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

Abstract

This invention belongs to the field of biomedicine, specifically relating to a novel compound and its applications. This invention designs a novel 2-(1H-indol-3-yl)-N-(2-nitrobenzyl)ethylamine derivative as a selective orthoallosteric modulator of nAChR, and discovers that compounds with this structure exhibit significant advantages in the prevention and / or treatment of cardiac dysfunction, possessing the characteristics of rapid, safe, and effective prevention and termination of various arrhythmias, providing a new drug option for the clinical treatment of cardiac dysfunction.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a new compound and its applications. Background Technology

[0002] In recent years, the incidence and mortality rates of cardiovascular disease (CVD) have been rising year by year. Arrhythmia, as a key risk factor for death, is defined as abnormalities in the frequency, rhythm, origin, conduction velocity, and excitation sequence of cardiac impulses. The clinical symptoms and prognoses of different types of arrhythmia vary significantly: mild cases may be asymptomatic and have no impact on quality of life; severe cases can lead to sudden death. Among these, fatal (malignant) arrhythmias mainly include supraventricular tachycardia, malignant atrial fibrillation, ventricular fibrillation, ventricular tachycardia, and sinus arrest. Studies have shown that ischemic heart disease is a major cause of malignant arrhythmias such as ventricular tachycardia and ventricular fibrillation (Podrid PJ, Myerburg RJ. Epidemiology and stratification of risk for sudden cardiac death[J]. Clin Cardiol, 2005, 28(11 suppl 1): I3-I11.). In addition, patients with severe heart failure often have ventricular tachycardia and ventricular fibrillation, which are also important causes of malignant arrhythmias (Janse MJ. Electrophysiological changes in heart failure and their relationship to arrhythmogenesis[J]. Cardiovasc Res,2004,61(2):208-217.).

[0003] The core mechanisms underlying cardiac arrhythmias are abnormal impulse formation (abnormal automaticity, abnormal triggering activity, the latter being related to delayed afterpolarization) and abnormal impulse conduction (conduction velocity impairment, re-entrant excitation), or a combination of both. From a molecular and electrophysiological perspective, the core of cardiac arrhythmia development is closely related to imbalances in myocardial electrical signal transduction regulation: on the one hand, disordered currents in transmembrane ion channels (sodium, potassium, calcium, etc.) of myocardial cells directly disrupt the balance of the electrical signal transduction system, leading to abnormal myocardial electrical activity and subsequently inducing arrhythmias; on the other hand, functional abnormalities in regulatory molecules such as connexin 43 (Cx43), connexin 40 (Cx40), lysophosphatidylcholine (LPC), and small RNA molecules, as well as receptors such as cardiac M3 receptors and AT1 receptors, can also participate in the development and progression of arrhythmias by interfering with myocardial electrophysiological homeostasis.

[0004] Current Western medicine clinical guidelines recommend primarily drug therapy and non-drug therapy for treating arrhythmias. Traditional antiarrhythmic drugs fall into four main categories: beta-blockers, sodium channel blockers, potassium channel blockers, and calcium channel blockers. While drug therapy remains an indispensable clinical tool, these drugs have a relatively singular therapeutic target. Although they can exert some therapeutic effect, they may induce or worsen existing arrhythmias to varying degrees, and are accompanied by other adverse reactions and individual differences in efficacy. Therefore, long-term use is not recommended (The CAST Investigators. Preliminary report: effect of encainide and flecainide on mortality in arandomized trial of arrhythmia suppression after myocardial infarction[J]. NEngI J Med, 1989, 321(6): 406-412.), which to some extent limits their clinical application. Furthermore, the Cardiac Arrhythmia Suppression Trial (CAST) showed that treating premature ventricular contractions and non-sustained ventricular tachycardia in patients with myocardial infarction with class I antiarrhythmic drugs not only failed to improve patient prognosis but also increased mortality. This has led to increasing attention being paid to the arrhythmic effects, negative inotropic effects, and organ toxicity of antiarrhythmic drugs in clinical practice. Non-pharmacological treatments mainly include electrical cardioversion, pacemaker implantation, implantable cardioverter-defibrillator (ICD) implantation, surgical treatment, and radiofrequency catheter ablation (RFCA). However, the indications for non-pharmacological treatments such as radiofrequency catheter ablation are relatively strict, limiting their clinical application.

[0005] In summary, current Western medicine treatments for arrhythmias suffer from limitations such as single target, significant adverse reactions, and restrictions on long-term use. Some drugs may even increase the risk of poor patient outcomes. Non-pharmacological treatments also have limitations, including strict indications. Therefore, there is an urgent need to explore more novel therapeutic drugs with high safety and stable efficacy to better meet clinical needs. Summary of the Invention

[0006] This invention designs a novel 2-(1H-indol-3-yl)-N-(2-nitrobenzyl)ethylamine derivative and discovers that compounds with this structure can be used to prevent and / or treat cardiac dysfunction, exhibiting the characteristics of rapid, safe, and effective prevention and termination of various arrhythmias, providing a new drug option for the clinical treatment of cardiac dysfunction. Based on this, this invention was completed.

[0007] In a first aspect, the present invention provides a compound or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, polymorph, stereoisomer or isotopic variant thereof; the structure of said compound is shown in formula (I):

[0008] Formula (I);

[0009] Wherein, R is selected from amino (NH2), halogen (F, Cl, Br), alkyl (-CH3, -CF3), methoxy (-OCH3), hydroxyl (-OH), substituted five-membered aromatic heterocycles, six-membered aromatic heterocycles, six-membered aromatic heterocycles or substituted fused rings.

[0010] Furthermore, the five-membered or six-membered aromatic heterocycle contains 1 to 3 heteroatoms.

[0011] Furthermore, the heteroatom is selected from N, O, or S.

[0012] Furthermore, the pharmaceutically acceptable salt of the compound is an acid addition salt.

[0013] Furthermore, the acids include inorganic acids and organic acids; the inorganic acids include hydrochloric acid, sulfuric acid, and phosphoric acid; and the organic acids include acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid, and tartaric acid.

[0014] Furthermore, the pharmaceutically acceptable salt of the compound may also be a salt formed by the compound of the present invention with a metal ion or a pharmaceutically acceptable amine, ammonium ion or choline.

[0015] Furthermore, the metal ions include, but are not limited to, sodium, potassium, and / or calcium.

[0016] Furthermore, the pharmaceutically acceptable amines include, but are not limited to, ethylenediamine and / or tromethamine.

[0017] In one embodiment of the present invention, the compound structural formula is selected from any one of the following:

[0018] .

[0019] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the first aspect (I) or a derivative thereof, and optionally a pharmaceutically acceptable excipient or carrier.

[0020] Furthermore, derivatives of the compound include pharmaceutically acceptable salts, prodrugs, hydrates or solvent compounds, polymorphs, stereoisomers or isotopic variants.

[0021] Furthermore, the carrier material includes, but is not limited to, one or more of water-soluble carrier materials, poorly soluble carrier materials, and / or enteric carrier materials.

[0022] Furthermore, the dosage form of the drug includes, but is not limited to, oral or injectable formulations.

[0023] Furthermore, the oral formulations include tablets, capsules, pills, solutions, and / or granules; the injectable formulations include powders and / or solutions for injection.

[0024] Furthermore, the formulation may be one or more of a conventional formulation, a sustained-release formulation, a controlled-release formulation, and / or a variety of microparticle delivery systems.

[0025] Furthermore, colorants, preservatives, flavorings, tasters, sweeteners, or other materials may be added to the pharmaceutical preparations if necessary.

[0026] Thirdly, the present invention provides an orthoallometric modulator targeting nicotinic acetylcholine receptors, the orthoallometric modulator comprising the compound or derivative thereof represented by the first aspect formula (I).

[0027] Furthermore, derivatives of the compound include pharmaceutically acceptable salts, prodrugs, hydrates or solvent compounds, polymorphs, stereoisomers or isotopic variants.

[0028] Furthermore, the nicotinic acetylcholine receptors include, but are not limited to, α7-nAChR, α4β2-nAChR, α3β4-nAChR, α6β2-nAChR, or α4α6β2-nAChR.

[0029] Fourthly, the present invention provides the use of the compound or derivative thereof represented by the first aspect formula (I) in the preparation of an orthoallosteric modulator of nicotinic acetylcholine receptor.

[0030] Furthermore, derivatives of the compound include pharmaceutically acceptable salts, prodrugs, hydrates or solvent compounds, polymorphs, stereoisomers or isotopic variants.

[0031] Furthermore, the nicotinic acetylcholine receptors include, but are not limited to, α7-nAChR, α4β2-nAChR, α3β4-nAChR, α6β2-nAChR, or α4α6β2-nAChR.

[0032] Fifthly, the present invention provides the use of the compound of the first aspect formula (I) or a derivative thereof in the preparation of a medicament for the prevention and / or treatment of cardiac dysfunction.

[0033] Furthermore, derivatives of the compound include pharmaceutically acceptable salts, prodrugs, hydrates or solvent compounds, polymorphs, stereoisomers or isotopic variants.

[0034] Furthermore, the drug can be used alone or in combination with other drugs for treating arrhythmias.

[0035] Furthermore, other drugs for treating arrhythmias include, but are not limited to, quinidine, procainamide, disopyramide, lidocaine, mexiletine, propafenone, or flecainide; beta-blockers include but are not limited to metoprolol, bisoprolol, atenolol, or propranolol; potassium channel blockers include but are not limited to amiodarone, sotalol, dronedarone, or ibutilide; calcium channel blockers include but are not limited to verapamil or diltiazem; and other unclassified drugs include but are not limited to digoxin, adenosine, or atropine.

[0036] Furthermore, the dosage form of the drug includes, but is not limited to, oral or injectable formulations.

[0037] Furthermore, the oral formulations include tablets, capsules, pills, solutions, and / or granules; the injectable formulations include powders and / or solutions for injection.

[0038] Furthermore, the cardiac dysfunction includes core types of diseases such as arrhythmia, heart failure, cardiomyopathy, valvular heart disease, myocardial ischemia / infarction-related functional abnormalities, and myocarditis and pericardial disease-related functional disorders.

[0039] Furthermore, the arrhythmias include, but are not limited to, ventricular arrhythmias such as premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation, or atrial arrhythmias such as premature atrial contractions, atrial tachycardia, and atrial fibrillation.

[0040] Furthermore, the arrhythmia is caused by heart failure, acute ischemic disease, cardiac structural abnormalities, primary electrophysiological diseases, electrolyte imbalances, endocrine disorders, autonomic nervous system disorders, drug or exogenous substance effects, lung diseases, as well as age and genetic factors.

[0041] Beneficial effects

[0042] This invention develops a series of 2-(1H-indol-3-yl)-N-(2-nitrobenzyl)ethylamine derivatives as selective orthoallosteric modulators of nAChR. These compounds exhibit significant advantages in anticardiac dysfunction, and there is a clear causal relationship between their technical effects and mechanisms of action, specifically reflected in the following aspects:

[0043] 1. Highly effective anti-cardiac dysfunction effect based on precise targeting mechanism

[0044] The compounds of this invention enhance the activity of nAChR through allosteric transformation, selectively increasing the acetylcholine-gated current in the myocardial injury region, thereby specifically improving electrical conduction and increasing the excitatory gradient in the infarct border region without affecting normal tissue. This mechanism directly results in its excellent efficacy in preventing and terminating FVTs in various animal models: In a rat ischemia / reperfusion in vitro model, 10 µM compound A1 of this invention reduced the FVT induction rate from 100% to 5% and shortened the duration from 9.0 ± 1.3 minutes to 0.020 ± 0.011 minutes; 10 µM compound A2 of this invention reduced the FVT induction rate from 100% to 4% and shortened the duration from 9.0 ± 1.3 minutes to 0.009 ± 0.0048 minutes; 10 µM compound A3 of this invention reduced the FVT induction rate from 100% to 3% and shortened the duration from 9.0 ± 1.3 minutes to 0.012 ± 0.0085 minutes; 10 µM compound A4 of this invention reduced the FVT induction rate from 100% to 5% and shortened the duration from 9.0 ± 1.3 minutes to 0.038 ± 0.018 minutes. In an in vitro ischemia / reperfusion model, a single intravenous bolus injection of 200 µM of compound A1 of this invention terminated 88.9% of persistent fibrillary thrombosis (FVT) episodes within 1.4 ± 0.62 minutes; a single intravenous bolus injection of 200 µM of compound A2 of this invention terminated 88.9% of FVT episodes within 1.5 ± 0.58 minutes; a single intravenous bolus injection of 200 µM of compound A3 of this invention terminated 90% of FVT episodes within 1.8 ± 0.60 minutes; and a single intravenous bolus injection of 200 µM of compound A4 of this invention terminated 75% of FVT episodes within 2.3 ± 0.71 minutes. In a large porcine I / R model, treatment with compound A1 of this invention restored sinus rhythm in all hearts and significantly reduced the duration of arrhythmia from 38 ± 2.8 minutes to 3.1 ± 0.34 minutes; treatment with compound A2 of this invention restored sinus rhythm in all hearts and significantly reduced the duration of arrhythmia from 38 ± 2.8 minutes to 2.7 ± 0.31 minutes; treatment with compound A3 of this invention restored sinus rhythm in all hearts and significantly reduced the duration of arrhythmia from 38 ± 2.8 minutes to 2.9 ± 0.44 minutes; treatment with compound A4 of this invention restored sinus rhythm in all hearts and significantly reduced the duration of arrhythmia from 38 ± 2.8 minutes to 2.9 ± 0.37 minutes.

[0045] 2. High safety profile stemming from the specificity of its mechanism of action.

[0046] Unlike the non-selective ion channel inhibition of the traditional sodium channel blocker lidocaine, the allosteric regulatory properties of the compounds in this invention enhance cholinergic signaling only under pathological conditions. This characteristic allows them to exert a potent therapeutic effect while exhibiting significantly superior safety compared to lidocaine: the compounds of this invention do not alter baseline heart rate, PR interval, QRS width, or QTc interval, while lidocaine carries the risk of affecting normal conduction and repolarization. Optical mapping results show that the compounds of this invention selectively increase conduction velocity in the infarct border region by up to 2.38 times (from 0.18 ± 0.054 mm / ms to 0.54 ± 0.051 mm / ms) and significantly reduce electrical dispersion from 15% to 2.9%, while lidocaine shows no significant improvement in conduction in either the damaged or non-damaged areas.

[0047] 3. Overall advantages compared to traditional drugs

[0048] In summary, the compounds of this invention achieve a balance between efficacy and safety through their unique mechanism of action, overcoming the core shortcomings of traditional antiarrhythmic drugs, such as "narrow therapeutic window and high risk of arrhythmia." They demonstrated rapid, potent, and sustained anti-FVT activity in various severe disease models (I / R, heart failure) while maintaining zero impact on normal electrophysiological parameters, providing a novel and reliable treatment option for clinical practice. Attached Figure Description

[0049] Figure 1 This study evaluates the antiarrhythmic activity of compounds A1–A4. (AB) Effects of 10 µM A1–A4 or the blank control group on the inducibility and duration of FVT in a rat model; (CD) Effects of A1–A4 or the blank control group on the efficacy of ongoing arrhythmia interventions and the duration of episodes; (EF) Effects of A1–A4 or the blank control group on the efficacy of interventions and the duration of episodes in a rat model of stress overload-induced heart failure (HF). Note: Veh stands for Vehicle, i.e., the blank control group.

[0050] Figure 2 To evaluate the antiarrhythmic activity of compounds A1-A4 in a porcine femoral heart VT model. (AB) Effects of A1-A4 or the blank control group on the intervention effect and duration of episodes in an isolated porcine heart FVT model.

[0051] Figure 3 The core electrophysiological mechanism of compound A1 in treating fatal ventricular arrhythmias is termination of reentry. (A) Effect of A1 or blank control group on the number of phase singularities in reentrant arrhythmias, (B) Effect of A1 or blank control group on the dominant frequency of reentrant arrhythmias, (C) Effect of A1 or blank control group on electrical conduction velocity in the infarct area of ​​reentrant arrhythmias.

[0052] Figure 4 For the electrophysiological safety assessment of compound A1. (A) Effects of blank control group, A1 or lidocaine on baseline cardiac electrophysiological parameters in isolated porcine hearts. (B) Effects of blank control group, A1 or lidocaine on electrical conduction velocity in undamaged myocardial regions in isolated porcine hearts.

[0053] Figure 5 The effects of A1 or blank control group on electrical conduction velocity and electrical dispersion in the damaged ventricular region of an isolated porcine heart FVT model. Detailed Implementation

[0054] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the embodiments described below can be combined with each other as long as they do not conflict with each other.

[0055] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0056] Definitions and Explanations

[0057] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0058] When the R substituent on the benzene ring does not have a fixed structure, it means that R can be attached to any position on the benzene ring, and R can be 0, 1, 2, 3, 4 or 5.

[0059] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0060] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmacologically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmacologically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and also include salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0061] The pharmacologically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0062] The compounds of this invention can exist in specific stereoisomer forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of protection claimed by this invention.

[0063] This invention also includes all suitable isotopic variants of the compounds of this invention. In this context, isotopic variants of the compounds of this invention should be understood as compounds in which at least one atom within the compound of this invention is replaced by another atom having the same atomic number but with a different atomic mass than that commonly or predominantly found in nature. Examples of isotopes that can be introduced into the compounds of this invention are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine, and iodine, such as...2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I. Certain isotopic variants of the compounds of the present invention (such as, in particular, those wherein one or more radioactive isotopes are introduced) can be used, for example, to study the mechanism of action or distribution of the active substance in vivo; because they are relatively easy to prepare and detect, using 3 H- or 14 C-isotope-labeled compounds are particularly suitable for this purpose. Furthermore, the introduction of isotopes (e.g., deuterium) can produce certain therapeutic advantages due to the increased metabolic stability of the compounds, such as prolonged in vivo half-life or reduced effective dose; the modifications described herein may therefore optionally also represent preferred embodiments of the invention. Isotope variants of the compounds of the invention can be prepared by methods known to those skilled in the art, thereby, for example, by means of the methods and specifications given in the embodiments below, using the respective reagents and / or corresponding isotope modifications of the starting compounds.

[0064] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention. "Optional" or "optionally" means that the events or conditions described below may occur but are not necessary, and the description includes both the occurrence of said events or conditions and the non-occurrence of said events or conditions.

[0065] Unless the stereochemistry is explicitly specified in the chemical structure or chemical name, the chemical structure or chemical name shall include all possible stereoisomers, conformational isomers, rotational isomers, and tautomers of the compound. For example, a compound containing a chiral carbon atom shall include (R) enantiomers and (S) enantiomers, as well as mixtures of enantiomers, including racemic mixtures; a compound containing two chiral carbons shall include all enantiomers and diastereomers (including (R,R), (S,S), (R,S) and (R,S) isomers).

[0066] In all uses of the compounds with the structures described herein, the invention also includes the use of any or all stereochemical forms, enantiomers, diastereomers, conformational isomers, rotational isomers, tautomers, solvates, hydrates, polymorphs, crystalline forms, amorphous forms, salts, pharmaceutically acceptable salts, metabolites, and prodrugs of the compounds.

[0067] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, to the extent of reliable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0068] Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Salts formed using methods conventional in the art are also included, such as ion exchange methods. Other pharmaceutically acceptable salts include: adipic acid salts, alginate salts, ascorbate salts, aspartate salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyrate salts, camphorate salts, camphor sulfonate salts, citrate salts, cyclopentylpropionate salts, diglucuronate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, fumarate salts, gluconate salts, glyceryl phosphate salts, glucuronate salts, hemisulfate salts, heptarate salts, hexanoate salts, hydroiodate salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, dihydroxynaphthalate salts, pectin ester salts, persulfate salts, 3-phenylpropionate salts, phosphate salts, picrate salts, p-pentanoate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and so on. Other pharmaceutically acceptable salts, if appropriate, include non-toxic ammonium salts, quaternary ammonium salts, and amine cations that form with counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonates, and aryl sulfonates.

[0069] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0070] The term "prodrug" includes compounds that are themselves biologically active or inactive, and which, when taken in a suitable manner, are metabolized or chemically reacted in the human body to form compounds of formula (I), or salts or solutions of compounds of formula (I). Prodrugs include (but are not limited to) compounds consisting of amino acid residues or polypeptide chains consisting of one or more (e.g., 2, 3, or 4) amino acid residues covalently linked by amide or ester bonds to the free amino, hydroxyl, or carboxyl group of the compound of the present invention. Amino acid residues include, but are not limited to, 20 naturally occurring amino acids typically represented by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, valine, ornithine, and sulfones. Other types of prodrugs are also included. For example, the free carboxyl group may be derived into an amide or alkyl ester. As described in *Advanced Drug Delivery Reviews* 1996, 19, 115, free hydroxyl groups are derivatized using groups including, but not limited to, hemisuccinates, phosphates, dimethylaminoacetate, and phosphoryloxymethoxycarbamates. Carbamate prodrugs of hydroxyl and amino groups, as well as carbonate prodrugs of hydroxyl groups, sulfonates, and sulfates, are also included. Derivatizations of hydroxyl groups such as (acyloxy)methyl and (acyloxy)ethyl ethers are also included, wherein the acyl group may be an alkyl ester, optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or wherein the acyl group is an amino acid ester as described above. This type of prodrug is described in the following literature: J. Med. Chem. 1996, 39, 10. Free hydroxyl groups can also be derivatized as amides, sulfonamides, or phosphoramides. All these other portions may be incorporated with groups including, but not limited to, ether, amine, and carboxylic acid functional groups.

[0071] The term "polymorphism" refers to the different arrangements of chemical drug molecules, generally manifested as the form in which the drug raw material exists in a solid state. A drug can exist in multiple crystalline forms, and different crystalline forms of the same drug may have different solubility and absorption in the body, thus affecting the dissolution and release of the formulation.

[0072] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0073] The pharmaceutical compositions of the present invention comprise at least one compound (including pharmaceutically acceptable salts of such compounds) according to any embodiment disclosed herein, mixed with at least one pharmaceutically acceptable excipient, carrier, or diluent. Preferably, the pharmaceutical composition is a sterile composition, or a composition consisting primarily of, or only of, the aforementioned compounds and one or more pharmaceutically acceptable excipients, carriers, and / or diluents. In some embodiments, the pharmaceutical composition comprises at least two pharmaceutically acceptable carriers and / or excipients described herein.

[0074] "Pharmaceutically acceptable excipients" refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0075] As used herein, the term "pharmaceutically acceptable carrier" and its analogues refer to excipients, binders, diluents, etc., known to those skilled in the art, suitable for application to individuals (e.g., mammals or non-mammals). Combinations of two or more carriers are also covered in this invention. The pharmaceutically acceptable carriers and any other components described herein are suitable for use in a particular dosage form and the intended route of administration (e.g., oral, parenteral). Such suitability is readily apparent to those skilled in the art, particularly based on the teachings provided herein. The pharmaceutical compositions described herein comprise at least one pharmaceutically acceptable carrier or excipient; preferably, the compositions comprise at least one carrier or excipient other than water, or at least one carrier or excipient in addition to water.

[0076] Pharmaceutical excipients can be pharmaceutically acceptable carriers, excipients, or excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form.

[0077] As used herein, the term "treatment" refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) and / or pharmaceutically acceptable salts thereof, to an individual suffering from or exhibiting symptoms of a disease, for the purpose of curing, alleviating, reducing, altering, treating, improving, modifying, or influencing the disease or its symptoms. The term "prevention" as used herein refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) and / or pharmaceutically acceptable salts thereof, to an individual with a predisposition to the disease, for the purpose of preventing the individual from contracting the disease. When a chemical reaction is involved, the terms "treatment," "contact," and "reaction" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction producing the indicated and / or desired product may not necessarily originate directly from the combination of the two initially added reagents; that is, one or more intermediates may be present in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0078] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral and injectable administration.

[0079] Solid dosage forms for oral administration include capsules, tablets, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or solubilizers, such as starch, lactose, sucrose, glucose, hydroquinone, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules and tablets, the dosage form may also contain buffers.

[0080] The compounds and compositions of this invention can be administered alone or advantageously in combination with other commercially available or developing therapeutic agents for the treatment of cardiac dysfunction, including but not limited to Class I drugs (sodium channel blockers): quinidine, procainamide, disopyramide, lidocaine, mexiletine, propafenone, flecainide, and moricizine; Class II drugs (β-blockers): metoprolol, bisoprolol, propranolol, nadolol, carvedilol, etc.; Class III drugs (potassium channel blockers): amiodarone, dronedarone, sotalol, ibutilide, dofetilide, nifekalan, and venakalan; Class IVa drugs (calcium channel blockers): verapamil and diltiazem; sinoatrial node I... f Inhibitors: ivabradine; β-receptor agonists isoproterenol and epinephrine; muscarinic M2 receptor blockers: including atropine and scopolamine; muscarinic M2 receptor agonists digitalis; adenosine A1 receptor agonists, adenosine, etc.

[0081] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment, wherein the dose administered is the pharmaceutically considered effective dose. The specific dose should take into account factors such as the route of administration and the patient's health condition, all of which are within the scope of a skilled physician's expertise.

[0082] The compounds of the present invention are preferably suitable for treating diseases of heart failure. Diseases that can be treated with the compounds of the present invention particularly include diseases that cause heart failure. In the context of the present invention, these diseases particularly include, but are not limited to, the following core types of diseases: arrhythmias, heart failure, cardiomyopathy, valvular heart disease, myocardial ischemia / infarction-related functional abnormalities, myocarditis, and pericardial disease-related functional disorders. Arrhythmias caused by the following diseases are all within the scope of diseases that can be treated with the compounds of the present invention: ① Cardiac factors, such as rheumatic heart disease, myocarditis, coronary heart disease, hypertensive heart disease, cardiomyopathy, etc. These organic heart lesions can be accompanied by myocardial ischemia, inflammation, myocardial damage, etc., leading to electrophysiological abnormalities of myocardial cells. Therefore, the above organic heart diseases can all induce arrhythmias. Hereditary arrhythmias such as long QT syndrome and Brugada syndrome often co-occur with malignant arrhythmias, resulting in serious clinical consequences. ② Systemic factors, such as electrolyte disturbances (hyperkalemia, hypokalemia), acid-base imbalances, infections, poisoning, etc. ③ Factors related to other organ dysfunction: Functional or organic changes in organs other than the heart can also induce arrhythmias, such as hyperthyroidism, anemia, fever, etc.

[0083] Preparation Example 1: Synthesis of 2-(5-methoxy-1H-indol-3-yl)-N-(2-nitrobenzyl)ethylamine (A1)

[0084]

[0085] 5-Methoxytryptamine (1.90 g, 10.0 mmol), 2-nitrobenzenebromo (2.18 g, 10.1 mmol), and potassium carbonate (2.76 g, 20.0 mmol) were sequentially added to a mixed solvent system containing tetrahydrofuran (THF, 100 mL) and water (10 mL). The resulting solution was heated to reflux at 80 °C with continuous stirring for 6 h, and the reaction was monitored by thin-layer chromatography (TLC). After completion, the reaction mixture was cooled and quenched with water. The mixture was then extracted three times with ethyl acetate. The collected organic layers were combined and dried on anhydrous sodium sulfate (Na₂SO₄). The solvent was then evaporated under reduced pressure, and the crude product was purified by rapid preparative chromatography to give the target product A1 (2.60 g, 80% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.97 (s,1H), 7.94 (dd, J = 8.1, 1.3 Hz, 1H), 7.62-7.51 (m, 2H), 7.42-7.38 (m, 1H),7.26 (dd, J = 8.8, 0.6 Hz, 1H), 7.04 (dd, J = 5.8, 2.4 Hz, 2H), 6.87 (dd, J =8.8, 2.4 Hz, 1H), 4.10 (s, 2H), 3.87 (s, 3H), 3.03 -2.96 (m, 4H). 13C NMR (151 MHz, DMSO-d6) δ 153.41, 149.49, 136.19, 133.35, 131.92, 131.06, 128.32, 128.05, 124.60, 123.68, 112.71, 112.43, 111.48, 100.60, 55.78, 50.08, 49.96, 26.05.

[0086] Preparation Example 2: Synthesis of 2-(1H-indol-3-yl)-N-(2-nitrobenzyl)ethylamine (A2)

[0087]

[0088] By replacing 5-methoxytryptamine with tryptamine and following the same synthesis method as A1, the target product A2 was obtained as a pale yellow solid with a yield of 82%. MS: 296.4 [M+H]+.

[0089] Preparation Example 3: Synthesis of 2-(6-fluoro-1H-indol-3-yl)-N-(2-nitrobenzyl)ethylamine (A3)

[0090]

[0091] By replacing 5-methoxytryptamine with 4-fluorotryptamine and following the same synthesis method as A1, the target product A3 was obtained as a light brown solid with a yield of 72%. MS: 314.2 [M+H]+.

[0092] Preparation Example 4: Synthesis of 2-(5-fluoro-1H-indol-3-yl)-N-(2-nitrobenzyl)ethylamine (A4)

[0093]

[0094] By replacing 5-methoxytryptamine with 5-fluorotryptamine and following the same synthesis method as A1, the target product A4 was obtained as a light brown solid with a yield of 75%. MS: 314.2 [M+H]+.

[0095] Validation Example 1: Preventive and therapeutic effects in a rat ischemia / reperfusion (I / R) model.

[0096] 1. Model Establishment

[0097] Ex vivo model: The Langendorff perfusion system was used to perform LAD ligation and reperfusion on the isolated heart, and electrophysiological recording and stimulation were performed simultaneously.

[0098] 2. Method

[0099] An isolated rat heart ischemia / reperfusion model was established by intraperitoneal injection of heparin 500 IU / kg and anesthetization with sodium pentobarbital 50 mg / kg. The heart was then rapidly removed and perfused using Langendorff technique. A stable and induced FVT model (which could induce arrhythmias lasting more than 3 minutes) was established by ligating the left anterior descending coronary artery for 60 minutes, followed by reperfusion for 60 minutes.

[0100] The efficacy of drugs in preventing arrhythmias was evaluated based on the above model: after perfusion administration of compounds A1-A4 (10 µM), rapid electrical stimulation was used to induce FVTs, and the incidence and duration of arrhythmias were recorded as the main evaluation indicators.

[0101] The effects of compounds A1-A4 on terminating arrhythmias were evaluated based on the above model: after rapid electrical stimulation to induce FVTs, compounds A1-A4 were administered via perfusion and injection, and the termination rate and duration of arrhythmias were recorded as the main evaluation indicators.

[0102] 3. Results

[0103] Preventive effects: In an in vitro model, 10 μM of compound A1 of the present invention significantly reduced the induction rate of febrile ventricular tachycardia (FVT) from 100% to 5% and drastically shortened the duration of arrhythmia from 9.0 ± 1.3 minutes to 0.020 ± 0.011 minutes; 10 μM of compound A2 of the present invention reduced the FVT induction rate from 100% to 4% and shortened the duration from 9.0 ± 1.3 minutes to 0.009 ± 0.0048 minutes; 10 μM of compound A3 of the present invention reduced the FVT induction rate from 100% to 3% and shortened the duration from 9.0 ± 1.3 minutes to 0.012 ± 0.0085 minutes; 10 μM of compound A4 of the present invention reduced the FVT induction rate from 100% to 5% and shortened the duration from 9.0 ± 1.3 minutes to 0.038 ± 0.018 minutes (Figures 1A and 1B).

[0104] Therapeutic effects: In an in vitro model, a single intravenous bolus injection of 200 μM of compound A1 of this invention successfully terminated 88.9% of induced persistent femoral head thrombosis (FVT) within 1.4 ± 0.62 minutes; a single intravenous bolus injection of 200 μM of compound A2 of this invention terminated 88.9% of FVT within 1.5 ± 0.58 minutes; a single intravenous bolus injection of 200 μM of compound A3 of this invention terminated 90% of FVT within 1.8 ± 0.60 minutes; and a single intravenous bolus injection of 200 μM of compound A4 of this invention terminated 75% of FVT within 2.3 ± 0.71 minutes. Figure 1 (C and D).

[0105] 4. Conclusion

[0106] This embodiment demonstrates that A1~A4 have both powerful therapeutic effects in the I / R model, namely, preventing the occurrence of FVT and rapidly terminating existing FVT.

[0107] Validation Example 2: Validation in a rat model of heart failure due to stress overload (HF)

[0108] 1. Model Establishment

[0109] A pressure overload heart failure model was induced by transverse aortic coarctation (TAC) surgery, which can spontaneously or easily induce FVT.

[0110] 2. Method

[0111] Rats with stress overload-induced heart failure were anesthetized by intraperitoneal injection of heparin 500 IU / kg for 20 min, followed by administration of sodium pentobarbital 50 mg / kg. The heart was then rapidly removed and perfused using Langendorff ablation, followed by rapid electrical stimulation to establish a stable and continuous heart thrombosis (FVT) model. The termination rate and duration of arrhythmias were recorded as the primary evaluation parameters after perfusion and administration of A1–A4 (0, 200 µM).

[0112] 3. Results

[0113] In this isolated FVT model induced by chronic heart failure, A1 effectively terminated 87.5% of FVT episodes, with a mean termination time of 2.0 ± 0.72 minutes; A2 effectively terminated 87.5% of FVT episodes, with a mean termination time of 2.6 ± 0.65 minutes; A3 effectively terminated 87.5% of FVT episodes, with a mean termination time of 3.2 ± 0.77 minutes; and A4 effectively terminated 75% of FVT episodes, with a mean termination time of 3.5 ± 0.92 minutes (Figures 1E and F).

[0114] 4. Conclusion

[0115] This example demonstrates that the antiarrhythmic effects of A1-A4 are not limited to the acute ischemic model, but are equally effective in the context of chronic heart failure, highlighting their broad-spectrum therapeutic potential.

[0116] Validation Example 3: Translational Study in a Large Animal (Pig) I / R Model

[0117] 1. Model Establishment

[0118] A large animal model of myocardial infarction with high clinical relevance was established by occluding the mid-LAD ​​in domestic pigs with a balloon catheter for 60 minutes, followed by reperfusion for 72 hours. Ex vivo electrophysiological assessments were performed using a Langendorff perfusion system.

[0119] 2. Method

[0120] The established in vivo porcine cardiac ischemia / reperfusion model was used. After anesthesia, the heart was quickly removed and perfused with Langendorff. A stable and continuous femoral heart thrombosis (FVT) model was then induced by rapid electrical stimulation. The effectiveness of drugs in terminating arrhythmias was evaluated based on this model: after inducing FVTs with rapid electrical stimulation, different drugs (A1-A4) were administered via perfusion and injection, and the termination rate and duration of arrhythmias were recorded as the primary evaluation indicators.

[0121] 3. Results

[0122] The administration regimen of compound A1 of the present invention, consisting of a bolus injection (200 μM) followed by continuous perfusion (10 μM), successfully restored sinus rhythm in all tested hearts and significantly reduced the duration of arrhythmia from 38 ± 2.8 minutes to 3.1 ± 0.34 minutes; treatment with compound A2 of the present invention restored sinus rhythm in all hearts and significantly reduced the duration of arrhythmia from 38 ± 2.8 minutes to 2.7 ± 0.31 minutes; treatment with compound A3 of the present invention restored sinus rhythm in all hearts and significantly reduced the duration of arrhythmia from 38 ± 2.8 minutes to 2.9 ± 0.44 minutes; treatment with compound A4 of the present invention restored sinus rhythm in all hearts and significantly reduced the duration of arrhythmia from 38 ± 2.8 minutes to 2.9 ± 0.37 minutes (Figure 2).

[0123] 4. Conclusion

[0124] This large-scale animal experiment successfully verified the potent antiarrhythmic effect of A1-A4 under conditions closer to human physiological conditions, providing key evidence for its clinical translation.

[0125] Validation Example 4: Study of Core Electrophysiological Mechanisms—High-Resolution Optical Mapping

[0126] 1. Method

[0127] Ex vivo rat hearts were obtained after I / R injury, loaded with the voltage-sensitive dye Di-4-ANEPPS, and administered with different drug (A1) concentrations (0, 10 μM) via perfusion. After rapid electrical stimulation, optical mapping was performed using a high-speed CMOS camera at 1000 frames / second to analyze key electrophysiological parameters (ventricular conduction velocity, dominant frequency, and phase singularity).

[0128] 2. Results

[0129] Suppression of re-entry: A1 treatment completely eliminated phase singularities (from 7 ± 0.6 to 0, P < 0.0001) (Figure 3A), which is an electrophysiological marker of the re-entry core. Simultaneously, it reduced the dominant frequency from 5.9 ± 1.1 Hz to 2.0 ± 0.18 Hz (Figure 3B).

[0130] Improved conduction: A1 specifically targets the infarct margin region, significantly increasing the conduction velocity (CV) in this region by 2.38 times, from 0.18 ± 0.054 mm / ms to 0.54 ± 0.051 mm / ms (P < 0.0001) (Figure 3C). This enhancement of CV and reduction in dispersion directly disrupts the conditions for the formation and maintenance of recurrent loops.

[0131] 3. Conclusion

[0132] This embodiment demonstrates from a mechanistic perspective that A1 achieves its powerful and precise anti-reversion effect by selectively enhancing electrical conduction and restoring electrical synchronicity in the damaged area.

[0133] Example 5: Comprehensive Cardiac Safety Assessment

[0134] 1. Method

[0135] In an isolated porcine heart model, the effects of A1 (10 μM) on baseline electrophysiological parameters and conduction function were systematically compared with those of lidocaine, a first-line clinical drug, after perfusion administration of the drug (A1).

[0136] 2. Results

[0137] No effect on baseline electrophysiology: Compared with the solvent control group, A1 at effective concentrations had no significant effect on heart rate, PR interval, QRS width, QTc interval, or conduction velocity in normal ventricular regions (Figure 4).

[0138] Targeted advantages: A1 selectively improved cardiac output (CV) in the damaged area (by 89%, P = 0.0178) without affecting the healthy area; while lidocaine had no effect on either. At the same time, A1 significantly reduced myocardial electrical dispersion from 15% to 2.9% (P = 0.0014), greatly improving electrical homogeneity (Figure 5).

[0139] 3. Conclusion

[0140] This safety assessment demonstrates that A1 has an excellent safety window. Its action exhibits pathological region selectivity, effectively combating arrhythmias while avoiding the risks of conduction block and cardiac function suppression caused by the non-selective inhibition of traditional drugs.

[0141] In summary, through a series of rigorous embodiments, this invention has demonstrated, from a multi-level and multi-species model, that the compound prepared by this invention, as an antiarrhythmic drug based on a novel mechanism, possesses three core advantages: potent prevention and termination of FVT, precise targeting of pathological regions, and excellent cardiac safety, providing a breakthrough solution for the treatment of fatal ventricular arrhythmias.

Claims

1. A compound, said compound having the following structural formula: 。 2. Use of a compound in the preparation of a medicament for the prevention and / or treatment of cardiac dysfunction; wherein the cardiac dysfunction is selected from arrhythmias or heart failure; and wherein the compound has a structural formula selected from any of the following: 。 3. The use as described in claim 2, characterized in that, The drug may be used alone or in combination with other drugs for treating arrhythmias.

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