Combination therapy

Abstract

The present invention provides a combination therapy comprising CV-8972 and CV-8814. The combination therapy improves cardiac efficiency and is therefore useful for treating cardiovascular conditions in subjects. The present invention also provides a method of treating conditions using both CV-8972 and CV-8814, as well as a pharmaceutical composition comprising both CV-8972 and CV-8814. The present invention solves this problem through the use of a combination therapy comprising administration of CV-8972 and CV-8814 as separate compounds. The combination therapy is based on the recognition that the metabolic products resulting from the breakdown of CV-8972 exert different functions, and uncoupling these functions allows for the remediation of cardiovascular conditions with greater precision.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to combination therapies, methods of treating conditions, and pharmaceutical compositions, all of which contain both CV-8972 and CV-8814. [Background technology]

[0002] background Cardiovascular disease is the leading cause of death worldwide, accounting for an estimated 17.9 million deaths worldwide in 2019 (WHO). In many forms of cardiac disease, reduced cardiac efficiency results from alterations in mitochondrial energy metabolism. Mitochondria are intracellular compartments that oxidize metabolites derived from glucose and fatty acids to generate high-energy molecules. Increased fatty acid oxidation in the heart reduces glucose oxidation and vice versa. Although glucose oxidation is a more oxygen-efficient energy source, in certain types of cardiac disease (e.g., heart failure, ischemic heart disease, and diabetic cardiomyopathy), there is an excessive reliance on fatty acid oxidation that dominates in cardiac mitochondria and / or an uncoupling of glycolysis from glucose oxidation. As a result, the efficiency of energy production and generation of ATP is reduced and, consequently, the pumping capacity of the heart is reduced.

[0003] The compound, 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate (referred to herein as CV-8972), has recently been identified as a therapeutic candidate for improving cardiac efficiency in patients with various cardiovascular conditions. CV-8972 is a prodrug that is broken down in the body into multiple metabolic products that exert distinct and synergistic effects to promote energy production by cardiac mitochondria. The metabolic products of CV-8972 include niacin, 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethanol (referred to herein as CV-8814), and trimetazidine. The latter two products are generated, in turn, from CV-8972 catabolism. CV-8972 is first hydrolyzed to yield CV-8814 and niacin, and the ethylene glycol portion of CV-8814 is subsequently removed to yield trimetazidine. Both CV-8814 and trimetazidine inhibit the oxidation of fatty acids, thus forcing the heart to obtain energy from the oxidation of glucose instead. Niacin is a hormone that helps the body produce nicotinamide adenine dinucleotide (NAD + ), which facilitates the transfer of electrons in mitochondria, allowing cells to obtain energy from molecular oxygen. In conclusion, providing niacin to the heart maximizes the heart's ability to generate energy from its oxygen supply. Thus, the metabolism of CV-8972 promotes the production of molecules that stimulate glucose oxidation and NAD. + Branching off to generate molecules that serve as precursors, the two classes of CV-8972 metabolic products act in complementary manners to stimulate cardiac efficiency. Summary of the Invention [Means for solving the problem]

[0004] Abstract The present invention provides a therapeutic combination of CV-8972 and CV-8814, which allows the delivery of two classes of CV-8972 metabolites in an optimized ratio. The present invention recognizes that each molecule of CV-8972 administered to a patient produces CV-8814 and niacin in equimolar amounts, and optimal therapeutic intervention often requires a CV-8814:niacin ratio of greater than 1. First, CV-8814 is relatively well tolerated by the body due to its pharmacological properties. Second, the conversion of CV-8814 to trimetazidine in vivo is gradual, so that the systemic peak level of trimetazidine after a dose of CV-8814 is lower and slower than the peak after a comparable dose of pure trimetazidine. However, compared to CV-8814, niacin is not well tolerated on a molar equivalent basis. Administration of high doses of niacin results in flushing and other side effects, which are niacin-mediated effects that limit the dose at which CV-8972 can be administered.

[0005] The present invention solves this problem through the use of a combination therapy involving the administration of CV-8972 and CV-8814 as separate compounds. The combination therapy is based on the recognition that the metabolic products resulting from the breakdown of CV-8972 exert different functions, and uncoupling of their functions allows for the remediation of cardiovascular conditions with greater precision. The metabolism of CV-8972 produces both niacin and other molecules that promote glucose oxidation, namely CV-8814 and trimetazidine, whereas the metabolism of CV-8814 produces only trimetazidine. By providing CV-8972 and CV-8814 as separate therapeutic agents, NAD + The administration of the precursor niacin and the product that promotes glucose oxidation can be independently adjusted. In conclusion, the combination therapy allows each of the active metabolic products of these drugs to be delivered at optimal therapeutic levels. The treatment and method of the present invention are useful for treating a wide range of cardiovascular conditions.

[0006] In one aspect, the present invention provides a compound of formula (X): [ka] or a pharma- ceutically acceptable salt thereof, and Formula (IX): [ka] or a pharma- ceutically acceptable salt thereof; The present invention provides a combination therapy comprising:

[0007] The combination therapy may include compounds of formula (X) and (IX) in a specified weight ratio. The weight ratio of the compound of formula (X) to the compound of formula (IX) may be about 10:1, about 5:1, about 2:1, about 1:1, about 1:2, about 1:5, about 1:10, about 1:20, about 1:50, or about 1:100. The weight ratio of the compound of formula (X) to the compound of formula (IX) may be about 10:1 to about 5:1, about 10:1 to about 2:1, about 10:1 to about 1:1, about 10:1 to about 1:2, about 10:1 to about 1:5, about 10:1 to about 1:10, about 10:1 to about 1:20, about 10:1 to about 1:50, about 10:1 to about 1:100, about 5:1 to about 2:1, about 5:1 to about 1:1, about 5:1 to about 1:2, about 5:1 to about 1:5, about 5:1 to about 1:10, about 5:1 to about 1:20, about 5:1 to about 1:50, about 5:1 to about 1:100, about 2:1 to about 1:1, about 2:1 to about 1:2, about 2:1 to about 1:5, about 2:1 to about 1:10, about 2:1 to about 1:20, about 2:1 to about 1:50, about 2:1 to about 1:100, about 1:1 to about 1:2, about 1:1 to about 1:5, about 1:1 to about 1:10, about 1:1 to about 1:20, about 1:1 to about 1:50, about 1:1 to about 1:100, about 1:2 to about 1:5, about 1:2 to about 1:10, about 1:2 to about 1:20, about 1:2 to about 1:50, about 1:2 to about 1 1:100, about 1:5 to about 1:10, about 1:5 to about 1:20, about 1:5 to about 1:50, about 1:5 to about 1:100, about 1:10 to about 1:20, about 1:10 to about 1:50, about 1:10 to about 1:100, about 1:20 to about 1:50, about 1:20 to about 1:100, or about 1:50 to about 1:100.

[0008] The combination therapy may include one or both of the compounds of formula (X) and (IX) in a prescribed daily dosage. The daily dosage of the compounds of formula (X) and (IX) may be, independently, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, about 1000 mg, about 2000 mg, or about 5000 mg. The daily doses of the compounds of formula (X) and (IX) are each independently about 10 mg to about 20 mg, about 10 mg to about 50 mg, about 10 mg to about 100 mg, about 10 mg to about 200 mg, about 10 mg to about 500 mg, about 10 mg to about 1000 mg, about 10 mg to about 2000 mg, about 10 mg to about 5000 mg, about 20 mg to about 50 mg, about 20 mg to about 100 mg, about 20 mg to about 200 mg, about 20 mg to about 500 mg, about 20 mg to about 1000 mg, about 20 mg to about 2000 mg, about 20 mg to about 5000 mg, about 50 mg to about 100 mg, about 50 mg to about 200 mg, about 50 mg to about 500 mg, about 50 mg to about 50 mg g to about 1000 mg, about 50 mg to about 2000 mg, about 50 mg to about 5000 mg, about 100 mg to about 200 mg, about 100 mg to about 500 mg, about 100 mg to about 1000 mg, about 100 mg to about 2000 mg, about 100 mg to about 5000 mg, about 200 mg to about 500 mg, about 200 mg to about 1000 mg, about 200 mg to about 2000 mg, about 200 mg to about 5000 mg, about 500 mg to about 1000 mg, about 500 mg to about 2000 mg, about 500 mg to about 5000 mg, about 1000 mg to about 2000 mg, about 1000 mg to about 5000 mg, or about 2000 mg to about 5000 mg.

[0009] The compounds of formula (X) and (IX) may be contained in separate formulations. The compounds of formula (X) and (IX) may be contained in a single formulation.

[0010] The combination therapy may be effective to treat any disease, disorder, or condition in which increased cardiac efficiency provides a therapeutic benefit. The disease, disorder, or condition may be a cardiovascular condition. The disease, disorder, or condition may be: Acute coronary syndrome, acute heart failure, advanced heart failure, aneurysm, angina pectoris, anthracycline-induced cardiotoxicity, atherosclerosis, cardiac allograft vasculopathy, cardiac steatosis, cardiac transplant vasculopathy, cardiomyopathy, cerebrovascular disease, chronic coronary syndrome, chronic heart failure, congestive heart failure, contrast nephropathy nephropathy, coronary artery disease (CAD), coronary heart disease, diabetic cardiomyopathy, dilated cardiomyopathy (DCM, including idiopathic), heart attack, heart disease, heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), heart failure, hibernating myocardium, high blood pressure (hypertension), hypertrophic cardiomyopathy (HCM, including non-obstructive or obstructive), intermittent claudication, ischemia with non-obstructive coronary arteries (INOCA), ischemia-reperfusion injury, ischemic cardiomyopathy, ischemic heart Disease, microvascular angina, myocardial dysfunction induced by anticancer drugs, myocardial infarction with nonobstructive coronary arteries (MINOCA), myocarditis (nonfamilial and familial / hereditary), nonischemic cardiomyopathy, pericardial disease, peripartum cardiomyopathy, peripheral arterial disease, peripheral vascular disease, pulmonary arterial hypertension, pulmonary hypertension, refractory angina, restrictive cardiomyopathy, rheumatic heart disease, right heart failure, right ventricular failure, stable angina, stroke, stunning, tachycardiomyopathy, Takotsubo cardiomyopathy, transient ischemic attack, unstable angina, or valvular heart disease.

[0011] In another aspect, the present invention provides a method of treating a disease, disorder, or condition in a subject, comprising administering to a subject a compound of formula (X): [ka] or a pharma- ceutically acceptable salt thereof, and Formula (IX): [ka] or a pharma- ceutically acceptable salt thereof to a subject having the disease, disorder, or condition.

[0012] The compounds of formula (X) and (IX) may be provided in a defined weight ratio, such as any of those described above.

[0013] Each of the compounds of formula (X) and (IX) may be independently provided in a defined daily dosage, such as any of those described above.

[0014] The compounds of formula (X) and (IX) may be provided in separate formulations. The compounds of formula (X) and (IX) may be provided in a single formulation.

[0015] The disease, disorder, or condition can be any disease, disorder, or condition (eg, any of those listed above) in which increased cardiac efficiency provides a therapeutic benefit.

[0016] In another aspect, the present invention relates to a compound of formula (X): [ka] or a pharma- ceutically acceptable salt thereof, and Formula (IX): [ka] or a pharma- ceutically acceptable salt thereof; The present invention provides a pharmaceutical composition comprising:

[0017] The pharmaceutical composition may contain compounds of formula (X) and (IX) in a defined weight ratio (eg, any of those described above).

[0018] The pharmaceutical compositions may contain one or both of the compounds of formula (X) and (IX) in a prescribed daily dosage amount (eg, any of those described above).

[0019] The pharmaceutical composition may be formulated for a specific delivery route or mode. The pharmaceutical composition may be formulated for administration intraorally, by injection, into the skin, enterally, intraarterially, intravenously, nasally, orally, parenterally, pulmonary, rectally, subcutaneously, topically, transdermally, or with or on an implanted medical device (e.g., a stent or drug-eluting stent or balloon equivalent).

[0020] The pharmaceutical composition may be a modified release formulation.

[0021] The pharmaceutical composition can be suitable for treating a particular disease, disorder, or condition, such as any of those mentioned above. BRIEF DESCRIPTION OF THE DRAWINGS [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 is a schematic diagram of the positron emission tomography (PET) imaging study design used to monitor 18F-fluorodeoxyglucose (18F-FDG) and 18F-14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid (18F-FTHA) uptake into rat cardiac tissue in response to treatment with CV-8972.

[0023] [Diagram 2] FIG. 2 is a graph showing the mean standardized uptake value (SUV) of FDG in the heart at various time points after administration of either saline or CV-8972 to rats.

[0024] [Diagram 3] FIG. 3 is a graph showing the mean SUV of FDG in skeletal muscle at various time points after administration of saline or CV-8972 to rats.

[0025] [Figure 4]FIG. 4 is a graph showing the mean SUV of FDG in blood at various time points after administration of either saline or CV-8972 to rats.

[0026] [Diagram 5] FIG. 5 is a graph showing the mean SUV of FTHA in the heart at various time points after administration of either saline or CV-8972 to rats.

[0027] [Figure 6] FIG. 6 is a graph showing the mean SUV of FTHA in skeletal muscle at various time points after administration of either saline or CV-8972 to rats.

[0028] [Figure 7] FIG. 7 is a graph showing the mean SUV of FTHA in blood at various time points after administration of either saline or CV-8972 to rats.

[0029] [Figure 8] Figure 8 shows PET / CT images of FDG and FTHA after administration of either saline or CV-8972 to rats.

[0030] [Figure 9] FIG. 9 is a graph showing the mean SUV of FDG in heart, skeletal muscle, and blood during the last 30 minutes of dynamic acquisition after administration of either saline or CV-8972 to rats.

[0031] [Figure 10] FIG. 10 is a graph showing the mean SUV of FTHA in heart, skeletal muscle, and blood during the final 30 minutes of dynamic acquisition after administration of either saline or CV-8972 to rats.

[0032] [Figure 11]FIG. 11 is a graph of FDG uptake in the myocardium following administration of either saline or CV-8972 to rats.

[0033] [Figure 12] FIG. 12 is a graph of the flow of FDG activity in the myocardium following administration of either saline or CV-8972 to rats.

[0034] [Figure 13] FIG. 13 is a graph of FDG uptake in skeletal muscle following administration of either saline or CV-8972 to rats.

[0035] [Figure 14] FIG. 14 is a graph of the flow of FDG activity in skeletal muscle following administration of either saline or CV-8972 to rats.

[0036] [Figure 15] FIG. 15 is a graph of FTHA uptake in the myocardium following administration of either saline or CV-8972 to rats.

[0037] [Figure 16] FIG. 16 is a graph of the pharmacokinetic parameter V1 of FTHA uptake in the myocardium following administration of either saline or CV-8972 to rats.

[0038] [Figure 17] FIG. 17 is a graph of the pharmacokinetic parameter V2 of FTHA uptake in the myocardium following administration of either saline or CV-8972 to rats.

[0039] [Figure 18] FIG. 18 is a graph of the flow of FTHA activity in the myocardium following administration of either saline or CV-8972 to rats.

[0040] [Figure 19] FIG. 19 is a graph of FTHA uptake in skeletal muscle following administration of either saline or CV-8972 to rats.

[0041] [Figure 20] FIG. 20 is a graph of the pharmacokinetic parameter V1 of FTHA uptake in skeletal muscle following administration of either saline or CV-8972 to rats.

[0042] [Figure 21] FIG. 21 is a graph of the pharmacokinetic parameter V2 of FTHA uptake in skeletal muscle following administration of either saline or CV-8972 to rats.

[0043] [Figure 22] FIG. 22 is a graph of the flow of activity of FTHA in skeletal muscle following administration of either saline or CV-8972 to rats.

[0044] [Diagram 23] FIG. 23 is a graph of gamma radioactivity from FDG in heart, skeletal muscle, and blood following administration of either saline or CV-8972 to rats.

[0045] [Figure 24] FIG. 24 is a graph of gamma radioactivity from FTHA in heart, skeletal muscle, and blood following administration of either saline or CV-8972 to rats.

[0046] [Diagram 25] FIG. 25 is a schematic diagram of the Langendorff ischemia-reperfusion protocol used to test the ability of various compounds to protect the heart from ischemic injury.

[0047] [Figure 26]FIG. 26 is a graph of coronary flow during ischemia-reperfusion injury in explanted mouse hearts treated with either saline or 20 μM CV-8814.

[0048] [Figure 27] FIG. 27 is a graph of infarct size following ischemia-reperfusion injury in explanted mouse hearts treated with either saline or 20 μM CV-8814.

[0049] [Figure 28] FIG. 28 is a graph of infarct size following ischemia-reperfusion injury in explanted mouse hearts treated with either saline or 20 μM trimetazidine.

[0050] [Figure 29] FIG. 29 is a graph of infarct size following ischemia-reperfusion injury in explanted mouse hearts treated with saline, 20 μM trimetazidine, trimetazidine+nicotinamide+succinate at 20 μM each, or trimetazidine+nicotinic acid+succinate at 20 μM each.

[0051] [Diagram 30] FIG. 30 is a schematic diagram of the transverse aortic constriction (TAC) protocol used to test the ability of various compounds to protect the heart from heart failure.

[0052] [Diagram 31] FIG. 31 shows images of mouse hearts after TAC-induced heart failure.

[0053] [Diagram 32] FIG. 32 is a graph of heart weight versus body weight following TAC-induced heart failure in mice treated with saline, trimetazidine, nicotinic acid, CV-8814, or CV-8972.

[0054] [Diagram 33] FIG. 33 is a graph of cardiac ejection fraction at various time points following TAC-induced heart failure in mice treated with either saline or CV-8972.

[0055] [Diagram 34] FIG. 34 is a graph of cardiac ejection fraction at various time points following TAC-induced heart failure in mice treated with either saline or CV-8814.

[0056] [Diagram 35] FIG. 35 is a graph of cardiac ejection fraction at various time points following TAC-induced heart failure in mice treated with either saline or trimetazidine.

[0057] [Diagram 36] FIG. 36 shows microscopic images of heart tissue from mice following TAC-induced heart failure.

[0058] [Figure 37] FIG. 37 is a graph of cardiac fibrosis following TAC-induced heart failure in mice treated with saline, trimetazidine, nicotinic acid, CV-8814, or CV-8972.

[0059] [Figure 38] FIG. 38 is a schematic diagram of the two-compartment model.

[0060] [Figure 39] FIG. 39 is a schematic diagram of the three compartment model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0061] Detailed Description In many forms of cardiac disease, changes in mitochondrial energy metabolism result in a decrease in cardiac efficiency. Cardiac mitochondria use oxygen to generate adenosine triphosphate (ATP), a high-energy molecule that drives many cellular processes, from metabolic products obtained from the oxidation of glucose or fatty acids. Increased fatty acid oxidation in the heart decreases glucose oxidation, and vice versa. Although glucose oxidation is a more oxygen-efficient energy source, there is an excessive reliance on fatty acid oxidation and / or uncoupling of glycolysis from glucose oxidation in cardiac mitochondria of patients suffering from certain types of cardiac disease (e.g., heart failure, ischemic heart disease, and diabetic cardiomyopathy). As a result, the efficiency of energy production and generation of ATP is reduced, and, ultimately, the pumping capacity of the heart is reduced.

[0062] The compound, 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate (referred to herein as CV-8972), has recently been identified as a therapeutic candidate to improve cardiac efficiency in patients with various cardiovascular conditions. CV-8972 is a dual prodrug that is broken down in the body into metabolic products that fall into two distinct functional classes. The first class of metabolic products promotes glucose oxidation by inhibiting the oxidation of fatty acids and includes trimetazidine and its ethylene glycol derivative, 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethanol (referred to herein as CV-8814). These products are generated sequentially from CV-8972 catabolism: CV-8972 is first hydrolyzed to yield CV-8814 and niacin, and the ethylene glycol portion of CV-8814 is subsequently removed to yield trimetazidine. Niacin represents the second functional class of CV-8972 metabolites because it is the nicotinamide adenine dinucleotide (NAD + This is because it acts as a precursor to NAD. +Niacin mediates electron transport (which allows mitochondria to obtain energy from the citric acid cycle) and oxidative phosphorylation in mitochondria. Thus, niacin increases the efficiency of energy production by cardiac mitochondria, regardless of whether the citric acid cycle is driven by products generated by the oxidation of glucose or fatty acids.

[0063] The insight of the present invention is that optimal therapeutic intervention often requires providing members of different functional classes of CV-8972 metabolites in different amounts. However, when CV-8972 is administered to a patient, it is important to provide promoters of glucose oxidation versus NAD. + The ratio of the precursor niacin is fixed. Furthermore, the upper limit of the therapeutic window of CV-8972 is determined by the side effects resulting from the effective dose of niacin that the patient receives. In contrast, side effects that can be attributed to the effective dose of CV-8814 and trimetazidine are relatively minor when CV-8972 is administered at the upper end of the tolerated dose, and the patient may benefit from higher levels of CV-8814 and trimetazidine than those provided by such doses of CV-8972. The present invention solves this problem through the use of a combination therapy that includes administration of CV-8972 and CV-8814 as separate compounds. The metabolism of CV-8972 produces both facilitators of glucose oxidation and niacin, whereas the metabolism of CV-8814 produces only glucose oxidation. By providing CV-8972 and CV-8814 as separate therapeutic agents, the administration of a product that promotes glucose oxidation and the administration of NAD + The administration of the precursor niacin can be independently adjusted. In conclusion, the combination therapy allows each of the active metabolic products of these drugs to be delivered at optimal therapeutic levels. The treatments and methods of the present invention are useful for treating a wide range of cardiovascular conditions.

[0064] Combination therapy including CV-8972 and 8814 The present invention provides a combination therapy comprising CV-8972 and CV-8814. CV-8972 has the formula (X): [ka] It has the structure: When CV-8972 is administered to a subject, it is first broken down into niacin (also known as nicotinic acid) and CV-8814, which has the formula (IX): [ka] It has the structure: CV-8814 is a hydroxyethyl derivative of trimetazidine, the hydroxyethyl group being subsequently removed in the body to provide trimetazidine. CV-8814 is described in U.S. Patent No. 4,100,285, and CV-8972 and its metabolic products are described in U.S. Patent No. 10,556,013, the contents of each of which are incorporated herein by reference.

[0065] The therapeutic properties of CV-8972 are due to the effects of its various metabolic products. As mentioned above, niacin acts as a nicotinamide adenine dinucleotide (NAD + ) (the oxidized form of the coenzyme essential in mitochondrial electron transport reactions). + The supply of precursors ensures that mitochondrial redox reactions are robust and drive ATP synthesis, regardless of whether glucose or fatty acid oxidation is used to feed the citric acid cycle.

[0066] Other important metabolic products of CV-8972 are CV-8814 and trimetazidine. Both CV-8814 and trimetazidine inhibit 3-ketoacyl-CoA thiolase, which is required for fatty acid oxidation. As a result, cells are forced to rely on glucose oxidation to generate metabolites that can drive the citric acid cycle and support oxidative phosphorylation to generate ATP. Thus, both 8814 and trimetazidine are active pharmaceutical ingredients (APIs) generated by the metabolism of CV-8972. However, CV-8814 does not produce the same undesirable side effects as trimetazidine. Furthermore, due to the sequential metabolism of CV-8972, the circulating levels of trimetazidine after a dose of CV-8972 are much lower than the levels after a comparable dose of trimetazidine itself. Thus, compared to pure trimetazidine, CV-8972 provides more sustained levels of circulating API and fewer side effects.

[0067] The combination therapy of the present invention includes CV-8972 and CV-8814 as separate compounds, and thus the treatment is NAD + This allows the relative amounts of the precursors niacin and glucose oxidation promoter to be adjusted for optimal therapeutic invention. For example, if it is determined that a patient benefits from a molar ratio of niacin to glucose oxidation promoter close to 1 (i.e., only slightly less than 1:1), a combination therapy with a high ratio of CV-8972:CV-8814 is used. However, for many patients, it is advantageous to deliver a much lower molar ratio of niacin to glucose oxidation promoter, e.g., ≦1:2, and a combination therapy with a low ratio of CV-8972:CV-8814 is suitable for those patients. The ratio of CV-8972:CV-8814 can be expressed as a mass ratio, a molar ratio, or any other suitable indicator of the relative amounts of the two compounds.

[0068] By way of example and not limitation, the mass ratio of the compound of formula (X) to the compound of formula (IX) can be about 10:1, about 5:1, about 2:1, about 1:1, about 1:2, about 1:5, about 1:10, about 1:20, about 1:50, or about 1:100. The mass ratio of the compound of formula (X) to the compound of formula (IX) can be about 10:1 to about 5:1, about 10:1 to about 2:1, about 10:1 to about 1:1, about 10:1 to about 1:2, about 10:1 to about 1:5, about 10:1 to about 1:10, about 10:1 to about 1:20, about 10:1 to about 1:50, about 10:1 to about 1:100, about 5:1 to about 2:1 ... :1 to about 1:1, about 5:1 to about 1:2, about 5:1 to about 1:5, about 5:1 to about 1:10, about 5:1 to about 1:20, about 5:1 to about 1:50, about 5:1 to about 1:100, about 2:1 to about 1:1, about 2:1 to about 1:2, about 2:1 to about 1:5, about 2:1 to about 1:10, about 2:1 to about 1:20, about 2:1 to about 1 :50, about 2:1 to about 1:100, about 1:1 to about 1:2, about 1:1 to about 1:5, about 1:1 to about 1:10, about 1:1 to about 1:20, about 1:1 to about 1:50, about 1:1 to about 1:100, about 1:2 to about 1:5, about 1:2 to about 1:10, about 1:2 to about 1:20, about 1:2 to about 1:50, about 1:2 to about 1: The ratio of the glycerol to the total amount of the glycerol may be about 1:100, about 1:5 to about 1:10, about 1:5 to about 1:20, about 1:5 to about 1:50, about 1:5 to about 1:100, about 1:10 to about 1:20, about 1:10 to about 1:50, about 1:10 to about 1:100, about 1:20 to about 1:50, about 1:20 to about 1:100, or about 1:50 to about 1:100.

[0069] The combination therapy of the present invention may include a specified daily dosage of CV-8972, CV8814, or both. The daily dosage of a compound indicates the amount of that compound to be provided to a subject over a 24-hour period. The daily dosage may be provided in a single dose, or it may be provided in multiple doses at different times over a 24-hour period. For example, the daily dosage may be provided in two, three, four, five, six, seven, eight, or more doses. By way of example and not limitation, the daily dosage of the compound of formula (X) and (IX) may each independently be about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, about 1000 mg, about 2000 mg, or about 5000 mg. The daily doses of the compounds of formula (X) and (IX) are each independently about 10 mg to about 20 mg, about 10 mg to about 50 mg, about 10 mg to about 100 mg, about 10 mg to about 200 mg, about 10 mg to about 500 mg, about 10 mg to about 1000 mg, about 10 mg to about 2000 mg, about 10 mg to about 5000 mg, about 20 mg to about 50 mg, about 20 mg to about 100 mg, about 20 mg to about 200 mg, about 20 mg to about 500 mg, about 20 mg to about 1000 mg, about 20 mg to about 2000 mg, about 20 mg to about 5000 mg, about 50 mg to about 100 mg, about 50 mg to about 200 mg, about 50 mg to about 500 mg, about 50 mg to about 50 mg g to about 1000 mg, about 50 mg to about 2000 mg, about 50 mg to about 5000 mg, about 100 mg to about 200 mg, about 100 mg to about 500 mg, about 100 mg to about 1000 mg, about 100 mg to about 2000 mg, about 100 mg to about 5000 mg, about 200 mg to about 500 mg, about 200 mg to about 1000 mg, about 200 mg to about 2000 mg, about 200 mg to about 5000 mg, about 500 mg to about 1000 mg, about 500 mg to about 2000 mg, about 500 mg to about 5000 mg, about 1000 mg to about 2000 mg, about 1000 mg to about 5000 mg, or about 2000 mg to about 5000 mg.

[0070] The combination therapy may include CV-8972 and CV-8814 that are contained or provided in separate formulations. The combination therapy may include CV-8972 and CV-8814 that are contained or provided in a single formulation.

[0071] In the combination therapy of the present invention, each of CV-8972 and CV-8814 may, independently, be present as a pharma- ceutically acceptable salt.

[0072] In the combination therapy of the present invention, each of CV-8972 and CV-8814 can independently contain one or more isotopically enriched atoms.For example, the compound can have one or more hydrogen atoms replaced with deuterium or tritium.Isotopic substitution or enrichment can occur at carbon, sulfur, or phosphorus, or other atoms.The compound can be isotopically substituted or enriched at a given atom at one or more positions within the compound, or the compound can be isotopically substituted or enriched at all instances of a given atom within the compound.

[0073] Pharmaceutical Compositions The present invention provides pharmaceutical compositions comprising CV-8972, CV-8814, or both. The compositions can be formulated for any route or mode of administration. By way of example and not limitation, the compositions can be formulated for oral, dermal, enteral, intraarterial, intramuscular, intraocular, intravenous, nasal, oral, parenteral, pulmonary, rectal, subcutaneous, topical, or transdermal administration. The compositions can be formulated for administration by injection or with or on an implantable medical device (e.g., a stent or drug-eluting stent or balloon equivalent).

[0074] Pharmaceutical compositions containing one or more of the above compounds may be in a form suitable for oral use (e.g., as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs). Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from sweeteners, flavoring agents, coloring agents and preservatives to provide pharmacopoeia-excellent and palatable preparations. Tablets contain the above compounds in admixture with non-toxic pharmacopoeia-exceptible excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate); granulating and disintegrating agents (such as corn starch, or alginic acid); binding agents (such as starch, gelatin or gum acacia), and lubricants (such as magnesium stearate, stearic acid or talc). The tablets can be uncoated or they can be coated by known techniques to delay disintegration in the stomach and absorption in the lower gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material (such as glyceryl monostearate or glyceryl distearate) can be used. They can also be coated by the techniques described in U.S. Pat. Nos. 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release. Preparation and administration of the compounds are discussed in US Pat. No. 6,214,841 and US Patent Publication No. 2003 / 0232877, which are incorporated by reference herein in their entireties.

[0075] Formulations for oral use may also be presented as hard gelatin capsules in which the compound is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the compound is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil). Alternative oral formulations, where control of the gastrointestinal hydrolysis of the compound is desired, may be achieved using controlled release formulations, in which the compound is encapsulated in an enteric coating.

[0076] Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); dispersing or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene containing partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate)). The aqueous suspensions may also contain one or more preservatives (e.g., ethyl or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, one or more sweetening agents (e.g., sucrose or saccharin).

[0077] Oily suspensions can be formulated by suspending the compound in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. The oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0078] 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 sweeteners, flavorings and coloring agents may also be present.

[0079] Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oil phase can be vegetable oil (e.g. olive oil or peanut oil) or mineral oil (e.g. liquid paraffin) or mixtures thereof. Suitable emulsifiers can be naturally occurring gums (e.g. acacia gum or tragacanth gum), naturally occurring phosphatides (e.g. soybean, lecithin), and esters or partial esters derived from fatty acids and hexitol anhydrides (e.g. sorbitan monooleate) and condensation products of the above partial esters with ethylene oxide (e.g. polyoxyethylene sorbitan monooleate). The emulsions can also contain sweeteners and flavoring agents.

[0080] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and a flavoring and / or coloring agent. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned above. Sterile injectable preparations may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any mild fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0081] The modified release formulation of the pharmaceutical composition may include a mixture that includes an erodible polymer that promotes the swelling of the mixture in an aqueous environment. Pharmaceutical compositions that include CV-8972 and one or more erodible polymers are described in co-pending co-owned application Ser. Nos. 63 / 046,115 and 63 / 046,117. An erodible polymer is any polymer that degrades within the body within a physiologically relevant time frame. The erodible polymer may have other properties that promote the gradual release of the modified form of trimetazidine from the mixture. By way of example and not limitation, the polymer may be one or more of the following: biocompatible, i.e., not harmful to living tissue; hydrophilic; hygroscopic; prone to form hydrogels.

[0082] Without wishing to be bound by theory, the polymer-containing mixture may promote gradual release by one or more mechanisms. For example, swelling of the mixture by absorption of water may facilitate diffusion of modified forms of trimetazidine from the mixture. Degradation of the polymer may also allow modified forms of trimetazidine to be released from the mixture. Osmotic pressure resulting from a high concentration gradient of the compound between the inside and outside of the mixture may also contribute to diffusion of modified forms of trimetazidine from the mixture.

[0083] By way of example and not limitation, the polymer may be a cellulose derivative, a gelatin derivative, such as a cross-linked gelatin derivative, or a polyester derivative.

[0084] Derivatives of cellulose, which is a linear chain of β(1→4) linked D-glucose units, include polymers containing substitutions on one or more of the hydroxyl groups of each glucose unit. The substitutions can be organic or inorganic and are typically linked via ester or ether bonds. Cellulose ester derivatives include carboxymethylcellulose (CMC), such as sodium carboxymethylcellulose, ethylcellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and methylcellulose. Cellulose ether derivatives include cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose propionate, cellulose sulfate, cellulose triacetate, and nitrocellulose. The use of cellulose-based polymers to form biodegradable hydrogels is known in the art and is described, for example, in Sannino et al., Biodegradable Cellulose-based Hydrogels: Design and Applications, Materials 2009, 2, 353-373; doi:10.3390 / ma2020353, the contents of which are incorporated herein by reference.

[0085] The mixture may contain multiple polymers or multiple polymer forms of the same polymer. For example, HPMC polymer forms may differ in various physical properties including viscosity, degree of methoxyl substitution, degree of hydroxypropoxyl substitution, or average molecular weight.

[0086] The viscosity of the HPMC polymer form can be determined by testing under standard conditions including the concentration of HPMC in solution and the temperature of the solution. By way of example and not limitation, the HPMC concentration can be 1%, 1.5%, 2%, 2.5%, or 3%. By way of example and not limitation, the temperature of the solution can be 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C.

[0087] Polymeric forms of cellulose derivatives (eg, HPMC) can have a defined viscosity. By way of example and not limitation, polymer forms of HPMC may have a viscosity of from about 2 cP to about 4 cP, from about 4 cP to about 6 cP, from about 5 cP to about 8 cP, from about 12 cP to about 18 cP, from about 40 cP to about 60 cP, from about 80 cP to about 120 cP, from about 300 cP to about 500 cP, from about 1200 cP to about 2400 cP, from about 2500 cP to about 5000 cP, from about 9000 cP to about 18,000 cP, from about 12,000 cP to about 24,000 cP, from about 12,000 cP to about 24,000 cP, from about 75,000 cP to about 150,000 cP, at least about 2 cP, at least about 4 cP, at least The viscosity may be less than about 5 cP, at least about 12 cP, at least about 40 cP, at least about 80 cP, at least about 300 cP, at least about 1200 cP, at least about 2500 cP, at least about 9000 cP, at least about 12,000 cP, at least about 12,000 cP, at least about 75,000 cP, less than about 4 cP, less than about 6 cP, less than about 8 cP, less than about 18 cP, less than about 60 cP, less than about 120 cP, less than about 500 cP, less than about 2400 cP, less than about 5000 cP, less than about 18,000 cP, less than about 24,000 cP, less than about 24,000 cP, or less than about 150,000 cP.

[0088] The polymeric forms of cellulose derivatives (e.g., HPMC) can vary in their degree of substitution of glucose units. The degree of substitution can be expressed as the weight percentage of the substituent or as the molar ratio of the substituent to the glucose unit. For cellulose derivatives (e.g., HPMC) with two different substituents, the polymeric forms can be described by the degree of substitution for each substituent.

[0089] Each polymeric form of HPMC can independently have a defined degree of methoxyl substitution. By way of example and not limitation, the degree of methoxyl substitution can be from about 19% to about 24%, from about 22% to about 24%, from about 27% to about 30%, from about 27% to about 30%, or from about 28% to about 32%.

[0090] Each polymeric form of HPMC can independently have a defined degree of hydroxypropoxyl substitution. By way of example and not limitation, the degree of hydroxypropoxyl substitution can be from about 4% to about 8%, from about 7% to about 10%, from about 7% to about 12%, from about 8% to about 10%, from about 8% to about 11%, or from about 9% to about 12%.

[0091] Each polymeric form of HPMC can independently have a defined average molecular weight, which can be about 10 kDa, about 13 kDa, about 20 kDa, about 26 kDa, about 41 kDa, about 63 kDa, about 86 kDa, about 110 kDa, about 120 kDa, about 140 kDa, about 180 kDa, or about 220 kDa.

[0092] When multiple forms of a polymer (e.g., HPMC) are present, one or more polymer forms may be present in a given amount. By way of example and not limitation, a polymer (e.g., HPMC) may comprise about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% by weight of one polymer form.

[0093] The pharmaceutical composition may include a crystalline form of CV-8972 or CV-8814. As described in co-pending co-owned U.S. Patent Application No. 63 / 046,120, CV-8972 may exist in at least five polymorphs: Form A, Form B, Form C, Form D, and Form E. The pharmaceutical composition may include one polymorph of CV-8972 and may be substantially free of one or more other polymorphs. For example, the composition may include a polymorph named Form A and may be substantially free of Form B, Form C, Form D, and Form E.

[0094] A composition containing a polymorph of CV-8972 may be substantially free of one or more other polymorphs of CV-8972 if the composition contains a predominant polymorph at a specified level of purity. Purity may be expressed as the amount of the predominant polymorph as a percentage of the total weight of two or more polymorphs of CV-8972.

[0095] In certain embodiments, the total weight is the weight of all polymorphs of CV-8972 in the composition. For example, a composition comprising the polymorph of Form A and substantially free of other polymorphs may comprise Form A in a specified weight percentage of all polymorphs of CV-8972 in the composition. For example, the composition may comprise at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of all polymorphs of CV-8972 in the composition.

[0096] In certain embodiments, the total weight is the weight of the selected polymorph of CV-8972 in the composition. For example, a composition comprising the Form A polymorph and substantially free of the Form B polymorph may comprise Form A in a specified percentage by weight of Forms A and B. For example, the composition may comprise Form A in at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9% by weight of Forms A and B of CV-8972 in the composition. Similarly, a composition comprising the Form A polymorph and substantially free of the Forms B and C polymorphs may comprise Form A in a specified percentage by weight of Forms A, B, and C. For example, the composition can comprise Form A in at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of Forms A, B, and C of CV-8972 in the composition.

[0097] Alternatively or additionally, a composition comprising a polymorph of CV-8972 may be substantially free of one or more other polymorphs of CV-8972, where the composition comprises the second polymorph at a level less than a specified level. The presence of a second polymorph may define the amount of the one or more second polymorphs as a percentage of the total weight of the two or more polymorphs of CV-8972.

[0098] In certain embodiments, the total weight is the weight of all polymorphs of CV-8972 in the composition. For example, a composition comprising the Form A polymorph and substantially free of other polymorphs may comprise all polymorphs other than Form A at a specified weight percentage of all polymorphs of CV-8972 in the composition. For example, the composition may comprise less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight of all polymorphs of CV-8972 in the composition other than Form A.

[0099] In certain embodiments, the total weight is the weight of the selected polymorph of CV-8972 in the composition. For example, a composition comprising the form A polymorph and substantially free of the form B polymorph may comprise form B in a specified percentage by weight of forms A and B. For example, the composition may comprise form B in less than 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by weight of forms A and B of CV-8972 in the composition. Similarly, a composition comprising the form A polymorph and substantially free of the forms B and C polymorphs may comprise forms B and C in a specified percentage by weight of forms A, B, and C. For example, the composition may contain less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight of forms B and C of CV-8972 in the composition.

[0100] The crystal may comprise a salt form of CV-8972. For example, the Form A polymorph of CV-8972 is a trihydrochloride salt. Thus, the composition may comprise CV-8972 and a defined stoichiometric ratio of chloride ions. The composition may comprise a 1:3 stoichiometric ratio of CV-8972 and chloride ions.

[0101] The crystals may include a hydrated form of CV-8972. For example, the Form A polymorph of CV-8972 is a monohydrate. Thus, the composition may include a monohydrate form of CV-8972 (e.g., the Form A polymorph). The composition may include an anhydrous form of CV-8972 (e.g., the Form B, Form D, or Form E polymorph).

[0102] The pharmaceutical composition may be formulated as a single unit dosage. The pharmaceutical composition may be formulated as split dosages.

[0103] The compositions may contain a defined amount of CV-8972 or CV-8814. The above doses are about 10 mg to about 2000 mg, about 10 mg to about 1000 mg, about 10 mg to about 800 mg, about 10 mg to about 600 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, about 25 mg to about 2000 mg, about 25 mg to about 1000 mg, about 25 mg to about 800 mg, about 25 mg to about 600 mg, about 25 mg to about 400 mg, about 25 mg to about 300 mg, about 25 mg to about 200 mg, about 50 mg to about 2000 mg, about 50 mg to about 1000 mg, about 50 mg to about 800 mg, about 50 mg to about 600 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, About 50mg to about 200mg, about 100mg to about 2000mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 100mg to about 400mg, about 100mg to about 300mg, The dose may include about 100 mg to about 200 mg, about 200 mg to about 2000 mg, about 200 mg to about 1000 mg, about 200 mg to about 800 mg, about 200 mg to about 600 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, about 300 mg to about 2000 mg, about 300 mg to about 1000 mg, about 300 mg to about 800 mg, about 300 mg to about 600 mg, or about 300 mg to about 400 mg of CV-8972 or CV-8814. The dose may include about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg of CV-8972 or CV-8814.

[0104] Providing a compound to a subject The present invention provides a method for treating diseases, disorders, and conditions by providing both CV-8972 and CV-8814 to a subject having the disease, disorder, or condition. Each of CV-8972 and CV-8814 can be independently provided by any suitable route or mode of administration. For example and not by way of limitation, each compound can be provided intraorally, intradermally, enterally, intraarterially, intramuscularly, intraocularly, intravenously, nasally, orally, parenterally, pulmonary, rectally, subcutaneously, topically, transdermally, by injection, or with or on an implantable medical device (e.g., a stent or a drug-eluting stent or a balloon equivalent).

[0105] Each of CV-8972 and CV-8814 can be independently provided according to a dosing regimen. The dosing regimen can include dosage amount, frequency of administration, or both.

[0106] Doses can be provided at any suitable interval. For example and not by way of limitation, doses can be provided once a day, twice a day, three times a day, four times a day, five times a day, six times a day, eight times a day, once every 48 hours, once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every week, twice a week, three times a week, four times a week, or five times a week.

[0107] The dose or administration may include a defined amount of CV-8972 or CV-8814 that improves cardiac mitochondrial function (e.g., any of the doses described above in connection with pharmaceutical compositions comprising CV-8972 or CV-8814).

[0108] The dose or dosage may be provided in a single unit, i.e., the dose may be provided as a single tablet, capsule, pill, etc. Alternatively, the dose or dosage may be provided in multiple units, i.e., the dose or dosage may be provided as multiple tablets, capsules, pills, etc.

[0109] Said administration may continue for a specified period or may continue indefinitely.For example and not limitation, doses may be provided for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks or longer.In the context of prevention, said administration may be performed before the planned intervention.

[0110] Diseases, Disorders, and Conditions The combination therapy, treatment method, and pharmaceutical composition of the present invention can be used to treat a disease, disorder, or condition in a subject. The disease, disorder, or condition can be any condition that can be improved by improving cardiac mitochondrial function. The disease, disorder, or condition can be a cardiovascular condition. The disease, disorder, or condition can be: Acute coronary syndrome, acute heart failure, advanced heart failure, aneurysm, angina pectoris, anthracycline-induced cardiotoxicity, atherosclerosis, cardiac allograft vasculopathy, cardiac steatosis, cardiac graft vasculopathy, cardiomyopathy, cerebrovascular disease, chronic coronary syndrome, chronic heart failure, congestive heart failure, contrast nephropathy, coronary artery disease (CAD), coronary heart disease, diabetic cardiomyopathy, dilated cardiomyopathy (DCM, including idiopathic), heart attack, heart disease, heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), heart failure, hibernating myocardium, high blood pressure (hypertension), hypertrophic cardiomyopathy (HCM, non-obstructive myocardial infarction (MI) with non-obstructive coronary arteries (including chronic or obstructive), intermittent claudication, ischemia with non-obstructive coronary arteries (INOCA), ischemia reperfusion injury, ischemic cardiomyopathy, ischemic heart disease, microvascular angina, myocardial dysfunction induced by anti-cancer drugs, myocardial infarction with non-obstructive coronary arteries (MINOCA), myocarditis (non-familial and familial / genetic), non-ischemic cardiomyopathy, pericardial disease, peripartum cardiomyopathy, peripheral arterial disease, peripheral vascular disease, pulmonary arterial hypertension, pulmonary hypertension, refractory angina, restrictive cardiomyopathy, rheumatic heart disease, right heart failure, right ventricular failure, stable angina, stroke, fainting myocardium, tachycardia-induced cardiomyopathy, takotsubo cardiomyopathy, transient ischemic attack, unstable angina, or valvular heart disease.

[0111] Angina pectoris (angina) is a pain or pressure in the chest that typically results from inadequate blood flow to the heart muscle. The pain or discomfort is retrosternal or to the left side and may radiate to the left arm, neck, jaw, or back. Several classifications of angina are known. Stable angina (also called exertional angina) is associated with myocardial ischemia. In stable angina, chest discomfort and related symptoms are usually precipitated by some form of physical activity, such as running or walking, but symptoms are minimal or absent when the patient is at rest or taking sublingual nitroglycerin. Symptoms typically abate after a few minutes of activity and recur when activity is resumed. Symptoms may also be induced by cold weather, meals that are slow to digest, and emotional stress. Unstable angina is angina that varies or worsens. Unstable angina has at least one of the following characteristics: (1) it occurs at rest or with minimal exertion and usually lasts longer than 10 minutes, (2) it is severe and new onset, i.e., occurring within the past 4-6 weeks, and (3) it occurs in an increasingly intense pattern, i.e., apparently more severe, longer lasting, or more frequent than before. Cardiac syndrome X (also called microvascular angina) is angina-like chest pain in the setting of angiographically normal epicardial coronary arteries. Its primary cause is unknown, but apparently contributing factors are endothelial dysfunction and reduced blood flow in the very small resistance vessels of the heart. Microvascular angina may be part of the pathophysiology of ischemic heart disease. Refractory angina is a chronic condition (duration ≥3 months) in which angina (1) occurs in the setting of coronary artery disease (CAD), (2) cannot be controlled by a combination of optimal medical therapy, angioplasty, or bypass surgery, and (3) it has been clinically established that reversible myocardial ischemia is the cause of the symptoms.

[0112] A subject having the disease, disorder, or condition may fall into a particular class of subject. By way of example and not limitation, the subject may be a child, newborn, neonate, infant, child, adolescent, child aged 9-12, child aged 13-19, adult, or elderly subject. The subject may be in a critical care, intensive care, neonatal intensive care, pediatric intensive care, coronary care, cardiothoracic care, surgical intensive care, medical intensive care, long-term intensive care, operating room, ambulance, hospital, field hospital, out-of-hospital field setting, standard office setting, community clinic, or local health care setting. EXAMPLES

[0113] Working Example The present invention can be better understood in view of the following examples.The examples are provided for illustrative purposes only and do not limit the scope of the present invention.Throughout the examples and the accompanying drawings, the following synonyms for the compounds of the present invention can be used: CV-8972 can be alternatively referred to as IMB-101 or IMB-1018972;CV-8814 can be alternatively referred to as IMB-102 or IMB-1028814.

[0114] Example 1 Test Overview The effects of CV-8972, a partial fatty acid oxidation inhibitor, on glucose and fatty acid metabolism was investigated using noninvasive positron emission tomography (PET) imaging. The PET radiotracer is a radiolabeled glucose analog. 18 Evaluate cardiac glucose metabolism using F fluorodeoxyglucose (FDG) and a PET radiotracer, a radiolabeled long-chain fatty acid (LCFA) analogue. 18F fluoro-6-thia-heptadecanoic acid (FTHA) was used to assess fatty acid β-oxidation. Both radioactive tracers are "trapped" in cells in a manner proportional to either glucose or fatty acid metabolism. For example, high 18 F-FDG or 18 An F-FTHA signal indicates high glucose or fatty acid metabolism, respectively, while conversely, decreased uptake indicates low metabolism.

[0115] 18 F-FDG and 18 PET imaging with F-FTHA was performed in healthy rats. PET images were dynamically acquired for 120 minutes after tracer injection to capture the dynamic changes of cardiac glucose and fatty acid metabolism. For each tracer, animals were imaged twice, once after injection of vehicle (phosphate buffered saline, PBS) or CV-8972 (80mg / 3mL / kg), subcutaneously injected into the back of the animal, 15 minutes before PET imaging.

[0116] Figure 1 shows the effect of CV-8972 on cardiac tissue in rats in response to treatment. 18 F-fluorodeoxyglucose ( 18 F-FDG) and 18 F-14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid ( 18 FIG. 1 is a schematic diagram of the positron emission tomography (PET) imaging study design used to monitor uptake of F-FTHA. 18 To monitor F-FDG uptake, rats were fasted for 16 hours prior to day 1. On day 1, rats were given phosphate-buffered saline (PBS) at time 0 and 15 minutes later, 18 F-FDG was administered and followed in vivo by PET for 2 hours after administration. Rats were fasted again for 16 hours before day 3. On day 3, rats were given CV-8972 at time 0 and 15 minutes later 18F-FDG was administered and followed in vivo by PET for 2 hours after administration. Immediately after the second PET scan, the animals were sacrificed and levels of gamma radioactivity in blood, heart, and skeletal muscle were measured. 18 To monitor the uptake of F-FTHA, rats were fed before day 1. On day 1, rats were given PBS at time 0 and 15 min later. 18 F-FTHA was administered and followed by in vivo PET for 2 hours after administration. Rats were fed before day 3. On day 3, rats were given CV-8972 at time 0 and 15 min later. 18 F-FTHA was administered and followed in vivo by PET for 2 hours after administration. Immediately after the second PET scan, the animals were sacrificed and levels of gamma radioactivity were measured in blood, heart, and skeletal muscle.

[0117] material and method animal Twenty-three female Crl:CD(SD) rats (mean weight 408±46.5 g at the time of the first scan) were purchased from Charles River Laboratories (MA, USA). Rats were housed in a temperature-controlled animal room with a 12-h (07:00 to 19:00) light and 12-h dark cycle. All animals were acclimated for at least 3 days before use for the current study. All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the Icahn School of Medicine at Mount Sinai.

[0118] Dynamic PET / CT Acquisition Dynamic positron emission tomography / computed tomography (PET / CT) imaging was obtained on a Mediso nanoScan 122S PET / CT system. Cardiac glucose and fatty acid metabolism were assessed using the following methods: 18 F-FDG (NCM-USA LLC, NY, USA) and 18Visualization was performed by tracing the F-FTHA (Department of Radiology, New York University School of Medicine, NY, USA). 18 Prior to F-FDG scanning, rats were fasted overnight for at least 16 hours to minimize physiological uptake of the radiotracer into cardiomyocytes. Either vehicle (phosphate-buffered saline) or CV-8972 (80 mg / 3 mL / kg) was injected subcutaneously into the back of the animals 15 minutes prior to PET imaging. The animals were then positioned on the scanner and high-resolution CT images were obtained. Dynamic PET was then performed. 18 Imaging was started simultaneously with injection of F-FDG (37 MBq, 1 mCi / 0.5 mL / body) via the tail vein and recorded for 120 min. Each animal underwent two scanning sessions (one after vehicle injection and one after CV-8972 injection), separated by at least 2 days (mean 2.9 days, range 2-6 days). The order of the two imaging sessions was randomized between rats. 18 For F-FTHA (37 MBq, 1 mCi / 0.5 mL / body), animals underwent two scanning sessions, except for the fed condition. 18 The study was performed under the same conditions as those for F-FDG. 18 Among animals undergoing F-FDG scanning, six animals were similarly spaced apart by more than 3 days (mean 6.0 days, range 2–14 days). 18 The other rats underwent F-FTHA scanning. 18 F-FDG scan or 18 Patients underwent either an F-FTHA scan or only an F-FTHA scan.

[0119] Dynamic PET / CT Reconstruction and Analysis PET images were reconstructed using 3D ordered-subset expectation maximization / maximum a posteriori (3D-OSEM / MAP). Voxel count rates in reconstructed images were attenuation corrected and converted to standardized uptake values ​​(SUVs) by a system calibration factor from a cylindrical phantom. 3D regions of interest (ROIs) for the heart (left ventricle), muscle (right upper arm), and blood (abdominal aorta) were extracted using AMIDE based on guidance from co-registered anatomical CT images. x) The software was used to plot organ activity normalized by body weight (g) and residual activity at the time of the scan. From the entire acquisition, dynamic frames were calculated for both radiotracers at the following frame rates: 8 frames at 15 sec / frame, 6 frames for 30 sec / frame, 3 frames for 300 sec / frame, and 10 frames for 600 sec / frame. Dynamic curves were calculated using the following: 18 A two-compartment model for F-FDG, and 18 A three-compartment model was used for F-FTHA and analyzed using PMOD software.

[0120] FIG. 38 shows the two-compartment model used to assess FDG uptake. i , K 1 , K 2 , K 3 , and K 4 was calculated as follows:

number

[0121] Figure 39 shows the three-compartment model used to evaluate FTHA uptake. i , K 1 , K 2 , K 3 , K 4 , K 5 , K 6 , V 1 , and V2 was calculated as follows:

number

[0122] Ex vivo validation of in vivo PET signals with gamma counting Immediately after the last PET / CT scan, blood was collected from the abdominal vein under isoflurane (3-5%) anesthesia, and the animals were then euthanized by exsanguination. After extensive perfusion with PBS, the heart and skeletal muscle (right upper arm) were harvested. Radioactivity in the heart, muscle, and blood was determined with a Wizard2 2480 automatic gamma counter (Perkin Elmer, Waltham, MA), and the %ID / g was calculated for each organ.

[0123] statistical analysis Results are expressed as mean ± standard deviation (SD). Differences between the control and CV-8972 groups were assessed by two-tailed paired t-test (scan data) or Student's t-test (ex vivo data). These analyses were performed using GraphPad Prism (GraphPad Software Inc., CA, USA) or Microsoft (登録商標) This was performed using Office Excel 2010 (Microsoft Corporation, WA, USA). A p value <0.05 was classified as a statistically significant change.

[0124] result Effects of CV-8972 on cardiac glucose and fatty acid metabolism: 18 F-FDG and 18 F-FTHA in vivo PET uptake To evaluate the effects of CV-8972 on cardiac glucose and fatty acid metabolism, 18 F-FDG and 18 The time course of F-FTHA uptake (measured as SUV) was monitored in the myocardium. Radiotracer uptake in skeletal muscle and blood was monitored as well.

[0125] In the first analysis, single equivalent dynamic frames were compared between treated and PBS-injected animals.

[0126] Figure 2 is a graph showing the mean SUV of FDG in the heart at various time points after administration of either saline (control, black circles) or CV-8972 (drug, red squares) to rats. *p<0.05, **p<0.01 by paired t-test.

[0127] Figure 3 is a graph showing the mean SUV of FDG in skeletal muscle at various time points after administration of saline (control, black circles) or CV-8972 (drug, red squares) to rats. *p<0.05, **p<0.01 by paired t-test.

[0128] FIG. 4 is a graph showing the mean SUV of FDG in blood at various time points after administration of either saline (control, black circles) or CV-8972 (drug, red squares) to rats.

[0129] Figure 5 is a graph showing the mean SUV of FTHA in the heart at various time points after administration of either saline (control, black circles) or CV-8972 (drug, red squares) to rats. *p<0.05 by paired t-test.

[0130] Figure 6 is a graph showing the mean SUV of FTHA in skeletal muscle at various time points after administration of either saline (control, black circles) or CV-8972 (drug, red squares) to rats. *p<0.05 by paired t-test.

[0131] FIG. 7 is a graph showing the mean SUV of FTHA in blood at various time points after administration of either saline (control, black circles) or CV-8972 (drug, red squares) to rats.

[0132] Figure 8 shows PET / CT images of FDG and FTHA after administration of either saline (control) or CV-8972 (drug) to rats. Images were created by overlaying the sum of PET images acquired from 0 to 120 min onto a CT image. Each panel includes an image on the left representing the short axis of the heart and an image on the right representing the long axis of the heart.

[0133] Overall, this analysis demonstrated that a single injection of CV-8972 significantly improved cardiac function compared to PBS injections. 18 CV-8972 significantly increased F-FDG uptake, indicating increased glucose uptake and metabolism after CV-8972 injection. The difference in SUV in the heart between control and CV-8972-injected animals became more pronounced over time toward the end of the 120-minute dynamic PET acquisition. The mean SUV in the heart of CV-8972-injected animals at 120 minutes was 12.56±7.82, approximately 14-fold higher than that of the control group (0.89±0.62, p<0.01). On the other hand, 18 No statistically significant changes were detected in the heart when F-FTHA was injected, but slightly higher uptake was consistently noted in CV-8972-injected animals throughout the entire scan acquisition period. 18 While slightly higher uptake of F-FTHA was also observed in skeletal muscle, 18 F-FDG was slightly lower. Examination of single dynamic frames showed that CV-8972 injection reduced 18 F-FDG and 18 There was no apparent effect on the F-FTHA signal.

[0134] In a second analysis, SUV values ​​were calculated from single frames representing the last 30 min (90–120 min) of PET acquisition.

[0135] Figure 9 is a graph showing the mean SUV of FDG in heart, skeletal muscle, and blood during the last 30 min of dynamic acquisition after administration of either saline (control, black bars) or CV-8972 (drug, red bars) to rats. **p<0.01 by paired t-test.

[0136] Figure 10 is a graph showing the mean SUV of FTHA in heart, skeletal muscle, and blood during the last 30 min of dynamic acquisition after administration of either saline (control, black bars) or CV-8972 (drug, red bars) to rats. *p<0.05 by paired t-test.

[0137] This analysis confirmed our previous analysis in a single dynamic frame. 18 F-FDG uptake was significantly higher in the myocardium but showed slightly lower signals (but reaching statistical significance) in skeletal muscle and blood of CV-8972-injected animals. 18 For F-FTHA, the myocardial signal in CV-8972 animals was slightly higher without reaching statistical significance, while the slightly higher signal in skeletal muscle reached statistical significance. 18 The F-FTHA blood signal was not affected by CV-8972 injection.

[0138] In a third analysis, the radiotracer uptake curves were analyzed using kinetic modeling.

[0139] FIG. 11 is a graph of FDG uptake in the myocardium after administration of either saline (control) or CV-8972 (drug) to rats. i Values ​​were determined using a two-compartment model. *p<0.05 by paired t-test.

[0140] FIG. 12 is a graph of the flow of FDG activity in the myocardium following administration of either saline (control, black bars) or CV-8972 (drug, red bars) to rats.1 , K 2 , K 3 , and K 4 Values ​​were determined using a two-compartment model.

[0141] FIG. 13 is a graph of FDG uptake in skeletal muscle following administration of either saline (control) or CV-8972 (drug) to rats. i Values ​​were determined using a two-compartment model. **p<0.01 by paired t-test.

[0142] FIG. 14 is a graph of the flow of FDG activity in skeletal muscle following administration of either saline (control, black bars) or CV-8972 (drug, red bars) to rats. 1 , K 2 , K 3 , and K 4 Values ​​were determined using a two-compartment model. **p<0.01 by paired t-test.

[0143] FIG. 15 is a graph of FTHA uptake in the myocardium after administration of either saline (control) or CV-8972 (drug) to rats. i Values ​​were determined using a three-compartment model.

[0144] FIG. 16 shows the pharmacokinetic parameters V of FTHA uptake in the myocardium after administration of either saline (control) or CV-8972 (drug) to rats. 1 This is a graph of V 1 Values ​​were determined using a three-compartment model.

[0145] FIG. 17 shows the pharmacokinetic parameters V of FTHA uptake in the myocardium after administration of either saline (control) or CV-8972 (drug) to rats. 2 This is a graph of V 2 Values ​​were determined using a three-compartment model. **p<0.01 by paired t-test.

[0146] FIG. 18 is a graph of the flow of FTHA activity in the myocardium after administration of either saline (control, black bars) or CV-8972 (drug, red bars) to rats. 1 , K 2 , K 3 , K 4 , K 5 , and K 6 Values ​​were determined using a three-compartment model.

[0147] FIG. 19 is a graph of FTHA uptake in skeletal muscle following administration of either saline (control) or CV-8972 (drug) to rats. i Values ​​were determined using a three-compartment model.

[0148] FIG. 20 shows the pharmacokinetic parameters V of FTHA uptake in skeletal muscle following administration of either saline (control) or CV-8972 (drug) to rats. 1 This is a graph of V 1 Values ​​were determined using a three-compartment model. *p<0.05 by paired t-test.

[0149] FIG. 21 shows the pharmacokinetic parameters V of FTHA uptake in skeletal muscle following administration of either saline (control) or CV-8972 (drug) to rats. 2 This is a graph of V 2 Values ​​were determined using a three-compartment model.

[0150] FIG. 22 is a graph of the flow of FTHA activity in skeletal muscle following administration of either saline (control, black bars) or CV-8972 (drug, red bars) to rats. 1 , K 2 , K 3 , K 4 , K 5 , and K 6Values ​​were determined using a three-compartment model. **p<0.01 by paired t-test.

[0151] 18 Kinetic modeling of F-FDG confirmed an overall significantly higher myocardial uptake of this tracer in CV-8972-injected animals, and lower uptake in skeletal muscle. 18 Kinetic modeling of F-FTHA confirmed an overall significantly higher uptake of this tracer in cardiac and skeletal muscle in CV-8972-injected animals.

[0152] Ex vivo quantification of radiotracer uptake by gamma counting Radioactivity in the heart, skeletal muscle, and blood was also determined in a gamma counter immediately after PET / CT imaging for further ex vivo validation.

[0153] Figure 23 is a graph of gamma radioactivity (expressed as % injected dose / g, %ID / g) from FDG in heart, skeletal muscle, and blood after administration of either saline (control, black bars) or CV-8972 (drug, red bars) to rats. Data are from 4 animals that received saline and 7 animals that received CV-8972. *p<0.05, **p<0.01 by Student's t-test.

[0154] Figure 24 is a graph of gamma radioactivity from FTHA in heart, skeletal muscle, and blood after administration of either saline (control, black bars) or CV-8972 (drug, red bars) to rats. Data are from 3 animals that received saline and 9 animals that received CV-8972. *p<0.05 by Student's t-test.

[0155] The mean radioactivity in the heart after CV-8972 injection was 18 4.25 ± 1.03 %ID / g for F-FDG, and 18For F-FTHA, it was 1.98±0.53 %ID / g, which were 5.6- and 3.6-fold higher than the control radioactivity, respectively. Radioactivity in skeletal muscle and blood was much lower than that in the heart and showed no obvious difference between control and CV-8972-injected animals.

[0156] conclusion In the study described in Example 1, non-invasive in vivo imaging with microPET / CT was performed in rats to quantify changes in glucose and fatty acid metabolism to the heart after a single injection of CV-8972. The results showed that higher 18 Demonstrate a significant increase in glucose metabolism in the myocardium, as demonstrated by F-FDG uptake. 18 F-FTHA (a fatty acid analog) showed slightly higher uptake in the myocardium of healthy animals. These results were substantiated by three different analyses of in vivo PET data and ex vivo gamma counting. In particular, 18 Differences in F-FDG uptake could be detected by static analysis of PET images between 90 and 120 min after radiotracer injection, demonstrating the feasibility of this approach for assessing drug effects in humans using validated static in vivo PET imaging.

[0157] The results showed that CV-8972 administration significantly improved cardiac function in rats compared to saline-treated rats. 18 Figure 2 shows increased F-FDG standardized uptake value (SUV), indicating increased glucose retention and utilization in myocardial tissue. 18 Imaging with F-FTHA PET tracer demonstrated that after administration of CV-8972, 18 F-FTHA) showed an initial approximately 2-fold increase, followed by rapid tissue uptake and uptake from rat heart tissue over the 120 min of image acquisition. 18 Furthermore, static analysis at 30 min showed that F-FTHA efflux in skeletal muscle 18 In rat cardiac tissue, compared with minimal changes in F-FDG SUV18 Showing a 12-fold increase in F-FDG SUV. These data suggest that CV-8972 induces a switch from fatty acid oxidation-based energy generation to glucose-dependent metabolism in cardiomyocytes.

[0158] In a toxicokinetic study of CV-8972 subcutaneously injected at 60 mg / kg in male rats, the exposures (AUC 0-8 hr) of CV-8814 and TMZ were 72.5 and 2.7 nmol.hr / ml, respectively. Thus, CV-8814 plasma AUC represented 96.4% of the combined exposure for CV-8814 and TMZ, and the pharmacological effects primarily reflected those of CV-8814.

[0159] Example 2 A study was conducted to evaluate the effect of CV-8814 (a pFOX inhibitor) on protecting cardiac tissue from ischemia / reperfusion (I / R) injury. Similar studies were also conducted with trimetazidine (TMZ) as a representative pFOX reference compound. For comparison of the pharmacological potency of single and combined agents, studies were conducted with TMZ alone and in combination with metabolic enhancers (e.g., nicotinic acid).

[0160] FIG. 25 is a schematic diagram of the Langendorff ischemia-reperfusion protocol used to test the ability of various compounds to protect the heart from ischemic injury. Test compounds were dissolved at 20 μM in Krebs-Henseleit buffer and perfused through mouse heart tissue at constant pressure starting at time 0. For each treatment group, 10-18 hearts were tested. A Mikro-tip catheter was inserted into the left ventricle to measure cardiac function, including heart rate, coronary flow, left ventricular systolic pressure, and left ventricular end-diastolic pressure, at the end of basal perfusion at 20 min. Hearts were reperfused at 50 min and cardiac function was measured again at 170 min. At the end of perfusion, hearts were transected into 5 slices and infarct size was measured by computerized planimetry of triphenyltetrazolium stained cardiac tissue sections.

[0161] In the first study, the single agent activity of CV-8814 was examined.

[0162] Figure 26 is a graph of coronary flow during ischemia-reperfusion injury in explanted mouse hearts treated with either saline (control, blue bars) or 20 μM CV-8814 (IMB-102, orange bars). *p<0.05 vs. control.

[0163] CV-8814 perfusion significantly increased coronary flow measured at the end of the reperfusion period (CV-8814: 90±14 μl / mL vs. control: 54±6 μl / mL, p<0.05), suggesting that CV-8814 protected coronary vessels from ischemic injury.

[0164] Figure 27 is a graph of infarct size following ischemia-reperfusion injury in explanted mouse hearts treated with either saline (control, blue bars) or 20 μM CV-8814 (IMB-102, orange bars). *p<0.001 vs. control.

[0165] CV-8814 perfusion preserved cardiac function as measured by maximum left ventricular pressure (LVDP; 48±8 mmHg at 20 min vs. 63±5 mmHg at 170 min, p<0.05) compared to the significant reduction in LVDP observed in control hearts (33±3 mmHg at 20 min vs. 56±3 mmHg at 170 min, p<0.001). CV-8814 perfusion also protected myocardial tissue from ischemia-associated cell death as measured by reduction in infarct size (CV-8814: 52±4% vs. control: 68±3%, p<0.001).

[0166] These results indicate that CV-8814 perfusion significantly reduced the myocardial tissue area at risk of ischemic injury while preserving coronary flow and cardiac function as measured in the Langendorff I / R model.

[0167] Comparative data with the reference compound TMZ alone was generated in a separate study.

[0168] Figure 28 is a graph of infarct size following ischemia-reperfusion injury in explanted mouse hearts treated with either saline (control, blue bars) or 20 μM trimetazidine (TMZ, light blue bars). *p<0.01 vs. control.

[0169] The results show that TMZ alone had comparable efficacy in preserving coronary flow (TMZ vs. control: 90±1.0 mL / min vs. 60±1.0 mL / min, p<0.05) and LVDP (TMZ vs. control: 49±5 vs. 56±6 mm Hg, p>0.05). TMZ also reduced myocardial infarct size, but only by about 9% compared to about 16% for CV-8814.

[0170] The concept of combining pFOX inhibitors with metabolic enhancers (e.g., nicotinamide, nicotinic acid, and succinate) in combination was evaluated in the Langendorff I / R test. The combinations included TMZ / nicotinamide / succinate (all at 20 μM; designated TNS) and TMZ / nicotinic acid / succinate (all at 20 μM; designated TNC).

[0171] 29 is a graph of infarct size following ischemia-reperfusion injury in explanted mouse hearts treated with saline (control, blue bars), 20 μM trimetazidine (TMZ, light blue bars), trimetazidine+nicotinamide+succinate 20 μM each (TNS, open bars), or trimetazidine+nicotinic acid+succinate 20 μM each (TNC, open bars). *P=0.01 vs. control, #p<0.05 vs. control / TMZ.

[0172] Perfusion with 20 μM TMZ / nicotinamide / succinate (TNS) provided the most significant increase in coronary flow (TNS vs. control: 62±9 μL / mL vs. 36±3 μL / mL, p<0.05), while TMZ / nicotinic acid / succinate (TNC: 54+9 μL / mL) was more effective than TMZ alone (40+6 μL / mL). Both the TNS triple combination and TMZ alone sustained cardiac function as measured by LVDP (TNS: T170 vs. T20=48±8 vs. 66±5 mmHg, p>0.05; TMZ: T170 vs. T20=49±5 vs. 56±6 mmHg, p>0.05). Perfusion with the triple combination of TNS and TNC both protected myocardial tissue from ischemia-related cell death as measured by reduction in infarct size (TNS vs. control: 44±4% vs. 68±2%, p<0.001; TNC vs. control: 47±2% vs. 68±2%, p<0.001). Both TNS and TNC combinations were more effective than TMZ alone (56±3% infarct tissue area).

[0173] Example 3 A study was conducted to evaluate and compare the efficacy of the reference compound TMZ with that of CV-8814 and CV-1018972 on vascular remodeling, preserving cardiac function and preventing fibrosis in a transaortic constriction (TAC) model of heart failure in mice.

[0174] Figure 30 is a schematic diagram of the transverse aortic coarctation (TAC) protocol used to test the ability of various compounds to protect the heart from heart failure. The aortic arch was exposed through a midline incision in the thoracic cavity of anesthetized mice. A 27-gauge needle was tied to the transverse aorta and then quickly removed to create a ligation stenosis. Treatments were administered via subcutaneous osmotic pumps at the concentrations indicated in the figure. In vivo cardiac function was assessed by transthoracic echocardiography performed at 24 hours, 3 weeks, and 6 weeks after TAC. Ventricular remodeling was determined by assessment of heart weight (HW) and heart weight to body weight ratio (HW / BW). At the end of the study, hearts were excised, fixed, sectioned at 6 μm, and stained with Masson's trichrome. The area of ​​fibrosis in the myocardial tissue was measured by computer planimetry in five random fields per heart. A total of 65–75 fields per treatment group were analyzed, and differences were analyzed by Student's t test.

[0175] Three separate studies were conducted to evaluate the efficacy of single agents and combinations with metabolic enhancers in the TAC model of heart failure. In the first study, mice were treated with either trimetazidine alone or trimetazidine + nicotinamide + succinate. In the second study, mice were treated with CV-8814 alone or trimetazidine + nicotinic acid + succinate. In the third study, mice were treated with nicotinic acid, CV-8814, or CV-8972. Overall, the activity of trimetazidine, CV-8814, and CV-8972 at most study endpoints was well matched across the three studies. In the third study, the three compounds were analyzed at equal mg / kg / day doses based on formulation weight: 6 mg / kg / day for trimetazidine, 7.5 mg / kg / day for CV-8814; and 10 mg / kg / day for CV-8972. Therefore, the results from the third study are summarized here.

[0176] Figure 31 shows images of mouse hearts after TAC-induced heart failure. The left panel shows the heart of a mouse that was given a sham procedure in which no TAC was performed. The remaining panels show the hearts of mice treated with saline (Saline), trimetazidine (TMZ), nicotinic acid (Nicotinic Acid), CV-8814 (8814), or CV-8972 (8972).

[0177] Figure 32 is a graph of heart weight versus body weight following TAC-induced heart failure in mice treated with saline (saline, blue bars), trimetazidine (TMZ, light blue bars), nicotinic acid (NA, light green bars), CV-8814 (IMB-102, light orange bars), or CV-8972 (IMB-101, dark orange bars). Heart weight versus body weight values ​​are expressed as mg / g. *p<0.05 versus saline treatment.

[0178] Administration of CV-8972 had a significant effect on ventricular remodeling and cardiac function in the TAC model of heart failure. Compared to the control group, CV-8972 prevented cardiac hypertrophy as measured by reduced heart weight (CV-8972 vs. control: 225±11 mg vs. 270±14 mg; p<0.05), reduced heart weight to body weight ratio (CV-8972 vs. control: 7.4±0.3 mg / g vs. 9.1±0.5 mg / g; p<0.05), and reduced left ventricular mass (CV-8972 vs. control: 156±10 mg vs. 195±12 mg; p<0.05). The effects of TMZ or CV-8814 treatment were similar to CV-8972.

[0179] Figure 33 is a graph of cardiac ejection fraction at various time points following TAC-induced heart failure in mice treated with either saline (saline, blue circles) or CV-8972 (CV-8972, orange circles). *p=0.011, #p=0.013.

[0180] Figure 34 is a graph of cardiac ejection fraction at various time points following TAC-induced heart failure in mice treated with either saline (saline, blue circles) or CV-8814 (CV-8814, orange circles). *p=0.021, #p=0.035.

[0181] Figure 35 is a graph of cardiac ejection fraction at various time points following TAC-induced heart failure in mice treated with either saline (saline, blue circles) or trimetazidine (TMZ, light blue circles). #p=0.052.

[0182] CV-8972 administration also preserved cardiac function in mice over the 6-week study period, as measured by increased left ventricular fractional shortening (FS) measured at 3 weeks (CV-8972 vs. control: 47%±3% vs. 37%±3%; p<0.05). FS continued to decrease (34%±3%) through 6 weeks in control TAC animals, but the effects of both CV-8972 (46%±3%; p<0.05) and CV-8814 (44%±3%; p<0.05) on FS persisted. In contrast, TMZ had no significant effect on FS. Treatment with both CV-8972 and CV-8814 also preserved left ventricular ejection fraction (EF) throughout the 6-week study, but neither TMZ nor nicotinic acid had a beneficial effect.

[0183] The treatment effects of CV-8972 and CV-8814 on diastolic function during TAC-induced heart failure were evaluated by measuring isovolumic relaxation time (IVRT). Both CV-8972 and CV-8814 prevented the prolongation of IVRT at 3 weeks of evaluation (CV-8972 vs. control: 32±1 ms vs. 36±1 ms; p<0.05; CV-8814 vs. control: 33±1 ms vs. 36±1 ms; p<0.05). The effect of CV-8814 persisted through 6 weeks (CV-8814 vs. control: 28±2 ms vs. 35±1 ms, p<0.0), whereas CV-8972 was slightly less effective (CV-8972 vs. control: 31±2 ms vs. 35±1 ms, p=0.06). In contrast, TMZ treatment did not preserve diastolic function during TAC-induced heart failure.

[0184] Figure 36 shows microscopic images of cardiac tissue from mice following TAC-induced heart failure. The left panel shows cardiac tissue from mice given a sham procedure in which no TAC was performed. The remaining panels show hearts from mice treated with saline (Saline), trimetazidine (TMZ), nicotinic acid (Nicotinic Acid), CV-8814 (8814), or CV-8972 (8972).

[0185] Figure 37 is a graph of cardiac fibrosis after TAC-induced heart failure in mice treated with saline (saline, blue bars), trimetazidine (TMZ, light blue bars), nicotinic acid (NA, light green bars), CV-8814 (IMB-102, light orange bars), or CV-8972 (IMB-101, dark orange bars). Values ​​represent the percentage of fibrotic cardiac tissue. *p<0.05 vs. saline treatment.

[0186] Finally, CV-8972 administration significantly reduced myocardial tissue fibrosis 6 weeks after TAC-induced heart failure (CV-8972 vs. control: 6.6±0.6 vs. 10.7±1%; p<0.01). The effect of CV-8814 was similar (6.6±0.6%; p<0.01), and both CV-8972 and CV-8814 were more effective than TMZ in preventing cardiac fibrosis (7.6±1% vs. 11±1%; p=0.08). Nicotinic acid alone had a moderate effect on fibrosis (8.2±1%).

[0187] Based on pharmacokinetic studies of CV-8972 at 10 mg / kg intravenous dose, CV-8972 was rapidly converted to CV-8814 and low but measurable levels of TMZ. Based on plasma exposure (AUC 0-8 hours), CV-8814 exhibited 93.9% of the combined AUC for CV-8814 and TMZ. Thus, the in vivo pharmacological effects in mice upon parenteral administration of CV-8972 primarily reflect the activity of CV-8814 in this species.

[0188] References References and citations to other documents, such as patents, patent applications, patent publications, journals, books, articles, web content, etc. are made throughout this disclosure. All such documents are incorporated by reference herein in their entirety for all purposes.

[0189] Equivalent Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire contents of this document, including references to the scientific and patent literature 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.

Claims

1. 1. A combination for treating a disease, disorder, or condition in a subject, said combination comprising: Formula (X): 【Chemistry 101】 or a pharmaceutically acceptable salt thereof, and Formula (IX): 【Chemical Engineering 102】 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (X) or its salt and the compound of formula (IX) or its salt are provided in a specified mass ratio of the compound of formula (X) to the compound of formula (IX) that is less than 1:1, and the disease, disorder, or condition is selected from the group consisting of acute coronary syndrome, acute heart failure, advanced heart failure, angina pectoris, anthracycline-induced cardiotoxicity, atherosclerosis, cardiac allograft vasculopathy, cardiac steatosis, cardiac graft vasculopathy, cardiomyopathy, chronic coronary syndrome, chronic heart failure, congenital heart disease, coronary artery disease (CAD), coronary heart disease, diabetic cardiomyopathy, dilated cardiomyopathy (DCM, including idiopathic), heart attack, heart disease, heart failure with mildly reduced ejection fraction (HFmrEF), heart failure, hibernating myocardium, high blood pressure (hypertension), hypertrophic cardiomyopathy (HCM), and a cardiovascular condition dependent on fatty acid oxidation selected from the group consisting of: coronary myocardial infarction (CM, including non-obstructive or obstructive), intermittent claudication, ischemia with non-obstructive coronary arteries (INOCA), ischemia-reperfusion injury, ischemic cardiomyopathy, ischemic heart disease, microvascular angina, myocardial dysfunction caused by anti-cancer drugs, myocardial infarction with non-obstructive coronary arteries (MINOCA), non-ischemic cardiomyopathy, pulmonary arterial hypertension, refractory angina, restrictive cardiomyopathy, rheumatic heart disease, right heart failure, right ventricular failure, stable angina, myocardial stunning, tachycardia-induced cardiomyopathy, takotsubo cardiomyopathy, transient ischemic attack, unstable angina, or valvular heart disease.

2. 2. The combination according to claim 1, wherein the mass ratio of the compound of formula (X) or salt thereof to the compound of formula (IX) or salt thereof is from about 1:1 to about 1:

100.

3. The combination of claim 2, wherein the mass ratio is from about 1:1 to about 1:

10.

4. the compound of formula (X) or salt thereof is provided in a daily dosage of about 50 mg to about 1000 mg; The compound of formula (IX) or its salt is provided in a daily dosage of about 50 mg to about 1000 mg. The combination according to claim 2.

5. 5. The combination according to claim 4, wherein the compound of formula (X) or a salt thereof is provided in a daily dosage of about 100 mg to about 500 mg.

6. 5. The combination according to claim 4, wherein the compound of formula (IX) or a salt thereof is provided in a daily dosage of about 100 mg to about 500 mg.

7. The combination according to claim 1, wherein the compound of formula (X) or a salt thereof and the compound of formula (IX) or a salt thereof are provided in separate formulations.

8. The combination according to claim 1, characterized in that the compound of formula (X) or a salt thereof and the compound of formula (IX) or a salt thereof are provided in a single formulation.

9. A pharmaceutical composition for treating a disease, disorder, or condition in a subject, wherein the pharmaceutical composition comprises a compound represented by formula (X): 【Chemistry 103】 or a pharmaceutically acceptable salt thereof, and Formula (IX): 【Chemical 104】 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (X) or a salt thereof and the compound of formula (IX) or a salt thereof are provided in a defined mass ratio of the compound of formula (X) to the compound of formula (IX) of less than 1:1, and the disease, disorder, or condition is selected from the group consisting of acute coronary syndrome, acute heart failure, advanced heart failure, angina pectoris, anthracycline-induced cardiotoxicity, atherosclerosis, cardiac allograft vasculopathy, cardiac steatosis, cardiac graft vasculopathy, cardiomyopathy, chronic coronary syndrome, chronic heart failure, congenital heart disease, coronary artery disease (CAD), coronary heart disease, diabetic cardiomyopathy, dilated cardiomyopathy (DCM, including idiopathic), heart attack, heart disease, heart failure with mildly reduced ejection fraction (HFmrEF), heart failure, hibernating myocardium, high blood pressure (hypertension), hypertrophic cardiomyopathy (HCM), and a pharmaceutical composition comprising a cardiovascular condition dependent on fatty acid oxidation selected from the group consisting of: coronary myocardial infarction (CM, including non-obstructive or obstructive), intermittent claudication, ischemia with non-obstructive coronary arteries (INOCA), ischemia-reperfusion injury, ischemic cardiomyopathy, ischemic heart disease, microvascular angina, myocardial dysfunction caused by anti-cancer drugs, myocardial infarction with non-obstructive coronary arteries (MINOCA), non-ischemic cardiomyopathy, pulmonary arterial hypertension, refractory angina, restrictive cardiomyopathy, rheumatic heart disease, right heart failure, right ventricular failure, stable angina, myocardial stunning, tachycardia-induced cardiomyopathy, takotsubo cardiomyopathy, transient ischemic attack, unstable angina, or valvular heart disease.

10. 10. The pharmaceutical composition of claim 9, wherein the mass ratio of the compound of formula (X) or salt thereof to the compound of formula (IX) or salt thereof is from about 1:1 to about 1:

100.

11. 10. The pharmaceutical composition of claim 9, wherein the mass ratio is from about 1:1 to about 1:

10.

12. The composition comprises: about 10 mg to about 500 mg of the compound of formula (X) or a salt thereof, and about 10 mg to about 500 mg of the compound of formula (IX) or a salt thereof; 10. The pharmaceutical composition of claim 9, comprising:

13. 13. The pharmaceutical composition of claim 12, wherein the composition comprises about 25 mg to about 200 mg of the compound of formula (X) or salt thereof.

14. 13. The pharmaceutical composition of claim 12, wherein the composition comprises about 25 mg to about 200 mg of the compound of formula (IX) or salt thereof.

15. 11. The pharmaceutical composition of claim 10, wherein the composition is formulated for oral administration.

16. 16. The pharmaceutical composition of claim 15, wherein the composition comprises a modified release formulation.

17. 1. A composition for treating a disease, disorder, or condition in a subject, comprising: Formula (X): 【Chemistry 105】 or a pharmaceutically acceptable salt thereof, wherein the composition comprises a compound represented by Formula (IX): 【Chemistry 106】 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (X) or its salt and the compound of formula (IX) or its salt are provided in a specified mass ratio of the compound of formula (X) to the compound of formula (IX) of less than 1:1, and the disease, disorder, or condition is selected from the group consisting of acute coronary syndrome, acute heart failure, advanced heart failure, angina pectoris, anthracycline-induced cardiotoxicity, atherosclerosis, cardiac allograft vasculopathy, cardiac steatosis, cardiac graft vasculopathy, cardiomyopathy, chronic coronary syndrome, chronic heart failure, congenital heart disease, coronary artery disease (CAD), coronary heart disease, diabetic cardiomyopathy, dilated cardiomyopathy (DCM, including idiopathic), heart attack, heart disease, heart failure with mildly reduced ejection fraction (HFmrEF), heart failure, hibernating myocardium, high blood pressure (hypertension), and hypertrophic cardiomyopathy.

20. A composition comprising a cardiovascular condition dependent on fatty acid oxidation selected from the group consisting of: coronary artery myocardial infarction (including HCM, non-obstructive or obstructive), intermittent claudication, ischemia with non-obstructive coronary arteries (INOCA), ischemia-reperfusion injury, ischemic cardiomyopathy, ischemic heart disease, microvascular angina, myocardial dysfunction caused by anti-cancer drugs, myocardial infarction with non-obstructive coronary arteries (MINOCA), non-ischemic cardiomyopathy, pulmonary arterial hypertension, refractory angina, restrictive cardiomyopathy, rheumatic heart disease, right heart failure, right ventricular failure, stable angina, myocardial stunning, tachycardia-induced cardiomyopathy, takotsubo cardiomyopathy, transient ischemic attack, unstable angina, or valvular heart disease.

18. 1. A composition for treating a disease, disorder, or condition in a subject, comprising: Formula (IX): 【Chemistry 107】 or a pharmaceutically acceptable salt thereof, wherein the composition comprises a compound represented by Formula (X): 【Chemistry 108】 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (X) or its salt and the compound of formula (IX) or its salt are provided in a specified mass ratio of the compound of formula (X) to the compound of formula (IX) of less than 1:1, and the disease, disorder, or condition is selected from the group consisting of acute coronary syndrome, acute heart failure, advanced heart failure, angina pectoris, anthracycline-induced cardiotoxicity, atherosclerosis, cardiac allograft vasculopathy, cardiac steatosis, cardiac graft vasculopathy, cardiomyopathy, chronic coronary syndrome, chronic heart failure, congenital heart disease, coronary artery disease (CAD), coronary heart disease, diabetic cardiomyopathy, dilated cardiomyopathy (DCM, including idiopathic), heart attack, heart disease, heart failure with mildly reduced ejection fraction (HFmrEF), heart failure, hibernating myocardium, high blood pressure (hypertension), and hypertrophic cardiomyopathy.

20. A composition comprising a cardiovascular condition dependent on fatty acid oxidation selected from the group consisting of: coronary artery myocardial infarction (including HCM, non-obstructive or obstructive), intermittent claudication, ischemia with non-obstructive coronary arteries (INOCA), ischemia-reperfusion injury, ischemic cardiomyopathy, ischemic heart disease, microvascular angina, myocardial dysfunction caused by anti-cancer drugs, myocardial infarction with non-obstructive coronary arteries (MINOCA), non-ischemic cardiomyopathy, pulmonary arterial hypertension, refractory angina, restrictive cardiomyopathy, rheumatic heart disease, right heart failure, right ventricular failure, stable angina, myocardial stunning, tachycardia-induced cardiomyopathy, takotsubo cardiomyopathy, transient ischemic attack, unstable angina, or valvular heart disease.

19. The combination of claim 7, wherein one or more of the separate formulations comprise a modified release formulation configured to facilitate gradual release of the compound of formula (X) and / or the compound of formula (IX).

20. The combination of claim 8, wherein the single formulation constitutes a modified release formulation configured to facilitate gradual release of the compound of formula (X) or a salt thereof and / or the compound of formula (IX) or a salt thereof.

21. The pharmaceutical composition of claim 16, wherein the modified release formulation is configured to promote a gradual release of the compound of formula (X) or a salt thereof and / or the compound of formula (IX) or a salt thereof.

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