合計量が、50~500mg、100~400mgであり、好ましくは、250mg以上、約300mg(例えば、200~400mg、250~400mg等)である。1日あたりの前記式(1)で表される化合物の投与量を250mg以上とすることにより、本発明の医薬は、例えば、心筋肥大の退縮、心不全死の予防または抑制を効果的に実施できる。1日あたりの投与回数は、例えば、1~5回、1~3回であり、好ましくは、約3回(例えば、2~4回)である。1日あたりの前記式(1)で表される化合物の投与量を約300mgとすることにより、前記投与対象における血中濃度は、例えば、300~1500ng/mLとなる。本発明の医薬は、継続的に投与してもよいし、非継続的に投与してもよい。前記非継続的投与は、例えば、間歇的投与ということもできる。前記継続的投与は、例えば、1、2、3、もしくは4週間以上、1、2、3、4、5、6、7、8、9、10、11、もしくは12ヶ月以上、または1、2、3、4、5、6、7、8、9、10、11、もしくは12年以上の投与であり、好ましくは、3ヶ月以上の投与である。前記継続的投与は、例えば、本発明の医薬を投与しない期間、いわゆる、休薬期間を含まない投与を意味する。前記非継続的投与は、例えば、本発明の医薬を投与しない期間、いわゆる、休薬期間を含む投与を意味する。本発明の医薬の投与間隔は、略等間隔であることが好ましい。このため、本発明の医薬の投与回数が3回の場合、約8時間(例えば、6~10時間)毎に投与されることが好ましい。成人に経口投与する場合、1日あたりの前記式(1)で表される化合物の量は、例えば、50、100、150、200、250、300、350、400、または450mgであり、1日あたりの投与回数は、1~5回である。前記医薬における、前記式(1)で表される化合物の含有量は、特に制限されず、例えば、前述の一日当たりの投与量に応じて適宜設定できる。 The dose of the medicament of the present invention is not particularly limited. When the medicament of the present invention is used in vivo, it can be appropriately determined depending on, for example, the type of subject to be administered, symptoms, age, administration method and the like. As a specific example, when administered to humans, the dose of the compound represented by the formula (1) per day is not particularly limited, and, for example, the blood concentration in the administration subject is 100 to 2000 ng/mL, Preferably, the dose can be set to 300 to 1500 ng/mL. With such a dose, the drug of the present invention can effectively suppress heart failure death in HNCM, for example. When administered to humans, the total dose of the compound represented by the above formula (1) is, for example, 50 to 500 mg, 100 to 400 mg, preferably 250 mg or more, about 300 mg. (Eg, 200 to 400 mg, 250 to 400 mg, etc.). By setting the dose of the compound represented by the above formula (1) to 250 mg or more per day, the pharmaceutical composition of the present invention can effectively prevent regression of myocardial hypertrophy and prevention or suppression of death from heart failure. .. The number of administrations per day is, for example, 1 to 5 times, 1 to 3 times, preferably about 3 times (eg, 2 to 4 times). By setting the dose of the compound represented by the formula (1) per day to about 300 mg, the blood concentration in the administration subject becomes, for example, 300 to 1500 ng/mL. The medicament of the present invention may be administered continuously or non-continuously. The non-continuous administration can also be referred to as intermittent administration, for example. The continuous administration is, for example, 1, 2, 3, or 4 weeks or more, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or 1, 2 or more. Administration for 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years or more, preferably 3 months or more. The continuous administration means, for example, administration without administration of the drug of the present invention, that is, so-called withdrawal period. The non-continuous administration means, for example, administration including a so-called drug holiday, in which the medicament of the present invention is not administered. The administration intervals of the pharmaceutical agent of the present invention are preferably approximately equal intervals. Therefore, when the drug of the present invention is administered three times, it is preferable that the drug is administered about every 8 hours (eg, 6 to 10 hours). When orally administered to an adult, the amount of the compound represented by the formula (1) per day is, for example, 50, 100, 150, 200, 250, 300, 350, 400, or 450 mg, and is 1 day. The number of times of administration is 1 to 5 times. The content of the compound represented by the formula (1) in the medicine is not particularly limited and can be appropriately set, for example, according to the above-mentioned daily dose.
 本発明の医薬の投与形態は、特に制限されない。本発明の医薬をin vivoで投与する場合、経口投与でもよいし、非経口投与でもよい。前記非経口投与は、例えば、静脈注射(静脈内投与)、筋肉注射(筋肉内投与)、経皮投与、皮下投与、皮内投与、経腸投与、直腸投与、経膣投与、経鼻投与、経肺投与、腹腔内投与、局所投与等があげられる。 The administration form of the medicament of the present invention is not particularly limited. When the pharmaceutical agent of the present invention is administered in vivo , it may be administered orally or parenterally. The parenteral administration includes, for example, intravenous injection (intravenous administration), intramuscular injection (intramuscular administration), transdermal administration, subcutaneous administration, intradermal administration, enteral administration, rectal administration, vaginal administration, nasal administration, Examples include pulmonary administration, intraperitoneal administration, and local administration.
 本発明の医薬の剤型は、特に制限されず、例えば、前記投与形態に応じて適宜決定できる。前記剤型は、例えば、液体状、固体状があげられる。具体例として、前記剤型は、放出調節製剤(腸溶性製剤、徐放性製剤等)、カプセル剤、経口液剤(エリキシル剤、懸濁剤、乳剤、芳香水剤、リモナーデ剤等)、シロップ剤(シロップ用剤等)、顆粒剤(発泡顆粒剤、細粒等)、散剤、錠剤(口腔内崩壊錠、チュアブル錠、発泡錠、分散錠、溶解剤、被覆錠剤等)、丸剤、経口ゼリー剤等の経口投与用製剤;口腔用錠剤(ガム剤、舌下剤、トローチ剤、ドロップ剤、バッカル錠、付着錠等)、口腔用スプレー剤、口腔用半固形剤、含嗽剤等の口腔内適用製剤;注射剤(埋め込み注射、持続性注射剤、輸液剤(点滴用製剤等)、凍結乾燥注射剤、粉末注射剤、充填済シリンジ剤、カートリッジ剤等)等の注射投与用製剤;透析用剤(腹膜透析用剤、血液透析用剤)等の透析用製剤;吸入剤(吸入エアゾール剤、吸入液剤、吸入粉末剤等)等の気管支・肺適用製剤;眼軟膏剤、点眼剤等の目投与用製剤;点耳剤等の耳投与製剤;点鼻剤(点鼻液剤、点鼻粉末剤等)等の鼻適用製剤;坐剤、直腸用半固形剤、注腸剤等の直腸適用製剤;膣用坐剤、膣錠等の膣適用製剤;外用液剤(酒精剤、リニメント剤、ローション剤等)、クリーム剤、ゲル剤、外用固形剤(外用散剤等)、スプレー剤(外用エアゾール剤、ポンプスプレー剤等)、貼付剤(テープ剤、パップ剤等)、軟膏剤等の皮膚適用剤;等があげられる。本発明の医薬を経口投与する場合、前記剤型は、例えば、錠剤、被覆錠剤、丸剤、細粒剤、顆粒剤、散剤、カプセル剤、液剤、シロップ剤、乳剤、懸濁剤等があげられる。本発明の医薬を非経口投与する場合、前記剤型は、例えば、注射投与用製剤、点滴用製剤等があげられる。本発明の医薬を経皮投与する場合、前記剤型は、例えば、貼付剤、塗布剤、軟膏、クリーム、ローション等の外用薬があげられる。 The dosage form of the medicament of the present invention is not particularly limited and can be appropriately determined depending on, for example, the above administration form. Examples of the dosage form include liquid form and solid form. Specific examples of the dosage form include modified release preparations (enteric-coated preparations, sustained-release preparations, etc.), capsules, oral liquid preparations (elixir preparations, suspensions, emulsions, aromatic water preparations, limonade preparations, etc.), syrup preparations. (Syrup preparations, etc.), granules (effervescent granules, fine granules, etc.), powders, tablets (orally disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, dissolving agents, coated tablets, etc.), pills, oral jelly Preparations for oral administration such as drugs; oral tablets (gums, sublingual tablets, troches, drops, buccal tablets, adhesive tablets, etc.), oral sprays, oral semisolids, gargles, etc. Preparations; injection preparations such as injections (implanted injections, continuous injections, infusions (drip preparations), freeze-dried injections, powder injections, filled syringes, cartridges, etc.); dialysis agents (Peritoneal dialysis agents, hemodialysis agents) and other dialysis preparations; Inhalants (inhalation aerosols, inhalation solutions, inhalation powders, etc.) and other bronchial and pulmonary preparations; Eye ointments, eye drops, etc. Preparations; ear preparations such as ear drops; nasal preparations such as nasal drops (nasal drops, nasal powders etc.); rectal preparations such as suppositories, semi-solids for rectal and enema preparations; Vaginal suppositories, vaginal preparations such as vaginal tablets; external liquids (sake, liniments, lotions, etc.), creams, gels, external solids (external powders, etc.), sprays (external aerosols, pumps) Spray agents, etc., patches (tapes, poultices, etc.), ointments and other skin application agents; and the like. When the medicament of the present invention is orally administered, examples of the dosage form include tablets, coated tablets, pills, fine granules, granules, powders, capsules, solutions, syrups, emulsions, suspensions and the like. Be done. When the pharmaceutical agent of the present invention is parenterally administered, examples of the dosage form include injection preparations and infusion preparations. When the medicament of the present invention is transdermally administered, examples of the dosage form include external preparations such as patches, coatings, ointments, creams and lotions.
 本発明の医薬は、例えば、必要に応じて、添加剤を含んでもよく、この場合、医薬組成物ということも出来る。前記添加剤は、薬学的に許容可能な添加剤または薬学的に許容可能な担体を含むことが好ましい。前記添加剤は、特に制限されず、例えば、基剤原料、賦形剤、着色剤、滑沢剤、結合剤、崩壊剤、安定化剤、保存剤、香料等の矯味矯臭剤等があげられる。本発明において、前記添加剤の配合量は、前記化合物の機能を妨げるものでなければ、特に制限されない。 The drug of the present invention may contain additives, for example, if necessary, and in this case, it can be referred to as a pharmaceutical composition. The additive preferably comprises a pharmaceutically acceptable additive or a pharmaceutically acceptable carrier. The additive is not particularly limited, and examples thereof include base materials, excipients, colorants, lubricants, binders, disintegrants, stabilizers, preservatives, and flavoring agents such as fragrances. .. In the present invention, the compounding amount of the additive is not particularly limited as long as it does not hinder the function of the compound.
 前記賦形剤は、例えば、乳糖、白糖、ブドウ糖、マンニトール、ソルビトール等の糖誘導体;トウモロコシデンプン、バレイショデンプン、αデンプン、デキストリン等のデンプン誘導体;結晶セルロース等のセルロース誘導体;アラビアゴム;デキストラン;プルラン等の有機系賦形剤;軽質無水珪酸、合成珪酸アルミニウム、珪酸カルシウム、メタ珪酸アルミン酸マグネシウム等のケイ酸塩誘導体;リン酸水素カルシウム等のリン酸塩;炭酸カルシウム等の炭酸塩;硫酸カルシウム等の硫酸塩等の無機系賦形剤があげられる。前記滑沢剤は、例えば、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウム等のステアリン酸金属塩;タルク;ポリエチレングリコール;シリカ;硬化植物油等があげられる。前記矯味矯臭剤は、例えば、ココア末、ハッカ脳、芳香散、ハッカ油、竜脳、桂皮末等の香料、甘味料、酸味料等があげられる。前記結合剤は、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、マクロゴール等があげられる。前記崩壊剤は、例えば、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム等のセルロース誘導体;カルボキシメチルスターチ、カルボキシメチルスターチナトリウム、架橋ポリビニルピロリドン等の化学修飾デンプンおよび化学修飾セルロース類等があげられる。前記安定剤は、例えば、メチルパラベン、プロピルパラベン等のパラオキシ安息香酸エステル類;クロロブタノール、ベンジルアルコール、フェニルエチルアルコール等のアルコール類;塩化ベンザルコニウム;フェノール、クレゾール等のフェノール類;チメロサール;デヒドロ酢酸;ソルビン酸等があげられる。 Examples of the excipient include sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; corn starch, potato starch, α-starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; pullulan. Organic excipients such as; light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, silicate derivatives such as magnesium aluminometasilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; calcium sulfate Inorganic excipients such as sulfates. Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, and other stearic acid metal salts; talc; polyethylene glycol; silica; hydrogenated vegetable oil and the like. Examples of the flavoring agents include cocoa powder, peppermint, aroma powder, peppermint oil, borneol, cinnamon powder and the like, sweeteners, acidulants and the like. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol and the like. Examples of the disintegrant include cellulose derivatives such as carboxymethyl cellulose and carboxymethyl cellulose calcium; chemically modified starch such as carboxymethyl starch, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone, and chemically modified celluloses. Examples of the stabilizer include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid. Sorbic acid and the like can be mentioned.
 前記式(1)または(2)で表される化合物(例えば、シベンゾリン)は、市販品を購入してもよいし、自家調製してもよい。後者の場合、前記式(1)または(2)で表される化合物は、公知の方法で製造でき、例えば、特開昭49-93363号公報(米国特許第3,903,104号明細書)の説明を参照でき、本明細書の一部として援用できる。 The compound represented by the above formula (1) or (2) (for example, cibenzoline) may be a commercially available product or may be prepared in-house. In the latter case, the compound represented by the above formula (1) or (2) can be produced by a known method, for example, JP-A-49-93363 (US Pat. No. 3,903,104). Can be referred to and is incorporated as part of this specification.
 本発明の医薬によれば、前述のように、HNCMにおいて生じる心筋の肥大を退縮させることができる。すなわち、本発明によれば、HNCMにおいて生じている心筋肥大を退縮できることから、HNCMの治療に用いることができる。 According to the medicine of the present invention, as described above, myocardial hypertrophy that occurs in HNCM can be regressed. That is, according to the present invention, myocardial hypertrophy that occurs in HNCM can be regressed, and thus can be used for treatment of HNCM.
 本発明の医薬は、前述のように、Naチャネルを遮断することにより、HNCMにおいて生じている心筋肥大を退縮できると推定される。このため、本発明の医薬は、例えば、前記式(1)で表される化合物またはその塩に代えて、または加えて、Naチャネル遮断薬、すなわち、Naチャネルを阻害する化合物を含んでもよい。前記Naチャネル遮断薬は、例えば、I群抗不整脈薬があげられる。前記I群抗不整脈薬は、例えば、キニジン(例えば、PubChem CID:5953)、プロカインアミド(例えば、PubChem CID:4913)、ジソピラミド(ジソピラマイド、例えば、Pub Chem CID:3114)、ピルメノール(例えば、Pub Chem CID: 65502)、アプリンジン(例えば、Pub Chem CID:2118)、メキシレチン(例えば、Pub Chem CID:4178)、ピルジカイニド(例えば、Pub Chem CID:4820)等があげられる。 As described above, it is presumed that the drug of the present invention can relieve myocardial hypertrophy occurring in HNCM by blocking Na channel. Therefore, the medicament of the present invention may include, for example, a Na channel blocker, that is, a compound that inhibits Na channel, instead of or in addition to the compound represented by the formula (1) or a salt thereof. Examples of the Na channel blocker include Group I antiarrhythmic drugs. Examples of the group I antiarrhythmic drug include quinidine (for example, PubChemCID:5953), procainamide (for example, PubChemCID:4913), disopyramide (disopyramide, for example, PubChemCID:3114), and pyrmenol (for example, PubChem). CID:65502), aplidine (for example, PubChemCID:2118), mexiletine (for example, PubChemCID:4178), pilsicainide (for example, PubChemCID:4820), and the like.
<非閉塞性肥大型心筋症の治療方法>
 本発明の非閉塞性肥大型心筋症の治療方法(以下、「治療方法」ともいう)は、患者に、前記本発明の非閉塞性肥大型心筋症用医薬を投与する投与工程を含む。本発明の治療方法は、前記本発明の医薬、すなわち、前記式(1)で表される化合物またはその塩を投与することが特徴であり、その他の工程および条件は、特に制限されない。本発明の治療方法は、前記本発明の医薬の説明を援用できる。本発明の治療方法によれば、非閉塞性肥大型心筋症において生じている心筋肥大を退縮できる。このため、本発明の治療方法によれば、非閉塞性肥大型心筋症を治療できる。本発明の治療方法によれば、非閉塞性肥大型心筋症の患者に対する処置を実施できる。このため、本発明の治療方法は、例えば、非閉塞性肥大型心筋症の処置方法ということもできる。
<Treatment method for non-obstructive hypertrophic cardiomyopathy>
The method for treating non-obstructive hypertrophic cardiomyopathy of the present invention (hereinafter, also referred to as “treatment method”) includes an administration step of administering the above-mentioned pharmaceutical for non-occlusive hypertrophic cardiomyopathy of the present invention to a patient. The therapeutic method of the present invention is characterized by administering the pharmaceutical agent of the present invention, that is, the compound represented by the formula (1) or a salt thereof, and other steps and conditions are not particularly limited. For the treatment method of the present invention, the description of the pharmaceutical agent of the present invention can be applied. According to the treatment method of the present invention, myocardial hypertrophy that occurs in non-obstructive hypertrophic cardiomyopathy can be regressed. Therefore, according to the treatment method of the present invention, non-obstructive hypertrophic cardiomyopathy can be treated. According to the therapeutic method of the present invention, it is possible to treat a patient with non-obstructive hypertrophic cardiomyopathy. Therefore, the therapeutic method of the present invention can be referred to as, for example, a method for treating non-obstructive hypertrophic cardiomyopathy.
 本発明の治療方法は、例えば、前記医薬を投与する投与工程を含み、具体的には、患者(投与対象)に、前記医薬を投与する投与工程を含む。前記医薬は、in vitroで投与されてもよいし、in vivoで投与してもよい。本発明の医薬の投与対象および投与条件は、例えば、本発明の医薬における投与対象および投与条件の説明を援用できる。 The treatment method of the present invention includes, for example, an administration step of administering the drug, and specifically includes an administration step of administering the drug to a patient (administration subject). The medicament may be administered in vitro or may be administered in vivo . For the administration subject and administration conditions of the medicament of the present invention, for example, the explanation of the administration subject and administration conditions in the medicament of the present invention can be cited.
<化合物またはその塩の使用>
 本発明は、非閉塞性肥大型心筋症の治療に使用するための、前記式(1)で表される化合物もしくはその塩、またはその使用である。また、本発明は非閉塞性肥大型心筋症の治療用医薬を製造するための、前記式(1)で表される化合物もしくはその塩の使用である。本発明は、例えば、前記本発明の医薬および治療方法の説明を援用できる。
<Use of compound or salt thereof>
The present invention is a compound represented by the above formula (1) or a salt thereof, or use thereof for use in the treatment of non-obstructive hypertrophic cardiomyopathy. Further, the present invention is the use of the compound represented by the above formula (1) or a salt thereof for producing a medicament for treating non-obstructive hypertrophic cardiomyopathy. In the present invention, for example, the description of the medicine and the treatment method of the present invention can be incorporated.
 つぎに、本発明の実施例について説明する。ただし、本発明は、以下の実施例により制限されない。市販の試薬は、特に示さない限り、それらのプロトコールに基づいて使用した。 Next, examples of the present invention will be described. However, the present invention is not limited to the following examples. Commercially available reagents were used based on their protocol unless otherwise indicated.
[実施例1]
 本発明の医薬により、HNCMの患者における心肥大が退縮することを確認した。
[Example 1]
It was confirmed that the drug of the present invention causes cardiac hypertrophy in patients with HNCM.
(1)患者の選定
 シベンゾリン(前記式(2)で表される化合物)の投与対象となるHNCMの患者(40名)は、肥大型心筋症と診断された患者において、心臓の左室内に圧較差が観測されない患者とした。肥大型心筋症の診断は、心エコー装置(a SEQUOIA-512(シーメンスヘルスケア社製)またはProSound II SSD-6500SV(Hitachi-Aloca社製))を用いて、心エコーを行なうことにより実施した。また、前記左室内圧較差は、心室中部または左室駆出路における連続波ドップラー速度を測定し、下記式(A)により算出した。なお、各患者に対するシベンゾリン投与については、市立宇和島病院倫理委員会の了承を得た後、各患者からインフォームドコンセントを得て実施した。なお、治療開始時に、心房細動もしくは心不全の既往のある患者、または血中クレアチニン値が1.2mg/mL以上の患者は、投与対象から除外した。
 
 P=4×V   ・・・(A)
  P:左室内圧較差
  V:心室中部または左室駆出路における連続波ドップラー速度の測定値
(1) Selection of Patients HNCM patients (40 patients) who are to be administered with cibenzoline (compound represented by the above formula (2)) have pressure in the left ventricle of the heart in patients diagnosed with hypertrophic cardiomyopathy. The patient was considered to have no difference. Diagnosis of hypertrophic cardiomyopathy was performed by echocardiography using an echocardiographic device (a SEQUOIA-512 (manufactured by Siemens Healthcare) or ProSound II SSD-6500SV (manufactured by Hitachi-Aloca)). The pressure gradient in the left ventricle was calculated by the following formula (A) by measuring the continuous wave Doppler velocity in the middle ventricle or the left ventricular ejection tract. Regarding the administration of cibenzoline to each patient, after obtaining approval from the ethics committee of Uwajima City Hospital, informed consent was obtained from each patient. At the start of treatment, patients with a history of atrial fibrillation or heart failure, or patients with a blood creatinine level of 1.2 mg/mL or more were excluded from the administration subjects.

P=4×V 2 (A)
P: Left ventricular pressure difference V: Measured value of continuous wave Doppler velocity in middle ventricle or left ventricular ejection tract
(2)シベンゾリンの投与
 HNCMの患者に、3年間以上経口投与(内服)によりシベンゾリンを投与した。シベンゾリンの内服は、100mg/1回を3回/日とした。服用時間は、朝食後、午後2時頃、および午後9時頃とした。これにより、HNCMの患者におけるシベンゾリンの血中濃度を、300~1500ng/mLに制御した。なお、患者の平均観察期間は、9.5年±3.0年であった。
(2) Administration of cibenzoline Cibenzoline was orally administered (internally) to a HNCM patient for 3 years or more. Oral administration of cibenzoline was 100 mg/dose 3 times/day. The dosing time was around 2:00 pm and 9:00 pm after breakfast. This controlled blood levels of cibenzoline in patients with HNCM to 300-1500 ng/mL. The average observation period of patients was 9.5±3.0 years.
(3)心肥大の評価
 心肥大の評価は、心エコー図および心電図を用いて行なった。具体的には、前記超音波診断装置を用いて、各患者から心エコー図を取得し、前記心エコー図から左室後壁厚(LVPWT)および心室中隔厚(IVST)を測定した。また、心電図測定装置(Cardiofax G、NIHON KOHDEN社製)を用いて、心電図を測定し、心肥大の指標であるSokolow-Lyon指標(SV1(胸部誘導心電図のVのS波)+RV5(胸部誘導心電図のVのR波))と、陰性T波の深さ(陰性T波深度)とを測定した。また、シベンゾリン投与前後の変化率は、下記式(B)に基づき算出した。また、対照として、健常者15名について同様に各測定値を測定した。
 
 R=(b-a)/b×100(%)   ・・・(B)
  R:変化率
  b:シベンゾリン投与前(投与開始時、治療前)の測定値
  a:シベンゾリン最終投与後(治療後)の測定値
(3) Evaluation of cardiac hypertrophy The cardiac hypertrophy was evaluated using an echocardiogram and an electrocardiogram. Specifically, an echocardiogram was obtained from each patient using the ultrasonic diagnostic apparatus, and the left ventricular posterior wall thickness (LVPWT) and the interventricular septal thickness (IVST) were measured from the echocardiogram. Further, by using the electrocardiogram measuring device (Cardiofax G, manufactured by NIHON Kohden Corporation), an electrocardiogram is measured, Sokolow-Lyon index is an indicator of cardiac hypertrophy (SV1 (S wave of V 1 of the chest lead electrocardiogram) + RV5 (chest leads The R wave of V 5 on the electrocardiogram)) and the depth of the negative T wave (negative T wave depth) were measured. The rate of change before and after administration of cibenzoline was calculated based on the following formula (B). Further, as a control, each measured value was similarly measured for 15 healthy persons.

R c =(ba)/b×100(%) (B)
R c : rate of change b: measured value before administration of cibenzoline (at the start of administration, before treatment) a: measured value after final administration of cibenzoline (after treatment)
(4)心機能の評価
 前記実施例1(3)と同様にして、心エコー図を取得後、左室拡張末期径(left ventricular end-diastolic dimension:LVDd)、左室収縮末期径(left ventricular end-systolic dimension:LVDs)、左室内径短縮率(fractional shortening:FS)、および左房径(left atrial dimension:LAD)を計測した。なお、FSは、下記式(C)に基づき算出した。また、対照として、健常者15名について同様に各測定値を測定した。
 
 FS=(LVDd-LVDs)/LDVd×100(%) ・・・(C)
  FS:左室内径短縮率
  LVDd:左室拡張末期径(mm)
  LVDs:左室収縮末期径(mm)
(4) Evaluation of cardiac function In the same manner as in Example 1 (3) above, after obtaining an echocardiogram, left ventricular end-diastolic dimension (LVDd), left ventricular end systolic diameter (left ventricular). End-systolic dimension (LVDs), left ventricular shortening rate (FS), and left atrial dimension (LAD) were measured. In addition, FS was calculated based on the following formula (C). Further, as a control, each measured value was similarly measured for 15 healthy persons.

FS=(LVDd−LVDs)/LDVd×100(%) (C)
FS: left ventricular diameter shortening rate LVDd: left ventricular end diastolic diameter (mm)
LVDs: Left ventricular end systolic diameter (mm)
(5)結果
 健常者および患者のシベンゾリン投与前後の心電図の代表例を図1~3に示す。図1は、健常者の心電図の結果を示す。図1において、左から、第1列が、双極誘導心電図(I、IIまたはIII)を示し、第2列が、単極誘導心電図(aV、aVまたはaV)を示し、第3列が、胸部誘導心電図(V、VまたはV)を示し、第4列が、胸部誘導心電図(V、VまたはV)を示す。つぎに、図2は、患者のシベンゾリン投与前(2013年3月18日)の心電図の結果を示す。図2において、左から、左列が、双極誘導心電図(I、IIまたはIII)および単極誘導心電図(aV、aVまたはaV)を示し、右列が、胸部誘導心電図(V、V、V、V、VまたはV)を示す。さらに、図3は、図2と同じ患者のシベンゾリン投与後(2018年8月28日)の心電図の結果を示す。図3において、左から、左列が、双極誘導心電図(I、IIまたはIII)および単極誘導心電図(aV、aVまたはaV)を示し、右列が、胸部誘導心電図(V、V、V、V、VまたはV)を示す。
(5) Results Representative examples of electrocardiogram before and after administration of cibenzoline in healthy subjects and patients are shown in FIGS. 1 to 3. FIG. 1 shows the results of electrocardiogram of healthy subjects. In Figure 1, from the left, the first column, shows a bipolar lead electrocardiogram (I, II or III), the second column shows the unipolar lead electrocardiogram (aV R, aV L or aV F), the third column Shows the chest lead electrocardiogram (V 1 , V 2 or V 3 ), and the fourth column shows the chest lead electrocardiogram (V 4 , V 5 or V 6 ). Next, FIG. 2 shows the results of the electrocardiogram of the patient before administration of cibenzoline (March 18, 2013). 2, from the left, the left column, bipolar lead electrocardiogram (I, II or III) and monopolar lead ECG (aV R, aV L or aV F) indicates, right column, chest-lead ECG (V 1, V 2 , V 3 , V 4 , V 5 or V 6 ) is shown. Furthermore, FIG. 3 shows the electrocardiographic results of the same patient as FIG. 2 after administration of cibenzoline (August 28, 2018). 3, from the left, the left column, bipolar lead electrocardiogram (I, II or III) and monopolar lead ECG (aV R, aV L or aV F) indicates, right column, chest-lead ECG (V 1, V 2 , V 3 , V 4 , V 5 or V 6 ) is shown.
 図1および2に示すように、シベンゾリン投与前のHNCMの患者は、健常者と比較して、VにおけるS波の深度(SV1)が深くなり、VにおけるR波の高さ(RV5)が高くなった。また、図1に示すように、健常者において、VにおけるT波は、上方向のスパイクを示す陽性T波であるのに対して、図2に示すように、シベンゾリン投与前のHNCMの患者は、VにおけるT波は、下方向のスパイクを示す陰性T波であった。これらのことから、シベンゾリン投与前のHNCMの患者では、心肥大が進展していることが分かった。これに対して、図3に示すように、シベンゾリン投与後のHNCMの患者は、シベンゾリン投与前のHNCMの患者と比較して、VにおけるS波の深度(SV1)が浅くなり、VにおけるR波の高さ(RV5)が低くなった。また、シベンゾリン投与後のHNCMの患者では、VにおけるT波は、上方向のスパイクを示す陽性T波であった。以上のことから、シベンゾリンの投与により、HNCMの患者における心肥大が改善したこと、すなわち、心肥大が退縮したことが分かった。なお、HNCMの患者の代表例の結果を示しているが、全てのHNCM患者において同様の結果が得られた。 As shown in FIGS. 1 and 2, in patients with HNCM before administration of cibenzoline, the depth of the S wave at V 1 (SV1) was deeper and the height of the R wave at V 5 (RV5) was deeper than that of healthy subjects. Became higher. Further, as shown in FIG. 1, in the healthy person, the T wave at V 5 is a positive T wave showing an upward spike, whereas as shown in FIG. 2, patients with HNCM before administration of cibenzoline. , The T wave at V 5 was a negative T wave showing a downward spike. From these, it was found that cardiac hypertrophy has progressed in patients with HNCM before administration of cibenzoline. On the other hand, as shown in FIG. 3, patients with HNCM after administration of cibenzoline had a shallower S-wave depth (SV1) at V 1 and those at V 5 as compared with patients with HNCM before administration of cibenzoline. The height of the R wave (RV5) has decreased. In addition, in the HNCM patients after administration of cibenzoline, the T wave at V 5 was a positive T wave showing an upward spike. From the above, it was found that administration of cibenzoline improved cardiac hypertrophy in patients with HNCM, that is, that cardiac hypertrophy regressed. In addition, although the result of the representative example of the patient of HNCM is shown, the same result was obtained in all HNCM patients.
 つぎに、健常者およびHNCM患者のシベンゾリン投与前後の心エコー図の代表例を図4~6に示す。図4は、健常者の心エコー図の結果を示す。図5は、患者のシベンゾリン投与前(2012年10月19日)の心エコー図の結果を示す。図6は、図5と同じ患者のシベンゾリン投与後(2018年9月27日)の心エコー図の結果を示す。図4~6において、(A)は、心臓の左室の心エコー図を示し、(B)は、心肥大が生じている部位におけるMモード法による心エコー図を示す。 Next, typical examples of echocardiograms before and after administration of cibenzoline in healthy subjects and HNCM patients are shown in FIGS. 4 to 6. FIG. 4 shows the result of an echocardiogram of a healthy person. FIG. 5 shows the results of echocardiography of the patient before administration of cibenzoline (October 19, 2012). FIG. 6 shows the results of echocardiography of the same patient as FIG. 5 after administration of cibenzoline (September 27, 2018). 4 to 6, (A) shows an echocardiogram of the left ventricle of the heart, and (B) shows an echocardiogram by the M-mode method in a region where cardiac hypertrophy occurs.
 図4および図5に示すように、シベンゾリンの投与前のHNCM患者では、心室中隔厚(IVST)および左室後壁厚(LVPWT)が増加し、心肥大が生じていた。また、左室拡張末期径(LVDd)および左室収縮末期径(LVDs)は、共に狭小化していた。これに対して、図5および6に示すように、シベンゾリンの投与後のHNCM患者では、心室中隔厚(IVST)および左室後壁厚(LVPWT)が減少し、心肥大が退縮していた。また、左室拡張末期径(LVDd)および左室収縮末期径(LVDs)は、共に拡大していた。 As shown in FIGS. 4 and 5, in patients with HNCM before administration of cibenzoline, ventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) were increased, and cardiac hypertrophy occurred. Further, both the left ventricular end diastolic diameter (LVDd) and the left ventricular end systolic diameter (LVDs) were narrowed. In contrast, as shown in FIGS. 5 and 6, in patients with HNCM after administration of cibenzoline, ventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) were decreased, and cardiac hypertrophy was regressed. .. In addition, the left ventricular end diastolic diameter (LVDd) and the left ventricular end systolic diameter (LVDs) were both increased.
 つぎに、健常者およびシベンゾリンの投与前後のHNCMの患者の全例の結果を、図7および8ならびに下記表1に示す。図7および8は、シベンゾリンの投与前後のHNCMの患者の全例の結果を示すグラフである。図7において、(A)は、左室拡張末期径(LVDd)の結果を示し、(B)は、左室収縮末期径(LVDs)の結果を示し、(C)は、左室内径短縮径(LVFS)の結果を示し、(D)は、左房径(LAD)の結果を示す。図8において、(A)は、心室中隔厚(IVST)の結果を示し、(B)は、左室後壁厚(LVPWT)の結果を示し、(C)は、SV1+RV5の結果を示し、(D)は、陰性T波深度の結果を示す。図7および8ならびに下記表1に示すように、HNCMの患者へのシベンゾリンの投与により、心室中隔厚(IVST)は、17.7%退縮し、左室後壁厚(LVPWT)は、9.3%退縮し、また、SV1+RV5は、32.9%減少した。これらの結果から、心肥大が改善されていること、すなわち、心筋肥大が退縮していることが分かった。さらに、陰性T波深度は、61.8%減少し、心筋虚血が改善していることが分かった。左室拡張末期径(LVDd)は、7.7%拡大し、左室内径短縮率(LVFS)に有意な変化はなかった。また、左房径(LAD)は、7.8%縮小していた。これらの結果から、左室拡張期の心機能が改善していることが分かった。 Next, the results of all healthy subjects and patients with HNCM before and after administration of cibenzoline are shown in FIGS. 7 and 8 and Table 1 below. 7 and 8 are graphs showing the results of all cases of HNCM patients before and after administration of cibenzoline. In FIG. 7, (A) shows the results of the left ventricular end diastolic diameter (LVDd), (B) shows the results of the left ventricular end systolic diameter (LVDs), and (C) shows the left ventricular shortened diameter. (LVFS) results are shown, (D) shows left atrial diameter (LAD) results. In FIG. 8, (A) shows the result of ventricular septal thickness (IVST), (B) shows the result of left ventricular posterior wall thickness (LVPWT), (C) shows the result of SV1+RV5, (D) shows the results of negative T-wave depth. As shown in FIGS. 7 and 8 and Table 1 below, administration of cibenzoline to patients with HNCM regressed the ventricular septal thickness (IVST) by 17.7% and left ventricular posterior wall thickness (LVPWT) by 9%. Regression was 0.3%, and SV1+RV5 was decreased 32.9%. From these results, it was found that cardiac hypertrophy was improved, that is, myocardial hypertrophy was regressed. Furthermore, the negative T-wave depth was reduced by 61.8%, which was found to improve myocardial ischemia. The left ventricular end diastolic diameter (LVDd) expanded by 7.7%, and there was no significant change in the left ventricular diameter shortening rate (LVFS). The left atrium diameter (LAD) was reduced by 7.8%. These results showed that the left ventricular diastolic heart function was improved.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
 以上のことから、本発明の医薬の投与により、非閉塞性肥大型心筋症の心肥大が退縮することがわかった。また本発明の医薬の投与により、左室収縮期の心機能の低下は、生じず、左室拡張期の心機能が改善することが分かった。 From the above, it was found that administration of the drug of the present invention causes regression of cardiac hypertrophy in non-obstructive hypertrophic cardiomyopathy. Further, it was found that administration of the drug of the present invention did not cause a decrease in cardiac function during left ventricular systole, and improved cardiac function during left ventricular diastole.
[実施例2]
 本発明の医薬により、非閉塞性肥大型心筋症の患者における心不全死の割合が減少することを確認した。
[Example 2]
It was confirmed that the drug of the present invention reduces the rate of heart failure death in patients with non-obstructive hypertrophic cardiomyopathy.
 前記実施例1におけるHNCMの患者の死因について、全例追跡した。その結果、全例において、心不全死の患者は存在しなかった。他方、明らかな左心機能障害のない肥大型心筋症の患者では、55%の患者において心不全が発症することが知られている。このため、本発明の医薬により、非閉塞性肥大型心筋症の患者における心不全死の割合が減少することが分かった。また、これらの結果に基づけば、本発明の医薬によれば、非閉塞性肥大型心筋症の患者における心不全死を抑制または予防できるといえる。 All the causes of death of patients with HNCM in Example 1 were followed. As a result, none of the patients died of heart failure in all cases. On the other hand, it is known that 55% of patients with hypertrophic cardiomyopathy without apparent left heart dysfunction develop heart failure. Therefore, it was found that the drug of the present invention reduces the rate of heart failure death in patients with non-obstructive hypertrophic cardiomyopathy. Moreover, based on these results, it can be said that the drug of the present invention can suppress or prevent heart failure death in a patient with non-obstructive hypertrophic cardiomyopathy.
 以上、実施形態および実施例を参照して本発明を説明したが、本発明は、上記実施形態および実施例に限定されるものではない。本発明の構成や詳細には、本願発明のスコープ内で当業者が理解しうる様々な変更をすることができる。 Although the present invention has been described with reference to the exemplary embodiments and examples, the present invention is not limited to the above-described exemplary embodiments and examples. Various changes that can be understood by those skilled in the art can be made to the configuration and details of the present invention within the scope of the present invention.
 この出願は、2018年11月30日に出願された日本出願特願2018-224404を基礎とする優先権を主張し、その開示のすべてをここに取り込む。 This application claims the priority on the basis of Japanese application Japanese Patent Application No. 2018-224404 filed on November 30, 2018, and incorporates all the disclosure thereof.
<付記>
 上記の実施形態および実施例の一部または全部は、以下の付記のように記載されうるが、以下には限られない。
(付記1)
下記式(1)で表される化合物またはその塩を含む、非閉塞性肥大型心筋症用医薬:
Figure JPOXMLDOC01-appb-C000009
前記式(1)において、
Rは、同じでも異なってもよく、それぞれ独立して、水素原子、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、または炭素数1~5のアルコキシ基であり、
は、水素原子、炭素数1~5のアルキル基、炭素数2~5のアルケニル基、炭素数2~5のアルキニル基、炭素数1~5のヒドロキシアルキル基、または、非置換もしくは置換アラルキル基であり、
前記置換アラルキル基は、その芳香環残基が、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、および炭素数1~5のアルコキシ基からなる群から選択された1種類の基により置換されたアラルキル基である。
(付記2)
前記式(1)において、
Rは、同じでも異なってもよく、それぞれ独立して、水素原子、フッ素原子、またはメチル基であり、
は、水素原子、メチル基、イソプロピル基、プロピレン基、n-ブチル基、ヒドロキシエチル基、ベンジル基、p-メチルベンジル基、フェネチル基、または3,4,5-トリメチルオキシベンジル基である、付記1記載の非閉塞性肥大型心筋症用医薬。
(付記3)
前記式(1)で表される化合物は、下記式(2)で表される、付記1または2記載の非閉塞性肥大型心筋症用医薬。
Figure JPOXMLDOC01-appb-C000010
(付記4)
前記式(1)で表される化合物を略等間隔で投与する、付記1から3のいずれかに記載の記載の非閉塞性肥大型心筋症用医薬。
(付記5)
前記式(1)で表される化合物を継続的に投与する、付記1から4のいずれかに記載の記載の非閉塞性肥大型心筋症用医薬。
(付記6)
前記式(1)で表される化合物を1ヶ月以上投与する、付記1から5のいずれかに記載の記載の非閉塞性肥大型心筋症用医薬。
(付記7)
前記式(1)で表される化合物を1日あたり250mg以上投与する、付記1から6のいずれかに記載の非閉塞性肥大型心筋症用医薬。
(付記8)
前記非閉塞性肥大型心筋症用医薬は、非閉塞性肥大型心筋症に起因する心不全死の抑制または予防用医薬である、付記1から7のいずれかに記載の非閉塞性肥大型心筋症用医薬。
(付記9)
付記1から7のいずれかに記載の非閉塞性肥大型心筋症用医薬を含む、非閉塞性肥大型心筋症における心筋肥大の退縮用医薬。
(付記10)
付記1から7のいずれかに記載の非閉塞性肥大型心筋症用医薬を含む、非閉塞性肥大型心筋症に起因する心不全死の抑制または予防用医薬。
(付記11)
患者に、付記1から7のいずれかに記載の非閉塞性肥大型心筋症用医薬を投与する投与工程を含む、非閉塞性肥大型心筋症の治療方法。
(付記12)
患者に、付記9記載の非閉塞性肥大型心筋症における心筋肥大の退縮用医薬を投与する投与工程を含む、非閉塞性肥大型心筋症における心筋肥大の退縮方法。
(付記13)
患者に、付記10記載の非閉塞性肥大型心筋症に起因する心不全死の抑制または予防用医薬を投与する投与工程を含む、非閉塞性肥大型心筋症に起因する心不全死の抑制または予防方法。
(付記14)
非閉塞性肥大型心筋症の治療に使用するための、下記式(1)で表される化合物またはその塩。
Figure JPOXMLDOC01-appb-C000011
前記式(1)において、
Rは、同じでも異なってもよく、それぞれ独立して、水素原子、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、または炭素数1~5のアルコキシ基であり、
は、水素原子、炭素数1~5のアルキル基、炭素数2~5のアルケニル基、炭素数2~5のアルキニル基、炭素数1~5のヒドロキシアルキル基、または、非置換もしくは置換アラルキル基であり、
前記置換アラルキル基は、その芳香環残基が、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、および炭素数1~5のアルコキシ基からなる群から選択された1種類の基により置換されたアラルキル基である。
(付記15)
前記式(1)において、
Rは、同じでも異なってもよく、それぞれ独立して、水素原子、フッ素原子、またはメチル基であり、
は、水素原子、メチル基、イソプロピル基、プロピレン基、n-ブチル基、ヒドロキシエチル基、ベンジル基、p-メチルベンジル基、フェネチル基、または3,4,5-トリメチルオキシベンジル基である、付記14記載の化合物またはその塩。
(付記16)
前記式(1)で表される化合物は、下記式(2)で表される、付記14または15記載の化合物またはその塩。
Figure JPOXMLDOC01-appb-C000012
(付記17)
前記式(1)で表される化合物は、略等間隔で投与される、付記14から16のいずれかに記載の化合物またはその塩。
(付記18)
前記式(1)で表される化合物は、継続的に投与される、付記14から17のいずれかに記載の記載の化合物またはその塩。
(付記19)
前記式(1)で表される化合物は、1ヶ月以上投与される、付記14から18のいずれかに記載の記載の化合物またはその塩。
(付記20)
前記式(1)で表される化合物は、1日あたり250mg以上投与される、付記14から19のいずれかに記載の化合物またはその塩。
(付記21)
非閉塞性肥大型心筋症における心筋肥大の退縮に使用するための、付記14から20のいずれかに記載の化合物またはその塩。
(付記22)
非閉塞性肥大型心筋症に起因する心不全死の抑制または予防に使用するための、付記14から20のいずれかに記載の化合物またはその塩。
<Appendix>
The whole or part of the exemplary embodiments and examples described above can be described as, but not limited to, the following supplementary notes.
(Appendix 1)
A medicament for non-obstructive hypertrophic cardiomyopathy, which comprises a compound represented by the following formula (1) or a salt thereof:
Figure JPOXMLDOC01-appb-C000009
In the formula (1),
R may be the same or different, and each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms,
R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted Is an aralkyl group,
The substituted aralkyl group has one aromatic ring residue selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms. It is an aralkyl group substituted with a group.
(Appendix 2)
In the formula (1),
R may be the same or different and each independently is a hydrogen atom, a fluorine atom, or a methyl group,
R 1 is a hydrogen atom, a methyl group, an isopropyl group, a propylene group, an n-butyl group, a hydroxyethyl group, a benzyl group, a p-methylbenzyl group, a phenethyl group, or a 3,4,5-trimethyloxybenzyl group. The drug for non-obstructive hypertrophic cardiomyopathy according to Appendix 1.
(Appendix 3)
The compound represented by the formula (1) is the pharmaceutical composition for non-obstructive hypertrophic cardiomyopathy according to appendix 1 or 2, represented by the following formula (2).
Figure JPOXMLDOC01-appb-C000010
(Appendix 4)
4. The pharmaceutical composition for non-obstructive hypertrophic cardiomyopathy according to any one of appendices 1 to 3, wherein the compound represented by the formula (1) is administered at substantially equal intervals.
(Appendix 5)
5. The pharmaceutical composition for non-obstructive hypertrophic cardiomyopathy according to any one of appendices 1 to 4, wherein the compound represented by the formula (1) is continuously administered.
(Appendix 6)
6. The pharmaceutical composition for non-obstructive hypertrophic cardiomyopathy according to any one of appendices 1 to 5, wherein the compound represented by the formula (1) is administered for 1 month or more.
(Appendix 7)
7. The pharmaceutical composition for non-obstructive hypertrophic cardiomyopathy according to any one of appendices 1 to 6, wherein the compound represented by the formula (1) is administered at 250 mg or more per day.
(Appendix 8)
8. The nonobstructive hypertrophic cardiomyopathy according to any one of appendices 1 to 7, wherein the nonobstructive hypertrophic cardiomyopathy is a pharmaceutical for suppressing or preventing death of heart failure caused by nonobstructive hypertrophic cardiomyopathy. Medicine.
(Appendix 9)
A medicament for regressing myocardial hypertrophy in non-obstructive hypertrophic cardiomyopathy, which comprises the pharmaceutical for non-occlusive hypertrophic cardiomyopathy according to any one of appendices 1 to 7.
(Appendix 10)
A medicament for suppressing or preventing death of heart failure due to non-obstructive hypertrophic cardiomyopathy, which comprises the medicament for non-occlusive hypertrophic cardiomyopathy according to any one of appendices 1 to 7.
(Appendix 11)
A method for treating non-obstructive hypertrophic cardiomyopathy, comprising the step of administering to the patient the pharmaceutical composition for non-occlusive hypertrophic cardiomyopathy according to any one of appendices 1 to 7.
(Appendix 12)
A method for regressing myocardial hypertrophy in non-obstructive hypertrophic cardiomyopathy, comprising the step of administering to a patient the pharmaceutical for regressing myocardial hypertrophy in non-obstructive hypertrophic cardiomyopathy according to Appendix 9.
(Appendix 13)
A method for suppressing or preventing death from heart failure due to non-obstructive hypertrophic cardiomyopathy, comprising an administration step of administering to a patient a pharmaceutical for suppressing or preventing death from heart failure due to non-obstructive hypertrophic cardiomyopathy. ..
(Appendix 14)
A compound represented by the following formula (1) or a salt thereof for use in the treatment of non-obstructive hypertrophic cardiomyopathy.
Figure JPOXMLDOC01-appb-C000011
In the formula (1),
R may be the same or different, and each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms,
R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted Is an aralkyl group,
The substituted aralkyl group has one aromatic ring residue selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms. It is an aralkyl group substituted with a group.
(Appendix 15)
In the formula (1),
R may be the same or different and each independently is a hydrogen atom, a fluorine atom, or a methyl group,
R 1 is a hydrogen atom, a methyl group, an isopropyl group, a propylene group, an n-butyl group, a hydroxyethyl group, a benzyl group, a p-methylbenzyl group, a phenethyl group, or a 3,4,5-trimethyloxybenzyl group. The compound or the salt thereof according to Appendix 14.
(Appendix 16)
The compound represented by the formula (1) is the compound or the salt thereof according to supplementary note 14 or 15, represented by the following formula (2).
Figure JPOXMLDOC01-appb-C000012
(Appendix 17)
The compound represented by the formula (1) is a compound or a salt thereof according to any one of supplementary notes 14 to 16, which is administered at substantially equal intervals.
(Appendix 18)
The compound represented by the formula (1), or a salt thereof, according to any one of appendices 14 to 17, wherein the compound is continuously administered.
(Appendix 19)
The compound represented by the formula (1), or a salt thereof, according to any one of appendices 14 to 18, which is administered for one month or more.
(Appendix 20)
The compound represented by the formula (1), or a salt thereof, according to any one of supplementary notes 14 to 19, which is administered in an amount of 250 mg or more per day.
(Appendix 21)
The compound or salt thereof according to any one of appendices 14 to 20, for use in the regression of myocardial hypertrophy in non-obstructive hypertrophic cardiomyopathy.
(Appendix 22)
The compound or a salt thereof according to any one of appendices 14 to 20, which is used for suppressing or preventing death of heart failure caused by non-obstructive hypertrophic cardiomyopathy.
 以上のように、本発明によれば、前記式(1)で表される化合物またはその塩を含むことにより非閉塞性肥大型心筋症において生じる心筋の肥大を退縮させることができる。すなわち、本発明によれば、非閉塞性肥大型心筋症において生じている心筋肥大を退縮できることから、非閉塞性肥大型心筋症の治療に用いることができる。このため、本発明は、医薬等の分野において、極めて有用といえる。 As described above, according to the present invention, myocardial hypertrophy that occurs in non-obstructive hypertrophic cardiomyopathy can be regressed by including the compound represented by the formula (1) or a salt thereof. That is, according to the present invention, since myocardial hypertrophy that occurs in non-obstructive hypertrophic cardiomyopathy can be regressed, it can be used for treatment of non-obstructive hypertrophic cardiomyopathy. Therefore, the present invention can be said to be extremely useful in the fields of medicine and the like.

Claims (21)

  1. 下記式(1)で表される化合物またはその塩を含む、非閉塞性肥大型心筋症用医薬:
    Figure JPOXMLDOC01-appb-C000001
    前記式(1)において、
    Rは、同じでも異なってもよく、それぞれ独立して、水素原子、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、または炭素数1~5のアルコキシ基であり、
    は、水素原子、炭素数1~5のアルキル基、炭素数2~5のアルケニル基、炭素数2~5のアルキニル基、炭素数1~5のヒドロキシアルキル基、または、非置換もしくは置換アラルキル基であり、
    前記置換アラルキル基は、その芳香環残基が、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、および炭素数1~5のアルコキシ基からなる群から選択された1種類の基により置換されたアラルキル基である。
    A medicament for non-obstructive hypertrophic cardiomyopathy, which comprises a compound represented by the following formula (1) or a salt thereof:
    Figure JPOXMLDOC01-appb-C000001
    In the formula (1),
    R may be the same or different, and each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms,
    R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted Is an aralkyl group,
    The substituted aralkyl group has one aromatic ring residue selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms. It is an aralkyl group substituted with a group.
  2. 前記式(1)において、
    Rは、同じでも異なってもよく、それぞれ独立して、水素原子、フッ素原子、またはメチル基であり、
    は、水素原子、メチル基、イソプロピル基、プロピレン基、n-ブチル基、ヒドロキシエチル基、ベンジル基、p-メチルベンジル基、フェネチル基、または3,4,5-トリメチルオキシベンジル基である、請求項1記載の非閉塞性肥大型心筋症用医薬。
    In the formula (1),
    R may be the same or different and each independently is a hydrogen atom, a fluorine atom, or a methyl group,
    R 1 is a hydrogen atom, a methyl group, an isopropyl group, a propylene group, an n-butyl group, a hydroxyethyl group, a benzyl group, a p-methylbenzyl group, a phenethyl group, or a 3,4,5-trimethyloxybenzyl group. The drug for non-obstructive hypertrophic cardiomyopathy according to claim 1.
  3. 前記式(1)で表される化合物は、下記式(2)で表される、請求項1または2記載の非閉塞性肥大型心筋症用医薬。
    Figure JPOXMLDOC01-appb-C000002
    The compound for non-occlusive hypertrophic cardiomyopathy according to claim 1 or 2, wherein the compound represented by the formula (1) is represented by the following formula (2).
    Figure JPOXMLDOC01-appb-C000002
  4. 前記式(1)で表される化合物を略等間隔で投与する、請求項1から3のいずれか一項に記載の記載の非閉塞性肥大型心筋症用医薬。 The pharmaceutical composition for non-occlusive hypertrophic cardiomyopathy according to any one of claims 1 to 3, wherein the compound represented by the formula (1) is administered at substantially equal intervals.
  5. 前記式(1)で表される化合物を継続的に投与する、請求項1から4のいずれか一項に記載の記載の非閉塞性肥大型心筋症用医薬。 The drug for non-obstructive hypertrophic cardiomyopathy according to any one of claims 1 to 4, wherein the compound represented by the formula (1) is continuously administered.
  6. 前記式(1)で表される化合物を1ヶ月以上投与する、請求項1から5のいずれか一項に記載の記載の非閉塞性肥大型心筋症用医薬。 The drug for non-occlusive hypertrophic cardiomyopathy according to any one of claims 1 to 5, wherein the compound represented by the formula (1) is administered for 1 month or more.
  7. 前記式(1)で表される化合物を1日あたり250mg以上投与する、請求項1から6のいずれか一項に記載の非閉塞性肥大型心筋症用医薬。 The pharmaceutical for non-occlusive hypertrophic cardiomyopathy according to any one of claims 1 to 6, wherein the compound represented by the formula (1) is administered at 250 mg or more per day.
  8. 請求項1から7のいずれか一項に記載の非閉塞性肥大型心筋症用医薬を含む、非閉塞性肥大型心筋症における心筋肥大の退縮用医薬。 A medicament for regressing myocardial hypertrophy in non-obstructive hypertrophic cardiomyopathy, comprising the medicament for non-occlusive hypertrophic cardiomyopathy according to any one of claims 1 to 7.
  9. 請求項1から7のいずれか一項に記載の非閉塞性肥大型心筋症用医薬を含む、非閉塞性肥大型心筋症に起因する心不全死の抑制または予防用医薬。 A medicament for suppressing or preventing death of heart failure due to non-obstructive hypertrophic cardiomyopathy, which comprises the medicament for non-occlusive hypertrophic cardiomyopathy according to any one of claims 1 to 7.
  10. 患者に、請求項1から7のいずれか一項に記載の非閉塞性肥大型心筋症用医薬を投与する投与工程を含む、非閉塞性肥大型心筋症の治療方法。 A method for treating non-obstructive hypertrophic cardiomyopathy, comprising the step of administering to the patient the pharmaceutical composition for non-occlusive hypertrophic cardiomyopathy according to any one of claims 1 to 7.
  11. 患者に、請求項8記載の非閉塞性肥大型心筋症における心筋肥大の退縮用医薬を投与する投与工程を含む、非閉塞性肥大型心筋症における心筋肥大の退縮方法。 A method for regressing myocardial hypertrophy in non-obstructive hypertrophic cardiomyopathy, comprising the step of administering to a patient the pharmaceutical for regressing myocardial hypertrophy in non-occlusive hypertrophic cardiomyopathy according to claim 8.
  12. 患者に、請求項9記載の非閉塞性肥大型心筋症に起因する心不全死の抑制または予防用医薬を投与する投与工程を含む、非閉塞性肥大型心筋症に起因する心不全死の抑制または予防方法。 Suppressing or preventing death from heart failure due to non-obstructive hypertrophic cardiomyopathy, comprising an administration step of administering a medicine for suppressing or preventing death from heart failure due to non-obstructive hypertrophic cardiomyopathy to a patient. Method.
  13. 非閉塞性肥大型心筋症の治療に使用するための、下記式(1)で表される化合物またはその塩。
    Figure JPOXMLDOC01-appb-C000003
    前記式(1)において、
    Rは、同じでも異なってもよく、それぞれ独立して、水素原子、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、または炭素数1~5のアルコキシ基であり、
    は、水素原子、炭素数1~5のアルキル基、炭素数2~5のアルケニル基、炭素数2~5のアルキニル基、炭素数1~5のヒドロキシアルキル基、または、非置換もしくは置換アラルキル基であり、
    前記置換アラルキル基は、その芳香環残基が、フッ素原子、塩素原子、臭素原子、炭素数1~5のアルキル基、および炭素数1~5のアルコキシ基からなる群から選択された1種類の基により置換されたアラルキル基である。
    A compound represented by the following formula (1) or a salt thereof for use in the treatment of non-obstructive hypertrophic cardiomyopathy.
    Figure JPOXMLDOC01-appb-C000003
    In the formula (1),
    R may be the same or different, and each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms,
    R 1 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, or unsubstituted or substituted Is an aralkyl group,
    The substituted aralkyl group has one aromatic ring residue selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms. It is an aralkyl group substituted with a group.
  14. 前記式(1)において、
    Rは、同じでも異なってもよく、それぞれ独立して、水素原子、フッ素原子、またはメチル基であり、
    は、水素原子、メチル基、イソプロピル基、プロピレン基、n-ブチル基、ヒドロキシエチル基、ベンジル基、p-メチルベンジル基、フェネチル基、または3,4,5-トリメチルオキシベンジル基である、請求項13記載の化合物またはその塩。
    In the formula (1),
    R may be the same or different and each independently is a hydrogen atom, a fluorine atom, or a methyl group,
    R 1 is a hydrogen atom, a methyl group, an isopropyl group, a propylene group, an n-butyl group, a hydroxyethyl group, a benzyl group, a p-methylbenzyl group, a phenethyl group, or a 3,4,5-trimethyloxybenzyl group. The compound of claim 13, or a salt thereof.
  15. 前記式(1)で表される化合物は、下記式(2)で表される、請求項13または14記載の化合物またはその塩。
    Figure JPOXMLDOC01-appb-C000004
    The compound represented by the formula (1) or a salt thereof according to claim 13 or 14, represented by the following formula (2).
    Figure JPOXMLDOC01-appb-C000004
  16. 前記式(1)で表される化合物は、略等間隔で投与される、請求項13から15のいずれか一項に記載の化合物またはその塩。 The compound or a salt thereof according to any one of claims 13 to 15, wherein the compound represented by the formula (1) is administered at substantially equal intervals.
  17. 前記式(1)で表される化合物は、継続的に投与される、請求項13から16のいずれか一項に記載の記載の化合物またはその塩。 17. The compound according to any one of claims 13 to 16, or a salt thereof, wherein the compound represented by the formula (1) is continuously administered.
  18. 前記式(1)で表される化合物は、1ヶ月以上投与される、請求項13から17のいずれか一項に記載の記載の化合物またはその塩。 18. The compound according to any one of claims 13 to 17, or a salt thereof, wherein the compound represented by the formula (1) is administered for 1 month or more.
  19. 前記式(1)で表される化合物は、1日あたり250mg以上投与される、請求項13から18のいずれか一項に記載の化合物またはその塩。 The compound or a salt thereof according to any one of claims 13 to 18, wherein the compound represented by the formula (1) is administered in an amount of 250 mg or more per day.
  20. 非閉塞性肥大型心筋症における心筋肥大の退縮に使用するための、請求項13から19のいずれか一項に記載の化合物またはその塩。 20. A compound or salt thereof according to any one of claims 13 to 19 for use in the regression of myocardial hypertrophy in non-obstructive hypertrophic cardiomyopathy.
  21. 非閉塞性肥大型心筋症に起因する心不全死の抑制または予防に使用するための、請求項13から19のいずれか一項に記載の化合物またはその塩。

     
    The compound or a salt thereof according to any one of claims 13 to 19, which is used for suppressing or preventing death of heart failure caused by non-obstructive hypertrophic cardiomyopathy.

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HAMADA, M ET AL.: "Antiarrhythmic drug, cibenzoline, can directly improve the left ventricular diastolic function in patients with hypertrophic cardiomyopathy", JPN CIRC J, vol. 65, 2001, pages 531 - 538, XP055706177 *
HAMADA, M ET AL.: "Effect of intravenous administration of cibenzoline on left ventricular diastolic pressures in patients with hypertrophic cardiomyopathy-its relationship to transmitral doppler flow profiles", CIRC J,, vol. 71, 2007, pages 1540 - 1544, XP055712944 *
HAMADA, MAREOMI: "Current State of Hypertrophic Cardiomyopathy: Importance of Heart Failure During Convalescence (Can the Onset of Heart Failure Be Prevented?)", MEBIO, vol. 25, no. 7, 2008, pages 86 - 93 *

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