JPH04139127A - Medicine for preventing or treating cardiopathy - Google Patents

Abstract

PURPOSE:To provide the title medicine free from side effects on the circulatory system, capable of regulating intracellular Ca<2+> concentration, containing, as active ingredient, an aminobenzenesulfonic acid derivative or its salt. CONSTITUTION:The objective medicine containing, as active ingredient, an aminobenzenesulfonic acid derivative of the formula[R1 is H, alkyl, cycloalkyl, haloalkyl, halogen or aryl; R2 is H or (cyano-, nitro-, alkoxy-, halogen-, alkyl-or amino-substituted) alkyl or aralkyl; (n) is 1-4] or its pharmaceutically permissible salt [e.g. 2-(1-piperazinyl)-5-methylbenzenesulfonate]. The present medicine is useful for the prevention or therapies of stenocardia, cardiac infarction, hypertension, heart failure, arrhythmia, etc., because of its activity for regulating the intracellular Ca<2+> concentration in the cardiac muscle or vascular smooth muscle.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a drug for preventing or treating heart disease containing an aminobenzenesulfonic acid derivative or a pharmaceutically acceptable salt as an active ingredient.

(Problem to be solved by the prior art and the invention) Calcium ions (C) into myocardium or vascular smooth muscle cells
Excessive accumulation of a'') can lead to myocardial damage, cardiac conduction abnormalities, or abnormal vascular contraction, causing cardiovascular disease (
John A., Watts, American
Journal of Physiology, No. 23
Volume 8, pages 909-916, 1980; Juni
chi Azuwa, 5ulfur An+ino A
c1ds, Volume 6, Pages 179-201, 1983; Gordon L, Todd, Cardiova
ScularResearch, Volume 20, 645-6
51 pages, 1986; Hideyuki 0ht
a et al, CardiovascularR
esearch, Volume 22, Pages 407-413, 1
988). Conversely, when intracellular Ca'' decreases significantly, the contraction of myocardium or blood vessels decreases, causing functional decline (Adawia Alousi et al.
I, Cardiovascular Research
, Vol. 19, pp. 483-494, 1985).

Therefore, drugs that regulate intracellular Ca concentration are useful preventive or therapeutic agents for cardiovascular diseases, such as ischemic heart disease (myocardial infarction, angina pectoris, etc.), heart failure, hypertension, arrhythmia, etc. becomes.

Conventionally, drugs that suppress hyperaccumulation of Ca 2+ in myocardial or vascular smooth cells include, for example, Ca antagonists or β-
Receptor blockers are known. However, depending on the dosage of these drugs, in the case of Ca antagonists, intracellular Ca
It is known that cardiac function is suppressed due to a decrease in Z + concentration, or in the case of β-blockers, blockade of catecholamine action, leading to heart failure (Keiji Ueda,
Sogo Clinical Research, Vol. 36, pp. 851-854, 1987), and its applicability to cardiovascular diseases was limited.

(Means for Solving the Problems) The present inventors searched for a compound that regulates intracellular Ca concentration, and as a result of intensive study, we found that aminebenzenesulfonic acid derivatives have no side effects on the circulatory system ( Inner Ca”
We have discovered that the concentration can be adjusted and have arrived at the present invention.

That is, the gist of the present invention is as follows: Shipman (I) (In the above formula, R is a hydrogen atom, an alkyl group of C1 to Cb, a cycloalkyl group of C8 to C1, a halogenated alkyl group of 01 to C4, Represents a halogen atom or a C6-C1□ aryl group, R2 is a hydrogen atom, a C1-C6 alkyl group or cyano group, nitro M, C, -C, alkoxy group, halogen atom, CI"" Cb alkyl group represents a C7-CI! aralkyl group which may have one or more substituents selected from and amino groups, and n is 1
Represents an integer from ~4. ) or a pharmaceutically acceptable salt thereof as an active ingredient for preventing or treating heart disease.

The present invention will be explained in detail below.

As RI, hydrogen atom; C0 to C such as methyl group, ethyl group, n-propyl group, 1so-propyl group, n-butyl group, t-butyl group, n-pentyl group, n-hexyl group, etc.
6 straight chain or branched alkyl group; 03-C1 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; 01-C4 halogenated alkyl group such as trifluoromethyl group; fluorine atom, Halogen atoms such as chlorine atom and bromine atom; or C6 to C1□ aryl groups such as phenyl group, tolyl group and naphthyl group, and R2 is a hydrogen atom-methyl group,
Ethyl group, n-propyl group, is.

-C1-C6(7) straight-chain or branched alkyl groups such as propyl group, n-butyl group, t-butyl group, n-hentyl group, n-hexyl group; cyano group, nitro group, methoxy group, ethoxy group , C2 to C8 alkoxy groups such as propoxy group, butoxy group, pentoxy group, hexyloxy group,
Aralkyl groups such as benzyl groups, phenethyl groups, and naphthylmethyl groups of 07 to CI□, which may have one or more substituents selected from halogen atoms such as fluorine atoms, chlorine atoms, and bromine atoms, and amino groups can be mentioned.

Specific examples of the compounds of the present invention represented by -Funenin (1) below include those listed in Table 1 below.

Also included within the scope of the present invention are drugs containing pharmaceutically acceptable salts of the above compounds as active ingredients.

The above salts are non-toxic salts such as alkali metal salts or alkaline earth metal salts, such as sodium salts,
Examples include potassium salts, magnesium salts, calcium salts, aluminum salts, and the like. Ammonium salts, lower alkyl amines [e.g. triethylamine] salts, hydroxy lower alkyl amines [e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tris(
hydroxymethyl)aminomethane or N-methyl-D
- glucamine] salt, cycloalkylamine [e.g. dicyclohexylamine] salt, benzylamine [e.g.
Suitable non-toxic amine salts, such as N,N-dibenzylethylenediamine salts and dibenzylamine salts, are likewise preferred.

When focusing on the heterocycle containing two nitrogen atoms contained in the compound of the present invention, preferable salts include hydrochloride, hydrobromide, sulfate, phosphate, fumarate, succinate, and oxalate. Examples include non-toxic salts such as acid salts and lactate salts.

One example of the specific compound is shown in Table 2 below.

When the compound according to the present invention is used as a drug for the cardiovascular system, it can be administered orally or parenterally to humans in a conventional manner. Dosage forms for oral administration include granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups,
Examples include emulsions, suspensions, and solutions. In addition, dosage forms for parenteral administration include injections, suppositories, transdermal preparations, and the like.

In the above dosage form, the compound represented by Shipin (1) above or a pharmaceutically acceptable salt thereof may be used as a solid or liquid pharmaceutical carrier or excipient, a stabilizer, a lubricant, a sweetener, It is included together with commonly used pharmaceutical additives such as preservatives and suspending agents, and the content ratio of the therapeutically active ingredient to the carrier component is preferably in the range of 1% to 90% by weight.

Examples of solid carriers that can be used include lactose, china clay, sucrose, crystalline cellulose, cornstarch, talc, agar,
Examples include pectin, acacia, stearic acid, magnesium stearate, lecithin, and sodium chloride. Examples of liquid carriers include syrup, glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, Hensyl alcohol, propylene glycol, water, and the like.

When the compound of the present invention is used orally, the amount used is in the range of 0.01 mg = 1000111 g per day (preferably 0.1 mg to 100 mg) for adults, depending on age, sex, It is more preferable to increase or decrease the amount as appropriate depending on the pathological condition, symptoms, presence or absence of simultaneous treatment, etc. Further, the administration frequency may be once a day or divided into several times a day at appropriate intervals.

When the compound of the present invention is used as an injection, it is preferable to administer the same amount of 0.01 mg to 100 mg continuously or intermittently to adults.

Next, a method for producing the compound of the present invention will be explained.

The compound of the present invention can be produced, for example, by the following method 1).

Route (1)> (II) (I[[) (■) (In the above formula, R,, R, and n are as defined above, and R3 is a hydrogen atom or a C+-C- lower alkyl group. )l and Y each independently represent a halogen atom, and Z represents a halogen atom or -CH.

] Aniline represented by the above formula (n) and aluminum isocyanate or a salt of isocyanate, such as sodium isocyanate, are mixed in a polar solvent such as acetic acid or a mixed solvent of acetic acid and water,
By reacting at 0"C to 100"C for several minutes to several hours, or by reacting isocyanate esters such as methyl isocyanate, ethyl isocyanate, etc. with ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, toluene, hexane, diethyl ether, acetone, etc. in an organic solvent or a mixed solvent thereof at O″C-100°C
By reacting for several minutes to several hours with the above formula (I[[
) is obtained.

By reacting the urea compound (III) obtained by the above reaction with concentrated sulfuric acid, fuming sulfuric acid, sulfuric anhydride, chlorosulfonic acid, etc. at -20°C to 100°C for several minutes to several hours, the above formula (IV) can be obtained. The ureidobenzenesulfonic acid shown is obtained.

Ureidobenzenesulfonic acid obtained by the above reaction (
By hydrolyzing IV) with an aqueous solution such as hydrochloric acid, sulfuric acid or sodium hydroxide for several minutes to several hours at room temperature to 150°C, aminobenzenesulfonic acid represented by the above formula (V) is obtained.

Aminobenzenesulfonic acid (V
) with the amine represented by the above formula (Vl) in a polar solvent such as water, ethanol, N,N-dimethylformamide or dimethyl sulfoxide at 50 to 200°C for several minutes to several hours. ) is obtained. In this case, if necessary, an appropriate amount of a base such as sodium hydroxide, triethylamine, etc. may be added to neutralize the acid component generated during the reaction.

The cyclic amine benzenesulfonic acid (■
) to a halogen compound represented by the above formula (■) (wherein Z
represents a halogen atom) in a polar solvent such as water, ethanol or N,N-dimethylformamide, at room temperature
By heating at 150°C for several minutes to several hours, aminobenzenesulfonic acid, which is the compound of the present invention represented by the above formula (1), is obtained.

In addition, when the compound represented by the above formula (■) is an aldehyde compound (in the formula, Z represents -CH), the cyclic aminobenzenesulfonic acid (■) obtained by the above reaction with the aldehyde compound A reductive amination reaction is carried out by hydrogenation using a conventional method in the presence of a catalyst such as palladium in a polar solvent such as methanol, ethanol, acetic acid, dimethylformamide, or water, or the above aldehyde compound (■)
and the above aminobenzenesulfonic acid (■) in the above polar solvent by adding a reducing agent such as sodium cyanoborohydride and reacting at 0 to 100''C for several minutes to several hours to perform a reductive amination reaction. Aminobenzenesulfonic acid (1), which is a compound of the present invention, can also be obtained by

Further, the cyclic aminobenzenesulfonic acid represented by the above formula (■) can also be produced by the following route (2).

<Route (2)> (IX) (X) (■) Represented by the above formula (IX). - Diazotize fluoroaniline with a nitrite such as nitrite and an acid such as hydrochloric acid or sulfuric acid at -20 to 10°C, and then diazotize it with sulfur dioxide in a polar solvent such as acetic acid or dioxane. 20~40°C
to form sulfonyl chloride, and these are mixed with water,
It is represented by the above formula (X) by hydrolysis in ethanol, methanol or a mixed solvent thereof in the presence of a strong alkali such as sodium hydroxide. -Fluorosulfonic acid is obtained.

The 0-fluorosulfonic acid (X) obtained in this reaction was
, a cyclic diamine represented by the above formula (XI) in a polar solvent such as N-dimethylformamide or without a solvent, and optionally in the presence of a catalyst such as copper powder or copper iodide.
By heating at 00'C for several hours to several tens of hours,
A cyclic aminohenzenesulfonic acid represented by the above formula (■) is obtained.

(Examples) Hereinafter, the present invention will be explained in more detail with reference to Synthesis Examples and Examples, but the present invention is not limited by the following Synthesis Examples and Examples unless the gist thereof is exceeded. Furthermore, the compounds in the Synthesis Examples and Examples correspond to the compounds in Table 1 or Table 2 above.

Reference Example 1 Synthesis of 2-7mi/-5-n-propylbenzenesulfonic acid
6n+1, and a mixed solution 20 consisting of 130 g of sodium isocyanate and 900 ml of water dissolved in 232 ml of water.
After adding the above solution dropwise to 0ml, it was stirred in a water bath for 30 minutes, and the precipitated crystals were collected by filtration, washed with water, and dried to give a volume of 38.88ml.
g of 4-n-propylphenyl urea was obtained. This 4
-n-propylphenylurea 20% oleum 107
．． Add it little by little to 6 ml, react at 60°C for 2 hours, cool in a water bath, add about 40 On+1 ice, heat under reflux for 4 hours, cool and collect the precipitated crystals by filtration, wash with water, After drying, 30.09 g (yield: 64.1%) of the desired product having the following physical properties was obtained. Melting point: 261.7-262.3°
C Reference Example 2 Synthesis of 2-fluoro-5-n-propylbenzenesulfonic acid 2-fluoro-5-n-propylaniline 12°53g
was dissolved in a mixed solution of 73 ml of concentrated sulfuric acid and 120 ml of water, cooled to -10°C, and sodium nitrite 6,
An aqueous solution of sodium nitrite in which 15 g of sodium nitrite was dissolved in 15 ml of water was added dropwise at a temperature below 15°C, followed by stirring at this temperature for 25 minutes to prepare a diazonium salt solution. This diazonium salt solution was mixed with 120 ml of sulfur dioxide saturated acetic acid and 2.0 ml of copper chloride.
92+wl was dissolved in 20 ml of water at a temperature of -20'C, and further incubated at -10°C for 30 minutes.
After stirring for 1 hour at °C, the oil that separated was extracted with ethyl acetate. Ethyl acetate was distilled off from this extract under reduced pressure, and 90ml of 2N sodium hydroxide and 200o+1 of dioxane were added, heated at 100°C for 5 minutes, neutralized with acetic acid, and the reaction product was subjected to silica gel column chromatography. Developing solvent: chloroform: methanol: acetic acid = 500: 50: 6),
7.13 g (yield 39.9%) of the above-mentioned target product was obtained in the form of a paste.

NMR (DMSO-d6) δp p m : 0.86
8 (t, 3H), 1.536 (m, 2H), 2.5
1 (t, 2H), 7.00 (q, IH), 7.15
5 (m, IH), 7.468 (dd, LH) Synthesis Example 1 Synthesis of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid (Compound No. 12) 2-fluoro-5-
Methylbenzenesulfonic acid 0.76 g and piperazine 3
．． 44 g to 0.76 g of copper iodide and 0.26 g of copper powder
After reacting for 8 hours at 160°C in a sealed tube in the presence of g, the reaction product was purified by silica gel column chromatography (developing solvent: chloroform: methanol: acetic acid = 100:100:3), the following physical properties The above object of 0.6
7 g (yield 65.0%) was obtained.

Melting point = 271°C (decomposition) Compound Nα95 was obtained in the same manner (yield 33°7%)
) Melting point: 300°C or higher Synthesis Example 2 Synthesis of 2-(1-piperazinyl)-5-n-propylbenzenesulfonic acid (Compound No. 14) Water 500 d
2-amino-5-n-propylbenzenesulfonic acid 5
0.0 g and 6.28 g of sodium carbonate were added and dissolved by heating. After adding 88.13 g of bis(2-chloroethyl)amine hydrochloride to this solution, the mixture was heated under reflux for 3 hours. Add 26.25 g of sodium carbonate to this reaction solution.
A suspension of o+1 in water was further added, and the mixture was heated under reflux for 12 hours. After concentrating the reaction solution under reduced pressure, it was extracted with methyl alcohol, and after concentrating the methyl alcohol under reduced pressure, 200% water was added to the residue.
After adding No. 11 and adjusting the pH to about 8.0 with sodium carbonate, 500 al of chloroform was added and stirred.

The precipitated crystals were filtered, washed with chloroform, and dried to obtain 44.83 g (yield: 67.9%) of the desired product.

Melting point: 286°C (decomposition) The following compounds were obtained in a similar manner.

Compound yield (%) Melting point (°C) 91
27.6 290 (decomposition) 93 50.7
230 (disassembly) 94 18.7 270
(Decomposition) Synthesis Example 3 Synthesis of 2-(1-piperazinyl)-5-n-propylbenzenesulfonic acid hydrochloride (compound No., 12-(1-
Add 50.0 g of (piperazinyl)-5-n-propylbenzenesulfonic acid to a mixed solution of 200 ml of ethyl alcohol and 185 n+1 of 1N hydrochloric acid, dissolve by heating, and concentrate under reduced pressure. The precipitated crystals are washed with acetone and dried. As a result, 51.46 g of the above target product (yield 95.4
%) was obtained.

Melting point: 275°C (decomposition) The following compounds were obtained in the same manner.

Compound Soru Melting point (°C) 111 220 (decomposition) 112 225 (decomposition) Synthesis example 4 Synthesis of 2-(1-homopiperazinyl)-5-n-propylbenzenesulfonic acid (compound Nα86) by the same method as synthesis example 2 , 0.61 g of 2-fluoro-5-n-propylbenzenesulfonic acid and 2.80 g of homopiperazine.
g, the above target product o with the following physical properties, 3tg (yield 37
．． 2%).

Melting point = 205-210°C (decomposition) Synthesis example 5 2- (4-(2,3,4-trimethoxybenzyl)-
Synthesis of 1-piperazinyl]-5-n-propylbenzenesulfonic acid (compound 69) 0.10 g of sodium cyanoborohydride was dissolved in 2 ml of methanol solution, and 0゜log of zinc chloride was added thereto. After stirring for a minute, 0.40 g of 2-(1-piperazinyl)-5-n-propylbenzenesulfonic acid and 0.58 g of 2.3.4-1-rimethoxybenzaldehyde were added, and the
The organic layer was extracted by adding saline and tetrahydrofuran, and the tetrahydrofuran was distilled off from this extract under reduced pressure. : 6), 0.39 g (yield 58.5%) of the above-mentioned target product having the following physical properties was obtained as a glassy solid.

Melting point: 175-180°C (decomposition) NMR (DMSO-d6) δp p m: 0.87
0 (t, 3H, J=7.4Hz), 1.529 (m,
2H), 2.458 (t, 2H, J=7.8Hz),
2゜637 (broad m, 4H), 3.090
(broad m, 4H), 3.601 (bro
ads, 2H), 3.752 (s, 3H), 3.
788 (s, 3H), 3.817 (s, 3H), 6.
795 (d, LH, J = 8.7Hz), 6.909 (
d, IH, J=8Hz), 7.050 (d, 2H, J
-8°7Hz), 7.638 (d, IH, J=
2.0 Hz) Compound Na66 was obtained as a glassy solid by the same method (yield 91.1%).

Examples Pharmacological tests showing the usefulness of the aminobenzenesulfonic acid derivatives obtained in the synthesis examples as drugs for heart diseases and 2. The sexual toxicity test is shown below.

1. Molmo In order to evaluate the degree of inhibition of hyperaccumulation of intracellular Ca, which is the pharmacological activity of the compound of the present invention, the inhibition of isoproterenol action by the compound of the present invention was measured.

In other words, isoproterenol releases Ca'' into myocardial cells.
It is known that excessive inflow of Ca causes overaccumulation of Ca'' (F 1 e ckenste
in A, Janke J, Dori
ng H, Leder O; Recent
advances in 5tudieson
cardioac 5structure and
metabolism, myocardial
biology, Vol. 4.563-580.
(1974), it can be said that compounds that suppress the action of isoproterenol suppress intracellular Ca'' hyperaccumulation.

<Method> Male Hartley guinea pig (weight 250-350g)
The isolated right ventricular papillary muscle was suspended in an organ bath filled with nutrient solution (Klebs-Henseleit solution). The temperature of the nutrient solution was maintained at 32°C, and a mixed gas of 95% oxygen and 5% carbon dioxide was bubbled through it. A resting tension of approximately 0.5 g was applied to the papillary muscles via a platinum electrode for a duration of 1 ms and a frequency of 1 Hz.
Electrical stimulation was performed using a square wave with a voltage 15% higher than the dark value.

The contractile force of the papillary muscles was measured via a tonic cadence juicer and recorded using a polygraph. After stabilizing the specimen for about 90 minutes, isoproterenol (10-' to 10-'M) was added to the organ bath so that the contraction increased by more than 100%, and at the point when the maximum response was obtained, the compound of the present invention was added. was similarly added to the organ bath, and the inhibition rate was determined by measuring the percentage of increase in contraction caused by isoproterenol.

<result> The inhibition rate of each compound is shown in Table 3 below.

According to Table 3 above, the drug of the present invention suppresses myocardial contraction caused by isoproterenol, so it is clear that the drug of the present invention suppresses the action of isoproterenol. It can be seen that this suppresses overaccumulation.

2. Ischemic myocardial protective effect When the myocardium falls into an ischemic state, a large amount of Ca' flows into myocardial cells, resulting in an increase in resting tension and a marked decrease in myocardial contractile function. It has been reported that drugs with cardioprotective effects alleviate these disorders (Araki, H.

& Lefer, AM, :Role of
prostacyclin in the pr
servation of ischemic
yocardial tissue in th
e perfused cat heartCi
rc, Res, 47:757-9763゜1
980).

Therefore, in order to evaluate the ischemic myocardial protective effect of the drug of the present invention, two parameters (increase in resting tension, increase in resting tension,
The effect on contraction tension reduction) was investigated. The method and results are shown below.

<Method> The heart was removed from a male Wistar rat (250-350 g) and infused with Krebs-Henseleit solution (37°C, 395% 0□-5% COz) according to the Langendorff method.
Irrigated with The thread attached to the apex of the heart was connected to a tension transducer, and a resting tension of 1.5 g was applied to measure the contractile tension. After stabilization for 1 hour, ischemia was induced by lowering the perfusion pressure from 80 CI + 1 water column pressure, and at the same time as the perfusion pressure was lowered, various concentrations of the drug of the present invention were injected into the perfusate. and continued low pressure perfusion for 90 minutes. After 90 minutes, the infusion of the agent of the invention was stopped and reperfusion was performed at the original perfusion pressure. Rise in resting tension Cg just before reperfusion
) and the contractile tension [%] 30 minutes after reperfusion (normalized with the contractile force before induction of ischemia as 100%).

〈Result〉 The results are shown in Table 4 below.

According to Table 4 above, the drug of the present invention suppresses the increase in resting tension caused by ischemic conditions, and also prevents the decrease in myocardial contractility accompanying myocardial damage caused by ischemic conditions.

Therefore, it is clear that the drug of the present invention has a protective effect on myocardium under ischemic conditions.

3. No. 1 Molecular weight The heart failure improving effect of the drug of the present invention was demonstrated using dogs with decreased cardiac function by administering high doses of β-blockers to reduce intracellular Ca. investigated.

The method and results are shown below.

Method> A mongrel dog was anesthetized with 30 μg/kg (intravenous injection) of bendoparbital, and artificial respiration was performed. After left thoracotomy, a blood flow measuring probe connected to an electromagnetic blood flow meter was attached to the aortic root to measure cardiac output. A catheter-tip manometer was inserted into the left ventricle from the left carotid artery to measure the left ventricular pressure, thereby electrically measuring the rate of change in left ventricular pressure (dP/dt). After the animals were stabilized, following the method of Narimatsu et al.
Forshung 37 (1), 39
8406.1987), the β-blocker propranolol was administered intravenously at 1.5 kg/kg, followed by 0°09
Intravenous administration of propranolol was continued at a rate of 1/kg/min to induce left ventricular failure. Thirty minutes after the start of propranolol administration, the drug of the present invention was administered intravenously, and observation was performed for 45 minutes.

As a control, a system in which physiological saline was administered instead of the drug of the present invention was used.

<Results> d P/d tma as an index representing the contractile force of the left ventricle
x, and set the left ventricular dP/dtmax before the start of the test to 10
The values after administration of propranolol and 45 minutes after administration of the drug of the present invention or physiological saline are shown in Table 5 below.
Shown below.

According to Table 5 above, the drug of the present invention increases the left ventricular contractile force, which had decreased due to the marked decrease in intracellular Ca'' due to propranolol, and therefore the drug of the present invention has an effect of improving heart failure. Recognize.

4.2 Blood status Among the compounds of the present invention, acute toxicity in mice was investigated for compound No. 110.

<Method> Compound No. 110 in physiological saline (0.9% chloride IJum) was administered to male mice (18-25 g) to give a 50% lethal dose of LDs. was calculated. The administration route was intravenous tail vein administration (LD), and calculations were done up and d.

wn method) as well as oral administration (LDs.

The calculation was carried out using two routes (based on the probit method).

<result> The results are shown in Table 6 below.

Table (Effects of the invention)
Since it has the effect of regulating concentration, it is useful for the prevention or treatment of various circulatory system diseases, such as angina pectoris, myocardial infarction, hyperdepression, heart failure, and arrhythmia.

Claims (2)

[Claims] (1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the above formula, R_1 is a hydrogen atom, C_1 to C_6 are alkyl groups, C_3 to C_7 are cycloalkyl groups, C_1 to
C_4 halogenated alkyl group, halogen atom or C
_6 to C_1_2 represents an aryl group, R_2 is a hydrogen atom, a C_1 to C_6 alkyl group or a cyano group, a nitro group, a C_1 to C_6 alkoxy group, a halogen atom, a C_1 to C_6 alkyl group, and an amino group. C_7-C_ which may have three or more substituents
1_2 represents an aralkyl group, and n represents an integer of 1 to 4. ) A drug for preventing or treating heart disease containing an aminobenzenesulfonic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient. (2) R_1 represents a hydrogen atom, an alkyl group of C_1 to C_6, a cycloalkyl group of C_5 to C_6, a trifluoromethyl group, a halogen atom or a phenyl group, and R_
2 is a hydrogen atom, C_1 to C_3 alkyl group or C_
C_7 which may be substituted with an alkyl group of 1 to C_3, an alkoxy group of C_1 to C_3 or a halogen atom
~C_1_2 represents an aralkyl group, and n is 2 or 3
The drug according to claim 1, characterized in that it represents.