Application of varenicline in preparation of medicine for treating arrhythmia

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a medicine for treating cardiac dysfunction. The invention finds that the compounds targeting the endogenous cholinergic system can be used for treating cardiac dysfunction; after intervention of the compound, myocardial conduction inhibition caused by ischemia reperfusion (I / R) injury can be effectively reversed, and endogenous cholinergic system function down-regulation caused by I / R injury can be repaired.

Description

Application of varenicline in the preparation of drugs for treating arrhythmias Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a drug for treating cardiac dysfunction. Background Technology

[0002] Cardiac arrhythmia refers to abnormal excitation of the sinoatrial node or excitation originating outside the sinoatrial node, with slow, blocked, or abnormal conduction, leading to abnormal heart rate and / or rhythm. Its clinical manifestations are significantly heterogeneous; mild cases may be asymptomatic, with typical presentations including chest tightness and palpitations, while severe cases may result in syncope, acute heart failure, or even cardiac arrest leading to sudden death (Qin Zengchuang. Clinical observation of the effect of amiodarone combined with metoprolol in the treatment of emergency arrhythmias [J]. Modern Medicine and Health Research, 2025, 9(8):65-67.). Clinically, based on the ventricular rate in adults at rest, arrhythmias are divided into two main categories: rapid arrhythmias (ventricular rate > 100 beats / min) and bradyarrhythmias (ventricular rate < 60 beats / min).

[0003] The severity of symptoms in patients with tachyarrhythmias is related to the duration of the episode: mild cases may be asymptomatic, while severe cases may present with palpitations, chest tightness, dizziness, etc.; if the heart rate is consistently >100 beats / min for several weeks, even if the heart structure is normal, it may induce dilated cardiomyopathy and severe heart failure. For elderly patients with underlying cardiovascular disease who cannot tolerate tachycardia, the clinical prognosis is worse (Byrnes TJ, Costantini O. Tachyarrhythmias and Bradyarrhythmias: Differential Diagnosis and Initial Management in the Primary Care Office[J]. Med Clin North Am. 2017 May;101(3):495-506.). The etiology of this type of arrhythmia is complex. In addition to heart disease itself, imbalances in the function of various systems in the body can induce or indirectly lead to the disease by changing the physiological state of the heart. Physiological triggers (such as strenuous exercise, emotional excitement, excessive drinking of tea or coffee, etc.) can activate the sympathetic nervous system and cause transient attacks. After the trigger is removed, the arrhythmia usually resolves on its own and usually does not require special treatment. Bradyarrhythmia is characterized by a slow heart rate. The progression of the disease can induce serious adverse events such as Adams-Stokes syndrome and sudden death. Timely intervention measures are required to control the disease (Qiu Jun, Zhang Yong. Effect of Ephedra-Aconite-Asarum Decoction combined with Erxian Shengmai Decoction on transmural repolarization dispersion in patients with chronic arrhythmia [J]. Global Traditional Chinese Medicine, 2017, 10(12): 1523-1525.).

[0004] The treatment goals for arrhythmias are to restore normal heart rhythm, adjust ventricular rate, relieve clinical symptoms, and prevent potential adverse cardiac events. Current clinical treatment strategies mainly include three major directions: drug therapy, catheter ablation, and device therapy. The clinical application of antiarrhythmic drugs (AADs) is mainly based on the Vaughan-Williams classification system, which classifies drugs into four categories according to their pharmacological mechanisms: Class I drugs (sodium channel blockers), Class II drugs (β-receptor antagonists), Class III drugs (potassium channel blockers), and Class IV drugs (calcium channel blockers). Each type of drug exerts its effect by regulating different ion channels. These limitations have prompted the medical community to continuously explore more targeted treatment strategies (Totolici S, Popescu R, Dan GA. Contemporary antiarrhythmic pharmacotherapy: revisiting the old, exploring the new[J]. Future Cardiol. 2025 Aug;21(10):789-794.). Catheter ablation, as an invasive procedure, is suitable for the treatment of localized and reversible arrhythmias, especially atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT), with a clear therapeutic effect (Dan GA, Martinez-Rubio A, Agewall S, et al. Antiarrhythmic drugs-clinical use and clinical decisionmaking: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP)[J]. Europace. 2018 May 1;20(5):731-732an.), and studies have confirmed its effectiveness in paroxysmal or persistent atrial fibrillation.

[0005] However, existing treatments are insufficient to fully reflect the complex electrophysiological properties of drugs, and the therapeutic window of traditional AADs overlaps with the risk of inducing fatal arrhythmias, presenting significant limitations: Class I drugs may increase the risk of death in patients with organic heart disease; Class II drugs, while reducing overall mortality, have limited direct antiarrhythmic effects; among Class III drugs, amiodarone is effective but accompanied by significant extracardiac toxicity; Class IV drugs are mainly suitable for the treatment of supraventricular arrhythmias. Therefore, when selecting AADs clinically, it is necessary to comprehensively assess whether the patient has underlying structural heart disease, complications, and drug side effects, which to some extent limits their application (Mankad P, Kalahasty G. Antiarrhythmic Drugs: Risks and Benefits[J]. Med Clin North Am. 2019 Sep;103(5):821-834.). With the development of new technologies such as catheter ablation, the status of AADs in the treatment of arrhythmias has declined. Secondly, as an invasive treatment, catheter ablation still has a low success rate for single ablation in long-term persistent atrial fibrillation. Repeated ablation not only increases the risk of complications and thromboembolic events, but also leads to increased treatment costs and a greater psychological burden on patients, seriously affecting their quality of life (Reddy VY, Gerstenfeld EP, Natale A, et al. Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation[J]. N Engl JMed. 2023 Nov 2;389(18):1660-1671.). Finally, although device therapy (such as implantable cardioverter defibrillators, ICDs) is effective, it is accompanied by surgical risks, high costs, and potential impacts on patients' quality of life.

[0006] Varenicline is a highly selective partial agonist of the α4β2 nAchR (nicotinic acetylcholine receptor, nAchR). α4β2 nAchR is widely distributed in mesolimbic dopamine (DA) neurons. Nicotine in cigarettes binds to this receptor, promoting DA release and acting on the nucleus accumbens (NAC), inducing a feeling of pleasure and other reward effects in smokers. Varenicline blocks nicotine-induced DA release through a dual regulatory effect of agonism and antagonism against α4β2 and α6β2 receptor subtypes, thereby alleviating withdrawal symptoms and increasing the success rate of smoking cessation (Jordan CJ, Xi ZX. Discovery and development of varenicline for smoking cessation. Expert Opin Drug Discov. 2018 Jul;13(7):671-683.). To date, there is no direct evidence that varenicline has an antiarrhythmic therapeutic effect. Summary of the Invention

[0007] This invention discovers that compounds targeting the endogenous cholinergic system can be used to treat cardiac dysfunction; after intervention with these compounds, not only can myocardial conduction inhibition caused by ischemia-reperfusion (I / R) injury be effectively reversed, but also the downregulation of endogenous cholinergic system function caused by I / R injury be repaired. Based on this, this invention was completed.

[0008] In a first aspect, the present invention provides a compound for treating cardiac dysfunction, or a pharmaceutically acceptable salt, prodrug, hydrate or solvent compound, polymorph, stereoisomer or isotopic variant thereof, the structure of which is shown in formula (I): Formula (I); wherein, R1 is an amino protecting group, which is selected from OCH, OCCH3, OCCl3, OCCF3, OCCH2CH3, OCC(CH3)3, OCOCH3, OCOCH2CH3, OCOCH2CCl3 or OCOC(CH3)3; and R2, R3, R4, R5, R6 and R7 are each independently selected from hydrogen (H), amino (NH2), halogen (F, Cl, Br), alkyl (-CH3, -CF3), methoxy (-OCH3) or hydroxyl (-OH).

[0009] Furthermore, the compound targets the endogenous cholinergic system.

[0010] Furthermore, the endogenous cholinergic system includes, but is not limited to, α7-nAChR, α4β2-nAChR, α3β4-nAChR, α6β2-nAChR, or α4α6β2-nAChR.

[0011] In one embodiment of the present invention, the compound is a compound that targets α4β2-nAChR, and its structural formula is shown in formula (II): Formula (II).

[0012] 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.

[0013] 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.

[0014] In a second aspect, the present invention provides the use of the compound or its derivatives described in the first aspect in the preparation of a medicament for treating cardiac dysfunction; wherein the medicament works by: 1) reversing myocardial conduction inhibition; 2) repairing the downregulation of nicotinic acetylcholine receptor function.

[0015] Furthermore, derivatives of the compound include pharmaceutically acceptable salts, prodrugs, hydrates or solvent compounds, polymorphs, stereoisomers or isotopic variants.

[0016] Furthermore, pharmaceutically acceptable salts of the compounds described in the first aspect include tartrates, hydrochlorides, dihydrochlorides, benzoates, and benzenesulfonates, etc.

[0017] Furthermore, the hydrate includes monohydrate or polyhydrate.

[0018] Furthermore, one or more pharmaceutically acceptable excipients or carriers may be added to the drug.

[0019] Furthermore, the dosage form of the drug includes, but is not limited to, oral formulations or injectable formulations.

[0020] Furthermore, the oral formulations include tablets, capsules, pills, solutions, and / or granules; the injectable formulations include powders and / or solutions for injection.

[0021] 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.

[0022] 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.

[0023] Furthermore, the arrhythmia is caused by heart failure, 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.

[0024] Furthermore, the nicotinic acetylcholine receptors include, but are not limited to, α7-nAChR, α4β2-nAChR, α3β4-nAChR, α6β2-nAChR, or α4α6β2-nAChR.

[0025] Furthermore, the causes of the aforementioned myocardial conduction inhibition include, but are not limited to, I / R damage, myocardial infarction, heart failure, myocarditis, cardiomyopathy, myocardial fibrosis, valvular heart disease, congenital heart disease, pericardial disease and other heart-related diseases, as well as electrolyte disturbances such as hyperkalemia, hypokalemia, hypomagnesemia, and hypercalcemia.

[0026] Furthermore, the causes of the downregulation of nicotinic acetylcholine receptor function include, but are not limited to, ischemia-reperfusion (I / R) injury, heart failure, myocardial infarction, myocarditis, cardiomyopathy, congenital heart disease, valvular heart disease and other heart-related diseases, as well as long-term nicotine exposure such as chronic smoking and chewing betel nut.

[0027] Thirdly, the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or a derivative thereof, and another active ingredient.

[0028] Furthermore, derivatives of the compound include pharmaceutically acceptable salts, prodrugs, hydrates or solvent compounds, polymorphs, stereoisomers or isotopic variants.

[0029] Furthermore, the other active ingredient includes other drugs for treating cardiac dysfunction, drugs for improving cardiac function, or drugs for increasing bodily functions, which are different from the compounds described in the first aspect.

[0030] Furthermore, the compound described in the first aspect of the pharmaceutical composition may be packaged individually or in combination with other drugs for treating cardiac dysfunction.

[0031] Furthermore, other medications for treating cardiac dysfunction 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 medications include but are not limited to digoxin, adenosine, or atropine.

[0032] Furthermore, one or more pharmaceutically acceptable excipients or carriers may be added to the pharmaceutical composition.

[0033] Furthermore, the dosage form of the drug includes, but is not limited to, oral or injectable formulations.

[0034] Furthermore, the oral formulations include tablets, capsules, pills, solutions, and / or granules; the injectable formulations include powders and / or solutions for injection.

[0035] Beneficial Effects 1. This invention found that at a concentration of 10 µM, the compound shown in formula (II) significantly reduced the incidence of FVT from 100% to 25%, and shortened the duration from 9.5 ± 1.6 minutes to 0.76 ± 0.31 minutes. In vivo rat I / R model experiments further confirmed that the compound shown in formula (II) can significantly inhibit FVT.

[0036] 2. This invention found that treatment with the compound shown in formula (II) significantly improved the conduction velocity in the damaged area, increasing it from 0.51 ± 0.017 mm / ms to 0.69 ± 0.04 mm / ms. This indicates that nicotinic acetylcholine receptor modulators can effectively reverse myocardial conduction inhibition caused by I / R injury, providing a key electrophysiological explanation for their antiarrhythmic effect.

[0037] 3. This invention found that after intervention with the compound shown in formula (II), the reduced acetylcholine-gated current in ventricular myocytes caused by I / R damage can be partially restored. This indicates that I / R damage causes downregulation of nicotinic acetylcholine receptor function, and compounds targeting this receptor can directly repair this pathological electrophysiological defect. Attached Figure Description

[0038] Figure 1 shows that α4β2 nAChRs regulation can inhibit fatal ventricular tachyarrhythmias and improve conduction function and restore receptor activity after I / R injury. (AB) In vitro and in vivo ventricular fibrillation models showed that the induction rate and duration of ventricular fibrillation were higher in the control group (Vehicle, Veh), while the compound shown in formula (II) reduced the induction rate and duration of ventricular fibrillation. Each group n = 5-10 rats. (C) Optical mapping showed that the compound shown in formula (II) could partially restore conduction velocity compared with the control group (each group n = 7-8 rats). (D) Whole-cell recording showed that the acetylcholine-gated current was significantly weakened after I / R, and the compound shown in formula (II) could partially restore the current intensity (each group n = 9-10 cells, derived from 3-4 rats). Data are expressed as mean ± standard error. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. Detailed Implementation

[0039] 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.

[0040] 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.

[0041] Definitions and Explanations 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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).

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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”).

[0056] 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.

[0057] "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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] The core of the myocardial conduction inhibition described in this invention is abnormal electrical activity of myocardial cells and damage to the structure / function of the conduction system. Besides ischemia-reperfusion (I / R) injury, it is also related to various cardiac diseases, systemic factors, and drugs. Myocardial conduction inhibition caused by the following diseases falls within the scope of diseases that can be treated by the compounds of this invention: ① Cardiac-related diseases: ischemia-reperfusion (I / R) injury, myocardial infarction, heart failure, myocarditis, cardiomyopathy, myocardial fibrosis, valvular heart disease, congenital heart disease, pericardial disease; ② Electrolyte disturbances: hyperkalemia, hypokalemia, hypomagnesemia, hypercalcemia; ③ Drugs / toxins: antiarrhythmic drugs (quinidine, propafenone, amiodarone, verapamil, etc.), β-blockers (metoprolol, bisoprolol, etc.), digitalis preparations. (Digoxin, worsens with poisoning), others (antipsychotics, tricyclic antidepressants, some antibiotics, organophosphorus pesticides); ④ Systemic diseases: endocrine diseases (hypothyroidism / hyperthyroidism), rheumatic immune diseases (systemic lupus erythematosus, sarcoidosis), infectious diseases (infective endocarditis, sepsis); ⑤ Surgery / trauma-related: cardiac surgery (coronary artery bypass grafting, valve replacement, etc., intraoperative damage to the conduction system), interventional cardiac treatment (radiofrequency ablation, accidental injury / aggravation of ischemia during coronary intervention), chest trauma (myocardial contusion affecting the conduction system).

[0067] The core mechanism of nicotinic acetylcholine receptor (nAChR) downregulation described in this invention includes reduced receptor expression, decreased affinity, decreased ion channel conduction efficiency, and increased receptor internalization / degradation. The causes of this downregulation include ischemia-reperfusion (I / R) injury, heart failure, myocardial infarction, as well as multiple dimensions such as disease, drugs, inflammation, metabolism, genetics, and age. The following diseases causing downregulation of nicotinic acetylcholine receptor (nAChR) function fall within the therapeutic range of the compounds of this invention: ① Cardiac-related diseases: ischemia / reperfusion (I / R) injury, heart failure (decreased vagal nerve activity, abnormal CHRNA7 gene expression), myocardial infarction (release of inflammatory factors, sympathetic remodeling), myocarditis (inflammation damaging the conduction system), cardiomyopathy (myocardial fibrosis affecting the conduction system), congenital heart disease (developmental abnormalities of the conduction system), valvular heart disease (myocardial hypertrophy compressing conduction fibers); ② Long-term nicotine exposure: chronic smoking (receptor desensitization, density reduction of 30%), chewing areca nut; ③ Inflammation and oxidative stress: systemic inflammation (sepsis, rheumatic immune diseases), local inflammation (myocarditis, pericarditis), oxidative stress (free radicals attacking receptor proteins); ④ Drug effects: antiarrhythmic drugs (quinidine, amiodarone, etc.), β-carotene... ⑤ Receptor blockers, antipsychotics, tricyclic antidepressants; ⑥ Electrolyte and metabolic disorders: hyperkalemia (inhibition of sodium channels), hypokalemia, hypomagnesemia, acid-base imbalance; ⑦ Neurological diseases: Alzheimer's disease (Aβ deposition inhibits receptor synthesis), myasthenia gravis (autoantibodies attack receptors), Parkinson's disease; ⑧ Other factors: genetic factors (CHRNA gene mutations), aging (reduced receptor expression).

[0068] The compound shown in formula (II) is a commercially available product purchased by the manufacturer, with the molecular formula C. 13 H 13 N3, CAS number 249296-44-4, molecular weight 211.26, structural formula as follows: Formula (II).

[0069] Example 1: Functional Screening and Validation of α4β2 nAChRs as Therapeutic Targets for FVTs 1. Methods: An isolated rat heart ischemia / reperfusion model was used. Rats were intraperitoneally injected with heparin 500 IU / kg, and 20 min later, anesthetized with sodium pentobarbital 50 mg / kg. The heart was then rapidly removed and perfused using Langendorff. A stable and induced FVT model (arrhythmias lasting longer than 3 minutes could be induced) was established by ligating the left anterior descending coronary artery for 60 minutes, followed by reperfusion for 60 minutes. FVTs were induced by rapid electrical stimulation after perfusion administration of different drug concentrations (0, 0.1, 1, 10 µM), and the incidence and duration of arrhythmias were recorded as the main evaluation indicators.

[0070] A rat model of cardiac ischemia / reperfusion was established. Rats were anesthetized with 50 mg / kg sodium pentobarbital, and endotracheal tubes were inserted. Ventilator parameters were adjusted to a respiratory rate of 60-80 breaths / min, tidal volume of 2-4 ml / min, and a respiratory ratio of 1:1. Subsequently, the thoracotomy was performed, and the left anterior descending coronary artery was ligated for 60 minutes, followed by 60 minutes of reperfusion, to establish a stable and induced FVT model. Different drug concentrations (0, 0.1, 1, 10 mg / kg) were administered via tail vein injection, followed by rapid electrical stimulation to induce FVT. The incidence and duration of cardiac arrhythmias were recorded as the primary evaluation indicators.

[0071] 2. Results screening showed that partial agonists of α4β2 nAChRs were highly effective. At a concentration of 10 µM, the compound shown in formula (II) significantly reduced the incidence of FVT from 100% to 25%, and shortened the duration from 9.5 ± 1.6 minutes to 0.76 ± 0.31 minutes (Figure 1A). In vivo rat I / R model experiments further confirmed that the compound shown in formula (II) could significantly inhibit FVT (Figure 1B).

[0072] 3. Conclusion This embodiment verifies the feasibility of α4β2 nAChRs as a therapeutic target for FVTs.

[0073] Example 2: Exploring the effect of α4β2 nAChRs modulators on myocardial conduction velocity. The electrophysiological basis of targeting α4β2 nAChRs to improve arrhythmia, especially its effect on conduction velocity.

[0074] 1. Methods: An isolated rat heart I / R model was used. Optical mapping was performed using Di-4-ANEPPS fluorescent dye. Different drug concentrations (0, 1, 10 µM) were administered via perfusion, and the conduction velocity of the ventricular myocardium was then quantitatively analyzed.

[0075] 2. Results After treatment with the compound shown in formula (II), the conduction velocity in the damaged area was significantly improved, increasing from 0.51 ± 0.017 mm / ms to 0.69 ± 0.04 mm / ms (Figure 1C).

[0076] 3. Conclusion: α4β2 nAChRs modulators can effectively reverse myocardial conduction inhibition caused by I / R injury, which provides a key electrophysiological mechanism explanation for their antiarrhythmic effect.

[0077] Example 3: Cellular-level verification of the effects of I / R injury on α4β2 nAChRs function and the intervention effect of candidate compounds. 1. Methods: Ventricular myocytes were isolated from the hearts of rats that had experienced I / R injury. After treating the cells with different drug concentrations (0, 1, 10 µM), acetylcholine-gated currents were recorded using whole-cell patch-clamp technique.

[0078] 2. Results: I / R injury significantly reduced the amplitude of the acetylcholine-gated current in ventricular myocytes. This current could be partially restored after intervention with the compound shown in formula (II) (Figure 1D).

[0079] 3. Conclusion: I / R damage causes downregulation of α4β2 nAChRs function, and compounds targeting this receptor can directly repair this pathological electrophysiological defect.

Claims

1. A compound for treating cardiac dysfunction, or a pharmaceutically acceptable salt, prodrug, hydrate, or solvent compound, polymorph, stereoisomer, or isotopic variant thereof, characterized in that, The structure of the compound is shown in formula (Ⅰ): Formula (I); wherein, R1 is an amino protecting group, which is selected from OCH, OCCH3, OCCl3, OCCF3, OCCH2CH3, OCC(CH3)3, OCOCH3, OCOCH2CH3, OCOCH2CCl3 or OCOC(CH3)3; and R2, R3, R4, R5, R6 and R7 are each independently selected from hydrogen (H), amino (NH2), halogen (F, Cl, Br), alkyl (-CH3, -CF3), methoxy (-OCH3) or hydroxyl (-OH).

2. The compound for treating cardiac dysfunction as described in claim 1, characterized in that, The compound targets the endogenous cholinergic system; the endogenous cholinergic system includes, but is not limited to, α7-nAChR, α4β2-nAChR, α3β4-nAChR, α6β2-nAChR or α4α6β2-nAChR.

3. The compound for treating cardiac dysfunction as described in claim 1, characterized in that, The compound is a target of α4β2-nAChR, and its structural formula is shown in formula (II): Formula (II).

4. The compound for treating cardiac dysfunction as described in claim 1, characterized in that, The cardiac dysfunctions mentioned include 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.

5. The use of the compound or its derivatives as described in claim 1 in the preparation of a medicament for treating cardiac dysfunction, characterized in that, The drug works by: 1) reversing myocardial conduction inhibition; and 2) repairing the downregulation of nicotinic acetylcholine receptor function.

6. The application as described in claim 5, characterized in that, Derivatives of the compound include pharmaceutically acceptable salts, prodrugs, hydrates or solvent compounds, polymorphs, stereoisomers or isotopic variants.

7. The application as described in claim 5, characterized in that, The cardiac dysfunctions mentioned include 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.

8. The application as described in claim 5, characterized in that, The nicotinic acetylcholine receptors include, but are not limited to, α7-nAChR, α4β2-nAChR, α3β4-nAChR, α6β2-nAChR, or α4α6β2-nAChR.

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises claim 1 or a derivative thereof, and another active ingredient.

10. The pharmaceutical composition of claim 9, characterized in that, The other active ingredient includes other drugs for treating cardiac dysfunction, drugs that help improve cardiac function, or drugs that increase bodily functions, which are different from the compound of claim 1.

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