Cyclo-hex-2,5-diene-1,4-dione for use in the treatment of cardiomyopathy

Abstract

The present disclosure provides methods, compounds, compositions / formulations / drugs, and related uses for treating, preventing, delaying progression of, or delaying onset of cardiomyopathy (such as hypertrophic cardiomyopathy) in a mammalian subject (such as a subject diagnosed with or suspected of having Friedreich’s ataxia). In some embodiments, administration of the disclosed compounds to the subject can result in one or more of the following in the subject: (i) increased survival, (ii) reduced iron deposition in cardiomyocytes, (iii) improvement and / or normalization of mitochondrial size in cardiomyocytes; (iv) reduced cardiac fibrosis, and (v) reverse remodeling of the subject’s heart.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 597,433, filed November 9, 2023, the entire contents of which are incorporated herein by reference for any and all purposes. Technical Field

[0003] This application generally relates to methods, compositions / formulations / medications, and related uses for treating, preventing, delaying the onset of, or delaying the progression of cardiomyopathy (e.g., hypertrophic cardiomyopathy) in mammalian subjects in need, such as subjects diagnosed with or suspected of having Friedreich ataxia. These methods, compositions / formulations / medications, and related uses all involve administering to a mammalian subject one or both of the two compounds specifically identified herein as compound A and compound B. Background Technology

[0004] The following description is provided to aid the reader's understanding. It is not acknowledged that the information provided herein or the references cited herein are prior art to the compounds, compositions, products, and / or methods disclosed herein.

[0005] Friedreich ataxia (FA) is a fatal, single-gene, autosomal recessive genetic disorder caused by mutations in the gene encoding the nuclear protein frataxin. Tissues in both the peripheral and central nervous systems are affected in FA, including the dentate nucleus, Clark's column, spinocerebellar tract, and dorsal root ganglia. Progressive degeneration of these tissues leads to worsening ataxia, and in most patients, the loss of independent walking ability occurs before the age of thirty.

[0006] Friedreich-type ataxia occurs when the FXN gene contains an expanded intronic GAA repeat sequence. The mutated FXN gene contains an expanded GAA triplet repeat sequence in the first intron; point mutations have also been detected in some families. Because the defect is located within an intron, which is removed from the mRNA transcript between transcription and translation, the mutated FXN gene does not lead to the production of abnormal proteins. Instead, the mutation causes gene silencing, i.e., it reduces gene transcription and thus reduces frataxin expression. Reduced frataxin expression leads to iron accumulation in the mitochondria, resulting in impaired respiratory chain activity. Right now(Improperty of oxidative phosphorylation). Iron accumulation in mitochondria has been observed in cardiomyocytes from frataxin knockout mouse models that result in the loss of frataxin in the heart and skeletal muscle. (See: Chiang et al., Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation, Redox Biology, 46 (2021) 102038; and Martelli et al., Dysregulation of cellular iron metabolism in Friedreich ataxia: from primary iron-sulfur cluster to mitochondrial iron accumulation, Frontiers in Pharmacology, 5 (2014) 130). A reduction in mitochondrial cross-sectional area has also been observed in cardiomyocytes from 10-week-old mice (but not 4-week-old mice) of the FA model examined. (See: Chiang et al., Section 3.1).

[0007] Symptoms typically begin between the ages of 5 and 15, but can sometimes appear in adulthood. The first symptom is usually gait ataxia or difficulty walking. The ataxia gradually worsens and slowly spreads to the arms and trunk. Loss of sensation in the limbs is common and may spread to other parts of the body. Other features include loss of tendon reflexes, especially in the knees and ankles. Most people with Friedreich's ataxia develop scoliosis, which usually requires surgical intervention. Articulation disorders (slow and slurred speech) may occur and can gradually worsen. Many people with advanced Friedreich's ataxia experience hearing and vision loss.

[0008] Heart disease is often accompanied by Friedreich-type ataxia, such as hypertrophic cardiomyopathy, myocardial fibrosis (the formation of fibrous material in the heart muscle), and heart failure. Arrhythmias, such as tachycardia (excessively fast heart rate) and heart block (impaired conduction of cardiac impulses within the heart), are also common. Other possible symptoms include chest pain, shortness of breath, and palpitations.

[0009] The rate of disease progression varies from person to person. Generally, within 10 to 20 years of the onset of initial symptoms, a person diagnosed with Friedreich's ataxia may be confined to a wheelchair, and in the later stages of the disease, the individual may become completely incapacitated. Friedreich's ataxia can shorten life expectancy, and heart disease is the most common cause of death.

[0010] There is currently no known cure for Friedreich's ataxia. Treatment generally involves managing the symptoms. Because patients with Friedreich's ataxia are at risk of heart disease, they are often treated with medications such as beta-blockers, ACE inhibitors, and / or diuretics. Since damage caused by oxidative stress is believed to be associated with the progression of Friedreich's ataxia, antioxidants such as vitamin E, idebenone, and coenzyme Q10 are often administered in combination to patients diagnosed with or suspected of having Friedreich's ataxia. These compounds have been used in various clinical trials.

[0011] Vatiquinone (also known as EPI743) has been clinically tested as a potential treatment for Friedreich-type ataxia, but has not yet been approved by the FDA for this purpose. Vatiquinone is believed to be an inhibitor of 15-lipoxygenase, an enzyme that regulates energy and oxidative stress pathways.

[0012] Omaveloxolone is a second-generation synthetic oleanolic triterpenoid compound believed to possess antioxidant and anti-inflammatory activities. Omaveloxolone has been clinically investigated for the treatment of various indications, including Friedreich's ataxia, mitochondrial myopathy, and ophthalmic conditions / diseases. Omaveloxolone was recently approved by the FDA for the treatment of Friedreich's ataxia. According to clinical trial data, at week 48, treatment with omaveloxolone resulted in a statistically significant reduction in the modified Friedreich's Ataxia Rating Scale (mFARS) score compared to placebo, with a placebo-adjusted difference of –2.41 points between the two groups. P = 0.0138). There appears to be no data indicating that treatment with omavidoxoron affects the heart of the treated subjects.

[0013] Treatment typically involves addressing the signs and symptoms of Friedreich ataxia based on the mFARS score. Better treatments are needed to address this devastating and rare disease. Summary of the Invention

[0014] In one aspect, this technology provides a method for treating, preventing, delaying the progression of, or delaying the onset of cardiomyopathy in mammalian subjects in need, the method comprising administering to the subject a therapeutically effective amount of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein compound A and compound B have the following structures: .

[0015] In some embodiments of the foregoing methods, the subject has been diagnosed with or is suspected of having Friedreich ataxia. In some embodiments of the foregoing methods, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments of the foregoing methods, the subject is a human being. In some embodiments of the foregoing methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to the subject reduces the subject's left ventricular mass, relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to the subject reduces the subject's left ventricular anterior wall thickness (both diastolic and systolic), relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing method, administering compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject to treat or prevent cardiac fibrosis in the subject's cardiac tissue. For exampleThe methods described above aim to delay the progression or onset of cardiac fibrosis. In some embodiments of the aforementioned methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject induces reverse remodeling of the subject's heart. In some embodiments of the aforementioned methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject reduces iron accumulation in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the aforementioned methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject improves or normalizes the size of mitochondria in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject improves the subject's hearing and / or vision. In some embodiments of the foregoing methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject increases the subject's lifespan. In some embodiments of the foregoing methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject via oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, ophthalmic, intrathecal, intraventricular, iontophoresis, transmucosal, intravitreal, or intramuscular routes.

[0016] In one aspect, this technology provides a composition, drug, or formulation comprising compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in treating, preventing, delaying the progression of, or delaying the onset of cardiomyopathy in mammalian subjects in need, wherein compound A and compound B have the following structures: .

[0017] In some embodiments of the aforementioned compositions, drugs, or formulations, the subject has been diagnosed with or is suspected of having Friedreich ataxia. In some embodiments of the aforementioned compositions, drugs, or formulations, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments of the aforementioned compositions, drugs, or formulations, the subject is a human being. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to the subject reduces the subject's left ventricular mass relative to an untreated control subject or an untreated control group. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to the subject reduces the subject's left ventricular anterior wall thickness (both diastolic and systolic) relative to an untreated control subject or an untreated control group. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to the subject treats, prevents, delays the progression of, or delays the onset of cardiac fibrosis in the subject's cardiac tissue. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to the subject induces reverse remodeling of the subject's heart. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to a subject reduces iron accumulation in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to a subject improves or normalizes the size of mitochondria in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to a subject improves the subject's hearing and / or vision. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to a subject increases the subject's lifespan. In some embodiments of the aforementioned compositions, drugs, or formulations, the composition, drug, or formulation is administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmologically, intrathecally, intraventricularly, via iontophoresis, transmucosally, intravitreally, or intramuscularly.

[0018] In one aspect, this technology provides the use of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate in mammalian subjects in need of treating, preventing, delaying the progression of, or delaying the onset of cardiomyopathy. Compound A and compound B have the following structures: .

[0019] In some embodiments of the foregoing uses, the subject has been diagnosed with or is suspected of having Friedreich ataxia. In some embodiments of the foregoing uses, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments of the foregoing uses, the subject is a human. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to the subject reduces the subject's left ventricular mass relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to the subject reduces the subject's left ventricular anterior wall thickness (both diastolic and systolic) relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject treats or prevents cardiac fibrosis in the subject's cardiac tissue, delays the progression of cardiac fibrosis, or delays the onset of cardiac fibrosis. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject induces reverse remodeling of the subject's heart. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject reduces iron accumulation in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject improves or normalizes the size of mitochondria in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject improves the subject's hearing and / or vision.In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject increases the subject's lifespan. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject via oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, ophthalmic, intrathecal, intraventricular, iontophoresis, transmucosal, intravitreal, or intramuscular routes.

[0020] In one aspect, this technology provides a method for reducing iron accumulation in cardiomyocytes of a mammalian subject in need, the method comprising administering to the subject a therapeutically effective amount of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein compound A and compound B have the following structures: In some embodiments of this method, the subject has been diagnosed with or is suspected of having Friedreich-type ataxia. In some embodiments of this method, the subject is a person.

[0021] In one aspect, this technology provides a method for improving or normalizing the size of mitochondria in cardiomyocytes of a mammalian subject in need, the method comprising administering to the subject a therapeutically effective amount of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein compound A and compound B have the following structures: In some embodiments of this method, the subject has been diagnosed with or is suspected of having Friedreich-type ataxia. In some embodiments of this method, the subject is a person. Attached Figure Description

[0022] Figure 1 This describes the chemical structures of compound A, compound B, and (comparative compound) vartiquinone.

[0023] Figure 2This is a graphical illustration of comparative data obtained from a mouse plasma pharmacokinetic (PK) profile study, in which compound B was studied with 20 mg / kg and 60 mg / kg SC, and compound A was studied with 60 mg / kg SC, as described in Example 1.

[0024] Figure 3 This is a graphical illustration of comparative data obtained from a plasma pharmacokinetic profile study, showing administration of 20 mg / kg SC in mice and 10 mg / kg SC in rats (effectively 60 mg / m²). 2 (Regardless of the species being examined) study compound B, as described in Example 1.

[0025] Figure 4 This is a graphical illustration of comparative data obtained from a PK profile study that examined drug uptake in mouse heart tissue induced by subcutaneous administration of compound B at 20 mg / kg and 60 mg / kg and subcutaneous administration of compound A at 60 mg / kg, as described in Example 1.

[0026] Figure 5 This is a graphical illustration of comparative data obtained from a PK profile study that examined drug uptake in mouse brain tissue induced by subcutaneous administration of compound B at 20 mg / kg and 60 mg / kg and subcutaneous administration of compound A at 60 mg / kg, as described in Example 1.

[0027] Figure 6 This is a graphical illustration of survival rates in a study on the effects of compound A and valtoquinone on mice, as described in Example 2 below.

[0028] Figure 7 This is a graphical illustration of the survival rate in a study on the effects of compound B and valtoquinone on mice, as described in Example 2 below.

[0029] Figure 8 Echocardiography of left ventricular mass obtained in a study of the effects of compound A and valtoquinone on mice. Right now Heart echo, Also known as A graphical illustration of echocardiographic data is shown in Example 2 below.

[0030] Figure 9 Echocardiography of left ventricular mass obtained in a study of the effects of compound B and valtoquinone on mice. Right now A graphical illustration of cardiac echo data is shown in Example 2 below.

[0031] Figure 10Echocardiography of left ventricular anterior wall thickness (diastolic) obtained in a study of the effects of compound A and valproicone on mice. Right now A graphical illustration of cardiac echo data is shown in Example 2 below.

[0032] Figure 11 Echocardiography of left ventricular anterior wall thickness (diastolic) obtained in a study of the effects of compound B and valproicone on mice. Right now A graphical illustration of cardiac echo data is shown in Example 2 below.

[0033] Figure 12 Echocardiography data of left ventricular anterior wall thickness (systolic phase) obtained in a study of the effects of compound A and valproicone on mice. Right now A graphical illustration of cardiac echo data is shown in Example 2 below.

[0034] Figure 13 Echocardiography of left ventricular anterior wall thickness (systolic) obtained in a study of the effects of compound B and valproicone on mice. Right now A graphical illustration of cardiac echo data is shown in Example 2 below.

[0035] Figure 14 Echocardiography of left ventricular anterior wall thickness (diastolic) obtained in a study of the effects of compound A and valproicone on mice. Right now A bar chart of cardiac echo data, as described in Example 2 below.

[0036] Figure 15 Echocardiography data of left ventricular anterior wall thickness (systolic phase) obtained in a study of the effects of compound A and valproicone on mice. Right now A bar chart of cardiac echo data, as described in Example 2 below.

[0037] Figure 16 Echocardiography of left ventricular anterior wall thickness (diastolic) obtained in a study of the effects of compound B and valproicone on mice. Right now A bar chart of cardiac echo data, as described in Example 2 below.

[0038] Figure 17 Echocardiography of left ventricular anterior wall thickness (systolic) obtained in a study of the effects of compound B and valproicone on mice. Right now A bar chart of cardiac echo data, as described in Example 2 below.

[0039] Figure 18AThis is a bar graph showing the absolute relative total cross-sectional area of ​​mitochondria in mouse heart (cardiac) tissue obtained from treatment for WT-untreated mice, MUT-untreated mice, and MUT mice treated with compound A, as described in Example 3.

[0040] Figure 18B This is a violin plot showing the size distribution of mitochondrial cross-sectional areas in mouse heart (cardiac) tissue obtained from treatment in WT-untreated mice, MUT-untreated mice, and MUT mice treated with compound A, as described in Example 3.

[0041] Figures 19A to 19C The image is a transmission electron micrograph (TEM) of mouse heart tissue obtained as described and processed in Example 3. Figure 19A From the WT untreated mouse group, Figure 19B From the MUT-untreated mouse group, and Figure 19C From the MUT mouse group treated with compound A. Detailed Implementation

[0042] It should be understood that certain aspects, methods, embodiments, variations, and features of this disclosure are described below at different levels of detail in order to provide a substantial understanding of the technology of the invention. Definitions of certain terms used in this specification are provided below. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0043] In practicing the techniques of this invention, many conventional techniques from molecular biology, protein biochemistry, cell biology, immunology, microbiology, and recombinant DNA are used. These techniques are well known and explained in the following literature: For example , Current Protocols in Molecular Biology Volumes I-III, edited by Ausubel (1997); Sambrook et al. Molecular Cloning: A Laboratory Manual Second edition (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989); DNA Cloning: A Practical Approach Volume I and Volume II, edited by Glover (1985); Oligonucleotide Synthesis Gait (ed., 1984); Nucleic Acid Hybridization Hames and Higgins (eds., 1985); Transcription and Translation Hames and Higgins (eds., 1984); Animal Cell CultureFreshney (ed., 1986); Immobilized Cells and Enzymes (… Immobilized Cells and Enzymes (IRL Press, 1986); Perbal, A Practical Guide to Molecular Cloning ; the series, Meth. Enzymol., (Academic Press, Inc., 1984); Gene Transfer Vectors for Mammalian Cells Miller and Calos (eds., Cold Spring Harbor Laboratory, NY, 1987); and Meth. Enzymol Volumes 154 and 155 were edited by Wu and Grossman, respectively.

[0044] I. Definition

[0045] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the following: Periodic Table of the Elements, GAS version, Handbook of Chemistry and Physics, 7Sh edition, inner page. Furthermore, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in the following literature: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0046] It should be understood that certain aspects, methods, embodiments, variations, and features of the present invention are described below at different levels of detail in order to provide a substantial understanding of this disclosure. Definitions of certain terms used in this specification are provided below. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this technology pertains.

[0047] As used in this specification and the accompanying embodiments, unless otherwise expressly indicated, the singular forms “a,” “an,” and “the” include plural referents. For example, references to “cell” include combinations of two or more types of cells, etc.

[0048] As used in this article, the reagent is “administered” or “administered” to the subject. Right now Therapeutic agents) or compound / drug products (including compositions) Right now (A compound or drug) includes any route by which a compound / drug product is introduced or delivered to a subject to exert its intended function. Administration can be performed by any suitable route, such as oral administration. Administration can be performed subcutaneously. Administration can be performed intravenously. Administration can be performed intraocularly. Administration can be performed systemically. Alternatively, administration can be performed locally, intranasally, intraperitoneally, intradermally, intraocularly, intrathecally, intraventricularly, via iontophoresis, transmucosally, intravitreal, or intramuscularly. Administration includes self-administration, administration by another person, or administration using a device ( For example (Infusion pump) is used.

[0049] As used herein, “ameliorate” or “ameliorating” means, in a statistical sample or specific subject, making the occurrence of a disease, condition, or symptom (or its signs, symptoms, or symptoms) better or more tolerable than in a control sample or subject.

[0050] As used herein, the term "carrier" or "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or mediator used with or formulated for administration of a compound / pharmaceutical product / composition (including formulations or drugs). Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oils, and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, silica particles (nanoparticles or microparticles), urea, etc. Additionally, adjuvants, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used. Other examples of suitable drug carriers are described in EW Martin's "..." Remington's Pharmaceutical Sciences) The full text of that document is incorporated into this paper by reference.

[0051] As used in this article, the phrase “delayed onset of…” means, in a statistical sample, the postponement or prevention of the onset of a disease, condition, or symptom (or its signs, symptoms, or symptoms) of a sample or subject who has been given one or more therapeutic agents, relative to a control sample or subject.

[0052] As used in this article, the phrase “delayed progression of…” means, in a statistical sample, that the disease, condition, or symptom (or its signs, symptoms, or symptoms) of a sample or subject treated with one or more therapeutic agents occurs more slowly than normal, relative to a control sample or subject.

[0053] As used herein, the term "effective amount" refers to the amount of a compound / composition / pharmaceutical product sufficient to achieve the desired therapeutic and / or preventative effects. For example The amount of a compound / composition / pharmaceutical product administered to a subject for the treatment, prevention, suppression, improvement, or delay of a disease, condition, or symptom, or the physiological signs, symptoms, or symptom of such a disease or condition. In the context of therapeutic or preventative application, in some embodiments, the amount of compound / composition / pharmaceutical product administered to the subject will depend on the type and severity of the disease and on individual characteristics such as general health status, age, sex, weight, and tolerance to the drug. In some embodiments, it also depends on the extent, severity, and type of the disease. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors. The compound / composition / pharmaceutical product may also be administered in combination with one or more other therapeutic compounds / agents (so-called "co-administration," where, for example, additional or other therapeutic agents may be administered simultaneously, sequentially, or by means of individual administration).

[0054] As used herein, the term "hydrate" refers to a substance that is associated with water (…). For example, A compound (complex). The number of water molecules in the hydrate of a compound may (or may not) be in a certain ratio to the number of compound molecules in the hydrate.

[0055] As used in this article, "inhibition" or "suppression" refers to the inhibition of a disease or symptom ( For example Signs, symptoms or symptoms related to Friedreich-type ataxia For exampleThe reduction of risk factors. In one embodiment, inhibition or inhibition means a reduction of at least a statistically significant amount compared to a control (or control subject). In one embodiment, inhibition or inhibition means a reduction of at least 5% compared to a control (or control subject). In various individual embodiments, inhibition or inhibition means a reduction of at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 33%, 40%, 50%, 60%, 67%, 70%, 75%, 80%, 90%, 95%, or 99% compared to a control (or control subject).

[0056] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a therapeutic compound that can be prepared using a relatively non-toxic acid or base, based on a specific substituent found on the compound described herein. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired base, either purely or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, magnesium, or similar salts. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired acid, either purely or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc salts, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, heparin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine (NEt3), trimethylamine, tripropylamine, tromethamine, etc., where the salt contains the protonated form of the organic base (e.g., [HNEt3]+). Salts derived from pharmaceutically acceptable inorganic acids include salts of the following acids: boric acid, carbonic acid, hydrohalic acids (hydrobromic acid, hydrochloric acid, hydrofluoric acid, or hydroiodic acid), nitric acid, phosphoric acid, aminosulfonic acid, and sulfuric acid. Salts derived from pharmaceutically acceptable organic acids include salts of the following acids: aliphatic hydroxy acids (e.g., citric acid, gluconic acid, glycolic acid, lactic acid, lactobionic acid, malic acid, and tartaric acid), aliphatic monocarboxylic acids (e.g., acetic acid, butyric acid, formic acid, propionic acid, and trifluoroacetic acid), amino acids (e.g., aspartic acid and glutamic acid), aromatic carboxylic acids (e.g., benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, gentianic acid, hippuric acid, and triphenylacetic acid), and aromatic hydroxy acids (e.g., o-hydroxybenzoic acid, p-hydroxybenzoic acid, etc.). Benzoic acid, 1-hydroxynaphthalene-2-carboxylic acid and 3-hydroxynaphthalene-2-carboxylic acid), ascorbic acid, dicarboxylic acids (e.g., fumaric acid, maleic acid, oxalic acid and succinic acid), glucuronic acid, mandelic acid, mucoic acid, nicotinic acid, orotic acid, dihydroxy acids, pantothenic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, hydroxyethylsulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid and p-toluenesulfonic acid (PTSA)), hydroxynaphthoic acid, etc.In some embodiments, pharmaceutically acceptable counterions are selected from the group consisting of: acetates, benzoates, benzenesulfonates, bromides, camphorsulfonates, chlorides, theophylline, citrates, ethanedisulfonates, fumarates, gluconate, gluconate, glucuronates, hippurates, iodides, hydroxyethanesulfonates, lactates, lactobionates, lauryl sulfate, malates, maleates, methanesulfonates, methyl sulfates, naphthates, sapsylates, nitrates, octadecanoates, oleates, oxalates, dihydroxynaphthyl salts, phosphates, polygalacturonates, succinates, sulfates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates. In some embodiments, the salt is a tartrate, fumarate, citrate, benzoate, succinate, octanoate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, maleate, trifluoroacetate, hydrochloride, or toluenesulfonate. It also includes salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds may contain both a basic functional group and an acidic functional group that allow the compound to be converted into a base addition salt or an acid addition salt, or to exist in zwitterionic form. These salts can be prepared by methods known to those skilled in the art. Any other pharmaceutically acceptable carrier known to those skilled in the art is also suitable for use with this technique.

[0057] As used herein, “prevention” or “preventing” of a disease, condition, or symptom (or its signs, symptoms, or symptoms) means, in a statistical sample, the result of a reduction in the occurrence of the disease, condition, or symptom compared to a control sample or subject, in a sample or subject receiving one or more therapeutic agents. Such prevention is sometimes referred to as preventive treatment.

[0058] As used in this article, the term “reverse remodeling” refers to physical changes in the heart and specifically to the restoration of the heart to a healthier form after it has been remodeled into an altered (e.g., less healthy) form. For example, this can be achieved by reversing the hypertrophic features of a subject's heart back to a normal heart. This reverse remodeling is known for physiological hypertrophy that occurs due to exercise (see: Nakamura et al., Mechanisms of Physiological and Pathological Cardiac Hypertrophy, Nature Reviews - Cardiology, (July 2018) 15: 387-407).

[0059] As used herein, the term "monotherapy" refers to the simultaneous or substantially simultaneous administration of at least two active ingredients via different routes. For example, Therapeutic agents).

[0060] As used herein, the term "sequential" therapeutic use refers to the application of at least two active ingredients at different times. For example, Therapeutic agents), administered via the same or different routes. More specifically, sequential use refers to the complete administration of one active ingredient (therapeutic agent) before the administration of another or other active ingredient. For example (Therapeutic agents). Therefore, an active ingredient may be applied minutes, hours, or days before the application of one or more other active ingredients. Concurrent treatment does not exist under this definition.

[0061] As used herein, the term "simultaneous" therapeutic use refers to the administration of at least two active ingredients via the same route and simultaneously or substantially simultaneously. For example (Therapeutic agents).

[0062] As used herein, the term "solvent" refers to a compound form that may associate with a solvent through a solvent decomposition reaction. This physical association can include hydrogen bonding. Common solvents include water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, acetone, hexane, DMSO, THF, diethyl ether, etc.

[0063] As used herein, “subject” refers to a live animal. In various embodiments, the subject is a mammal. In various embodiments, the subject is a non-human mammal, including but not limited to mice, rats, hamsters, guinea pigs, rabbits, sheep, goats, cats, dogs, pigs, miniature pigs, horses, cattle, or non-human primates. In some embodiments, the subject is a human. As used herein, the term “patient” may be used interchangeably with the term “subject.”

[0064] It should also be understood that the various methods of treating or preventing medical conditions as described herein are intended to mean “basic” in some embodiments, which includes complete treatment or prevention but also less than all treatment or prevention, and in which some biologically or medically relevant results are achieved.

[0065] As used herein, the term "synergistic therapeutic effect" refers to a therapeutic effect that is greater than the sum of its components, resulting from a combination of at least two agents and exceeding the effect of any single agent administered alone.

[0066] As used herein, the term "tautomer" refers to a compound that is an interchangeable form of a particular compound structure, varying in the displacement of hydrogen atoms and electrons. Thus, two structures can reach equilibrium through the movement of π electrons and one atom (usually H). For example, enols and ketones are tautomers because they can rapidly interconvert by treatment with acids or bases. The tautomer form can be related to the attainment of optimal chemical reactivity and biological activity of the compound of interest.

[0067] As used herein, the term "treating" or "treatment" refers to therapeutic treatment in which the aim is to reduce, alleviate, or slow down (relieve) a pre-existing disease condition or symptom or its associated signs or symptoms. By example, but not limited to, a subject's disease is successfully "treated" if, after receiving an effective amount of a compound / composition / pharmaceutical product or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates, the subject exhibits an observable and / or measurable reduction or absence of one or more signs, symptoms, or symptom associated with the disease, condition, or symptom. It should also be understood that the various modes of treatment for medical conditions described are intended to represent "fundamental," which includes complete improvement of the disease or condition's symptoms, signs, or symptoms, and "partial," in which some biological or medically relevant outcome is achieved.

[0068] II. Pharmaceutical composition / formulation / drug, route of administration and administration

[0069] The methods, uses, and compositions of this application utilize therapeutically effective amounts of compound A, compound B, or mixtures of compounds A and B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, wherein compounds A and B have the following structures:

[0070] Compounds A and B, or mixtures of compounds A and B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, may be formulated into a pharmaceutical product suitable for administration to a subject in need. Such pharmaceutical products may be referred to as compositions, formulations, or drugs, depending on their intended use. Any mixture prepared by mixing compounds A and B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates thereof, with solvents and / or other compounds is a composition or formulation and may or may not be intended for administration to a subject. A drug is generally considered to be specifically prepared for administration to a subject to address a disease, symptom, or illness ( For example,Friedreich-type ataxia), including compositions or formulations of its signs or symptoms. For the purpose of brevity, whenever this document refers to “compound A,” “compound B,” or “a mixture of compounds A and B,” the reference is intended to implicitly include pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates of compounds A and B, unless intended to imply a clear contrary meaning.

[0071] The compounds A, B, or mixtures of compounds A and B disclosed herein can be used alone or in combination with other therapeutic agents to meet the needs of subjects with Friedreich-type ataxia. For administration to subjects in need, compounds A, B, or mixtures of compounds A and B typically need to be formulated for the intended route of administration (for administration alone or as a combination formulation). In some embodiments, the same route of administration may be used to deliver compounds A, B, or mixtures of compounds A and B. Formulated products may be considered to contain compounds A, B, or mixtures of compounds A and B, and optionally one or more other compounds. Right now Other) compositions or drugs of therapeutic agents.

[0072] In some embodiments, therapeutic agents ( For example Compound A, compound B, or a mixture of compounds A and B with one or more other therapeutic agents can be formulated with little or no excipients or carriers. In some embodiments, the therapeutic agents can be formulated such that the majority of the formulation is an excipient or carrier. In short, those skilled in the art will adjust the formulation to have appropriate amounts of excipients or carriers based on: the needs / symptoms of the subject, the type and severity of the disease to be treated, the nature of the one or more therapeutic agents to be delivered, and the selected administration mode of the particular one or more therapeutic agents.

[0073] In some embodiments, the pharmaceutical composition may further comprise at least one therapeutic agent other than compound A, compound B, or a mixture of compounds A and B. This at least one other / additional therapeutic agent may be a medicament useful in treating Friedreich-type ataxia, or may be administered, for example, to mitigate the side effects of administering compound A, compound B, or a mixture of compounds A and B. Therefore, in some embodiments, the pharmaceutical composition may be prepared, for example, by combining compound A, compound B, or a mixture of compounds A and B with a pharmaceutically acceptable carrier and optionally one or more additional therapeutic agents, or by administering the other / additional therapeutic agent only in combination with the administration of compound A, compound B, or a mixture of compounds A and B.

[0074] The pharmaceutical composition may contain an effective amount of one or more therapeutic agents as described herein, and may optionally be distributed ( For exampleThe pharmaceutical composition is in a pharmaceutically acceptable carrier (dissolved, suspended, or otherwise). Components of the pharmaceutical composition may also be miscible with the compounds of this application and mix with each other in a manner that does not significantly impair the desired pharmaceutical efficiency.

[0075] As stated above, "effective amount" refers to any amount of a specific therapeutic agent sufficient to achieve the desired biological effect. Combining the teachings presented herein, an effective prophylaxis can be planned by selecting from a variety of therapeutic compounds and weighing factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and administration method. Right now A therapeutic regimen (preventive) or therapeutic treatment regimen that does not cause significant undesirable toxicity and is effective in addressing a specific symptom, condition, or disease in a therapeutic manner for a particular subject. The effective amount of a therapeutic agent for any particular indication can vary depending on factors such as the disease, condition, or symptom being treated, the specific compound or one compound administered, the size of the subject, the age of the subject, the overall health condition of the subject, and / or the severity of the disease, condition, or symptom. The effective amount can be determined during preclinical and / or clinical trials using methods familiar to physicians and clinicians. Those skilled in the art can determine the effective amount of a particular therapeutic agent or one compound empirically without unnecessary experimentation. A maximum dose can be used, i.e., the highest safe dose based on some medical judgment. Multiple daily doses can be envisioned to achieve appropriate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by measuring the patient's peak or sustained plasma levels. "Dose" and "dosage" are used interchangeably herein. A dose can be administered by oneself, by another person, or via a device ( For example (Pump) application.

[0076] For any therapeutic compound described herein, the therapeutically effective dose can be determined, for example, initially from animal models. The therapeutically effective dose can also be determined based on human data from compounds already tested in humans and compounds known to exhibit similar pharmacological activity, such as other relevant active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on relative bioavailability and the potency of the administered compound. Adjusting the dose to achieve maximum efficacy based on the methods described above and other methods well known in the art is entirely within the capabilities of a person skilled in the art.

[0077] Therapeutic compounds (alone or formulated in a pharmaceutical composition / drug) for therapeutic or preventative purposes can be tested in suitable animal model systems. Suitable animal model systems include, but are not limited to, rats, mice, chickens, cattle, monkeys, rabbits, pigs, miniature pigs, etc., prior to testing in human subjects. Any animal model system known in the art can be used prior to administration to human subjects. in vivo Testing. In some embodiments, drug administration can be tested directly in the human body.

[0078] Any therapeutic agent or composition ( For example The dosage, toxicity, and therapeutic efficacy of a drug (containing compound A, compound B, or a mixture of compounds A and B, other / additional therapeutic agents, or formulations of mixtures thereof) can be determined through standard pharmaceutical procedures in cell cultures or laboratory animals. For example To determine the LD50 (the dose that is lethal to 50% of the population) and ED50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, and it can be expressed as the ratio LD50 / ED50. Compounds exhibiting a high therapeutic index are advantageous. Although compounds exhibiting toxic side effects can be used, in such cases, delivery systems that target such compounds to the site of the affected tissue can be carefully designed to minimize potential damage to uninfected cells and thus reduce side effects.

[0079] Exemplary treatment regimens may require administration once daily, twice daily, three times daily, weekly, or monthly. In therapeutic applications, relatively high doses are sometimes required at relatively short intervals until disease progression is delayed, reduced, or terminated, or until the subject shows partial or complete improvement in disease symptoms. Afterward, a prophylactic regimen may be administered to the patient. Right now A program designed to prevent or contain the progression or recurrence of a disease, condition, or symptom.

[0080] For use in therapy, an effective amount of the therapeutic compound (alone or formulated) may be administered to a subject by any mode of delivery of the compound to the desired surface or tissue. Administration of the pharmaceutical composition may be performed by any means known to those skilled in the art. Routes of administration include, but are not limited to, oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, ocular, intrathecal, intraventricular, via iontophoresis, transmucosal, intravitreal, or intramuscular administration. Administration includes self-administration, administration by another person, and administration by a device ( For example (Pump) application.

[0081] The therapeutic compounds / pharmaceuticals disclosed in this article ( For example Compound A, compound B, or a mixture of compounds A and B can be formulated into formulations or drugs. Right now The formulation and the drug may be delivered to the subject in the form of, for example, the therapeutic compounds / pharmaceuticals disclosed herein. For example Compound A, compound B, or a mixture of compounds A and B) are dissolved or suspended in water, solvents, pharmaceutically acceptable carriers, or salts. For example It is prepared in the presence of NaCl or sodium phosphate, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutically acceptable ingredients.

[0082] Pharmaceutical composition ( For example A formulation or drug may contain a carrier ( For example A pharmaceutically acceptable carrier), which may contain, for example, water, ethanol, or polyols ( For example Solvents or dispersion media for (such as glycerol, propylene glycol, and liquid polyethylene glycol) and suitable mixtures thereof. Appropriate flowability can be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. Glutathione and other antioxidants can be included to prevent oxidation. In many cases, it will be advantageous to include isotonic agents, such as sugars ( For example (e.g., trehalose), polyols (such as mannitol, sorbitol), or sodium chloride. Extended absorption of injectable compositions can be achieved by including delay-absorption agents such as aluminum monostearate or gelatin in the composition.

[0083] Solutions or suspensions for parenteral, intradermal, subcutaneous or intraocular use ( For example A preparation (or drug) may include the following components: a sterile diluent, such as water for injection, saline solution, fixative oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent, such as benzyl alcohol or methylparaben; an antioxidant, such as ascorbic acid or sodium bisulfite; a chelating agent, such as ethylenediaminetetraacetic acid; a buffer, such as acetate, citrate, or phosphate; and a tonic agent, such as sodium chloride or dextrose. The pH may be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be sealed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. For the convenience of the patient or treating physician, the preparation may be provided alone or in a package containing ingredients for the treatment process (…). For example All necessary equipment for treatment lasting 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or longer. For example The kit contains vials of medicine, vials of diluent, syringes, and needles.

[0084] When systemic delivery of a therapeutic compound / pharmaceutical agent or pharmaceutical composition is desired, the therapeutic compound / pharmaceutical agent or pharmaceutical composition can be formulated for injection. For example Parenteral administration is performed via bolus injection or continuous infusion (e.g., via IV injection or metered administration over a defined time period via pump). The formulation for injection may be available in unit dosage form. For example Preservatives are added to ampoules or multi-dose containers. Pharmaceutical compositions may be in the form of suspensions, solutions, or emulsions in oily or aqueous media, and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants. Additionally, therapeutic compounds ( For example Suspensions of compounds A, B, or mixtures thereof can be prepared as oily injection suspensions, depending on the application. Suitable lipophilic solvents or mediators include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of high-concentration solutions.

[0085] Systemic formulations include those designed for use via injection ( For example Compounds intended for administration via subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as compounds designed for oral, transmucosal, or pulmonary administration.

[0086] For intravenous and other parenteral administration routes, the compound ( For example Compound A, compound B, or a mixture of compounds A and B can be formulated as lyophilized formulations, lyophilized formulations of therapeutic compounds with liposome embedding or lipid encapsulation, lipid complexes, or salt complexes in aqueous suspensions. Lyophilized formulations are typically prepared in a suitable aqueous solution shortly before administration. For example Reconstitute in sterile water or saline.

[0087] Suitable pharmaceutical compositions for injection ( For example Compositions (preparations or drugs) may include sterile aqueous solutions (in the case of water solubility) or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). Compositions intended for injection will generally be sterile and should have a degree of flowability sufficient for easy injection. They should be stable under manufacturing and storage conditions and be preserved against contamination by microorganisms such as bacteria and fungi.

[0088] Sterile injectable solutions ( For example (A compound or drug) can be prepared by applying the required amount of therapeutic compound ( For example Dispersions are prepared by incorporating one or more of the ingredients listed above (as needed) into a suitable solvent, followed by filtration and sterilization. Typically, dispersions are prepared by incorporating the therapeutic compound into a sterile medium containing a basic dispersion medium and any other desired components from the ingredients listed above. In the case of sterile powders used to prepare sterile injectable solutions, typical preparation methods include vacuum drying and freeze-drying, which can produce powders containing the active ingredient plus any additional desired components from its previously sterile filtered solution.

[0089] For oral administration, the therapeutic compound ( For example Compound A, compound B, or a mixture of compounds A and B, and optionally other therapeutic agents, can be readily formulated into compounds by combination with pharmaceutically acceptable carriers well known in the art. Such carriers enable the therapeutic compound to be formulated into tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a subject to treatment. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginate, Primogel®, or corn starch; lubricants such as magnesium stearate or stearates; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0090] Pharmaceutical formulations for oral use can be obtained as solid excipients. After adding suitable excipients, the resulting mixture is optionally ground and processed into granules to obtain tablets or sugar-coated pellet cores, if desired. Suitable excipients are particularly fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrants, such as cross-linked polyvinylpyrrolidone, agar, or alginate or its salts, such as sodium alginate, can be added. Optionally, oral formulations can also be prepared in saline or buffer solutions. For example EDTA is used to neutralize internal acidic conditions, or it can be applied without any carrier.

[0091] Specifically, chemically modified oral dosage forms of the above are also envisioned to enable effective oral delivery of the derivatives. Typically, the envisioned chemical modification involves attaching at least one portion to the therapeutic agent, ingredient, and / or excipient, wherein said portion allows for: (a) inhibition of acid hydrolysis; and (b) uptake from the stomach or intestine into the bloodstream. Increased overall stability of the therapeutic agent, ingredient, and / or excipient, as well as increased circulation time in vivo, are also desired. Examples of such portions include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. (Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts,” in: Enzymes as Drugs, edited by Hocenberg and Roberts, Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that can be used are poly-1,3-dioxolane and poly-1,3,6-trioxane. As mentioned above, polyethylene glycol (PEG) moieties of various molecular weights are suitable for pharmaceutical applications.

[0092] For formulations of therapeutic agents, ingredients, and / or excipients, the site of release can be the stomach, small intestine (duodenum, jejunum, or ileum), or large intestine. Those skilled in the art have available formulations that do not dissolve in the stomach but release the material in the duodenum or other parts of the intestine. Preferably, release will avoid harmful effects on the gastric environment by protecting the therapeutic compound / pharmaceutical or by releasing the bioactive material outside the gastric environment (such as into the intestine).

[0093] Coatings or mixtures of coatings can also be used on tablets, and are not intended to protect against stomach upset. This may include sugar coatings or coatings that make the tablets easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivering dry therapeutic agents. For example For powders, a soft gelatin shell can be used for liquid forms. The shell material for capsules can be thick starch or other edible paper. For pills, lozenges, molded tablets, or tablet grounds, a wet massing technique can be used.

[0094] Therapeutic compounds / agents (as used herein) are intended to refer to compound A, compound B, or a mixture of compounds A and B, and any other active pharmaceutical ingredient that may be administered in combination with compound A, compound B, or a mixture of compounds A and B. For example Other therapeutic agents). Formulations may comprise fine microparticles or pellets with a particle size of about 1 to 2 mm in particulate form. Formulations for materials used in capsule administration may also be powders, lightly compressed, or even tablets. Therapeutic compounds / pharmaceuticals or pharmaceutical compositions may be prepared by compression.

[0095] Colorants and flavorings can both be included. For example, therapeutic compounds / pharmaceuticals or pharmaceutical compositions can be formulated and then further included in edible products, such as chilled beverages containing colorants and flavorings.

[0096] Inert materials can be used to dilute or increase the volume of therapeutic compounds / pharmaceuticals or pharmaceutical compositions. These diluents may contain carbohydrates, particularly mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextran, and starch. Certain inorganic salts may also be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents include Fast-Flo®, Emdex®, STARCH 1500®, Emcompress®, and Avicel®.

[0097] Disintegrants can be included in formulations of therapeutic compounds / pharmaceuticals or pharmaceutical compositions in solid dosage forms. Materials used as disintegrants include, but are not limited to, starch, including the commercially available starch-based disintegrant Explotab. Sodium glycolate starch, Amberlite®, sodium carboxymethyl cellulose, hyperbranched starch, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponges, and bentonite are all possible applications. Another form of disintegrant is an insoluble cation exchange resin. Powdered gums can be used as both disintegrants and binders, and these can include powdered gums such as agar, Calaya gum, or astragalus gum. Alginic acid and its sodium salts can also be used as disintegrants.

[0098] Binders can be used to hold therapeutic agents together to form rigid tablets and contain materials derived from natural products such as gum arabic, astragalus gum, starch, and gelatin. Other binders include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Both polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) can be used in alcoholic solutions to granulate therapeutic agents.

[0099] Anti-friction agents can be included in formulations of therapeutic compounds / pharmaceuticals or pharmaceutical compositions to prevent adhesion during the formulation process. Lubricants can be used as a layer between the therapeutic agent and the mold wall, and these can include, but are not limited to: stearic acid (including its magnesium and calcium salts), polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils, and waxes. Water-soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol (PEG) of various molecular weights, Carbowax™ 4000, and 6000 can also be used.

[0100] A gliding agent may be added to improve the flow properties of the drug during dispensing and to facilitate rearrangement during compression. Gliding agents may include starch, talc, pyrolytic silica, and hydrated aluminosilicates.

[0101] To facilitate the dissolution of therapeutic compounds / pharmaceuticals or pharmaceutical compositions in an aqueous environment, surfactants may be added as wetting agents. Surfactants may include anionic detergents such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate. Cationic detergents may be used, and these may include benzalkonium chloride and benzyl chloride. Potential nonionic detergents that may be included as surfactants in formulations or pharmaceuticals include polidocanol 400, polyethylene glycol 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glyceryl monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants may be present alone or as mixtures in varying proportions in the formulations, pharmaceuticals, or derivatives disclosed herein.

[0102] Orally administered pharmaceutical compositions include compressed capsules made of gelatin, and soft, sealed capsules made of gelatin and plasticizers such as glycerin or sorbitol. Such compressed capsules may contain active ingredients mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, therapeutic compounds may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Furthermore, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres are well defined in the art. All formulations for oral administration should be at doses suitable for such administration.

[0103] For buccal administration, the composition can be in the form of tablets or lozenges prepared in a conventional manner.

[0104] For topical application, therapeutic compounds / agents or pharmaceutical compositions can be formulated into solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Solutions, gels, ointments, creams, or suspensions can be applied topically. These compounds can also be formulated into... For example Rectal or vaginal compositions (such as suppositories or retention enemas) containing a conventional suppository base (such as cocoa butter or other glycerides).

[0105] For administration by inhalation, the therapeutic compound / pharmaceutical agent or pharmaceutical composition used according to this application may be administered by using a suitable propellant ( For example Dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases can be conveniently delivered from pressurized packages or nebulizers in the form of an aerosol spray. In some embodiments, formulations, drugs, and / or therapeutic compounds / pharmaceuticals can be delivered from a container containing a suitable propellant ( For example This refers to the delivery of a pressurized container or dispenser of a gas (such as carbon dioxide) or from a nebulizer in the form of an aerosol spray. Such methods are included in the methods described in U.S. Patent No. 6,468,798. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a measured amount. For example, capsules and cartridges for inhalers or blow-throughs (…) can be… For example Gelatin) is formulated into a powder mixture containing a therapeutic compound / pharmaceutical and a suitable powder matrix (such as lactose or starch). Alternatively, the therapeutic compound / pharmaceutical or pharmaceutical composition may be in powder form so as to be mixed with a suitable carrier ( For example It consists of sterile and pyrogen-free raw water.

[0106] Nasal delivery of therapeutic compounds / pharmaceuticals or pharmaceutical compositions is also envisioned. Nasal delivery allows the therapeutic compound / pharmaceutical or pharmaceutical composition to be delivered directly into the bloodstream after application to the nose, without the need for product deposition in the lungs. Formulations for nasal delivery include formulations containing dextran or cyclodextrin.

[0107] For nasal administration, one type of useful device is a small, rigid bottle to which a metered-dose nebulizer is attached. In some embodiments, the metered dose is delivered by inhaling a pharmaceutical composition (in solution form) into a defined-volume chamber having an orifice sized to atomize the aerosol formulation by forming a spray when the liquid in the chamber is compressed. The chamber is compressed to administer the therapeutic compound / agent or pharmaceutical composition. In a particular embodiment, the chamber is arranged as a piston. Such devices are commercially available.

[0108] Alternatively, a plastic squeeze bottle with an orifice or opening sized to atomize the aerosol formulation by forming a spray upon squeezing. The opening is typically located at the top of the bottle, and the top is usually tapered to partially align with the nasal passage for efficient application of the aerosol formulation. Preferably, the nasal inhaler will deliver a metered amount of the aerosol formulation to administer a measured dose of a therapeutic compound / pharmaceutical or pharmaceutical composition.

[0109] This paper also envisions pulmonary delivery of the compounds disclosed herein. Therapeutic compounds / pharmaceuticals or pharmaceutical compositions are delivered to the lungs of mammals upon inhalation and cross the pulmonary epithelial lining to reach the bloodstream. Other reports of inhaled molecules include those by Adjei et al. Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (Leuprolide Acetate); Braquet et al., J Cardiovasc Pharmacol 13 (Supplement 5): 143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (α1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (α-1-protease); Oswein et al., 1990, “Aerosolization of Proteins”, Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March (Recombinant Human Growth Hormone); Debs et al., 1988, J Immunol 140:3482-3488 (Interferon-γ and Tumor Necrosis Factor α) and Platz et al., U.S. Patent No. 5,284,656 (Granocyte Colony-Stimulating Factor; incorporated by reference). Methods and compositions for pulmonary delivery of drugs to exert systemic effects are described in U.S. Patent No. 5,451,569 (incorporated by reference), issued September 19, 1995 to Wong et al.

[0110] It is envisioned that the technology used in practice will be a wide range of mechanical devices designed for the transpulmonary delivery of therapeutic products, including but not limited to nebulizers, metered inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0111] Some specific examples of commercially available devices suitable for practicing this technology are the Ultravent™ nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II® nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin® metered inhaler, manufactured by GlaxoInc., Research Triangle Park, North Carolina; and the Spinhaler® powder inhaler, manufactured by Fisons Corp., Bedford, Mass.

[0112] All such devices require the use of formulations suitable for dispensing therapeutic compounds / pharmaceuticals or pharmaceutical compositions. Typically, each formulation is specific to the type of device employed, and may involve the use of appropriate propellant materials in addition to the usual diluents, adjuvants, and / or carriers used in therapy. Furthermore, the use of liposomes, microcapsules, microspheres, nanoparticles, nanospheres, inclusion complexes, or other types of carriers is envisioned.

[0113] Formulations suitable for use with nebulizers (jet or ultrasonic) may, for example, contain a therapeutic compound / pharmaceutical or pharmaceutical composition dissolved in water at a concentration of about 0.01 mg to 50 mg of a bioactive compound per mL of solution. The formulation may also contain buffers and optional monosaccharides. For example (For inhibitor stabilization and osmotic pressure regulation). The aerosol formulation may also contain surfactants to reduce or prevent surface-induced aggregation of the therapeutic compounds / pharmaceuticals or pharmaceutical compositions disclosed herein caused by solution atomization during aerosol formation.

[0114] The formulation used with a metered-dose inhaler generally comprises a fine powder containing a therapeutic compound / pharmaceutical or pharmaceutical composition disclosed herein, which is suspended in a propellant with the aid of a surfactant. The propellant can be any conventional material used for this purpose, such as chlorofluorocarbons, chlorofluorocarbons, hydrofluorocarbons, or hydrocarbons, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane or combinations thereof. Suitable surfactants include sorbitan trioleate and soybean lecithin. Oleic acid can also be used as a surfactant.

[0115] The formulation used for dispensing from a powder inhaler device may comprise a finely divided dry powder containing a therapeutic compound / agent or pharmaceutical composition, and may also include a spreader, such as lactose, sorbitol, sucrose, or mannitol, in an amount that facilitates the dispersion of the powder from the device. For example 50% to 90% by weight of the compound / therapeutic agent / pharmaceutical composition. The compound / therapeutic agent / pharmaceutical composition can be advantageously prepared in the form of particles or nanoparticles with an average particle size of less than 10 micrometers (μm), most preferably 0.5 to 5 μm, for most efficient delivery to deep lungs.

[0116] For ophthalmic or intraocular indications, any suitable mode of delivery of a therapeutic compound / pharmaceutical or pharmaceutical composition to the eye or an area near the eye may be used. Typically, for ophthalmic formulations, See Mitra (editor), Ophthalmic Drug Delivery Systems , Marcel Dekker, Inc., New York, NY (1993) and Havener, WH, Ocular Pharmacology CV Mosby Co., St. Louis (1983). Non-limiting examples of pharmaceutical compositions suitable for intraocular or periocular application include, but are not limited to, ocular inserts, microtablets, and topical preparations such as eye drops, ointments, and In situ Gel. In one embodiment, the contact lens is coated with a pharmaceutical composition comprising a therapeutic compound / agent (or comprising a pharmaceutical composition encapsulated therein). In some embodiments, a single dose may comprise 0.1 ng to 5000 μg, 1 ng to 500 μg, or 10 ng to 100 μg of a therapeutic compound / agent or pharmaceutical composition administered to the eye.

[0117] Eye drops may contain a sterile liquid formulation that can be applied directly to the eye. In some embodiments, the eye drops contain at least one therapeutic agent (and may contain several), and may further contain one or more preservatives. In some embodiments, the optimal pH of the eye drops is equal to the pH of the tear fluid and is about 7.4, and the pH may be within any range that is harmless to the subject's eyes. For eye drops, the therapeutic compound / agent may be present at about 0.1% to about 5% (w / v or v / v, depending on the physical properties of the active ingredient). Right now The therapeutic compound / agent (in solid or liquid form) is present in the drop solution. In some embodiments, the therapeutic compound / agent may be present in the drop solution at about 1% to about 3% (w / v or v / v, as applicable). In some embodiments, the therapeutic compound / agent may be present in the drop solution at about 0.2% to about 1.5% (w / v or v / v, as applicable). In some embodiments, the therapeutic compound / agent may be present in the drop solution at about 0.1% to about 1.0% (w / v or v / v, as applicable).

[0118] In situGels are viscous liquids that, when influenced by external factors such as appropriate pH, temperature, pressure, and / or the presence of electrolytes, exhibit the ability to undergo a sol-to-gel transition. This property results in a slower rate of drug excretion from the ocular surface and an increased bioavailability of the active ingredient. In situ Commonly used polymers in gel formulations include, but are not limited to, gellan gum, poloxamer, silicone-containing formulations, silica-based formulations, and cellulose acetate phthalate. In some embodiments, a therapeutic compound / pharmaceutical or pharmaceutical composition is formulated into an in-situ gel (as a formulation / pharmaceutical).

[0119] For topical ophthalmic application, therapeutic compounds / pharmaceuticals or pharmaceutical compositions can be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Ointments are semi-solid dosage forms for external use, such as for topical application to the eyes or skin. In some embodiments, ointments comprise a solid or semi-solid hydrocarbon matrix with a melting or softening point close to the core temperature of the human body. In some embodiments, ointments applied to the eyes break down into small droplets, which remain in the conjunctival sac for a longer period of time, thereby improving bioavailability.

[0120] Ocular inserts are solid or semi-solid dosage forms, avoiding the disadvantages of traditional ophthalmic drug dosage forms. They are less susceptible to defense mechanisms (such as outflow through the nasolacrimal duct), can remain in the conjunctival sac for a longer period, and are more stable than conventional dosage forms. They also offer advantages such as precise delivery of one or more therapeutic compounds / agents or drug compositions, slow and constant release of one or more therapeutic compounds / agents, and limitation of systemic absorption of one or more therapeutic compounds / agents. In some embodiments, the ocular insert comprises one or more therapeutic compounds / agents and one or more polymeric materials. The polymeric materials may include, but are not limited to, methylcellulose and its derivatives (…). For example Hydroxypropyl methylcellulose (HPMC), ethyl cellulose, polyvinylpyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethyl chitosan, gelatin, and various mixtures of the above polymers. Ocular inserts may include silica. Ocular inserts may include liposomes, nanoparticles, or microparticles of degradable or biodegradable polymers (as described in more detail below).

[0121] Microtablets are biodegradable solid drug dosage forms that transform into a gel after application to the conjunctival sac, thereby prolonging the duration of action of the active ingredient (…). Right nowThe contact time between the therapeutic compound / agent and the ocular surface is extended, thereby improving the bioavailability of the therapeutic compound / agent. The advantages of microtablets include easy application to the conjunctival sac, independence from defense mechanisms such as tearing or drainage through the nasolacrimal duct, longer contact with the cornea due to the presence of mucosal adhesion polymers, and gradual release of the active ingredient from the formulation at the application site due to swelling of the external carrier layer. Microtablets may include one or more therapeutic compounds / agents and one or more polymers. Non-limiting examples of polymers suitable for use in microtablet formulations include cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose, ethyl cellulose, and acrylates (…). For example Polyacrylic acid and its crosslinked forms), Carbopol® or Carbomer, chitosan and starch ( For example (Drum-dried waxy corn starch). In some embodiments, the microtablets further comprise one or more excipients. Non-limiting examples of excipients include mannitol and magnesium stearate.

[0122] Ophthalmic or intraocular preparations and medications may contain non-toxic adjuvants, such as antibacterial components that are generally harmless when used, such as thimerosal, benzalkonium chloride, methylparaben and propylparaben, benzyl dimethyl dodecyl ammonium bromide, benzyl alcohol or phenethyl alcohol; buffering agents, such as sodium chloride, sodium borate, sodium acetate, sodium citrate or gluconate buffers; and other conventional ingredients, such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitate, ethylenediaminetetraacetic acid (EDTA), etc.

[0123] In some embodiments, the viscosity of ocular formulations comprising one or more therapeutic compounds / agents is increased to improve contact with the cornea and bioavailability in the eye. Viscosity can be increased by adding a high molecular weight hydrophilic polymer that does not diffuse through biological membranes and forms a three-dimensional network in water. Non-limiting examples of such polymers include polyvinyl alcohol, poloxamer, hyaluronic acid, carbomer and polysaccharides, cellulose derivatives, gellan gum, and xanthan gum.

[0124] In addition to the formulations described above, therapeutic compounds / pharmaceuticals or pharmaceutical compositions may also be formulated as reservoir formulations. Such long-acting formulations may be formulated with suitable polymeric or hydrophobic materials (e.g., emulsions in acceptable oils) or ion exchange resins, or formulated as sparingly soluble derivatives, such as sparingly soluble salts.

[0125] In some embodiments, a therapeutic compound / pharmaceutical agent or pharmaceutical composition is administered as a reservoir formulation, wherein the active therapeutic agent is encapsulated in or disposed within silica-based microparticles. Such formulations may be controlled-release formulations, delayed-release formulations, or extended-release formulations (terms defined below). Such controlled-release, delayed-release, or extended-release formulations may include particles, such as microparticles or nanoparticles.

[0126] The pharmaceutical composition may also contain a suitable solid or gel-phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, silica / silicone, and polymers (such as polyethylene glycol).

[0127] Suitable liquid or solid drug formulation ( For example The pharmaceutical composition / formulation may be, for example, an aqueous or saline solution for inhalation; a microencapsulated, embedded, coated onto microscopic gold particles, contained in liposomes, or atomized aerosol for implantation into the skin or dried onto a sharp object for scraping into the skin. The pharmaceutical composition / formulation may also include formulations of granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or sustained-release therapeutic compounds, in which excipients and additives and / or adjuvants (such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers) are typically used as described above. The pharmaceutical composition may be suitable for a variety of drug delivery systems. For a brief overview of drug delivery methods, see Langer R. Science 249:1527-33 (1990).

[0128] Therapeutic compounds / pharmaceuticals or pharmaceutical compositions may be provided in particulate form. As used herein, "particulate" means nanoparticles or microparticles (or, in some cases, larger particles) that may consist wholly or partially of the therapeutic compounds / pharmaceuticals described herein. The particles may contain the therapeutic compound / pharmaceutical within a coated core, including, but not limited to, enteric coatings. Therapeutic compounds / pharmaceuticals may also be dispersed throughout the particle. Therapeutic compounds / pharmaceuticals may also be adsorbed into the particle. The particles may have any order of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to any therapeutic compound / pharmaceutical, the particles may include any of those materials conventionally used in the pharmaceutical and medical fields, including, but not limited to, soluble, insoluble, biodegradable, or non-biodegradable materials, or combinations thereof. The particles may be microcapsules containing the therapeutic compound / pharmaceutical in a solution or semi-solid state. The particles may have virtually any shape.

[0129] Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for delivering therapeutic compounds / pharmaceuticals. These polymers can be natural or synthetic. The polymer can be selected based on the desired release time period. Bioadhesive polymers of particular interest include those by Sawhney HS et al. (1993). Macromolecules Biodegradable hydrogels described in 26:581-7, the teachings of which are incorporated herein by reference. These comprise polyhyaluronic acid, casein, gelatin, gelatin protein, polyanhydride, polyacrylic acid, alginate, chitosan, polyethylene glycol (PEG), polyvinyl alcohol (PVA), poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(laurate methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), and poly(ε-caprolactone), or mixtures of two or more of the foregoing. Biodegradable polymeric materials can be substantially pure single polymers or mixtures of two or more polymers, wherein the material comprises a single monomer, a block copolymer, or a mixture thereof.

[0130] A therapeutic compound / pharmaceutical, or a mixture of two or more therapeutic compounds / pharmaceuticals, can be formulated into a carrier system. The carrier can be a colloidal system. The carrier or colloidal system can be a liposome or a phospholipid bilayer medium. In one embodiment, a therapeutic compound / pharmaceutical, or a mixture of two or more therapeutic compounds / pharmaceuticals, can be encapsulated in liposomes while maintaining the integrity of the therapeutic compound / pharmaceutical. Those skilled in the art will understand that various methods exist for preparing liposomes. See Lichtenberg et al. , Methods Biochem. Anal ., 33:337-462 (1988); Anselem et al. , Liposome Technology CRC Press (1993). Liposome formulations can delay clearance and increase cellular uptake ( See Reddy, Ann. Pharmacother., 34(7-8):915-923 (2000)). For example, therapeutic agents can also be loaded into particles prepared from pharmaceutically acceptable ingredients, including but not limited to soluble, insoluble, permeable, impermeable, biodegradable, or gastric-retention polymers or liposomes. Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles, and viral vector systems.

[0131] The carrier can also be a polymer. For example A biodegradable, biocompatible polymer matrix. In one embodiment, a therapeutic compound / pharmaceutical or a mixture of two or more therapeutic compounds / pharmaceuticals can be embedded in the polymer matrix while maintaining the integrity of the composition. The polymer can be microparticles or nanoparticles encapsulating the therapeutic compound / pharmaceutical. The polymer can be natural, such as peptides, proteins, or polysaccharides, or synthetic, such as polyalphahydroxy acids. Examples include those made from... For example A carrier made of collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharides, fibrin, gelatin, and combinations thereof. In some embodiments, the polymer is polylactic acid (PLA), polylactic acid / glycolic acid (PLGA), or a mixture thereof. The polymer matrix can be prepared and separated in a variety of forms and sizes, including microspheres and nanospheres. Polymer formulations can result in a prolonged duration of therapeutic effect. See Reddy, Ann. Pharmacother ., 34(7-8):915-923(2000)). Polymer formulations for human growth hormone (hGH) have been used in clinical trials. See Kozarich and Rich, Chemical Biology , 2:548-552 (1998)).

[0132] Examples of slow-release formulations of polymer microspheres are described in the following: PCT Publication WO 99 / 15154 (Tracy wait people U.S. Patent Nos. 5,674,534 and 5,716,644 (both Zale et al. ), PCT Public WO 96 / 40073 (Zale) et al. ) and PCT Public WO 00 / 38651 (Shah et al. U.S. Patent Nos. 5,674,534 and 5,716,644, and PCT Publication WO 96 / 40073 describe polymer matrices containing erythropoietin particles stabilized with salt to prevent aggregation.

[0133] In some embodiments, nanoparticles or microparticles may be based on silica or silane (see, for example, WO2002 / 080977, entitled “Biodegradable carrier and method for preparation thereof”).

[0134] In some embodiments, a therapeutic compound / agent or a mixture of two or more therapeutic compounds / agents may be prepared together with a carrier (such as a controlled-release formulation, including implants and microencapsulated delivery systems) that protects the therapeutic compound / agent or other therapeutic agent or mixture thereof from rapid elimination from the body. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such formulations can be prepared using known techniques. These materials can also... For example Commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (containing liposomes targeting monoclonal antibodies against cell-specific antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0135] Therapeutic compounds / pharmaceuticals or mixtures of two or more therapeutic compounds / pharmaceuticals may be included in a controlled-release system. The term "controlled release" is intended to refer to any formulation containing a drug in which the manner and profile of drug release from the formulation are controlled. This refers to immediate-release and non-immediate-release formulations, where non-immediate-release formulations include, but are not limited to, sustained-release and delayed-release formulations. The term "sustained-release" (also known as "extended-release") is used in its conventional sense to refer to a drug formulation that provides a gradual release of the drug over an extended period of time and preferably, but not necessarily, results in a substantially constant blood level of the drug over the extended period of time. The term "delayed-release" is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and release of the drug from it, thereby making it available to a subject. "Delayed-release" may or may not involve a gradual release of the drug over an extended period of time and therefore may or may not be "sustained-release."

[0136] The use of long-term controlled-release or sustained-release implants or reservoir preparations may be particularly suitable for the treatment of chronic conditions. The terms "implant" and "reservoir preparation" are intended to comprise a single composition (such as a mesh) or a composition comprising multiple components. example likeAn implant or repositories may be configured to deliver a therapeutic or preventative level of active pharmaceutical ingredient for at least 2 days. This can be achieved by a fibrous mesh composed of several individual mesh materials or by a combination of multiple individual compositions, wherein the multiple compositions remain localized and provide sustained release of an active pharmaceutical ingredient from an aggregate of one or more compositions. As used herein, “long-term” release means that the implant or repositories are constructed and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for at least 7 days. In some embodiments, the implant or repositories are constructed and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for at least 14 days. In some embodiments, the implant or repositories are constructed and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for at least 30 days. In some embodiments, the implant or repositories are constructed and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for at least 60 days. In some embodiments, the implant or repositories are constructed and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for at least 90 days. In some embodiments, the implant or depot preparation is configured and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for at least 180 days. In some embodiments, the implant or depot preparation is configured and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for at least one year. In some embodiments, the implant or depot preparation is configured and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for 15 to 30 days. In some embodiments, the implant or depot preparation is configured and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for 30 to 60 days. In some embodiments, the implant or depot preparation is configured and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for 60 to 90 days. In some embodiments, the implant or depot preparation is configured and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for 90 to 120 days. In some embodiments, the implant or depot preparation is configured and arranged to deliver a therapeutic or preventative level of active pharmaceutical ingredient for 120 to 180 days. In some embodiments, the implant or reservoir preparation is configured and arranged to deliver a therapeutic or prophylactic level of active pharmaceutical ingredient for up to one year. In some embodiments, long-release implants or reservoir preparations are well known to those skilled in the art and include some of the release systems described above. In some embodiments, such implants or reservoir preparations can be administered surgically. In some embodiments, such implants or reservoir preparations can be administered topically or by injection.

[0137] III. Characteristics of Myocardial Hypertrophy

[0138] Cardiac hypertrophy is a compensatory response to increased cardiac stress due to preload or afterload. It is classified into two distinct categories: physiological hypertrophy and pathological hypertrophy. Physiological hypertrophy is reversible and maintains cardiac function, while pathological hypertrophy is typically degenerative, leading to arrhythmias, heart failure, and ultimately death. (Nakamura et al., Mechanisms of Physiological and Pathological Cardiac Hypertrophy) Nature Reviews – Cardiology , (2018) 15: 387-407.

[0139] Physiological hypertrophy is characterized by increased heart mass and cardiomyocyte growth, usually a result of physical stress (such as pregnancy or endurance training). This physical change in heart structure occurs to compensate for the increased stress. Once the stress is relieved, the heart will return to its normal size. Right now The subject's heart will return to its original quality without any lasting adverse effects. Same as above.

[0140] Pathological hypertrophy is characterized by increased heart mass and increased left ventricular wall thickness, with the width (thickness) of individual cardiomyocytes increasing more than their length. As a result of these changes, the size of the left ventricle decreases as the heart wall thickens. Right now The size of the left ventricle is reduced. These changes in cardiac structure are often referred to as maladaptive remodeling or cardiac remodeling. Common stimuli that cause pathological hypertrophy include, but are not limited to, myocardial infarction, valvular disease, diabetes, metabolic syndrome, and genetic causes (such as Friedreich ataxia). Pathological hypertrophy typically leads to decreased cardiomyocyte contractility, cardiomyocyte death, and fibrosis. For example, Myocardial fibrosis). The exact nature of maladaptive remodeling is currently unclear. Right now While cardiac remodeling may be reversible, treatments / medications offer the potential to eventually "reverse remodel" the heart, similar to what happens with physiological hypertrophy. Without treatment, pathological hypertrophy can worsen, leading to arrhythmias, heart failure, and ultimately death. Same as above.

[0141] IV. Cardiac fibrosis

[0142] Cardiac fibrosis is characterized by extracellular matrix proteins in the cardiac interstitium ( For example, The net accumulation of collagen leads to systolic and diastolic dysfunction in many cardiac pathophysiological conditions. Cardiac fibrosis and remodeling can result from the production of matrix proteins (…). For example Fibroblasts (the cells that produce fibroblasts) can do so directly, or they can do so by secreting fibroblast formation mediators. (For exampleIt occurs indirectly (through macrophages, mast cells, lymphocytes, cardiomyocytes, and vascular cells). Hypertrophic cardiomyopathy is also often associated with the development of significant cardiac fibrosis. Whether cardiac fibrosis is reversible is currently unclear, but experimental and clinical evidence suggests that cardiac fibrotic changes may be reversible. (Kong et al., The Pathogenesis of Cardiac Fibrosis,) Cell Mol. Life Sci., (2014) 71(4): 549-574.

[0143] V. Cardiac remodeling and reverse cardiac remodeling

[0144] As mentioned above, cardiac remodeling is a term used to refer to adaptive changes in the physical structure of the heart that occur naturally in response to stimuli such as stress caused by pregnancy, exercise, or disease. Myocardial hypertrophy is an example of cardiac remodeling. Cardiac fibrosis is an example of cardiac remodeling. Physiological myocardial hypertrophy is naturally reversible, while pathological hypertrophy is usually permanent and progressively maladaptive. It is currently unclear whether cardiac fibrosis is reversible, but recent evidence suggests that it may be reversible with appropriate intervention. As used herein, the term “reverse remodeling” or “cardiac remodeling” is intended to refer to any positive changes in the physical structure of the heart that reverse a destructive cardiac remodeling event that has already occurred. In the case of myocardial hypertrophy, such remodeling can be a reduction in heart mass or a reduction in ventricular (usually the left ventricle, but can be either the left or right ventricle) wall thickness that occurs in response to stimuli such as the use (application) of compound A, compound B, or mixtures thereof (including, of course, any pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof). For myocardial hypertrophy or cardiac fibrosis, such reversal can be a reduction in the amount of cardiac fibrosis observed after treatment with (administered) compound A, compound B or mixtures thereof (including, of course, any pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates and / or solvates thereof), or inhibition or delay of the progression of cardiac fibrosis.

[0145] Refer to Example 2 and Figures 8 to 17 The data presented indicate that administration of compound A or compound B to mouse models can not only reduce the formation of myocardial hypertrophy, but may also reverse myocardial hypertrophy (i.e., reverse cardiac remodeling).

[0146] VI. Improve / normalize mitochondrial size in cardiomyocytes

[0147] In at least one known Friedreich-type ataxia mouse model, a decrease in the cross-sectional area of ​​mitochondria in cardiomyocytes was observed with increasing age compared to wild-type mice. (See: Chiang et al., Section 3.1) (Refer to Example 3 and...) Figure 18A and Figure 18B Data showed that, compared with untreated mouse models, administration of compound A to the FA mouse models studied in this experiment helped improve or normalize the size of mitochondria (making them more like wild-type mice).

[0148] VII. Reduces iron in cardiomyocytes

[0149] Iron is known to accumulate in cardiomyocytes in a Friedreich-type ataxia mouse model (see: Chiang et al.). Iron accumulation can be visualized in transmission electron microscopy (TEM). Same as above. exist Figure 2 A.

[0150] Refer to Example 3 and Figures 19A to 19C Data showed that, compared with mitochondria in cardiomyocytes of untreated mice in a disease model, cardiomyocytes from a mouse model known to exhibit myocardial hypertrophy treated with compound A showed reduced iron accumulation in their mitochondria.

[0151] VIII. The disclosed compounds are used to treat cardiomyopathy, including hypertrophic cardiomyopathy.

[0152] The examples provided below suggest that compounds A and B are particularly well-suited for treating cardiomyopathy in mammalian subjects because they are well-tolerated in animal models and are efficiently absorbed by cardiac tissue in amounts believed to be therapeutically active. Furthermore, compounds A and B (and by extension, mixtures of compounds A and B) appear to have a protective effect on the heart in animals (i.e., mice) that would otherwise undergo maladaptive cardiac remodeling, such as the development of pathological myocardial hypertrophy and cardiac fibrosis. Compounds A and B also appear to have a superior effect on the heart of subjects compared to the comparative molecule vartiquinone, a small molecule that has been extensively studied in laboratory and human clinical trials. Therefore, compounds A, B, and mixtures thereof (including their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and / or solvates) appear well-suited for treating, preventing, delaying the progression of, or delaying the onset of cardiomyopathy, including hypertrophic cardiomyopathy and cardiac fibrosis, such as those common in subjects with Friedreich-type ataxia.

[0153] In addition to the severe cardiac dysfunction observed in subjects with Friedreich ataxia, the disease is also known for its neurodegenerative effects and its impact on hearing and vision in later life. Data in Example 1 below indicate that compounds A and B are absorbed by the brain at amounts believed to be therapeutically effective. Therefore, in addition to the cardiac dysfunction associated with the disease, these compounds may also be well-suited for treating the neurodegenerative effects of Friedreich ataxia.

[0154] Therefore, in one aspect, this disclosure provides a method for treating, preventing, delaying the progression of, or delaying the onset of cardiomyopathy in a mammalian subject in need, the method comprising administering to the subject a therapeutically effective amount of compound A, or compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein compound A and compound B have the following structures: .

[0155] In some embodiments of the foregoing methods, the subject has been diagnosed with or is suspected of having Friedreich ataxia. In some embodiments of the foregoing methods, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments of the foregoing methods, the subject is a human being. In some embodiments of the foregoing methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to the subject reduces the subject's left ventricular mass, relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to the subject reduces the subject's left ventricular anterior wall thickness (both diastolic and systolic), relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing method, administering compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject to treat or prevent cardiac fibrosis in the subject's cardiac tissue. For exampleThe methods described above aim to delay the progression or onset of cardiac fibrosis. In some embodiments of the aforementioned methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject induces reverse remodeling of the subject's heart. In some embodiments of the aforementioned methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject reduces iron accumulation in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the aforementioned methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject improves or normalizes the size of mitochondria in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject improves the subject's hearing and / or vision. In some embodiments of the foregoing methods, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject increases the subject's lifespan. In some embodiments of the foregoing methods, administration of compound A, compound B, or a mixture comprising compound A and compound B to a subject via oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, ophthalmic, intrathecal, intraventricular, iontophoresis, transmucosal, intravitreal, or intramuscular routes.

[0156] IX. Compositions, formulations, or drugs comprising the disclosed compounds for the treatment of cardiomyopathy, including hypertrophic cardiomyopathy.

[0157] On the other hand, this disclosure provides a composition, medicament, or formulation comprising compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in treating, preventing, delaying the progression of, or delaying the onset of cardiomyopathy in mammalian subjects in need, wherein compound A and compound B have the following structures: .

[0158] In one aspect, this technology provides a composition, drug, or formulation comprising compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in treating, preventing, delaying the progression of, or delaying the onset of cardiomyopathy in mammalian subjects in need, wherein compound A and compound B have the following structures: .

[0159] In some embodiments of the aforementioned compositions, drugs, or formulations, the subject has been diagnosed with or is suspected of having Friedreich ataxia. In some embodiments of the aforementioned compositions, drugs, or formulations, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments of the aforementioned compositions, drugs, or formulations, the subject is a human being. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to the subject reduces the subject's left ventricular mass relative to an untreated control subject or an untreated control group. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to the subject reduces the subject's left ventricular anterior wall thickness (both diastolic and systolic) relative to an untreated control subject or an untreated control group. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to the subject treats, prevents, delays the progression of, or delays the onset of cardiac fibrosis in the subject's cardiac tissue. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to the subject induces reverse remodeling of the subject's heart. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to a subject reduces iron accumulation in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to a subject improves or normalizes the size of mitochondria in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to a subject improves the subject's hearing and / or vision. In some embodiments of the aforementioned compositions, drugs, or formulations, administration of the composition, drug, or formulation to a subject increases the subject's lifespan. In some embodiments of the aforementioned compositions, drugs, or formulations, the composition, drug, or formulation is administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmologically, intrathecally, intraventricularly, via iontophoresis, transmucosally, intravitreally, or intramuscularly.

[0160] X. The disclosed compounds are used to treat cardiomyopathy, including hypertrophic cardiomyopathy.

[0161] In one aspect, this technology provides the use of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate in mammalian subjects in need of treating, preventing, delaying the progression of, or delaying the onset of cardiomyopathy. Compound A and compound B have the following structures: 。

[0162] In some embodiments of the foregoing uses, the subject has been diagnosed with or is suspected of having Friedreich ataxia. In some embodiments of the foregoing uses, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments of the foregoing uses, the subject is a human. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to the subject reduces the subject's left ventricular mass relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to the subject reduces the subject's left ventricular anterior wall thickness (both diastolic and systolic) relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject treats or prevents cardiac fibrosis in the subject's cardiac tissue, delays the progression of cardiac fibrosis, or delays the onset of cardiac fibrosis. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject induces reverse remodeling of the subject's heart. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject reduces iron accumulation in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject improves or normalizes the size of mitochondria in the subject's cardiomyocytes, relative to an untreated control subject or an untreated control group. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomers, hydrates, and / or solvates thereof to a subject improves the subject's hearing and / or vision. In some embodiments of the foregoing uses, administration of compound A, compound B, or a mixture comprising compound A and compound B to a subject increases the subject's lifespan.In some embodiments of the foregoing uses, compound A, compound B, or a mixture comprising compound A and compound B are administered to a subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmologically, intrathecally, intraventricularly, via iontophoresis, transmucosal, intravitreal, or intramuscularly.

[0163] XI. Other methods.

[0164] In one aspect, this technology provides a method for reducing iron accumulation in cardiomyocytes of a mammalian subject in need, the method comprising administering to the subject a therapeutically effective amount of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein compound A and compound B have the following structures: In some embodiments of this method, the subject has been diagnosed with or is suspected of having Friedreich-type ataxia. In some embodiments of this method, the subject is a person.

[0165] In one aspect, this technology provides a method for improving or normalizing the size of mitochondria in cardiomyocytes of a mammalian subject in need, the method comprising administering to the subject a therapeutically effective amount of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein compound A and compound B have the following structures: In some embodiments of this method, the subject has been diagnosed with or is suspected of having Friedreich-type ataxia. In some embodiments of this method, the subject is a person.

[0166] Example

[0167] The following examples further illustrate the technology of the present invention, and these examples should not be construed as limiting it in any way.

[0168] Example 1: Determination of plasma and tissue uptake in mice and rats (compounds A and B)

[0169] I. Pharmacokinetic evaluation of compounds A and B in male C57BL / 6 mice after five daily subcutaneous administrations.

[0170] a) Dosing regimen:

[0171] ● Animals: Male / C57Bl / 6 mice, 18 to 25 grams, purchased from an approved supplier.

[0172] ● Fasting is not required for this study.

[0173] ● Record the body weight before administering the dose. The delivery volume (mL / kg) for each dose is based on the body weight of each animal.

[0174] ● This was a multiple-dose final study, with administration once daily for 5 days. Mice were euthanized after receiving the 5th and final dose.

[0175] ● Administer the dosage according to the standard operating procedures of the testing facility. If applicable, perform a post-administration rinse.

[0176] ● Weigh all dose syringes before and after administration to determine the amount of preparation administered via gravimetric analysis.

[0177] ● Observe all animals at administration and each scheduled collection. Record any abnormalities.

[0178] ● Pre-formulated compounds A, B, and the comparative agent vanitone were prepared for administration according to the research design listed in Table 1 below. These compounds (i.e., compounds A and B) were prepared as described in WO2021 / 202986. Vanitone was prepared using the procedure suitable for the production of vanitone described in WO2021 / 202986.

[0179] Table 1: Research Design

[0180] SC = Subcutaneous application

[0181] b) Sample collection—post-drug administration:

[0182] ● In accordance with the standard operating procedures of the testing facility, terminal blood samples were collected via cardiac puncture after inhalation of an anesthetic.

[0183] ● Collect blood samples into test tubes containing an appropriate anticoagulant. Store the tubes on wet ice until processed into plasma by centrifugation (3500 rpm, 5°C, 10 min) within 20 minutes of collection. Aliquot the sample into 100 μL portions and transfer to individually labeled matrix tubes, and store at nominal -80°C until transfer to analytical chemistry for analysis by LC / MS / MS.

[0184] ● Animals were euthanized immediately after each terminal blood collection in all groups and perfused with cold PBS. The following tissues were collected according to Table 2: heart and brain.

[0185] ● Process plasma and tissue samples for analysis by LC / MS / MS to determine Figures 2 to 5 The amount / concentration reported in the report.

[0186] Table 2: Sample Collection Design

[0187] c) Results: The results are discussed below and in... Figures 2 to 5 The results are presented graphically. It is also worth noting that, under the concentrations and conditions used, both compound A and compound B exhibited good tolerability.

[0188] II. Pharmacokinetic evaluation of compound B in male spradoli rats after repeated (5-day) subcutaneous administration.

[0189] a) Dosing regimen:

[0190] ● Animals: Rats / Spradolly / male / juveniles 225 to 250 grams purchased from an approved supplier.

[0191] ● Fasting is not required for this study.

[0192] ● Record the body weight before administering the dose. The delivery volume (mL / kg) for each dose is based on the body weight of each animal.

[0193] ● This was a multiple-dose final study, with administration once daily for 5 days. Rats were euthanized after receiving the 5th and final dose.

[0194] ● Administer the dosage according to the standard operating procedures of the testing facility. If applicable, perform a post-administration rinse.

[0195] ● Weigh all dose syringes before and after administration to determine the amount of preparation administered via gravimetric analysis.

[0196] ● Observe all animals at administration and each scheduled collection. Record any abnormalities.

[0197] ● Prepare pre-formulated compound B for administration according to the research designs listed in Table 3 below.

[0198] Table 3: Research Design

[0199] SC = Subcutaneous application

[0200] b) Sample collection—post-drug administration:

[0201] ● In accordance with the standard operating procedures of the testing facility, terminal blood samples were collected via cardiac puncture after inhalation of an anesthetic.

[0202] ● Collect blood samples into test tubes containing an appropriate anticoagulant. Store the tubes on wet ice until processed into plasma by centrifugation (3,500 rpm, 5°C, 10 min) within 20 minutes of collection. Transfer 100 μL aliquots of the sample to individually and uniquely labeled matrix tubes and store at nominal -80°C until transferred to analytical chemistry for analysis.

[0203] ● Animals were euthanized immediately after each terminal blood collection in all groups and perfused with cold PBS. The following tissues were collected according to Table 4: heart and brain.

[0204] ● Process plasma and tissue samples for analysis by LC / MS / MS to determine Figure 2 The amount / concentration in plasma reported in the study.

[0205] Table 4: Sample Collection Design

[0206] c) Results: This is discussed below in Section III and... Figure 3 The results are presented graphically. It is also worth noting that compound B exhibits good tolerability under the concentrations and conditions employed.

[0207] III. Relevant Results of PK Experiments in Mice and Rats

[0208] refer to Figure 2 Plasma concentrations of compound B (administered at both 20 mg / kg and 60 mg / kg doses) and compound A (administered at 60 mg / kg dose only) were plotted from 30 minutes to 24 hours post-administration. Because the route of administration was subcutaneous injection (SC), the drug (… Right now Each of compounds A and B needs to migrate within tissues to be absorbed into the bloodstream to provide potentially effective systemic tissue administration. Data showed that both compounds A and B migrated into the bloodstream in mouse plasma, and higher doses caused a roughly proportional increase in plasma concentrations. Furthermore, plasma concentrations decreased over time, as expected, as they were cleared from the subjects.

[0209] exist Figure 3 In this study, plasma concentration data of compound B obtained in mice at a dose of 20 mg / kg during the period from 30 minutes to 24 hours after administration were graphically compared with data obtained in rats at a dose of 10 mg / kg (also compound B). Because the comparison was conducted in species (…),… Right now The study was conducted between mice and rats, therefore, if based on mg / m² for each species... 2 Body area ( Right now In this case, it is 60 mg / m³2 These doses are roughly equal. (Reference) Figure 3 The data indicate that, during the testing period, the uptake of compound B into the plasma induced by administration via SC was roughly equivalent in both mammals.

[0210] Drug delivery to the heart may be difficult due to certain barriers in the body (see: Sahoo et al., Targeted Delivery of Therapeutic Agents to the Heart, Nat. Rev Cardiol., (2021) 18(6): 389-399). Reference Figure 4 The concentrations of compound B (administered at both 20 mg / kg and 60 mg / kg doses) and compound A (administered at 60 mg / kg dose only) in heart tissue were plotted from 30 minutes to 24 hours post-administration. The data showed that up to micrograms of the drug were found per gram of heart tissue 2 hours after administration (5 days later), and drug clearance from the tissue proceeded as expected over time. These data demonstrate that effective amounts of compounds B and A can be delivered to mouse heart tissue under these administration conditions, and that these compounds can be readily removed from the tissues of subjects.

[0211] Drug delivery to the brain may be difficult because the blood-brain barrier, or BBB, protects the brain (and other central nervous system (CNS) tissues) from the penetration of certain types of molecules. (Reference) Figure 5 The concentrations of compound B (administered at both 20 mg / kg and 60 mg / kg doses) and compound A (administered at 60 mg / kg dose only) in brain tissue were plotted from 30 minutes to 24 hours post-administration. The data showed that up to micrograms of the drug were found per gram of brain tissue 2 hours after administration (5 days later), and drug clearance from the tissue proceeded as expected over time. These data demonstrate that effective amounts of compounds B and A can be delivered to mouse brain tissue under these administration conditions, and that these compounds can be readily removed from the tissues of subjects.

[0212] d) Summary / discussion of results:

[0213] Both compounds A and B were well tolerated in mice at dose levels up to 60 mg / kg (administered via SC injection).

[0214] In rodents, the dosage of compound B was well modulated by allometric growth (20 mg / kg in mice ≈ 10 mg / kg in rats).

[0215] Plasma exposure to compound B is roughly proportional to the dose (compare data at 20 mg / kg and 60 mg / kg).

[0216] The plasma concentration of compound A is usually higher than that of compound B.

[0217] The Tmax of compound A is usually later than that of compound B, and its half-life is often longer.

[0218] The exposure levels of compound B in the heart (Cmax (maximum observed concentration) and AUC (area under the concentration-time curve)) were higher than those in the brain; there was no significant difference in the exposure levels of compound A between the two tissues.

[0219] Based on AUC, the cardiac exposure of the two compounds was similar; the brain exposure of compound A was slightly higher than that of compound B.

[0220] The concentrations achieved in plasma and cardiac tissue represent the amounts expected to be effective for the treatment, prevention of cardiomyopathy, particularly hypertrophic cardiomyopathy, and for delaying the onset or progression of cardiomyopathy, particularly hypertrophic cardiomyopathy.

[0221] Example 2: Small molecule compounds (compound A, compound B, and comparative compound vantiquinone) in Friedreich-type co-... Efficacy study in a FA mouse model

[0222] a) Disease characteristics and mouse models

[0223] Friedreich ataxia (FA) is a mitochondrial disease characterized by heart failure, hypertrophic cardiomyopathy, and diabetes (Weidemann et al., 2012). FA patients present with a wide range of symptoms across multiple bodily systems, including neurodegeneration, cardiac damage, gait disturbances, scoliosis, and diabetes. Optic neuropathy and retinitis pigmentosa-like syndromes have also been documented in human FA patients.

[0224] Mouse model B6.Cg- Fxn em2Lutzy Fxn em2.1LutzyThe Tg(Ckmm-cre)5Khn / J mouse (Jackson Laboratory (JAX) catalog number 029720) contains a transgene with a conditional frataxin allele (flanking exon 2), a null frataxin allele (exon 2), and a cre recombinase expressing a muscle-specific promoter-driven creatine kinase, similar to but not identical to the conditional frataxin allele created by Helene Puccio. This allele combination results in specific ablation of frataxin expression in cardiac and skeletal muscle. The phenotype generated in this model includes progressive weight loss associated with functional cardiac defects, leading to onset at 10 to 12 weeks of age. Therefore, this mouse model provides a suitable approach to study progressive heart disease that mimics the condition observed in patients with Friedreich-type ataxia.

[0225] This FA mouse model was generated by crossing the following two mouse strains: Strain #1: B6.Cg- Fxn em2.1Lutzy Tg(Ckmm-cre)5Khn / J (JAX catalog number 029100) contains the frataxin systemic knockout allele and the heart / skeletal muscle-specific Cre recombinase transgene. When Fxn flox / null When heterozygous and MCK-Cre hemizygous or homozygous, these double-mutant mice exhibit normal phenotypes. Strain #2: C57BL / 6J- Fxn em2Lutzy The / J (JAX catalog number 028520) mouse possesses the CRISPR / Cas9-derived conditional FXN allele of Cre. The mice produced in this study are referred to as the mutant (MUT; 5F / 5M Fxn) in Example 2. flox / null The mice were bred (MCK-Cre), and the control non-transgenic animals were designated wild-type (WT; JAX catalog number 000664). Mouse breeding and the resulting research were conducted at the Jackson Laboratory.

[0226] b) Research Objective

[0227] This study was designed to evaluate the effects of long-term exposure to novel small molecule therapeutics administered via subcutaneous injection. Right now After compounds A and B) Heart-specific FA mouse model The efficacy of the drug was investigated. Vatiquinone was also studied as a comparison molecule (but administered orally as is its usual form), as vatiquinone has been extensively investigated as a treatment for FA, including in human clinical trials in FA patients. The study protocol has been approved by the IACUC.

[0228] c) Test items, media, and formulations

[0229] As shown in Table 5 below, stock solutions of vantiquinone (5 mg / mL), compound A (6 mg / mL), and compound B (6 mg / mL) were prepared and stored. Compound A, compound B, and vantiquinone were obtained as described in Example 1 above.

[0230] Table 5

[0231] d) Basic research and experimental design

[0232] Table 6: Basic Research Information

[0233] Table 7: Grouping of mice used in the study

[0234] SC = subcutaneous administration; PO = oral administration via tube feeding. Vatiquinone was included in this study as a comparative molecule because it has been studied in this mouse model and in human patients diagnosed with Friedreich-type ataxia.

[0235] e) SC administration

[0236] Frequency: Once daily for approximately 8 weeks (until mice reach the endpoint) — Groups 1, 2, 4, and 5.

[0237] Procedure: Administer the injection on the flank using a 27G needle. Restrain the animal and hold the syringe parallel to the mouse. Insert the needle directly under the skin on the mouse's flank. Lift the needle; if a "tent" bulge forms on the skin above the needle, the needle is in the subcutaneous position. If / when the needle cannot be easily lifted, slightly withdraw it, as it may have pierced the underlying muscle mass. Administer the required dose volume per mouse (10 mL / kg (BW x 10)). The formation of a blister or "bubble" under the skin indicates a correct injection. Then return the mouse to its cage.

[0238] f) Oral tube feeding (PO) administration

[0239] Frequency: Once daily for approximately 8 weeks (until the mice reach their endpoint) — Group 3

[0240] Procedure: Animals aged 21 to 27 days should be injected with a 22 or 23G needle, and animals aged 28 days and older should be injected with a 20 or 22G needle.

[0241] Restrain the animals vertically so that the restrained mice can see the ball, syringe, and their mouths. Hold the syringe firmly and insert the needle into the mouse's mouth, advancing it along the roof of the mouth. Once the ball of the needle reaches the back of the throat, gently lift the mouse's nose upward by moving the syringe vertically until it is parallel to the spine, allowing the mouse to swallow and the needle to slide easily down the esophagus. The needle will then empty itself. Once the needle stops moving, slowly depress the syringe plunger (without moving the syringe or needle) until the required amount of fluid has been injected into the mouse. Then gently remove the needle from the animal's mouth. Wipe the reusable tube feeding needles between each enclosure with a paper towel (or similar) soaked in 70% ethanol. The required dose volume per mouse is 10 mL / kg (BW x 10). After correctly administering the test item / media, return the mice to their cages.

[0242] g) Echocardiography

[0243] Cardiac function was measured using echocardiography at the Jackson Biometrics Core Services Laboratory Center. Cardiac assessment was performed using a Vevo 770 / 2100 high-frequency ultrasound system (VisualSonics Inc., Toronto, Canada) with 30 and 40 MHz probes. Mice were anesthetized with up to 5% isoflurane in oxygen at a flow rate of 0.8 to 2.0 L / min. Hair was removed using depilatory cream prior to imaging. B-mode and M-mode images were recorded in parasternal short-axis (PSA) views to measure left ventricular wall thickness and diameter. Based on these direct measurements, diastolic and systolic blood volumes, ejection fraction, fractional shortening, cardiac output, and stroke volume were calculated / determined. For detailed information on echocardiographic measurements and calculations, please refer to Table 8 below: Table 8: Echocardiographic Measurements and Calculations

[0244] h) Organization Collection

[0245] Collect the heart and then quickly freeze it for further analysis (if needed).

[0246] i) Survival analysis

[0247] Animal survival rates were continuously assessed through side observation of the cages. Survival rates for all groups were monitored and included in the study records. Survival data were... Figure 6 and Figure 7 This will be summarized in the following section.

[0248] j) result

[0249] refer to Figure 6The survival data of mice treated with rotiquinone (Group 3) and compound A (Group 4) are presented graphically compared with the control groups treated with WT mediator (Group 1) and MUT mediator (Group 2). No wild-type mice died during the study period (top line). Mutant mice treated with mediators ( Right now The FA mouse model (Group 2) and mice treated with cortiquinone (Group 3) began to die at approximately 50 days. In contrast, MUT mice treated with compound A (Group 4) began to die only at approximately 70 days. All mutant mice (regardless of treatment type) died before 80 days. In short, these data appear to suggest that administration of compound A to the FA mouse model delayed the onset of death by approximately 20 days compared to Group 2 (MUT, mediator control) and Group 3 (cortiquinone-treated comparison molecule). Therefore, these data support the conclusion that administration of compound A (Group 4) can increase the lifespan / survival rate of the FA mouse model compared to the control groups 2 and 3.

[0250] refer to Figure 7 The survival data of mice treated with rotiquinone (Group 3) and compound B (Group 5) are presented graphically compared with the WT mediated (Group 1) and MUT mediated (Group 2) control groups. No wild-type mice died during the study period (top line). Mutant mice treated with the mediated agents ( Right now The FA mouse model (Group 2) and mice treated with vartiquinone (Group 3) began to die at approximately 50 days. In contrast, MUT mice treated with compound B (Group 5) only began to die at approximately 70 days. All mutant mice (regardless of treatment type) died before 80 days. In short, the data appear to suggest that administration of compound B to the FA mouse model delayed the onset of death by approximately 20 days in this group of mice. Therefore, these data support the conclusion that administration of compound B (Group 5) can increase the lifespan / survival rate of the FA mouse model compared to the control groups 2 and 3.

[0251] refer to Figure 8Echocardiographic data of left ventricular mass normalized relative to body weight were presented for each group of mice at time points of 4 weeks and 7 weeks after the first administration of the drug. In this figure, mice treated with rotiquinone (Group 3) and compound A (Group 4) were compared with control groups treated with WT mediator (Group 1) and MUT mediator (Group 2). Referring to this figure, both Group 2 (MUT, mediator) and Group 3 (MUT, rotiquinone) mice showed a significant increase in left ventricular mass between weeks 4 and 7, with rotiquinone appearing to show at least some benefit compared to the Group 2 control. In contrast, the increase in left ventricular mass observed between weeks 4 and 7 in Group 1 (WT, mediator) and Group 4 (MUT, compound A) mice was much smaller, and in fact, the increase in left ventricular mass in Group 4 mice was substantially similar to that observed in the WT control. These data indicate that administration of compound A effectively prevents or at least delays the progression or onset of increased left ventricular mass in the FA mouse model, and its effect is superior to that of valproic acid. Since increased left ventricular mass is a hallmark of myocardial hypertrophy, these data suggest that compound A can be used to treat, prevent, or delay the onset or progression of myocardial hypertrophy in this FA mouse model.

[0252] refer to Figure 9 Echocardiographic data of left ventricular mass normalized relative to body weight were presented for each group of mice at time points of 4 weeks and 7 weeks after the first administration of the drug. In this figure, mice treated with rotiquinone (Group 3) and compound B (Group 5) were compared with control groups treated with WT mediator (Group 1) and MUT mediator (Group 2). Referring to this figure, both Group 2 (MUT, mediator) and Group 3 (MUT, rotiquinone) mice showed a significant increase in left ventricular mass between weeks 4 and 7, with rotiquinone appearing to show at least some benefit. In contrast, between weeks 4 and 7, the increase in left ventricular mass observed in Group 1 (WT, mediator) mice was smaller, while the increase in left ventricular mass was slightly larger in Group 5 (MUT, compound B) mice. Although the increase in left ventricular mass in group 5 (MUT, compound B) mice appeared to be greater than that observed in group 4 (MUT, compound A) mice, this increase was less than that observed against the comparative compound, rotiquinone. These data suggest that administration of compound B is effective in preventing or at least delaying the progression or onset of increased left ventricular mass in the FA mouse model, and is superior to rotiquinone. Since increased left ventricular mass is a marker of myocardial hypertrophy, these data suggest that compound B may be used to treat, prevent, or delay the onset or progression of myocardial hypertrophy in the FA mouse model.

[0253] refer to Figure 10Echocardiographic data of left ventricular anterior wall thickness (diastolic) in each group of mice were presented at time points of 4 weeks and 7 weeks after the first administration of the drug. In this figure, mice treated with rotiquinone (Group 3) and compound A (Group 4) were compared with control groups treated with WT mediator (Group 1) and MUT mediator (Group 2) over a three-week treatment period. Referring to this figure, Group 2 (MUT, mediator) mice showed a slight increase in wall thickness over the three-week treatment period. Similarly, Group 3 (MUT, rotiquinone) mice showed a slight increase in wall thickness over the three-week treatment period, although the increase was significantly smaller than that observed in Group 2 (MUT, mediator) mice. In contrast, control Group 1 (WT, mediator) mice showed a slight decrease in wall thickness over the three-week period, while Group 4 (MUT, compound A) mice appeared to show a more significant decrease in wall thickness over the three-week period. These data indicate that administration of compound A can effectively prevent or at least delay the progression or onset of increased left ventricular anterior wall thickness (diastolic) in a FA mouse model. Since increased left ventricular anterior wall thickness (diastolic) is a marker of myocardial hypertrophy, these data suggest that compound A can be used to treat and prevent myocardial hypertrophy in a FA mouse model, and to delay the onset or progression of myocardial hypertrophy.

[0254] refer to Figure 11 Echocardiographic data of left ventricular anterior wall thickness (diastolic) in each group of mice were presented at time points of 4 weeks and 7 weeks after the first administration of the drug. In this figure, mice treated with rotiquinone (Group 3) and compound B (Group 5) were compared with control groups treated with WT mediator (Group 1) and MUT mediator (Group 2) over a three-week treatment period. Referring to this figure, Group 2 (MUT, mediator) mice showed a slight increase in wall thickness over the three-week treatment period. Similarly, Group 3 (MUT, rotiquinone) mice showed a slight increase in wall thickness, although the increase was significantly smaller than that observed in Group 2 (MUT, mediator) mice. In contrast, control Group 1 (WT, mediator) mice showed a slight decrease in wall thickness over the three-week period, while Group 5 (MUT, compound B) mice appeared to show a substantially similar decrease in wall thickness over the three-week period (compared to Group 1 mice). These data indicate that administration of compound B can effectively prevent or at least delay the progression or onset of increased left ventricular anterior wall thickness (diastolic) in a FA mouse model. Since increased left ventricular anterior wall thickness (diastolic) is a marker of myocardial hypertrophy, these data suggest that compound B can be used to treat and prevent myocardial hypertrophy in a FA mouse model, and to delay the onset or progression of myocardial hypertrophy.

[0255] refer to Figure 12Echocardiographic data of left ventricular anterior wall thickness (systolic) in each group of mice were presented at time points of 4 weeks and 7 weeks after the first administration of the drug. In this figure, mice treated with rotiquinone (Group 3) and compound A (Group 4) were compared with control groups treated with WT mediator (Group 1) and MUT mediator (Group 2) over a three-week treatment period. Referring to this figure, Group 2 (MUT, mediator) mice showed a significant increase in wall thickness over the three-week treatment period. Similarly, Group 3 (MUT, rotiquinone) mice showed a small increase in wall thickness over the three-week treatment period, although the increase was significantly smaller than that observed in Group 2 (MUT, mediator) mice. In contrast, control Group 1 (WT, mediator) mice showed a small decrease in wall thickness over the three-week period, while Group 4 (MUT, compound A) mice appeared to show a more significant decrease in wall thickness over the three-week period. These data indicate that administration of compound A can effectively prevent or at least delay the progression or onset of increased left ventricular anterior wall thickness (systolic) in a FA mouse model. Since increased left ventricular anterior wall thickness (systolic) is a hallmark of myocardial hypertrophy, these data suggest that compound A can be used to treat and prevent myocardial hypertrophy in a FA mouse model, and to delay the onset or progression of myocardial hypertrophy.

[0256] refer to Figure 13 Echocardiographic data of left ventricular anterior wall thickness (diastolic) in each group of mice were presented at time points of 4 weeks and 7 weeks after the first administration of the drug. In this figure, mice treated with rotiquinone (Group 3) and compound B (Group 5) were compared with control groups treated with WT mediator (Group 1) and MUT mediator (Group 2) over a three-week treatment period. Referring to this figure, Group 2 (MUT, mediator) mice showed a significant increase in wall thickness over the three-week treatment period. Similarly, Group 3 (MUT, rotiquinone) mice showed an increase in wall thickness, although the increase was significantly smaller than that observed in Group 2 (MUT, mediator) mice. In contrast, control Group 1 (WT, mediator) mice showed a slight decrease in wall thickness over the three-week period, while Group 5 (MUT, compound B) mice appeared to show a substantially similar decrease in wall thickness over the three-week period (compared to Group 1 mice). These data indicate that administration of compound B can effectively prevent or at least delay the progression or onset of increased left ventricular anterior wall thickness (systolic) in a FA mouse model. Since increased left ventricular anterior wall thickness (systolic) is a marker of myocardial hypertrophy, these data suggest that compound B can be used to treat and prevent myocardial hypertrophy in a FA mouse model, and to delay the onset or progression of myocardial hypertrophy.

[0257] refer to Figure 14Echocardiographic data on left ventricular anterior wall thickness (diastolic) in each group of mice are presented in bar graph format, using data from 7 weeks after the first drug administration. Referring to the graph, a statistically significant increase in left ventricular anterior wall thickness (diastolic) was observed between group 1 (WT, mediator) and group 2 (MUT, mediator) mice. This is expected in mutant mice compared to wild-type mice, based on the known phenotype of the FA mouse model. Furthermore, a statistically significant decrease in left ventricular anterior wall thickness (diastolic) was observed between group 2 (MUT, mediator) and group 4 (MUT, compound A) mice. However, no statistically significant difference was found between group 1 (WT, mediator) and group 4 (MUT, compound A). These data further support the conclusion that compound A can be used to treat and prevent myocardial hypertrophy in the FA mouse model, and to delay the onset or progression of myocardial hypertrophy. These data may even suggest that compound A can reverse cardiac remodeling in the FA mouse model.

[0258] refer to Figure 15 Using data from 7 weeks after the first drug administration, echocardiographic data of left ventricular anterior wall thickness (systolic) in each group of mice are presented in bar graph format. Referring to this graph, there was no statistically significant increase in left ventricular anterior wall thickness (systolic) between group 1 (WT, mediator) and group 2 (MUT, mediator). However, there was a statistically significant decrease in left ventricular anterior wall thickness (systolic) between group 2 (MUT, mediator) and group 4 (MUT, compound A). Furthermore, the statistically significant difference between group 1 (WT, mediator) and group 4 (MUT, compound A) strongly suggests that compound A inhibits the increase in left ventricular anterior wall thickness (systolic) and may have the ability to reverse cardiac tissue remodeling. Right now Reversing myocardial hypertrophy). These data further support the conclusion that compound A can be used to treat and prevent myocardial hypertrophy in FA mouse models, delay the onset or progression of myocardial hypertrophy, and may even be suitable for reversing cardiac tissue remodeling. Right now Reversing myocardial hypertrophy.

[0259] refer to Figure 16Using data from 7 weeks after the first drug administration, echocardiographic data on left ventricular anterior wall thickness (diastolic) in each group of mice are presented as a bar graph. Referring to this graph, a statistically significant increase in left ventricular anterior wall thickness (diastolic) was observed between group 1 (WT, mediator) and group 2 (MUT, mediator) mice, as expected for mutant versus wild-type mice. Furthermore, a statistically significant decrease in left ventricular anterior wall thickness (diastolic) was observed between group 2 (MUT, mediator) and group 5 (MUT, compound B) mice. Additionally, no statistically significant difference was found between group 1 (WT, mediator) and group 5 (MUT, compound B). These data further support the conclusion that compound B can be used to treat and prevent myocardial hypertrophy in FA mouse models, and to delay the onset or progression of myocardial hypertrophy.

[0260] refer to Figure 17 Using data from 7 weeks after the first drug administration, echocardiographic data of left ventricular anterior wall thickness (systolic) in each group of mice are presented as a bar graph. Referring to this graph, there was no statistically significant increase in left ventricular anterior wall thickness (systolic) between group 1 (WT, mediator) and group 2 (MUT, mediator). However, there was a statistically significant decrease in left ventricular anterior wall thickness (systolic) between group 2 (MUT, mediator) and group 5 (MUT, compound B). These data further support the conclusion that compound B can be used to treat and prevent myocardial hypertrophy in FA mouse models, delay the onset or progression of myocardial hypertrophy, and may even be suitable for reversing cardiac tissue remodeling. Right now Reversing myocardial hypertrophy.

[0261] Example 3: Small molecule compounds (compound A and comparative compound omavilosorone) in Friedreich-type conjugates Efficacy study in a FA mouse model

[0262] a) Disease characteristics and mouse models

[0263] The same mouse model was used as in Example 2. The study was conducted essentially as described in Example 2, with the following modifications. For the purposes of this Example 3, only the results from cardiac tissues from groups 1, 2, and 4 (described below) are presented and discussed below.

[0264] b) Research Objective

[0265] This study was designed to evaluate the effects of long-term exposure to novel small molecule therapeutics administered via subcutaneous injection. Right now After compound A) Heart-specific FA mouse modelThe efficacy of omavidoxorubicin was also studied as a comparison molecule (but administered orally as it is usually given), since omavidoxorubicin was recently approved by the FDA for the treatment of Friedreich-type ataxia.

[0266] c) Test items, media, and formulations

[0267] A stock solution of compound A (stock solution 6 mg / mL) was prepared as shown below. Compound A was obtained as described in Example 1 above. Omavirol lossoron was purchased from a commercially available source.

[0268] Table 9

[0269] d) Basic research and experimental design

[0270] Table 10: Basic Research Information

[0271] Table 11: Grouping of mice used in the study

[0272] SC = Subcutaneous administration; PO = Oral administration via tube feeding. Omavilosorone was included in this study as a comparative molecule because it is currently an FDA-approved treatment for patients aged 16 years and older with Friedreich-type ataxia.

[0273] For the purposes of this Example 3, only the results from cardiac tissues from Group 1, Group 2, and Group 4 are presented and discussed below.

[0274] e) SC administration

[0275] Frequency: Once daily for approximately 8 weeks (until mice reach the endpoint) — Groups 1, 2, 4, and 5.

[0276] Procedure: Administer the injection on the flank using a 27G needle. Restrain the animal and hold the syringe parallel to the mouse. Insert the needle directly under the skin on the mouse's flank. Lift the needle; if a "tent" bulge forms on the skin above the needle, the needle is in the subcutaneous position. If / when the needle cannot be easily lifted, slightly withdraw it, as it may have pierced the underlying muscle mass. Administer the required dose volume per mouse (10 mL / kg (BW x 10)). The formation of a blister or "bubble" under the skin indicates a correct injection. Then return the mouse to its cage.

[0277] f) Oral tube feeding (PO) administration

[0278] Frequency: Once daily for approximately 8 weeks (until mice reach their endpoint) — Groups 3 and 5

[0279] Procedure: Animals aged 21 to 27 days should be injected with a 22 or 23G needle, and animals aged 28 days and older should be injected with a 20 or 22G needle.

[0280] Restrain the animals vertically so that the restrained mice can see the ball, syringe, and their mouths. Hold the syringe firmly and insert the needle into the mouse's mouth, advancing it along the roof of the mouth. Once the ball of the needle reaches the back of the throat, gently lift the mouse's nose upward by moving the syringe vertically until it is parallel to the spine, allowing the mouse to swallow and the needle to slide easily down the esophagus. The needle will then empty itself. Once the needle stops moving, slowly depress the syringe plunger (without moving the syringe or needle) until the required amount of fluid has been injected into the mouse. Then gently remove the needle from the animal's mouth. Wipe the reusable tube feeding needles between each enclosure with a paper towel (or similar) soaked in 70% ethanol. The required dose volume per mouse is 10 mL / kg (BW x 10). After correctly administering the test item / media, return the mice to their cages.

[0281] g) Organization Collection

[0282] The hearts are collected and then rapidly frozen for further analysis when needed.

[0283] h) Preparation and TEM analysis of cardiac tissue

[0284] Dissect the heart tissue collected from mice and immediately place it in 0.1M sodium dimethylarsinate buffer (pH 7.4) containing 2.5% glutaraldehyde / 2.5% paraformaldehyde. Cut the tissue sample into small pieces (approximately 1 to 2 mm in size). Store the samples at 4°C until processed as described below.

[0285] Fixed tissue samples were washed in 0.1 M dimethylarsine buffer and post-fixed for 1 hour with 1% osmium tetroxide (OsO4) / 1.5% potassium ferricyanide (KFeCN6). They were then washed twice in water, once in 50 mM maleate buffer (pH 5.15, MB), and incubated in MB with 1% uranium acetate for 1 hour. The samples were then washed once in MB, twice in water, and dehydrated in various grades of alcohol (10 minutes each; 50%, 70%, 90%, 2x 10 minutes 100%). The samples were then immersed in propylene oxide for 1 hour and infiltrated overnight in a 1:1 mixture of propylene oxide and TAAB Epon (TAAB Laboratories Equipment Ltd, https: / / taab.co.uk). The next day, the samples were embedded in TAAB Epon and polymerized at 60°C for 48 hours.

[0286] Ultrathin sections (approximately 50 to 80 nm) were cut on a Reichert Ultracut-S microtome, picked up onto a copper grid, and stained with 1% uranyl acetate in acetone solution (5 minutes), followed by staining with 0.2% lead citrate (20 seconds). The sections were examined under a JEOL 1200EX transmission electron microscope (TEM), and TEM images were recorded using an AMT 2k CCD camera. Approximately 10 images were taken for each sample at a magnification of 9300x.

[0287] Mitochondrial cross-sectional areas were determined using the ImageJ open-source program (National Institutes of Health). ImageJ was used to convert pixel sizes to metric units based on the image scale bar to obtain a uniform final measurement. The regions of interest for the mitochondria were then manually delineated in ImageJ to determine the mitochondrial cross-sectional area. Only mitochondria that appeared completely within the frame were quantified. Mitochondria were quantified from n=3 mice in each group. >150 mitochondria were measured from the transgenic treatment group and >80 mitochondria were measured from wild-type mice. The data were plotted as a bar chart (…). Figure 18A ) and violin picture ( Figure 18B Both were analyzed using GraphPad Prism. Outliers were removed, and significance was determined using one-way ANOVA (P < 0.0001). The captured TEM images can be... Figures 19A to 19C The dark areas observed in TEM images of mitochondria (see pointer) were found and are thought to be caused by iron deposition / accumulation, as is known from images available in the literature (see: Martelli et al. and Chiang et al. discussed above).

[0288] i) Results and discussion

[0289] refer to Figure 18A The cross-sectional area of ​​mitochondria in heart tissue is presented in bar chart format (in nm). 2 (Units are not specified). Compared to the WT (mediator-treated) group, the cross-sectional area of ​​mitochondria in the MUT (mediator-treated) group was sharply (statistically significant). Compared to the MUT (mediator-treated) group, the cross-sectional area of ​​mitochondria in the MUT (compound A-treated) group was also statistically significantly increased (improved). These data suggest that treatment with compound A improves or helps normalize mitochondria, making them more comparable to mitochondria in wild-type mice.

[0290] exist Figure 18B The data presented further supports this inference. Figure 18BThe same data was plotted in the violin diagram. The violin diagram shows the size distribution of individual mitochondria in the sample. (As shown in...) Figure 18B As can be seen, the mitochondrial size distribution was larger in the WT group. However, the mitochondrial size distribution in the MUT (untreated group) was much smaller, and individual mitochondria were also much smaller. Although disproportionate to the WT group, the MUT (compound A-treated) group showed a significantly larger mitochondrial size distribution and a larger average overall number of mitochondria compared to the MUT (untreated group). In this sense, these data also support the conclusion that treatment with compound A improves or normalizes the mitochondria of cardiomyocytes in subjects exhibiting cardiac symptoms compared to untreated control subjects or control groups—at least in terms of the association between cardiac symptoms and Friedreich-type ataxia.

[0291] about Figure 19A In mice treated with WT mediator, virtually no black spots were observed in the mitochondria. By comparison, in... Figure 19B Numerous black spots were observed in the TEM images of mice treated with MUT mediated by compound A. These black spots are believed to be iron deposits in the mitochondria. These iron deposits are consistent with the disease state of mutant mouse strains described in the literature. In contrast, while black spots were still present in the TEM images of mice treated with MUT mediated by compound A, these black spots appeared to be much fewer and smaller than those seen in the TEM images of mice treated with MUT mediated by compound A. This data further supports the conclusion that treatment with compound A can improve or normalize the mitochondrial health of cardiomyocytes in subject organisms exhibiting cardiac symptoms—at least in relation to its association with Friedreich-type ataxia.

[0292] equivalent

[0293] The technology of this invention is not limited to the specific embodiments described herein, which are intended as separate illustrations of a single aspect of the technology of this invention. Many modifications and variations of the technology of this invention can be made without departing from the spirit and scope of the invention, as will be apparent to those skilled in the art. Based on the above description, functionally equivalent methods and apparatuses within the scope of the technology of this invention, in addition to those methods and apparatuses listed herein, will be apparent to those skilled in the art. Such modifications and variations are intended to fall within the scope of the appended claims. This technology is limited only by the terms of the appended claims and the full scope of equivalents enjoyed by such claims. It should be understood that the technology of this invention is not limited to specific methods, reagents, compounds, compositions, or biological systems, although such specific methods, reagents, compounds, compositions, or biological systems can vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be restrictive.

[0294] Furthermore, when features or aspects of this disclosure are described in accordance with the Markush group, those skilled in the art will recognize that this disclosure is also described in accordance with any individual member or subgroup of the Markush group.

[0295] As those skilled in the art will understand, for any and all purposes, particularly in providing a written description, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any listed scope can be readily considered sufficiently descriptive and such that the same scope can be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. wait As a non-limiting example, each range discussed in this paper can easily be divided into a lower third, a middle third, and an upper third. wait As those skilled in the art will also understand, all language, such as “up to,” “at least,” “greater than,” “less than,” etc., including the enumerated numbers, refers to a range that can subsequently be decomposed into subranges as described above. Finally, as those skilled in the art will understand, a range includes each individual member. Thus, for example, a group having 1-3 cells means a group having 1, 2, or 3 cells. Similarly, a group having 1-5 cells means a group having 1, 2, 3, 4, or 5 cells, and so on.

[0296] All patents, patent applications, provisional applications and publications mentioned or cited herein are incorporated in their entirety by reference to the extent that they are not inconsistent with the express teachings of this specification, including all figures and tables.

[0297] Other embodiments are set forth in the appended claims.

Claims

1. A method for treating, preventing, delaying the progression of, or delaying the onset of cardiomyopathy in a mammalian subject in need, the method comprising administering to the subject a therapeutically effective amount of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein compound A and compound B have the following structures: 。 2. The method of claim 1, wherein the subject has been diagnosed with or is suspected of having Friedreich ataxia.

3. The method according to claim 1 or 2, wherein the cardiomyopathy is hypertrophic cardiomyopathy.

4. The method according to any one of claims 1 to 3, wherein the subject is a human being.

5. The method according to any one of claims 1 to 4, wherein, relative to an untreated control subject or an untreated control group, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to the subject reduces the left ventricular mass of the subject.

6. The method according to any one of claims 1 to 4, wherein, relative to an untreated control subject or an untreated control group, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to the subject reduces the thickness of the left ventricular anterior wall (both diastolic and systolic) of the subject.

7. The method according to any one of claims 1 to 5, wherein the administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate and / or solvate thereof to the subject treats, prevents, cardiac fibrosis (e.g., myocardial fibrosis) in the heart tissue of the subject, delays the progression of cardiac fibrosis, or delays the onset of cardiac fibrosis.

8. The method according to any one of claims 1 to 7, wherein administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to the subject induces reverse remodeling of the heart in the subject.

9. The method according to any one of claims 1 to 8, wherein administering compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to the subject, relative to an untreated control subject or an untreated control group, reduces iron accumulation in the cardiomyocytes of the subject.

10. The method according to any one of claims 1 to 8, wherein, relative to an untreated control subject or an untreated control group, administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to the subject improves or normalizes the size of mitochondria in the cardiomyocytes of the subject.

11. The method according to any one of claims 1 to 10, wherein administering compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate to the subject improves the subject's hearing and / or vision.

12. The method according to any one of claims 1 to 11, wherein administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to the subject increases the lifespan of the subject.

13. The method according to any one of claims 1 to 12, wherein compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomers, hydrates and / or solvates thereof are administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, intrathecally, intravaginally, intracranially, intramurally, intramurally, intramurally, intramucosally, intravitreally, or intramuscularly.

14. A composition, drug, or formulation comprising compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, for use in treating, preventing, delaying the progression of, or delaying the onset of cardiomyopathy in mammalian subjects in need, wherein compound A and compound B have the following structures: 。 15. The composition, drug or formulation of claim 14, wherein the subject has been diagnosed with or is suspected of having Friedreich ataxia.

16. The composition, drug or formulation according to claim 14 or 15, wherein the cardiomyopathy is hypertrophic cardiomyopathy.

17. The composition, drug or formulation according to any one of claims 14 to 16, wherein the subject is a human.

18. The composition, drug, or formulation according to any one of claims 14 to 17, wherein administration of the composition, drug, or formulation to the subject, relative to an untreated control subject or an untreated control group, reduces the left ventricular mass of the subject.

19. The composition, drug, or formulation according to any one of claims 14 to 18, wherein administration of the composition, drug, or formulation to the subject, relative to an untreated control subject or an untreated control group, reduces the thickness of the left ventricular anterior wall (both diastolic and systolic).

20. The composition, drug, or formulation according to any one of claims 14 to 19, wherein administration of the composition, drug, or formulation to the subject treats, prevents, delays the progression of, or delays the onset of cardiac fibrosis in the subject's heart tissue.

21. The composition, drug, or formulation according to any one of claims 14 to 20, wherein administration of the composition, drug, or formulation to the subject causes reverse remodeling of the subject's heart.

22. The composition, drug, or formulation according to any one of claims 14 to 21, wherein administration of the composition, drug, or formulation to the subject, relative to an untreated control subject or an untreated control group, reduces iron accumulation in the subject's cardiomyocytes.

23. The composition, drug, or formulation according to any one of claims 14 to 21, wherein administration of the composition, drug, or formulation to the subject, relative to an untreated control subject or an untreated control group, improves or normalizes the size of mitochondria in the subject's cardiomyocytes.

24. The composition, drug, or formulation according to any one of claims 14 to 23, wherein administration of the composition, drug, or formulation to the subject improves the subject's hearing and / or vision.

25. The composition, drug, or formulation according to any one of claims 14 to 24, wherein administration of the composition, drug, or formulation to the subject increases the lifespan of the subject.

26. The composition, drug, or formulation according to any one of claims 14 to 25, wherein the composition, drug, or formulation is prepared for administration to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmologically, intrathecally, intraventricularly, via iontophoresis, through mucosa, intravitreally, or intramuscularly.

27. Use of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate in mammalian subjects in need of treatment for, prevention of, delay of progression of, or delay of onset of cardiomyopathy, wherein compound A and compound B have the following structures: 。 28. The use according to claim 27, wherein the subject has been diagnosed with or is suspected of having Friedreich-type ataxia.

29. The use according to claim 27 or 28, wherein the cardiomyopathy is hypertrophic cardiomyopathy.

30. The use according to any one of claims 27 to 29, wherein the subject is a human.

31. The use according to any one of claims 27 to 30, wherein administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to the subject, relative to an untreated control subject or an untreated control group, reduces the left ventricular mass of the subject.

32. The use according to any one of claims 27 to 31, wherein administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to said subject, relative to an untreated control subject or an untreated control group, reduces the thickness of the left ventricular anterior wall (both diastolic and systolic) of said subject.

33. The use according to any one of claims 27 to 32, wherein administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate and / or solvate thereof to the subject treats, prevents, delays the progression of, or delays the onset of cardiac fibrosis in the heart tissue of the subject.

34. The use according to any one of claims 27 to 33, wherein administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to the subject causes reverse remodeling of the heart in the subject.

35. The use according to any one of claims 27 to 34, wherein administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to said subject, relative to an untreated control subject or an untreated control group, reduces iron accumulation in the cardiomyocytes of said subject.

36. The use according to any one of claims 27 to 34, wherein administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to the subject, relative to an untreated control subject or an untreated control group, improves or normalizes the size of mitochondria in the subject's cardiomyocytes.

37. The use according to any one of claims 27 to 36, wherein administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to the subject improves the subject's hearing and / or vision.

38. The use according to any one of claims 27 to 37, wherein administration of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof to the subject increases the lifespan of the subject.

39. The use according to any one of claims 27 to 38, wherein compound A, compound B, or a mixture comprising compound A and compound B is administered to the subject orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, ophthalmologically, intrathecally, intraventricularly, via iontophoresis, through a mucosa, intravitreal, or intramuscular route.

40. A method for reducing iron accumulation in cardiomyocytes of a mammalian subject in need, the method comprising administering to the subject a therapeutically effective amount of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein compound A and compound B have the following structures: 。 41. The method of claim 40, wherein the subject has been diagnosed with or is suspected of having Friedreich ataxia.

42. The method of claim 40 or 41, wherein the subject is a human being.

43. A method for improving or normalizing the size of mitochondria in cardiomyocytes of a mammalian subject in need, the method comprising administering to the subject a therapeutically effective amount of compound A, compound B, or a mixture comprising compound A and compound B, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate, and / or solvate thereof, wherein compound A and compound B have the following structures: 。 44. The method of claim 43, wherein the subject has been diagnosed with or is suspected of having Friedreich ataxia.

45. The method of claim 43 or 44, wherein the subject is a human being.

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