JPH10298077A - Agent for treating and preventing cardiac myopathy - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an agent for treating or preventing cardiac myopathy, having both improving action on cardiac function and life lengthening action, by using a specific readily obtainable piperazinylbenzenesulfonic acid derivative as an active ingredient. SOLUTION: This agent for treating or preventing cardiac myopathy comprises a 2-(1-piperazinyl)-5-methylbenzenesulfonic acid derivative, its salt, its hydrate or its solvate as an active ingredient. 2-(1-Piperazinyl-5- methylbenzenesulfonic acid derivative monohydrate is preferably among the compound of the formula. The medicine is effective especially for sudden cardiac myopathy and specific cardiac myopathy. A daily oral dose of the compound of the formula as the active ingredient is 0.01-1,000 mg per adult.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an agent for treating or preventing cardiomyopathy, and more particularly to a 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative, a salt thereof, a hydrate or a solvent thereof. The present invention relates to a therapeutic or prophylactic agent for cardiomyopathy containing a Japanese drug as an active ingredient.

[0002]

2. Description of the Related Art Cardiomyopathy such as idiopathic cardiomyopathy and specific cardiomyopathy is defined as a general term for a group of diseases in which the pathological symptoms appear for unknown reasons or for a specific cause, and are once extremely onset. Therefore, it is required to establish an urgent treatment method for this group of diseases (R
report of the 1995 WHO / ISF
Ctask force on the define
Tion and Classification o
f cardiomyopathy. Circulat
ion. 93: 841-842, 1996; Ministry of Health and Welfare Spontaneous Disease Idiopathic Cardiomyopathy Investigation and Research Group (Group Leader: Hironori Toshima, Stage I and II Group Leader: Chuichi Kawai): Idiopathic Cardiomyopathy (idio)
Guide for the diagnosis of pathogenic cardiomyopathy (1986). Regarding idiopathic dilated cardiomyopathy, which is one of the representative examples of this disease group, treatment by heart transplantation has been common in the United States and other countries as a treatment method. Treatment of patients is virtually impossible and many domestic patients travel abroad each year in search of transplant surgery. On the other hand, there is a strong demand for establishing an effective treatment method by drug treatment for all cardiomyopathy syndromes including idiopathic cardiomyopathy. Currently, clinically, β-receptor stimulants and inotropics are used for the acute pump failure of the heart, and β-receptor blockers are used to improve myocardial energy metabolism. Or Ca channel antagonists have been used for the purpose of improving cardiac function, for the purpose of improving local myocardial blood flow.

[0003] However, the above-mentioned existing drugs temporarily have the effect of improving the heart function, energy metabolism, or local blood flow, but ultimately have an effect on the survival of the patient in correlation with the effect of improving the heart function. The effect of clearly increasing the rate has not been obtained. In the treatment of patients with extremely fatal cardiomyopathy, the first priority is to prolong the life of the patient, and there is no drug that directly improves cardiac function and has the effect of prolonging the life of the patient. That is, at present, pharmacological treatment for cardiomyopathy patients is still considered to be inadequate, and the development of a drug that satisfies the above conditions is an urgent medical need.

[0004] By the way, aminobenzenesulfonic acid derivatives having an action of suppressing the hyperaccumulation of intracellular calcium ions in cardiac muscle or vascular smooth muscle are known (JP-A-3-72).
No. 63). Regarding these compounds, they do not have a β-receptor stimulant-like action, a β-receptor blocker-like action, or a Ca ²⁺ channel antagonist-like action to suppress myocardial injury, cardiac stimulation conduction disorder, etc. It is disclosed that the drug can be reduced and can be used as a useful prophylactic or therapeutic agent for ischemic heart disease, heart failure, hypertension, arrhythmia, and the like (JP-A-3-7263 and JP-A-4-139127). However, in these publications, 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivatives, salts thereof, hydrates or solvates thereof show cardiomyopathy such as idiopathic cardiomyopathy and specific cardiomyopathy. No suggestion or teaching that it is useful for the treatment or prevention of the disease or has a life-prolonging effect on cardiomyopathy.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a medicament capable of treating or preventing cardiomyopathy such as idiopathic cardiomyopathy and specific cardiomyopathy. More specifically, it is an object of the present invention to provide a medicament capable of treating or preventing cardiomyopathy, which has an effect of improving cardiac function in these cardiomyopathy patients and also has a life-prolonging effect.

[0006]

The present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, have found that the above-mentioned 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative, its salt, and their water The present inventors have found that a solvate or a solvate has a favorable action such as a cardiac function improving action also for cardiomyopathy symptoms and also has a life-prolonging effect for cardiomyopathy patients, and has completed the present invention.

That is, the gist of the present invention is to provide a 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative, a salt thereof,
The present invention relates to a therapeutic or prophylactic agent for cardiomyopathy comprising a hydrate or solvate thereof as an active ingredient.

A preferred embodiment of the present invention is a therapeutic or prophylactic agent for cardiomyopathy containing 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative monohydrate as an active ingredient. ) An agent for treating or preventing idiopathic cardiomyopathy containing the above active ingredient, and (2) an agent for treating or preventing specific cardiomyopathy containing the above active ingredient.

According to another aspect of the present invention, there is provided a method for preventing and treating cardiomyopathy by administering the above-mentioned medicament to a mammal, and a method for administering a medicament to a mammal, wherein the cardiomyopathy is reduced. How to improve functionality,
There is provided a method for improving the survival rate in cardiomyopathy by administering the above medicine to a mammal.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The cardiomyopathy according to the present invention refers to cardiomyopathy syndrome including idiopathic cardiomyopathy and specific cardiomyopathy.
Specific examples of idiopathic cardiomyopathy include dilated cardiomyopathy, hypertrophic obstructive cardiomyopathy, non-obstructive hypertrophic cardiomyopathy, restricted cardiomyopathy, etc., and specific examples of specific cardiomyopathy Is associated with postpartum heart, alcoholic myocardial disease, primary endocardial fibroelastosis, myocarditis, myocardial disease associated with neuromuscular disease, myocardial disease associated with connective tissue disease, nutritional heart disease, or heart associated with metabolic disease. And heart disease associated with amyloidosis / sarcoidosis.

The 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative which is an active ingredient of the medicament of the present invention is represented by the following formula.

Embedded image

The salts of the above-mentioned 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative include mineral salts such as hydrochloride and sulfate, acetate, malonate, fumarate and maleate. And organic acid salts such as oxalate, lactate and metasulfonate. Any hydrate or solvate thereof may be used as an active ingredient of the present invention, in addition to a salt or a compound in a free form. Examples of the solvent capable of forming the above solvate include methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride and the like. As the active ingredient of the medicament of the present invention, 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative monohydrate is most preferred.

The 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative, which is an active ingredient of the medicament of the present invention, is disclosed in JP-A-3-7263 and JP-A-4-139127. It is a known compound which can be easily synthesized by the method described in Example 1 of JP-A-3-7263, for example, and can be easily obtained by those skilled in the art. The salts, their hydrates or solvates are
It can be synthesized according to a known method.

Without wishing to be bound by any particular theory, the 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative described above can be used in animal models that genetically develop idiopathic cardiomyopathy. Since it has the effect of improving the deterioration of cardiac function that progresses with the worsening of symptoms, the medicament of the present invention is effective for the prevention and treatment of sudden cardiomyopathy syndrome.

In particular, the medicament of the present invention not only has the above-mentioned favorable pharmacological action but also has an action of reducing the mortality of this pathological animal in an animal model that genetically develops sudden cardiomyopathy. I have. Therefore, the medicament of the present invention not only improves the decline of cardiac function in idiopathic cardiomyopathy,
It can be said that it also has the effect of improving survival rate, which is the most important and final goal in the treatment of this group of highly lethal diseases.

Further, the medicament of the present invention has an effect of improving reduced cardiac function and a prolonged life effect in cardiomyopathy.
It is not limited to the above-mentioned spontaneous cardiomyopathy that is genetically developed, but is used for the prevention and treatment of other idiopathic cardiomyopathy, specific cardiomyopathy, and myocarditis such as myocarditis exhibiting similar pathophysiology. It can be used.

The 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative, a salt thereof, a hydrate or a solvate thereof, which is an active ingredient of the medicament of the present invention, is itself administered to a patient as a medicament. In general, it is preferable to prepare a pharmaceutical composition containing one or more of these active ingredients and administer it to a patient. Examples of such a pharmaceutical composition include preparations for oral administration such as tablets, capsules, fine granules, powders, pills, troches, sublinguals, and liquids, and non-injectable preparations such as injections, suppositories, ointments, and patches. Preparations for oral administration can be exemplified.

Tablets or capsules for oral administration are usually presented as unit dosages, containing binders, fillers, diluents, tablets, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents. It can be produced by adding such ordinary carriers for pharmaceuticals. Tablets may be coated according to methods well known in the art, for example, with an enteric coating, for example, a filler such as cellulose, mannitol, or lactose; starch, polyvinylpolypyrrolidone, a starch derivative, or sodium. A disintegrating agent such as starch glycolate; a lubricant such as magnesium stearate; and a wetting agent such as sodium lauryl sulfate may be used.

Liquid preparations for oral administration are provided, for example, as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or as dry preparations which can be redissolved with water or a suitable vehicle before use. . Such solutions include conventional additives such as sorber, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, suspending agents such as aluminum stearate gel or hydrogenated edible fat, lecithin, sorbitan monooleate, Arabic Emulsifiers such as gums, almond oil, refined coconut oil, oily esters (eg glycerin esters), non-aqueous media (including edible oils) such as propylene glycol, ethyl alcohol, methyl esters of p-hydroxybenzoic acid Preservatives such as, for example, ethyl ester, or propyl ester, or sorbic acid, and, if necessary, usual flavoring or coloring agents.

Preparations for oral administration can be produced by methods known in the art, such as mixing, filling, or tableting. Further, the active ingredient may be distributed in a preparation using a large amount of a filler or the like by using a repetitive blending operation. Formulations for parenteral administration are generally provided as liquid carrier dosage formulations containing the compound, the active ingredient, and a sterile vehicle. Solvents for parenteral administration are usually prepared by dissolving the compound in a vehicle, sterile-filtering and then filling suitable vials or ampoules and sealing. After freezing the composition to enhance stability, it may be filled into vials and the water removed under vacuum. Parenteral suspensions are prepared substantially in the same manner as for parenteral solutions, but can be suitably prepared by suspending the active ingredient in a vehicle and sterilizing with an ethylenoxide or the like. Further, a surfactant, a wetting agent, and the like may be added as necessary so that the active ingredient has a uniform distribution.

The dose of the compound as an active ingredient may be appropriately determined in consideration of the purpose of treatment or prevention, the type of disease to be treated or prevented, the condition, weight, age, sex, etc. of the patient. Usually, by oral administration per adult per day
About 0.01 mg to 1000 mg can be administered. It is desirable to administer such a dosage in one to several portions per day.

[0022]

【Example】

Synthesis Example 1: Production of 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative monohydrate 2-fluoro-5-methyl according to the method described in Example 1 of JP-A-3-7263. 0.76 g of copper iodide and 0.26 g of copper powder with 0.76 g of benzenesulfonic acid and 3.44 g of piperazine
The reaction product was reacted at 160 ° C. for 8 hours in a sealed tube in the coexistence of the above, and the reaction product was subjected to silica gel column chromatography (developing solvent; chloroform: methanol: acetic acid = 100: 100: 3).
) To obtain a crystal-free 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative (0.67 g, yield 65.
0%).

In a 5 ml eggplant-shaped flask, crystal-free of the above 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative
0.4506 g and 1.35 ml of distilled water were added, and the mixture was stirred at 5 ° C for 2 hours. The crystals were collected from the suspension by suction filtration, and then the crystals remaining in the eggplant flask were washed with the filtrate and collected. The combined crystals were dried at 50 ° C. and 90 mmHg for 3 hours to obtain 0.4485 g (yield: 93.0%) of white 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative monohydrate. From the results of the elemental analysis shown below, it was confirmed that the present compound was a monohydrate. Elemental analysis: Monohydrate crystal theoretical value: C: 48.16, H: 6.62, N: 10.21, S: 11.69 Observed value: C: 48.16, H: 6.55, N: 10.09, S: 11.87 (Reference) Anhydrous crystal Theoretical value: C: 51.54, H: 6.29, N: 10.93, S: 12.51

Hereinafter, in the examples, 2- (1-
Piperazinyl) -5-methylbenzenesulfonic acid derivative monohydrate was used. Example 1 Improvement Effect on Cardiac Function Decrease in Cardiomyopathy Thirty spontaneous cardiomyopathy hamsters (Bio.14.6) purchased from Charles River Japan were randomly divided into three groups. Inventive drug 3mg / kg / day
(Drug low dose group) and 10 mg / kg / day of the drug of the present invention (Drug high dose group) were administered by drinking water, and tap water was given to the remaining one group (disorder control group). In addition, as a normal control group,
Similarly, four groups of experiments were performed using 10 normal control hamsters (F1B) purchased from Charles River Japan.

In this spontaneously occurring cardiomyopathy hamster model, it is known that cardiomyopathy is genetically expressed from around 30 days to around 150 days after birth (Canadian Journal of Physs).
iology and Pharmacology. 6
2 (7): 891-898, 1983). The drug was continuously administered from the 30th to 150th days after birth, the period during which the cardiomyopathy developed, and the heart was excised on the day of administration. The isolated heart was perfused with Krebs-Henseleit solution (37 ° C., 95% O ₂ -5% CO ₂ aerated) according to the Langendorff method. The perfusion pressure was 100 mmHg. Two platinum electrodes were attached to the base of the heart and stimulated with an electric stimulator (280 beats per minute, stimulation time 3 ms). The change in the internal pressure of the left ventricle at that time was measured via a polyethylene tube filled with Krebs-Henseleit solution. Then, it was led to a transducer for measuring blood pressure, and the change in left ventricular pressure was measured. Further, the left ventricular pressure signal was input to a differential amplifier, and the maximum rate of change (LV (+) dP / dtmax, LV (-) dP / dtmax) of the left ventricular pressure ascending limb and descending limb was measured. End-diastolic pressure was determined from the left ventricular pressure and the waveform of the rate of change, and the left ventricular end-diastolic pressure (LVEDP) was measured. The above three indicators (LV (+) dP / dtmax, LV
(-) dP / dtmax and LVEDP) were used. On the other hand, F1B hamsters and Bio14.6 hamsters (10 each), which were purchased in the same manner, were measured at the stage of the 30th day after birth for three indices in the same manner as described above.

As a result, in the normal control group (F1B), the value of cardiac function at 150 days after birth was within the physiologically normal range (LV (+)
Change in dP / dtmax: 110.62%, change in LV (-) dP / dtmax: 8
6.52%) compared to 150 in the disabled control group.
The values at day of age showed a significant and significant decrease in LV (+) dP / dtmax, 43.89% of the value before onset of cardiomyopathy, and in LV (-) dP / dtmax, 34.71% of the previous value. The medicament of the present invention showed a significant dose-dependent improvement in this significant decrease in cardiac function. Expressing this degree of improvement as the recovery rate from the damaged control group to the normal control group at 150 days of age, LV (+) dP /
The dtmax was 78.33% in the low dose group, 102.32% in the high dose group, and the LV (-) dP / dtmax was 92.37% in the low dose group and 113.99% in the high dose group, respectively. The results are shown in Tables 1 and 2 below. On the other hand, left ventricular end diastolic pressure (LVE
DP) was 30 days after birth and 1 in the normal control group.
In contrast to the physiological range of 5 mmHg or less even at 50 days, the disabled control group showed 30 days after birth (6.
At 150 days of age, it increased to about 2.73 times (17.2 mmHg) compared to 3 mmHg. In contrast, the LVEDP values in the drug-treated group were 2.6 mmHg at the low dose and 2.0 mHg at the high dose, respectively.
mHg remained low. The results are shown in Table 3 below. From the above, it was suggested that the medicament of the present invention has a strong ameliorating effect on reduction of cardiac function in cardiomyopathy.

[0027]

[Table 1] * Values are expressed as mean ± standard error. (Same for the following results)

[0028]

[Table 2]

[0029]

[Table 3]

Example 2: Long-term survival effect on cardiomyopathy Cardiomyopathy hamsters purchased in the same manner as in Example 1 (Bio.
6) The 285 animals were randomly divided into three groups, two of which were 3 mg / kg / day of the drug of the present invention (low-dose group) and 10 mg / kg / day of the drug of the present invention (high-dose group of drug). ) In drinking water,
Tap water was given to the remaining one group (disability control group),
There were three groups of experiments. The drug was administered from the time when cardiomyopathy almost completely developed (150 days after birth), and the administration was terminated until the animal in the disorder control group died 100%. Survival curves were drawn by plotting the deaths for each group over time during the period, and the survival rate was calculated.

As a result, the day when the first fatal case was observed in the disorder control group (first death day) was 193 days after birth, whereas the group administered with the drug was 21 days after birth in the low dose group.
3 days (20 days longer than the disabled control group) and 243 days in the high dose group (also 50 days longer). When the mortality rate of each group reached 75%, that is, the day when the survival rate decreased to 25% (25% survival time) was 411 days after birth in the disabled control group, In the group to which the dose of the medicament of the present invention was administered, the period was 439 days (28 days longer than the disorder control group). By the end of the study period (467 days after birth), the survival rate did not decrease to 25% in the high dose group (final survival rate = 25.3%), so that the 25% survival time in the high drug dose group was 467. Days or more (extended by 56 days or more with respect to the disabled control group). In addition, the number of animals that finally survived (the number of surviving animals) at this time was 14 in the low-dose group and 24 in the high-dose group, respectively. As a result of statistically comparing the survival curves between the groups during the test period, the survival rate of the group to which the medicament of the present invention was administered was significantly improved over the survival rate of the disorder control group (P
<0.0001, Test: After the Log-rank Test, the significance level was adjusted (Bonferoni-type adjustment) by multiple comparisons. ). The results are shown in FIG.

[0032]

EFFECT OF THE INVENTION The medicament of the present invention has the effect of remarkably improving the decline of cardiac function under cardiomyopathy conditions,
It has the effect of improving long-term survival and prolonging life in sudden cardiomyopathy. Therefore, the medicament of the present invention is widely effective not only for idiopathic cardiomyopathy but also for other cardiomyopathy diseases in which a similar decrease in cardiac function occurs, for example, various specific cardiomyopathy and myocarditis, etc. It is also extremely effective both therapeutically and therapeutically.

[0033]

[Brief description of the drawings]

FIG. 1 is a diagram showing that the medicament of the present invention has a survival effect in a long-term survival test in cardiomyopathy.

Claims (4)

[Claims] 1. An agent for treating or preventing cardiomyopathy, comprising a 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative, a salt thereof, a hydrate or a solvate thereof as an active ingredient. 2. A therapeutic or prophylactic agent for cardiomyopathy comprising 2- (1-piperazinyl) -5-methylbenzenesulfonic acid derivative monohydrate as an active ingredient. 3. The method according to claim 1, wherein the cardiomyopathy is idiopathic cardiomyopathy. 4. The method according to claim 1, wherein the cardiomyopathy is specific cardiomyopathy.
The therapeutic or prophylactic agent for cardiomyopathy described above.