Cardioprotective lipids and methods of use

Abstract

The present invention provides a method for reducing or eliminating the cardiotoxic or cardiac effects of one or more active agents by administering to a subject in need thereof an effective amount of one or more lipids that reduces or eliminates the cardiotoxic effects of the one or more active agents, wherein the lipid has the formula: [Formula 1] The method includes a step of encoding the encoded data as JPEG2025532111000023.jpg38170.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a PCT international patent application claiming priority to a continuation-in-part application filed as U.S. Patent Application No. 17 / 950,898, filed September 22, 2022, the contents of each of which are incorporated herein by reference in their entirety.

[0002] STATEMENT OF FEDERALLY FUNDED RESEARCH none.

[0003] The present invention relates generally to the field of novel lipids that reduce or eliminate cardiac pathology, such as QT prolongation, myocardial damage or AV block, whether drug-induced or caused by a disease or condition. [Background technology]

[0004] Without limiting the scope of the invention, its background is described in relation to drug-induced QT prolongation and other cardiac diseases and toxicity.

[0005] There are many medications designed to treat various diseases that are commonly prescribed despite being known or suspected to have adverse effects on the patient's heart. In addition to cardiac arrhythmias, including QT prolongation, supraventricular tachycardias (SVT), and atrial fibrillation (AF), several other cardiac toxicities can occur as side effects of medications, including myocardial damage, cardiomyopathy, congestive heart failure, and left ventricular hypertrophy (LVH).

[0006] Cardiotoxicity of such pharmaceuticals can cause significant complications that can affect patients being treated for various diseases, such as proliferative malignancies. The severity of such toxicity depends on many factors, including the immediate and cumulative dose, the method of administration, the presence of any underlying cardiac conditions, and various congenital or acquired cardiac risk factors specific to a particular patient. Furthermore, toxicity can be influenced by current or previous treatment with other pharmaceuticals. Cardiotoxic effects can occur immediately during administration of the drug, or the effects may not manifest themselves until months or years after the patient has been treated.

[0007] High-dose chemotherapy remains the treatment of choice for aggressive malignancies. Numerous clinical studies have demonstrated that high-dose chemotherapy can significantly extend patient survival, but its use and effectiveness are limited by significant side effects, particularly cardiac toxicity. In mid- to late-stage cardiac toxicity, heart failure can manifest many years after chemotherapy has ceased. Treatment with chemotherapeutic agents is known to result in pericardial and endomyocardial fibrosis, heart failure, myocarditis, or pericarditis. Chemotherapy has also been associated with hemorrhagic myocardial necrosis and cardiomyopathy.

[0008] Furthermore, anti-cancer monoclonal antibodies have also been linked to cardiotoxicity. Infusion-related cardiotoxic effects, such as left ventricular dysfunction, congestive heart failure, and other cardiac dysfunction, can occur. The risk of such complications increases if the patient has pre-existing heart disease, advanced age, previous cardiotoxic treatment, or chest radiation.

[0009] Tyrosine kinase inhibitors (TKIs) have well-known cardiotoxic effects: anthracyclines, trastuzumab, imatinib mesylate, dasatinib, nilotinib, sunitinib, sorafenib, vandetanib, and lapatinib have all been associated with various mechanical and electrical dysfunctions.

[0010] Among the toxic effects associated with TKIs are QT prolongation, sudden cardiac death (both considered rhythmic dysfunction), 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 are being used to attempt to mitigate the cardiotoxicity of cancer treatment. The primary method for preventing cardiotoxicity is to limit the dose of cardiotoxic drugs. There is also some evidence that the method of drug administration can affect the risk of cardiotoxicity. Rapid administration of cardiotoxic agents results in high blood levels, which can cause greater cardiac damage than the same amount of drug given over a longer period of time. Giving smaller doses of drug more frequently can also reduce toxicity compared with giving larger doses of drug at longer intervals.

[0011] The risk of cardiotoxicity from certain chemotherapy agents has been reduced by encapsulating these drugs in liposomes. For example, studies indicate that the cardiotoxicity of liposomal doxorubicin formulations is significantly lower than that of conventional doxorubicin.

[0012] 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 blocking the formation of oxygen free radicals. One way that radiation and chemotherapy 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 the combustion of fuel for energy. They are also formed from exposure to environmental factors such as cigarette smoke, radiation, and chemotherapy drugs. Summary of the Invention [Problem to be solved by the invention]

[0013] However, there remains a need for new compositions and methods for reducing heart disease, whether drug-induced or the result of a disease or condition. [Means for solving the problem]

[0014] As embodied and broadly described herein, embodiments of the present disclosure include compounds of formula I: [ka] The present invention relates to the compound

[0015] In one embodiment, the compound of Formula I exists as a single entity, a solvate, a hydrate, a crystal, an amorphous solid, a liquid, or an oil. In another embodiment, the compound is a hydrochloride salt. In another embodiment, the pharmaceutical composition further comprises one or more agents that induce cardiac disease as a side effect. In another embodiment, the one or more agents that induce cardiac disease as a side effect are: 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, benzodiazepine, benzocaine, benzophenone, benzocaine ... Loxacin, 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, estrogen Fedrine, 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 , melipramine, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl, lisdexamfetamine, 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, perflutren lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salbutamol, salmetazolone and / or 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-sulfa, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, or ziprasidone. In another embodiment, the pharmaceutical composition further comprises one or more excipients, binders, antiadherents, coatings, disintegrating tablets, fillers, flavors, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, or combinations thereof. In another embodiment, the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, and dairy derivatives thereof. In another embodiment, the compound of formula I is present in an amount per unit dose 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, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000,9,000 or 10,000 milligrams. In another embodiment, the pharmaceutical composition is a formulation for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. In another embodiment, the formulation for oral administration is a tablet, capsule, caplet, pill, powder, troche, lozenge, slurry, solution, suspension, emulsion, elixir, or oral thin film (OTF).

[0016] As embodied and broadly described herein, embodiments of the present disclosure include compounds of formula I [ka] 1. A method for preparing a compound of formula (I) comprising: [ka] Related to methods, including

[0017] As embodied and broadly described herein, aspects of the present disclosure include: [ka] The present invention relates to a pharmaceutical composition comprising a compound of formula I comprising: and a pharmaceutically acceptable diluent or carrier.

[0018] In one embodiment, the compound of Formula I exists as a single entity, solvate, hydrate, crystal, amorphous solid, liquid, or oil. In another embodiment, the compound is a hydrochloride salt. In another embodiment, the pharmaceutical composition further comprises one or more agents that induce cardiac disease as a side effect. In another embodiment, the one or more agents that induce cardiac disease as a side effect are: 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 Flin, 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, melipramine, indapamide , isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl, lisdexamfetamine, 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, perflutren lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salbutamol, salmeterol, saquinavir In another embodiment, the pharmaceutical composition further comprises one or more excipients, binders, antiadherents, coatings, disintegrating tablets, fillers, flavorings, dyes, colorings, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, or combinations thereof. In another embodiment, the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethyl cellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums and dairy derivatives thereof. In another embodiment, the amount per unit dose of the pharmaceutical composition comprises 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, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 milligrams of the compound of Formula I per unit dose. In another aspect,The pharmaceutical composition is a formulation for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. In another embodiment, the formulation for oral administration is a tablet, capsule, caplet, pill, powder, troche, lozenge, slurry, liquid, suspension, emulsion, elixir, or oral thin film (OTF). In another embodiment, the formulation is in solid form, solution, suspension, or softgel form.

[0019] As embodied and broadly described herein, aspects of the present disclosure include a method of reducing or eliminating one or more of a cardiac channelopathy, myocardial damage, or a condition resulting from irregularities or alterations in cardiac pattern in a human or animal subject, comprising administering to the human or animal subject a compound of formula I [ka] The present invention relates to a method comprising administering one or more of the compounds of the formula:

[0020] In one embodiment, the compound of Formula I exists as a single entity, solvate, hydrate, crystal, amorphous solid, liquid, or oil. In another embodiment, the compound is the hydrochloride salt. In another embodiment, the compound of Formula I reduces or eliminates one or more of the conditions resulting from irregularities or changes in cardiac patterns caused by cardiac channelopathies or active agents used to treat these diseases. In another embodiment, the amount of the pharmaceutical composition per unit dose comprises 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, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 milligrams of the compound of Formula I per unit dose. In another embodiment, the compound of Formula I is formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. In another embodiment, the compound of Formula I is formulated for oral administration as a tablet, capsule, caplet, pill, powder, lozenge, lozenge, slurry, solution, suspension, emulsion, elixir, or oral thin film (OTF). In another embodiment, the compound of Formula I is formulated as a solid form, solution, suspension, or softgel form. In another embodiment, the solid form further comprises one or more excipients, binders, antiadherents, coatings, disintegrating tablets, fillers, flavors, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, or combinations thereof. In another embodiment, a compound of Formula I is co-administered with one or more active agents that induce cardiac disease as a side effect. In another embodiment, the one or more active agents that induce cardiac disease as a side effect are: 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, dromedine Nedalone, 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, melipramine, indapamide, isoprenaline Loterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl, lisdexamfetamine, lithium, mesoridazine, metaproterenol, methadone, methamphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondancetro oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perflutren, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salbutamol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine,In another embodiment, the compound of Formula I is selected from at least one of solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfa, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, or ziprasidone. In another embodiment, the compound of Formula I reduces or eliminates cardiac disease, such as QT prolongation, myocardial damage, or AV block, that is drug-induced or caused by a disease or condition.

[0021] As embodied and broadly described herein, aspects of the disclosure include a method of reducing or eliminating the cardiotoxic or cardiac effects of one or more active agents, comprising: administering to a subject in need of treatment for a disease or disorder, one or more active agents that are cardiotoxic; and administering to a subject in need of treatment for a disease or disorder, one or more active agents that are cardiotoxic; and administering to a subject in need of treatment for a disease or disorder, one or more lipids in an amount effective to reduce or eliminate the cardiotoxic effects of the one or more active agents, wherein the lipids have the formula: [ka] The present invention relates to a method comprising administering a combination therapy comprising:

[0022] In one embodiment, the cardiotoxicity or cardiac disease is selected from at least one of: minimal left ventricular dilation, systolic dysfunction, moderate valvular regurgitation, reduced left ventricular ejection fraction (LVEF), cardiac hypertrophy, reduced cardiac contractility, reduced cardiac output, pressure overload and volume overload cardiac hypertrophy, myocardial dysfunction, cardiac remodeling, post-myocardial infarction heart failure, or cardiac disease. In another embodiment, the one or more active agents are selected from doxorubicin, trastuzumab, or both. In another embodiment, the one or more active agents and lipid are administered simultaneously. In another embodiment, the one or more active agents and lipid are formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. In another embodiment, the compound is a hydrochloride salt. In another embodiment, the one or more lipids, the one or more active agents, or both are infused over a 3-hour period. In another embodiment, the one or more agents that induce cardiotoxic or cardiac effects are: 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, dexmedeto amide, 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, melipramine, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl, lisdexamfetamine, 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, perflutren lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pi Mozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salbutamol, 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-sulfa, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, or ziprasidone. In another embodiment, the pharmaceutical composition comprising one or more lipids further comprises one or more excipients, binders, antiadherents, coatings, disintegrating tablets, fillers, flavors, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, or combinations thereof. In another embodiment, the pharmaceutical composition comprises a compound of Formula I in an amount per unit dose of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 24, 30, 40, 50, 60,In another embodiment, the pharmaceutical composition comprises 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, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 milligrams. In another embodiment, the pharmaceutical composition is formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration. In another embodiment, the composition formulated for oral administration is a tablet, capsule, caplet, pill, powder, troche, lozenge, slurry, liquid, suspension, emulsion, elixir, or oral thin film (OTF). In another embodiment, the formulation is in solid form, solution, suspension, or softgel form. In another embodiment, the compound of Formula I: [ka] Compound.

[0023] As embodied and broadly described herein, an aspect of the disclosure is a method of reducing or eliminating the cardiotoxic effects of one or more antiproliferative agents, comprising: administering to a subject in need of treatment for a proliferative disorder one or more antiproliferative agents that are cardiotoxic; and administering to a subject in need of treatment for a proliferative disorder one or more antiproliferative agents that are cardiotoxic; and administering to a subject in need of treatment for a proliferative disorder one or more lipids in an amount effective to reduce or eliminate the cardiotoxic effects of the one or more antiproliferative agents, wherein the lipids have the formula: [ka] and administering a combination therapy, wherein the reduction in cardiotoxicity is at least 25, 30, 40, 50, 60, 70, 75, 80, 90, 95, or 100% compared to treatment without the lipid. In one embodiment, the cardiotoxicity is selected from at least one of: minimal left ventricular dilation, systolic dysfunction, moderate valvular regurgitation, reduced left ventricular ejection fraction (LVEF), cardiac hypertrophy, reduced cardiac contractility, reduced cardiac output, pressure overload and volume overload cardiac hypertrophy, myocardial dysfunction, cardiac remodeling, post-myocardial infarction heart failure, or heart disease. In another embodiment, the one or more antiproliferative agents are selected from doxorubicin, trastuzumab, or both. In another embodiment, the one or more antiproliferative agents and the lipid are administered simultaneously. In another embodiment, the one or more antiproliferative agents and the lipid are administered orally or intravenously. In another embodiment, the one or more lipids, the one or more antiproliferative agents, or both are infused over a 3 hour period. In another embodiment, the one or more antiproliferative agents that induce cardiac disease as a side effect are selected from at least one of: bosutinib, crizotinib, dabrafenib, dasatinib, doxorubicin, lapatinib, nilotinib, sorafenib, sunitinib, vandetanib, or vemurafenib. In another embodiment, the pharmaceutical composition comprises a compound of Formula I in an amount per unit dose 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, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 milligrams. [Brief explanation of the drawings]

[0024] For a more complete understanding of the features and advantages of the present invention, reference should now be made to the following detailed description taken in conjunction with the accompanying drawings, in which: [Figure 1] 1 is a graph showing the effect of Compound I on moxifloxacin-induced QT prolongation in an animal model. [Figure 2]FIG. 1 shows an outline of a 9-week study to determine the cardioprotective effects of lipids. [Figure 3] FIG. 1 shows M-mode echocardiographic images comparing the effects of sham treatment, doxorubicin (Doxo) and trastuzumab (Herceptin), and treatment with doxorubicin and trastuzumab plus lipid SP005. [Figure 4] FIG. 1 shows left ventricular pressure recordings comparing sham treatment, doxorubicin and trastuzumab, and treatment with doxorubicin and trastuzumab plus lipid SP005 at two concentrations: 10 mg.kg and 50 mg / kg. [Figure 5A] ~ [Figure 5I] Graphs showing left ventricular systolic pressure (FIG. 5A), heart rate (FIG. 5B), stroke volume (FIG. 5C), left ventricular ejection fraction (FIG. 5D), percent left ventricular fractional shortening (FIG. 5E), N-terminal (NT)-pro hormone BNP (NT-proBNP) at day 59 (FIG. 5F), anterior wall thickness end-diastole (AWT-ED) (mm) (FIG. 5G), anterior wall thickness end-systole (AWT-ES) (mm) (FIG. 5H), and left ventricular echo mass (FIG. 5I). DETAILED DESCRIPTION OF THE INVENTION

[0025] While the making and use of various embodiments of the invention are discussed in detail below, it should be recognized that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.

[0026] The compounds of the present invention include those generally described above and are further illustrated by the classes, subclasses, and chemical species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. In at least some embodiments, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Furthermore, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0027] To facilitate understanding of the present invention, several terms are defined below. Terms defined herein have meanings commonly understood by one of ordinary skill in the areas relevant to the present invention.

[0028] For example, the terms "a," "an," and "the" are not intended to refer exclusively to a singular entity, but include the general class for which a specific example may be used to illustrate. While terminology herein is used to describe specific embodiments of the invention, its use does not limit the invention except as outlined in the claims. Specifically, the use of the words "a" or "an," when used in conjunction with the word "comprising" in the claims and / or specification, can mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more than one." While the present disclosure supports definitions that refer to alternatives only and "and / or," the use of the word "or" in the claims is used to mean "and / or" unless expressly indicated to refer to alternatives only or unless the alternatives are mutually exclusive. Throughout this application, the term "about" is used to refer to values ​​that include the inherent error variation of the measurement device, method used to determine the value, or the variation that exists among study subjects.

[0029] Compounds and Definitions: As used in the specification and claim(s), the words "comprising" (and any form of comprising, e.g., "comprise" and "comprises"), "having" (and any form of having, e.g., "have" and "has"), "including" (and any form of including, e.g., "includes" and "include"), or "containing" (and any form of containing, e.g., "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. In any of the composition and method embodiments provided herein, "comprising" can be replaced with "consisting essentially of" or "consisting of." As used herein, the phrase "consisting essentially of" requires the specified integer(s) or steps, as well as those that do not materially affect the properties or function of the claimed invention. As used herein, the term "consisting of" is used to indicate the presence of only the recited integers (e.g., features, elements, properties, properties, method / process steps, or limitations) or group of integers (e.g., features(s), elements(s), properties(s), properties(s), method / process steps, or limitations). As used herein, each of the compounds may be used in formulations or methods that include one or more components or steps, but may also be used in compositions or methods that consist essentially of, or even consist of, the recited components.

[0030] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the items listed preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and, where order is important in a particular context, BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, combinations containing repeats of one or more items or terms, e.g., BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, are expressly included. Those of skill in the art will understand that there is typically no limit to the number of items or terms in any combination unless otherwise apparent from the context.

[0031] As used herein, approximation terms, such as, but not limited to, "about," "substantial," or "substantially," when so modified, are understood to be not necessarily absolute or perfect, but refer to a state that one of ordinary skill in the art would consider close enough to justify specifying the state as existing. The degree to which the description can vary depends on how large a change can be made, while still allowing one of ordinary skill in the art to understand that the modified feature still possesses the required properties and capabilities of the unmodified feature. Generally, but in accordance with the preceding discussion, numerical values ​​herein modified by approximation terms, such as "about," can vary from the stated value by at least ±1, 2, 3, 4, 5, 6, 7, 10, 12, or 15%.

[0032] "Pharmaceutically acceptable cation" refers, in one embodiment, to an organic or inorganic cation that is pharmaceutically acceptable and well known in the art for use in mammals. For example, inorganic 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, glucamine, N-methylglucamine, glycine, lysine, ornithine, arginine, ethanolamine, choline, and the like. In one embodiment, the amine cation is a cation in which X+ is of the formula YH+, where Y is ammonia, triethylamine, trimethylamine (TRIS), triethanolamine, ethylenediamine, glucamine, N-methylglucamine, glycine, lysine, ornithine, arginine, ethanolamine, choline, and the like. In one embodiment, suitable cationic organic or inorganic salts that can be used include cationic moieties that can form ionic associations with O moieties in the compounds and that do not significantly adversely affect the desirable properties of the compounds for purposes of the present invention, such as solubility, increased stability, etc.

[0033] Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the present compounds are within the scope of the invention. Additionally, unless otherwise specified, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen with deuterium or tritium, or the replacement of a carbon with a C- or C-enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools in biological assays, as probes, or as therapeutic agents according to the present invention.

[0034] As used herein, the term "in vivo" refers to being within the body. The term "in vitro" as used in this application should be understood to refer to operations performed in a non-living system.

[0035] As used herein, the term "treatment" refers to the treatment of a condition referred to herein, particularly in a patient who describes the symptoms of a disease or disorder.

[0036] As used herein, the terms "treatment" or "treating" refer to any administration of a compound of the invention and include (i) inhibiting disease (i.e., arresting further development of pathology and / or symptomology) in an animal suffering from or exhibiting pathology or symptomology in an affected patient; or (ii) ameliorating disease (i.e., reversing pathology and / or symptomology) in an animal suffering from or exhibiting pathology or symptomology in an affected patient. The term "controlling" includes preventing, treating, eradicating, ameliorating, or otherwise reducing the severity of the condition being controlled.

[0037] As used herein, the term "effective amount" or "therapeutically effective amount" as described herein means an amount of the subject compound that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, physician or other clinician.

[0038] As used herein, the terms "administration of" or "administering" a compound as used herein should be understood to mean providing a compound of the present invention to an individual in need of treatment in a therapeutically useful form and in a therapeutically useful amount in a form that can be introduced into the individual's body, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.

[0039] As used herein, the term "intravenous administration" includes infusion and other modes of intravenous administration.

[0040] As used herein, the term "pharmaceutically acceptable" to describe a carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0041] As generally defined above, each stereocenter is independently R, S, or racemic.

[0042] In a different embodiment, the present invention provides a compound having the structure: [ka] It has.

[0043] The compound may be paired with H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium as a pharmaceutically acceptable salt. In one embodiment, the compound is a hydrochloride salt.

[0044] 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 a compound of Formula I in an amount between about 1 mg and about 1 gram per unit dose. In some embodiments, the amount per unit dose is between about 1 mg and about 500 mg. In some embodiments, the amount per unit dose is between about 500 mg and about 10 grams. In some embodiments, the amount per unit dose is between about 250 mg and about 750 mg. In some embodiments, the amount per unit dose is between about 50 mg and about 450 mg. In some embodiments, the amount per unit dose is between about 100 mg and about 300 mg. In another embodiment, the pharmaceutical composition comprises, in an amount per unit dose, a compound of Formula I 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, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 milligrams per unit dose.

[0045] 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 a compound of Formula I in an amount per unit dose of between about 1 mg and about 1 gram per unit dose. In some embodiments, the amount per unit dose is between about 1 mg and about 500 mg. In some embodiments, the amount per unit dose is between about 500 mg and about 1 gram. In some embodiments, the amount per unit dose is between about 250 mg and about 750 mg. In some embodiments, the amount per unit dose is between about 50 mg and about 450 mg. In some embodiments, the amount per unit dose is between about 100 mg and about 300 mg. In another embodiment, the pharmaceutical composition comprises, in an amount per unit dose, a compound of Formula I 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, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 milligrams per unit dose.

[0046] In some embodiments, the pharmaceutical composition further comprises one or more agents that induce heart disease as a side effect, and the compound of Formula I or the compound of Formula IA reduces or eliminates the heart disease. In some embodiments, the one or more agents that induce heart disease as a side effect are: 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, adriamycin Renaline, 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, melipramine, indapamide, isoproterenol, Isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl, lisdexamfetamine, 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, perflutren lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salbutamol, 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-sulfa, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, or ziprasidone. Those skilled in the art will recognize that additional agents that induce cardiac disease exist and could benefit from inclusion in the formulations of the present invention.

[0047] In some embodiments, the present invention includes compositions comprising a cardiac active agent and a compound of Formula I, represented by one or more compounds of Formula I described above.

[0048] One embodiment of the present invention provides a pharmaceutical composition comprising or as a structure of Formula I, as described above, formulated 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, troche, lozenge, slurry, liquid, suspension, emulsion, elixir, or oral thin film (OTF). In some embodiments, the composition is in solid form, solution, suspension, or softgel form.

[0049] One embodiment of the present invention provides a pharmaceutical composition comprising an active agent that causes cardiac disease as a side effect and a compound of formula I as described above.

[0050] One embodiment of the present invention provides a method of reducing or eliminating one or more of the conditions resulting from cardiac channelopathy, myocardial damage, or irregularities or changes in cardiac pattern in a human or animal subject caused by an active agent used to treat the disease, comprising: administering to the human or animal subject a pharmaceutical composition comprising a compound of formula I.

[0051] In some embodiments, the pharmaceutical composition further comprises one or more excipients, binders, antiadherents, coatings, disintegrating tablets, fillers, flavors, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, or combinations thereof. In some embodiments, the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, and milk derivatives.

[0052] In some embodiments, the pharmaceutical composition further comprises one or more excipients, binders, antiadherents, coatings, disintegrating tablets, fillers, flavors, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, or combinations thereof. In some embodiments, the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, and milk derivatives.

[0053] In one embodiment, the present invention relates to an active agent that causes cardiac disease as a side effect, and the active agent is selected from the group consisting of: 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, and chloramphenicol. Romipramine, 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, phen Fluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, melipramine, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl, lisdexamin methamphetamine, 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, perflutren lipid microspheres, phentermine, phenylephrine,Phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salbutamol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, The present invention also includes compositions, pharmaceutical compositions, and methods for treating heart disease, including those selected from at least one of sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfa, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, or ziprasidone. Those skilled in the art will recognize that additional agents that induce heart disease exist and could benefit from inclusion in the formulations of the present invention.

[0054] 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, troche, lozenge, slurry, liquid, suspension, emulsion, elixir, or oral thin film (OTF). In some embodiments, the composition is in solid form, solution, suspension, or softgel form. In some embodiments, the solid form further comprises one or more excipients, binders, antiadherents, coatings, disintegrating tablets, fillers, flavors, dyes, colors, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, or combinations thereof. In some embodiments, the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethyl cellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, and milk derivatives.

[0055] In one embodiment, the method provides a pharmaceutical composition 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, troche, lozenge, slurry, liquid, suspension, emulsion, elixir, or oral thin film (OTF). In some embodiments, the composition is in solid form, solution, suspension, or softgel form. In some embodiments, the solid form further comprises one or more excipients, binders, antiadherents, coatings, disintegrating tablets, fillers, flavors, dyes, colors, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, or combinations thereof. In some embodiments, the binder is selected from the group consisting of hydroxypropyl methylcellulose, ethyl cellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, and milk derivatives.

[0056] In one embodiment, the method provides a pharmaceutical composition. One embodiment of the present invention provides for the administration of a compound of Formula I, wherein the compound is a lipid that reduces or eliminates cardiac pathology, e.g., QT prolongation, myocardial damage, or AV block, whether drug-induced or caused by a disease or condition.

[0057] The single most common reason for discontinuing or limiting use of over-the-counter medications was QT interval prolongation associated with polymorphic ventricular tachycardia, or torsades de pointes, a potentially life-threatening condition.

[0058] 5-HT3 antagonists block serotonin binding. Aloxi (or palonosetron HCL) is an antiemetic drug for chemotherapy-induced nausea and vomiting, and 5-HT3 antagonists block serotonin binding to 5-HT3. In a study, there was no significant difference in QTc interval during the perioperative period whether 0.075 mg of palonosetron was administered before or after sevoflurane anesthesia. Palonosetron may be safe in terms of QTc interval during sevoflurane anesthesia.

[0059] 5-HT4 receptor agonist. Cisapride is a gastrointestinal prokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Cisapride dose-dependently prolongs the QT interval. Neither torsades de pointes nor ventricular tachycardia were noted when 33 patients were monitored during the higher dose phase.

[0060] Histamine Antagonists. Antihistamines used in the treatment of allergies act by competing with histamine for H1 receptor sites on effector cells. Antihistamines thereby prevent, but do not reverse, responses mediated by histamine alone.

[0061] H1 antagonists, which relieve pain and premenstrual symptoms, are most useful in the acute exudative form of allergy, presenting with symptoms of rhinitis, urticaria, and conjunctivitis, but their effect is purely symptomatic and limited to suppressing symptoms resulting from the histamine-antibody response.

[0062] Pyrilamine is a first-generation histamine H1 antagonist and diuretic. Cases of QT interval prolongation following pyrilamine overdose have been reported in young adults. Fatalities resulting from ventricular tachyarrhythmias have been reported.

[0063] Terfenadine is an antihistamine used to treat allergies, hives (urticaria), and other allergic inflammatory conditions. The brand name Seldane has been discontinued in the United States. Reports of serious cardiovascular adverse effects, including ventricular tachyarrhythmias (torsades de pointes, ventricular tachycardia, ventricular fibrillation, and cardiac arrest), hypotension, palpitations, or syncope, have been rare.

[0064] Loratadine is a first-line antihistamine and a second-generation peripheral histamine H1 receptor blocker. It is structurally closely related to tricyclic antidepressants, such as imipramine, and less related to the atypical antipsychotic quetiapine. Some antihistamines, such as mizolastine and ebastine, can prolong the QT interval and induce severe cardiac arrhythmias. As of mid-2009, there was very little published clinical data on the risk of QT prolongation with loratadine. The extremely rare reported cases of torsades de pointes associated with loratadine appear to involve drug interactions, particularly with amiodarone and enzyme inhibitors. There have been no reports of QT prolongation due to desloratadine, the main metabolite of loratadine. Patients with risk factors for torsades de pointes or taking certain enzyme inhibitors should avoid loratadine.

[0065] Astemizole is a long-acting, highly selective H1 antagonist that acts on histamine H1 and H3 receptors. It has antipruritic and anticholinergic effects. It is also a functional inhibitor of acid sphingomyelinase. Overdosage of astemizole predisposes the myocardium to ventricular rhythm disturbances, including torsades de pointes. However, rhythm disturbances only occurred in patients with a corrected QT interval greater than 500 ms.

[0066] Calcium Channel Blocker. Prenylamine is a calcium channel blocker of the amphetamine chemical class 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 daily. The QT interval was significantly prolonged after 1 week of treatment. The prolongation persisted as long as treatment continued, up to 6 months. After cessation of treatment, the QT interval returned to normal within 2 weeks.

[0067] Lidoflazine is a piperazine calcium channel blocker and coronary vasodilator with some antiarrhythmic activity. As a tricyclic antihistamine, it acts as a selective inverse agonist of peripheral histamine H1 receptors. This carries a significant risk of QT interval prolongation and ventricular arrhythmias. Lidoflazine potently inhibits the HERG current (I(HERG)) recorded from HEK293 cells stably expressing wild-type HERG (IC(50) approximately 16 nM). It is approximately 13-fold more potent than verapamil against HERG under similar conditions in preferentially inhibiting activated / open HERG channels. Lidoflazine produces high-affinity blockade of the alpha subunit of the HERG channel by binding to aromatic amino acid residues within the channel pore, which likely represents a second molecular mechanism for QT interval prolongation by this drug.

[0068] Bepridil acts by blocking calcium (Ca) transport through calcium channels. 2+ Bepridil is an antihypertensive drug that interferes with the transport of thrombus (QTc) in the ventricle. This, in turn, prolongs the QT interval. Bepridil prolongs the QT and refractory state, and a linear correlation can be demonstrated between the percent change in QTc and the refractory period prolongation. In one patient, bepridil reduced the number of stimuli required to induce VT by one, but no spontaneous arrhythmias were noted, suggesting that it possesses antiarrhythmic properties with minimal proarrhythmic effects.

[0069] Chloroquine-chlorpheniramine (chloroquine and chlorpheniramine) is a histamine H1 receptor blocker that reverses chloroquine insensitivity in Plasmodium falciparum in vitro, and chloroquine / chlorpheniramine produces a higher cure rate than chloroquine alone. Short QT syndrome (SQTS) is a sporadic or autosomal dominant disorder characterized by markedly accelerated cardiac repolarization, ventricular arrhythmias, and sudden cardiac death. To date, mutations in five different ion channel genes (KCNH2, KCNQ1, KCNJ2, CACNA1C, and CACNB2) have been identified to cause SQTS. The risk of ventricular arrhythmias and sudden death is significantly elevated in SQTS, with cardiac arrest reported as the presenting symptom in 31% of SQTS patients. Chloroquine blocks mutant Kir2.1 channels responsible for short QT syndrome and normalizes repolarization in silico.

[0070] Halofantrine is an antimalarial drug containing a substituted phenanthrene, related to the antimalarials quinine and lumefantrine. It may be associated with cardiotoxicity. The most dangerous side effect is cardiac arrhythmia: halofantrine causes significant QT prolongation, an effect seen even at standard doses. Therefore, the drug should not be given to patients with cardiac conduction disorders and should not be combined with mefloquine. The mechanism of action of halofantrine is unknown.

[0071] Quinidine is an antimalarial drug that acts as a Class I antiarrhythmic (Ia) agent in the heart. It is a stereoisomer of quinine, an alkaloid that attenuates cardiac and skeletal muscle excitability by blocking sodium and potassium currents across cell membranes. This prolongs cellular action potentials and reduces automaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission. Quinidine induces longer QT interval prolongation in women than in men at equivalent serum concentrations. This difference may contribute to the higher incidence of drug-induced torsades de pointes observed in women taking quinidine, and is related to other cardiac and noncardiac drugs that prolong the QTc interval.

[0072] Antipsychotics. First-generation antipsychotics, known as classic antipsychotics, were discovered in the 1950s. While most second-generation drugs, known as atypical antipsychotics, were developed more recently, the first-generation atypical antipsychotic, clozapine, was discovered in the 1960s and introduced clinically in the 1970s. Both generations of drugs tend to block receptors in the brain's dopamine pathways, while atypical drugs tend to act similarly on serotonin receptors. Both generations of drugs tend to block receptors in the brain's dopamine pathways, while atypical drugs tend to act similarly on serotonin receptors. QTc interval prolongation can occur as a result of treatment with both conventional and novel antipsychotic drugs and is a clinical concern because it is associated with the potentially fatal ventricular arrhythmia, torsades de pointes.

[0073] Pimozide is an antipsychotic drug of the diphenylbutylpiperidine class that can induce QT interval prolongation. Pimozide is contraindicated in individuals with acquired or congenital QT interval prolongation or a family history of QT interval prolongation. Its use is not recommended for individuals or people with a personal or family history of arrhythmia or torsades de pointes. Pimozide acts as an antagonist of D2, D3, and D4 receptors and 5-HT7 receptors. It is also an hERG blocker.

[0074] Sertindole is an antipsychotic drug. Like other atypical antipsychotics, it has dopamine and serotonin receptor activity in the brain. Abbott Labs first filed for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996 but withdrew the application in 1998 following 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 was not approved by the FDA for use in the United States. In Europe, sertindole was approved and marketed in 19 countries beginning in 1996, but marketing authorization was withdrawn by the European Medicines Agency in 1998, and the drug was removed from the market. In 2002, based on new data, the EMA's CHMP suggested that sertindole could be reintroduced for restricted use in clinical trials, with strong protection for patients at risk of cardiac rhythm disorders, including extensive contraindications and warnings, a recommended reduction in the maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive ECG monitoring requirements before and during the procedure.

[0075] Chlorpromazine, marketed as Thorazine and Largactil, is a typical antipsychotic drug in the antipsychotic class. Its mechanism of action is not entirely clear but is thought to be related to its dopamine antagonist properties. Chlorpromazine also possesses antiserotonergic and antihistamine properties. It is a highly potent antagonist of D2 dopamine receptors and similar receptors, such as D3 and D5. Unlike most other drugs in this genre, chlorpromazine also has a high affinity for D1 receptors. ECG QT interval prolongation has only been reported in a few individuals taking Thorazine. In a study of 2,633 individuals who experienced side effects while taking Thorazine, based on FDA and social media, five individuals experienced ECG QT interval prolongation.

[0076] Thioridazine is a typical antipsychotic piperidine, a member of the phenothiazine class of drugs. The brand-name product was removed worldwide in 2005 due to the risk of severe cardiac arrhythmias, but generic versions are available in the United States. The drug was voluntarily discontinued worldwide by its manufacturer, Novartis, due to the risk of severe cardiac arrhythmias. Thioridazine prolongs the QTc interval in a dose-dependent manner. The 5-HT2A to D2 receptor binding ratio is thought to determine whether most antipsychotics are atypical or typical. In the case of thioridazine, the 5-HT2A to D2 receptor binding ratio is below the level considered necessary for atypicality, despite a relatively low propensity for extrapyramidal side effects in clinical practice.

[0077] Haldol, haloperidol. A typical antipsychotic drug that prolongs the QT interval is meperidine. It is listed on the WHO Model List of Essential Medicines and is the most commonly used typical antipsychotic. Special caution: Patients at particular risk for the development of QT prolongation (hypokalemia, concurrent use of other drugs that cause QT amiodarone): Q-Tc interval prolongation (potentially dangerous changes in cardiac rhythm).

[0078] Mesoridazine is a piperidine neuroleptic drug that belongs to a class of drugs called phenothiazines and is used to treat schizophrenia. It is a metabolite of thioridazine. Mesoridazine was removed from the U.S. market in 2004 due to dangerous side effects, namely irregular heartbeat and QT prolongation on the electrocardiogram.

[0079] Selective serotonin reuptake inhibitor. Celexa (citalopram) is an antidepressant in the group of drugs called selective serotonin reuptake inhibitors (SSRIs). Its chemical structure, defined as (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, a racemic bicyclic phthalan derivative, is unrelated to that of other SSRIs or other available antidepressants. Citalopram can cause a condition that affects heart rhythm (QT prolongation).

[0080] Antibiotics. Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent. It functions by inhibiting type II topoisomerase, DNA gyrase; topoisomerase IV (an enzyme required to separate bacterial DNA, thereby inhibiting cell replication) can cause torsades de pointes. Coadministration of moxifloxacin with other drugs that also prolong the QT interval or induce bradycardia (e.g., beta-blockers, amiodarone) should be avoided. Careful consideration should be given to the use of moxifloxacin in patients with cardiovascular disease, including those with conduction abnormalities. Drugs that prolong the QT interval may have additive effects on QT prolongation, increasing the risk of ventricular arrhythmias.

[0081] Pentamidine is an antimicrobial drug given to prevent and treat Pneumocystis pneumonia. The exact mechanism of its antiprotozoal action is unknown (although it may involve interaction with ubiquitin and mitochondrial function). Severe or fatal arrhythmias and heart failure are quite frequent. Pentamidine, an aromatic diamidine, acts via inhibition of hERG channel trafficking. Pentamidine had no acute effect on currents generated by hERG, KvLQT1 / mink, Kv4.3, or SCNA5. However, after overnight exposure, pentamidine reduced hERG currents and inhibited hERG trafficking and maturation with IC50 values ​​of 5-8 μM, similar to therapeutic concentrations.

[0082] Clarithromycin is an antibiotic derived from erythromycin, known chemically as 6-O-methylerythromycin. It is a macrolide that works by stopping the production of proteins by some bacteria that can cause QT prolongation or ventricular arrhythmias, including torsades de pointes.

[0083] Erythromycin is an antibiotic with serious side effects, including common cardiac arrhythmias with prolonged QT intervals, including torsades de pointes.

[0084] Grepafloxacin is an oral fluoroquinolone broad-spectrum antibacterial agent used to treat bacterial infections. Grepafloxacin was removed from the market worldwide in 1999 due to its side effect of prolonging the QT interval on the electrocardiogram, causing cardiac events and sudden death.

[0085] Sparfloxacin is a fluoroquinolone broad-spectrum antibiotic used to treat bacterial infections. It has a controversial safety profile. The use of sparfloxacin is contraindicated in patients with known QTc prolongation and in patients concomitantly treated with class IA or III antiarrhythmic drugs. In studies, the maximum plasma concentration (Cmax) after administration of 1200 and 1600 mg was lower than expected from a linear dose relationship. This was also true for the mean increase and mean maximum increase in the QTc interval. The increase in the QTc interval was significantly greater than the Cmax. max It correlated well with AUCo-infinity but not with AUCo-infinity.

[0086] Curcumin (diferuloylmethane) is a bright yellow chemical produced by several plants. It is the major curcuminoid in turmeric (Curcuma longa) and exhibits 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 the hERG channel in a dose-dependent manner with an IC50 value of 5.55 μM. The deactivation, inactivation, and recovery times from inactivation of the hERG channel were significantly altered by acute treatment with 10 μM curcumin.

[0087] Antiarrhythmic drugs. Antiarrhythmic drugs are used to suppress cardiac rhythm disorders (cardiac arrhythmias), such as atrial fibrillation, ventricular tachycardia, and ventricular fibrillation. Procainamide is a class of antiarrhythmic drugs used to treat cardiac arrhythmias. It is classified as Class Ia according to the Vaughan Williams classification system and is used for both supraventricular and ventricular arrhythmias. The antiarrhythmic drug procainamide has also been found to interfere with pacemakers. Toxic levels of procainamide lead to a decrease in ventricular conduction velocity and an increase in ventricular refractory period. This disrupts the artificial membrane potential, leading to supraventricular tachycardia, which can lead to pacemaker failure and death. It induces rapid blockade of batrachotoxin (BTX)-activated sodium channels in the myocardium and acts as an antagonist of long-term gating closure. Procainamide belongs to the aminobenzamide family, which has cardiac effects similar to those of quinidine and has an identical toxicity profile.

[0088] Propafenone is a Class 1C antiarrhythmic drug that treats conditions associated with rapid heart rate, such as atrial and ventricular arrhythmias, and works by slowing the influx of sodium ions into cardiac muscle cells, causing a decrease in cellular excitability. Propafenone is more selective for cells with high heart rates, but also blocks normal cells better than Class Ia or Ib. Propafenone differs from the prototypical Class 1c antiarrhythmic drugs in that it has additional activity as a beta-adrenergic blocker and can cause bradycardia.

[0089] Methanesulfonanilide (E-4031) is an experimental Class III antiarrhythmic drug that blocks potassium channels. E-4031 acts on a specific class of voltage-gated potassium channels, the hERG channel, which is primarily found in the heart. The hERG channel (Kv11.1) mediates the IKr current, which repolarizes cardiomyocytes. The hERG channel is encoded by the human ether-a-go-go related gene (hERG). E-4031 blocks hERG-type potassium channels by binding to the open channel. Although its structural target within the hERG channel is unknown, several other methanesulfonanilide Class III antiarrhythmic drugs are known to bind to the S6 domain or C-terminus of the hERG channel. E-4031 can prolong the QT interval, which can lead to fatal arrhythmias. To date, one clinical trial has been conducted to test the effect of E-4031 on QT interval prolongation.

[0090] Amiodarone is a Class III antiarrhythmic drug for ventricular fibrillation or tachycardia, prolonging the third phase of the cardiac action potential. Amiodarone is a known antiarrhythmic agent that causes prolongation of the action potential duration, which is reflected as QT prolongation on the electrocardiogram. Amiodarone has multiple effects on myocardial depolarization and repolarization, making it a highly effective antiarrhythmic drug. Its primary effect is to block potassium channels, but it can also block sodium and calcium channels, as well as beta and alpha adrenergic receptors. Amiodarone significantly prolongs the QT interval and QTc value.

[0091] Dronedarone, a benzofuran derivative related to amiodarone, is a drug primarily used to treat cardiac arrhythmias (approved by the FDA in 2009). It is a "multichannel blocker," but it is unclear which channel(s) play a central role in its efficacy. Dronedarone's actions at the cellular level are controversial, with most studies suggesting inhibition of multiple outward potassium currents, including the rapid delayed rectifier, slow delayed rectifier, and ACh-activated inward rectifier. It also appears to reduce rapid inward Na current and L-type Ca channels. Reduction of K current in some studies has been attributed to inhibition of K-ACh channels or related GTP-binding proteins. A 69% reduction in K current leads to increased AP duration and effective refractory period, demonstrating amiodarone-like class III antiarrhythmic activity in vitro and in clinical trials. The drug also appears to exhibit activity in each of the four Vaughan-Williams antiarrhythmic drug classes. Concomitant use of drugs or herbal products that can prolong the QT interval and induce torsades de pointes with a QTc Bazett interval ≥ 500 ms, or 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) is contraindicated.

[0092] Disopyramide is an antiarrhythmic drug used to treat ventricular tachycardia. It is a sodium channel blocker and therefore classified as a Class 1a antiarrhythmic agent. Disopyramide's Class 1a activity is similar to that of quinidine in that it targets sodium channels to inhibit conduction. Disopyramide inhibits the increase in sodium permeability of cardiac myocytes during phase 0 of the cardiac action potential, subsequently attenuating the inward sodium current. This increases the excitation threshold and attenuates upstroke rate. Disopyramide prolongs the PR interval by lengthening both the QRS and P wave durations. Concerns about disopyramide have been the hypothesized potential for sudden death due to its Type 1 antiarrhythmic effect.

[0093] Dofetilide is a Class III antiarrhythmic agent. Because of its proarrhythmic potential, it is available only by prescription from physicians who have undergone specific training regarding the risks of treatment with dofetilide. Furthermore, it is available only by mail order or through specially trained local pharmacies. Dofetilide works by selectively blocking the rapid component of the delayed rectifier outward potassium current. There is a dose-dependent increase in the QT interval and corrected QT interval (QTc). For this reason, many physicians initiate dofetilide therapy only in individuals under telemetric monitoring or when continuous EKG measurements of QT and QTc are available.

[0094] Sotalol is a nonselective competitive beta-adrenergic receptor blocker that also exhibits Class III antiarrhythmic properties. The U.S. Food and Drug Administration recommends that sotalol be used only for severe arrhythmias because its QT interval prolongation carries a small risk of life-threatening torsades de pointes. Sotalol also acts on potassium channels, causing a delay in ventricular relaxation. By blocking these potassium channels, sotalol inhibits the outflow of K+ ions, thereby increasing the time before another electrical signal can be generated in ventricular myocytes. This increase in the period before a new signal for contraction occurs.

[0095] Ibutilide is a Class III antiarrhythmic agent indicated for acute cardioversion of atrial fibrillation and atrial flutter, prolonging the action potential and refractory period of myocardial cells. Due to its Class III antiarrhythmic activity, it should not be coadministered with Class Ia and Class III agents. Unlike most other Class III antiarrhythmic drugs, ibutilide does not prolong the action potential via blockade of the cardiac delayed rectifier potassium current, nor does it possess the sodium-blocking, antiadrenergic, and calcium-blocking activities of other Class III agents. Therefore, it is often referred to as a "pure" Class III antiarrhythmic drug. Like other Class III antiarrhythmic drugs, ibutilide blocks the delayed rectifier potassium current. It acts on slow sodium channels, promoting sodium influx through these channels. Like other antiarrhythmic drugs, ibutilide's ability to prolong the QT interval can lead to abnormal cardiac rhythms, potentially causing a potentially fatal condition known as torsades de pointes. The drug is contraindicated in patients prone to developing abnormal heart rhythms; those with a history of polymorphic ventricular tachycardia, especially those with a long QT interval, sick sinus syndrome, or subacute myocardial infarction.

[0096] Dopamine receptor antagonists. Dopamine antagonists (antidopamine agonists) are a type of drug that blocks dopamine receptors through receptor antagonism. Most antipsychotic drugs are dopamine antagonists, and therefore they have found use in the treatment of schizophrenia, bipolar disorder, and psychostimulant psychosis. Some other dopamine antagonists are antiemetics used to treat nausea and vomiting.

[0097] Droperidol is an antidopaminergic butyrophenone used as an antiemetic and antipsychotic. It is a potent D2 (dopamine receptor) antagonist with some histamine and serotonin antagonist activity. Concerns exist about QT prolongation and torsades de pointes. Evidence for this is disputed; nine cases of torsades have been reported over a 30-year period, all of which involved doses exceeding 5 mg. QT prolongation is a dose-dependent effect, and droperidol is not significantly dangerous at low doses, but prolongation of the QT interval may lead to torsades de pointes.

[0098] Domperidone is a peripherally selective dopamine D2 receptor antagonist useful in treating Parkinson's disease. Its cardiotoxic side effects require caution, particularly in elderly patients and when given intravenously at high doses (greater than 30 mg per day). A potential cardiac toxicity of domperidone is prolongation (lengthening) of the QT interval (a segment of the heart's electrical pattern). Domperidone use is associated with an increased risk of sudden cardiac death (70%), likely through its prolongation of the cardiac QT interval and ventricular arrhythmias. This is thought to be due to blockade of the hERG voltage-gated potassium channel. The risk is dose-dependent and appears greatest in elderly patients at high / very high doses administered intravenously, as well as with drugs that interact with domperidone and increase its circulating concentrations (i.e., CYP3A4 inhibitors). However, conflicting reports exist. In neonates and infants, QT prolongation is controversial and uncertain.

[0099] Anticancer drugs. Doxorubicin and anthracyclines exhibit QTc prolongation, increased QT dispersion, and the development of late potentials, indicating abnormal ventricular depolarization and repolarization induced by doxorubicin. Both QT dispersion and late potentials are known to be associated with serious ventricular rhythm disturbances and an increased risk of sudden death in various cardiac diseases.

[0100] Arsenic trioxide is an anti-leukemia drug that can prolong the QTc interval. Cardiac conduction abnormalities: Before initiating treatment, obtain a 12-lead ECG, 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 potentially fatal torsades de pointes-type ventricular arrhythmias. The risk of torsades de pointes is related to the degree of QT prolongation, concomitant administration of QT-prolonging drugs, a history of torsades de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that produce hypokalemia or hypomagnesemia. One patient (also receiving amphotericin B) developed torsades de pointes during induction treatment of recurrent APL with arsenic trioxide. Arsenic trioxide (As2O3), used to treat acute promyelocytic leukemia, reduced the hERG / IKr current not by direct blocking but by inhibiting hERG protein processing in the endoplasmic reticulum (ER), thereby attenuating hERG surface expression.

[0101] Opioid. Levomethadyl is the levorotatory isomer of α-methadyl acetate, a synthetic opioid structurally similar to methadone. It has a long duration of action due to its active metabolite. In 2001, levacetylmethadol was removed from the European market after reports of life-threatening ventricular rhythm disturbances.

[0102] Methadone is an opioid used to treat pain and drug addiction. Serious risks include opioid abuse, and cardiac arrhythmias, including prolonged QT, can also occur. The number of deaths in the United States associated with methadone intoxication was 4,418 in 2011, accounting for 26% of all deaths from opioid intoxication.

[0103] Lipid-lowering agent. Lovastatin, a drug used to reduce cholesterol, is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), an enzyme that catalyzes the conversion of HMG-CoA to mevalonate. Mevalonate is a required component of cholesterol biosynthesis, and lovastatin interferes with its production by acting as a reversible, competitive inhibitor of HMG-CoA binding to HMG-CoA reductase. Antipsychotic-associated QTc prolongation 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 potential for a drug interaction between quetiapine and lovastatin that could cause QTc prolongation during the management of dyslipidemia in patients with schizophrenia.

[0104] Probucol is an antihyperlipidemic drug originally developed for the treatment of coronary artery disease. Probucol is associated with QT interval prolongation. Probucol exacerbates long QT syndrome associated with a novel missense mutation, M124T, in the N-terminus of HERG.

[0105] Channelopathies. The human ether-a-go-go gene, associated with the cardiac tetrameric potassium channel, when mutated can sensitize patients to over 163 drugs that inhibit ion conduction and deregulate action potentials. Action potential prolongation follows the effect on potassium channels. Ion channel-active drugs can directly increase the QTc interval and increase the risk of torsades de pointes and sudden cardiac death. Increased sensitivity of cardiomyocyte potassium channels to drugs can also accompany metabolic disease states, including diabetes, or may be idiopathic in origin.

[0106] As used herein, the term "liposome" refers to a capsule whose wall or membrane is formed from 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 a specific, non-limiting example, the novel lipids form or are used in liposomes, which can be empty liposomes, formulated from a single type of phospholipid or a combination of phospholipids. In one embodiment, the liposomes can be empty liposomes that can further include one or more surface modifications, such as proteins, carbohydrates, glycolipids, or glycoproteins, and even nucleic acids, such as aptamers, thio-modified nucleic acids, protein nucleic acid mimics, protein mimics, and stealth agents. [Example]

[0107] Cardioprotection against cardiotoxic agents. The highly active chemotherapeutic agent doxorubicin is associated with acute but reversible cardiotoxic effects and a longer-term, dose-dependent cardiomyopathy characterized by minimal left ventricular dilation and global systolic dysfunction, often accompanied by moderate valvular regurgitation (Keefe, D. (2001). Anthracycline-induced cardiomyopathy. Seminars in oncology, 28(12), 2-7). More than half of all patients exposed to doxorubicin will develop cardiac dysfunction within 10-20 years following chemotherapy, and 5% of them will develop overt HF (Cardinale, DC (2010). Anthracycline-Induced Cardiomyopathy. Journal of the American College of Cardiology, 55(3), 213-220). The incidence of cardiomyopathy in patients treated with doxorubicin, here used as an adjuvant in combination with safer, albeit often less effective, therapies, is unclear. One such treatment is HERCEPTIN® (trastuzumab), a blockbuster humanized monoclonal antibody that targets the extracellular domain of HER2 in patients with breast cancer. However, HERCEPTIN treatment is also hampered by cardiac toxicity, in this case, a decline in left ventricular ejection fraction (LVEF), with reported morbidity rates of up to 27% (Bouwer, NJ-D. (2020). Cardiac monitoring in HER2-positive patients on trastuzumab treatment: A review and implications for clinical practice. The Breast, 52, 33-44).

[0108] Clinical studies have shown that the combination of doxorubicin and herceptin improves overall survival in 24-33% of breast cancer patients (Romond, EP (2005). Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. New England Journal of Medicine, 353, 1673-1684). Because doxorubicin-induced and herceptin-induced cardiomyopathy are largely irreversible and cumulative, finding ways to minimize the cardiac side effects of this combination is an important strategy if these highly potent oncology tools are to remain in clinical use.

[0109] Vitamin D, with its iron chelator, dexrazoxane, has been reported to provide some protection against anthracyclines (Lee, KW (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). The mechanism of protection is not fully understood but may involve prevention of oxidation within biological membranes. In this ongoing research project, rats and mice were used to evaluate the protection offered by an anti-inflammatory conjugated lipid (SPP05) that preferentially incorporates into cardiac muscle cell membranes.

[0110] 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 IPST IACUC. The IPST is accredited by AAALAC.

[0111] Test System and Treatment: Adult female C57 / BL6 mice (n=10 / group) weighing 25 grams at the start of the study were administered 24 mg / kg DOX ip for 2 weeks. Following a 1-week rest period, 10 mg / kg HER ip was administered for 2 weeks. In parallel, an anti-inflammatory lipid (SPP05) was administered to one group of animals at 10 mg / kg / day and to the other group at 50 mg / kg, beginning on day -10 and continuing throughout the project.

[0112] Experimental endpoints. Body weights were measured weekly.

[0113] Echocardiography was performed on days -10, 14, and 42, and on day 49, using a Vivid 9 and 13 MHz linear probe. Blood samples were taken on days -7, 0, 21, and 49. Invasive hemodynamics was measured by cannulating the left ventricle with a fluid-filled PE15 catheter connected to a Millar pressure transducer.

[0114] Troponin I, NT-Pro-BNP and caspase-3 activity were measured by Q-ELISA.

[0115] Histological examination of the heart and liver was performed following fixation in 10% NBF, histological examination, and staining with H&E and picrosirius red.

[0116] Doxorubicin in combination with Herceptin was considered the standard of care for patients with HER-2-expressing breast cancer until the incidence of drug-induced heart failure prompted a shift in clinical approach. In this mouse model, Doxo+Herc animals exhibited LV systolic dysfunction as evidenced by reduced ejection fraction, stroke volume, left ventricular fractional shortening, and pulse pressure. Furthermore, Doxo+Herc animals also exhibited LV tissue loss, both globally and at end-systole and end-diastole. Finally, the biomarker HF NT-Pro-BNP levels were higher in Doxo+Herc compared with healthy (sham) animals.

[0117] Treatment of animals with SP005, an anti-inflammatory conjugated lipid with known membrane-altering properties, partially prevented the damage caused by oncological treatment in female mice. Given the mechanism of toxicity with Doxo+Herc, it is hypothesized that prevention of sphingomyelinase activation by reactive oxygen species is involved in the protection afforded by SP005.

[0118] FIG. 1 shows the effect of Compound I on QT prolongation when used with moxifloxacin.

[0119] FIG. 2 shows an outline of a 9-week study to determine the cardioprotective effects of lipids.

[0120] FIG. 3 shows M-mode echocardiographic images comparing the effects of sham treatment, doxorubicin and trastuzumab, and treatment with doxorubicin and trastuzumab plus lipid SP005.

[0121] FIG. 4 shows left ventricular pressure recordings comparing sham treatment, doxorubicin and trastuzumab, and treatment with doxorubicin and trastuzumab plus lipid SP005 at two concentrations, 10 mg.kg and 50 mg / kg.

[0122] 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), percent left ventricular fractional shortening (Figure 5E), N-terminal (NT) prohormone BNP (NT-proBNP) at day 49 (Figure 5F), anterior wall thickness at end diastole (AWT-ED) (mm) (Figure 5G), anterior wall thickness at end systole (AWT-ES) (mm) (Figure 5H), and left ventricular mass (echo) (Figure 5I).

[0123] The novel lipids of the present invention may be prepared in their native form or in the form of their salts, hydrates or solvates. Salts further include, by way of example only, lithium, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.

[0124] In at least some embodiments of the present invention, compounds of Formula I are prepared according to the following schemes: For reference, all variables contained in the schemes below relate to the corresponding variables generally defined above. Those skilled in the art will recognize that alternative reagents and reactants can be used to produce the same target compounds and intermediates. [ka]

[0125] It is contemplated that any embodiment discussed herein can be practiced with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, the compositions of the invention can be used to achieve the methods of the invention.

[0126] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes and equivalents will occur to those skilled in the art. It is therefore to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention. [Example]

[0127] (2R)-3-(((2,3-bis((3-aminopropanoyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl ditetradecanoate hydrochloride (Compound 35) [ka] Step 1: Sodium 2,3-bis((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate. To a stirred solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (10.30 g, 54.4 mmol, 2.5 equiv) in DCM (325 mL) was added dicyclohexylmethanediimine (13.48 g, 65.3 mmol, 3 equiv) at RT and stirred for 30 min. 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 at RT. The reaction mixture was stirred at RT for 16 h and monitored by LCMS. Upon completion, the reaction mixture was diluted with DCM (100 mL), stirred for 10 min, and filtered. The filtrate was washed with water (100 ml × 1), 0.5 N HCl (50 ml × 1), and 10% NaHCO3 (50 ml × 1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 24.2 g of crude product. The crude product was purified by column chromatography using basic 230-400 mesh silica gel (pre-basified using ammonia). The product was eluted with 0%-10% methanol in ethyl acetate. The pure fractions were collected and concentrated to give 11.8 gm of pure product. The 11.8 gm product was dissolved in DCM (200 ml) and washed with 0.5 N HCl (50 ml × 2), 10% NaHCO3 solution (50 ml × 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, 47.35% yield) as a pale yellow syrup.

[0128] 1H NMR(400MHz,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=6.5,12.8Hz,2H), 3.74(br dd,J=6.0,12.0Hz,4H), 3.22~3.08(m,4H), 2.42(br t,J=6.8Hz,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:Mol.Formula:C 50 H 92 N2NaO 16 P, Formula mass: 1031.25, Exact mass: 1008.63, Observed mass: 1009.7[M+1] + , RT=3.49 min, Purity: 98.40%. Method: Mobile phase A: 1 ml of 25% ammonia solution in 1000 ml of MilliQ water (pH: 9 with acetic acid). Mobile phase B: acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 μm.

[0129] Step 2: (2R)-3-(((2,3-bis((3-aminopropanoyl)oxy)propoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl ditetradecanoate hydrochloride. To a stirred solution of sodium 2,3-bis((3-((tert-butoxycarbonyl)amino)propanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (6 g, 5.82 mmol) in DCM (60 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 30 ml, 120 mmol) at 0 °C. The reaction mixture was stirred at 10-15 °C for 2.5 h and monitored by LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure at RT. 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-diylditetradecanoate dihydrochloride (4.9 g, 99.62% yield) as an off-white solid.

[0130] 1 H NMR(400MHz,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=5.8Hz,4H), 2.74(dt,J=3.2,6.5Hz,4H), 2.33~2.22(m,4H), 1.60~1.43(m,4H), 1.24(s,40H), 0.91~0.80(m,6H). LCMS:Mol.Formula:C 40 H 78 ClNO 12 P, Formula mass: 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 with acetic acid). Mobile phase B: acetonitrile. Flow rate: 1.0 ml / min. Column: XBridge C8 (50 x 4.6) mm, 3.5 μm. HPLC: RT = 6.60 min; Purity: 99.98%. Column: XBridge C8 (50 x 4.6) mm, 3.5 μm, Mobile phase A: 0.1% TFA in water, Mobile phase B: acetonitrile, Flow rate: 2.0 ml / min. [Example]

[0131] Cardiac response testing. Efficacy evaluation of compounds of the present invention involved ECG measurements in adult male Hartley guinea pigs, recording PR, QRS, QT, QTc, JT, and RR. In a typical experiment, a subcutaneous Kaha TR50B biopotential telemeter was surgically implanted in adult male Hartley guinea pigs weighing 300-350 g at enrollment. One lead was sutured to the apex of the heart, while another lead was sutured to the lateral side of the aorta. Animals were allowed to recover from surgery for 5 days before being returned to the test colony. Following recovery, animals underwent two rounds of evaluation as follows:

[0132] In Round 1 of the study, baseline ECG recordings were obtained for 5 minutes before the animals were exposed to a single oral dose of moxifloxacin (20 mg / kg), administered orally to eight guinea pigs. ECG signals were acquired continuously for 6 hours after administration of moxifloxacin. The animals were then returned to their homes and the drug was allowed to wash out over 5-7 days.

[0133] In Round 2 of the study, eight guinea pigs were given baseline ECGs for 5 minutes, and these baseline intervals were compared to those measured before the first exposure to moxifloxacin (above). Animals were administered a single oral dose of 2 mg / kg of a test compound (selected from Compounds 1-12). Concurrently, six animals were given the same batch of moxifloxacin (20 mg / kg) by oral gavage. Two additional animals received moxifloxacin (20 mg / kg) alone. The purpose of administering moxifloxacin alone to these animals was to verify whether a second exposure to moxifloxacin could result in enhanced QT prolongation. ECGs were obtained continuously for 6 hours. The animals were then returned to their homes and allowed to wash out of the drug over a 5-7 day period.

[0134] ECG analysis for 5 minutes pre-dose and 6 hours post-dose was automated based on a pattern recognition algorithm. Analyzed data were binned into 5-minute segments. Intervals such as PR, QRS, QT, QTc, JT, and RR were automatically analyzed using LabChart Pro v8 (AD Instruments). Measurement accuracy was manually verified using a digital cursor by randomly selecting 3 to 5 segments at a given post-dose time. Outside of arrhythmia episodes, there was no significant discrepancy between the automated and manual intervals. Arrhythmic frequency was quantified and expressed as the percentage of ECG time spent in abnormal sinus rhythm over the entire duration of the recording.

[0135] The following table lists the protection observed by test compounds against moxifloxacin-induced QTc prolongation. [Table 1]

[0136] It will be understood that the specific embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.

[0137] All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0138] All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations can be applied to the compositions and / or methods, and to the steps or sequence of steps of the methods, described herein without departing from the concept, spirit, and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the invention as defined by the appended claims.

[0139] To assist the Patent Office, and any reader of any patent that may issue on this application, in interpreting the claims appended hereto, Applicant wishes to note that it does not intend that paragraph 6 of 35 U.S.C. § 112, paragraph (f) of 35 U.S.C. § 112, or any equivalent, as existing on the filing date of this application, apply to any of the appended claims, unless the words "means for" or "step for" are expressly used in a particular claim.

[0140] In each claim, each dependent claim may depend on both the independent claim and each preceding dependent claim, provided that the preceding claim indicates the proper antecedent basis for a claim term or element, for each and every claim.

[0141] (References) 1. Bouwer, NJ-D. (2020). Cardiac monitoring in HER2-positive patients on trastuzumab treatment: A review and implications for clinical practice. The Breast, 52, 33-44. 2. Cardinale, D. C. (2010). Anthracycline-Induced Cardiomyopathy. Journal of the American College of Cardiology, 55(3), 213-220. 3. Keefe, D. (2001). Anthracycline-induced cardiomyopathy. Seminars in oncology, 28(12), 2-7. 4. 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. 5. Romond, E. P. (2005). Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. New England Journal of Medicine, 353, 1673-1684. 6. 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. Compounds of Formula I 【Chemical 1】 or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is formulated into a pharmaceutical composition.

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

4. 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, and dabrafenib. Phenib, 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 acetaminophen, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, melipramine, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl, lisdexamfetamine, lithium, mesoridazine, metaproterenol, methadone, methapterone amphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perflutren lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol,Procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salbutamol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, terap 10. The compound of claim 1, further comprising one or more agents that induce cardiac disease as a side effect selected from at least one of levir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfa, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, or ziprasidone.

5. 10. The compound of claim 1, wherein the pharmaceutical composition further comprises one or more excipients, binders, anti-adherents, coatings, disintegrating tablets, fillers, flavors, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums, and milk derivatives, or combinations thereof.

6. 10. The compound of claim 1, wherein the amount per unit dose of the pharmaceutical composition comprises 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, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 mg of the compound of Formula I per unit dose.

7. 10. The compound of claim 1, wherein the pharmaceutical composition is a formulation for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration.

8. 10. The compound of claim 1, wherein the formulation for oral administration is a tablet, capsule, caplet, pill, powder, troche, lozenge, slurry, liquid, suspension, emulsion, elixir, or oral thin film (OTF), which may be in solid form, solution, suspension, or softgel form.

9. Formula I 【Chemistry 2】 1. A method for preparing a compound of formula (I), comprising: 【Chemistry 3】 A method comprising:

10. Formula I 【Chemistry 4】 and a pharmaceutically acceptable diluent or carrier, or a pharmaceutically acceptable salt thereof.

11. 11. The pharmaceutical composition of claim 10, wherein the compound of formula I is present as a single entity, a solvate, a hydrate, a crystal, an amorphous solid, a liquid, or an oil.

12. 11. The pharmaceutical composition of claim 10, further comprising one or more agents that induce heart disease as a side effect.

13. 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, and dabrafenib. Phenib, 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 acetaminophen, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, melipramine, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl, lisdexamfetamine, lithium, mesoridazine, metaproterenol, methadone, methapterone amphetamine, methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine, norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perflutren lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol,Procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salbutamol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir 11. The pharmaceutical composition of claim 10, further comprising one or more agents that induce cardiac disease as a side effect, selected from at least one of vir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfa, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, or ziprasidone.

14. 11. The pharmaceutical composition of claim 10, further comprising one or more excipients, binders, anti-adherents, coatings, disintegrating tablets, fillers, flavors, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, hydroxypropyl methylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid copolymers, pharmaceutical glazes, gums and milk derivatives, or combinations thereof.

15. 11. The pharmaceutical composition of claim 10, wherein the amount per unit dose of the pharmaceutical composition comprises 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, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 mg of the compound of Formula I per unit dose.

16. 11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is a formulation for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration.

17. 11. The pharmaceutical composition of claim 10, wherein the formulation for oral administration is a tablet, capsule, caplet, pill, powder, troche, lozenge, slurry, liquid, suspension, emulsion, elixir or oral thin film (OTF), which may be in solid form, solution, suspension or softgel form.

18. A method of reducing or eliminating one or more of cardiac channelopathies, myocardial damage, or conditions resulting from irregularities or alterations in cardiac pattern in a human or animal subject, comprising administering to said human or animal subject one or more compounds of formula I. 【Chemistry 5】 or a pharmaceutically acceptable salt thereof.

19. When the compound of formula I is: Exists as a single entity, solvate, hydrate, crystal, amorphous solid, liquid or oil; reducing or eliminating one or more of the conditions resulting from cardiac channelopathies or irregularities or changes in cardiac patterns caused by active agents used to treat the disease; 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, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 mg per unit dose; or or formulated for oral, sublingual, transdermal, suppository, intrathecal, enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscular administration, wherein the compound of Formula I is formulated for oral administration as a tablet, capsule, caplet, pill, powder, troche, lozenge, slurry, liquid, suspension, emulsion, elixir, or oral thin film (OTF), solid form, solution, suspension, or softgel form; or the solid form may further comprise one or more excipients, binders, antiadherents, coatings, disintegrating tablets, fillers, flavors, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, or combinations thereof.

19. The method of claim 18, wherein the at least one of

20. 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. One or more active agents that induce cardiac disease as a side effect are: 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, chloramphenicol ... Rosapine, 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, fin Golimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, melipramine, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl, lisdexamfetamine, 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, perflutren, phentermine, phenylephrine, phenylpropanolamine, pimozide,Posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salbutamol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, Sparf loxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfamethasone, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat or ziprasidone, 21. The method of claim 20, wherein the at least one of

22. 21. The method of claim 20, wherein the compound of formula I reduces or eliminates cardiac pathology, such as QT prolongation, myocardial damage or AV block, whether drug-induced or caused by a disease or condition.

23. 1. A method for reducing or eliminating the cardiotoxic or cardiac effects of one or more active agents, comprising: administering to a subject in need of treatment for a disease or disorder one or more active agents that are cardiotoxic; and An effective amount of one or more lipids is used to reduce or eliminate the cardiotoxic effect of one or more active agents, wherein the lipid has the formula: 【Chemistry 6】 20. The method of claim 19, further comprising administering a combination therapy comprising:

24. Cardiotoxic or cardiac: Minimal left ventricular dilation, systolic dysfunction, moderate valvular regurgitation, reduced left ventricular ejection fraction (LVEF), cardiac hypertrophy, reduced cardiac contractility, reduced cardiac output, pressure-overload and volume-overload cardiac hypertrophy, myocardial dysfunction, cardiac remodeling, post-myocardial infarction heart failure or heart disease 24. The method of claim 23, wherein the at least one of

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

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

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

28. 24. The method of claim 23, wherein the compound and / or one or more active agents are injected over a period of 3 hours.

29. One or more agents that induce cardiotoxic or cardiac effects include: 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 fluconazole, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, fosphenytoin, furosemide, frusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halofantrine, haloperidol, hydrochlorothiazide, ibutilide, iloperidone, imipramine, melipramine, indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levomethadyl, lisdexamin methamphetamine, 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, perflutrenone lipid microspheres, phentermine, phenylephrine,Phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salbutamol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin 24. The method of claim 23, wherein the antiviral agent is selected from at least one of fluconazole, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfa, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, or ziprasidone.

30. 24. The method of claim 23, wherein the pharmaceutical composition comprising one or more lipids further comprises one or more excipients, binders, anti-adherents, coatings, disintegrating tablets, fillers, flavors, dyes, colorants, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, or combinations thereof.

31. 24. The method of claim 23, wherein the amount per unit dose of the pharmaceutical composition comprises 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, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000 milligrams of the compound of Formula I per unit dose.

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

33. 24. The method of claim 23, wherein the formulation for oral administration is a tablet, capsule, caplet, pill, powder, troche, lozenge, slurry, solution, suspension, emulsion, elixir, or oral thin film (OTF).

34. 24. The method of claim 23, wherein the formulation is in solid form, solution, suspension or softgel form. 【Chemistry 7】 。

35. 1. A method of reducing or eliminating the cardiotoxic effects of one or more antiproliferative agents, comprising: administering to a subject in need of treatment for a proliferative disorder one or more antiproliferative agents that are cardiotoxic; and using an effective amount of one or more lipids that reduces or eliminates the cardiotoxic effects of one or more antiproliferative agents; The lipid has the formula: 【Chemistry 8】 or a pharmaceutically acceptable salt thereof.

36. 36. The method of claim 35, wherein the one or more antiproliferative agents are selected from doxorubicin, trastuzumab, or both.

37. 36. The method of claim 35, wherein the one or more antiproliferative agents and the lipid are administered simultaneously.

38. 36. The method of claim 35, wherein the one or more antiproliferative agents and lipids are administered orally or intravenously.

39. 36. The method of claim 35, wherein the one or more lipids, the one or more antiproliferative agents, or both are injected over a period of 3 hours.

40. 36. The method of claim 35, wherein the one or more antiproliferative agents that induce cardiac disease as a side effect are selected from at least one of: bosutinib, crizotinib, dabrafenib, dasatinib, doxorubicin, lapatinib, nilotinib, sorafenib, sunitinib, vandetanib, or vemurafenib.

41. The lipids 【Chemistry 9】 36. The method of claim 35, wherein:

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