JPH0826995A - Antiarrhythmic agent containing benzimidazole derivative - Google Patents

Abstract

PURPOSE:To obtain an arrhythmic agent or an inhibitor of a potassium channel or a calcium channel, containing a specific benzimidazole derivative (salt) as an active ingredient without any defect of inverse frequency dependence or deterioration in myocardial contractive force, etc. CONSTITUTION:This antiarrhythmic agent contains a benzimidazole derivative (salt) of the formula [R1 and R2 are each H or a lower alkyl; (n) is 1-4] as an active ingredient. A maleate is preferred as the salt. The active ingredient is orally administered in the form of a tablet, a sugar-coated tablet. a hard capsule, a soft capsule, a granule, a powder, a solution, an emulsion, a suspension, etc., or parenterally administered in the form of a parenteral injection, a suppository, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antiarrhythmic agent, a potassium channel inhibitor, containing a benzimidazole derivative and a pharmacologically acceptable salt thereof as an active ingredient,
It relates to a calcium channel inhibitor.

[0002]

2. Description of the Related Art Arrhythmia, which is one of the important cases of heart disease, has been extensively studied and several compounds have already been put to practical use as therapeutic agents. . A particularly good prognosis is expected, so recently, according to Vaughan Williams classification, Class III
Antiarrhythmic drugs, which extend the action potential duration, that is, the refractory period, classified as, are attracting attention. However, antiarrhythmic drugs classified into class III generally have a drawback called inverse frequency dependence in which the action as an antiarrhythmic becomes weaker as the heart rate increases. Vaugha as an antiarrhythmic drug
n Calcium channel inhibitors defined in class IV according to Williams classification, such as verapamil, are effective in treating arrhythmias involving sinoatrial and atrioventricular nodules because they suppress calcium currents. It has the drawback of weakening. Therefore, development of an excellent antiarrhythmic drug that overcomes these drawbacks has been expected.

On the other hand, inotropic agents known as therapeutic agents for heart diseases similar to those of the present invention usually induce arrhythmia as a side effect, and thus the use of these inotropic agents as therapeutic agents for arrhythmia has hitherto been considered. There wasn't. That is, for example, a catecholamine drug, which is a drug having a cardiotonic effect, is not used for the treatment of arrhythmia because it is known to induce arrhythmia as a side effect. In addition, it has been revealed that long-term administration of phosphodiesterase inhibitors such as amrinone and milrinone, which are recently developed cardiotonic agents, increases lethal ventricular arrhythmia (Packer, M. et a
l., New Engl. J. Med., 325: 1468-1475 (1991)).

On the other hand, the present inventors have previously described the following general formula (2):

Embedded image [In the formula, R ₁ is a hydrogen atom, an alkyl group or the like, and n is 1-
4, R ₂ is a hydrogen atom, an alkyl group, alkyl-piperazinylbenzoyl, etc., A is —NR ₃ — (R ₃ is a hydrogen atom or an alkyl group), B is triazolyl, pyridyl, etc.]
The inventors have found that the benzimidazole derivative represented by the formula (3) is a compound having a cardiotonic action, and completed the invention of a pharmaceutical composition having a cardiotonic action (see JP-A-63-146871). And in this invention, a compound included in the scope of the benzimidazole derivative of the present invention was disclosed as a compound useful as a cardiotonic agent, but this compound also has the above-mentioned technical field that the cardiotonic agent cannot be used as a therapeutic agent for arrhythmia. It was never expected that it could be used as a therapeutic agent for arrhythmia according to the general knowledge of.

[0005]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that the benzimidazole derivative is Vaughan.
Combining antiarrhythmic effects classified as Class III and Class IV by the Williams classification,
They have completed the present invention by finding that they do not have the peculiar drawbacks found in many of the antiarrhythmic drugs classified as Class III and Class IV, such as inverse frequency dependence and reduction in myocardial contractility.

That is, the present invention has the following general formula (1):

Embedded image [Wherein R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, and n is 1 to 4] and a pharmaceutically acceptable salt thereof is contained as an active ingredient. And an antiarrhythmic agent characterized by:

More specifically, an antiarrhythmic drug containing the above-mentioned benzimidazole derivative and a pharmacologically acceptable salt thereof as an active ingredient is a conventional class III drug.
Similar to antiarrhythmic drugs, it exhibits antiarrhythmic effects by inhibiting potassium channels and prolonging the effective refractory period. However, unlike conventional drugs, no inverse frequency dependence is observed. At the same time, like the conventional class IV antiarrhythmia, it exhibits antiarrhythmic effects by inhibiting calcium channels and exerting an inhibitory effect on sinus node and atrioventricular node. However, unlike conventional drugs, it does not have an inhibitory effect on myocardial contraction, but rather increases it.

That is, a drug containing the above-mentioned benzimidazole derivative and a pharmacologically acceptable salt thereof as an active ingredient has both of these two antiarrhythmic actions, and further, does not have two inherent defects. Have found that it can be used as an excellent antiarrhythmic agent.

The lower alkyl group represented by R ₁ and R ₂ in the above general formula is a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl group, ethyl group, n-propyl group, Isopropyl group, n-butyl group,
An isobutyl group, a tert-butyl group and the like are included.
Specific examples of the compound represented by the general formula include the following compounds.

[0010]

[Table 1]

[0011]

[Table 2]

[0012]

[Table 3]

[0013]

[Table 4]

The benzimidazole derivative represented by the above general formula can be converted into an addition salt with a pharmacologically acceptable acid, if desired, and an antiarrhythmic agent or potassium channel antagonist containing the acid addition salt. Agents and calcium channel antagonists are also included in the present invention. Examples of the acid addition salt include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and salts with organic acids such as acetic acid, succinic acid, oxalic acid, malic acid and tartaric acid, but especially Organic acids and even maleates are preferred.

When the benzimidazole derivative of the present invention or a pharmacologically acceptable salt thereof is used as an antiarrhythmic agent, potassium channel antagonist or calcium channel antagonist, various dosage forms can be prepared. . That is, this preparation can be orally administered in the form of tablets, dragees, hard capsules, soft capsules, granules, powders and the like, and solutions such as solutions, emulsions or suspensions. Further, in the case of parenteral administration, it is administered in the form of injection solution, suppository or the like.

In preparing these formulations, conventional additives for formulation such as excipients, stabilizers, preservatives,
A solubilizer, a wetting agent, an emulsifying agent, a lubricant, a sweetening agent, a coloring agent, a flavoring agent, a tonicity adjusting agent, a buffering agent, an antioxidant and the like can be added to prepare a formulation.

Examples of the additives include starch, sucrose,
Fructose, lactose, glucose, mannitol, sorbitol-precipitating calcium carbonate, crystalline cellulose, carboxymethyl cellulose, dextrin, gelatin, gum arabic, magnesium stearate, talc, hydroxypropyl methylcellulose and the like can be mentioned.

When the compound of the present invention is used as a solution or injection, the active ingredient can be dissolved or suspended in a conventional diluent (aqueous or non-aqueous carrier). As the diluent, physiological saline, Ringer's solution, glucose aqueous solution, alcohols, fatty acid esters, glycols,
Glycerin fatty acid glyceride, oil source derived from plants and animals,
Paraffins are included.

Further, these preparations can be manufactured by a usual method. And, as a usual clinical dose, it is used in the range of 1 to 1000 mg in the case of oral administration per adult. More preferably, it is used in the range of 10 to 200 mg. The compound of the present invention has low toxicity as shown in Example 9. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 N-Methyl-N- (4,6-dimethylpyrid-2-yl-1- [2- (4-3,4-dimethoxybenzoyl) piperazin-1-yl] to calcium current in guinea pig cardiomyocytes ) Effect of ethyl] benzimidazole-2-carboxamide (Compound 1) After removing the heart from the guinea pig, cannulate the aorta and fix it in a constant temperature bath at 37 ° C, then use Krebs' solution (112).
mM NaCl, 4.7 mM KCl, 2.2 mM CaCl ₂ ,
1.2 mM MgCl ₂ , 25 mM NaHCO ₃ , 1.2 mM K
Langendorff perfusion was performed with H ₂ PO ₄ , 14 mM Glucose). 0.04% dissolved in Ca-removing Krebs' solution
Collagenase (Yakult) was perfused to obtain ventricular myocytes. Electrode solution (100mM K-aspartate, 50mM KC
1, 5 mM ATP2Na, 0.552 mM CaCl ₂ , 1 mM M
gCl ₂ , 5 mM N-2-hydroxyethylpiperazine-N ′
-3-propanesulfonic acid (HEPES), 1mM O, O'-B
is (2-aminoethyl) ethyleneglycol-N, N ', N',
1-5 filled with N'-tetraacetic acid (EGTA))
The current was measured by the Hall cell clamp method, in which the film on the contact surface between the cell and the electrode was destroyed using the MΩ glass electrode and the current of the entire cell was recorded. HEPES solution (137 mM Na
Cl, 5.9 mM KCl, 1.2 mM MgCl ₂ , 2.2 mM
CaCl ₂ , 14mM glucose, 10mM HEPES)
Amplifier for patch clamp (Made by Nihon Kohden)
CEZ-2300) and computer software pClamp (manufactured by Axon) were used for stimulation and recording.

At room temperature, the holding potential was changed from -30 mV to +10 mV by 1
The current obtained when a depolarizing pulse of 50 ms was given with a stimulation frequency of 0.2 Hz was measured. The drug was dissolved in dimethyl sulfoxide (DMSO) and acted by perfusion. As shown in FIG. 1, it was found that Compound 1 inhibited the inward calcium current at 10 ⁻⁶ M and inhibited the calcium channel.

Example 2 Action of Compound 1 on Potassium Current in Guinea Pig Cardiomyocytes Using ventricular myocytes obtained in the same manner as in Example 1
In the presence of nicardipine (synthesized by Nisshin Flour Milling Co., Ltd.) by the Lucelle clamp method, the holding potential was changed from -40 mV to +50 mV for 225 ms
The trailing current obtained when the depolarizing pulse was applied at 0.1 Hz was measured. HEPES solution (137 mM
NaCl, 5.9 mM KCl, 1.2 mM MgCl ₂ , 1 mM
CaCl ₂ , 14mM glucose, 10mM HEPES)
The drug was dissolved in DMSO and acted by perfusion. Figure 2
As shown in (1), it was found that Compound 1 suppressed potassium current at a concentration of 10 ⁻⁷ M or more in a concentration-dependent manner and inhibited potassium channels.

Example 3 Effect of Compound 1 on Refractory Period of Guinea Pig Papillary Muscles The right ventricular papillary muscles were isolated from guinea pigs and artificial nutrient solution (1
12 mM NaCl, 4.7 mM KCl, 2.2 mM CaC
l ₂ , 1.2 mM MgCl ₂ , 25 mM NaHCO ₃ , 1.2 mM
KH ₂ PO _4, 14mM glucose) fixed to warm constant temperature bath to 35 ° C. containing, were recorded action potentials using a glass electrode 10-20MΩ filled with 3M potassium chloride solution was added to electrical stimulation of 1Hz . A microelectrode amplifier (MEZ-8300 manufactured by Nihon Kohden) was used for the measurement. The stimulus intensity is first,
The second pulse gave 1.5 times the strength of the stimulus that evoked an action potential. A second pulse was added in the middle of the action potential every 8 pulses, and the interval between the first pulse and the second pulse when no response to the second pulse was measured as the refractory period. The drug is DM
It was dissolved in SO and acted by perfusion. As shown in FIG. 3, Compound 1 prolongs the refractory period at a concentration of 10 ⁻⁶ M or more, and has an action as a class III antiarrhythmic agent.

Example 4 Effect of Compound 1 on Guinea Pig Papillary Muscle Calcium Spike Action potentials were recorded as in Example 3. However, for the purpose of suppressing sodium and potassium channels, 20
27 mM with mM tetraethylammonium (TEA)
The action potential (calcium spike) due to activation of calcium channel was obtained by the KCl-Krebs solution. Electrical stimulation is twice as intense as the stimulation that evokes action potentials.
The drug was dissolved in DMSO and acted by perfusion. As shown in FIG. 4, Compound 1 suppressed the calcium spike in a concentration-dependent manner at a concentration of 10 ⁻⁶ M or higher, and showed the action of inhibiting the calcium channel similarly to the class IV antiarrhythmic agent.

Example 5 Effect of Compound 1 on Atrioventricular Conduction Time in Canine Atrioventricular Nodule Another dog anesthetized by cannulating the right coronary artery, anterior septal artery, or left circumflex branch of the heart isolated from a dog ( Blood donation dog)
Arterial blood was introduced from the carotid artery of the mouse and heated to 37 ° C., and constant pressure perfusion was performed using a peristaltic pump (1203 manufactured by Harvard) and a pump controller (SCS-22 manufactured by Datagraph). The perfused blood was returned from the blood reservoir into the jugular vein of the donor dog. An electrical stimulus of 1.5 times the reaction threshold was applied from an electrode attached to the upper right atrium (2 Hz), and a stimulus conduction pulse was sent from each of electrodes attached to the lower right atrium and the septum of the left ventricle by an AV interval meter (Data Graph Co., Ltd.). ,
H-110) and the interval was measured as the AV conduction time. The drug was dissolved in 0.1 N hydrochloric acid, diluted with physiological saline to the required concentration, and injected into the coronary artery in a volume of 30 μl using a microdispenser. As shown in FIG.
Intraarterial administration of Compound 1 into the left circumflex branch resulted in 3
At 0 nmol or more, the AV conduction time was prolonged in a dose-dependent manner.
From this, an action as a class IV antiarrhythmic agent was shown.

Example 6 Rat Coronary Artery Ligation / Reperfusion Arrhythmia Model Anesthetized rats were subjected to thoracotomy under artificial respiration to obtain coronary arteries (anterior descending branch).
Was ligated for 5 minutes and then reperfused, and the occurrence of arrhythmia was observed by a second lead electrocardiogram using an electrocardiograph (manufactured by Nihon Kohden, OEC-3200). The drug was dissolved in 0.01N hydrochloric acid by intravenous administration and inserted into the femoral vein 15 minutes before ligation, and by oral administration, it was dissolved in 0.1N hydrochloric acid and administered by an oral probe 1 hour before ligation. As shown in Table 5, Compound 1 was administered intravenously at 0.3-3 mg / kg and at 30-100 mg / k.
Oral administration of g dose-dependently reduced the incidence of ventricular fibrillation and arrhythmic death.

[0027]

[Table 5]

Example 7 Examination of Stimulus Frequency Dependence on Guinea Pig Papillary Muscle Action Potential The action potential was recorded in the same manner as in Example 3. Time to repolarize 90% of repolarization phase of action potential obtained when the frequency of electrical stimulation was changed to 0.5 to 2 Hz (APD ₉₀ ).
The effect on As shown in FIG. 6, compound 1
Prolonged APD ₉₀ at 10 ⁻⁶ M or more at any stimulation frequency. Unlike conventional class III antiarrhythmic drugs, no inverse frequency dependence was observed, and the degree increased rather depending on the frequency.

Example 8 Effect of Compound 1 on Guinea Pig Atria 95% O _{2 of} the left and right atriums isolated from the guinea pig respectively
Krebs heated to 32 ° C with aeration of -5% CO ₂ mixed gas
-Henseleit solution (118 mM NaCl, 4.7 mM KCl,
_{2.5mM CaCl 2, 1.2mM MgSO 4 ·} 7H 2 O, 1.
2 mM KH ₂ PO ₄ , 24.9 mM NaHCO ₃ , 11 mM gluc
It was suspended in a Magnus tube filled with ose. Response threshold of 1.
The contraction tension of the left atrium driven at 0.5 Hz by 5 times electrical stimulation was measured using an isometric transducer (TSB612T, manufactured by Nihon Kohden), and the effect on myocardial contraction force was examined. Moreover, the heart rate of the spontaneously moving right atrium was measured using a tachometer (Nihon Kohden, AT600G), and the effect on the heart rate of the sinoatrial node was examined. The drug was dissolved in DMSO, diluted to the required concentration with purified water, and added into the Magnus tube. As shown in FIG. 7, unlike the conventional class IV antiarrhythmia, Compound 1 did not show a myocardial contraction inhibitory action, and at a concentration of 10 ⁻⁵ M or higher, it decreased the pulsation rate of sinoatrial node at the same time. Increased myocardial contractility.

Example 9 Acute toxicity After fasting male rats, Compound 1 was suspended in 0.5% carboxymethylcellulose aqueous solution and orally administered at a volume of 10 ml / kg, and the progress was observed. As a result, LD _{50 of} compound 1
The value was 1200 mg / kg or more.

Formulation Example 1 Tablet (1 tablet) N-methyl-N- (4,6-dimethylpyrid-2-yl-1- [2- (4-3,4-dimethoxybenzoyl) piperazin-1-yl) ethyl ] Benzimidazole-2-carboxamide maleate 20 mg Magnesium silicate 20 mg Lactose 98 mg Hydroxypropylcellulose 7.5 mg Magnesium stearate 1 mg Vegetable hydrogenated oil 3 mg 150 mg Active ingredient, magnesium silicate and lactose are mixed and this is mixed with 5%. Kneading with an alcohol solution containing hydroxypropyl cellulose, then granulating to an appropriate particle size, drying,
After sizing, magnesium stearate and hardened vegetable oil are further added and mixed to obtain uniform granules. Then, using a rotary tableting machine, the diameter is 7.0 mm, the weight is 150 mg, and the hardness is 6 kg.
Tablets were prepared.

Formulation Example 2 Granules N-methyl-N- (4,6-dimethylpyrid-2-yl-1- [2- (4-3,4-dimethoxybenzoyl) piperazin-1-yl) ethyl] benzimidazole -2-Carboxamide maleate 10 mg Magnesium oxide 40 mg Calcium hydrogen phosphate 38 mg Lactose 10 mg Hydroxypropyl cellulose 20 mg After mixing each raw material except hydroxypropyl cellulose in the above formulation example, after uniformly mixing with 5% thereof, An alcohol solution containing hydroxypropyl cellulose was added and kneaded, then granulated by an extrusion granulator and dried to obtain granules. The granules were sized to obtain granules (12 to 48 mesh).

Formulation Example 3 Syrup N-methyl-N- (4,6-dimethylpyrid-2-yl-1- [2- (4-3,4-dimethoxybenzoyl) piperazin-1-yl) ethyl] benzimidazole 2-Carboxamide maleate 1.000 g Sucrose 30.000 g D-sorbitol 70 w / v% 25.000 g Ethyl paraoxybenzoate 0.030 g Propyl paraoxybenzoate 0.015 g Flavor 0.200 g Glycerin 0.150 g 96% ethanol 0.500 g Distilled water qs Total amount 100 ml Sucrose, D-sorbitol, methyl paraoxybenzoate,
Propyl paraoxybenzoate and the above active ingredients are dissolved in 60 g of warm water. After cooling, a solution of flavoring agent dissolved in glycerin and ethanol is added. Then water is added to the mixture to bring it to 100 ml.

Formulation Example 4 Injection Solution N-methyl-N- (4,6-dimethylpyrid-2-yl-1- [2- (4-3,4-dimethoxybenzoyl) piperazin-1-yl) ethyl] benzimidazole -2-Carboxamide maleate 10.0 mg Sodium chloride 81.0 mg Sodium hydrogen carbonate 8.40 mg Distilled water for injection Appropriate amount 10.0 ml Sodium hydrogen carbonate, sodium chloride and the active ingredient are added to distilled water and dissolved to make 10. Make up to 0 ml.

Formulation Example 5 Suppository N-methyl-N- (4,6-dimethylpyrid-2-yl-1- [2- (4-3,4-dimethoxybenzoyl) piperazin-1-yl) ethyl] benzimidazole -2-Carboxamide maleate 2 g Polyethylene glycol 4000 20 g Glycerin 78 g Total amount 100 g Glycerin is added to the active ingredient and dissolved. Polyethylene glycol 4000 is added thereto, heated and dissolved, and then poured into a suppository mold and cooled and solidified to produce 1.5 g of a suppository.

[0036]

INDUSTRIAL APPLICABILITY The benzimidazole derivative and the pharmacologically acceptable salt thereof of the present invention are classified as class III antiarrhythmic drugs and are classified into potassium channel inhibitory activity and class.
It also has a calcium channel inhibitory action classified as an antiarrhythmic drug of IV and is expected to be used as an excellent antiarrhythmic drug. Further, it is an antiarrhythmic drug which does not have the peculiar drawbacks found in many of the antiarrhythmic drugs classified as class III or class IV, such as inverse frequency dependence and decrease in myocardial contractile force.

[Brief description of drawings]

1 shows the effect of Compound 1 on calcium current in guinea pig cardiomyocytes.

FIG. 2 shows the effect of Compound 1 on the potassium current in guinea pig cardiomyocytes.

FIG. 3 shows the effect of Compound 1 on the refractory period of guinea pig papillary muscle of Compound 1.

FIG. 4 shows the effect of Compound 1 on guinea pig papillary muscle calcium spikes.

FIG. 5 shows the effect of Compound 1 on stimulated atrioventricular conduction time in the atrioventricular node of dogs.

FIG. 6 shows changes in the action of Compound 1 on guinea pig papillary muscle action potential depending on the stimulation frequency.

FIG. 7 shows the effect of Compound 1 on cardiac contractility and heart rate in guinea pig atria.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 213: 40 235: 24) (72) Inventor Yukiko Goto 5 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Prefecture 3-3-1 Nisshin Seifun Co., Ltd. Pharmaceutical Research Center (72) Inventor Tatsuhiro Sahara 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd. Pharmaceutical Research Center (72) Inventor Sueda Noriyoshi 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd. Pharmaceutical Research Institute (72) Makoto Taniuchi 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Pharmaceutical Research Institute Co., Ltd. (72) Inventor Kazuhiko Yamada 483, Sunahara, Wada, Komoro City, Nagano 12 Nisshin Seifun Co., Ltd., Komoro Plant

Claims (3)

[Claims] 1. The following general formula (1): [Wherein R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, and n is 1 to 4] and a benzimidazole derivative or a pharmaceutically acceptable salt thereof is contained as an active ingredient. An antiarrhythmic agent characterized by the following: 2. A potassium channel inhibitor comprising the benzimidazole derivative according to claim 1 and a pharmacologically acceptable salt thereof as an active ingredient. 3. A calcium channel inhibitor comprising the benzimidazole derivative according to claim 1 and a pharmacologically acceptable salt thereof as an active ingredient.