Cardiac protective lipids and methods of use

Abstract

The present invention includes a method of reducing or eliminating cardiac toxic effects or cardiac pathological effects of one or more active agents comprising administering to a subject in need thereof an effective amount of one or more lipids that reduce or eliminate cardiac toxic effects of one or more active agents wherein the lipids have the formula: # imgabs0 #.

Description

[0001] Cross - Reference to Related Applications

[0002] This application is a PCT international patent application that claims priority to a partial continuation patent application filed as a United States patent application Ser. No. 17 / 950,898 on September 22, 2022, which is hereby incorporated by reference in its entirety.

[0003] Statement of Federally Sponsored Research

[0004] None.

[0005] Field of the Invention

[0006] The present invention generally relates to the field of new lipids for reducing or eliminating drug - induced or disease - or disorder - induced heart diseases, such as QT prolongation, myocardial injury, or AV block. Background of the Invention

[0008] Without limiting the scope of the present invention, its background is described in terms of drug - induced QT prolongation and other heart diseases and cardiotoxicities.

[0009] There are many medicaments designed to treat various diseases that are commonly prescribed despite being known or suspected to have an adverse effect on the patient's heart. In addition to arrhythmias including QT prolongation, supraventricular tachycardia (SVT), and atrial fibrillation (AF), many other cardiotoxicities occur as side effects of medicaments, including myocardial injury, cardiomyopathy, congestive heart failure, and left ventricular hypertrophy (LVH).

[0010] The cardiotoxicity of these medicaments can lead to serious complications that affect patients being treated for various diseases, such as proliferative malignancies. The severity of such toxicity depends on many factors, such as the immediate and cumulative dose, the method of administration, the presence of any underlying heart condition, and various congenital or acquired heart risk factors specific to the particular patient. In addition, the toxicity may be affected by the treatment with other medicaments currently or previously used. The cardiotoxic effects may occur immediately during drug administration or may not become apparent until the patient has been treated for months or years.

[0011] High - dose chemotherapy remains the preferred therapy for aggressive malignancies. Numerous clinical studies have shown that high - dose chemotherapy can significantly prolong the survival of patients; however, its use and effectiveness are limited by significant side effects, particularly cardiotoxicity. In mid - to - late - stage cardiotoxicity, heart failure can occur years after chemotherapy has ended. It is known that treatment with chemotherapeutic agents results in pericardial and endomyocardial fibrosis, heart failure, myocarditis, or pericarditis. Chemotherapy is also associated with hemorrhagic myocardial necrosis and cardiomyopathy.

[0012] In addition, anti-tumor monoclonal antibodies are also associated with cardiotoxicity. Infusion-related cardiotoxic effects may occur, such as left ventricular dysfunction, congestive heart failure, and other cardiac insufficiencies. The risk of such complications is increased if the patient has pre-existing heart disease, advanced age, prior cardiotoxic treatment, or radiotherapy to the chest.

[0013] Tyrosine kinase inhibitors (TKIs) have well-known cardiotoxic effects. Anthracyclines, trastuzumab, imatinib mesylate, dasatinib, nilotinib, sunitinib, sorafenib, vandetanib, and lapatinib are all associated with a range of mechanical and electrical dysfunctions.

[0014] Toxic effects associated with TKIs include QT prolongation, sudden cardiac death (both considered rhythm dysfunctions), and contractility problems such as reduced left ventricular ejection fraction (LVEF), congestive heart failure (CHF), acute coronary disease, hypertension, and myocardial infarction (MI). Given the therapeutic potential of drugs such as tyrosine kinase inhibitors, various strategies have been used to attempt to mitigate the cardiotoxicity of cancer treatment. The main method for preventing cardiotoxicity is to limit the dose of cardiotoxic drugs. There is also evidence that some dosing methods may affect the risk of cardiotoxicity. Rapid administration of cardiotoxic agents results in high blood levels, which may cause more cardiac damage than giving the same amount of drug over a longer period of time. Giving smaller doses of the drug more frequently can also reduce toxicity compared to larger doses at longer intervals.

[0015] The risk of cardiotoxicity due to certain chemotherapeutic agents has been reduced by encapsulating them in liposomes. For example, studies have shown that the cardiotoxicity of liposomal doxorubicin formulations is much lower than that of conventional doxorubicin.

[0016] Dexrazoxane is an aminopolycarboxylic acid that has been shown to prevent or reduce the severity of cardiac damage caused by doxorubicin. Dexrazoxane is thought to protect the myocardium by preventing the formation of oxygen free radicals. One way in which radiation and chemotherapeutic drugs damage cells is by forming free radicals. Free radicals are unstable molecules that are formed during many normal cellular processes involving oxygen, such as burning fuel to obtain energy. They are also formed due to exposure to environmental factors such as tobacco smoke, radiation, and chemotherapeutic drugs.

[0017] However, there is still a need for new compositions and methods for reducing drug-induced or disease- or disorder-induced heart disease. Summary of the Invention

[0019] As embodied and broadly described herein, one aspect of the present disclosure relates to compounds of Formula I:

[0020] .

[0021] On the one hand, the compound of formula I exists as a single entity, solvate, hydrate, crystal, amorphous solid, liquid or oil. On the other hand, the compound is a hydrochloride salt. On the other hand, the pharmaceutical composition further comprises one or more agents that induce heart disease as a side effect.On the other hand, the one or more agents that induce heart disease as a side effect are selected from at least one of the following: albuterol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, arformoterol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, curcumin, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphenidate, dextroamphetamine, amphetamine, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, epinephrine, adrenaline, eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, imipramine hydrochloride, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl acetate, lysine methylamphetamine, lithium, mesoridazine, metaproterenol, methadone, methamphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perfluoropropane lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, albuterol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfamethoxazole, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat or ziprasidone.On the other hand, the pharmaceutical composition further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweeteners, their derivatives, or combinations thereof. On the other hand, the binder is selected from hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, copolymers of acrylic acid and methacrylic acid, pharmaceutical glaze, gums, and their milk derivatives. On the other hand, the amount of the compound of formula I per unit dose is about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or 10000 milligrams per unit dose. On the other hand, the pharmaceutical composition is a preparation for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. On the other hand, the preparation for oral administration is tablets, capsules, cachets, pills, powders, troches, lozenges, syrup preparations, liquid solutions, suspensions, emulsions, elixirs, or oral thin films (OTF).

[0022] As embodied and broadly described herein, one aspect of the present disclosure relates to a method for preparing a compound of formula I

[0023]

[0024] I

[0025] The method comprises:

[0026] 。

[0027] As embodied and broadly described herein, one aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable diluent or carrier, the pharmaceutical composition comprising:

[0028] 。

[0029] On the one hand, the compound of formula I exists as a single entity, solvate, hydrate, crystal, amorphous solid, liquid or oil. On the other hand, the compound is a hydrochloride salt. On the other hand, the pharmaceutical composition further comprises one or more agents that induce heart disease as a side effect.On the other hand, the one or more agents that induce heart disease as a side effect are selected from at least one of the following: albuterol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, arformoterol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, curcumin, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphenidate, dextroamphetamine, amphetamine, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, epinephrine, adrenaline, eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, imipramine hydrochloride, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl acetate, lysine methylamphetamine mesylate, lithium, mesoridazine, metaproterenol, methadone, methamphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perfluoropropane lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, albuterol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfamethoxazole, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat or ziprasidone.On the other hand, the pharmaceutical composition further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof. On the other hand, the binder is selected from hydroxypropyl methylcellulose, ethylcellulose, povidone, copolymers of acrylic acid and methacrylic acid, pharmaceutical coating materials, gums, and their milk derivatives. On the other hand, the pharmaceutical composition comprises the compound of formula I in an amount of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 mg per unit dose. On the other hand, the pharmaceutical composition is a preparation for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, topical, pulmonary, rectal, vaginal or intramuscular administration. On the other hand, the preparation for oral administration is a tablet, capsule, cachet, pill, powder, lozenge, troche, pasty preparation, liquid solution, suspension, emulsion, elixir or oral thin film (OTF). On the other hand, the preparation is in solid form, solution, suspension or soft gel form.

[0030] As embodied and broadly described herein, one aspect of the present disclosure relates to a method of reducing or eliminating one or more of cardiac ion channelopathies, myocardial injury, or conditions resulting from irregularities or alterations in cardiac patterns in a human or animal subject, which comprises the step of administering to the human or animal subject one or more of the compounds of formula I

[0031] .

[0032] On the one hand, the compound of formula I exists as a single entity, solvate, hydrate, crystal, amorphous solid, liquid or oil. On the other hand, the compound is a hydrochloride salt. On the other hand, the compound of formula I reduces or eliminates one or more of cardiac ion channelopathies caused by an active agent used to treat a disease or conditions resulting from irregularities or alterations in cardiac patterns. On the other hand, the pharmaceutical composition contains the compound of formula I in an amount of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 milligrams per unit dose. On the other hand, the compound of formula I is formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, topical, pulmonary, rectal, vaginal or intramuscular administration. On the other hand, the compound of formula I is formulated as tablets, capsules, caplets, pills, powders, lozenges, troches, pasty preparations, liquid solutions, suspensions, emulsions, elixirs or oral thin films (OTFs) for oral administration. On the other hand, the compound of formula I is formulated in solid form, solution, suspension or soft gel form. On the other hand, the solid form further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof. On the other hand, the compound of formula I is co-administered with one or more agents that induce heart disease as a side effect.On the other hand, the one or more active agents that induce heart disease as a side effect are selected from at least one of the following: albuterol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, arformoterol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, curcumin, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphenidate, dextroamphetamine, amphetamine, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, epinephrine, adrenaline, eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, imipramine hydrochloride, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl acetate, lysine methylamphetamine, lithium, mesoridazine, orciprenaline, methadone, methamphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perfluoropropane, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, albuterol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfamethoxazole, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat or ziprasidone. On the other hand, the compound of formula I reduces or eliminates heart disease induced by drugs or caused by diseases or disorders, such as QT interval prolongation, myocardial injury or AV block.

[0033] As embodied and broadly described herein, one aspect of the present disclosure relates to a method of reducing or eliminating the cardiotoxic or cardiopathologic effects of one or more active agents, comprising: administering to a subject in need of treatment for a disease or disorder one or more cardiotoxic active agents; and providing combination therapy with an effective amount of one or more lipids that reduce or eliminate the cardiotoxic effects of the one or more active agents, wherein the lipid has the following formula:

[0034] .

[0035] On the one hand, the cardiac toxicity or cardiac lesion is selected from at least one of the following: minimal left ventricular dilation, systolic dysfunction, moderate valvular regurgitation, reduced left ventricular ejection fraction (LVEF), cardiac hypertrophy, reduced cardiac contractility, reduced cardiac output, pressure and volume overload hypertrophy, myocardial dysfunction, cardiac remodeling, heart failure after myocardial infarction or heart disease. On the other hand, the one or more active agents are selected from doxorubicin, trastuzumab, or both. On the other hand, the one or more active agents and the lipid are administered simultaneously. On the other hand, the one or more active agents and the lipid are formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, topical, transpulmonary, rectal, vaginal, or intramuscular administration. On the other hand, the compound is a hydrochloride salt. On the other hand, the one or more lipids, the one or more active agents, or both are infused within 3 hours.On the other hand, the one or more agents that induce cardiotoxic or cardiopathic effects are selected from at least one of the following: albuterol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, arformoterol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, curcumin, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphenidate, dextroamphetamine, amphetamine, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, epinephrine, adrenaline, eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, imipramine hydrochloride, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl acetate, lysine methylamphetamine, lithium, mesoridazine, orciprenaline, methadone, methamphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perfluoropropane lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, albuterol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfamethoxazole, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat or ziprasidone.On the other hand, the pharmaceutical composition comprising the one or more lipids further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweeteners, their derivatives, or combinations thereof. On the other hand, the pharmaceutical composition comprises the compound of formula I in an amount of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 mg per unit dose. On the other hand, the pharmaceutical composition is a formulation for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, topical, pulmonary, rectal, vaginal or intramuscular administration. On the other hand, the composition is formulated as a tablet, capsule, caplet, pill, powder, lozenge, troche, syrup formulation, liquid solution, suspension, emulsion, elixir or oral thin film (OTF) for oral administration. On the other hand, the formulation is in solid form, solution, suspension or soft gel form. On the other hand, the compound of formula I:

[0036] .

[0037] As embodied and broadly described herein, one aspect of the present disclosure relates to a method of reducing or eliminating the cardiotoxic effects of one or more anti-proliferative agents, comprising: administering to a subject in need of treatment for a proliferative disorder one or more anti-proliferative agents having cardiotoxicity; and providing combination therapy with an effective amount of one or more lipids that reduce or eliminate the cardiotoxic effects of the one or more anti-proliferative agents, wherein the lipid has the following formula:

[0038] ;

[0039] And wherein the reduction in cardiotoxicity is at least 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95% or 100% compared to treatment without using lipids. In one aspect, the cardiotoxicity is selected from at least one of the following: minimal left ventricular dilation, systolic dysfunction, moderate valvular regurgitation, reduced left ventricular ejection fraction (LVEF), cardiac hypertrophy, reduced cardiac contractility, reduced cardiac output, pressure and volume overload hypertrophy, myocardial dysfunction, cardiac remodeling, heart failure after myocardial infarction or heart disease. In another aspect, the one or more anti-proliferative agents are selected from doxorubicin, trastuzumab or both. In another aspect, the one or more anti-proliferative agents and the lipids are administered simultaneously. In another aspect, the one or more anti-proliferative agents and the lipids are administered orally or intravenously. In another aspect, the one or more lipids, the one or more anti-proliferative agents, or both are infused within 3 hours. In another aspect, the one or more anti-proliferative agents that induce heart disease as a side effect are selected from at least one of the following: bosutinib, crizotinib, dabrafenib, dasatinib, doxorubicin, lapatinib, nilotinib, sorafenib, sunitinib, vandetanib or vemurafenib. In another aspect, the pharmaceutical composition comprises a compound of formula I in an amount of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 mg per unit dose. Brief Description of the Drawings

[0041] To more fully understand the features and advantages of the present invention, reference is now made to the detailed description of the invention and the drawings, wherein:

[0042] Figure 1 is a graph showing the effect of Compound I on moxifloxacin-induced QT prolongation in an animal model.

[0043] Figure 2 shows the outline of a 9-week study for determining the cardioprotective effect of lipids.

[0044] Figure 3 shows M-mode echocardiogram images comparing the effects of sham treatment, treatment with doxorubicin and trastuzumab, and treatment with doxorubicin and trastuzumab + lipid SP005.

[0045] Figure 4 Displays left ventricular pressure recordings that compare sham treatment, treatment with doxorubicin and trastuzumab, and treatment with doxorubicin and trastuzumab + two concentrations of lipid SP005, namely 10 mg / kg and 50 mg / kg.

[0046] Figures 5A - 5H are graphs showing left ventricular systolic pressure (Figure 5A), heart rate (Figure 5B), stroke volume (Figure 5C), left ventricular ejection fraction (Figure 5D), percentage shortening fraction (Figure 5E), N - terminal (NT) - prohormone BNP (NT - proBNP) on day 59 (Figure 5F), end - diastolic anterior wall thickness (AWT - ED) (mm) (Figure 5G), end - systolic anterior wall thickness (AWT - ES) mm (Figure 5H), and left ventricular mass (echo) (Figure 5I). DETAILED DESCRIPTION OF THE INVENTION

[0048] Although the formation and use of various embodiments of the present invention are discussed in detail below, it should be understood that the present invention provides many applicable inventive concepts that can be embodied in many specific contexts. The specific embodiments discussed herein merely illustrate the specific ways of forming and using the present invention and do not limit the scope of the present invention.

[0049] The compounds of the present invention include those outlined above and are further illustrated by the classes, sub - classes, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions will apply. In at least some embodiments, chemical elements are determined according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th edition. Additionally, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, edited by Smith, M.B. and March J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0050] To facilitate understanding of the present invention, a number of terms are defined below. The terms defined herein have the meanings commonly understood by those of ordinary skill in the art relevant to the present invention.

[0051] Terms such as "a", "an", and "the" are not intended to refer to only a single entity, but rather include the broad class for which they may be illustrated by a specific instance. The terms herein are used to describe specific embodiments of the invention, but their use does not limit the invention unless outlined in the claims. Specifically, when used in conjunction with the term "comprising" in the claims and / or the specification, the use of the word "a" or "an" may refer to "one", but it also conforms to the meaning of "one or more", "at least one", and "one or more than one". The use of the term "or" in the claims is used to mean "and / or", unless expressly stated to refer only to alternative items or that the alternative items are mutually exclusive, but the present disclosure supports definitions that refer only to alternative items and "and / or". Throughout this application, the term "about" is used to indicate that a value includes the inherent variations of error of the measuring device, the method for determining the value, or the variations that exist in the subject under study.

[0052] Compounds and Definitions:

[0053] As used in this specification and the claims (if any), the word "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. In any embodiments of the compositions and methods provided herein, "comprising" may be replaced by "consisting essentially of" or "consisting of". As used herein, the phrase "consisting essentially of" requires the specified integer(s) or steps and those that do not materially affect the characteristics or functions of the claimed invention. As used herein, the term "consisting" is used to indicate that only the recited integers (e.g., features, elements, characteristics, properties, method / process steps or limitations) or groups of integers (e.g., features, elements, characteristics, properties, method / process steps or limitations) are present. As used herein, each compound may be used in a formulation or method that includes one or more components or one or more steps, but may also be used in a composition or method consisting essentially of the listed components, or even in a composition or method consisting of the listed components.

[0054] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the items listed prior to that term. For example, "A, B, C or combinations thereof" is intended to include at least one of the following: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also includes BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, explicitly included are combinations that contain one or more repetitions of an item or entry, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. Those skilled in the art will understand that there is generally no limit to the number of items or entries in any given combination, unless otherwise apparent from the context.

[0055] As used herein, approximate terms such as but not limited to "about", "substantial" or "substantially" refer to the situation that when so modified, it is understood not to have to be absolute or precise, but will be considered close enough for a person of ordinary skill in the art to ensure that the indicated situation exists. The degree to which the description can vary will depend on the degree of variation that can be implemented and still enable a person of ordinary skill in the art to recognize that the modified feature still has the characteristics and capabilities of the unmodified feature that are desired. Generally, but subject to the previous discussion, the numerical values herein modified by approximate terms such as "about" can vary from the stated value by at least ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±10%, ±12% or ±15%.

[0056] "Pharmaceutically acceptable cations" in one embodiment refer to those organic or inorganic cations that are pharmaceutically acceptable for mammals and are well known in the art. For example, inorganic cations or organic cations include but are not limited to lithium, sodium, potassium, magnesium, calcium, barium, zinc, aluminum, cesium and amine cations. Amine cations include but are not limited to cations derived from ammonia, triethylamine, tromethamine (TRIS), triethanolamine, ethylenediamine, glucosamine, N-methylglucosamine, glycine, lysine, ornithine, arginine, ethanolamine, choline, etc. In one embodiment, the amine cation is a cation in which X+ has the formula YH+, where Y is ammonia, triethylamine, tromethamine (TRIS), triethanolamine, ethylenediamine, glucosamine, N-methylglucosamine, glycine, lysine, ornithine, arginine, ethanolamine, choline, etc. In one embodiment, suitable cationic organic or inorganic salts that can be used include a cationic moiety that can form an ionic association with the O moiety on the compound and will not significantly and adversely affect the desired properties of the compound for the purposes of the present invention, such as increased solubility, improved stability, etc.

[0057] Unless otherwise indicated, structures depicted herein also intend to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations of each asymmetric center, the Z and E double bond isomers, and the Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present invention are within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. Additionally, unless otherwise indicated, structures depicted herein also intend to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention that include the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with 13C- or 14C-enriched carbon are within the scope of the present invention. Such compounds can be used, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention.

[0058] As used herein, the term "in vivo" refers to inside the body. The term "in vitro" as used in this application should be understood to mean an operation performed in a non-living system.

[0059] As used herein, the term "treatment" refers to the treatment of the disorders mentioned herein, particularly in patients presenting symptoms of a disease or disorder.

[0060] As used herein, the term "treatment" or "treating" refers to any administration of a compound of the present invention and includes (i) inhibiting a disease in an animal that is experiencing or presenting the pathology or symptoms of a disease (i.e., preventing the further development of the pathology and / or symptoms); or (ii) alleviating a disease in an animal that is experiencing or presenting the pathology or symptoms of a disease (i.e., reversing the pathology and / or symptoms). The term "control" includes preventing, treating, eradicating, alleviating, or otherwise reducing the severity of the condition being controlled.

[0061] As used herein, the term "effective amount" or "therapeutically effective amount" as described herein refers to the amount of the subject compound that will elicit a biological or medical response in a tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician.

[0062] As used herein, the terms "administration" or "administering" of a compound as used herein shall be understood to mean providing a compound of the present invention to an individual in need of treatment in such a form that can be introduced into the individual in a therapeutically useful form and in a therapeutically useful amount, including but not limited to, oral dosage forms such as tablets, capsules, syrups, suspensions, etc.; injectable dosage forms such as IV, IM or IP, etc.; transdermal dosage forms including creams, gels, powders or patches; buccal dosage forms; inhaled powders, sprays, suspensions, etc.; and rectal suppositories.

[0063] As used herein, the term "intravenous administration" includes injection and other means of intravenous administration.

[0064] As used herein, the term "pharmaceutically acceptable" used to describe a carrier, diluent or excipient must be compatible with the other components of the formulation and harmless to its recipient.

[0065] As generally defined above, each stereocenter is independently R, S or racemic.

[0066] In different embodiments, the present invention has the following structures:

[0067] 。

[0068] The compound can be paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium to form a pharmaceutically acceptable salt. In one aspect, the compound is a hydrochloride salt.

[0069] One embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable diluent or carrier. In one embodiment, the pharmaceutical composition comprises the compound of formula I in an amount of from about 1 mg to about 1 g per unit dose. In some embodiments, the amount per unit dose is from about 1 mg to about 500 mg. In some embodiments, the amount per unit dose is from about 500 mg to about 1 g. In some embodiments, the amount per unit dose is from about 250 mg to about 750 mg. In some embodiments, the amount per unit dose is from about 50 mg to about 450 mg. In some embodiments, the amount per unit dose is from about 100 mg to about 300 mg. On the other hand, the pharmaceutical composition comprises the compound of formula I in an amount of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 mg per unit dose.

[0070] Another embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable diluent or carrier. In one embodiment, the pharmaceutical composition comprises the compound of formula I in an amount of from about 1 mg to about 1 g per unit dose. In some embodiments, the amount per unit dose is from about 1 mg to about 500 mg. In some embodiments, the amount per unit dose is from about 500 mg to about 1 g. In some embodiments, the amount per unit dose is from about 250mg to about 750 mg. In some embodiments, the amount per unit dose is from about 50 mg to about 450 mg. In some embodiments, the amount per unit dose is from about 100 mg to about 300 mg. On the other hand, the pharmaceutical composition comprises the compound of formula I in an amount of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 mg per unit dose.

[0071] In some embodiments, the pharmaceutical composition further comprises one or more agents that induce heart disease as a side effect, and wherein the compound of formula I or the compound of formula IA reduces or eliminates heart disease.In some embodiments, the one or more agents that induce heart disease as a side effect are selected from at least one of the following: albuterol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, arformoterol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, curcumin, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphenidate, dextroamphetamine, amphetamine, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, epinephrine, adrenaline, eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, imipramine hydrochloride, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl acetate, lysine methylamphetamine, lithium, mesoridazine, orciprenaline, methadone, methamphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perfluoropropane lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, albuterol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfamethoxazole, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat or ziprasidone.One of ordinary skill in the art will recognize that there are other agents that induce heart disease, and that other agents that induce heart disease can benefit from being included in the formulations of the present invention.

[0072] In some embodiments, the present invention includes a composition that comprises an active agent that causes heart disease and a compound of formula I represented by one or more of the compounds of formula I as described above.

[0073] One embodiment of the present invention provides a pharmaceutical composition comprising a structure of formula I or being a structure of formula I, which is formulated as described above for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal, vaginal or intramuscular administration. In some embodiments, the composition formulated for oral administration is a tablet, capsule, caplet, pill, powder, lozenge, troche, syrup formulation, liquid solution, suspension, emulsion, elixir or oral thin film (OTF). In some embodiments, the composition is in solid form, solution, suspension or soft gel form.

[0074] One embodiment of the present invention provides a pharmaceutical composition that comprises an active agent that causes heart disease as a side effect and a compound of formula I as described above.

[0075] One embodiment of the present invention provides a method of reducing or eliminating one or more of cardiac ion channelopathies, myocardial injury, or conditions resulting from irregularities or alterations in cardiac patterns in a human or animal subject caused by an active agent for treating a disease, the method comprising the step of administering to the human or animal subject a pharmaceutical composition that comprises a compound of formula I.

[0076] In some embodiments, the pharmaceutical composition further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweetening agents, derivatives thereof, or combinations thereof. In some embodiments, the binder is selected from hydroxypropyl methylcellulose, ethylcellulose, povidone, copolymers of acrylic acid and methacrylic acid, pharmaceutical coating materials, gums and milk derivatives.

[0077] In some embodiments, the pharmaceutical composition further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweetening agents, derivatives thereof, or combinations thereof. In some embodiments, the binder is selected from hydroxypropyl methylcellulose, ethylcellulose, povidone, copolymers of acrylic acid and methacrylic acid, pharmaceutical coating materials, gums and milk derivatives.

[0078] In one embodiment, the present invention includes compositions, pharmaceutical compositions, and methods, wherein the active agent that causes heart disease as a side effect is selected from at least one of the following: albuterol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, arformoterol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, curcumin, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphenidate, dextroamphetamine, amphetamine, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, Epinephrine, Adrenaline, eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, Furosemide, Frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, imipramine hydrochloride, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl acetate, lysine methylamphetamine mesylate, lithium, mesoridazine, orciprenaline, methadone, methamphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perfluoropropane lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, albuterol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, sulfamethoxazole trimethoprim, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, or ziprasidone.One of ordinary skill in the art will recognize that there are other agents that induce heart disease, and that other agents that induce heart disease may benefit from being included in the formulations of the present invention.

[0079] In some embodiments, the pharmaceutical composition is formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. In some embodiments, the pharmaceutical composition formulated for oral administration is a tablet, capsule, caplet, pill, powder, lozenge, troche, slurry formulation, liquid solution, suspension, emulsion, elixir, or oral thin film (OTF). In some embodiments, the composition is in solid form, solution, suspension, or soft gel form. In some embodiments, the solid form further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweetening agents, derivatives thereof, or combinations thereof. In some embodiments, the binder is selected from hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, copolymers of acrylic and methacrylic acid, pharmaceutical coating materials, gums, and milk derivatives.

[0080] In one embodiment, the method provides a pharmaceutical composition that is formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. In some embodiments, the pharmaceutical composition formulated for oral administration is a tablet, capsule, caplet, pill, powder, lozenge, troche, slurry formulation, liquid solution, suspension, emulsion, elixir, or oral thin film (OTF). In some embodiments, the composition is in solid form, solution, suspension, or soft gel form. In some embodiments, the solid form further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweetening agents, derivatives thereof, or combinations thereof. In some embodiments, the binder is selected from hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, copolymers of acrylic and methacrylic acid, pharmaceutical coating materials, gums, and milk derivatives.

[0081] In one embodiment, the method provides a pharmaceutical composition. One embodiment of the present invention provides the administration of a compound of Formula I, wherein the compound is a lipid that reduces or eliminates drug-induced or disease- or disorder-induced heart disease, such as QT prolongation, myocardial injury, or AV block.

[0082] The single most common reason for the withdrawal or restricted use of commercially available drugs has been QT interval prolongation associated with polymorphic ventricular tachycardia or the potentially fatal disorder, torsades de pointes.

[0083] 5-HT3 antagonists block serotonin binding. Aloxi (or palonosetron HCL) is an antiemetic used for chemotherapy-induced nausea and vomiting, a 5-HT3 antagonist that blocks serotonin from binding to 5-HT3. In one study, there was no significant difference in the QTc interval during the perioperative period whether 0.075 mg of palonosetron was given before or after sevoflurane anesthesia. Palonosetron may be safe with respect to the QTc interval during sevoflurane anesthesia.

[0084] 5-HT4 receptor agonists. Cisapride is a gastrokinetic agent, a drug that increases upper gastrointestinal motility. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Cisapride prolongs the QT interval in a dose-dependent manner. When 33 patients were monitored during the higher-dose phase, neither torsades de pointes nor ventricular tachycardia was recorded.

[0085] Histamine antagonists. Antihistamines used to treat allergies act by competing with histamine for H1 receptor sites on effector cells. Thus, they prevent but do not reverse reactions mediated solely by histamine.

[0086] Pain and premenstrual symptom relief H1 antagonists are most useful in acute exudative allergies presenting with symptoms such as rhinitis, urticaria, and conjunctivitis. However, their effects are purely palliative and are limited to suppressing symptoms attributable to the histamine-antibody reaction.

[0087] Pyrilamine is a diuretic first-generation histamine H1 antagonist. There have been cases of prolonged QT interval after overdose of pyrilamine in adolescents. Reports of death due to ventricular tachyarrhythmias have been made.

[0088] Terfenadine is an antihistamine used to treat allergies, hives (urticaria), and other allergic inflammatory conditions. The brand name Seldane was withdrawn in the United States. Rare reports of serious cardiovascular adverse reactions have been received, including ventricular tachyarrhythmias (torsades de pointes, ventricular tachycardia, ventricular fibrillation, and cardiac arrest), hypotension, palpitations, or syncope.

[0089] Loratidine is a first-line antihistamine and a second-generation peripheral histamine H1 receptor blocker. Structurally, it is closely related to tricyclic antidepressants such as imipramine and distantly related to the atypical antipsychotic quetiapine. Some antihistamines, such as mizolastine and ebastine, can prolong the QT interval and trigger serious arrhythmias. As of mid-2009, very little clinical data had been published on the risk of QT prolongation with loratidine. The very rare reported cases of torsades de pointes associated with loratidine appear to mainly involve drug interactions, especially with amiodarone and enzyme inhibitors. There are no reports of QT prolongation attributed to desloratadine, the major metabolite of loratidine. Patients with risk factors for torsades de pointes or taking certain enzyme inhibitors should avoid using loratidine.

[0090] Astemizole is a long-acting and highly selective H1 antagonist that acts on histamine H-1 and H-3 receptors. It has antipruritic and anticholinergic effects. It is also a loss-of-function inhibitor of acid sphingomyelinase. Overdose of astemizole renders the myocardium prone to ventricular arrhythmias, including torsades de pointes. However, arrhythmias occur only in patients with a corrected QT interval greater than 500 milliseconds.

[0091] Calcium channel blockers. Prenylamine is a phenylalkylamine chemical class calcium channel blocker that is used as a vasodilator in the treatment of angina pectoris. Resting ECGs were recorded in 29 patients with angina pectoris before, during, and after treatment with 180 mg of prenylamine per day. The QT interval was significantly prolonged after one week of treatment. The prolongation persisted as long as treatment continued, up to 6 months. After withdrawal of treatment, the QT interval returned to normal within 2 weeks.

[0092] Lidoflazine is a piperazine calcium channel blocker and a coronary vasodilator with some antiarrhythmic effects. As a tricyclic antihistamine, it acts as a selective inverse agonist of the peripheral histamine H1 receptor. It has a significant risk of QT interval prolongation and ventricular arrhythmias. Lidoflazine potently inhibits the HERG current (I(HERG)) recorded from HEK 293 cells stably expressing wild-type HERG (IC(50) of approximately 16 nM). Under similar conditions that preferentially inhibit activated / open HERG channels, it is approximately 13-fold more potent than verapamil against HERG. Lidoflazine produces a high-affinity block of the α-subunit of the HERG channel by binding to aromatic amino acid residues within the channel pore, and secondly, this most likely represents the molecular mechanism by which the drug prolongs the QT interval.

[0093] Bepridil is an antihypertensive drug that disrupts calcium (Ca 2+(1) Through the movement of calcium channels. At the same time, it prolongs the QT interval. Bepridil prolongs the QT and refractoriness, and a linear correlation can be demonstrated between the percentage change in QTc and the prolongation of the refractory period. In one patient, bepridil reduced the number of stimuli required to induce VT by one, but no spontaneous arrhythmias were recorded. It has antiarrhythmic properties with minimal proarrhythmic effects.

[0094] Antimalarial drugs. Chloroquine-chlorpheniramine (chloroquine plus chlorpheniramine) is a histamine H1 receptor blocker that reverses chloroquine insensitivity of Plasmodium falciparum in vitro. Chloroquine / chlorpheniramine produces a higher cure rate than chloroquine alone. Short QT syndrome (SQTS) is a sporadic or autosomal dominant disorder characterized by significantly accelerated cardiac repolarization, ventricular arrhythmias, and sudden cardiac death. To date, mutations in 5 different ion channel genes (KCNH2, KCNQ1, KCNJ2, CACNA1C, and CACNB2) have been identified to cause SQTS. In SQTS, the risk of ventricular arrhythmias and sudden death is very high, and cardiac arrest has been reported as the main symptom in 31% of SQTS subjects. Chloroquine blocks the mutated Kir2.1 channels that cause short QT syndrome and normalizes the repolarization properties in silico.

[0095] Halofantrine is an antimalarial agent with a substituted phenanthrene and is related to the antimalarial drugs quinine and lumefantrine. It may be associated with cardiotoxicity. The most dangerous side effect is arrhythmia: halofantrine causes significant QT prolongation, and this effect is seen even at standard doses. Therefore, the drug should not be given to patients with cardiac conduction defects, and the drug should not be used in combination with mefloquine. The mechanism of action of halofantrine is unknown.

[0096] Quinidine is an antimalarial drug that is used as a class I antiarrhythmic agent (Ia) in the heart. It is the stereoisomer of quinine, and this alkaloid inhibits the excitability of the myocardium and skeletal muscle by blocking sodium and potassium currents across the cell membrane. It prolongs the cell action potential and reduces automaticity. Quinidine also blocks muscarinic and α-adrenergic neurotransmission. At the same serum concentration, quinidine causes a greater QT prolongation in women than in men. This difference may contribute to the higher incidence of drug-induced torsades de pointes tachycardia observed in women taking quinidine and is relevant for other cardiac and non-cardiac drugs that prolong the QTc interval.

[0097] Antipsychotic drugs. The first-generation antipsychotic drugs, known as typical antipsychotics, were discovered in the 1950s. Although the first atypical antipsychotic, clozapine, was discovered in the 1960s and introduced into clinical practice in the 1970s, most of the second-generation drugs known as atypical antipsychotics have only recently been developed. Both generations of drugs tend to block receptors in the dopamine pathways of the brain, but atypical drugs also tend to act on serotonin receptors. Prolongation of the QTc interval can occur with the use of both conventional and novel antipsychotic drugs and is of clinical concern because of its association with potentially fatal ventricular arrhythmias, torsades de pointes.

[0098] Pimozide is a diphenylbutylpiperidine antipsychotic drug that can induce prolongation of the QT interval. Pimozide is contraindicated in individuals with acquired or congenital QT interval prolongation or a family history of QT interval prolongation. In individuals with a personal or family history of arrhythmia or torsades de pointes, it is recommended that its use be prohibited in individuals. It acts as an antagonist at D2, D3, and D4 receptors, as well as the 5-HT7 receptor. It is also an hERG blocker.

[0099] Sertindole is an antipsychotic drug. Like other atypical antipsychotics, it is active at dopamine and serotonin receptors in the brain. Abbott Labs first applied to the US Food and Drug Administration (FDA) for approval of sertindole in 1996 but withdrew the application in 1998 due to concerns about an increased risk of sudden death from QTc prolongation. In a trial of 2,000 patients taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths. The drug has not been approved for use in the United States by the FDA. In Europe, sertindole was approved and marketed in 19 countries from 1996, but its marketing authorization was suspended by the European Medicines Agency in 1998 and the drug was withdrawn from the market. In 2002, based on new data, the CHMP of the EMA recommended that sertindole could be reintroduced for restricted use in clinical trials, with strong protective measures, including widespread contraindication and warnings for patients at risk of arrhythmia, a recommended reduction of the total maximum dose from 24 mg to 20 mg, except in exceptional cases, and extensive ECG monitoring required before and during treatment.

[0100] Chlorpromazine, sold as Thorazine and Largactil, is a typical antipsychotic drug in the class of typical antipsychotics. Its mechanism of action is not fully understood, but it is believed to be related to its ability to act as a dopamine antagonist. It also has antiserotonergic and antihistaminergic properties. Chlorpromazine is a very potent antagonist of the D2 dopamine receptor and similar receptors such as D3 and D5. Unlike most other drugs of this type, it also has a high affinity for the D1 receptor. Only a few people taking chlorpromazine have reported prolongation of the corrected QT interval on electrocardiogram. In a study of 2,633 people who had side effects while taking chlorpromazine from the FDA and social media, 5 had prolongation of the corrected QT interval on electrocardiogram.

[0101] Thioridazine is a piperidine typical antipsychotic and belongs to the phenothiazine drugs. The branded product was withdrawn globally in 2005 because it caused severe arrhythmias. However, generic versions are available in the United States. The drug was voluntarily withdrawn globally by its manufacturer Novartis because it caused severe arrhythmias. Thioridazine prolongs the QTc interval in a dose-dependent manner. It is believed that the ratio of 5-HT2A to D2 receptor binding determines whether most antipsychotics are atypical or typical. In the case of thioridazine, the ratio of its 5-HT2A to D2 receptor binding is lower than the level considered necessary for atypicity, although in practice its likelihood of extrapyramidal side effects is relatively low.

[0102] Haloperidol (Haldol) or Haloperidol. A typical antipsychotic drug that prolongs the QT interval is pethidine. It is on the World Health Organization's List of Essential Medicines. It is the most commonly used typical antipsychotic drug. Special note: Patients at special risk of developing QT prolongation (hypokalemia), while using other drugs that cause QT, such as amiodarone: Q-Tc interval prolongation (a potentially dangerous change in heart rhythm).

[0103] Mesoridazine is a piperidine antipsychotic and belongs to the drug class called phenothiazines and is used to treat schizophrenia. It is a metabolite of thioridazine. Mesoridazine was withdrawn from the US market in 2004 due to dangerous side effects, namely irregular heartbeats and QT prolongation on electrocardiogram.

[0104] Selective Serotonin Reuptake Inhibitor. Celexa (citalopram) is an antidepressant in a group called selective serotonin reuptake inhibitors (SSRI). Its chemical structure, the racemic bicyclic phthalane derivative named (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, is not related to the chemical structures of other SSRIs or other available antidepressants. Citalopram may cause conditions that affect the heart rhythm (QT prolongation).

[0105] Antibiotic. Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent. It acts by inhibiting DNA gyrase, type II topoisomerase, and topoisomerase IV (enzymes necessary for separating bacterial DNA and thus inhibiting cell replication), and may cause torsades de pointes. Co-administration of moxifloxacin with other drugs that also prolong the QT interval or induce bradycardia (such as beta-blockers, amiodarone) should be avoided. Caution should be exercised when using moxifloxacin in patients with cardiovascular diseases, including those with conduction abnormalities. Drugs that prolong the QT interval may have an additive effect on QT prolongation and lead to an increased risk of ventricular arrhythmias.

[0106] Pentamidine is an antibacterial drug given to prevent and treat Pneumocystis pneumonia. The exact mechanism of its antiprotozoal action is unknown (although it may involve reactions with ubiquitin and mitochondrial function). Severe or fatal arrhythmias and heart failure are very frequent. The aromatic diamidine pentamidine acts by inhibiting hERG channel trafficking. Pentamidine has no acute effect on the currents generated by hERG, KvLQT1 / mink, Kv4.3, or SCNA5. However, after overnight exposure, pentamidine reduces hERG current and inhibits hERG trafficking and maturation, with an IC50 value of 5 to 8 μM, similar to the therapeutic concentration.

[0107] Clarithromycin is an antibiotic made from erythromycin and is chemically known as 6-O-methylerythromycin. It belongs to the macrolide class and acts by preventing certain bacteria from making proteins. It causes QT prolongation or ventricular arrhythmias, including torsades de pointes.

[0108] Erythromycin is an antibiotic with common side effects, including the serious side effect of arrhythmia, accompanied by QT interval prolongation, including torsades de pointes.

[0109] Grepafloxacin is an oral broad-spectrum fluoroquinolone antibacterial drug used to treat bacterial infections. Grepafloxacin was withdrawn from the market globally in 1999 due to its side effect of prolonging the QT interval on the electrocardiogram, leading to cardiac events and sudden death.

[0110] Sparfloxacin is a broad-spectrum fluoroquinolone antibiotic used to treat bacterial infections. It has controversial safety characteristics. The use of sparfloxacin is contraindicated in patients with known QTc prolongation and in patients being treated concurrently with class IA or III antiarrhythmic drugs. In one study, the maximum plasma concentrations (C 最大 ) after 1200 mg and 1600 mg doses were lower than would be expected for a linear dose relationship. The same was true for the mean increase and mean maximum increase in the QTc interval. The increase in the QTc interval was well correlated with C 最大 but not with AUC 0-无穷大 .

[0111] Curcumin (diarylheptanoid) is a bright yellow chemical produced by some plants. It is the main curcuminoid of turmeric (Curcuma longa) and exerts antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal and antitumor activities. In whole-cell patch-clamp experiments, curcumin inhibited hERG K + currents in HEK293 cells stably expressing hERG channels in a dose-dependent manner, with an IC50 value of 5.55 μM. Acute treatment with 10 μM curcumin significantly altered the deactivation, inactivation and recovery from inactivation times of the hERG channels.

[0112] Antiarrhythmic drugs. Antiarrhythmic drugs are used to suppress abnormal rhythms of the heart (arrhythmias), such as atrial fibrillation, ventricular tachycardia and ventricular fibrillation. Procainamide belongs to the class of antiarrhythmic drugs used to treat arrhythmias. It is classified as class Ia by the Vaughan Williams classification system and is used for both supraventricular and ventricular arrhythmias. The antiarrhythmic drug procainamide has also been detected to interfere with the pacemaker. Because the toxic levels of procainamide result in a decrease in ventricular conduction velocity and an increase in ventricular refractory period. This results in interference with the artificial membrane potential and leads to supraventricular tachycardia, which induces the failure and death of the pacemaker. It induces rapid blockade of the myocardial batrachotoxin (BTX)-activated sodium channels and acts as an antagonist of the long-lasting gated closure. Procainamide belongs to the aminobenzamide class, which has cardiac effects similar to quinidine and has the same toxic characteristics as quinidine.

[0113] Propafenone is a class IC antiarrhythmic drug that treats conditions associated with rapid heartbeats, such as atrial and ventricular arrhythmias, and acts by slowing the influx of sodium ions into myocardial cells, resulting in reduced excitability of the cells. Propafenone is more selective for cells at high rates and also blocks normal cells more than classes Ia or Ib. Propafenone differs from the prototype class IC antiarrhythmic drugs in that it has additional activity as a β-adrenergic blocker, which can cause bradycardia.

[0114] Methanesulfonanilide (E-4031) is an experimental class III antiarrhythmic drug that blocks the potassium channels of class III antiarrhythmic drugs. E-4031 acts on a specific type of voltage-gated potassium channels mainly present in the heart, namely the hERG channels. The hERG channels (Kv11.1) mediate the IKr current, which repolarizes cardiomyocytes. The hERG channels are encoded by the ether-a-go-go related gene (hERG). E-4031 blocks the hERG-type potassium channels by binding to the open channels. Its structural target within the hERG channels is unknown, but it is known that some other methanesulfonanilide class III antiarrhythmic drugs bind to the S6 domain or the C-terminus of the hERG channels. Since E-4031 can prolong the QT interval, it can cause fatal arrhythmias. So far, a clinical trial has been conducted to test the effect of E-4031 on prolonging the QT interval.

[0115] Amiodarone is a class III antiarrhythmic drug used for ventricular fibrillation or tachycardia, prolonging phase 3 of the cardiac action potential. Amiodarone is an antiarrhythmic drug known to cause prolongation of the action potential duration, which is reflected as prolongation of QT in the electrocardiogram. Amiodarone has multiple effects on myocardial depolarization and repolarization, making it an extremely effective antiarrhythmic drug. Its main effect is to block potassium channels, but it can also block sodium and calcium channels as well as β- and α-adrenergic receptors. Amiodarone significantly prolongs the QT interval and QTc value.

[0116] Dronedarone is a benzofuran derivative related to amiodarone and is a drug mainly used for arrhythmias (approved by the FDA in 2009). It is a "multi-channel blocker", however, it is not clear which channels play a key role in its success. The action of dronedarone at the cellular level is controversial, and most studies have shown inhibition of multiple outward potassium currents, including rapid delayed rectifier, slow delayed rectifier, and ACh-activated inward rectifier. It is also thought to reduce the inward fast Na current and L-type Ca channels. The reduction of K current in some studies has been shown to be due to the inhibition of K-ACh channels or related GTP-binding proteins. K +A 69% reduction in current results in increased AP duration and effective refractory period, showing amiodarone-like class III antiarrhythmic activity in in vitro and clinical trials. The drug also appears to exhibit activity in each of the four Vaughan-Williams antiarrhythmic classes. Concurrent use of drugs or herbal products that prolong the QT interval and may induce torsades de pointes (QTc Bazett interval ≥ 500 ms) is prohibited, or use with drugs or herbal supplements that prolong the QT interval or increase the risk of torsades de pointes (class I or III antiarrhythmics, phenothiazines, tricyclic antidepressants, certain oral macrolides, Ephedra species).

[0117] Disopyramide is an antiarrhythmic drug used to treat ventricular tachycardia. It is a sodium channel blocker and is thus classified as a class 1a antiarrhythmic. The class 1a activity of disopyramide is similar to that of quinidine in that it targets the sodium channel to inhibit conduction. During phase 0 of the cardiac action potential, disopyramide inhibits the increase in sodium permeability of myocardial cells, thereby reducing the inward sodium current. This results in an increased excitation threshold and a reduced rate of rise. Disopyramide prolongs the PR interval by prolonging the duration of the QRS complex and the P wave. Concerns regarding disopyramide have been the hypothetical possibility of sudden death induced by its class 1 antiarrhythmic action.

[0118] Dofetilide is a class III antiarrhythmic drug. Due to the proarrhythmic potential of dofetilide, it is only available by prescription from physicians who have received specialized training in the risks of dofetilide treatment. In addition, it is only available by mail order or through specially trained local pharmacies. Dofetilide acts by selectively blocking the rapid component of the delayed rectifier outward potassium current. There is a dose-dependent increase in the QT interval and the corrected QT interval (QTc). Therefore, many practitioners will initiate dofetilide treatment only in individuals under telemetry monitoring or if continuous EKG measurements of QT and QTc can be made.

[0119] Sotalol is a non-selective competitive β-adrenergic receptor blocker that also exhibits class III antiarrhythmic properties. The US Food and Drug Administration recommends that sotalol be used only for severe arrhythmias because its prolongation of the QT interval carries a smaller risk of life-threatening torsades de pointes. Sotalol also acts on potassium channels and causes a delay in ventricular relaxation. By blocking these potassium channels, sotalol inhibits the outflow of K + ions, which results in an increased time before another electrical signal can be generated in ventricular muscle cells. This increase occurs during the time period before the new contraction signal.

[0120] Ibutilide is a class III antiarrhythmic agent that is indicated for the acute cardiac conversion of atrial fibrillation and flutter and prolongs the action potential and refractory period of myocardial cells. Because of its class III antiarrhythmic activity, class Ia and class III drugs should not be given concomitantly. Unlike most other class III antiarrhythmic drugs, ibutilide does not produce its action potential prolongation by blocking the cardiac delayed rectifier potassium current and does not have the sodium-blocking, antiadrenergic, and calcium-blocking activities that other class III drugs possess. Thus, it is commonly referred to as a "pure" class III antiarrhythmic agent. Like other class III antiarrhythmic drugs, ibutilide blocks the delayed rectifier potassium current. It does act on slow sodium channels and promotes the influx of sodium through these slow channels. Like other antiarrhythmic drugs, ibutilide can cause cardiac arrhythmias because it is capable of prolonging the QT interval, which can lead to a potentially fatal abnormal cardiac rhythm known as torsades de pointes. The drug is contraindicated in patients who may develop abnormal cardiac rhythms; especially those who have had polymorphic ventricular tachycardia in the past, those with a long QT interval, those with sick sinus syndrome, or those with a recent myocardial infarction, etc.

[0121] Dopamine receptor antagonists. Dopamine antagonists (antidopaminergic) are a class of drugs that block dopamine receptors through receptor antagonism. Most antipsychotic drugs are dopamine antagonists and have thus been found useful in the treatment of schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used to treat nausea and vomiting.

[0122] Droperidol is an antidopaminergic butyrophenone used as an antiemetic and antipsychotic agent and is an effective D2 (dopamine receptor) antagonist with some histamine and serotonin antagonist activity. There are concerns regarding QT prolongation and torsades de pointes. The evidence for this is controversial, with 9 cases of torsades de pointes reported over 30 years and all of these patients having received a dose of more than 5 mg. QT prolongation is a dose-related effect and it appears that droperidol is not a significant risk at low doses; however, QT interval prolongation can lead to torsades de pointes.

[0123] Domperidone is a peripherally selective dopamine D2 receptor antagonist and is a drug used for Parkinson's disease. Due to the cardiac toxic side effects of domperidone, especially when given intravenously, in the elderly, and at high doses ( > 30 mg per day), caution is required. The clinical sign of the potential cardiac toxicity of domperidone is the prolongation (lengthening) of the QT interval (a part of the electrocardiogram). The use of domperidone is likely to be associated with an increased risk of sudden cardiac death (a 70% increase) through its prolongation of the cardiac QT interval and ventricular arrhythmias. The cause is thought to be the blockade of the hERG voltage-gated potassium channel. The risk is dose-dependent and appears to be greatest with intravenous administration at high / very high doses, in the elderly, and when used together with drugs that interact with domperidone and increase its circulating concentration (i.e., CYP3A4 inhibitors). However, there are conflicting reports. In neonates and infants, QT prolongation is controversial and uncertain.

[0124] Anticancer agents. The QTc prolongation, increased QT dispersion, and development of late potentials in doxorubicin and anthracyclines are markers of doxorubicin-induced abnormal ventricular depolarization and repolarization. Both QT dispersion and late potentials are known to be associated with an increased risk of severe ventricular arrhythmias and sudden death in various cardiac diseases.

[0125] Arsenic trioxide is an anti-leukemia drug that can prolong the QTc interval. Cardiac conduction abnormalities: Before starting treatment, perform a 12-lead electrocardiogram, assess serum electrolytes and creatinine, correct pre-existing electrolyte abnormalities, and consider discontinuing drugs known to prolong the QT interval. Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to torsades de pointes ventricular arrhythmia, which can be fatal. The risk of torsades de pointes ventricular tachycardia is related to the degree of QT prolongation, the concomitant administration of QT-prolonging drugs, a history of torsades de pointes ventricular tachycardia, pre-existing QT interval prolongation, congestive heart failure, the administration of potassium-wasting diuretics, or other conditions that cause hypokalemia or hypomagnesemia. One patient (also receiving amphotericin B) had torsades de pointes ventricular tachycardia during induction treatment of relapsed APL with arsenic trioxide. Arsenic trioxide (As2O3) used for the treatment of acute promyelocytic leukemia reduces hERG / IKr current not by direct blockade but by inhibiting the processing of hERG protein in the endoplasmic reticulum (ER), thereby reducing the surface expression of hERG.

[0126] Opioids. Levacetylmethadol is the levorotatory isomer of α-methadyl acetate, a synthetic opioid drug with a structure similar to that of methadone. Due to its active metabolites, it has a long duration of action. In 2001, levacetylmethadol was removed from the European market due to reports of life-threatening ventricular arrhythmias.

[0127] Methadone is an opioid drug used to treat pain and drug addiction. Severe risks include opioid abuse, and arrhythmias including QT prolongation may also occur. In 2011, the number of deaths in the United States involving methadone poisoning was 4,418, which accounted for 26% of the total deaths due to opioid poisoning.

[0128] Hypolipidemic agents. Lovastatin is a drug used to lower cholesterol and is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), an enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid. Mevalonic acid is a component required for cholesterol biosynthesis, and lovastatin acts by interfering with cholesterol production as a reversible competitive inhibitor of HMG-CoA that binds to HMG-CoA reductase. QTc prolongation associated with antipsychotic drugs occurs in a dose-dependent manner. The addition of lovastatin causes an increase in plasma quetiapine levels through competitive inhibition of cytochrome P (450) (CYP) isoenzyme 3A4. This highlights the possibility of a drug interaction between quetiapine and lovastatin leading to QTc prolongation during the management of dyslipidemia in patients with schizophrenia.

[0129] Probucol is an antihyperlipidemic drug initially developed for the treatment of coronary artery disease. Probucol is associated with QT interval prolongation. Probucol exacerbates the long QT syndrome associated with a novel missense mutation M124T at the N-terminus of HERG.

[0130] Ion channelopathies. Mutations in the human ether-à-go-go gene-related cardiac tetrameric potassium channel can render patients sensitive to more than 163 drugs that inhibit ion conduction and deregulate action potentials. After acting on the potassium channel, the action potential is prolonged. Ion channel-active drugs can directly increase the QTc interval and increase the risk of torsades de pointes ventricular tachycardia and sudden cardiac death. The worsening of drug sensitivity of myocardial cell potassium channels may also be related to metabolic disease states including diabetes or may be of idiopathic origin.

[0131] As used herein, the term "liposome" refers to a vesicle in which its wall or membrane is formed by one or more of the novel lipids of the present invention. The lipids of the present invention can be used alone or in combination with other known lipids. In one specific non-limiting example, the novel lipids form or are used in liposomes which are empty liposomes and can be formulated from a single type of phospholipid or a combination of phospholipids. In one embodiment, the liposome can be an empty liposome which can further include one or more surface modifications such as proteins, sugars, glycolipids or glycoproteins, and even nucleic acids such as aptamers, thiol-modified nucleic acids, peptide nucleic acid mimics, protein mimics, stealthing agents, etc.

[0132] Example 1. Cardioprotection against cardiotoxic agents.

[0133] The highly active chemotherapeutic agent doxorubicin is associated with acute but reversible cardiotoxic effects and long-term dose-related cardiomyopathy. This cardiomyopathy is characterized by minimal left ventricular dilation and global systolic dysfunction, often accompanied by moderate valvular regurgitation (Keefe, 2001). More than half of all patients exposed to doxorubicin will develop cardiac dysfunction 10 to 20 years after chemotherapy, and 5% of them will develop overt HF (Cardinale, 2010). The incidence of cardiomyopathy in patients treated with doxorubicin has led to its current use as an adjuvant drug in combination with safer but often less effective therapies. One such therapy is HERCEPTIN® (trastuzumab), a blockbuster humanized monoclonal antibody that targets the extracellular domain of HER2 in breast cancer patients. However, HERCEPTIN treatment is also hampered by cardiotoxicity, in which case the incidence of reported decreases in left ventricular ejection fraction (LVEF) is as high as 27% (Bouwer, 2020).

[0134] Clinical studies have shown that the combination of doxorubicin and HERCEPTIN increases the overall survival rate of breast cancer patients by 24 - 33% (Romond, 2005). Since doxorubicin-induced and HERCEPTIN-induced cardiomyopathies are mostly irreversible and cumulative, a key strategy is to find ways to minimize the cardiac side effects of the combination if these very potent cancer treatment tools are to continue to be used clinically.

[0135] It has been reported that, like the iron chelator dexrazoxane, vitamin D provides some protection against anthracyclines (Lee, 2021). Although the protective mechanism is not fully understood, it may involve preventing oxidation within biological membranes. In this ongoing research project, rats and mice were used to evaluate the protection provided by an anti-inflammatory complex lipid (SPP05) that preferentially integrates into the myocardial cell membrane.

[0136] All experiments were conducted in accordance with the guidelines for the use of laboratory animals of the Canadian Council against Animal Cruelty (CCAC) and the IACUC of IPST. IPST is AAALAC accredited.

[0137] Test system and treatment: Adult female C57 / BL6 mice weighing 25 g at the start of the study (n = 10 per group) were given 24 mg / kg DOX intraperitoneally over 2 weeks. After a 1-week rest, 10 mg / kg of HER was given intraperitoneally over 2 weeks. Meanwhile, throughout the project, starting from day -10, a group of animals was given an anti-inflammatory lipid (SPP05) at 10 mg / kg / day, and another group of animals was given the anti-inflammatory lipid at 50 mg / kg.

[0138] Experimental endpoints. Body weight was measured weekly.

[0139] Echocardiography was performed using a Vivid 9 instrument and a linear 13 MHz probe on days -10, 14, 42, and 49. Blood samples were taken on days -7, 0, 21, and 49. Invasive hemodynamics were measured by inserting a fluid-filled PE15 catheter connected to a Millar pressure sensor into the left ventricle.

[0140] Troponin I, NT-Pro-BNP, and caspase-3 activity were measured by Q-ELISA.

[0141] The heart and liver were examined histologically after fixation in 10% NBF and staining with H&E and Picro Sirius Red.

[0142] The combination of doxorubicin and trastuzumab was once considered the standard treatment for HER-2-expressing breast cancer patients until the occurrence of drug-induced heart failure prompted a change in clinical treatment approaches. In this mouse model, animals treated with Doxo + Herc showed left ventricular systolic dysfunction, as evidenced by the loss of ejection fraction, stroke volume, fractional shortening, and pulse pressure. In addition, animals treated with Doxo + Herc also showed overall as well as end-systolic and end-diastolic left ventricular tissue loss. Finally, the level of the HF biomarker NT-Pro-BNP was higher in animals treated with Doxo + Herc than in healthy (sham-operated) animals.

[0143] Using SP005, a complex anti-inflammatory lipid with known membrane-altering properties, partially prevented the damage caused by tumor treatment in female mice. Considering the toxicity mechanism of Doxo + Herc, it is speculated that the protection provided by SP005 is related to preventing the activation of sphingomyelinase by reactive oxygen species.

[0144] Figure 1 Show the effect on QT prolongation when compound I is used together with moxifloxacin.

[0145] Figure 2 Show the 9-week study outline for determining the cardioprotective effect of lipids.

[0146] Figure 3 Show M-mode echocardiogram images that compare the effects of sham treatment, treatment with doxorubicin and trastuzumab, and treatment with doxorubicin and trastuzumab + lipid SP005.

[0147] Figure 4 Show left ventricular pressure recordings that compare the effects of sham treatment, treatment with doxorubicin and trastuzumab, and treatment with doxorubicin and trastuzumab + lipid SP005 at two concentrations, namely 10 mg / kg and 50 mg / kg.

[0148] Figures 5A to 5H are graphs showing left ventricular systolic pressure (Figure 5A), heart rate (Figure 5B), stroke volume (Figure 5C), left ventricular ejection fraction (Figure 5D), percentage shortening fraction (Figure 5E), N-terminal (NT)-prohormone BNP (NT-proBNP) on day 49 (Figure 5F), end-diastolic anterior wall thickness (AWT-ED) (mm) (Figure 5G), end-systolic anterior wall thickness (AWT-ES) mm (Figure 5H), and left ventricular mass (echo) (Figure 5I).

[0149] The novel lipids of the present invention can be prepared in their natural form or in the form of their salts, hydrates, or solvates. By way of example only, salts also include lithium, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.

[0150] In at least some embodiments of the present invention, the compounds of formula I are prepared according to the following scheme. For reference, all variable groups included in the following scheme are related to the corresponding variables as generally defined above. Those of ordinary skill in the art will recognize that alternative reagents and reactants can be used to produce the same target compounds and intermediates.

[0151] .

[0152] It is contemplated that for any method, kit, reagent, or composition of the present invention, any embodiment discussed in this specification can be implemented, and vice versa. In addition, the compositions of the present invention can be used to implement the methods of the present invention.

[0153] Although certain features of the present invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. Accordingly, it is to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the present invention.

[0154] Example 2. (2R)-3-(((2,3-bis((3-aminopropanoyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl ditetradecanoate hydrochloride (Compound 35)

[0155] 。

[0156] Step 1: Sodium 2,3-bis((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propyl ((R)-2,3-bis(tetradecanoyloxy)propyl) phosphate

[0157] To a stirred solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (10.30 g, 54.4 mmol, 2.5 equiv) in DCM (325 ml) at room temperature was added dicyclohexylmethane diimide (13.48 g, 65.3 mmol, 3 equiv), and the mixture was stirred for 30 minutes. At room temperature, N,N-dimethylpyridin-4-amine (1.330 g, 10.89 mmol, 0.5 equiv) and sodium (R)-2,3-bis(tetradecanoyloxy)propyl (2,3-dihydroxypropyl) phosphate (15.0 g, 21.78 mmol, 1 equiv) were added. The reaction mixture was stirred at room temperature for 16 hours and monitored by LCMS. After completion, the reaction mixture was diluted with DCM (100 ml), stirred for 10 minutes and filtered. The filtrate was washed with water (100 ml x 1), 0.5 N HCl (50 ml x 1) and 10% NaHCO3 (50 ml x 1). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 24.2 g of a crude product. The crude product was purified by column chromatography using basic silica gel (230 - 400 mesh, pre-alkalized with ammonia). The product was eluted with ethyl acetate containing 0% - 10% methanol. The pure fractions were collected and concentrated to give 11.8 g of a pure product. The 11.8 g of product was dissolved in DCM (200 ml) and washed with 0.5 N HCl (50 ml x 2) and 10% NaHCO3 solution (50 ml x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give sodium 2,3-bis((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propyl ((R)-2,3-bis(tetradecanoyloxy)propyl) phosphate (10.66 g, yield 47.35%) as a pale yellow syrup.

[0158] 11H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.09 - 6.89 (m, 2H), 5.08 - 4.99(m, 2H), 4.32 - 4.19 (m, 2H), 4.09 (dt, J = 6.5, 12.8 Hz, 2H), 3.74 (br dd, J= 6.0, 12.0 Hz, 4H), 3.22 - 3.08 (m, 4H), 2.42 (br t, J = 6.8 Hz, 4H), 2.29 -2.22 (m, 4H), 1.55 - 1.45 (m, 4H), 1.37 (s, 18H), 1.24 (s, 40H), 0.90 - 0.81(m, 6H). LCMS: Molecular formula: C 50 H 92 N2NaO 16 P, molecular weight: 1031.25, exact mass: 1008.63, observed mass: 1009.7 [M+1] + , RT = 3.49 minutes, purity: 98.40%. Method: Mobile phase A: 1 ml of 25% ammonia solution in 1000 ml of MilliQ water (pH: 9, containing acetic acid). Mobile phase B: acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50x 4.6) mm, 3.5 µ.

[0159] Step 2: (2R)-3-(((2,3-bis((3-aminopropanoyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl distearate hydrochloride.

[0160] To a stirred solution of sodium (2R)-2,3-bis((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propyl (R)-2,3-bis(stearoyloxy)propyl phosphate (6 g, 5.82 mmol) in DCM (60 ml) at 0 °C was added hydrogen chloride (4 M in 1,4-dioxane solution, 30 ml, 120 mmol). The reaction mixture was stirred at 10 - 15 °C for 2.5 h and monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure at room temperature. The residue was co-evaporated with ethyl acetate (75 ml) and dried to give (2R)-3-(((2,3-bis((3-aminopropanoyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl distearate dihydrochloride (4.9 g, 99.62% yield) as an off-white solid.

[0161] 11H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.26 - 8.02 (m, 6H), 5.18 - 5.09(m, 2H), 4.32 - 4.26 (m, 2H), 4.18 - 4.00 (m, 4H), 3.98 - 3.93 (m, 2H), 3.03(br d, J = 5.8 Hz, 4H), 2.74 (dt, J = 3.2, 6.5 Hz, 4H), 2.33 - 2.22 (m, 4H),1.60 - 1.43 (m, 4H), 1.24 (s, 40H), 0.91 - 0.80 (m, 6H). LCMS: Molecular formula: C 40 H 78 ClN2O 12 P, molecular weight: 881.95, exact mass: 808.52. Observed mass: 809.5 [M+1] + , RT = 2.96 min, purity: 97.87%. Method: Mobile phase A: 1 ml of 25% ammonia solution in 1000 ml of MilliQ water (pH: 9, containing acetic acid). Mobile phase B: Acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 µ. HPLC: RT = 6.60 min; purity: 99.98%. Column: Xbridge C8 (50 x 4.6) mm, 3.5 μm, mobile phase A: 0.1% aqueous TFA solution, mobile phase B: Acetonitrile, flow rate: 2.0 ml / min.

[0162] Example 3. Cardiac response test.

[0163] The efficacy evaluation of the compounds of the present invention involves the measurement of ECG in adult male Hartley guinea pigs, in which PR, QRS, QT, QTc, JT, and RR are recorded. In a typical experiment, a subcutaneous Kaha TR50B biopotential telemetry device was surgically implanted into adult male Hartley guinea pigs weighing 300 to 350 g at the time of enrollment. One wire was sutured to the apex of the heart, and the other wire was sutured to the side of the aorta. The animals were allowed to recover from the surgery for 5 days and then returned to the test population. After recovery, the animals were evaluated in the following two rounds:

[0164] In the first round of testing, a 5-minute baseline ECG recording was obtained before exposing the animals to a single oral dose of moxifloxacin (20 mg / kg). Moxifloxacin was orally administered to 8 guinea pigs. ECG signals were continuously acquired for 6 hours after administration of moxifloxacin. The animals were then returned to their cages and the drug was cleared over 5 to 7 days.

[0165] In the second round of testing in 8 guinea pigs, a 5-minute baseline ECG was obtained to compare these baseline intervals with the intervals measured before the first exposure to moxifloxacin (see above). A single oral dose of 2 mg / kg of the test compound (selected from Compounds 1 - 12) was administered to the animals. concomitantly, 6 animals were gavaged with the same batch of moxifloxacin (20 mg / kg). Another 2 animals were administered only moxifloxacin (20 mg / kg). The purpose of administering only moxifloxacin to these animals was to verify whether a second exposure to moxifloxacin would result in an increase in QT prolongation. ECG was continuously acquired for 6 hours. The animals were then returned to their cages and the drug was cleared over 5 to 7 days.

[0166] ECG analysis within 5 minutes before dosing and 6 hours after dosing was present in the pattern recognition algorithm and automated based on the pattern recognition algorithm. The data analyzed was divided into 5-minute segments. Intervals such as PR, QRS, QT, QTc, JT, and RR were automatically analyzed using AD Instruments LabChart Pro v8. The accuracy of the measurements was manually verified by randomly selecting 3 to 5 segments at any given time after dosing using digital cursors. There was no significant difference between the automated and manual intervals except during arrhythmia episodes. The frequency of arrhythmia was quantified and expressed as "the percentage of ECG time with abnormal sinus rhythm during the entire recording period".

[0167] The following table lists the protection of the observed test compounds against moxifloxacin-induced QTc prolongation.

[0168]

[0169] It should be understood that the specific embodiments described herein are shown by way of illustration and not as a limitation of the invention. Without departing from the scope of the invention, the main features of the invention can be employed in various embodiments. Those skilled in the art will recognize, or be able to determine using only routine experimentation, many equivalents to the specific processes described herein. Such equivalents are considered to be within the scope of the invention and are covered by the claims.

[0170] All publications and patent applications mentioned in the specification represent the state of the art of those skilled in the art to which the present invention pertains. All publications and patent applications are hereby incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0171] According to the present disclosure, all compositions and / or methods disclosed and claimed herein can be prepared and implemented without undue experimentation. Although the compositions and methods of the present invention have been described with respect to preferred embodiments, it will be apparent to those skilled in the art that changes can be made in the compositions and / or methods described herein and in the steps or in the order of the steps of the methods without departing from the spirit, scope, and concept of the present invention. It will be apparent to those skilled in the art that all such similar substitutions and modifications are considered to be within the spirit, scope, and concept of the present invention as defined by the appended claims.

[0172] To assist the Patent Office and any readers of any patent issued on the basis of this application in interpreting the appended claims, the Applicants wish to note that they do not intend any of the appended claims to invoke 35 U.S.C. § 112, paragraph 6, 35 U.S.C. § 112, paragraph (f), or equivalents as they existed on the date of filing of this application, unless the terms "means for" or "step for" are expressly used in a particular claim.

[0173] For each claim, each dependent claim can depend either from an independent claim or from each preceding dependent claim of each claim, provided that the preceding claim provides an appropriate basis for reference in terms of claim terms or elements.

[0174] References

[0175] Bouwer, N. J.-D. (2020). Cardiac monitoring in HER2-positive patients on trastuzumab treatment: A review and implications for clinical practice. The Breast, 52, 33-44.

[0176] Cardinale, D. C. (2010). Anthracycline-Induced Cardiomyopathy. Journal of the American College of Cardiology, 55(3), 213-220.

[0177] Keefe, D. (2001). Anthracycline-induced cardiomyopathy. Seminars in oncology, 28(12), 2-7.

[0178] Lee, K. W. (2021). Cytoprotective Effect of Vitamin D on Doxorubicin-Induced Cardiac Toxicity in Triple Negative Breast Cancer. International Journal of Molecular Sciences, 22(14), 7439-7456.

[0179] Romond, E. P. (2005). trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. New England Journal of Medicine, 353, 1673-1684.

[0180] Sordillo, P. S. (2015). The Prolonged QT Interval: Role of Pro-inflammatory Cytokines, Reactive Oxygen Species and the Ceramide and Sphingosine-1 Phosphate Pathways. In vivo, 29(6), 619-636.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, I。 2. The compound according to claim 1, wherein the compound is formulated into a pharmaceutical composition.

3. The compound according to claim 1, wherein the compound further comprises one or more agents that induce heart disease as a side effect.

4. The compound according to claim 1, which further comprises one or more agents that induce heart disease as a side effect, and the agents are selected from at least one of the following: albuterol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, arformoterol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, curcumin, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphenidate, dextroamphetamine, amphetamine, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, epinephrine, adrenaline, eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, imipramine hydrochloride, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl acetate, lysine methylamphetamine mesylate, lithium, mesoridazine, orciprenaline, methadone, methamphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perfluoropropane lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, albuterol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfamethoxazole, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat or ziprasidone.

5. The compound according to claim 1, wherein the pharmaceutical composition further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweeteners, their derivatives, hydroxypropyl methylcellulose, ethylcellulose, povidone, copolymers of acrylic acid and methacrylic acid, pharmaceutical coating materials, gums and milk derivatives, or combinations thereof.

6. The compound according to claim 1, wherein the pharmaceutical composition comprises the compound of formula I in an amount per unit dose of about 1, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 473, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 mg per unit dose.

7. The compound according to claim 1, wherein the pharmaceutical composition is a preparation for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, topical, pulmonary, rectal, vaginal or intramuscular administration.

8. The compound according to claim 1, wherein the preparation for oral administration is a tablet, capsule, caplet, pill, powder, troche, lozenge, slurry, liquid solution, suspension, emulsion, elixir or oral thin film (OTF), and optionally in solid form, solution, suspension or soft gel form.

9. A method for preparing the compound of formula I I The method comprises: 。 10. A pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier I。 11. The pharmaceutical composition according to claim 10, wherein the compound of formula I is present as a single entity, solvate, hydrate, crystal, amorphous solid, liquid or oil.

12. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition further comprises one or more agents that induce heart disease as a side effect.

13. The pharmaceutical composition according to claim 10, which further comprises one or more agents that induce heart disease as a side effect, and the agents are selected from at least one of the following: albuterol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, arformoterol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, curcumin, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphenidate, dextroamphetamine, amphetamine, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, epinephrine, adrenaline, eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, imipramine hydrochloride, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl acetate, lysine methylamphetamine mesylate, lithium, mesoridazine, orciprenaline, methadone, methamphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perfluoropropane lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, albuterol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, sulfamethoxazole-trimethoprim, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat or ziprasidone.

14. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweeteners, their derivatives, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, copolymers of acrylic acid and methacrylic acid, pharmaceutical coating materials, gums and milk derivatives, or combinations thereof.

15. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition comprises the compound of formula I in an amount per unit dose of about 1, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 473, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 mg per unit dose.

16. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is a preparation for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, topical, pulmonary, rectal, vaginal or intramuscular administration.

17. The pharmaceutical composition according to claim 10, wherein the preparation for oral administration is a tablet, capsule, caplet, pill, powder, lozenge, troche, syrup preparation, liquid solution, suspension, emulsion, elixir or oral thin film (OTF), and optionally in solid form, solution, suspension or soft gel form.

18. A method of reducing or eliminating one or more of cardiac ion channelopathies, myocardial injury or conditions resulting from irregularities or alterations in cardiac patterns in a human or animal subject, comprising the step of administering to the human or animal subject one or more of the compounds of formula I or a pharmaceutically acceptable salt thereof I。 19. The method according to claim 18, wherein the compound of formula I is at least one of the following: Present as a single entity, solvate, hydrate, crystal, amorphous solid, liquid or oil; Reducing or eliminating one or more of cardiac ion channelopathies caused by an active agent used to treat a disease or conditions resulting from irregularities or alterations in cardiac patterns; Administered in an amount per unit dose of about 1, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 473, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 mg per unit dose; or Formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, topical, pulmonary, rectal, vaginal or intramuscular administration, and optionally, the compound of formula I is formulated as a tablet, capsule, caplet, pill, powder, lozenge, troche, syrup preparation, liquid solution, suspension, emulsion, elixir or oral thin film (OTF), in solid form, solution, suspension or soft gel form for oral administration; or optionally, the solid form further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweeteners, derivatives thereof, or combinations thereof.

20. The method of claim 18, wherein the compound of formula I is co-administered with one or more agents that induce heart disease as a side effect.

21. The method according to claim 20, wherein the one or more active agents that induce heart disease as a side effect are selected from at least one of the following: albuterol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, arformoterol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, curcumin, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphenidate, dextroamphetamine, amphetamine, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, Epinephrine, Adrenaline, eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, Furosemide, Frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, imipramine hydrochloride, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl acetate, lysine methylamphetamine, lithium, mesoridazine, metaproterenol, methadone, methamphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perfluoropropane, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, albuterol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, sulfamethoxazole-trimethoprim, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat or ziprasidone.

22. The method according to claim 20, wherein the compound of formula I reduces or eliminates heart diseases induced by drugs or caused by diseases or disorders, such as QT interval prolongation, myocardial injury or AV block.

23. A method for reducing or eliminating the cardiotoxic or cardiopathologic effects of one or more active agents, comprising: administering to a subject in need of treatment for a disease or disorder one or more cardiotoxic active agents; and providing combination therapy with an effective amount of one or more lipids that reduce or eliminate the cardiotoxic effects of the one or more active agents, wherein the lipid has the following formula: 。 24. The method according to claim 23, wherein the cardiotoxicity or cardiopathy is selected from at least one of the following: minimal left ventricular dilation, systolic dysfunction, moderate valvular regurgitation, reduced left ventricular ejection fraction (LVEF), cardiac hypertrophy, reduced cardiac contractility, reduced cardiac output, pressure and volume overload hypertrophy, myocardial dysfunction, cardiac remodeling, heart failure after myocardial infarction or heart disease.

25. The method according to claim 23, wherein the one or more active agents are selected from doxorubicin, trastuzumab or both.

26. The method according to claim 23, wherein the one or more active agents and the lipid are administered simultaneously.

27. The method according to claim 23, wherein the one or more active agents and the lipid are formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal, vaginal or intramuscular administration.

28. The method according to claim 23, wherein the compound and the one or more active agents, or both, are infused within 3 hours.

29. The method according to claim 23, wherein one or more agents that induce cardiotoxic effects or cardiopathic effects are selected from at least one of the following: albuterol, alfuzosin, amantadine, amiodarone, amisulpride, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, arformoterol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, curcumin, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphenidate, dextroamphetamine, amphetamine, dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, epinephrine, adrenalin, eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, imipramine hydrochloride, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl acetate, lysine methylamphetamine mesylate, lithium, mesoridazine, orciprenaline, methadone, methamphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perfluoropropane lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, albuterol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfamethoxazole, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat or ziprasidone.

30. The method according to claim 23, wherein the pharmaceutical composition comprising the one or more lipids further comprises one or more excipients, binders, anti-adhesives, coatings, disintegrants, fillers, flavoring agents, dyes, pigments, glidants, lubricants, preservatives, adsorbents, sweetening agents, derivatives thereof, or combinations thereof.

31. The method according to claim 23, wherein the pharmaceutical composition comprises the compound of formula I in an amount of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10000 mg per unit dose.

32. The method according to claim 23, wherein the pharmaceutical composition is a formulation for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, topical, pulmonary, rectal, vaginal or intramuscular administration.

33. The method according to claim 23, wherein the formulation for oral administration is a tablet, capsule, cachet, pill, powder, lozenge, troche, syrup formulation, liquid solution, suspension, emulsion, elixir or oral thin film (OTF).

34. The method according to claim 23, wherein the formulation is in solid form, solution, suspension or soft gel form. 。 35. A method of reducing or eliminating the cardiotoxic effects of one or more anti-proliferative agents, comprising: administering to a subject in need of treatment for a proliferative disorder one or more cardiotoxic anti-proliferative agents; and providing combination therapy with an effective amount of one or more lipids that reduce or eliminate the cardiotoxic effects of the one or more anti-proliferative agents, wherein the lipid has the following formula: or a pharmaceutically acceptable salt thereof.

36. The method according to claim 35, wherein the one or more anti-proliferative agents are selected from doxorubicin, trastuzumab, or both.

37. The method according to claim 35, wherein the one or more anti-proliferative agents and the lipid are administered simultaneously.

38. The method according to claim 35, wherein the one or more anti-proliferative agents and the lipid are administered orally or intravenously.

39. The method according to claim 35, wherein the one or more lipids, the one or more anti-proliferative agents, or both are infused within 3 hours.

40. The method according to claim 35, wherein the one or more anti-proliferative agents that induce heart disease as a side effect are selected from at least one of the following: bosutinib, crizotinib, dabrafenib, dasatinib, doxorubicin, lapatinib, nilotinib, sorafenib, sunitinib, vandetanib or vemurafenib.

41. The method according to claim 35, wherein the lipid is 。

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