Compositions and methods for increasing the efficiency of cardiac metabolism

Abstract

To provide a method for enhancing metabolic efficiency of the heart SOLUTION: Compositions and methods for increasing metabolic efficiency of the heart are provided. The present invention provides compositions that stimulate cardiac glucose oxidation and mitochondrial respiration. The composition comprises a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, such as trimetazidine, and a compound that promotes mitochondrial respiration, such as succinate. The compositions may also include molecules such as nicotinic acid, which serves as a precursor for nicotinamide adenine dinucleotide (NAD +) synthesis and also facilitates mitochondrial respiration. Preferably, the composition comprises a compound in which the trimetazidine derivative, the succinate and optionally the NAD + precursor are covalently linked in a single molecule.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 647,926, filed March 26, 2018, U.S. Provisional Patent Application No. 62 / 637,434, filed March 2, 2018, U.S. Provisional Patent Application No. 62 / 710,316, filed February 16, 2018, U.S. Provisional Patent Application No. 62 / 524,237, filed June 23, 2017, and U.S. Provisional Patent Application No. 62 / 522,214, filed June 20, 2017, the contents of each of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION FIELD OF THE INVENTION This application relates to compositions and methods for increasing cardiac metabolic efficiency. [Background technology]

[0003] Heart disease is a leading cause of death worldwide, accounting for 15 million deaths worldwide in 2015. In many forms of heart disease, decreased cardiac efficiency results from alterations in mitochondrial energy metabolism. Mitochondria are intracellular compartments where glucose- and fatty acid-derived metabolites are oxidized to produce high-energy molecules. As fatty acid oxidation increases in the heart, glucose oxidation decreases, and vice versa. Although glucose oxidation is a more efficient energy source, fatty acid oxidation predominates in cardiac mitochondria in certain types of heart disease, such as heart failure, ischemic heart disease, and diabetic cardiomyopathy. As a result, the heart's pumping capacity decreases.

[0004] Existing drugs that correct the balance between glucose and fatty acid oxidation in cardiac mitochondria have significant drawbacks. Chief among these is that they address only part of the problem. Relying on fatty acid oxidation instead of glucose oxidation reduces the efficiency of energy production by 10%, yet patients with heart disease often exhibit up to a 30% reduction in cardiac efficiency. Consequently, existing approaches to improving cardiac function by altering mitochondrial metabolism are inadequate, and millions of people continue to die from heart disease each year. Summary of the Invention [Means for solving the problem]

[0005] The present invention provides a composition for stimulating cardiac glucose oxidation and mitochondrial respiration. The composition includes a compound, such as trimetazidine, that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, and a compound, such as succinate, that promotes mitochondrial respiration. The composition stimulates nicotinamide adenine dinucleotide (NAD) oxidation and mitochondrial respiration. + The composition may also include molecules such as nicotinic acid, which serves as a precursor for NAD synthesis and also facilitates mitochondrial respiration. + Preferably, the compounds include compounds in which the precursors are covalently linked in a single molecule. Such compounds, when metabolized in the body, allow the individual components to exert different biochemical effects, such as increasing glucose oxidation relative to fatty acid oxidation and improving overall mitochondrial respiration in the heart. The present invention also provides a method for altering cardiac metabolism by providing the compounds of the present invention.

[0006] The composition also shifts cardiac metabolism toward glucose oxidation and increases mitochondrial respiration, making it useful as a therapeutic agent for treating cardiac diseases characterized by elevated fatty acid oxidation, such as heart failure, ischemic heart disease, and diabetic cardiomyopathy. By shifting cardiac metabolism from fatty acid oxidation to glucose oxidation, the composition promotes more efficient use of energy sources. In addition, the compositions stimulate metabolic pathways common to both glucose and fatty acid oxidation, which may be impaired in patients with heart disease. Some compositions of the present invention comprise a compound comprising trimetazidine covalently linked to one or more activators of mitochondrial respiration.

[0007] Additionally, trimetazidine may induce Parkinson's-like symptoms in a portion of the population. Without being limited to a particular theory or mechanism of action, it is believed that delivering trimetazidine as a component of a larger molecule may improve its efficacy and mitigate its side effects.

[0008] In one aspect, the present invention provides a compound of formula (I): ALB (I) wherein A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, L is a linker, and B is a compound that promotes mitochondrial respiration.

[0009] The compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation can be trimetazidine, etomoxir, perhexiline, a PPAR agonist, a malonyl CoA decarboxylase inhibitor, or dichloroacetate.

[0010] The compound that promotes mitochondrial respiration can be a citric acid cycle intermediate or a molecule that can be metabolized into the citric acid cycle. For example, the compound can be succinate, fumarate, malate, oxaloacetate, citrate, isocitrate, α-ketoglutarate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, or β-hydroxypentanoate.

[0011] The linker can be any suitable linker that can be cleaved in vivo. The linker can be an alkoxy group. The linker can be polyethylene glycol of any length. The linker can be (CH2CH2O) xwhere x=1 to 15 is preferred.

[0012] The compound contains NAD that is covalently linked to another component of the compound. + May contain precursor molecules. NAD + The precursor molecule can be nicotinic acid, nicotinamide, or nicotinamide riboside. NAD + The precursor molecule may be linked to a compound that shifts cardiac metabolism, a compound that promotes mitochondrial respiration, or a linker. + The precursor molecule may be linked to another component via an additional linker. + Preferably, the precursor molecule is attached to a compound that promotes mitochondrial respiration via a 1,3-propanediol linkage.

[0013] The compound of formula (I) may be a compound of formula (II): [ka] (y=1 to 3).

[0014] The compound of formula (I) may be represented by formula (III): [ka] (y=1 to 3).

[0015] In another aspect, the present invention includes compounds represented by formula (IV). [ka] In the formula, R 1 , R 2 , and R 3 are independently H or a (C1-C4) alkyl group, and R 4 and R 5 are taken together to form =O, -O(CH2) m O- or -(CH2) m - and m=2 to 4, or R4 is H and R 5 is OR 14 , S.R. 14 , or (CH2CH2O) n H and R 14 is H or a (C1-C4) alkyl group, n=1-15, and R 6 is a monocyclic or polycyclic structure optionally substituted with heteroatoms at one or more ring positions, and each ring position optionally contains one or more substituents.

[0016] R 6 One or more ring positions of may contain a substituent that includes a compound that promotes mitochondrial respiration, such as succinate, fumarate, malate, oxaloacetate, citrate, isocitrate, α-ketoglutarate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, or β-hydroxypentanoate. The substituent is (CHCHO). x (where x=1 to 15) may be included. The substituent may be an NAD such as nicotinic acid, nicotinamide, or nicotinamide riboside. + It may also contain precursor molecules.

[0017] R 6 The substituents on the ring positions of [ka] (y=1 to 3)

[0018] R 6 The substituents on the ring positions of [ka] (y=1 to 3)

[0019] R 6 teeth, [ka] It may be the case.

[0020] The compound of formula (IV) may be represented by formula (IX) or formula (X): [ka] The polymer may have a structure represented by:

[0021] In another aspect, the present invention provides a compound of formula (V): [ka] The compound includes a compound represented by In the formula, R 1 , R 2 , and R 3 are independently H or a (C1-C4) alkyl group, and R 4 and R 8 are taken together to form =O, -O(CH2) m O- or -(CH2) m - and m=2 to 4, or R 4 is H and R 8 H, OR 14 , S.R. 14 , or (CH2CH2O) n H and R 14 is H or a (C1-C4) alkyl group, n=1-15, and R 9 , R 10 , R 12 , and R 13 are independently H or (CH2CH2O) z H, z=1 to 6, and R 11 contains compounds that promote mitochondrial respiration.

[0022] The compound that promotes mitochondrial respiration can be an intermediate of the citric acid cycle or a molecule that can be metabolized into the citric acid cycle. For example, the compound can be succinate, fumarate, malate, oxaloacetate, citrate, isocitrate, α-ketoglutarate, or the like. The hydroxybutyrate may be β-hydroxypentanoate, β-ketopentanoate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, or β-hydroxypentanoate.

[0023] R 11 may include a linker such as polyethylene glycol. For example, R 11 is (CH2CH2O) x (x=1 to 15) may be included.

[0024] R 11 teeth, [ka] (y=1~3) may occur.

[0025] R 11 is NAD + It may also contain precursor molecules, for example, R 11 may contain nicotinic acid, nicotinamide, or nicotinamide riboside.

[0026] R 11 teeth, [ka] (y=1~3) may occur.

[0027] In one aspect, the present invention provides a compound of formula (VII): AC (VII) where A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, and C is a compound that inhibits NAD + The precursor molecule includes a compound, A and C, which may be covalently linked.

[0028] The compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation can be trimetazidine, etomoxir, perhexiline, a PPAR agonist, a malonyl CoA decarboxylase inhibitor, or dichloroacetate.

[0029] The compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation may be PEGylated with an ethylene glycol moiety. The compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation may also have multiple ethylene glycol moieties, such as one, two, three, four, five, or more ethylene glycol moieties. The ethylene glycol moiety is (CH2CHO) x (x = 1 to 15). The ethylene glycol moiety is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation and NAD + The ethylene glycol moiety can form a covalent linkage between precursor molecules and NAD compounds that shift cardiac metabolism from fatty acid oxidation to glucose oxidation. + The covalent linkage between the precursor molecules may be separate. The compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation may be a PEGylated form of trimetazidine.

[0030] NAD + The precursor molecule can be nicotinic acid, nicotinamide, or nicotinamide riboside.

[0031] The compound of formula (VII) may comprise nicotinic acid covalently linked to a PEGylated form of trimetazidine. The nicotinic acid may be covalently linked via the PEGylated moiety, i.e., via an ethylene glycol linkage. The nicotinic acid may also be covalently linked via the trimetazidine moiety.

[0032] Compounds of formula (VII) may also have a structure represented by formula (X) as shown above.

[0033] In one aspect, the present invention provides a compound of formula (VIII): ALC (VIII) wherein A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, L is a linker, and C is an NAD +A may be covalently linked to L, and L may be covalently linked to C, which is a precursor molecule.

[0034] Compounds, linkers, and NAD that shift cardiac metabolism from fatty acid oxidation to glucose oxidation + The precursor molecules may be as described above for compounds of other formulas.

[0035] Compounds of formula (VIII) may also have a structure represented by formula (X) as shown above.

[0036] Any of the above compounds may contain one or more atoms that are isotopically enriched. For example, a compound may have one or more hydrogen atoms replaced with deuterium or tritium. The isotopically enriched atoms may be located at any position within the compound.

[0037] In one aspect, the invention relates to a method for treating cardiac neuropathy comprising administering to a subject at least two compounds: A, B, and C, wherein A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation as described above; B is a compound that promotes mitochondrial respiration as described above; and C is a compound that promotes NAD oxidation as described above. + The present invention includes a composition that is a precursor molecule. The composition may include components A, B, and C. Components A, B, and C may each be provided as separate molecules, or two or more of the components may be covalently linked in a single molecule. For example, components A and B may be covalently linked in a single molecule, and C may be provided as a separate molecule.

[0038] The composition may also include a co-crystal of two or more separate molecules, including two or more of components A, B, and C. For example, the co-crystal may include (1) a compound of formula (I), (III), (IV), or (V) and (2) nicotinic acid, nicotinamide, or nicotinamide riboside. Preferably, the co-crystal includes nicotinamide.

[0039] In one aspect, the present invention includes a method for increasing cardiac metabolic efficiency in a subject. The method includes providing a compound represented by formula (I) as described above. In the method, the compound of formula (I) may include any of the features described above for the compounds of the present invention.

[0040] In one aspect, the invention includes a method of increasing cardiac metabolic efficiency in a subject, the method comprising: Compounds that shift cardiac metabolism from fatty acid oxidation to glucose oxidation, compounds that promote mitochondrial respiration, and, if necessary, NAD + This involves providing a compound that is a precursor molecule.

[0041] The compound that shifts cardiac metabolism from fatty acid oxidation to glucose can be trimetazidine, etomoxir, perhexiline, a PPAR agonist, a malonyl CoA decarboxylase inhibitor, or dichloroacetate.

[0042] The compound that promotes mitochondrial respiration can be a citric acid cycle intermediate or a molecule that can be metabolized into the citric acid cycle, such as citrate, fumarate, malate, oxaloacetate, citrate, isocitrate, α-ketoglutarate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, or β-hydroxypentanoate.

[0043] NAD + The precursor molecule can be nicotinic acid, nicotinamide, or nicotinamide riboside.

[0044] The compounds can be provided in any suitable manner. The compounds may be provided in a single composition. Alternatively, the compounds may not be provided in a single composition. For example, one or two of the compounds may be provided in a single composition, and another compound may be provided in a separate composition. Alternatively, each compound may be provided in a separate composition. The compounds can be provided simultaneously or sequentially. The compounds can be provided at different intervals, at different frequencies, or in different amounts.

[0045] Any disease that can be treated by using trimetazidine will benefit from the compound of the present invention as described herein, and the results will be more effective and side effects will be less.Typical diseases are those that involve the impaired mitochondrial function or the altered fatty acid oxidation, such as heart failure disease, cardiac dysfunction disease, muscle myopathy disease, etc.Typical methods include the administration of the composition as described herein, or a compound that shifts cardiac metabolism from fatty acid oxidation to glucose metabolism, a compound that promotes mitochondrial respiration, and / or a compound that optionally increases NAD + This includes providing any combination of precursor molecules. [Brief explanation of the drawings]

[0046] [Figure 1] FIG. 1 is a table summarizing the effects of various compounds on mitochondrial function. [Figure 2] FIG. 2 is a table summarizing the effects of nicotinamide on various parameters of mitochondrial function. [Figure 3] FIG. 3 is a series of graphs showing the effect of nicotinamide on oxygen consumption rate and reserve capacity. [Figure 4] FIG. 4 is a series of graphs showing the effect of nicotinamide on extracellular acidification rate. [Figure 5]FIG. 5 is a table summarizing the effects of the combination of trimetazidine and nicotinamide on various parameters of mitochondrial function. [Figure 6] FIG. 6 is a series of graphs showing the effect of a combination of trimetazidine and nicotinamide on oxygen consumption rate and reserve capacity. [Figure 7] FIG. 7 is a series of graphs showing the effect of a combination of trimetazidine and nicotinamide on extracellular acidification rate. [Figure 8] FIG. 8 is a table summarizing the effects of succinate on various mitochondrial function parameters. [Figure 9] FIG. 9 is a series of graphs showing the effect of succinate on oxygen consumption rate and reserve capacity. [Figure 10] FIG. 10 is a series of graphs showing the effect of succinate on extracellular acidification rate. [Figure 11] FIG. 11 is a table summarizing the effects of compound CV-8816 on various mitochondrial function parameters. [Figure 12] FIG. 12 is a series of graphs showing the effect of compound CV-8816 on oxygen consumption rate and reserve capacity. [Figure 13] FIG. 13 is a series of graphs showing the effect of compound CV-8816 on extracellular acidification rate. [Figure 14] FIG. 14 is a table summarizing the effects of compound CV-8814 on various mitochondrial function parameters. [Figure 15] FIG. 15 is a series of graphs showing the effect of compound CV-8814 on oxygen consumption rate and reserve capacity. [Figure 16] FIG. 16 is a series of graphs showing the effect of compound CV-8814 on extracellular acidification rate. [Figure 17] FIG. 17 is a table summarizing the effects of trimetazidine on various mitochondrial function parameters. [Figure 18]FIG. 18 is a series of graphs showing the effect of trimetazidine on oxygen consumption rate and reserve capacity. [Figure 19] FIG. 19 is a series of graphs showing the effect of trimetazidine on extracellular acidification rate. [Figure 20] FIG. 20 is a table summarizing the effects of compound CV-8815 on various mitochondrial function parameters. [Figure 21] FIG. 21 is a series of graphs showing the effect of compound CV-8815 on oxygen consumption rate and reserve capacity. [Figure 22] FIG. 22 is a series of graphs showing the effect of compound CV-8815 on extracellular acidification rate. [Figure 23] FIG. 23 is a table summarizing the effects of a combination of succinate, nicotinamide, and trimetazidine on various parameters of mitochondrial function. [Figure 24] FIG. 24 is a series of graphs showing the effect of a combination of succinate, nicotinamide and trimetazidine on oxygen consumption rate and reserve capacity. [Figure 25] FIG. 25 is a series of graphs showing the effect of a combination of succinate, nicotinamide and trimetazidine on extracellular acidification rate. [Figure 26] FIG. 26 is a table summarizing the effects of the combination of trimetazidine analog 2 and nicotinamide on various mitochondrial function parameters. [Figure 27] FIG. 27 is a series of graphs showing the effect of a combination of trimetazidine analog 2 and nicotinamide on oxygen consumption rate and reserve capacity. [Figure 28] FIG. 28 is a series of graphs showing the effect of a combination of trimetazidine analog 2 and nicotinamide on extracellular acidification rate. [Figure 29] FIG. 29 is a table summarizing the effects of the combination of trimetazidine analog 1 and nicotinamide on various mitochondrial function parameters. [Figure 30]FIG. 30 is a series of graphs showing the effect of a combination of trimetazidine analog 1 and nicotinamide on oxygen consumption rate and reserve capacity. [Figure 31] FIG. 31 is a series of graphs showing the effect of a combination of trimetazidine analog 1 and nicotinamide on extracellular acidification rate. [Figure 32] FIG. 32 is a table summarizing the effects of the combination of trimetazidine analog 3 and nicotinamide on various mitochondrial function parameters. [Figure 33] FIG. 33 is a series of graphs showing the effect of a combination of trimetazidine analog 3 and nicotinamide on oxygen consumption rate and reserve capacity. [Figure 34] FIG. 34 is a series of graphs showing the effect of the combination of trimetazidine analog 3 and nicotinamide on extracellular acidification rate. [Figure 35] FIG. 35 is a table summarizing the effects of succinate and nicotinamide combinations on various mitochondrial function parameters. [Figure 36] FIG. 36 is a series of graphs showing the effect of a combination of succinate and nicotinamide on oxygen consumption rate and reserve capacity. [Figure 37] FIG. 37 is a series of graphs showing the effect of a combination of succinate and nicotinamide on extracellular acidification rate. [Figure 38] FIG. 38 is a schematic representation of the ischemia-reperfusion (IR) method used to analyze the effects of the compositions of the present invention on coronary flow. [Figure 39] FIG. 39 is a graph of coronary blood flow after IR. [Figure 40] FIG. 40 is a graph of peak left ventricular pressure (LVDP) after IR. [Figure 41] FIG. 41 shows images of TTC stained heart sections after IR. [Figure 42] Figure 42 is a graph of infarct size after IR. [Figure 43]FIG. 43 is a schematic representation of the method used to analyze the effect of compositions of the present invention on cardiac function. [Figure 44] FIG. 44 is an image showing a heart from a mouse 6 weeks after aortic coarctation surgery. [Figure 45] FIG. 45 is a graph of heart weight versus body weight 6 weeks after aortic coarctation surgery. [Figure 46] FIG. 46 is a graph of heart weight 6 weeks after aortic coarctation surgery. [Figure 47] FIG. 47 is a graph of fractional shortening (FS) and ejection fraction (EF) at the indicated post-coarctation time points. [Figure 48] FIG. 48 is a graph of left ventricular end-systolic diameter at the indicated post-aortic coarctation time points. [Figure 49] FIG. 49 is a graph of intraventricular septal dimension at indicated post-coarctation time points. [Figure 50] FIG. 50 is a graph of left ventricular mass at indicated post-coarctation time points. [Figure 51] FIG. 51 is a graph of isovolumic relaxation time at indicated time points after aortic coarctation surgery. [Figure 52] FIG. 52 is a graph of the ratio of early to late diastolic peak velocity flow at the indicated post-aortic coarctation time points. [Figure 53] FIG. 53 is a graph of maximum left ventricular pressure at 6 weeks after aortic coarctation surgery. [Figure 54] FIG. 54 is a graph of the rate of left ventricular pressure rise at 6 weeks after aortic coarctation surgery. [Figure 55] FIG. 55 is a graph showing CV-8814 and trimetazidine levels after intravenous administration of CV-8834. [Figure 56] FIG. 56 is a graph showing CV-8814 and trimetazidine levels after oral administration of CV-8834. [Figure 57]FIG. 57 is a graph showing CV-8814 and trimetazidine levels after oral administration of CV-8834. [Figure 58] FIG. 58 is a graph showing CV-8814 and trimetazidine levels after oral administration of CV-8834. [Figure 59] FIG. 59 is a graph showing CV-8814 and trimetazidine levels after oral administration of CV-8834. [Figure 60] FIG. 60 is a graph showing trimetazidine levels after oral administration of CV-8972 or intravenous administration of trimetazidine. [Figure 61] Figure 61 is a graph showing the levels of CV-8814 after oral administration of CV-8972 or intravenous administration of CV-8814. [Figure 62] Figure 62 is a graph showing the levels of CV-8814 after intravenous administration of CV-8834 or oral administration of CV-8834. [Figure 63] Figure 63 is a graph showing the levels of CV-8814 following intravenous administration of CV-8814 or oral administration of CV-8814. [Figure 64] Figure 64 is a graph showing the HPLC elution profile of a batch of CV-8972. [Figure 65] Figure 65 is a graph showing an analysis of molecular species present in batches of CV-8972. [Figure 66] Figure 66 is a pair of graphs showing the HPLC elution profiles of molecular species present in batches of CV-8972. [Figure 67] Figure 67 is a pair of graphs showing the HPLC elution profiles of molecular species present in batches of CV-8972. [Figure 68] Figure 68 is a graph showing X-ray powder diffraction analysis of a batch of CV-8972. [Figure 69] Figure 69 is a graph showing X-ray powder diffraction analysis of batches of CV-8972. [Figure 70]FIG. 70 is a graph showing differential scanning calorimetry and thermogravimetric analysis of a batch of CV-8972. [Figure 71] FIG. 71 is a graph showing dynamic vapor sorption (DVS) of a batch of CV-8972. [Figure 72] FIG. 72 is a graph showing differential scanning calorimetry and thermogravimetric analysis of a batch of CV-8972. [Figure 73] Figure 73 is a graph showing dynamic vapor sorption measurements (DVS) of batches of CV-8972. [Figure 74] FIG. 74 is a graph showing an X-ray powder diffraction analysis of a sample of CV-8972. [Figure 75] FIG. 75 is a graph showing differential scanning calorimetry and thermogravimetric analysis of a batch of CV-8972. [Figure 76] FIG. 76 is a graph showing an X-ray powder diffraction analysis of a sample of CV-8972. [Figure 77] FIG. 77 is a graph showing an X-ray powder diffraction analysis of a sample of CV-8972. [Figure 78] FIG. 78 is a graph showing differential scanning calorimetry and thermogravimetric analysis of a sample containing Form A of CV-8972. [Figure 79] FIG. 79 is a graph showing differential scanning calorimetry and thermogravimetric analysis of a sample containing Form A of CV-8972. DETAILED DESCRIPTION OF THE INVENTION

[0047] The present invention provides a composition that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation while simultaneously increasing mitochondrial respiration, thereby improving cardiac metabolic efficiency. Glucose oxidation and fatty acid oxidation are energy-producing metabolic pathways that compete with each other for substrates. In glucose oxidation, glucose is broken down into pyruvate by glycolysis in the cytosol of cells. Pyruvate then enters mitochondria, where it is converted into acetyl-coenzyme A (acetyl-CoA). In fatty acid beta-oxidation, which occurs in mitochondria, two-carbon units from long-chain fatty acids are sequentially converted to acetyl-CoA.

[0048] The remaining steps in energy production from the oxidation of glucose or fatty acids are common to both pathways: acetyl-CoA is oxidized via the citric acid cycle to carbon dioxide; (CO2), which results in nicotinamide adenine dinucleotide (NAD + ) is converted to its reduced form, NADH. NADH then drives the mitochondrial electron transport chain. The electron transport chain contains a series of four mitochondrial membrane-bound complexes that transfer electrons through redox reactions and pump protons across the membrane, creating a proton gradient. The redox reactions in the electron transport chain require molecular oxygen (O2). Ultimately, the proton gradient enables another membrane-bound enzyme complex to generate high-energy ATP molecules, the energy source for most cellular reactions.

[0049] In many types of heart disease, the overall efficiency of energy production by cardiac mitochondria is reduced. This is in part due to an increased reliance on fatty acid oxidation over glucose oxidation in many types of heart disease. Glucose oxidation is a more efficient pathway for energy production than fatty acid oxidation, as measured by the number of ATP molecules produced per O2 molecule consumed. However, in patients with heart disease, other metabolic changes also contribute to reduced cardiac efficiency. For example, in heart failure, overall mitochondrial oxidative metabolism may be impaired, and in ischemic heart disease, energy production is reduced due to limited oxygen supply. As noted above, the final step in ATP synthesis, which involves several redox reactions and oxygen-driven proton transport, is common to both glucose and fatty acid oxidation pathways. Therefore, shifting the balance from fatty acid oxidation to glucose oxidation alone is not sufficient to restore full cardiac efficiency in many situations, as downstream processes are also affected.

[0050] The present invention provides a composition that improves cardiac efficiency by altering mitochondrial metabolism using multiple mechanisms.The composition includes a component that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, and one or more other components that promote mitochondrial respiration, thereby inducing changes in the pathways used for energy production and concomitantly improving the overall oxidative function of mitochondria.As a result, the composition of the present invention is more effective than compounds that simply shift to glucose oxidation in restoring cardiac capacity in patients with heart disease, such as heart failure, ischemic heart disease, and diabetic cardiomyopathy.

[0051] In some embodiments, the composition has Formula (I): ALB (I) wherein A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, L is a linker, and B is a compound that promotes mitochondrial respiration.

[0052] Component A can be any suitable compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation. Such compounds can be classified based on their mechanism of action. See Fillmore, N., et al., Mitochondrial fatty acid oxidation alterations in heart failure, ischemic heart disease and diabetic cardiomyopathy, Brit. J. Pharmacol. 171:2080-2090 (2014), which is incorporated herein by reference.

[0053] A class of compounds that shifts to glucose includes compounds that directly inhibit fatty acid oxidation. Compounds in this class include inhibitors of malonyl-CoA decarboxylase (MCD), carnitine palmitoyltransferase 1 (CPT-1), or mitochondrial fatty acid oxidation. Mitochondrial fatty acid oxidation inhibitors include trimetazidine and other compounds described in WO2002 / 064576, which is incorporated herein by reference. Trimetazidine binds to distinct sites on the inner and outer membranes of mitochondria, , affecting both ion permeability and metabolic function of mitochondria. Morin, D., et al., Evidence for the existence of [ 3 H]-trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore, Brit. J. Pharmacol. 123:1385-1394 (1998). MCD inhibitors include CBM-301106, CBM-300864, ​​CBM-301940, 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamide, methyl 5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)morpholine-4-carboxamido)pentanoate, and the compounds described in Chung, JF, et al., Discovery of Potent and Orally Available Malonyl-CoA Decarboxylase Inhibitors as Cardioprotective Agents, J. Med. Chem. 49:4055-4058 (2006), Cheng JF et al., Synthesis and structure-activity relationship of small-molecule malonyl coenzyme A decarboxylase inhibitors, J. Med. Chem. 49:1517-1525 (2006), U.S. Publication No. 2004 / 0082564, and other compounds described in WO2002 / 058698. CPT-1 inhibitors include oxfenicine, perhexiline, etomoxir, and other compounds described in WO2015 / 018660, WO2008 / 109991, WO2009 / 015485, U.S. Publication No. 2011 / 0212072, and WO2009 / 156479, which are incorporated herein by reference.

[0054] Another class of glucose-shifting compounds includes compounds that directly stimulate glucose oxidation, examples of which are described in U.S. Publication No. 2003 / 0191182, WO2006 / 117686, and U.S. Patent No. 8,202,901, which are incorporated herein by reference.

[0055] Another class of compounds that shifts to glucose includes compounds that reduce the level of circulating fatty acids that supply the heart. Examples of such compounds include fibrate drugs such as clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, thiazolidinediones, GW-9662, and PPARα and PPARγ agonists, including other compounds described in U.S. Patent No. 9,096,538, which is incorporated herein by reference.

[0056] Component L can be any suitable linker. Preferably, the linker can be cleaved in vivo to release components A and B. The linker can be an alkoxy group. The linker can be polyethylene glycol of any length. The linker can be (CH2CHO) x (x=1 to 15) or (CH2CH2O) x (wherein x=1 to 3). Other suitable linkers include 1,3-propanediol, diazo linkers, phosphoramidite linkers, disulfide linkers, cleavable peptides, iminodiacetic acid linkers, thioether linkers, and other linkers described in Leriche, G., et al., Cleavable linkers in chemical biology, Bioorg. Med. Chem. 20:571-582 (2012), WO1995000165, and U.S. Pat. No. 8,461,117, which are incorporated herein by reference.

[0057] Component B can be any compound that promotes mitochondrial respiration. For example, component B can be a citric acid cycle intermediate or a molecule that can be metabolized into the citric acid cycle, such as succinate, fumarate, malate, oxaloacetate, citrate, isocitrate, α-ketoglutarate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, or β-hydroxypentanoate. Citric acid cycle intermediates can be depleted when used for biosynthesis, resulting in insufficient ATP production from the citric acid cycle. However, by providing one citric acid cycle intermediate through a supplemental effect, all intermediates can be restored as the cycle progresses. Therefore, citric acid cycle intermediates can promote mitochondrial respiration.

[0058] The compound is NAD + May contain precursor molecules. NAD + NAD is an important oxidant that acts as a coenzyme in several reactions in the citric acid cycle. + Conversely, when NADH donates electrons to the mitochondrial electron transport chain, it is oxidized to NAD + In humans, NAD + Although NAD can be synthesized de novo from tryptophan, the amount is not sufficient to meet metabolic demands. + NAD can also be synthesized by a salvage pathway that uses precursors that must be supplied from the diet. + The precursors used in the synthesis are, among others, nicotinic acid, nicotinamide, and nicotinamide riboside. + By providing precursors, NAD + Facilitates synthesis.

[0059] NAD +The inclusion of precursors in the compounds of the present invention allows the compounds to stimulate energy production in cardiac mitochondria in multiple ways. First, component A shifts cardiac metabolism from fatty acid oxidation to the inherently more efficient oxidation of glucose. Second, component B ensures that citric acid cycle intermediates are present at sufficient levels and are not depleted or limited. As a result, glucose-derived acetyl-CoA is efficiently oxidized. Finally, NAD + Precursors power respiration by providing essential coenzymes that cycle between oxidized and reduced forms. In the oxidized form, NAD + drives the reactions of the citric acid cycle. In its reduced form, NADH drives electron transport, creating a proton gradient that enables ATP synthesis. As a result, the chemical potential resulting from the oxidation of acetyl-CoA is efficiently converted into ATP, which can be used for various cellular functions.

[0060] NAD + The precursor molecule may be covalently linked to the compound in any suitable manner, e.g., to A, L, or B, either directly or via another linker. Preferably, it is linked via a linker that is cleavable in vivo. NAD + The precursor molecules may be attached via a 1,3-propanediol linkage.

[0061] The compound may be covalently linked to one or more molecules of polyethylene glycol (PEG), i.e., the compound may be PEGylated. In many instances, PEGylation of a molecule reduces its immunogenicity, thereby preventing the molecule from being cleared from the body and allowing it to remain in circulation longer. The compound may comprise a PEG polymer of any size. For example, a PEG polymer may have 1 to 500 (CH2CHO) units. The PEG polymer may have any suitable geometry, such as linear, branched, star-shaped, or comb-shaped configurations. The compound may be PEGylated at any site. For example, the compound may be PEGylated to component A, component B, component L, or, if present, NAD. + The PEGylated compound may be PEGylated on a precursor. The compound may be PEGylated at multiple sites. For compounds that are PEGylated at multiple sites, the various PEG polymers may be of the same or different size and composition.

[0062] The compound may be a PEGylated form of trimetazidine. For example, the compound may be represented by formula (VI): [ka] and one or more of the carbon atoms at positions A, B, C, D, and E, and / or the nitrogen atom at position F, are -(CH2CH2O) n H, where n=1-15. Carbon atoms at positions A, B, C, D, and E may have two PEG substituents. In molecules with multiple PEG chains, the different PEG chains may be the same or different lengths.

[0063] The compound of formula (I) may be a compound of formula (II): [ka] (y=1 to 3).

[0064] The compound of formula (I) may be represented by formula (III): [ka] (y=1 to 3).

[0065] The present invention relates to a compound of formula (IV): [ka] Also provided is a compound represented by: In the formula, R 1 , R 2 , and R 3 are independently H or a (C1-C4) alkyl group, and R 4 and R 5 are taken together to form =O, -O(CH2) m O- or -(CH2) m - and m=2 to 4, or R 4 is H and R 5 is OR 14 , S.R. 14 , or (CH2CH2O) n H and R 14 is H or a (C1-C4) alkyl group, n=1-15, and R 6 is a monocyclic or polycyclic structure optionally substituted with heteroatoms at one or more ring positions, and each ring position optionally contains one or more substituents.

[0066] R 6 may be a monocyclic or polycyclic structure of any size. For example, the structure may contain 3 to 22 atoms, not including hydrogen atoms bonded to atoms at ring positions. The structure may contain one or more alkyl, alkenyl, or aromatic rings. The structure may contain one or more heteroatoms, i.e., atoms other than carbon. For example, the heteroatoms may be oxygen, nitrogen, sulfur, or phosphorus.

[0067] R 6may contain a substituent comprising a compound that promotes mitochondrial respiration, as described above for component B of formula (I). The substituent may include a linker, as described above for component L of formula (I). The substituent may include a NAD, as described above for compounds of formula (I). + It may also include precursor molecules.

[0068] R 6 The substituents on the ring positions of [ka] (y=1 to 3)

[0069] R 6 The substituents on the ring positions of [ka] (y=1 to 3)

[0070] R 6 teeth, [ka] It may be the case.

[0071] For some compounds of the present invention, including trimetazidine prodrugs, analogs, and derivatives, it is advantageous to have the trimetazidine moiety substituted with a single ethylene glycol moiety. Thus, preferred compositions of the present invention include compounds of formulas (I) and (VIII) containing a linker where x=1, compounds of formulas (II) and (III) where y=1, compounds of formula (V) where z=1, compounds of formula (VI) where n=1, and compounds of formula (VII) where A is linked to C via a single ethylene glycol moiety. Without wishing to be bound by theory, the attachment of a single ethylene glycol moiety to the trimetazidine moiety may improve the bioavailability of trimetazidine.

[0072] The compound of formula (IV) may be represented by formula (IX) or formula (X): [ka] The polymer may have a structure represented by:

[0073] The present invention relates to a compound of formula (V): [ka] Also provided is a compound represented by: In the formula, R 1 , R 2 , and R 3 are independently H or a (C1-C4) alkyl group, and R 4 and R 8 are taken together to form =O, -O(CH2) m O- or -(CH2) m - and m=2 to 4, or R 4 is H and R 8 H, OR 14 , S.R. 14 , or (CH2CH2O) n H and R 14 is H or a (C1-C4) alkyl group, n=1-15, and R 9 , R 10 , R 12 , and R 13 are independently H or (CH2CH2O) z H, z=1 to 15, and R 11 R comprises a compound that promotes mitochondrial respiration, as described above with respect to component B of formula (I). 11 may include a linker as described above for component L of formula (I).

[0074] R 11 teeth, [ka] (y=1~3) may occur.

[0075] R 11is an NAD as described above for compounds of formula (I) + It may also include precursor molecules.

[0076] R 11 teeth, [ka] (y=1~3)

[0077] In some of the above-described embodiments, the compounds of the present invention comprise multiple active agents linked by a linker in a single molecule. Delivering multiple active agents as components of a single molecule may be advantageous. While not wishing to be bound by theory, there are several reasons why co-delivery of active agents as a single molecule may be advantageous. One possibility is that a large single molecule may have reduced side effects compared to component drugs. Free trimetazidine can cause symptoms similar to Parkinson's disease in some patients. However, derivatizing trimetazidine to include other moieties, such as succinate, makes the molecule bulkier and prevents free trimetazidine from accessing sites where it may cause unintended effects. Derivatized trimetazidine as described above is also more hydrophilic and therefore less likely to cross the blood-brain barrier and cause neurological effects. Another possibility is that modifying trimetazidine may alter its pharmacokinetic properties. The derivatized molecule is metabolized to yield the active agent, resulting in gradual release of the active agent. Therefore, the level of the active agent in the body will not reach a peak as high as when the same amount is administered as a single bolus.Another possibility is that because the compound of the present invention contains multiple active agents, a smaller amount of each active agent, such as trimetazidine, is required.For example, trimetazidine shifts metabolism from fatty acid oxidation to glucose oxidation, and succinate generally improves mitochondrial respiration.Therefore, a compound that provides both agents stimulates a greater increase in glucose-driven ATP production for a given amount of trimetazidine than a compound that delivers only trimetazidine.

[0078] The present invention relates to a compound of formula (VII): AC (VII) where A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, and C is a compound that inhibits NAD + Also provided is a compound that is a precursor molecule. A and C may be covalently linked.

[0079] The compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation may be PEGylated with an ethylene glycol moiety. The compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation may also have multiple ethylene glycol moieties, such as one, two, three, four, five, or more ethylene glycol moieties. The ethylene glycol moiety is (CH2CHO) x (x = 1 to 15). The ethylene glycol moiety is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation and NAD + The ethylene glycol moiety can form a covalent linkage between precursor molecules and NAD compounds that shift cardiac metabolism from fatty acid oxidation to glucose oxidation. + There may be a covalent bond between the precursor molecules.

[0080] The compound of formula (VII) may comprise nicotinic acid covalently linked to a PEGylated form of trimetazidine. The nicotinic acid may be covalently linked via the PEGylated moiety, i.e., via an ethylene glycol linkage. The nicotinic acid may also be covalently linked via the trimetazidine moiety.

[0081] The present invention relates to a compound of formula (VIII): ALC (VIII) wherein A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, L is a linker, and C is an NAD + Also provided are compounds that are precursor molecules: A can be covalently linked to L, and L can be covalently linked to C.

[0082] Compounds, linkers, and NAD that shift cardiac metabolism from fatty acid oxidation to glucose oxidation + The precursor molecules may be as described above for compounds of other formulas.

[0083] The present invention relates to (1) compounds that shift cardiac metabolism from fatty acid oxidation to glucose oxidation, (2) compounds that promote mitochondrial respiration, and (3) compounds that promote NAD + Also provided is a composition comprising at least two of the precursor molecules. The aforementioned components of the composition may be provided as separate molecules.

[0084] The composition comprises (1) a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, (2) a compound that promotes mitochondrial respiration, and (3) a compound that promotes NAD + The composition may comprise a precursor molecule of each of the three components. In such a composition, each of the three components can be provided as a separate molecule. Alternatively, in such a composition, two of the components can be covalently linked as part of a single molecule, and the third component can be provided as a separate molecule. For example, a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation can be linked to a compound that promotes mitochondrial respiration, and NAD + The precursors can be provided as separate molecules.

[0085] The compounds of the present invention can also be provided as co-crystals with other compounds. A co-crystal is a crystalline material composed of two or more different molecules in the same crystal lattice. The different molecules can be neutral and have non-ionic interactions within the lattice. Co-crystals of the present invention can be used to combine one or more compounds of the present invention with other compounds that stimulate mitochondrial respiration or NAD. + It may also be included with one or more other molecules that act as precursors. For example, a co-crystal may include any of the following combinations: (1) a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation; and (2) NAD + Precursor molecules: (1) compounds that promote mitochondrial respiration and (2) NAD +precursor molecules, (1) a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation and (2) a compound that promotes mitochondrial respiration, a molecule comprising (1) a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation covalently linked to a compound that promotes mitochondrial respiration, and (2) NAD + Precursor Molecules. In particular embodiments, the co-crystal may include (1) a compound of Formula (I), (III), (IV), or (V) and (2) nicotinic acid, nicotinamide, or nicotinamide riboside.

[0086] A compound may contain one or more atoms that are isotopically enriched. For example, a compound may have one or more hydrogen atoms replaced with deuterium or tritium. The isotopic substitution or enrichment may be at carbon, sulfur, or phosphorus, or at other atoms. A compound may be isotopically substituted or enriched at a given atom at one or more positions within the compound, or the compound may be isotopically substituted or enriched at all instances of a given atom within the compound.

[0087] The present invention provides pharmaceutical compositions containing one or more of the compounds described above. Pharmaceutical compositions containing the compounds can be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melt preparations, aqueous or oily suspensions, dispersible powders or granules, emulsions, soft or hard capsules, syrups, or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets contain the compounds mixed with pharmaceutically acceptable, non-toxic excipients suitable for tablet manufacture. Such excipients include, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, such as corn starch; and the like. The tablet may contain starch or alginic acid, binders such as starch, gelatin, acacia, and lubricants such as magnesium stearate, stearic acid, and talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration in the stomach and reduce absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Tablets may be coated by techniques described in U.S. Pat. Nos. 4,256,108, 4,166,452, and 4,265,874 to produce osmotic therapeutic tablets for controlled release. Compound preparation and administration are discussed in U.S. Pat. No. 6,214,841 and U.S. Publication No. 2003 / 0232877, which are incorporated herein by reference.

[0088] Formulations for oral use may also be presented as hard gelatin capsules in which the compound is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the compound is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0089] An alternative oral formulation, where control of the gastrointestinal hydrolysis of the compound is desired, may be obtained using a controlled release formulation in which the compound of the invention is encapsulated in an enteric coating.

[0090] Aqueous suspensions may contain the compound in admixture with excipients suitable for the manufacture of aqueous suspensions, such as suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia; dispersing or wetting agents, for example, naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters obtained from fatty acids and hexitols, for example, polyoxyethylene with partial esters obtained from fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0091] Oily suspensions can be prepared by suspending compounds in vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils such as liquid paraffin.Oily suspensions may contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol.To make oral preparations palatable, sweeteners such as those listed above and flavoring agents can be added.These compositions can also be preserved by adding antioxidants such as ascorbic acid.

[0092] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compound in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, and for example, sweetening agents, flavoring agents, and coloring agents may also be present.

[0093] The pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phosphatides, such as soybean, lemongrass, or the like. The emulsion may also contain sweeteners and flavoring agents.

[0094] Syrups and elixirs can be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. These preparations may also contain demulcents, preservatives, and flavoring and / or coloring agents. The pharmaceutical compositions can also be in the form of sterile injectable aqueous or oleaginous suspensions. These suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as mentioned above. Sterile injectable preparations can also be injectable sterile solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution, among others. Additionally, sterile fixed oils are conventionally employed as solvents or suspending media. Any non-irritating fixed oil may be employed for this purpose, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable solutions.

[0095] The compounds of the present invention are useful for improving cardiac efficiency. There are various definitions of cardiac efficiency in the medical literature, see, for example, Schipke, JD, Cardiac efficiency, Basic Res. Cardiol. 89:207-40 (1994), and Gibbs, CL and Barclay, CJ, Cardiac efficiency, See Cardiovasc. Res. 30:627-634 (1995). One definition of cardiac mechanical efficiency is the ratio of external cardiac power to cardiac energy expenditure by the left ventricle. Lopaschuk GD, et al., Myocardial Fatty Acid Metabolism in Health and Disease, Phys. Rev. 90:207-258 (2010). Another definition is the ratio of stroke work to oxygen consumption, which in a normal human heart is in the range of 20-25%. Visser, F., Measuring cardiac efficiency: is it useful? Hear Metab. 39:3-4 (2008), incorporated herein by reference. Another definition is the ratio of stroke volume to mean arterial pressure. Any suitable definition of cardiac efficiency may be used to measure the effects of the compounds of the present invention.

[0096] The present invention also provides a method for altering cardiac metabolism in a subject to increase glucose oxidation relative to fatty acid oxidation, which may include providing a composition of the invention, such as any of the compounds described above, including compounds represented by Formula (I), (II), (III), (IV), or (V), or a formulation thereof.

[0097] The method may include providing a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation as described above, and a compound that promotes mitochondrial respiration as described above. The compounds may be provided as components of a single molecule, as separate molecules in a single composition, or in separate compositions.

[0098] The method is as described above. + This may include providing precursor molecules, such as compounds that shift cardiac metabolism from fatty acid oxidation to glucose oxidation, compounds that promote mitochondrial respiration, and NAD + In methods involving providing precursor molecules, the compounds may be provided as components of a single molecule, two different molecules, or three different molecules. The compounds can be provided in one, two, three, or any number of different compositions. The compounds can be provided together, separately, or in any combination. The compounds can be provided simultaneously or sequentially. The compounds can be provided at different intervals, at different frequencies, in different amounts, or at different dosages.

[0099] The present invention also provides a method of treating a condition by providing a composition of the present invention. The condition may be a cardiac disease such as heart failure, ischemic heart disease, diabetic cardiomyopathy, rheumatic heart disease, valvular heart disease, aneurysm, atherosclerosis, high blood pressure (hypertension), peripheral artery disease, angina, atherosclerosis, coronary artery disease, coronary heart disease, heart attack, atherosclerosis, cerebrovascular disease, stroke, transient ischemic attack, atherosclerosis, cardiomyopathy, pericardial disease, valvular heart disease, congenital heart disease, etc. [Example]

[0100] Protocol The effects of compounds of the present invention on mitochondrial function were analyzed. HepG2 cells were dosed with test compounds, and extracellular oxygen levels and pH were measured in real time using an XFe96 flux analyzer (Seahorse Biosciences). XFe technology uses solid-state sensors to simultaneously measure both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to simultaneously determine effects on oxidative phosphorylation (OXPHOS) and glycolysis. Cells were then sequentially exposed to various inhibitors of mitochondrial function to assess cellular metabolism.

[0101] Data interpretation Compounds were identified as positive mitochondrial active compounds when they caused changes in the oxygen consumption rate (OCR) or extracellular acidification rate (ECAR) without cytotoxicity. Cytotoxicity was determined when both OXPHOS (OCR) and glycolysis (ECAR) were inhibited.

[0102] Definition of mitochondrial parameters Oxygen consumption rate (OCR) is a measure of the oxygen content in the extracellular medium. Changes in OCR suggest an effect on mitochondrial function and can be bidirectional. A decrease may be due to inhibition of mitochondrial respiration, while an increase may suggest an uncoupler in which respiration is uncoupled from energy production. [ka]

[0103] The extracellular acidification rate (ECAR) is a measure of the extracellular proton concentration (pH). An increase in signal indicates an increase in the ratio of pH ions (i.e., a decrease in pH value), which is recognized as an increase in glycolysis. The ECAR is expressed as a fraction of the basal control (the ratio before the addition of compound). [ka]

[0104] Reserve capacity is a measure of a cell's ability to meet increasing energy demands. A decline indicates mitochondrial dysfunction. This measurement indicates how close a cell is to reaching its bioenergetic limit. [ka]

[0105] Mitochondrial stress test A series of compounds are added sequentially to the cells to assess the effect of the test compounds on parameters such as bioenergetic profile, proton leak, and reserve capacity, which can be used to aid in understanding possible mechanisms of mitochondrial toxicity. The following compounds were added sequentially: (1) oligomycin, (2) FCCP, and (3) rotenone and antimycin A.

[0106] Oligomycin is a known inhibitor of ATP synthase, preventing the production of ATP. Oligomycin treatment provides a measure of oxygen consumption related to ATP production and ATP turnover. Addition of oligomycin results in a decrease in OCR under normal conditions, with the residual OCR being associated with spontaneous proton leak.

[0107] FCCP is a protonophore and a known uncoupler of oxygen consumption from ATP production. FCCP treatment allows for the maximum achievable electron transport and oxygen consumption rates, providing a measure of reserve capacity.

[0108] Rotenone and antimycin A are known inhibitors of complexes I and III of the electron transport chain, respectively. Treatment with these compounds completely inhibits electron transport, and the remaining oxygen consumption is due to non-mitochondrial activity by oxygen-requiring enzymes.

[0109] Mechanism definition Electron transport chain inhibitors are inhibitors of mitochondrial respiration that cause increased glycolysis (eg, decreased OCR and increased ECAR) as an adaptive response.

[0110] Inhibition of oxygen consumption can also be due to reduced substrate (e.g., glucose, fatty acids, glutamine, pyruvate) availability, for example, due to transporter inhibition. Compounds that reduce substrate availability are substrate inhibitors. Substrate inhibitors do not result in an increase in glycolysis (e.g., decreased OCR, no response in ECAR).

[0111] Compounds that inhibit the coupling of oxidative processes to ATP production are known as uncouplers. Such compounds result in an increase in mitochondrial respiration (OCR) but an inhibition of ATP production.

[0112] FIG. 1 is a table summarizing the effects of various compounds on mitochondrial function.

[0113] FIG. 2 is a table summarizing the effects of nicotinamide on various parameters of mitochondrial function.

[0114] FIG. 3 is a series of graphs showing the effect of nicotinamide on oxygen consumption rate and reserve capacity.

[0115] FIG. 4 is a series of graphs showing the effect of nicotinamide on extracellular acidification rate.

[0116] FIG. 5 is a table summarizing the effects of the combination of trimetazidine and nicotinamide on various parameters of mitochondrial function.

[0117] FIG. 6 is a series of graphs showing the effect of a combination of trimetazidine and nicotinamide on oxygen consumption rate and reserve capacity.

[0118] FIG. 7 is a series of graphs showing the effect of a combination of trimetazidine and nicotinamide on extracellular acidification rate.

[0119] FIG. 8 is a table summarizing the effects of succinate on various mitochondrial function parameters.

[0120] FIG. 9 is a series of graphs showing the effect of succinate on oxygen consumption rate and reserve capacity.

[0121] FIG. 10 is a series of graphs showing the effect of succinate on extracellular acidification rate.

[0122] FIG. 11 is a table summarizing the effects of compound CV-8816 on various mitochondrial function parameters.

[0123] FIG. 12 is a series of graphs showing the effect of compound CV-8816 on oxygen consumption rate and reserve capacity.

[0124] FIG. 13 is a series of graphs showing the effect of compound CV-8816 on extracellular acidification rate.

[0125] FIG. 14 is a table summarizing the effects of compound CV-8814 on various mitochondrial function parameters.

[0126] FIG. 15 is a series of graphs showing the effect of compound CV-8814 on oxygen consumption rate and reserve capacity.

[0127] FIG. 16 is a series of graphs showing the effect of compound CV-8814 on extracellular acidification rate.

[0128] FIG. 17 is a table summarizing the effects of trimetazidine on various mitochondrial function parameters.

[0129] FIG. 18 is a series of graphs showing the effect of trimetazidine on oxygen consumption rate and reserve capacity.

[0130] FIG. 19 is a series of graphs showing the effect of trimetazidine on extracellular acidification rate.

[0131] FIG. 20 is a table summarizing the effects of compound CV-8815 on various mitochondrial function parameters.

[0132] FIG. 21 is a series of graphs showing the effect of compound CV-8815 on oxygen consumption rate and reserve capacity.

[0133] FIG. 22 is a series of graphs showing the effect of compound CV-8815 on extracellular acidification rate.

[0134] FIG. 23 is a table summarizing the effects of a combination of succinate, nicotinamide, and trimetazidine on various parameters of mitochondrial function.

[0135] FIG. 24 is a series of graphs showing the effect of a combination of succinate, nicotinamide and trimetazidine on oxygen consumption rate and reserve capacity.

[0136] FIG. 25 is a series of graphs showing the effect of a combination of succinate, nicotinamide and trimetazidine on extracellular acidification rate.

[0137] FIG. 26 is a table summarizing the effects of the combination of trimetazidine analog 2 and nicotinamide on various mitochondrial function parameters.

[0138] FIG. 27 is a series of graphs showing the effect of a combination of trimetazidine analog 2 and nicotinamide on oxygen consumption rate and reserve capacity.

[0139] FIG. 28 is a series of graphs showing the effect of a combination of trimetazidine analog 2 and nicotinamide on extracellular acidification rate.

[0140] FIG. 29 is a table summarizing the effects of the combination of trimetazidine analog 1 and nicotinamide on various mitochondrial function parameters.

[0141] FIG. 30 is a series of graphs showing the effect of a combination of trimetazidine analog 1 and nicotinamide on oxygen consumption rate and reserve capacity.

[0142] FIG. 31 is a series of graphs showing the effect of a combination of trimetazidine analog 1 and nicotinamide on extracellular acidification rate.

[0143] FIG. 32 is a table summarizing the effects of the combination of trimetazidine analog 3 and nicotinamide on various mitochondrial function parameters.

[0144] FIG. 33 is a series of graphs showing the effect of a combination of trimetazidine analog 3 and nicotinamide on oxygen consumption rate and reserve capacity.

[0145] FIG. 34 is a series of graphs showing the effect of the combination of trimetazidine analog 3 and nicotinamide on extracellular acidification rate.

[0146] FIG. 35 is a table summarizing the effects of succinate and nicotinamide combinations on various mitochondrial function parameters.

[0147] FIG. 36 is a series of graphs showing the effect of a combination of succinate and nicotinamide on oxygen consumption rate and reserve capacity.

[0148] FIG. 37 is a series of graphs showing the effect of a combination of succinate and nicotinamide on extracellular acidification rate.

[0149] Effect of the composition on coronary blood flow, cardiac function, and infarct size The effects of the compositions on coronary blood flow, cardiac function, and infarct size were analyzed.

[0150] Figure 38 is a schematic diagram of the ischemia-reperfusion (IR) method used to analyze the effects of compositions of the present invention on coronary blood flow, cardiac function, and infarct size. At time 0, mice were administered (1) 2 (1) 0 μM trimetazidine (TMZ), (2) 2 μM each of trimetazidine, nicotinamide, and succinate (TNF), (3) 20 μM each of trimetazidine, nicotinamide, and succinate (TNS), or (4) delivery vehicle (CON). At 20 min, ischemia was induced and coronary blood flow was analyzed. At 50 min, reperfusion was initiated to restore blood flow. At 170 min, coronary blood flow and cardiac function were analyzed, and then the hearts were preserved, dissected, and infarct size was measured by triphenyltetrazolium chloride (TTC) staining.

[0151] Figure 39 is a graph of coronary blood flow after IR. Data are presented as the ratio of cardiac blood flow at 170 minutes to that at 20 minutes. TNS treatment preserved coronary blood flow after IR. Raw data are shown in Tables 1-2. [Table 1-1] [Table 1-2] [Table 2]

[0152] Figure 40 is a graph of maximum left ventricular pressure (LVDP) after IR. The blue bar shows LVDP at 20 minutes, and the orange bar shows LVDP at 170 minutes. TMZ, TNS, and TNF treatment prevented the decline in cardiac function after IR. The raw data are shown in Tables 3-6. Shown below. [Table 3-1] [Table 3-2] [Table 4-1] [Table 4-2] [Table 5-1] [Table 5-2] [Table 6]

[0153] Figure 41 shows images of TTC stained heart sections after IR. TMZ and TNS treatment reduced infarct size after IR.

[0154] Figure 42 is a graph of infarct size after IR. TMZ and TNS treatment reduced infarct size after IR. Raw data are shown in Tables 7-55. [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 [Table 51] [Table 52] [Table 53] [Table 54] [Table 55]

[0155] The results show that the combination of trimetazidine, nicotinamide, and succinate at 20 μM preserved coronary blood flow and cardiac function recovery and reduced infarct size in isolated hearts after ischemia-reperfusion. This combination was more effective than TMZ alone in reducing infarct size. The combination of trimetazidine, nicotinamide, and succinate at 2 μM did not appear to reduce myocardial ischemia-reperfusion injury. .

[0156] This study suggested that the combination of trimetazidine, nicotinamide, and succinate at 20 μM provided better protection against ischemia-reperfusion injury in the Langendorff system.

[0157] Figure 43 is a schematic diagram of the method used to analyze the effects of compositions of the present invention on cardiac function. After transaortic coronary artery (TAC) or a sham procedure, mice received one of the following via osmotic minipumps: CV8814 at 5.85 mg / kg / day (CV4), CV8814 at 5.85 mg / kg / day with nicotinic acid at 1.85 mg / kg / day and succinate at 2.43 mg / kg / day (TV8), or saline (SA). Echocardiograms were performed immediately after TAC, 3 weeks after TAC, and 6 weeks after TAC. Mice were sacrificed at 6 weeks, and tissues were analyzed.

[0158] FIG. 44 shows hearts from mice 6 weeks after a sham procedure (Sham), TAC followed by saline administration (TAC), TAC followed by CV4 administration (CV4), or TAC followed by TV8 administration.

[0159] Figure 45 is a graph of heart weight versus body weight 6 weeks after aortic coarctation. Treatments are as described for Figure 44.

[0160] Figure 46 is a graph of heart weight 6 weeks after aortic coarctation. Treatments are as described for Figure 44.

[0161] Figure 47 shows graphs of fractional shortening (FS) and ejection fraction (EF) at indicated post-coarctation time points. Treatments were as described with respect to Figure 44.

[0162] 48 is a graph of left ventricular end-systolic diameter at the indicated post-aortic coarctation time points. Treatment was as described with respect to FIG.

[0163] 49 is a graph of interventricular septal dimensions at indicated post-coarctation time points. The procedure was as described with respect to FIG.

[0164] 50 is a graph of left ventricular mass at indicated post-coarctation time points. Treatments were as described with respect to FIG.

[0165] 51 is a graph of isovolumic relaxation time at indicated time points after aortic coarctation. Treatments were as described with respect to FIG.

[0166] 52 is a graph of the ratio of early to late diastolic peak velocity flow at the indicated post-coarctation time points. Treatments were as described with respect to FIG.

[0167] Figure 53 is a graph of maximum left ventricular pressure at 6 weeks after aortic coarctation. Treatments were as described with respect to Figure 44.

[0168] Figure 54 is a graph of the rate of left ventricular pressure rise at 6 weeks after aortic coarctation surgery. Treatments were as described for Figure 44.

[0169] Chemical synthesis scheme The compounds of the present invention include 2-(4-(2,3,4-trimethoxybenzyl)piperazine- 1-yl)ethan-1-ol (referred to herein as CV8814) and 2-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl nicotinate (referred to herein as CV-8972). These compounds can be synthesized according to the following scheme: [ka] [ka] [ka]

[0170] The product was converted to the desired polymorph by recrystallization. In different batches using 2.5 g of product, the percentage of water and the methanol:methyl ethyl ketone (MEK) ratio were varied.

[0171] Batch MBA25 used 5% water for precipitation based on the total volume (23 vol) of solvent containing 30% methanol:70% MEK. The yield was 67% CV-8972 monohydrate. The water content was determined by KF to be 3.46%.

[0172] For Batch MBA26, 1.33% water was used for precipitation based on the total volume (30 vol) of solvent containing 20% ​​methanol:80% MEK. The yield was 86.5% CV-8972 monohydrate. The water content was determined by KF to be 4.0%. The product was dried under vacuum at 40°C for 24 hours to reduce the water content to 3.75%.

[0173] For Batch MBA27, 3% water was used for precipitation based on the total volume (32 vol) of solvent containing 22% methanol:78% MEK. The yield was 87.22% CV-8972 monohydrate. After drying under vacuum at room temperature for 18 hours, the water content was determined by KF to be 3.93%. The product was further dried under vacuum at 40°C for 24 hours, reducing the water content to 3.54%.

[0174] In other batches, the solvent ratio and total volume was kept constant at 20% methanol:80% MEK and 30 volumes in batches using 2.5 g of product, and only the percentage of water was varied.

[0175] For Batch MBA29, 1.0 equivalent of water was added. The material was isolated and dried under vacuum at 40° C. for 24 hours. The water content was determined by KF to be 0.89%, indicating that the monohydrate form was not formed in stoichiometric amounts.

[0176] For batch MBA30, 3% water was added. The material was isolated and dried under vacuum at 40° C. for 24 hours. The water content was determined by KF to be 3.51%, indicating that the addition of excess water resulted in the formation of the monohydrate.

[0177] In batch MBA31, 5% water was added. The material was isolated and dried under vacuum at 40° C. for 24 hours. The water content was determined by KF to be 3.30%, indicating that the addition of excess water resulted in the formation of the monohydrate.

[0178] The results are summarized in Table 56. [Table 56]

[0179] Metabolism of compounds in dogs The metabolism of various compounds was analyzed in dogs.

[0180] Figure 55 is a graph showing the levels of CV-8814 (filled triangles, solid line) and trimetazidine (open triangles, dashed line) following intravenous administration of CV-8834 at 2.34 mg / kg. CV-8834 is a compound of formula (II) where y=1.

[0181] FIG. 56 is a graph showing the levels of CV-8814 (filled triangles, solid line) and trimetazidine (open triangles, dashed line) following oral administration of CV-8834 at 77.4 mg / kg.

[0182] FIG. 57 is a graph showing the levels of CV-8814 (filled triangles, solid line) and trimetazidine (open triangles, dashed line) following oral administration of CV-8834 at 0.54 mg / kg.

[0183] FIG. 58 is a graph showing the levels of CV-8814 (filled triangles, solid line) and trimetazidine (open triangles, dashed line) following oral administration of CV-8834 at 1.08 mg / kg.

[0184] FIG. 59 is a graph showing the levels of CV-8814 (filled triangles, solid line) and trimetazidine (open triangles, dashed line) following oral administration of CV-8834 at 2.15 mg / kg.

[0185] The data from Figures 55-59 are summarized in Table 57. [Table 57]

[0186] FIG. 60 is a graph showing trimetazidine levels after oral administration of CV-8972 at 1.5 mg / kg (triangles) or intravenous administration of trimetazidine at 2 mg / kg (squares).

[0187] Figure 61 shows the results after oral administration of CV-8972 at 1.5 mg / kg (triangles) or CV-8 1 is a graph showing CV-8814 levels following intravenous administration of 814 at 2.34 mg / kg (squares).

[0188] FIG. 62 is a graph showing the levels of CV-8834 following intravenous administration of CV-8834 at 4.3 mg / kg (squares) or oral administration of CV-8834 at 2.15 mg / kg (triangles).

[0189] Figure 63 is a graph showing the levels of CV-8814 following intravenous administration of CV-8814 at 2.34 mg / kg (squares) or oral administration of CV-8814 at 2.34 mg / kg (triangles).

[0190] The data from Figures 60-63 are summarized in Table 58. [Table 58]

[0191] Effect of CV-8814 on enzyme activity The effect of CV-8814 on the activity of various enzymes was analyzed in in vitro assays. Enzyme activity was assayed in the presence of 10 μM CV-8814 using time, temperature, substrate, and buffer conditions optimized for each enzyme based on published literature. No inhibition of 50% or greater was observed for any of the following enzymes: ATPase, Na + / K + , Pig heart; Cholinesterase, acetylcholinesterase, ACES, human; Cyclooxygenase COX-1, human; Cyclooxygenase COX-2, human; Monoamine oxidase MAO-A, human; Monoamine oxidase MAO-B, human; Peptidase, angiotensin-converting enzyme, rabbit; Peptidase, CTSG (cathepsin G), human; Phosphodiesterase PDE3, human; Phosphodiesterase PDE4, human; Protein serine / threonine kinase, PKC, nonselective, rat; Protein tyrosine kinase, insulin receptor, human; Protein tyrosine kinase, LCK, human; Adenosine A1, human; Adenosine A 2A, human; adrenaline α 1A , rat; adrenaline α 1B , rat; adrenaline α 1D , human; adrenaline α 2A , human; adrenaline α 2B , human; adrenaline β1, human; adrenaline β2, human; androgen (testosterone), human; angiotensin AT1, human; bradykinin B2, human L-type calcium channel, benzodiazepines, rat; L-type calcium channel, dihydropyridines, rat; L-type calcium channel, phenylalkylamines, rat; N-type calcium channel, rat; cannabinoid CB1, human; cannabinoid CB2, human; chemokine CCR1, human; chemokine CXCR2 (IL-8R B ), human; cholecystokinin CCK1 (CCK A ), human; cholecystokinin CCK2 (CCK B ), human; dopamine D1, human; dopamine D 2L , human; dopamine D 2S , human; endothelin ET A , human; estrogen ERα, human; GABA A , chloride ion channel, TBOB, rat; GABA A , flunitrazepam, central nervous system, rat; GABA A , Ro-15-1788, Hippocampus, Rat; GABA B1A, human; glucocorticoid, human; glutamate, AMPA, rat; glutamate, kainate, rat; glutamate, metabotropic, mGlu5, human; glutamate, NMDA, agonism, rat; glutamate, NMDA, glycine, rat; glutamate, NMDA, phencyclidine, rat; glutamate, NMDA, polyamine, rat; glycine, strychnine-sensitive, rat; histamine H1, human; histamine H2, human; melanocortin MC1, human; melanocortin MC4, human; muscarinic M1, human; muscarinic M2, human; muscarinic M3, human; muscarinic M4, human; neuropeptide Y Y1, human; Nicotinic acetylcholine, human; Nicotinic acetylcholine α1, bungarotoxin, human; Opiate δ1 (OP1, DOP), human; Opiate κ (OP2, KOP), human; Opiate μ (OP3, MOP), human; Platelet-activating factor (PAF), human; Potassium channel [KATP], hamster; Potassium channel hERG, human; PPARγ, human; Progesterone PR-B, human; Serotonin (5-hydroxytryptamine) 5-HT 1A , human; serotonin (5-hydroxytryptamine) 5-HT 1B , human; serotonin (5-hydroxytryptamine) 5-HT 2A , human; serotonin (5-hydroxytryptamine) 5-HT 2B , human; serotonin (5-hydroxytryptamine) 5-HT 2C , human; serotonin (5-hydroxytryptamine) 5-HT3, human; sodium channel, site 2, rat; tachykinin NK1, human; transporter, adenosine, guinea pig; transporter, dopamine (DAT), human; transporter, GABA, rat; transporter, norepinephrine (NET), human; transporter, serotonin (5-hydroxytryptamine) (SERT), human; and vasopressin V 1A , human.

[0192] Analysis of CV-8972 batch characteristics CV-8972 (2-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)ethyl nicotinate HCl salt monohydrate) was prepared and analyzed. The batch was determined to be 99.62% pure by HPLC.

[0193] Figure 64 is a graph showing the HPLC elution profile of a batch of CV-8972.

[0194] Figure 65 is a graph showing an analysis of molecular species present in batches of CV-8972.

[0195] Figure 66 is a pair of graphs showing the HPLC elution profiles of molecular species present in batches of CV-8972.

[0196] Figure 67 is a pair of graphs showing the HPLC elution profiles of molecular species present in batches of CV-8972.

[0197] Figure 68 is a graph showing X-ray powder diffraction analysis of a batch of CV-8972.

[0198] Figure 69 is a graph showing X-ray powder diffraction analysis of batches of CV-8972. Batch 289-MBA-15-A, shown in blue, contains Form B of CV-8972, batch 276-MBA-172, shown in black, contains Form A of CV-8972, and batch 276-MBA-172, shown in red. 289-MBA-16 contains a mixture of Forms A and B.

[0199] FIG. 70 is a graph showing the differential scanning calorimetry and thermogravimetric analysis of CV-8972 batch 276-MBA-172.

[0200] FIG. 71 is a graph showing the dynamic vapor sorption measurements (DVS) of CV-8972 batch 276-MBA-172.

[0201] FIG. 72 is a graph showing the differential scanning calorimetry and thermogravimetric analysis of CV-8972 Batch 289-MBA-15-A.

[0202] FIG. 73 is a graph showing the dynamic vapor sorption measurements (DVS) of CV-8972 batch 289-MBA-15-A.

[0203] Figure 74 is a graph showing X-ray powder diffraction analysis of samples of CV-8972. The pre-DVS sample from batch 276-MBA-172 is shown in blue, the pre-DVS sample from batch 289-MBA-15-A is shown in red, and the post-DVS sample from batch 289-MBA-15-A is shown in black.

[0204] FIG. 75 is a graph showing the differential scanning calorimetry and thermogravimetric analysis of CV-8972 batch 289-MBA-16.

[0205] Figure 76 is a graph showing X-ray powder diffraction analysis of samples of CV-8972. Form B is shown in green, Form A is shown in blue, a sample from an ethanol slurry of Batch 289-MBA-15-A is shown in red, and a sample from an ethanol slurry of Batch 289-MBA-16 is shown in black.

[0206] The stability of CV-8972 was analyzed.

[0207] Samples from Batch 289-MBA-15-A (containing Form B) were spiked into various solvents, incubated under various conditions, and analyzed by X-ray powder diffraction. The results are summarized in Table 59. [Table 59]

[0208] Samples from Batch 289-MBA-16 (containing Forms A and B) were added to various solvents, incubated under various conditions, and analyzed by X-ray powder diffraction. The results are summarized in Table 60. [Table 60]

[0209] Figure 77 is a graph showing X-ray powder diffraction analysis of samples of CV-8972. Samples containing Form B are shown in blue, samples containing Form A are shown in red, and samples containing a mixture of Forms A and C are shown in black.

[0210] The stability of CV-8972 was analyzed. Aqueous samples containing CV-8972 at different concentrations and pH were incubated for various periods and analyzed. The results are shown in Table 61. [Table 61-1] [Table 61-2]

[0211] Samples from Batch S-18-0030513 (containing Form A) were spiked into various solvents, incubated under various conditions, and analyzed by X-ray powder diffraction. The results are summarized in Table 62. [Table 62]

[0212] Samples from Batch 289-MBA-16 (containing Forms A and B) were added to various solvents, incubated under various conditions, and analyzed by X-ray powder diffraction. The results are summarized in Table 63. [Table 63]

[0213] Figure 78 is a graph showing differential scanning calorimetry and thermogravimetric analysis of samples containing CV-8972 Form A. The sample from an ethanol acetate-water slurry is shown as a solid line, the sample from a methanol-water slurry is shown as a regular dashed line, and the sample from an ethanol-water slurry is shown as a dash-dot line.

[0214] Figure 79 is a graph showing differential scanning calorimetry and thermogravimetric analysis of a sample containing CV-8972 Form A. Prior to analysis, the sample was dried at 100°C for 20 minutes.

[0215] Samples containing Form A of CV-8972 were analyzed for stability as a function of humidity. Samples were incubated at 40° C. and 75% relative humidity for various periods and analyzed. The results are shown in Table 64. [Table 64]

[0216] Form A of CV-8972 was analyzed for stability in aqueous solutions. Aqueous samples containing CV-8972 at different concentrations and pH were incubated for various periods of time and analyzed. The results are shown in Table 65. [Table 65]

[0217] The amount of CV-8972 present in the various dosage compositions was analyzed, and the results are shown in Table 66. [Table 66]

[0218] In vivo brain-to-plasma ratio of compounds After intravenous administration of the compounds to rats, the brain-to-plasma ratios of trimetazidine and CV-8814 were analyzed. The administration solution was analyzed by liquid chromatography tandem mass spectrometry (LC-MS / MS). The results are shown in Table 67. [Table 67]

[0219] Brain and plasma compound concentrations were analyzed 2 hours after administration of the compound to rats at 1 mg / kg. Results from trimetazidine-treated rats are shown in Table 68. Results from CV-8814-treated rats are shown in Table 69. [Table 68] [Table 69]

[0220] The mean B:P ratio for trimetazidine-treated rats was 2.33±0.672. The mean B:P ratio for trimetazidine-treated rats was 1.32±0.335.

[0221] Incorporation by Reference Throughout this disclosure, references and citations are made to other documents, such as patents, patent applications, patent publications, journals, books, articles, web content, etc. All such documents are incorporated herein by reference in their entirety for all purposes.

[0222] equivalent Various modifications of the invention and numerous further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the complete contents of this document, including the scientific and patent references cited herein. The subject matter herein contains important information, exemplification, and guidance that can be adapted to the practice of the invention in its various embodiments and equivalents thereof.

[0223] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Formula (VII): AC (VII) A compound represented by the formula: A contains compounds that shift cardiac metabolism from fatty acid oxidation to glucose oxidation, C is NAD + The precursor molecule, compound. (Section 2) The compound according to item 1, wherein C is covalently linked to A. (Section 3) The compound according to item 2, wherein A is PEGylated with an ethylene glycol moiety. (Section 4) The ethylene glycol moiety is (CH2CH2O) x wherein x=1 to 15. (Section 5) Item 5. The compound according to item 4, wherein the covalent linkage is via the ethylene glycol moiety. (Section 6) Item 5. The compound according to item 4, wherein the covalent linkage is not via the ethylene glycol moiety. (Section 7) Item 1. The compound according to item 1, wherein A is selected from the group consisting of trimetazidine, etomoxir, perhexiline, PPAR agonists, malonyl-CoA decarboxylase inhibitors, and dichloroacetate. (Section 8) Item 1. The compound according to item 1, wherein C is selected from the group consisting of nicotinic acid, nicotinamide, and nicotinamide riboside. (Section 9) Item 9. The compound according to item 8, wherein C is nicotinic acid. (Section 10) Item 6. The compound according to item 5, wherein the compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation is a PEGylated form of trimetazidine. (Section 11) 11. The compound according to claim 10, wherein C is nicotinic acid covalently linked to said PEGylated form of trimetazidine. (Section 12) 12. The compound according to claim 11, wherein the nicotinic acid is covalently linked to the PEGylated form of trimetazidine via a PEGylated moiety. (Section 13) Formula (X): [ka] Item 13. The compound according to item 12, which is represented by: (Section 14) 12. The compound according to claim 11, wherein the nicotinic acid is covalently linked to the PEGylated form of trimetazidine via the trimetazidine moiety. (Section 15) Item 1. The compound according to item 1, wherein A is trimetazidine covalently linked to C, which is nicotinic acid. (Section 16) Formula (VIII): ALC (VIII) A compound represented by the formula: A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, L is a linker, C is NAD + The precursor molecule, compound. (Section 17) Item 17. The compound according to item 16, wherein A is selected from the group consisting of trimetazidine, etomoxir, perhexiline, PPAR agonists, malonyl-CoA decarboxylase inhibitors, and dichloroacetate. (Section 18) Item 18. The compound according to item 17, wherein A is trimetazidine. (Section 19) 17. The compound according to item 16, wherein C is selected from the group consisting of nicotinic acid, nicotinamide, and nicotinamide riboside. (Section 20) 20. The compound according to item 19, wherein C is nicotinic acid. (Section 21) L is (CH2CH2O) x Item 17. The compound according to item 16, comprising the formula: wherein x=1 to 15. (Section 22) 22. The compound according to item 21, wherein A is trimetazidine. (Section 23) Formula (X): [ka] 23. The compound according to item 22, which is represented by: (Section 24) Formula (VI): [ka] A compound represented by the formula: At least one of the A, B, C, D, E, and F positions is -(CH2CH2O) n substituted with H, and n=1 to 15; compound. (Section 25) 25. The compound according to item 24, wherein the F position is substituted. (Section 26) Formula (IX): [ka] 26. The compound according to item 25, which is represented by: (Section 27) Formula (I): ALB (I) A compound represented by the formula: A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, L is a linker, B is a compound that promotes mitochondrial respiration, compound. (Section 28) 28. The compound according to item 27, wherein A is selected from the group consisting of trimetazidine, etomoxir, perhexiline, PPAR agonists, malonyl-CoA decarboxylase inhibitors, and dichloroacetate. (Section 29) 29. The compound according to item 28, wherein A is trimetazidine. (Section 30) 30. The compound according to item 29, wherein B is selected from the group consisting of succinate, fumarate, malate, oxaloacetate, citrate, isocitrate, α-ketoglutarate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, and β-hydroxypentanoate. (Section 31) 31. The compound according to item 30, wherein B is succinate. (Section 32) L is (CH2CH2O) x 28. The compound according to item 27, comprising the formula: wherein x=1 to 15. (Section 33) and further comprising C chemically linked to said compound of formula (I), wherein C is NAD + 28. The compound according to item 27, which is a precursor molecule. (Section 34) 34. The compound according to claim 33, wherein C is selected from the group consisting of nicotinic acid, nicotinamide, and nicotinamide riboside. (Section 35) C is nicotinic acid and the compound of formula (I) has formula (II): [ka] 35. The compound according to item 34, which is represented by the formula: (Section 36) The compound of formula (I) is represented by formula (III): [ka] 32. The compound according to item 31, which is represented by the formula: (Section 37) Formula (IV): [ka] A compound represented by the formula: R 1 , R 2 , and R 3 are independently selected from the group consisting of H and (C1-C4) alkyl groups; R 4 and R 5 are taken together to form =O, -O(CH2) m O- or -(CH2) m - and m=2 to 4, or R 4 is H and R 5 is OR 14 , S.R. 14, or (CH2CH2O) n H and R 14 is H or a (C1-C4) alkyl group, and n=1 to 15; R 6 is a monocyclic or polycyclic structure optionally substituted with heteroatoms at one or more ring positions, each ring position optionally containing one or more substituents; compound. (Section 38) R 6 38. The compound according to claim 37, wherein at least one ring position of the formula (I) contains a substituent comprising a compound that promotes mitochondrial respiration. (Section 39) Item 39. The compound according to item 38, wherein the compound that promotes mitochondrial respiration is selected from the group consisting of succinate, fumarate, malate, oxaloacetate, citrate, isocitrate, α-ketoglutarate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, and β-hydroxypentanoate. (Section 40) 40. The compound according to item 39, wherein the compound that promotes mitochondrial respiration is succinate. (Section 41) The substituent is (CH2CH2O) x 39. The compound according to item 38, comprising: wherein x=1 to 15. (Section 42) The substituent is NAD + 39. The compound according to claim 38, comprising a precursor molecule. (Section 43) The NAD + 43. The compound according to claim 42, wherein the precursor molecule is selected from the group consisting of nicotinic acid, nicotinamide, and nicotinamide riboside. (Section 44) The NAD + The precursor molecule is nicotinic acid and the substituent is [ka] 44. The compound according to item 43, wherein y is 1 to 3. (Section 45) The substituent [ka] 41. The compound according to item 40, wherein y=1 to 3. (Section 46) R 6 but [ka] Item 38. The compound according to item 37, wherein (Section 47) Formula (IX) and formula (XO: [ka] 38. The compound according to item 37, which is represented by a structure selected from the group consisting of: (Section 48) Formula (V): [ka] A compound represented by the formula: R 1 , R 2 , and R 3 are independently selected from the group consisting of H and (C1-C4) alkyl groups; R 4 and R 8 are taken together to form =O, -O(CH2) m O- or -(CH2) m - and m=2 to 4, or R 4 is H and R 8 H, OR 14 , S.R. 14 , or (CH2CH2O) n H and R 14 is H or a (C1-C4) alkyl group, and n=115; R 9 , R 10 , R 12 , and R 13 is H and (CH2CH2O) zH, and z=1 to 6; R 11 contains compounds that promote mitochondrial respiration, compound. (Section 49) The respiration-promoting compound is a succinate, fumarate, malate, oxaloacetate, or 49. The compound according to item 48, wherein the compound is selected from the group consisting of acetone, citrate, isocitrate, α-ketoglutarate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, and β-hydroxypentanoate. (Section 50) 50. The compound according to claim 49, wherein the respiration-promoting compound is succinate. (Section 51) R 11 But (CH2CH2O) x 49. The compound according to item 48, further comprising: wherein x=1 to 15. (Section 52) R 11 but [ka] 52. The compound according to item 51, wherein y is 1 to 3. (Section 53) R 11 NAD + 49. The compound according to paragraph 48, further comprising a precursor molecule. (Section 54) The NAD + 54. The compound according to claim 53, wherein the precursor molecule is selected from the group consisting of nicotinic acid, nicotinamide, and nicotinamide riboside. (Section 55) NAD + The precursor molecule is nicotinic acid, and R 11 but [ka] 55. The compound according to item 54, wherein y=1 to 3. (Section 56) 1. A method for increasing cardiac metabolic efficiency in a subject, comprising administering to a subject a compound of formula (I): ALB (I) wherein: A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, L is a linker, B is a compound that promotes mitochondrial respiration, method. (Section 57) 57. The method according to item 56, wherein A is selected from the group consisting of trimetazidine, etomoxir, perhexiline, PPAR agonists, malonyl-CoA decarboxylase inhibitors, and dichloroacetate. (Section 58) 58. The method according to item 57, wherein A is trimetazidine. (Section 59) B is succinate, fumarate, malate, oxaloacetate, citrate, isopropyl 59. The method according to claim 58, wherein the hydroxybenzoate is selected from the group consisting of citrate, α-ketoglutarate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, and β-hydroxypentanoate. (Section 60) 60. The method according to claim 59, wherein B is succinate. (Section 61) L is (CH2CH2O) x 57. The method according to item 56, wherein x=1 to 15. (Section 62) The compound represented by formula (I) further comprises C chemically linked to the compound of formula (I), wherein C is an NAD + 57. The method according to claim 56, wherein the compound is a precursor molecule. (Section 63) 63. The method of claim 62, wherein C is selected from the group consisting of nicotinic acid, nicotinamide, and nicotinamide riboside. (Section 64) C is nicotinic acid and the compound of formula (I) has formula (II): [ka] 64. The method according to item 63 above, wherein the compound is represented by the formula: (Section 65) The compound of formula (I) is represented by formula (III): [ka] 61. The method according to item 60 above, wherein the formula is: (Section 66) 1. A method of increasing cardiac metabolic efficiency in a subject, comprising: The first compound to shift cardiac metabolism from fatty acid oxidation to glucose oxidation, a second compound that promotes mitochondrial respiration, and NAD + A third compound, which is a precursor molecule A method comprising: (Section 67) 67. The method of claim 66, wherein the first compound is selected from the group consisting of trimetazidine, etomoxir, perhexiline, PPAR agonists, malonyl-CoA decarboxylase inhibitors, and dichloroacetate. (Section 68) 68. The method of claim 67, wherein the first compound is trimetazidine. (Section 69) 67. The method of claim 66, wherein the second compound is selected from the group consisting of succinate, fumarate, malate, oxaloacetate, citrate, isocitrate, α-ketoglutarate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, and β-hydroxypentanoate. (Section 70) 70. The method of claim 69, wherein the second compound is a succinate. (Section 71) 67. The method of claim 66, wherein the third compound is selected from the group consisting of nicotinic acid, nicotinamide, and nicotinamide riboside. (Section 72) 72. The method of claim 71, wherein the third compound is nicotinic acid. (Section 73) 67. The method of claim 66, wherein the first compound, the second compound, and the third compound are provided in a single composition. (Section 74) 67. The method of claim 66, wherein the first compound, the second compound, and the third compound are not provided in a single composition. (Section 75) A composition comprising at least two selected from the group consisting of A, B, and C, A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, B is a compound that promotes mitochondrial respiration, C is NAD + The precursor molecule, composition. (Section 76) 76. The composition according to item 75, wherein the compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation is trimetazidine. (Section 77) 76. The composition according to claim 75, wherein the compound that promotes mitochondrial respiration is selected from the group consisting of succinate, fumarate, malate, oxaloacetate, citrate, isocitrate, α-ketoglutarate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, and β-hydroxypentanoate. (Section 78) The NAD + 76. The composition of claim 75, wherein the precursor molecule is selected from the group consisting of nicotinic acid, nicotinamide, and nicotinamide riboside. (Section 79) 76. The composition according to claim 75, comprising A, B, and C. (Section 80) a first molecule comprising A and B; a second molecule containing C; 80. The composition according to claim 79, comprising a cocrystal comprising: (Section 81) A is trimetazidine, B is a succinate, C is nicotinamide; Item 80. The composition according to item 80. (Section 82) The first molecule is a triglyceride covalently linked to a succinate via a linker. 82. The composition according to claim 81, comprising metazidine. (Section 83) The linker is (CH2CH2O) x 83. The composition according to item 82, comprising: (Section 84) 1. A method of treating heart failure, cardiac dysfunction, muscle myopathy, impaired mitochondrial function, or a condition associated with altered fatty acid oxidation in a subject, the method comprising administering to a subject a compound of formula (I): ALB (I) wherein: A is a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, L is a linker, B is a compound that promotes mitochondrial respiration, method. (Section 85) 85. The method according to item 84, wherein A is selected from the group consisting of trimetazidine, etomoxir, perhexiline, PPAR agonists, malonyl-CoA decarboxylase inhibitors, and dichloroacetate. (Section 86) 86. The method according to item 85, wherein A is trimetazidine. (Section 87) 87. The method of claim 86, wherein B is selected from the group consisting of succinate, fumarate, malate, oxaloacetate, citrate, isocitrate, α-ketoglutarate, pyruvate, acetone, acetoacetate, β-hydroxybutyrate, β-ketopentanoate, and β-hydroxypentanoate. (Section 88) 88. The method according to claim 87, wherein B is succinate. (Section 89) L is (CH2CH2O) x 85. The method according to item 84, wherein x=1 to 15. (Section 90) The compound represented by formula (I) further comprises C chemically linked to the compound of formula (I), wherein C is an NAD + 85. The method according to claim 84, wherein the compound is a precursor molecule. (Section 91) 91. The method of claim 90, wherein C is selected from the group consisting of nicotinic acid, nicotinamide, and nicotinamide riboside. (Section 92) C is nicotinic acid and the compound of formula (I) has formula (II): [ka] 92. The method according to item 91, wherein the compound is represented by the formula: (Section 93) The compound of formula (I) is represented by formula (III): [ka] 89. The method according to item 88, wherein the compound is represented by the formula: (Section 94) 1. A method of treating heart failure, cardiac dysfunction, muscle myopathy, impaired mitochondrial function, or a condition associated with altered fatty acid oxidation in a subject, comprising: The first compound to shift cardiac metabolism from fatty acid oxidation to glucose oxidation, a second compound that promotes mitochondrial respiration, and NAD + A third compound, which is a precursor molecule A method comprising:

Claims

[Claim 1] The invention described in the specification.

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