JP2020083871A - Therapeutic agent for nonobstructive hypertrophic cardiomyopathy - Google Patents

Abstract

To provide a drug for nonobstructive hypertrophic cardiomyopathy.SOLUTION: The drug for nonobstructive hypertrophic cardiomyopathy contains a compound represented by a formula (1) in the figure or a salt thereof.SELECTED DRAWING: Figure 8

Description

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 project for the treatment of 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.

Intractable Diseases Research Foundation/Intractable Disease Information Center, "Intractable Disease Information Center Hypertrophic Cardiomyopathy (Designated Intractable Disease 58)", [online], [Search on November 27, 2018], Internet <http://www. nanbyou.or.jp/entry/320>

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.

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 when the ventricular septum is enlarged. 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.

Moreover, at present, no therapeutic drug effective for non-obstructive hypertrophic cardiomyopathy is known. Then, this invention aims at provision of the pharmaceutical for non-obstructive hypertrophic cardiomyopathy.

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:
In the formula (1),
R may be the same or different, and each independently 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,
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.

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.

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. 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.

<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:
In the formula (1),
R may be the same or different, and each independently 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,
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.

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, the compound represented by the above formula (1) activates the Na ⁺ -Ca ²⁺ exchange system in the myocardial cell membrane, resulting in a decrease in intracellular Ca ²⁺ ion, which causes non-occlusive hypertrophic cardiomyopathy. It is estimated that cardiac hypertrophy will regress.

In the present invention, “hypertrophic non-obstructive cardiomyopathy (HNCM)” means, for example, hypertrophic cardiomyopathy, a disease in which no left ventricular pressure difference is observed. 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.

In the medicament of the present invention, “treatment” may be used to mean any of treatment, improvement, suppression of progression of symptoms, and/or termination of progression of cardiac hypertrophy. 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.

As described above, the medicament 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.

Since the pharmaceutical agent of the present invention can relieve 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.

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).

Hereinafter, each substituent in the compound represented by the formula (1) will be described with reference to 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).

The compound represented by the 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.

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.

The C1-C5 alkyl group is, for example, a C1-C5 linear, branched, or cyclic saturated or unsaturated alkyl group. 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 a methoxy group, an ethoxy group, a propyloxy group, a butyloxy group and a pentyloxy group.

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 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.

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. As a specific example, the alkynyl group having 2 to 5 carbon atoms is, for example, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group or a 1-methyl-2. Examples include -propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group and 1-methyl-3-butynyl group.

As 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 referred to.

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.

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.

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.

The compound represented by the 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.

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, and brocaine salt; aralkylamine salts such as N,N-dibenzylethylenediamine; pyridine salt, picoline salt, quinoline salt, isoquinoline salt. Heterocyclic aromatic amine salts such as; tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, tetrabutylammonium salts, etc. quaternary ammonium salts; arginine salts, 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.

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.

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.

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 and the like can be appropriately set according to the type of administration subject.

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 formula (1) per day is, for example, 50 to 500 mg or 100 to 400 mg, preferably about 300 mg (200 to 200 mg). 400 mg), and the number of administrations per day is, for example, 1 to 5 times, 1 to 3 times, and preferably about 3 times (for example, 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 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 (for example, 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 administration frequency 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. 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.

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-mentioned 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.

The medicament 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.

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.

The compound represented by the 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 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.

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.

As described above, the drug of the present invention is presumed to be capable of regressing 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 (eg PubChem CID:5953), procainamide (eg PubChem CID:4913), disopyramide (disopyramide, eg Pub Chem CID:3114), pyrmenol (eg Pub Chem). CID: 65502), aplindine (eg Pub Chem CID: 2118), mexiletine (eg Pub Chem CID: 4178), pilsicainide (eg Pub Chem CID: 4820) and the like.

<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.

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.

<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.

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.

[Example 1]
It was confirmed that the drug of the present invention causes cardiac hypertrophy in patients with HNCM.

(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) 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. By this, the blood concentration of cibenzoline in HNCM patients was controlled to 300 to 1500 ng/mL. The average observation period of patients was 9.5±3.0 years.

(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 =(b−a)/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) 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) Results Representative examples of electrocardiograms before and after administration of cibenzoline to healthy subjects and patients are shown in FIGS. 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.

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.

Next, typical examples of echocardiograms before and after administration of cibenzoline in healthy subjects and HNCM patients are shown in FIGS. 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 at the site where cardiac hypertrophy occurs.

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.

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.

From the above, it was found that the administration of the pharmaceutical agent of the present invention causes the cardiac hypertrophy of non-obstructive hypertrophic cardiomyopathy to regress. 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.

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.

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.

<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:
In the formula (1),
R may be the same or different, and each independently 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,
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 medicament 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).
(Appendix 4)
4. The nonobstructive hypertrophic cardiomyopathy according to any one of appendices 1 to 3, wherein the nonobstructive hypertrophic cardiomyopathy is a medicament for suppressing or preventing death of heart failure due to nonobstructive hypertrophic cardiomyopathy Medicine.
(Appendix 5)
A method for treating non-obstructive hypertrophic cardiomyopathy, comprising the step of administering to the patient the pharmaceutical for non-occlusive hypertrophic cardiomyopathy according to any one of Supplementary Notes 1 to 4.
(Appendix 6)
A compound represented by the following formula (1) or a salt thereof for use in the treatment of non-obstructive hypertrophic cardiomyopathy.
In the formula (1),
R may be the same or different, and each independently 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,
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 7)
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 according to Supplementary Note 6, or a salt thereof.
(Appendix 8)
The compound represented by the formula (1) is the compound according to supplementary note 6 or 7, represented by the following formula (2), or a salt thereof.

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 (4)

A medicament for non-obstructive hypertrophic cardiomyopathy, which comprises a compound represented by the following formula (1) or a salt thereof:
In the formula (1),
R may be the same or different, and each independently 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,
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. 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. 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).
The nonobstructive manure according to any one of claims 1 to 3, wherein the nonobstructive hypertrophic cardiomyopathy drug is a drug for suppressing or preventing death of heart failure due to nonobstructive hypertrophic cardiomyopathy. Medicine for large cardiomyopathy.