Drug-induced bradycardia and bradyarrhythmia medications

Abstract

[Problem] To provide a therapeutic agent for drug-induced bradycardia and bradyarrhythmia. [Solution] A therapeutic agent for drug-induced bradycardia and bradyarrhythmia, the agent containing compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient. (In the formula, Ph represents a phenyl group.)

Description

[Technical Field]

[0001] The present invention relates to drugs for treating drug-induced bradycardia and bradyarrhythmia. [Background technology]

[0002] Arrhythmia is an irregular heart rate or rhythm, resulting in various electrocardiogram abnormalities. Arrhythmias caused by abnormal heart rates can be classified as tachyarrhythmia and bradyarrhythmia. The normal resting human heart rate is about 50 to 100 beats per minute; a rate lower than this is called bradycardia, and a rate higher than this is called tachycardia. Examples of bradyarrhythmia include sick sinus syndrome (SSS), atrioventricular block (AV block), atrioventricular dissociation, and junctional rhythm.

[0003] Sick sinus syndrome (SOS) is a condition characterized by a slow pulse rate, primarily due to impaired function of the sinus node, leading to dysfunction of the brain, heart, and kidneys. Electrocardiographically, it is classified into three types: 1) sinus bradycardia (heart rate below 50 beats per minute), 2) sinus arrest or sinoatrial block, and 3) bradycardia-tachycardia syndrome. Clinically, symptoms such as Adams-Stokes attacks, heart failure, and fatigue appear chronically. Treatment options include oral or intravenous anticholinergics (atropine sulfate) and beta-agonists to increase the rate of spontaneous sinus node activation. If these treatments do not improve bradycardia or if symptoms worsen when medication is discontinued, a pacemaker may be used.

[0004] The sinus node, where electrical impulses originate in the heart, is a specialized part of the myocardium that has acquired automaticity and expresses specific proteins. Among these, a group of membrane proteins called channels are most important for the function of the sinus node. Channels contribute to the formation of an electrical potential gradient between the cell and the outside of the cell by allowing ions to pass through the cell membrane, and are involved in the propagation of electrical signals not only in the sinus node but in all myocardial cells, and the subsequent cardiac contraction and relaxation, which are essential cardiac functions.

[0005] Drug-induced bradyarrhythmia refers to a state in which the bradyarrhythmia is induced by a drug administered for the purpose of treating some disease.

[0006] Regarding drug-induced bradyarrhythmia, it has long been known that certain drugs can cause arrhythmias. In recent years, it has been reported that bradyarrhythmia can be induced by sphingosine-1-phosphate (S1P) receptor modulators such as fingolimod and siponimod, which are used to treat multiple sclerosis and other conditions (e.g., Non-Patent Documents 1 and 2).

[0007] The mechanisms of these drug-induced bradyarrhythmias have yet to be fully elucidated. The same is true for the mechanisms of bradyarrhythmias caused by S1P receptor modulators. For example, with regard to the mechanism of bradyarrhythmias induced by fingolimod, an S1P receptor modulator, it has been reported that activation of the cardiac acetylcholine-activated potassium channel (KACh channel) involving S1P1 or S1P3, an S1P receptor subtype, may be involved (e.g., Non-Patent Document 3), or that fingolimod may directly inhibit the channel (e.g., Non-Patent Documents 4 and 5). However, the mechanisms of these events, including the above possibilities, have not been fully elucidated, and no drugs are known that are effective in treating such drug-induced bradyarrhythmias.

[0008] In addition, beta-blockers, calcium channel blockers, and digitalis preparations are also known to induce bradycardia, which can pose a therapeutic problem. For example, when using beta-blockers to treat heart failure, it is recommended to start at a low dose and gradually increase the dose while monitoring heart rate and other drug tolerability. The effects of beta-blockers are thought to be dose-responsive. The MUCHA trial, which compared the efficacy and safety of two doses of the beta-blocker carvedilol (5 mg / day and 20 mg / day (divided twice)) to determine the optimal dose in Japanese patients with mild to moderate chronic heart failure, showed a dose-dependent increase in left ventricular ejection fraction improvement, suggesting that increasing the dose to a higher level is desirable. During the initiation and increase of beta-blockers, if patients experience symptoms of cerebral ischemia associated with bradycardia or heart failure symptoms associated with bradycardia, reduction or discontinuation of the drug should be considered. However, if drugs such as beta-blockers are effective in treating heart failure and continuation or dose increase is deemed necessary, pacemaker implantation may be considered (e.g., Non-Patent Documents 6 and 7). In fact, in cardiac resynchronization therapy (CRT), a pacemaker therapy for heart failure, it has been reported that after CRT implantation, it is possible to maintain long-term administration of high doses of beta-blockers, and that this is associated with an extension of survival time (e.g., Non-Patent Document 8). In this case, it would be even more desirable if the bradycardia could be eliminated by medication.

[0009] Therefore, there is a need for the development of new therapeutic and preventive agents for drug-induced bradycardia and bradyarrhythmia. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Journal of the American Society of Nephrology, 2002;13:1073-1083. [Non-patent document 2] British Journal of Clinical Pharmacology, 2013;75:831-841. [Non-patent document 3] American Journal of Transplantation, 2005;5:529-36. [Non-patent document 4] Toxicology and Applied Pharmacology, 2014;15:281:39-47. [Non-Patent Document 5] Fundamental & Clinical Pharmacology, 2017;31:392-402. [Non-patent document 6] Joint Japanese Circulation Society / Japanese Heart Failure Society Guidelines for the Treatment of Acute and Chronic Heart Failure (2017 revised edition), 58-59. [Non-Patent Document 7] Am Heart J,2004;147:324-330. [Non-patent document 8] Optimization of Heart Failure Medication After Cardiac Resynchronization Therapy and the Impact on Long-Term Survival, Eur Heart J Cardiovasc Pharmacother. 2015;1(3):182-188. Summary of the Invention [Problem to be solved by the invention]

[0011] An object of the present invention is to provide a novel therapeutic agent for drug-induced bradycardia and bradyarrhythmia. [Means for solving the problem]

[0012] The aforementioned KACh channel is a cardiac acetylcholine-activated potassium channel. When acetylcholine is released from the vagus nerve terminal, the KACh channel opens via activation of the M2 receptor, a muscarinic acetylcholine receptor, and potassium ions flow out of the cell, controlling the heart rate to a constant level. In particular, it plays a physiological role in reducing the heart rate when the parasympathetic nervous system is activated. (3R,4S)-7-Hydroxymethyl-2,2,9-trimethyl-4-(phenethylamino)-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol (hereinafter also referred to as Compound (I) or the compound of the present invention) is a compound that selectively prolongs the refractory period of the atrium and has been reported to be effective against arrhythmias such as atrial fibrillation (see International Publication No. 2005 / 090357, etc.). The present inventors have found that Compound (I) has an inhibitory effect on KACh channels. As mentioned above, the compounds of the present invention are known to have anti-atrial fibrillation effects through the inhibitory effect of KACh channels. However, atrial fibrillation, which often leads to high tachycardia upon sympathetic nerve activation, is considered to be the exact opposite pathology from drug-induced bradyarrhythmia. However, as a result of extensive investigations by the present inventors, it has surprisingly been revealed that the compounds of the present invention have a high effect of preventing and terminating drug-induced bradyarrhythmia. Therefore, the present invention is as follows.

[0013] (1) A therapeutic agent for drug-induced bradycardia and bradyarrhythmia, comprising the following compound (I) or a pharmacologically acceptable salt thereof as an active ingredient: [ka] (In the formula, Ph represents a phenyl group.) (2) The therapeutic agent according to (1), wherein the drug-induced bradyarrhythmia is an S1P receptor modulator-induced bradyarrhythmia. (3) The therapeutic agent according to (1), wherein the drug-induced bradyarrhythmia is S1P1 modulator-induced bradyarrhythmia. (4) The therapeutic agent according to (1), wherein the drug-induced bradyarrhythmia is bradyarrhythmia induced by fingolimod. (5) The therapeutic agent according to (1), wherein the drug-induced bradyarrhythmia is bradyarrhythmia induced by siponimod. (6) The therapeutic agent according to (1), wherein the drug-induced bradyarrhythmia is β-blocker-induced bradyarrhythmia. (7) The therapeutic agent according to (1), wherein the drug-induced bradyarrhythmia is propranolol-induced bradyarrhythmia. (8) The therapeutic agent according to (1), wherein the drug-induced bradyarrhythmia is any of the following bradycardias: (a) Sinus bradycardia, (b) sinus arrest, (c) sinoatrial block, (d) atrioventricular block, (e) sinus dysfunction, (f) bradycardiac heart failure, (g) bradycardiac atrial fibrillation.) (9) The therapeutic agent according to (1), wherein the drug-induced bradyarrhythmia is either sinus bradycardia or atrioventricular block. (10) The therapeutic agent according to (1), wherein the drug-induced bradyarrhythmia is sinus bradycardia. (11) The therapeutic agent according to (1), wherein the drug-induced bradyarrhythmia is atrioventricular block. (12) The therapeutic agent according to (1), which is a therapeutic agent for preventive purposes. (13) The therapeutic agent according to (1), wherein the therapeutic agent is a therapeutic agent for the purpose of stopping. (14) A therapeutic agent for drug-induced bradycardia and bradyarrhythmia, comprising as an active ingredient a compound having an inhibitory effect on KACh channels or a pharmacologically acceptable salt thereof. (15) The therapeutic agent according to any one of (1) to (14), wherein the therapeutic agent for drug-induced bradycardia and bradyarrhythmia is a therapeutic agent for drug-induced bradyarrhythmia. (16) The therapeutic agent according to any one of (1) to (14), wherein the therapeutic agent for drug-induced bradycardia and bradyarrhythmia is a therapeutic agent for bradyarrhythmia. [Effects of the Invention]

[0014] The present invention provides a therapeutic agent for drug-induced bradycardia and bradyarrhythmia. [Brief explanation of the drawings]

[0015] [Figure 1] 1 is a graph showing the effect of Compound (I) on fingolimod-induced bradyarrhythmia in anesthetized guinea pigs. [Figure 2] 1 shows representative electrocardiogram waveforms obtained when evaluating the preventive effect of Compound (I) on fingolimod-induced bradyarrhythmia in anesthetized guinea pigs. [Figure 3] 1 is a graph showing the effect of Compound (I) on siponimod-induced bradyarrhythmia in anesthetized guinea pigs. [Figure 4] 1 shows representative electrocardiogram waveforms obtained when evaluating the preventive effect of Compound (I) on siponimod-induced bradyarrhythmia in anesthetized guinea pigs. [Figure 5] 1 shows a representative electrocardiogram waveform obtained when Compound (I) was shown to have an inhibitory effect on fingolimod-induced bradyarrhythmia in anesthetized guinea pigs. [Figure 6] 1 is a graph showing the effect of Compound (I) on siponimod-induced decrease in heart rate in iPS cell-derived atrial myocytes. [Figure 7] 1 is a graph showing the effect of Compound (I) on the fingolimod-induced decrease in peripheral blood lymphocytes in guinea pigs. [Figure 8]FIG. 1 shows heart rates before and after administration of Compound (I) or saline in conscious rats when the therapeutic effect of Compound (I) or saline on propranolol-induced bradyarrhythmia was evaluated by telemetry (error bars indicate standard error). [Figure 9] 1 is a graph showing the effect of Compound (I) on propranolol-induced bradycardia in conscious beagle dogs. [Figure 10] Representative electrocardiogram waveforms obtained in conscious beagle dogs when verapamil-induced bradyarrhythmia (2:1 atrioventricular block) was converted to Wenckebach atrioventricular block by administration of compound (I) and then restored to 1:1 atrioventricular conduction. DETAILED DESCRIPTION OF THE INVENTION

[0016] As mentioned above, the resting human heart rate is usually about 50 to 100 beats per minute, and a heart rate below this is called bradycardia. Bradyarrhythmia in the present invention is a concept well known to those skilled in the art, and is not particularly limited, but in one embodiment, it is a disease that is determined to be bradycardia in a clinical setting. More specifically, bradycardia, which is the target of treatment by the compound of the present invention, is a pathological condition in which the symptoms of heart failure are improved by increasing the heart rate and cardiac output using the compound of the present invention. As mentioned above, drug-induced bradyarrhythmia refers to a state in which the bradyarrhythmia is induced by a drug administered for the purpose of treating some disease. Drugs known to induce bradycardia include beta-blockers, non-dihydropyridine calcium channel blockers, digitalis preparations, and S1P receptor modulators.

[0017] The term "S1P receptor modulator" refers to a modulator of the sphingosine-1-phosphate (S1P) receptor. The S1P receptor modulator is typically an antagonist of the S1P receptor. The S1P receptor modulator is typically a functional antagonist of the S1P receptor. The S1P receptor modulator of the present invention is not particularly limited as long as it is a drug that affects the S1P receptor. In the most typical embodiment, the S1P receptor modulator of the present invention is a drug that affects the S1P receptor and induces bradycardia. In one embodiment, the S1P receptor modulator of the present invention is fingolimod, siponimod, cenerimod, ponesimod, or ozanimod.

[0018] A β-blocker is a drug that blocks only β-receptors among the sympathetic adrenoceptors. β-blockers are also called beta-blockers. The β-blocker of the present invention is not particularly limited as long as it is a drug that blocks β-adrenergic receptors of the sympathetic nerve. In the most typical embodiment, the β-blocker of the present invention is a drug that has β-blocking activity and induces bradycardia. In one embodiment, the β-blocker of the present invention is carvedilol, bisoprolol, metoprolol, atenolol, propranolol, landiolol, arotinolol, pindolol, labetalol, alprenolol, nadolol, aceptolol, carteolol, or bevantolol. The β-blocker of the present invention is more preferably carvedilol, bisoprolol, metoprolol, atenolol, propranolol, or arotinolol.

[0019] Calcium channel blockers are drugs that act on L-type calcium channels, a type of membrane voltage-dependent calcium channel, and inhibit the influx of calcium ions into cells. Based on their chemical structure, they are classified as dihydropyridines (nifedipine, nicardipine, amlodipine, felodipine, nitrendipine, nilvadipine, manidipine, barnidipine, cilnidipine, benidipine, avinidipine, aranidipine, and efonidipine), benzothiazepines (diltiazem), or phenylalkylamines (verapamil). Dihydropyridine calcium channel blockers primarily work by preventing calcium ions from entering vascular smooth muscle, dilating blood vessels and thereby exerting a hypotensive effect, and are therefore used to treat hypertension. While dihydropyridine calcium channel blockers primarily lower blood pressure by dilating peripheral blood vessels, non-dihydropyridine calcium channel blockers primarily act on coronary artery dilation and myocardium. Non-dihydropyridine calcium antagonists antagonistically inhibit the influx of calcium ions into coronary artery calcium channels, thereby dilating the coronary arteries and improving angina pectoris. Furthermore, cardiac beating is related to calcium ion influx, and non-dihydropyridine calcium antagonists inhibit calcium ion influx into cardiac myocytes, thereby improving tachyarrhythmia. The calcium antagonist of the present invention is not particularly limited as long as it acts on voltage-dependent calcium channels in blood vessels and cardiac myocytes and inhibits the influx of calcium ions into the cells. In the most typical embodiment, the calcium antagonist of the present invention is a drug that has a vasodilatory effect and exhibits an anti-tachycardiac effect, thereby reducing the heart rate, by suppressing cardiac contractility and excitation conduction in the sinoatrial node and atrioventricular node. In one embodiment, the calcium antagonist of the present invention is nifedipine, nicardipine, amlodipine, felodipine, nitrendipine, nilvadipine, manidipine, barnidipine, cilnidipine, benidipine, avilidipine, aranidipine, efonidipine, diltiazem, or verapamil.

[0020] For example, regarding the S1P receptor modulator fingolimod, the package insert states that "after starting administration of this drug, a decrease in heart rate may be observed for several days," and that "heart rate may decrease significantly, particularly in the early stages of administration, so administration should be initiated under supervision where appropriate measures can be taken, such as in collaboration with a doctor specializing in cardiology." Among S1P receptor modulators, fingolimod, siponimod, cenerimod, ponesimod, and ozanimod have been reported to affect heart rate, and all of these drugs are known to act on S1P1. Therefore, drug-induced bradyarrhythmia in the present invention is understood to mean the diseases described below. (1) Drug-induced bradyarrhythmia (2) S1P receptor modulator-induced bradyarrhythmia (3) S1P1 modulator-induced bradyarrhythmia

[0021] Furthermore, as described below, the present inventors have found that the compound of the present invention is effective against bradyarrhythmia induced by fingolimod or siponimod. Therefore, drug-induced bradyarrhythmia in the present invention is understood to mean the diseases described below. (4) Fingolimod-induced bradyarrhythmia (5) Siponimod-induced bradyarrhythmia

[0022] Regarding beta-blockers, the package insert for carvedilol lists "severe bradycardia" and "complete atrioventricular block" as "serious side effects." Similarly, the package insert for bisoprolol lists "severe bradycardia," "complete atrioventricular block," and "sick sinus syndrome" as "serious side effects." Furthermore, as side effects of arrhythmias listed in the package inserts of other beta-blockers, the package insert for metoprolol lists atrioventricular block, bradycardia, and sinus dysfunction; the package insert for atenolol lists bradycardia, atrioventricular block, and sinoatrial block; the package insert for propranolol lists bradycardia and atrioventricular block; and the package insert for landiolol lists complete atrioventricular block, sinus arrest, and severe bradycardia. Furthermore, as described below, the present inventors have found that the compound of the present invention is effective against bradycardia-induced arrhythmias induced by propranolol. β-blockers are drugs that block β-receptors among the adrenergic receptors of the sympathetic nervous system, and their bradycardia-inducing effect is also based on β-blocking activity. Therefore, the compound of the present invention is equally effective against bradycardia induced by all β-blockers.

[0023] Beta-blockers are drugs with a wide range of applications, including the treatment of hypertension, heart failure, angina pectoris, and heart rate control in atrial fibrillation. To date, there is no established treatment for resolving bradycardia caused by β-blockers with other drugs. On the other hand, as mentioned above, it has been reported that for heart failure patients with drug-induced bradyarrhythmia caused by beta-blockers, survival can be expected to be extended by continuing to administer beta-blockers while improving bradycardia through cardiac resynchronization therapy, etc. Therefore, the inventors thought that if a drug could be found that can improve bradycardia without affecting the effects of beta-blockers other than their heart rate inhibitory effect (such as their cardiac contractility inhibitory effect), i.e., a "drug for treating drug-induced bradyarrhythmia," it could be used as a drug for treating chronic heart failure by taking it in combination with a bradycardia-inducing drug (such as a beta-blocker) or by taking a combination of a drug-induced bradycardia-inducing drug for treating bradycardia and a bradycardia-inducing drug (such as a beta-blocker). In addition, the purpose of administering beta-blockers to treat angina pectoris is to reduce myocardial oxygen consumption by inhibiting contraction, not to reduce heart rate. Therefore, in the case of angina pectoris, lowering contractile force and blood pressure while maintaining heart rate is a feasible and appropriate use. Furthermore, the present invention is expected to improve bradycardia induced when beta-blockers are used to control the heart rate of atrial fibrillation, particularly at night when the parasympathetic nervous system is dominant, and is also suitable for the treatment of atrial fibrillation. Therefore, the treatment (correction) of bradycardia with the compounds of the present invention is considered appropriate whether the bradycardia is induced by the use of beta-blockade for heart failure, hypertension, angina pectoris, or heart rate control in atrial fibrillation. Therefore, in one embodiment, drug-induced bradyarrhythmia in the present invention is understood to be the diseases described below. (6) Beta-blocker-induced bradyarrhythmia (7) Propranolol-induced bradyarrhythmia

[0024] Calcium channel blockers are drugs widely used as antihypertensives, antiarrhythmics, and antianginal drugs. The effects of calcium channel blockers can be divided into vasodilatory effects, including coronary arteries, inhibition of cardiac contractility, and inhibition of the conduction system. Calcium channel blockers are broadly divided into dihydropyridines, benzothiazepines, and phenylalkylamines. There are many types of dihydropyridine calcium channel blockers, and they are primarily used to treat hypertension, including nifedipine, nicardipine, amlodipine, and cilnidipine. Benzothiazepines are represented by diltiazem, and phenylalkylamines are represented by verapamil.

[0025] Phenylalkylamine calcium antagonists, such as verapamil, have a negative chronotropic effect on the sinus node and atrioventricular node, and are therefore used as antiarrhythmic agents for tachyarrhythmias such as supraventricular tachycardia. However, serious side effects include sinus arrest, atrioventricular block, and bradycardia. Furthermore, due to their strong negative inotropic effect (cardiac contraction inhibitory effect), they are contraindicated in patients with congestive heart failure. Therefore, the present inventors considered that if a drug could be found that can improve bradycardia, which is a side effect of verapamil, a drug used to treat tachyarrhythmias such as supraventricular tachycardia, or bradycardia associated with bradycardia-tachycardia syndrome, i.e., a "drug for treating drug-induced bradyarrhythmia," then it could become a drug for treating these bradyarrhythmia conditions by taking it in combination with verapamil or by taking a combination of a drug for treating drug-induced bradyarrhythmia and verapamil. Furthermore, calcium channel blockers, including verapamil, generally have negative chronotropic, vasodilatory (antihypertensive), and negative inotropic effects, and their use as a "drug for treating drug-induced bradyarrhythmia" to prevent and treat excessive bradycardia and atrioventricular block caused by the negative chronotropic effects is highly possible and considered to be appropriate. Therefore, the treatment (correction) of bradycardia with the compound of the present invention is considered appropriate for bradycardia induced by the use of calcium channel blockers for supraventricular tachyarrhythmia such as atrial fibrillation, hypertension, or angina pectoris. Therefore, in one embodiment, drug-induced bradyarrhythmia in the present invention is understood to be the diseases described below. (8) Calcium antagonist-induced bradyarrhythmia (9) Verapamil-induced bradyarrhythmia

[0026] The bradycardia-inducing drugs, β-blockers, S1P receptor modulators, digitalis preparations and calcium channel blockers of the present invention include existing drugs, existing drugs that will be found to have the relevant effect in the future, and novel drugs that will be found to have the relevant effect in the future.

[0027] The drug-induced bradycardia and bradyarrhythmia targeted by the therapeutic agent of the present invention are not limited, so long as the therapeutic agent is effective. Furthermore, as described above, the present inventors have found that the compound of the present invention improves bradyarrhythmia induced by drugs with completely different mechanisms, namely, β-blockers, calcium channel blockers, and S1P receptor modulators. That is, the compound of the present invention is effective against bradyarrhythmia induced by drugs with all mechanisms, not limited to β-blockers, calcium channel blockers, and S1P receptor modulators.

[0028] The present inventors have found that the compound of the present invention is effective for sinus arrest and atrioventricular block in genetically modified animal models. As mentioned above, bradycardia induced by beta-blockers and calcium channel blockers includes bradycardia, severe bradycardia, complete atrioventricular block, atrioventricular block, sick sinus syndrome, sinus dysfunction, sinus arrest, and severe bradycardia, and bradycardia induced by S1P receptor modulators includes a heart rate-lowering effect lasting for several days. The present inventors have demonstrated the effectiveness of the compound of the present invention against β-blockers, calcium antagonists, and S1P receptor modulators that induce various types of bradycardia. Therefore, symptoms targeted by the therapeutic agent of the present invention may include the following: (8) Any of the following bradycardia: (a) Sinus bradycardia, (b) sinus arrest, (c) sinoatrial block, (d) atrioventricular block, (e) sinus dysfunction, (f) bradycardiac heart failure, (g) bradycardiac atrial fibrillation.

[0029] Furthermore, the present inventors have found that the compounds of the present invention are particularly effective against drug-induced atrioventricular block or sinus bradycardia, as described below. Therefore, the drug-induced bradyarrhythmia for which the compound of the present invention is particularly effective is understood to be the diseases described below. (9) Either sinus bradycardia or atrioventricular block (10) Sinus bradycardia (11) Atrioventricular block

[0030] In the present invention, sinus bradycardia refers to a symptom of arrhythmia in which the heart rate slows down despite a normal, regular heartbeat rhythm. Sinus bradycardia is generally understood as a condition in which the heart rate decreases to 50 beats per minute or less. Sinus bradycardia is understood to be a group I condition of sick sinus syndrome according to the Rubenstein classification.

[0031] In the present invention, sinus arrest refers to a pathological condition in which the sinus node no longer generates electrical signals, resulting in no atrial excitation.

[0032] In the present invention, sinoatrial block refers to a pathological condition in which atrial excitation does not occur due to impaired excitation conduction between the sinus node and the atrium.

[0033] In the present invention, atrioventricular block refers to a pathological condition in which ventricular excitation does not occur due to impaired excitation conduction between the atrium and ventricle. Atrioventricular block includes the following pathological classifications: (1) First-degree atrioventricular block The conduction time between the atria and ventricles is prolonged (the conduction of excitation is maintained). (2) Second-degree atrioventricular block: sudden interruption of conduction between the atria and ventricles. Includes the following four types: (2-1) Wenckebach type: Conduction between the atria and ventricles is gradually prolonged, followed by loss of ventricular excitation. (2-2) Mobitz type II: sudden loss of ventricular excitation without prolongation of conduction between the atria and ventricles. (2-3) 2:1 atrioventricular block: A block in which the atrioventricular conduction ratio is 2:1. (2-4) Severe atrioventricular block: Block with an atrioventricular conduction ratio of 3:1 or more. (3) Third-degree atrioventricular block: Complete interruption of conduction between the atria and ventricles.

[0034] In the present invention, the term "sinus node dysfunction" refers to a disorder in the conduction of electrical impulses from the sinus node to the atria, and refers to several pathological conditions that cause atrial excitation at a physiologically inappropriate heart rate. Examples of sick sinus syndrome include: Inappropriate sinus bradycardia, alternating bradycardia and atrial tachyarrhythmia (bradycardia-tachycardia syndrome), sinus arrest or sinus pause, sinoatrial block.

[0035] In the present invention, bradycardia heart failure refers to a clinical syndrome in which an excessive decrease in heart rate prevents the maintenance of the circulating blood volume required for physical activity, resulting in the breakdown of the compensatory mechanism of cardiac pump function, resulting in the appearance of dyspnea, fatigue, and edema, and a corresponding decrease in exercise tolerance. Bradycardia here does not necessarily mean a heart rate of 50 beats per minute or less, and any condition in which heart failure symptoms may be improved by increasing the heart rate is included in bradycardia heart failure and is a target for treatment with this drug.

[0036] In the present invention, bradycardiac atrial fibrillation refers to a pathological condition in which, in a patient with atrial fibrillation, the function of the atrioventricular node, which transmits electrical excitation from the atrium to the ventricle, is impaired for some reason, resulting in a decrease in atrioventricular conduction, which in turn leads to atrioventricular block, resulting in ventricular bradycardia.

[0037] Furthermore, as described below, the present inventors have found that the compounds of the present invention are particularly effective in preventing or terminating drug-induced bradyarrhythmia. Therefore, the therapeutic agent for drug-induced bradyarrhythmia in the present invention is understood to be the therapeutic agent described below. (12) Preventive treatment (13) Therapeutic agents aimed at stopping

[0038] Prevention is a concept well known to those skilled in the art, and in one aspect it means "preventing a bad situation from occurring in advance" (Kojien). Therefore, in one aspect, the "therapeutic agent intended for the prevention of drug-induced bradyarrhythmia" of the present invention is "a therapeutic agent intended for the prevention of drug-induced bradyarrhythmia in advance." In the present invention, the term "before" is not particularly limited as long as it refers to a time before the onset of drug-induced bradyarrhythmia. Therefore, the administration of the compound of the present invention for the purpose of prevention is not limited to before, after, or multiple times before and after administration of a compound that induces arrhythmia (hereinafter referred to as an inducer). The first administration of the compound of the present invention for preventive purposes is, in one embodiment, before administration of the inducer, in one embodiment, up to one day before administration of the inducer, and in one embodiment, up to 12 hours before administration of the inducer. Furthermore, administration for the purpose of prevention is determined in clinical practice, taking into consideration the pharmacokinetics of the inducer and the compound of the present invention. Therefore, all cases that are understood as "for the purpose of prevention" by those skilled in the art in clinical practice fall within the category of prevention. The category of prevention mentioned here also includes cases where it is difficult to administer an effective dose of drugs that cause bradyarrhythmia, such as S1P receptor modulators and β-blockers, for the applicable disease (multiple sclerosis in the case of S1P receptor modulators, and chronic heart failure in the case of β-blockers) due to the appearance of bradyarrhythmia, but administration can be initiated or increased by combining the drug with the compound of the present invention.

[0039] The term "arrest" is a concept well known to those skilled in the art, and in one aspect it means "to temporarily stop movement" (Kojien). Therefore, in one aspect, the "therapeutic agent intended to terminate drug-induced bradyarrhythmia" of the present invention is a "therapeutic agent intended to stop drug-induced bradyarrhythmia." Furthermore, when a person skilled in the art in a clinical setting would understand "intended to terminate," all of these terms fall within the category of "arrest."

[0040] Furthermore, as mentioned above, the compounds of the present invention have the effect of selectively prolonging the refractory period of the atrium, and have been reported to be effective against arrhythmias such as atrial fibrillation. When the compounds of the present invention are used in combination with an inducer, rather than when the compounds of the present invention are expected to be effective as a single agent, it is presumed that the purpose is to treat, prevent, or stop drug-induced bradyarrhythmia.

[0041] As described above, the compound of the present invention (compound (I)) has an inhibitory effect on the KACh channel, and this effect may be responsible for the effects of the present invention. In other words, any compound that has an inhibitory effect on the KACh channel, not limited to compound (I), is likely to exhibit the effects of the present invention. Therefore, in one embodiment, the therapeutic agent of the present invention is as follows. (14) A therapeutic agent for drug-induced bradycardia and bradyarrhythmia, comprising as an active ingredient a compound having an inhibitory effect on KACh channels or a pharmacologically acceptable salt thereof.

[0042] In one embodiment, the present invention provides a therapeutic agent for drug-induced bradycardia and bradyarrhythmia. As demonstrated herein, the compounds of the present invention are effective against both drug-induced and non-drug-induced bradycardia. Therefore, the therapeutic agent for drug-induced bradycardia and bradyarrhythmia in the present invention is understood to be the therapeutic agent described below. Furthermore, as described in the Examples, the compounds of the present invention have the effect of increasing the heart rate and increasing cardiac output even when the initial heart rate is 50 beats per minute or higher. Therefore, bradyarrhythmia as used herein is not limited to heart rates of 50 beats per minute or less, but also includes pathological conditions in which the compound may increase the heart rate and improve heart failure symptoms. (15) Drug-induced bradyarrhythmia treatment. (16) A drug for treating bradyarrhythmia.

[0043] In one embodiment, in light of the above-mentioned clinical situation, it is preferable that a therapeutic agent for drug-induced bradycardia does not affect the efficacy of the drug. For example, it is preferable that a therapeutic agent for S1P receptor modulator-induced bradycardia does not inhibit the peripheral blood lymphocyte reduction effect of S1P receptor modulators. However, there are many unknowns regarding the mutual influence of multiple pharmacological effects between multiple drugs, making it difficult to predict the presence or absence of drug interaction. The present inventors have surprisingly also found that compound (I) does not inhibit the peripheral blood lymphocyte reduction effect of S1P receptor modulators.

[0044] As described above, compound (I) contained in the therapeutic agent of the present invention is (3R,4S)-7-hydroxymethyl-2,2,9-trimethyl-4-(phenethylamino)-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol. In one embodiment, compound (I) may be a racemic mixture or a diastereomeric mixture containing a (3R,4S) form. In another embodiment, the compound contained in the therapeutic agent of the present invention may be an analog of Compound (I). Examples of such analogs include the compounds described in WO 2005 / 090357.

[0045] Compound (I) contained in the therapeutic agent of the present invention may be in the form of a pharmacologically acceptable salt. Examples of pharmacologically acceptable salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, acetate, benzoate, tartrate, phosphate, lactate, maleate, fumarate, malate, gluconate, salicylate, and the like. Preferred salts of Compound (I) are the hydrochloride, maleate and methanesulfonate salts.

[0046] The compound contained in the therapeutic agent of the present invention may be crystalline. The crystal may be in any crystalline form as long as it does not impede the objectives of the present invention. Examples of preferred crystalline forms of Compound (I) include those described in International Publication No. 2010 / 126138. In one embodiment, the crystal exhibits characteristic peaks at diffraction angles 2θ = 5.6, 8.2, 12.0, 14.7, 16.6, 16.9, 17.9, 18.4, 22.5, 24.5, and 27.6 (±0.2°) in a powder X-ray diffraction pattern obtained using Cu·Kα as the X-ray source. In another embodiment, the crystal exhibits any three, five, seven, or nine of the eleven peaks. Identification of crystalline forms by powder X-ray diffraction is performed based on common technical knowledge of those skilled in the art, for example, the descriptions in the Japanese Pharmacopoeia. When X-rays other than Cu·Kα are used, the diffraction angle patterns are compared by converting the 2θ values ​​based on the Bragg equation. The measurement error of 2θ values ​​is usually within the range of ±0.2°, but even if there are a few peaks with an error of 0.2° or more, this does not prevent a person skilled in the art from making a reasonable identification.

[0047] Compound (I) contained in the therapeutic agent of the present invention can be produced by known methods. Examples of such known methods include International Publication Nos. 2005 / 090357 and 2010 / 126138. Furthermore, when producing Compound (I), reference can be made to International Publication Nos. 2007 / 105658, 2014 / 050613, 2014 / 051077, and 2015 / 012271.

[0048] The present invention provides a pharmaceutical or veterinary composition comprising a therapeutically effective amount of a compound of the invention. The administration form of the compound according to the present invention may be parenteral administration using injections (subcutaneous, intravenous, intramuscular, or intraperitoneal injection), ointments, suppositories, aerosols, etc., or oral administration using tablets, capsules, granules, pills, syrups, liquids, emulsions, suspensions, etc. The above-mentioned pharmaceutical or veterinary compositions containing the compound of the present invention contain the compound of the present invention in an amount of about 0.01% to 99.5%, preferably about 0.1% to 30%, by weight of the total composition.

[0049] In addition to the compounds of the present invention or to compositions containing the compounds, other pharmaceutically or veterinarily active compounds may be included. These compositions may also contain more than one compound according to the invention.

[0050] The clinical dose of the compound of the present invention varies depending on the age, body weight, patient sensitivity, severity of symptoms, etc., but the usually effective dose for an adult is about 0.003 g to 1.5 g, preferably about 0.01 g to 0.6 g per day. However, an amount outside the above range can be used if necessary.

[0051] The compounds of this invention may be formulated for administration in any conventional manner for pharmacy. That is, tablets, capsules, granules, and pills for oral administration are prepared using excipients such as sucrose, lactose, glucose, starch, and mannitol; binders such as hydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose, and polyvinylpyrrolidone; disintegrants such as starch, carboxymethylcellulose or a calcium salt thereof, microcrystalline cellulose, and polyethylene glycol; lubricants such as talc, magnesium or calcium stearate, and silica; and lubricants such as sodium laurate and glycerol. Injections, solutions, emulsions, suspensions, syrups and aerosols are prepared using solvents for the active ingredient, such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol; surfactants, such as sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ethers of hydrogenated castor oil, lecithin; suspending agents, such as carboxymethyl sodium salt, cellulose derivatives such as methylcellulose, natural gums such as tragacanth, gum arabic and the like; preservatives, such as esters of parahydroxybenzoic acid, benzalkonium chloride, sorbic acid salts and the like. Ointments, which are transdermal preparations, include white petrolatum, liquid paraffin, higher alcohols, macrogol ointment, hydrophilic ointment, and aqueous gel bases. Suppositories are prepared using, for example, cacao butter, polyethylene glycol, lanolin, fatty acid triglyceride, coconut oil, polysorbate, and the like. [Example]

[0052] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0053] Evaluation example 1 Preventive effect of compound (I) against fingolimod-induced bradyarrhythmia in an isoflurane-anesthetized guinea pig model Hartley guinea pigs (7-10 weeks old, male, Japan SLC Co., Ltd.) were orally administered vehicle or compound (I) (free form) at 1, 3, or 10 mg / kg (5 mL / kg). After administration, they were anesthetized with isoflurane (Pfizer Inc.) and restrained on a heated operating table. The trachea was incised, and a tracheal cannula (KN-375 / Natsume Seisakusho Co., Ltd.) was inserted. The animals were connected to a ventilator (SN-480-7 / Shinano Seisakusho Co., Ltd.) and maintained on a heated operating table with 100% oxygen at a volume of 10 mL and a ventilation rate of 60 breaths / min. A 0.5 w / v% methylcellulose 400 solution (Fujifilm Wako Pure Chemical Industries, Ltd.) was used as the vehicle. Maintenance anesthesia was performed with isoflurane (Pfizer Inc.) at approximately 1-4% (carrier gas: 100% oxygen). Catheters (BD intramedic polyethylene tubing PE50 / Becton Dickinson and Company) filled with 50 units / mL heparin (AY Pharmaceuticals Corporation) were inserted into the carotid artery and jugular vein and left in place within the respective blood vessels. Systemic blood pressure was measured using a high-sensitivity DC amplifier (AD-611J / Nihon Kohden Corporation) via the catheter placed in the carotid artery. Electrodes were attached to the body surface, and a body surface electrocardiogram was measured using a high-sensitivity amplifier (AB-611J / Nihon Kohden Corporation). Blood pressure and electrocardiogram data were acquired and analyzed using a PowerLab / Labchart system (ADInstruments). Analyzed parameters were systolic blood pressure, diastolic blood pressure, mean blood pressure, heart rate, P wave width, PR interval, QRS width, QT interval, and corrected QT interval. The corrected QT interval was calculated using the Fridelicia formula (QTc = QT interval / RR interval). 1 / 3) were used for calculations. After each parameter was stabilized, 0.1 mg / kg of fingolimod hydrochloride (synthesized with reference to International Publication No. 2000 / 027798) was administered intravenously for 10 minutes via a catheter placed in the jugular vein, and the animals were observed for the occurrence of bradyarrhythmia over a 60-minute period. Physiological saline (Otsuka Pharmaceutical Factory, Inc.) was used as the vehicle. Data were recorded and blood samples were collected 5, 10, 15, 20, 30, and 60 minutes after the start of fingolimod hydrochloride administration. Sixty minutes after the start of administration, observations were terminated, and the animals were euthanized by exsanguination or by intravenous administration of a large volume of pentobarbital or saturated potassium chloride solution under isoflurane anesthesia. Data were analyzed for atrial rate over time, ventricular rate over time, electrocardiogram parameters, the occurrence of atrioventricular block, and plasma concentrations of Compound (I), fingolimod, and fingolimod phosphorylated form. Plasma was collected by centrifuging the blood and stored frozen at approximately -20°C. After thawing the plasma, it was deproteinized with acetonitrile and the drug concentration in the plasma was measured using LC / MS / MS. Atrioventricular block was defined as follows: Second-degree atrioventricular block: Atrial excitation waves (P waves) are normal, and some are followed by ventricular excitation waves (QRS waves) and some are not. Third-degree atrioventricular block: There is no electrical conduction between the atria and ventricles, and atrial and ventricular excitation waves occur independently, resulting in atrioventricular dissociation. The time course of the measured values ​​of each parameter in each group is shown in Figure 1, and the representative electrocardiogram waveforms obtained are shown in Figure 2. In Figure 1, the measured values ​​are expressed as mean ± standard error. The abbreviations are as follows: ·(I): Compound (I) Atrioventricular block: Presence or absence of atrioventricular block (X indicates second- or third-degree atrioventricular block) PR & QRS: Atrioventricular conduction time and ventricular activation time QT & QTcF: Ventricular repolarization time and heart rate corrected ventricular repolarization time Plasma concentrations: Plasma concentrations of fingolimod, phosphorylated fingolimod (-P), and compound (I)

[0054] Figure 1 compares the effects of compound (I) at doses of 1 mg / kg, 3 mg / kg, and 10 mg / kg, with no administration. Looking at the ventricular rate section, the ventricular rate was reduced by approximately half in the unadministered group, demonstrating the pronounced bradycardia induced by fingolimod. In contrast, the compound (I) administration group showed a dose-dependent improvement in bradycardia, with the 3 mg / kg group showing almost complete recovery and the 10 mg / kg group showing complete recovery. Furthermore, in the section on the occurrence of atrioventricular block, fingolimod-induced atrioventricular block was observed in all cases (4 out of 4 cases) in the non-administration group. In contrast, atrioventricular block was abolished in 3 cases (75%) in the 1 mg and 3 mg / kg groups of Compound (I), and atrioventricular block was suppressed in 4 cases (100%) in the 10 mg / kg group. A similar almost complete suppression effect was observed for fingolimod-induced QT interval prolongation. Figure 2 shows typical electrocardiograms in the untreated and 10 mg / kg treated groups of Compound (I). In the untreated group, the heart rate was reduced to about half, and significant bradycardia was observed, whereas in the 10 mg / kg treated group, such fingolimod-induced bradycardia was completely eliminated.

[0055] As is clear from Figures 1 and 2, Compound (I) dose-dependently prevented the onset of bradyarrhythmia (atrioventricular block) caused by fingolimod and prevented the decrease in heart rate.

[0056] Evaluation example 2 Preventive effect of compound (I) against siponimod-induced bradyarrhythmia in an isoflurane-anesthetized guinea pig model Hartley guinea pigs (7-10 weeks old, male, Japan SLC Co., Ltd.) were orally administered 0.3, 1, or 3 mg / kg (5 mL / kg) of vehicle or compound (I) (free form). After administration, they were anesthetized with isoflurane (Pfizer Inc.) inhalation and restrained on a heated operating table. The trachea was incised, and a tracheal cannula (KN-375 / Natsume Seisakusho Co., Ltd.) was inserted. The animals were connected to a ventilator (SN-480-7 / Shinano Seisakusho Co., Ltd.) and maintained on a heated operating table with 100% oxygen at a volume of 10 mL and a ventilation rate of 60 breaths / min. A 0.5 w / v% methylcellulose 400 solution (Fujifilm Wako Pure Chemical Industries, Ltd.) was used as the vehicle. Maintenance anesthesia was performed with isoflurane (Pfizer Inc.) at approximately 1-4% (carrier gas: 100% oxygen). Catheters (BD intramedic polyethylene tubing PE50 / Becton Dickinson and Company) filled with 50 units / mL heparin (AY Pharmaceuticals Corporation) were inserted into the carotid artery and jugular vein and left in place within the respective blood vessels. Systemic blood pressure was measured using a high-sensitivity DC amplifier (AD-611J / Nihon Kohden Corporation) via the catheter placed in the carotid artery. Electrodes were attached to the body surface, and a body surface electrocardiogram was measured using a high-sensitivity amplifier (AB-611J / Nihon Kohden Corporation). Blood pressure and electrocardiogram data were acquired and analyzed using a PowerLab / Labchart system (ADInstruments). Analyzed parameters were systolic blood pressure, diastolic blood pressure, mean blood pressure, heart rate, P wave width, PR interval, QRS width, QT interval, and corrected QT interval. The corrected QT interval was calculated using the Fridelicia formula (QTc = QT interval / RR interval). 1 / 3) were used to calculate the parameters. After stabilization of each parameter, siponimod (synthesized according to International Publication No. 2017 / 120124) was administered intravenously for 10 minutes via a catheter placed in the jugular vein. The animals were observed for the presence or absence of bradyarrhythmia over a 60-minute period. The vehicle was a 9:1 (volume) mixture of polyethylene glycol 400 (Kanto Chemical Co., Ltd.) and dimethyl sulfoxide (Fujifilm Wako Pure Chemical Industries, Ltd.). Data were recorded and blood samples were collected 5, 10, 15, 20, 30, and 60 minutes after the start of siponimod administration. After 60 minutes of administration, the animals were euthanized by exsanguination or by intravenous administration of a large volume of saturated potassium chloride solution under isoflurane anesthesia. Data were analyzed for atrial rate, ventricular rate, electrocardiogram parameters, the presence or absence of atrioventricular block, and plasma concentrations of Compound (I) and siponimod. Plasma was collected by centrifuging the blood and stored frozen at approximately -20°C. After thawing the plasma, it was deproteinized with acetonitrile and the drug concentration in the plasma was measured using LC / MS / MS. The changes in the measured values ​​of each parameter over time in each group are shown in Figure 3, and the representative electrocardiogram waveforms obtained are shown in Figure 4. In Figure 3, the measured values ​​are expressed as mean ± standard error. The abbreviations are as follows: ·(I): Compound (I) Atrioventricular block: Presence or absence of atrioventricular block (X indicates second- or third-degree atrioventricular block) PR & QRS are atrioventricular conduction time and ventricular activation time QT & QTcF: Ventricular repolarization time and heart rate corrected ventricular repolarization time Plasma concentration: Plasma concentration of siponimod, compound (I)

[0057] Figure 3 compares the effects of Compound (I) at doses of 0.3 mg / kg, 1 mg / kg, and 3 mg / kg, with no administration. Looking at the ventricular rate, significant bradycardia induced by siponimod was observed in the unadministered group. In contrast, in the Compound (I)-administered group, bradycardia improved in a dose-dependent manner, and in particular, bradycardia was completely restored in the 3 mg / kg-administered group. Furthermore, in the section on the occurrence of atrioventricular block, siponimod-induced atrioventricular block was observed in many cases (3 out of 4 cases) in the non-administration group. In contrast, atrioventricular block was not observed in 2 cases (50%) in the 0.3 mg / kg group and 3 cases (75%) in the 1 mg / kg group of Compound (I), and atrioventricular block was suppressed in all 4 cases (100%) in the 3 mg / kg group. Siponimod-induced QT interval prolongation was also almost completely suppressed. Figure 4 shows typical electrocardiograms in the untreated and 3 mg / kg treated groups of Compound (I). In the untreated group, significant bradycardia was observed, with the heart rate reduced by approximately half, whereas in the 3 mg / kg treated group, such siponimod-induced bradycardia was completely eliminated.

[0058] As is clear from Figures 3 and 4, compound (I) dose-dependently prevented the onset of bradyarrhythmia (atrioventricular block) caused by siponimod and prevented the decrease in heart rate.

[0059] Evaluation example 3 Terminating effect of compound (I) on fingolimod-induced bradyarrhythmia in an isoflurane-anesthetized guinea pig model Hartley guinea pigs (7-10 weeks old, male, Japan SLC Co., Ltd.) were anesthetized with isoflurane (Pfizer Inc.) and placed on a heated operating table. The trachea was incised, and a tracheal cannula (KN-375 / Natsume Seisakusho Co., Ltd.) was inserted. The animal was connected to a ventilator (SN-480-7 / Shinano Seisakusho Co., Ltd.) and maintained on artificial respiration with 100% oxygen at a volume of 10 mL and a ventilation rate of 60 breaths per minute. Maintenance anesthesia was performed with isoflurane (Pfizer Inc.) at approximately 1-4% (carrier gas: 100% oxygen). Catheters (BD intramedic polyethylene tubing PE50 / Becton Dickinson and Company) filled with 50 units / mL heparin (AY Pharmaceuticals Co., Ltd.) were inserted into the carotid artery and jugular vein and placed in the respective vessels. Systemic blood pressure was measured using a high-sensitivity DC amplifier (AD-611J / Nihon Kohden Corporation) via a catheter placed in the carotid artery. Electrodes were attached to the body surface, and a high-sensitivity amplifier (AB-611J / Nihon Kohden Corporation) was used to measure the surface electrocardiogram. Blood pressure and electrocardiogram data were acquired and analyzed using a PowerLab / Labchart system (ADInstruments). After stabilization of each parameter, 0.1 mg / kg of fingolimod hydrochloride (Nissan Chemical Co., Ltd.) was administered intravenously for 10 minutes via a catheter placed in the jugular vein, and the presence or absence of atrioventricular block was observed. After confirming that atrioventricular block had developed and continued for 10 minutes, vehicle or Compound (I) dihydrochloride 0.1 mg / kg was administered intravenously for 30 minutes, and the effects of terminating the atrioventricular block were observed during this period. Physiological saline (Otsuka Pharmaceutical Factory, Inc.) was used as the vehicle. After the start of administration of Compound (I) dihydrochloride, data were recorded and blood samples were taken 10, 20, and 30 minutes later, and at the time of atrioventricular block termination. Observation was terminated 30 minutes after the start of administration, and the animals were euthanized under isoflurane anesthesia by exsanguination or by intravenous administration of a large amount of saturated potassium chloride solution. Data were analyzed for the presence or absence of block, the time to block, and the plasma concentration of Compound (I) at the time of block termination. Plasma was collected by centrifugation and stored frozen at approximately -20°C.After thawing the plasma, the drug concentration in the plasma was measured using LC / MS / MS after deproteinization with acetonitrile. Representative electrocardiogram waveforms are shown in Figure 5. The number of cases in which atrioventricular block was stopped, the time required for the block to be stopped, and the concentration of Compound (I) at the time of the block to be stopped are shown in Table 1. The measured values ​​in the table are expressed as the mean ± standard error.

[0060] [Table 1]

[0061] As is clear from Table 1, compound (I) completely terminated the bradyarrhythmia (atrioventricular block: AV block) caused by fingolimod administration. Figure 5 shows typical electrocardiograms taken before fingolimod administration, before compound (I) administration, and 30 minutes after the start of administration of 0.1 mg / kg of compound (I) dihydrochloride. Before administration of compound (I), significant bradycardia, in which the heart rate was reduced by approximately half, was observed. However, 30 minutes after the start of administration of 0.1 mg / kg of compound (I) dihydrochloride, this fingolimod-induced bradycardia had completely disappeared.

[0062] Evaluation example 4 Terminating effect of compound (I) on siponimod-induced bradyarrhythmia in an isoflurane-anesthetized guinea pig model Hartley guinea pigs (7-10 weeks old, male, Japan SLC Co., Ltd.) were anesthetized with isoflurane (Pfizer Inc.) and placed on a heated operating table. The trachea was incised, and a tracheal cannula (KN-375 / Natsume Seisakusho Co., Ltd.) was inserted. The animal was connected to a ventilator (SN-480-7 / Shinano Seisakusho Co., Ltd.) and maintained on artificial respiration with 100% oxygen at a volume of 10 mL and a ventilation rate of 60 breaths per minute. Maintenance anesthesia was performed with isoflurane (Pfizer Inc.) at approximately 1-4% (carrier gas: 100% oxygen). Catheters (BD intramedic polyethylene tubing PE50 / Becton Dickinson and Company) filled with 50 units / mL heparin (AY Pharmaceuticals Co., Ltd.) were inserted into the carotid artery and jugular vein and placed in the respective vessels. Systemic blood pressure was measured using a high-sensitivity DC amplifier (AD-611J / Nihon Kohden Corporation) via a catheter placed in the carotid artery. Surface electrocardiograms (ECGs) were recorded using electrodes attached to the body surface using a high-sensitivity amplifier (AB-611J / Nihon Kohden Corporation). Blood pressure and ECG data were acquired and analyzed using a PowerLab / Labchart system (ADInstruments). After stabilization of all parameters, siponimod (Nissan Chemical Co., Ltd.) 0.01 mg / kg was administered intravenously for 10 minutes via a catheter placed in the jugular vein, and the presence or absence of atrioventricular block was observed. A 9:1 (volume) mixture of polyethylene glycol 400 (Kanto Chemical Co., Ltd.) and dimethyl sulfoxide (Fujifilm Wako Pure Chemical Industries, Ltd.) was used as the vehicle. After confirming that atrioventricular block had continued for 10 minutes after onset, vehicle or Compound (I) dihydrochloride 0.1 mg / kg was administered intravenously for 30 minutes, and the effects of the block on termination were observed. Physiological saline (Otsuka Pharmaceutical Factory, Inc.) was used as the vehicle. After the start of administration of Compound (I) dihydrochloride, data were recorded and blood samples were taken 10, 20, and 30 minutes later, and at the time of atrioventricular block termination. Observation was terminated 30 minutes after the start of administration, and the animals were euthanized under isoflurane anesthesia by exsanguination or by intravenous administration of a large amount of saturated potassium chloride solution. Data were analyzed for the presence or absence of block, the time to block, and the plasma concentration of Compound (I) at the time of block termination.Plasma was collected by centrifuging the blood and stored frozen at approximately -20°C. After thawing the plasma, it was deproteinized with acetonitrile and the drug concentration in the plasma was measured using LC / MS / MS. The number of cases in which atrioventricular block was stopped, the time required for the block to be stopped, and the concentration of Compound (I) at the time of the block to be stopped are shown in Table 2. The measured values ​​in the table are expressed as the mean ± standard error.

[0063] [Table 2]

[0064] As is clear from Table 2, compound (I) completely stopped the bradyarrhythmia (atrioventricular block) caused by administration of siponimod.

[0065] Evaluation example 5 Therapeutic effect of compound (I) on siponimod-induced bradyarrhythmia in human iPS cell-derived atrial myocytes Cryopreserved human iPSC-derived atrial cardiomyocytes (Axol Bioscience) were thawed and seeded at 1,400,000 cells / well onto fibronectin-coated 6-well plates. Cultures were cultured for 11 days in a 37°C, 5% CO2 incubator. The medium was replaced every other day. After 11 days, beating human iPSC-derived atrial cardiomyocytes were detached from the plates and collected using TrypLE Select Enzyme (ThermoFisher Scientific). Cells were seeded at 25,000 cells / 2 μL onto a fibronectin-coated 6-well MEA chip (60-6wellMEA200 / 30iR-Ti-tcr: MultiChannel Systems) and cultured for 1 hour in a 37°C, 5% CO2 incubator. After that, 400 μL of medium was added, and the cells were cultured for 13 days in a 37°C, 5% CO2 incubator. Half of the medium was replaced every other day. After 8 days, the MEA chip was placed in a multi-electrode array system (MEA2100: Multi Channel Systems) to record extracellular potentials during spontaneous beating. After the beating rate stabilized, 0.1 μM siponimod was added, and the effect on beating rate was observed for 10 minutes. Subsequently, 0.1 μM compound (I) or solvent (dimethyl sulfoxide (Fujifilm Wako Pure Chemical Corporation)) was added, and the effect on beating rate was observed for 10 minutes. Data analysis was performed using a Labchart system (ADInstruments). The effect of adding siponimod on the heart rate and the effect of compound (I) on improving the heart rate are shown in Figure 6. The measured values ​​in the figure are expressed as mean ± standard error, and (I) in the figure indicates compound (I).

[0066] As is clear from Figure 6, the addition of siponimod caused bradyarrhythmia (sinus bradycardia) with a pulse rate of 50 beats / min or less, and the addition of Compound (I) increased the pulse rate and improved the bradyarrhythmia.

[0067] Evaluation Example 6 Study of the effect of compound (I) on the blood lymphocyte reduction effect of fingolimod in guinea pigs Hartley guinea pigs (8 weeks old, male, Japan SLC Co., Ltd.) were fasted for approximately 16 hours and then orally administered vehicle or compound (I) (free form) at 10 or 30 mg / kg (volume: 5 mL / kg) by gavage. 0.5 w / v% methylcellulose 400 solution (Fujifilm Wako Pure Chemical Industries, Ltd.) was used as the vehicle. 30 minutes after administration, vehicle or fingolimod hydrochloride at 0.1 mg / kg (volume: 5 mL / kg) was orally administered by gavage. Physiological saline (Otsuka Pharmaceutical Factory, Inc.) was used as the vehicle. Blood samples were collected from the jugular vein, subclavian vein, or abdominal vena cava before administration of compound (I) and 5 and 24 hours after administration of fingolimod hydrochloride. Blood cell component analysis was performed using a multiparameter automated hematology analyzer (XN-1000 / Sysmex Corporation). Plasma was collected by centrifugation and stored frozen at approximately -20°C. After thawing the plasma, the drug concentration in the plasma was measured using LC / MS / MS after deproteinization with acetonitrile. The effects of fingolimod and compound (I) on the number of peripheral blood lymphocytes in guinea pigs are shown in Figure 7. The measured values ​​in the figure are expressed as mean ± standard error, and (I) in the figure indicates compound (I).

[0068] As is clear from Figure 7, administration of fingolimod reduced the number of lymphocytes in the peripheral blood of guinea pigs, and this effect was observed even in the presence of compound (I), indicating that compound (I) does not inhibit the main pharmacological effect of fingolimod, which is the reduction of peripheral blood lymphocytes.

[0069] Evaluation Example 7 Therapeutic effect of compound (I) on propranolol-induced bradyarrhythmias in conscious rats implanted with telemetry transmitters for heart rate monitoring. Wistar rats (10 weeks old, male, Kiwa Laboratory Animal Research Institute, Inc.) were anesthetized with Sebofren inhalation anesthetic solution (Maruishi Pharmaceutical Co., Ltd.) and restrained on the operating table. An implantable telemetry transmitter ETA-F10 (DSI) was placed subcutaneously, with one lead fixed to the right upper chest and one to the left lower chest. After fully awakening, the rat was placed in a cage on a receiving board, and a body surface electrocardiogram (ECG) was recorded using a high-sensitivity amplifier. ECG data was acquired and analyzed using LabChart Pro & LabChart module (BioResearch Center Co., Ltd.). After heart rate stabilization, 1 mg / kg of propranolol (Inderal Injection, AstraZeneca KK) was administered intraperitoneally. After confirming heart rate stabilization approximately 30 minutes later, saline or 1 mg / kg of Compound (I) dihydrochloride was administered intraperitoneally. Heart rate was measured and assessed approximately 30 minutes after administration. Physiological saline (Otsuka Pharmaceutical Factory, Inc.) was used as the solvent. After the observation period, the animals were anesthetized with sevoflurane, the telemetry transmitters were removed, and the animals were euthanized by exsanguination or by administering an overdose of sevoflurane. FIG. 8 shows the changes in heart rate obtained before and after administration of Compound (I) or saline against propranolol-induced bradyarrhythmia.

[0070] As is clear from FIG. 8, Compound (I) improved the bradycardia caused by the administration of propranolol.

[0071] Evaluation Example 8 Therapeutic effect of compound (I) on propranolol-induced bradycardia in conscious beagle dogs. A female beagle (approximately 10 kg, Oriental Yeast Co., Ltd.) was secured to the right forelimb with an 18-gauge needle via a peripheral venous line and restrained on the operating table. Heart rate was monitored using an electrocardiogram (ECG) monitor, blood pressure was measured using an Omron automated digital blood pressure monitor via a cuff attached to the left forelimb, and left ventricular function was measured using M-mode echocardiography in a left parasternal short-axis two-chamber view. After heart rate stabilization, 2 mg / kg of propranolol (Inderal Injection, AstraZeneca) was administered by rapid intravenous injection, followed by continuous intravenous infusion at 1 mg / min via a syringe pump. After confirming heart rate stabilization approximately 30 minutes later, saline was administered, followed by rapid intravenous injection of Compound (I) dihydrochloride at 0.01 mg / kg, 0.1 mg / kg, and 1 mg / kg at 10-minute intervals. Heart rate, blood pressure, and left ventricular function were measured approximately 10 minutes after each administration. Physiological saline (Otsuka Pharmaceutical Factory, Inc.) was used as the solvent. FIG. 9 shows the changes in heart rate and left ventricular ejection fraction (LVEF) obtained before and after administration of saline and Compound (I) for propranolol-induced bradycardia.

[0072] As is clear from Figure 9, Compound (I) improved the bradycardia caused by the administration of propranolol, and Compound (I) did not affect the cardiac contractility inhibitory effect of the administration of propranolol.

[0073] Evaluation Example 9 Therapeutic effect of compound (I) on verapamil-induced bradycardia in conscious beagle dogs. A female beagle (approximately 10 kg, Oriental Yeast Co., Ltd.) was secured to the right forelimb with an 18-gauge needle via a peripheral venous line and restrained on the operating table. An electrocardiogram (ECG) was attached to monitor heart rate, a cuff was attached to the left forelimb to measure blood pressure with an Omron automated digital blood pressure monitor, and left ventricular function was measured using M-mode echocardiography in a left parasternal short-axis two-chamber view. After stabilizing the heart rate, verapamil (Vasolan Injection, Eisai Co., Ltd.) was administered at a continuous intravenous infusion rate of 0.8 mg / kg / h using a syringe pump. Approximately 30 minutes after the start of administration, the dose was increased to 2.4 mg / kg / h and the continuous infusion was continued. However, 17 minutes after the dose increase, persistent 2:1 atrioventricular block was observed, and verapamil administration was discontinued. Physiological saline, followed by Compound (I) dihydrochloride at 0.01 mg / kg, 0.1 mg / kg, and 1 mg / kg was administered intravenously at 10-minute intervals, and electrocardiogram, heart rate, blood pressure, and left ventricular function were measured and evaluated at a stable state approximately 10 minutes after each administration. Physiological saline (Otsuka Pharmaceutical Factory, Inc.) was used as the vehicle. The changes in heart rate obtained before and after administration of Compound (I) or saline against verapamil-induced bradycardia are shown in Figure 10. A representative electrocardiogram waveform obtained when demonstrating the arresting effect of 0.1 mg / kg of Compound (I) against verapamil-induced bradyarrhythmia (2:1 atrioventricular block) is shown in Figure 10.

[0074] As is clear from FIG. 10, Compound (I) improved bradyarrhythmia (2:1 atrioventricular block) caused by verapamil administration. [Industrial Applicability]

[0075] According to the present invention, the compound (I) of the present invention can be used as a therapeutic agent for drug-induced bradycardia and bradyarrhythmia.

Claims

1. A therapeutic agent for drug-induced bradyarrhythmia, comprising the following compound (I) or a pharmacologically acceptable salt thereof as an active ingredient: 【Chemical 1】 (In the formula, Ph represents a phenyl group.)

2. The therapeutic agent according to claim 1, wherein the drug-induced bradyarrhythmia is an S1P receptor modulator-induced bradyarrhythmia.

3. The therapeutic agent according to claim 1, wherein the drug-induced bradyarrhythmia is an S1P1 modulator-induced bradyarrhythmia.

4. The therapeutic agent according to claim 1, wherein the drug-induced bradyarrhythmia is bradyarrhythmia induced by fingolimod.

5. The therapeutic agent according to claim 1, wherein the drug-induced bradyarrhythmia is bradyarrhythmia induced by siponimod.

6. The therapeutic agent according to claim 1, wherein the drug-induced bradyarrhythmia is a beta-blocker-induced bradyarrhythmia.

7. The therapeutic agent according to claim 1, wherein the drug-induced bradyarrhythmia is propranolol-induced bradyarrhythmia.

8. The therapeutic agent according to claim 1, wherein the drug-induced bradyarrhythmia is any of the following bradycardia: (a) sinus bradycardia, (b) sinus arrest, (c) sinoatrial block, (d) atrioventricular block, (e) sinus dysfunction, (f) bradycardiac heart failure, (g) bradycardiac atrial fibrillation.

9. The therapeutic agent according to claim 1, wherein the drug-induced bradyarrhythmia is either sinus bradycardia or atrioventricular block.

10. The therapeutic agent according to claim 1, wherein the drug-induced bradyarrhythmia is sinus bradycardia.

11. The therapeutic agent according to claim 1 , wherein the drug-induced bradyarrhythmia is atrioventricular block.

12. The therapeutic agent according to claim 1 , which is a therapeutic agent for preventive purposes.

13. The therapeutic agent according to claim 1, wherein the therapeutic agent is a therapeutic agent for the purpose of stopping.

Images