CN-121426729-B - Preparation of 2- (1H-indol-3-yl) -N- (2-nitrobenzyl) ethylamine derivatives and their use in the treatment of cardiac arrhythmias

Abstract

The invention belongs to the field of biological medicine, and in particular relates to a novel compound and application thereof. The invention designs a novel 2- (1H-indole-3-yl) -N- (2-nitrobenzyl) ethylamine derivative as a selective positive allosteric modulator of nAChR, and discovers that the compound with the structure shows remarkable advantages in the aspect of preventing and/or treating cardiac dysfunction diseases, has the characteristics of rapidly, safely and effectively preventing and stopping various cardiac arrhythmias, and provides a novel drug choice for treating clinical cardiac dysfunction diseases.

Inventors

• CHEN YIHAN
• HAO HAIPING
• Xie Duanyang
• LIU YI
• YANG PENG
• LIANG DANDAN

Assignees

• 上海市东方医院（同济大学附属东方医院）
• 中国药科大学

Dates

Publication Date

20260505

Application Date

20260104

Claims (3)

1. 1. A compound having the structural formula: 。
2. 2. Use of a compound for the preparation of a medicament for the prophylaxis and/or treatment of cardiac dysfunction selected from cardiac arrhythmias or heart failure, wherein the compound has a structural formula selected from any of the following: 。
3. 3. The use according to claim 2, wherein the medicament is used alone or in combination with other medicaments for the treatment of cardiac arrhythmias.

Description

Preparation of 2- (1H-indol-3-yl) -N- (2-nitrobenzyl) ethylamine derivatives and their use in the treatment of cardiac arrhythmias Technical Field The invention belongs to the field of biological medicine, and in particular relates to a novel compound and application thereof. Background In recent years, the incidence and mortality of cardiovascular disease (CardiovascularDisease, CVD) has risen year by year, and arrhythmias are defined as critical lethal risk factors, as abnormal frequency, rhythm, site of origin, conduction velocity and activation sequence of heart impulses. The clinical symptoms and prognosis of different types of arrhythmia are obvious, the light patients can have no obvious symptoms, the quality of life is not affected, and the heavy patients can have sudden death. Among these, fatal (malignant) arrhythmias mainly include supraventricular tachycardia, malignant atrial fibrillation, ventricular tachycardia, sinus arrest, and the like. Research shows that ischemic heart disease is the main cause （Podrid PJ,Myerburg RJ. Epidemiology and stratification of risk for sudden cardiac death[J]. Clin Cardiol,2005,28(11 suppl 1):I3-I11.）. of malignant arrhythmia such as ventricular tachycardia, ventricular fibrillation and the like, and in addition, severe heart failure patients often combine ventricular tachycardia and ventricular fibrillation and are also the important cause of malignant arrhythmia （Janse MJ. Electrophysiological changes in heart failure and their relationship to arrhythmogenesis[J]. Cardiovasc Res,2004,61 (2):208-217.）. The heart rhythm is characterized by abnormal impulse formation (automatic abnormality, abnormal triggering activity, the latter associated with delayed depolarization), abnormal impulse conduction (conduction velocity disorder, reentry activation), or the synergistic effect of the two. From the aspect of molecular and electrophysiological mechanism, the occurrence core of arrhythmia is closely related to the imbalance of myocardial electrical signal conduction regulation, namely, on one hand, the current disorder of a myocardial cell transmembrane ion channel (sodium, potassium, calcium and the like) can directly destroy the balance of an electrical signal conduction system to cause abnormal myocardial electrical activity so as to induce arrhythmia, and on the other hand, the gap junction protein 43 (Cx 43), the gap junction protein 40 (Cx 40), lysophosphatidylcholine (LPC), small molecular RNA and other regulatory molecules and the abnormal functions of receptors such as a cardiac M3 receptor, an AT1 receptor and the like can also participate in the occurrence and development of arrhythmia by interfering with myocardial electrophysiological steady state. Current western clinical guidelines recommend treatment of cardiac arrhythmias primarily in drug therapy and non-drug therapy. Among them, the traditional antiarrhythmic drugs include four general classes, beta blockers, sodium channel blockers, potassium channel blockers, and calcium channel blockers. Although the drug therapy is still an indispensable important means in clinic, the drug has the problem of relatively single therapeutic target, and although the drug can exert a certain curative effect, arrhythmia can be induced or aggravated to different degrees, and other adverse reactions, curative effect individual differences and other conditions are accompanied, so that the long-term use （The CAST Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction[J]. N EngI J Med, 1989, 321(6): 406-412.）, of patients is not recommended, and the clinical application of the drug is limited to a certain extent. In addition, the results of the arrhythmia suppression test (CAST) show that when the class I antiarrhythmic drugs are used for treating the ventricular premature contraction and the non-sustained ventricular rate of the myocardial infarction patient, the prognosis of the patient cannot be improved, but the mortality is increased. The problems of arrhythmia-causing effect, negative stress effect, organ toxicity and the like of the antiarrhythmic drugs are increasingly and widely paid attention to in clinical practice. Non-drug therapies mainly cover cardioversion, cardiac pacemaker implantation, implantable cardioverter defibrillator (Implantable Cardioverter Defibrillator, ICD) implantation, surgical treatment, catheter radiofrequency ablation (Radiofrequency Catheter Ablation, RFCA), etc. However, the indications of non-drug treatments such as radio frequency catheter ablation are strict, so that the clinical application of the catheter has certain limitations. In summary, the current western medicine drugs for treating arrhythmia have the problems of single target point, obvious adverse reaction, limited long-term use and the like, and part of the drugs can also increase the risk of poor prognosis of patients