Succinic acid prodrugs, compositions containing succinic acid prodrugs, and uses thereof

Abstract

To provide an effective and safe new compound for diseases having their origin in mitochondrial dysfunction or for enhancing metabolism by delivering a substrate of metabolism.SOLUTION: There is provided a novel isolated succinate prodrug as the free compound or a salt, hydrate, solvate or complex thereof being cell permeable and aimed for increasing the ATP-production in mitochondria. The succinate prodrug is an isolated solid form of the following methyl 3-[(2-acetylaminoethylthio)carbonyl]propionate (Compound 1).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to chemical, pharmacologically active compounds, pharmaceutical compositions containing such compounds, and nutritional Specifically, the present invention relates to the preparation of succinic acid useful as a pharmaceutical and nutritional supplement. Regarding cell-permeable precursors. [Background technology]

[0002] BACKGROUND OF THE INVENTION Mitochondria are the cellular supplier of adenosine triphosphate (ATP), which is used as an energy source. Mitochondria are eukaryotic organelles that generate the majority of nutrients. They are essential for energy production, eukaryotic cell survival, and proper cellular function. In addition to providing energy, mitochondria also play a role in several other processes, such as oxidation-reduction and Ion balance, cell signaling, cell differentiation, cell death, and metabolic processes, cell cycle Mitochondria are involved in the regulation of cell proliferation and cell cycles. In particular, mitochondria are important regulators of cell apoptosis. Regulatory factors that mediate various forms of non-apoptotic cell death, such as necrosis. also plays a major role.

[0003] Mitochondrial dysfunction contributes to a wide variety of diseases, and the mitochondrial and nuclear Genomic mutations or deletions, primary or secondary disorders of the mitochondrial respiratory system, or abnormalities It may be caused by other mechanisms related to normal mitochondrial function. There is no available treatment that can cure mitochondrial disease.

[0004] The oxidation of nutrients to produce usable chemical energy in the form of ATP is Most of the reactions occur in the mitochondria through a series of chemical reactions in the phosphoric acid cycle and electron transport chain. NADH produced in the tricarboxylic acid cycle is supplied to Complex I of the electron transport chain. Vinyl acetate is a metabolic intermediate in the tricarboxylic acid cycle in mitochondria and is involved in electron transfer. It is unique in that it is directly metabolized by the enzyme succinate dehydrogenase of complex II of the endothelial system. Succinate can also act as a signaling molecule that reflects the metabolic state of cells. can.

[0005] Treatment of diseases and disorders associated with mitochondrial dysfunction or enhancement of mitochondrial function Maintaining or restoring normal mitochondrial function or cellular energy production (ATP) in Given the recognized importance of enhancing cell permeability, intracellular succinate or succinate uptake, The ability to liberate precursors, the low toxicity of the compounds and the by-products released within the cells, and There is a need for compounds with physicochemical properties that are compatible with administration to animals or patients. .

[0006] Succinic acid compounds have been prepared as prodrugs of other active agents, e.g., WO 200 No. 2 / 28345 contains succinic acid bis(2,2-dimethylpropionyloxymethyl) ester, ... Succinic acid dibutyryloxymethyl ester, and succinic acid bis-(1-butyryloxy-ethyl) ester These compounds, as prepared, release formaldehyde. and is intended for a different medical use compared to current compounds.

[0007] A variety of succinate compounds are known in the art.

[0008] WO97 / 47584 discloses succinic acid polyols containing multiple linked succinic acid moieties. It has been done.

[0009] WO2015 / 155231 discloses cell-permeable succinic acid and precursors of succinic acid. There are.

[0010] Murli et al. (Appl. Environ. Microbiol. 71:2005:4503-4509) reported that the bacteria Escherichia coli (E scherichia coli and Streptomyces coelicolor Chemobiosynthesis of 6-deoxyerythronolide B analogues by supplying silyl thioesters The structure table shows methyl 3-[(2-acetylaminoethylthio)carboxamide] Various acyl thioesters containing the formal structure of [bornyl]propionate have been disclosed. However, the synthesis was unsuccessful and did not yield the desired product.

[0011] By providing substrates for diseases caused by mitochondrial dysfunction or for metabolism There is a need for new effective and safe therapeutic options to enhance metabolism. A novel method for stimulating energy in a subject and for acting as an antioxidant. The need for healthy nutritional supplements, nutricosmetics, cosmeceuticals, and cosmetics There are also new treatments, nutritional supplements, nutricosmetics, Cosmeceuticals and cosmetics are intended to enhance mitochondrial energy production and / or High activity to act as an antioxidant, excellent bioavailability, long blood It has an attractive set of properties, including plasma half-life, stability when formulated into products, and low toxicity. In particular, it is necessary to have a combination of high solubility in water, excellent cell permeability, and Preferably, the active ingredient is based on an active ingredient that has high blood-brain barrier penetration and / or a low lactic acid production. Bringing you new treatments, nutritional supplements, nutricosmetics, There is a need for cosmeceuticals and cosmetics. Summary of the Invention

[0012] (Summary of the Invention) In a first aspect, the present invention provides isolated methyl 3-[(2-acetylamino)methyl]- ... ethylthio)carbonyl]propionate (Compound 1), which may be in the free form or The compound may be a salt, hydrate, solvate, or complex of the compound.

[0013] Compound 1 has the structure (Formula 1): [ka] It has.

[0014] It has now been surprisingly discovered that cell-permeable Compound 1 possesses a remarkable combination of advantageous properties. This is a powerful inhibitor of mitochondrial energy production. It has in vivo activity, excellent oral bioavailability, blood-brain barrier penetration, and excellent plasma Compound 1 is stable, reduces lactate production, and restores succinate levels. It has a remarkably high solubility in water and aqueous systems. Solubility evaluation indicates a solubility of ~2.1M. The solubility of Compound 1 in water was higher than 500 mg / mL. This extremely high water solubility is due to the low melting point ( This is likely to occur when an aqueous solvent is added (below 55°C), and is miscible with the aqueous solvent. This allows for extremely concentrated aqueous formulations, effectively increasing the amount of substrate for metabolism. This allows for high oral administration of the prodrug compound.

[0015] In certain embodiments, isolated Compound 1 has a melting point or melting point ranging from about 35°C to about 55°C. In a preferred embodiment, isolated Compound 1 is a solid product having a range of at least 80% w / w, for example at least 85% w / w, at least 90% w / w, for example at least Although the present invention has a purity of at least 95% w / w, it is understood that the present invention may have a lower purity, for example, at least 30% w / w, at least 40% w / w, at least 45% w / w, at least 50% w / w, at least 55% w / w, at least or at least 60% w / w, at least 65% w / w, at least 70% w / w, or at least 75% w / w. Depending on the manufacturing method and storage conditions, Compound 1 may contain crystals and / or This may include non-crystalline, such as amorphous forms of Compound 1, and mixtures thereof. As can be seen from the examples in the specification, all of the methods used produced polymers with some degree of crystallinity. This gives compound 1.

[0016] It is understood that multiple crystalline forms of Compound 1 may exist, and that Compound 1 may also exist as an amorphous solid. In this regard, all forms of Compound 1, including mixtures of two or more forms of Compound 1, are contemplated. is within the scope of this application. Thus, the term "Compound 1" refers to a compound of formula 1 in solid form. wherein the compound is in a crystalline form, an amorphous form, a polymorphic form, or the like. It does not matter whether it is in solid form, powder form, or a mixture thereof.

[0017] In particular, Compound 1 has been found to have several solid forms with different properties. For example, as an amorphous solid or a predominantly amorphous solid, it may have a higher kinetic dissolution rate. It exhibits other improved properties when produced and processed as a solid form. It also has a crystalline form (or a predominantly crystalline form) that is crystalline in nature. Purity can affect the properties of the preparation. In particular, its melting point is low, close to body temperature, and changes depending on the presence of impurities. The stability of preparations of Compound 1 also depends on the presence of impurities that reduce the stability of Compound 1, e.g., impurities in non-purified water. It changes depending on the presence of pure matter.

[0018] In a second aspect, the present invention provides a composition comprising isolated Compound 1.

[0019] In a third aspect, the present invention provides a cosmeceutical comprising isolated Compound 1.

[0020] In a fourth aspect, the present invention provides nutricosmetics comprising isolated Compound 1. to provide.

[0021] In a fifth aspect, the present invention provides a process for preparing isolated Compound 1, comprising: To provide isolated Compound 1, a) N-acetylcysteamine and monomethyl succinate are reacted with a coupling agent to form a A process of reacting in an organic solvent at 0°C to 100°C b) isolating compound 1 : Provide a process, including:

[0022] The method typically includes a purification step to increase the purity of the compound.

[0023] The compound of Compound 1 of the present invention can be used to enhance or inhibit energy production in mitochondria. In particular, the compounds are useful in pharmaceutical, nutricosmetics and nutritional applications. It can be used in supplements, cosmeceuticals, and cosmetics. The substance has a component related to mitochondrial dysfunction and / or a component of energy (ATP) deficiency. and the cell signaling properties and metabolism of succinic acid in the prevention or treatment of disorders or diseases It can be used to exploit its anaplerotic effect on intermediates.

[0024] Additionally, known succinic acid prodrugs (such as those mentioned in WO 97 / 47584) may be used. The isolated compound 1 of the present invention has superior cell permeability, a longer plasma half-life, and Short life, excellent oral bioavailability, reduced toxicity, increased mitochondrial activity Use for therapeutic purposes, including energy release, as nutritional supplements and cosmetics Improved properties for the preparation of hydroxybenzoates, as well as improved formulation, e.g., due to improved aqueous solubility. Show characteristics.

[0025] In another aspect, the present invention provides a pharmaceutical composition comprising the compound Compound 1.

[0026] The pharmaceutical composition may be a solid formulation, or it may be a solid formulation that is reconstituted before use. It may also be an agent.

[0027] Alternatively, it may be in a liquid form, such as an aqueous solution, including, for example, an aqueous phosphate buffer solution (PBS) formulation. Generally, the pharmaceutical compositions of the present invention contain at least 10% w / w, at least at least 30% w / w, at least 50% w / w, at least 60%, or at least 70% w / w In one embodiment, the pharmaceutical composition comprises purified water, optionally made isotonic with blood. A solution of compound 1 in

[0028] In another aspect, the present invention relates to a method for treating metabolic diseases, diseases of mitochondrial dysfunction, mitochondrial Diseases associated with mitochondrial dysfunction, mitochondrial disorders, mitochondrial energy deficiency, Drug-induced mitochondrial side effects, cancer, diabetes, traumatic brain injury, acute liver injury, and atrial fibrillation The present invention provides the use of Compound 1 or a composition thereof in the treatment or prevention of heart disease.

[0029] In one aspect, the present invention provides a process for preparing a pharmaceutical composition comprising Compound 1. provide. [Brief explanation of the drawings]

[0030] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figure 1. LCMS analysis of Compound 1 batch 3 showing absorbance units (AU) versus time using HPLC method 2. [Figure 2] Figure 2. LCMS analysis of Compound 1 Batch 3 using HPLC Method 2 showing total ion counts on a normalized scale versus time. [Figure 3] Figure 3. LCMS analysis of Compound 1 batch 3 showing intensity (%) vs. m / z using HPLC method 2. [Figure 4] Figure 4. LCMS analysis of Compound 1 batch 12 using HPLC method 2 showing absorbance units (AU) versus time. [Figure 5] Figure 5. LCMS analysis of Compound 1 batch 12 using HPLC method 2 showing total ion counts on a normalized scale versus time. [Figure 6] Figure 6. LCMS analysis of Compound 1 batch 12 showing intensity (%) vs. m / z using HPLC method 2. [Figure 7]Figure 7A-B. Intravenous infusion of PBS or Compound 1 in anesthetized pigs showing plasma succinate concentration versus infusion time (A) and tissue fumarate concentration (B). Figure 7C. Intravenous infusion of PBS or Compound 1 in anesthetized pigs showing the effect on blood lactate concentration. [Figure 8] Figure 8. Intravenous infusion of PBS or Compound 1 in anesthetized pigs co-infused with the complex 1 inhibitor rotenone, showing succinate concentrations in tissue at the end of the infusion (A) and lactate concentrations during cerebral microdialysis expressed as a percentage of the baseline value before the start of the infusion versus time (B). [Figure 9] Figure 9. Treatment of Ndufs4 KO mice with Compound 1 in drinking water showing weight development versus time (A) and survival versus time (B). [Figure 10] Figure 10. Treatment of rotenone-injected rats with Compound 1 in drinking water showing number of rearing attempts vs. treatment (A), displacement distance in the postural instability test vs. treatment (B), and blood lactate concentration vs. treatment (C). [Figure 11] Figure 11. XRPD analysis of Compound 1 Batch 12. [Figure 12] Figure 12. XRPD analysis of Compound 1 batch 15. [Figure 13] Figure 13. LCMS analysis of Compound 1 batch 3 showing absorbance units (AU) versus time using HPLC method 1. [Figure 14] Figure 14. LCMS analysis of Compound 1 batch 3 showing total ion counts on a normalized scale versus time using HPLC method 1. [Figure 15] Figure 15. LCMS analysis of Compound 1 batch 3 showing intensity (%) vs. m / z using HPLC method 1. [Figure 16] Figure 16. LCMS analysis of Compound 1 batch 12 showing absorbance units (AU) versus time using HPLC method 1. [Figure 17] Figure 17. LCMS analysis of Compound 1 batch 12 using HPLC method 1 showing total ion counts on a normalized scale versus time. [Figure 18] Figure 18. LCMS analysis of Compound 1 batch 12 showing intensity (%) vs. m / z using HPLC method 1. [Figure 19] Figure 19. XRPD analysis of Compound 1 Batch 3. [Figure 20] Figure 20. XRPD analysis of Compound 1 batch 18. [Figure 21] Figure 21. XRPD analysis of compound 1 batch 13. [Figure 22] Figure 22. XRPD analysis of Compound 1 batch 14. [Figure 23] Figure 23. XRPD analysis of Compound 1 batch 19. [Figure 24] Figure 24. XRPD analysis of Compound 1 batch 16. [Figure 25] Figure 25. XRPD analysis of Compound 1 batch 17. DETAILED DESCRIPTION OF THE INVENTION

[0031] Description of the Invention In a first aspect, the present invention provides isolated methyl 3-[(2-acetylamino)methyl]- ... ethylthio)carbonyl]propionate (Compound 1), which may be in the free form or The compound may be a salt, hydrate, solvate, or complex of the compound.

[0032] Compound 1 has the structure (Formula 1): [ka] It has.

[0033] As mentioned above, Compound 1 may be in the form of a salt. Suitable salts include those having pharmaceutically acceptable salts. Acceptable salts, such as hydrochloride, hydrobromide, acetate, citrate, lactate, maleate salts, malonates, etc.

[0034] Compound 1 may also be a solvate. Suitable solvates include hydrates, ethanolates, and the like. Examples of suitable hydrates include hydrates of the hydroxybenzoates.

[0035] Compound 1 may also be in the form of a complex. Examples of suitable complexes include cyclodextrins. Compound 1 may be complexed with lipids, triglycerides, carbohydrates, and PVA.

[0036] In certain embodiments, isolated Compound 1 has a melting point or melting point ranging from about 35°C to about 55°C. As can be seen from the examples herein, Compound 1 is a solid product having a range of Possibly depending on the content of different forms of Compound 1, e.g., crystalline form, amorphous form, etc. In particular, melting points in the range of 39 to 51°C, for example, a melting point of 39°C, as well as a melting point of 46°C. Melting points in the ranges of about 46-47°C, 48-49°C, and 50-51°C have been found.

[0037] In a preferred embodiment, the isolated Compound 1 is at least 80% w / w, e.g., at least at least 85% w / w, at least 90% w / w, for example, at least 95% w / w, or at least 97% w / w / w purity, but this may be lower, for example at least 30% w / w, at least 4 0% w / w, at least 45% w / w, at least 50% w / w, at least 55% w / w, at least 60% w / w may have at least 65% w / w, at least 70% w / w, or at least 75% w / w. Depending on the manufacturing method and storage conditions, Compound 1 may contain crystals and / or may include non-crystalline forms, such as amorphous forms of Compound 1, and mixtures thereof. As can be seen from the examples in the table, all of the methods used yield compounds with some degree of crystallinity. This gives compound 1. Compound 1 can also appear as a powder.

[0038] As can be seen from the examples herein, Compound 1 has excellent water solubility at room temperature (20 to 25°C). At pH 7.4 and in the aqueous media tested in the Examples, Compound 1 has at least The aqueous solubility of Compound 1 is dependent on the crystallinity of the compound. Therefore, the lower the crystallinity, the higher the water solubility. As can be seen, the predominantly amorphous material can have an aqueous solubility of 850 mg / mL. The aqueous solubility of 1 is expected to be in the range of 300 mg / mL to approximately 900 mg / mL.

[0039] The kinetic solubility has also been determined, with the rate constants ranging from 0.005 to 0.2 s -1 Range of, e.g. For example, 0.01 to 0.15 seconds -1 Dynamic solubility is known to be in the range of It depends on various factors such as the degree of crystallinity and the content of amorphous material.

[0040] Regarding the crystallinity of Compound 1, this may be 0% to 100%, for example, 10% to 100%, 20% to 100%, %, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100% As can be seen from the examples herein, the compounds prepared by the methods described herein can be Many of the batches tested have a crystallinity of at least 50%, e.g., in the range of about 50% to about 80%. do.

[0041] As can be seen from the XRPD data herein, the crystals of Compound 1 have the following peaks: 21.4, 22.2, 22.8, 23. 1, and 23.3 (±0.2 degrees, 2-θ value) It is characterized by:

[0042] Crystals of Compound 1 also showed the following peaks: 10.9, 13.1, 14.9, 16.2, 20.1, 24.0, 24.8, 26.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 For example, it may have 2 or more, 3 or more, 4 or more, 6 or more, 7 or more, or 8 signals. As can be seen, almost all compounds tested exhibited signatures within these degrees (±0.2 degrees, 2-theta values). It has a nal.

[0043] From the data of the example, the signals at 11.1 and 16.9 (±0.2 degrees, 2-θ value) correspond to the polymorph ( It is assumed that the crystals of Compound 1 are related to Form 1. Therefore, the crystals of Compound 1 are related to Form 1. By supplementing one or more of them or by another form, it is possible to set the angle to 11.1 and 16.9 (±0.2 degrees, 2-theta value). The compound may have an X-ray powder diffraction pattern having a specific signal.

[0044] As mentioned above, Compound 1 is in solid form, particularly including crystalline forms of the compound. Although it is unlikely, it is advantageous that Compound 1 is not in the form of an oil. Compound 1 is easy to process (e.g., powder) in the manufacture of pharmaceutical / cosmeceutical compositions. Second, the crystalline form is usually the most stable form. Over time, amorphous (less ordered) materials change their morphology to crystalline (more ordered, more elastic). It tends to convert the energy into something (one with lower energy).

[0045] (Definition:) The term "Compound 1" means the compound of Formula 1 in solid form, and includes all compounds. crystalline forms, all amorphous forms, all polymorphic forms, and in the same or different forms Compound 1 may also be in powder form, including mixtures thereof. stomach.

[0046] The term "purity" as used herein with respect to Compound 1 means that the composition of Compound 1 is Compound 1 and By-Products, Unusual Forms of Compound 1 (Closely Related Structures), and Synthesis of Compound 1 Methyl 3-[(2-acetylaminoethylthio)carbamate] is a precursor of methyl 3-[(2-acetylaminoethylthio)carbamate] in relation to the total amount of related impurities. Therefore, 10% w / w of Compound 1 In a composition containing the compound 1, the purity of the compound 1 is, for example, 95% w / w or 50% w / w. and Compound 1 used to prepare the composition may be 95% w / w or 50% w / w, respectively. Purity can be measured by several methods, including qNMR, HPLC, etc. In qNMR, a known amount of analyte is mixed with a known amount of an internal standard. Dissolve in an NMR solvent together with the standard. 1 H NMR spectra have a reduced signal-to-noise ratio Acquire enough scans to integrate representative resonances for the internal standard and analyte. Then, this, along with the knowledge of how many protons are in the signal, The ratio of these integrals to the molecular weights of both the analyte and the internal standard was used to determine purity (in w / w%). In HPLC, purity is determined by the curve of the analyte compared to other signals with different retention times. Evaluate as area under the line (AUC).

[0047] The term "isolated" as used herein with respect to Compound 1 means that the compound is obtained from a synthetic reaction. and for example, purification from various by-products, synthetic precursors, and unusual compound 1 forms. Compound 1 product methyl 3-[(2-acetylaminoethylthio)carbonyl] It means propionate.

[0048] As used herein, the term "nutricosmetics" has become more widely used over time. With active ingredients that maintain physiological functions to achieve a healthier and more youthful appearance Nutritional supplements or chemicals specially formulated to help maintain healthy skin, hair, and nails Unlike topical creams or topical treatments, nutricosmetics are oral It is ingested and works from within to promote healthy skin, hair, and nails from the inside out.

[0049] As used herein, the term "cosmeceutical" refers to any substance that is said to have medical benefits. Cosmeceutical products are intended to mean cosmetics that have bioactive ingredients. They are marketed as cosmeceuticals and are reputed to contain at least one bioactive ingredient. Examples of such products include wrinkle-reducing skin care products containing ingredients such as alpha lipoic acid and dimethylaminoethanol. cream and a "cell-replenishing serum" that claims to have "anti-aging properties." Examples of creams that contain this ingredient include:

[0050] As used herein, the term "treatment" refers to any treatment intended to reduce the severity or frequency of symptoms. As used herein, "treatment" is intended to mean the performance of treatment involving The term refers to both therapeutic treatment and prophylactic or preventative measures. vinegar.

[0051] As used herein, the term "prevention" refers to the total or partial prevention of or to improve, mitigate, or control .

[0052] Compound 1 is a cell-permeable succinic acid and a precursor of succinic acid, as disclosed in WO2015 / 155231. However, upon identification of Compound I, the present inventors They have made several surprising discoveries, highlighting the potential of Compound I for several therapeutic and non-therapeutic uses. It has been shown to have an unexpectedly excellent combination of properties that make it suitable for therapeutic use. Additionally, surprising discoveries have been made surrounding the benefits of certain forms and formulations of Compound I.

[0053] General Uses of the Compounds of the Invention The compounds described herein in free form or in the form of salts, hydrates, solvates, or complexes thereof may be used. Thiol 3-[(2-acetylaminoethylthio)carbonyl]propionate (Compound 1) is used in medicine. in particular for the medical treatment or prevention of mitochondrial-related diseases, disorders, or disorders. It can be used in prevention, in nutricosmetics or in cosmetics. Compound I can be used in such medical treatment or prevention, nutricosmetics, or Compound 1, or a salt thereof, can also be used in the preparation of cosmetic compositions. The hydrates, solvates, or complexes are useful for enhancing or restoring energy production (ATP). It can be used in any situation, for example, in the medical treatment of disease. Treatments may be directed to metabolic disorders or diseases of mitochondrial dysfunction. or a disease associated with a decreased level of succinic acid or the functional activity of succinic acid, or Treatment of diseases where the anaplerotic effect or signaling properties of citric acid are useful The present invention may be directed to treating or suppressing mitochondrial disorders. Compounds of Compound 1 have been shown to be effective in stimulating mitochondrial energy production and in treating e.g. Neuropathic hearing loss or tinnitus (a side effect of certain antibiotics due to mitochondrial toxicity), Poisoning by chemicals or gases that affect endocrine metabolism, or lactic acidosis It can be used in the restoration of any drug or chemical induced mitochondrial dysfunction. The compound has been shown to have anti-cancer properties, including anti-diabetic properties, anti-inflammatory ... Deficiency syndrome and subsequent hypoxia, ischemia, stroke, myocardial infarction, acute angina, acute kidney injury, In the treatment of coronary artery occlusion and atrial fibrillation, or to avoid or eliminate reperfusion injury Furthermore, the compounds of the present invention can be used to treat male infertility and female menopause. It is anticipated that these compounds may be beneficial in the treatment of rheumatoid arthritis.

[0054] The compounds of Compound 1 of the present invention are capable of cellular permeation of components of the Krebs cycle and optionally the glycolytic pathway. After entering the cell, it is expected to be converted to ATP by enzymatic or chemical hydrolysis. As the released thiol group has reducing properties, succinic acid is expected to be liberated. This hydrolysis of compound 1 is also considered to be particularly advantageous. Many diseases are caused by the and have undesirable oxidative stress components that can lead to damage to cellular function. Oxidative stress is thought to be involved in the aging process. Components that can act as catalysts to scavenge free radicals or reduce oxygen reactive species. The release of It is expected to bring additional benefits.

[0055] Compound 1 is used to enhance or restore mitochondrial energy production. Compound 1 can be used as an antioxidant to scavenge free radicals or Compound 1 can also reduce reactive oxygen species associated with mitochondrial dysfunction. Disorders or diseases that have a component of deficiency of succinic acid or / and energy (ATP) deficiency or diseases associated with a decreased level of the functional activity of succinic acid, or anaplerotic in the prevention or treatment of diseases in which its steroid effect or signaling properties are useful. It is possible.

[0056] Enhanced energy production may be useful, for example, for those suffering from mitochondrial defects, disorders, or diseases. Mitochondrial diseases are caused by special mitochondrial proteins present in all cells of the body except red blood cells. This is due to the dysfunction of mitochondria, which are compartments of the body that have become cellular functions. When this occurs, the energy produced within the cell decreases, resulting in cell damage or death.

[0057] Mitochondrial diseases most often affect the retina, cochlea, brain, heart, liver, skeletal muscle, and kidneys. It occurs in organs with high energy demands, such as the liver, endocrine system, and respiratory system. Symptoms of chondriac disorders include loss of motor control, muscle weakness and pain, seizures, vision / hearing disturbances, and sensory problems, heart disease, liver disease, gastrointestinal disorders, difficulty swallowing, fatigue, and many more. Mitochondrial diseases can be hereditary or can be caused by factors that affect the mitochondria. due to spontaneous mutations that result in changes in the function of normally occurring proteins or RNA molecules Many diseases are caused by complex I, II, III, or IV deficiencies or by other disorders such as associated with mitochondrial defects, such as enzyme deficiencies like benzoyl benzoate dehydrogenase deficiency. However, the reality is complex, and many factors are involved in this disease. It is possible that this is the case.

[0058] To date, no curative treatment is available. The only treatments available are those that alleviate symptoms and reduce the severity of the disease. This is something that can slow down the progression of the disease.

[0059] Thus, the findings described herein by the inventors suggest that mitochondrial energy The cell-permeable compound 1, a thioester prodrug of succinic acid, was used to treat erythema production. This is very important as it shows beneficial effects.

[0060] Additionally, known succinic acid prodrugs (such as those mentioned in WO 97 / 47584) may be used. In comparison with the compounds of the present invention, the isolated compound 1 has better cell permeability, Longer plasma half-life, reduced toxicity, increased energy release to mitochondria, and Medical treatments, including improved formulations (due to improved properties including increased solubility) , as well as nutricosmetics, nutritional supplements, cosmeceuticals, and cosmetics Optionally, the isolated compound of Compound 1 exhibits improved properties for use in It is also orally bioavailable, which allows for easier administration.

[0061] Thus, advantageous properties of the isolated compounds of the present invention include one of the following: One or more of the following may be mentioned: -Increased cell permeability -Increased oral bioavailability -Longer half-life in plasma -Reduced toxicity -Increased energy release to mitochondria -Increased antioxidant activity -Improved formulation -Increased solubility

[0062] The present invention relates to the treatment of cellular energy (ATP) deficiency, particularly in the treatment of cellular energy (ATP) deficiency, and the like, by the use of pharmaceutical active compounds. Compound 1 is provided for use as a substance.

[0063] The compounds of the present invention inhibit the functioning of either the complex itself or the limited supply of NADH to complex I. Any disease or disorder that affects, for example, the Krebs cycle, glycolysis, β-oxidation, pyruvate metabolism and also dysfunction of glucose or complex I-related substance transport. , can be used in the treatment of Complex I disorders.

[0064] The present invention is directed to, but not limited to, Leigh syndrome, Leber's hereditary optic neuropathy (LHON), MELAS (Mitochondrial Syndrome), and Chondriac encephalomyopathy, lactic acidosis, and stroke-like episodes), mitochondrial deficiency syndrome, Mitochondrial myopathy and MERRF (myoclonic epilepsy with ragged-red fibers) A method for treating a mitochondrial complex I-associated disorder, such as and administering to said patient an effective amount of a compound of the present invention.

[0065] The present invention provides a method for the treatment of toxin- or drug-induced lactic acidosis / mitochondrial dysfunction. Also provided is the use of a compound of the invention for the manufacture of a medicament for

[0066] Isolated compound 1 may be used in any condition where additional energy production is potentially beneficial, e.g. For example, but not limited to, they may be useful in prolonged surgical procedures and intensive care.

[0067] (mitochondria) Mitochondria are organelles in eukaryotic cells and are commonly referred to as the "power plants" of the cell. One of its main functions is oxidative phosphorylation, which is the synthesis of adenosine triphosphate (ATP). Molecules function as the energy "currency" or energy carrier within the cell, and eukaryotic cells The majority of our ATP comes from biochemical reactions carried out by mitochondria. The chemical process involves the production of oxidized nicotinamide adenine dinucleotide (NAD + ) to reduced form Nicotinamide adenine dinucleotide (NADH) is converted to oxidized flavin adenine dinucleotide (ADN). The citric acid cycle generates reduced flavin adenine dinucleotide (FADH2) from FADH2 (tricarboxylic acid cycle, or Krebs cycle), during which NADH and FADH2 are converted to NAD + and FAD This includes oxidative phosphorylation, in which ATP is oxidized to ATP.

[0068] The electrons released by the oxidation of NADH are transported through a series of steps known as the electron transport chain or respiratory chain. It is inherited by the protein complexes (Complex I, Complex II, Complex III, and Complex IV). Oxidation of succinate occurs in complex II (succinate dehydrogenase complex), and FAD is converted to succinate dehydrogenase. It is a prosthetic group in the enzyme complex called hydrogenase (complex II). It is embedded in the inner membrane of the mitochondria. Complex IV at the end of this chain transfers electrons to oxygen. These electrons are released as they pass through the complex. Energy is used to generate a proton gradient across the inner membrane of the mitochondria. This generates an electrochemical potential across the inner membrane. Complex V (which is not directly related to complexes I, II, III, and IV) is transported by the electrochemical gradient Stored energy is used to convert ADP into ATP.

[0069] Before the citrate / tricarboxylic acid cycle and oxidative phosphorylation, one molecule of glucose is converted to two molecules of In glycolysis, one glucose molecule is broken down into two molecules of pyruvate. A net production of ATP occurs. The pyruvate molecule then enters the mitochondria, where it It is completely oxidized to CO2 and H2O by oxidative phosphorylation (the entire process is (This is known as aerobic respiration.) The complete oxidation of two molecules of pyruvate to carbon dioxide and water is called In addition to the two molecules of ATP produced by the conversion of glucose to two molecules of pyruvate, a small amount of If oxygen is not available, the pyruvate molecule will produce at least about 28-29 molecules of ATP. Rather than entering the mitochondria, it is converted to lactate in the process of anaerobic respiration. can be.

[0070] Therefore, the net overall yield per glucose molecule is approximately at least 30–31 ATP molecules. ATP directly or indirectly powers almost every other biochemical reaction in the cell. Therefore, oxidative phosphorylation during aerobic respiration contributes to An additional (approximately) at least 28 or 29 molecules of ATP are crucial for the proper functioning of cells. The lack of oxygen prevents aerobic respiration and ultimately leads to the death of almost all aerobic organisms. A few organisms, such as yeast, live using either aerobic or anaerobic respiration. It can be extended.

[0071] When oxygen is temporarily deprived from the cells of an organism, they are able to use it again. Anaerobic respiration is used until the cell is depleted or the cell dies. Acid is converted to lactic acid during anaerobic respiration. Lactic acid buildup prevents oxygen from reaching muscle cells. It is thought to be the cause of muscle fatigue during periods of intense activity when the body is unable to recycle oxygen. Once available, lactate is converted and made available for use in oxidative phosphorylation. Back to bic acid.

[0072] Mitochondrial dysfunction contributes to a variety of disease states. The disease is due to mutations or deletions in the mitochondrial genome or the nucleus. When there is a defect in the threshold proportion of mitochondrial cells, and when there is a defect in the threshold proportion of such cells in the tissue, Symptoms of tissue or organ dysfunction can occur when you have defective mitochondria. Any organization can be affected, and the extent to which different organizations are involved can lead to a wide variety of impacts. Symptoms may be present.

[0073] Use of the Compounds of the Invention The compounds of the present invention are useful in any situation where it is desirable to enhance or restore energy production (ATP). Examples include, for example, increasing mitochondrial ATP production or in all clinical diseases where there is potential benefit from restoration of neural function, e.g., by drugs or chemically induced mitochondrial dysfunction or succinate levels or Lactic acidosis state associated with decreased functional activity of succinic acid, succinic anaplerosis amelioration of diseases where the blockade effect or signaling properties thereof are useful, as well as inborn errors of metabolism; Cancer, diabetes, acute starvation, endotoxemia, sepsis, hearing loss, systemic inflammatory response syndrome, and and in the treatment of multiple organ dysfunction syndrome.

[0074] In particular, Compound 1 is useful for, among other things, treating mitochondrial-related diseases, conditions, or disorders. or in preventive medicine, in nutricosmetics or in cosmetics It can be used in

[0075] Mitochondrial dysfunction is a contributing factor in renal tubular acidosis, motor neuron disease, and other neurological disorders. Genetic disorders; epilepsy; Huntington's disease; mood disorders; schizophrenia; bipolar disorder; aging It has also been described in association with cerebrovascular accidents, macular degeneration, diabetes, menopausal symptoms, and cancer. There are.

[0076] Compound 1 for use in mitochondrial-related disorders or diseases The compound according to the present invention is useful for the prevention or treatment of mitochondrial-related diseases selected from the following: Can be used in: ·Aging, Alpers disease (progressive infantile poliodystrophy), Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), ·autism, Barth syndrome (fatal infantile cardiomyopathy), β-oxidation defects, bioenergetic metabolic defects, Carnitine-acyl-carnitine deficiency, Carnitine deficiency, Creatine deficiency syndrome (CCDS) is a condition caused by methyl guanidinoacetate Transferase deficiency (GAMT deficiency), L-arginine:glycine amidinotransferase enzyme deficiency (AGAT deficiency), and SLC6A8-associated creatine transporter deficiency (SLC6A8 deficiency): including, Coenzyme Q10 deficiency, Complex I deficiency (NADH dehydrogenase (NADH-CoQ reductase deficiency), Complex II deficiency (succinate dehydrogenase deficiency), Complex III deficiency (ubiquinone-cytochrome c oxidoreductase deficiency), Complex IV deficiency / COX deficiency (cytochrome c oxidase deficiency is a deficiency of complex IV in the respiratory chain) caused by a defect), Complex V deficiency (ATP synthase deficiency), COX deficiency, CPEO (chronic progressive external ophthalmoplegia syndrome), CPT I deficiency, CPT II deficiency, ·Type II diabetes, Friedreich's ataxia (FRDA or FA), Glutaric acidemia type II, Kearns-Sayre syndrome (KSS), Lactic acidosis, LCAD (long-chain acyl-CoA dehydrogenase deficiency), · LC-FAOD (long-chain fatty acid oxidation disorder), LCHAD, Leigh disease or Leigh syndrome (subacute necrotizing encephalomyelopathy), LHON (Leber's hereditary optic neuropathy), Luft's disease, MCAD (medium-chain acyl-CoA dehydrogenase deficiency), MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), · MERRF (myoclonic epilepsy and ragged red fibrosis), Methylmalonyl-CoA epimerase deficiency, Methylmalonyl-CoA mutase deficiency, Mitochondrial DNA depletion syndrome 5, Mitochondrial DNA depletion syndrome 9, Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) (1 family), Maternally inherited diabetes and hearing loss, MIRAS (Mitochondrial recessive ataxia syndrome), Mitochondrial cytopathy, Mitochondrial DNA depletion, Mitochondrial encephalopathies, including encephalomyopathy and encephalomyelopathy, mitochondrial myopathy, MNGIE (Muscle Neurogastrointestinal Encephalopathy, NARP (neuropathy, ataxia, and retinitis pigmentosa), Neurodegenerative disorders associated with Parkinson's disease, Alzheimer's disease, or Huntington's disease, Parkinson's disease, Pearson syndrome, ·Progressive external ophthalmoplegia, Propionic acidemia, Pyruvate dehydrogenase deficiency, ·POLG mutation, Respiratory chain deficiency, SCAD (short-chain acyl-CoA dehydrogenase deficiency), SCHAD, and ·VLCAD (Very Long Chain Acyl-CoA Dehydrogenase Deficiency).

[0077] Of particular interest are Leigh syndrome, LHON, MELAS, and MERRF (myoclonus with ragged red fibers). and the use of Compound 1 in the treatment of complex I deficiency (epilepsy), and other disorders / diseases related to complex I deficiency. be.

[0078] Use of the compounds of the present invention in cosmetics The compounds according to the invention can be used in cosmetic products for: Improves metabolic function of skin cells (aging skin) Astringent (acne)

[0079] Use of the Compounds of the Invention as Nutritional Supplements The compounds according to the invention can be used as nutritional supplements for: Increased energy demands due to intense physical activity Increased energy demands due to metabolic decompensation during infection and surgery Enhanced muscle recovery through rapid tissue distribution and bypass of glycolysis

[0080] (Pharmaceutical compositions containing the compounds of the present invention) The present invention also provides an isolated compound of the present invention together with one or more pharmaceutically acceptable diluents or carriers. Pharmaceutical compositions containing the compound of formula 1 are also provided.

[0081] The compounds of the present invention or formulations thereof can be administered by any conventional method, including For example, but not limited to, it can be parenterally, orally, topically (mucosally, buccal), , sublingual, transdermal, or cutaneous), by medical devices (e.g., stents), Administered by inhalation or by injection or infusion (intravenous, subcutaneous, intramuscular, etc.) Treatment may consist of a single dose or multiple doses over a period of time.

[0082] Treatment may involve once-daily, twice-daily, three-daily, four-daily, etc. Treatment may be by continuous administration, for example, intravenous administration by infusion. It can also be done as follows.

[0083] The compounds of the present invention can be administered alone or in combination with one or more acceptable carriers. It is preferred to provide the compound as a pharmaceutical formulation together with the carrier. "acceptable" in the sense that it is safe and not harmful to its recipient Examples of suitable carriers are described in more detail below.

[0084] The formulations may conveniently be presented in dosage form, such as in unit dosage form, and may be prepared in any suitable manner well known in the art of pharmacy. Such a method can be used to prepare the active ingredient (of the present invention) by any of the following methods. In general, the formulation includes the step of bringing into association the compound (of formula (I)) with the carrier which constitutes one or more accessory ingredients. The active ingredient is uniformly and intimately associated with liquid carriers or finely divided solid carriers or both. The product is prepared by combining the components in a mixture and then, if necessary, shaping the product.

[0085] The compounds of the present invention are generally administered intravenously, orally, or by any parenteral route to achieve active in the form of a pharmaceutical preparation containing the component, optionally in the form of a non-toxic organic or inorganic acid or addition salt thereof, The disorder and patient to be treated and the method of administration will be determined. Depending on the route, the composition can be administered in various doses.

[0086] Pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, preferably It should be protected from the contaminating action of microorganisms such as bacteria and fungi. Depending on the type of formulation and the route of administration, the carrier may be, for example, water, ethanol, polyol ( (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), The solvent or dispersion medium may be a solvent or dispersion medium containing hexane, hexane oil, or a suitable mixture thereof.

[0087] For example, the compounds of the present invention may be used as flavoring or coloring agents for immediate, delayed, or controlled release applications. tablets, capsules, ovules, elixirs, gels, solutions, emulsions, which may contain It can also be administered orally, bucally, or sublingually in the form of a gel or suspension.

[0088] Formulations according to the invention suitable for oral administration include capsules, each containing a predetermined amount of the active ingredient; as discrete units such as cachets or tablets; as powders or granules; as aqueous liquids or As a solution or suspension in a non-aqueous liquid; or as an oil-in-water liquid emulsion or water-in-oil The active ingredient can be presented as a bolus, electuary, or penetrant. It can also be presented as a post.

[0089] Solutions or suspensions of compounds of the invention suitable for oral administration may contain excipients such as solvents, e.g. , water, ethanol, N,N-dimethylacetamide, dispersing agent, e.g., polysorbate 80 , surfactants, and solubilizers, such as polyethylene glycol, Phosal 50 PG (which , Phosphatidylcholine, Soybean Fatty Acids, Ethanol, Mono / Diglycerides, Propylene The formulations according to the present invention may also contain hydroxypropyl methylcellulose, ... can also be in the form of an emulsion, where the compound of Compound 1 is in the form of a water-in-oil or The oil may be present in an oil-in-water emulsion. The oil may be, for example, soybean oil, safflower oil, or the like. Triglycerides, such as medium chain triglycerides (MCT oils), such as coconut oil and palm oil It may be any oily substance or combination thereof.

[0090] Tablets may contain pharmaceutically acceptable excipients, such as fillers, binders, dispersants, disintegrants, lubricants, The composition may contain additives, pH adjusters, stabilizers, flavoring agents, etc. Specific examples include microcrystalline cellulose, Sucrose, lactose (e.g., lactose monohydrate or lactose anhydrous), sodium citrate Calcium carbonate, dibasic calcium phosphate, and glycine, butylated hydroxybenzoate. ruene (E321), crospovidone, hypromellose, disintegrants such as starch (preferably (corn, potato, or tapioca starch), sodium starch glycolate cereals, croscarmellose sodium, and certain complex silicates, as well as granulation binders, For example, polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl Hydroxypropyl cellulose (HPC), macrogol 8000, sucrose, gelatin, and arabic Also contains magnesium stearate, stearic acid, glycerin, behenate, Lubricants such as acrylate and talc may be included.

[0091] Tablets are prepared by compression or molding, optionally with one or more pharmaceutically acceptable excipients. Compressed tablets can be made by optionally adding a binder (e.g., povidone, gelatin, hydroxybenzoates, etc.). Hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., Sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose Active ingredient in free-flowing form such as powder or granules, mixed with a cellulose, surfactant, or dispersing agent. The ingredients can be prepared by compressing them in a suitable machine. Molded tablets can be prepared by adding an inert liquid to the mixture. by molding in a suitable machine a mixture of the powdered compound moistened with a diluent The tablets may optionally be coated or scored, e.g. Hydroxypropylmethylcellulose in various proportions to provide the desired release profile The formulation may be used to provide slow or controlled release of the active ingredient therein. can.

[0092] Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, milk sugar, or high molecular weight polyethylene glycol. Therefore, the compounds of the present invention may be used in combination with various sweeteners or flavoring agents, coloring substances or pigments, emulsifiers and and / or suspending agents, such as water, ethanol, propylene glycol, and glycerin. and combinations thereof.

[0093] Suitable formulations for topical administration in the mouth include those containing a flavored base, usually sucrose and aloe. Film preparations or lozenges containing the active ingredient in gum labia or tragacanth; gelatin and Pastilles containing the active ingredient in an inert base such as glycerin or sucrose and gum arabic and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0094] Pharmaceutical compositions adapted for topical administration include ointments, creams, suspensions, emulsions, lotions, and the like. powder, solution, paste, gel, impregnated dressing, spray, aerosol, or oil, transdermal These compositions can be formulated as devices, dusting powders, etc. These compositions contain an active agent. They can be prepared by conventional methods and therefore can be used in suitable conventional carriers. and additives such as preservatives, solvents to aid in drug penetration, emollients in creams or ointments. It may also contain ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the composition. may form up to about 80% of the composition. By way of example only, a cream or ointment may contain about 5-10 A sufficient amount of hydrophilic material containing 100% by weight of the compound and water is added to form a cleaner having the desired consistency. The compositions are prepared by mixing sufficient quantities to form a cream or ointment.

[0095] Pharmaceutical compositions adapted for transdermal administration are intended to be in intimate contact with the epidermis of the recipient for a prolonged period of time. It can be presented as a separate patch that is intended to remain in place, e.g. The active agent may be delivered from the patch by iontophoresis.

[0096] For applications to external tissues, for example the mouth and skin, the compositions preferably are presented as a topical ointment or is applied as a cream. When formulated in an ointment, the active agent is a paraffin-based ointment. It can be utilized with either a base or a water-miscible ointment base.

[0097] Alternatively, the active agent may be formulated in a cream having an oil-in-water cream base or a water-in-oil base. It can be made into

[0098] For parenteral administration, fluid unit dosage forms or infusion solutions contain the active ingredient and a sterile vehicle, e.g. The solvents may include, but are not limited to, water, alcohol, polyols, glycerin, and vegetable oils. The active ingredient is prepared in a range of concentrations depending on the vehicle and concentration used. It is either colloidal, suspended, or dissolved in a vehicle. In preparing the solution, the active ingredient can be dissolved in water for injection and then sterilized by, for example, filtration. After sterilization by means of a suitable vial or ampule, the compound can be filled into a suitable vial or ampule and sealed.

[0099] Advantageously, agents such as a local anesthetic, preservatives and buffering agents can be dissolved in the vehicle. To enhance stability, the composition can be, for example, filled into a vial and then freezable. The mixture can be frozen by dry-drying and the water removed under vacuum. The dry powder is sealed in a vial and the accompanying bottle of water for injection is used to reconstitute the liquid before use. We can supply ial.

[0100] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. The compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile, and It must be an efficient liquid for ease of injection.

[0101] The pharmaceutical compositions of the present invention include formulations suitable for intraocular administration. These contain a therapeutically effective amount of a compound 1, comprising one or more pharmaceutically acceptable excipients or pharmaceutically acceptable carriers. Such pharmaceutical compositions have superior bioavailability compared to conventional dosage forms of eye drops or The present invention can be applied to overcome intraocular drug delivery barriers and to provide improved intraocular bioavailability. Such compositions having a high availability include, for example, emulsions, ointments, suspensions, etc. , aqueous gels, nanomicelles, nanoparticles, liposomes, dendrimers, nanosuspensions, micro needle, and an in-situ thermosensitive gel.

[0102] Parenteral suspensions are sterile, in which the active ingredient is suspended in a vehicle rather than being dissolved. Prepared in substantially the same manner as a solution, except that the addition of the solution cannot be accomplished by filtration. The active ingredient is sterilized by exposure to ethylene oxide and then suspended in a sterile vehicle. Advantageously, the surfactant or wetting agent promotes uniform distribution of the active ingredient. It is included in the composition to achieve this.

[0103] As can be seen from the examples herein, carbonate-containing excipients are, inter alia, liquid or should be avoided in semi-solid formulations. Preferably, the carbonate concentration is less than 0.85 mM. should be.

[0104] In addition to the ingredients specifically mentioned above, the formulations of the present invention may contain, taking into account the type of formulation in question, Other agents conventional in the art may be included; for example, formulations suitable for oral administration may contain flavorings. It should be understood that the formulation may include an agent. Those skilled in the art will appreciate how to select a suitable formulation. and methods for preparing the same (see, for example, Remington's Pharmaceutical Sciences, (See, for example, "Patent's Pharmaceutical Sciences," 18th Edition or later). Those skilled in the art will be familiar with the appropriate route of administration and You will also know how to choose a dosage.

[0105] The present invention provides a process for preparing a liquid pharmaceutical composition according to any of the preceding claims. and the process for obtaining the pharmaceutical composition comprises: a) Methyl 3-[(2-acetylaminoethylthio)carbonyl]propionate (compound 1) was obtaining the compound in its isolated form or as a salt, hydrate, solvate, or complex thereof; b) optionally heating to less than 90°C, for example to 60°C, or holding at room temperature. c) Add an aqueous liquid (e.g., phosphate buffered saline at pH 7.4), saline solution, or pure water. Adding process d) optionally, sonication to aid dissolution e) mixing at room temperature Includes:

[0106] The optimal dosage and interval for each administration of the compounds of the invention will depend on the nature of the disease being treated and the The degree, form, route, and site of administration, as well as the age and condition of the particular subject being treated. that the dosage to be used is determined by the physician and that the physician will ultimately determine the appropriate dosage to be used. It will be appreciated by those skilled in the art that the dosage should be adjusted as frequently as appropriate. If side effects occur, the amount and / or frequency of the dosage may be adjusted according to normal clinical practice. The amount of the ion exchange reaction can be changed or reduced according to the following:

[0107] All percentage values ​​referred to herein are % w / w unless the context requires otherwise. do.

[0108] Nutricosmetic compositions containing the compounds of the present invention Nutricosmetics are orally administered products. The present invention contains the compound Compound 1. The nutricosmetic composition also includes: The free form of Compound 1 or a salt thereof, water, or the like may be administered together with the orally acceptable diluent or carrier. The nutricosmetic composition may be a hydrate, solvate, or complex. The pharmaceutical composition is very similar to that of

[0109] Thus, typical compositions include tablets, capsules, ointments, elixirs, gels, solutions, and the like. It is a liquid or suspension.

[0110] Cosmeceutical compositions containing compounds of the present invention Cosmeceutical compositions are usually administered to the skin or mucous membranes. Sometimes this is done by injection. The present invention also provides cosmeceutical compositions containing the compound Compound 1. Cosmeceutical compositions include a free form of niacin, together with one or more orally acceptable diluents or carriers. The present invention includes Compound 1 in the form of a hydroxybenzoate or a salt, hydrate, solvate, or complex thereof.

[0111] Typical cosmeceutical compositions include those of the present invention suitable for application to the skin, to mucous membranes, or by injection. Including those mentioned above in the specification.

[0112] (Other Aspects of the Invention) The present invention relates to compounds of formula (I) as defined above (e.g. for the treatment of mitochondrial dysfunction). the compound or a pharmaceutically acceptable form thereof; Quinone derivatives, such as ubiquinone, idebenone, MitoQ Vitamins, such as tocopherols, tocotrienols, and trolox (vitamin E ), ascorbic acid (C), thiamine (B1), riboflavin (B2), nicotinamide (B3), menadione On (K3), Antioxidants in addition to vitamins, e.g., TPP-compounds (MitoQ), Sk-compounds, epicatechin , catechin, lipoic acid, uric acid, melatonin Dichloroacetic acid Methylene blue L-arginine Szeto-Schiller peptide, elamipretide, and elamipretide analogues Creatine Benzodiazepines PGC-1α modulator AMPK modulator Modulators of mitochondrial fission and fusion PPARα / β / γ agonists Trolox analogues, carboxamide derivatives Nrf-2 activator NAD + Modulator NAD +precursor Ketogenic diet Also provided are combinations of one or more agents independently selected from:

[0113] Another aspect of the present invention is the use of any of the compounds of Compound 1 disclosed herein, e.g. , sodium bicarbonate (as a bolus (e.g., 1 mEq / kg) followed by a continuous infusion) Other compounds may be administered as co-medications to the compounds disclosed herein. That is what it means.

[0114] (Lactic acidosis or drug-induced mitochondrial oxidative phosphorylation due to complex I-related impairment of mitochondrial oxidative phosphorylation) (onset side effects) The present invention also provides a method for preventing or treating lactic acidosis and mitochondrial-related drug-induced side effects. In particular, the compound of formula 1 according to the present invention is a compound of formula 1 in the complex I or in the upstream thereof. for use in the prevention or treatment of mitochondrial-related drug- or toxin-induced side effects, or Expressed in another way, the present invention provides a method for the direct inhibition of drug-induced complex I in accordance with the present invention. Prevention or treatment of harm or any drug-induced effect that limits the supply of NADH to Complex I (e.g. For example, but not limited to, the Krebs cycle, glycolysis, β-oxidation, pyruvate metabolism, and For drugs that affect the transport or levels of glucose or other complex I-related substrates The present invention provides prevention or treatment of the following:

[0115] Drug-induced mitochondrial toxicity may be part of the desired therapeutic effect. Although there are cases where mitochondrial toxicity is induced by anticancer drugs, in most cases, The mitochondrial toxicity induced by this is an undesirable effect. significantly increased glycolysis and prevented the intracellular loss of mitochondrial ATP formation by oxidative phosphorylation. This can lead to increased plasma levels of lactate, In excess, this can result in lactic acidosis, which can be fatal. Type A lactic acidosis is primarily associated with tissue hypoxia, whereas type B aerobic Lactic acidosis can be caused by drugs, toxins, or liver disease, diabetes, cancer, and congenital disorders of metabolism (e.g., It is associated with systemic disorders such as genetic defects of mitochondria.

[0116] Many known drug substances have a negative effect on mitochondrial respiration (e.g., antipsychotics). drugs, local anesthetics, and antidiabetic drugs), and therefore, the use of such drug substances and measures that can be used to avoid or mitigate negative mitochondrial effects that may be produced. Furthermore, some chemical agents and gases have been shown to affect mitochondria. It has a negative effect on the metabolism and function of the liver.

[0117] The present invention relates to the prevention or treatment of lactic acidosis and the treatment of mitochondrial-related drug or toxin induction. In particular, the present invention provides a compound of Compound 1 for use in the prevention or treatment of allergic side effects, Succinate prodrugs induce mitochondrial-associated drug-induced vasoconstriction in complex I or its upstream. The present invention provides a method for the prevention or treatment of a combination of Prevention or treatment of drug-induced direct inhibition of Complex I, other respiratory complexes, or NA to Complex I Any drug-induced effect that limits the supply of DH (e.g., but not limited to, the Krebs cycle, Sugar, β-oxidation, pyruvate metabolism, and also glucose or other Complex I-related substrates Amber for the prevention or treatment of Acid prodrugs are provided.

[0118] As mentioned above, increased plasma levels of lactate may be due to drugs that may have mitochondrial-related side effects. This is often observed in patients treated with metformin (first-line treatment for type 2 diabetes). is the treatment of choice and is associated with lactic acidosis as a rare side effect), Human endocrine disruption in complex I in a time- and dose-dependent manner at concentrations relevant to luminal toxicity. It is based on experimental evidence showing that it inhibits mitochondrial function in peripheral blood cells. Min also causes a significant increase in lactate production by intact platelets over time.

[0119] Thus, the present invention provides a compound of formula (I) for use in the prevention or treatment of lactic acidosis. However, the results reported herein do not support the direct synthesis of complex I. Lactic acid is associated with a specific inhibition or a defect in complex I or its upstream. Since the compound of the present invention is based on the mitochondrial pathway, it inhibits the mitochondrial pathway in complex I or its upstream. It is envisaged that these compounds may be suitable for use in the prevention or treatment of chondriac-related drug-induced side effects. The compounds according to the present invention have the effect of disrupting the metabolism upstream of Complex I (N-transfer to Complex I). Any drug action that limits the supply of ADH, e.g., Krebs cycle, glycolysis, β-oxidation, pyruvate Affects acid metabolism and, in turn, levels of glucose or other Complex I-associated substrates. The compound will neutralize the effects of the compound on the indirect inhibition of complex I (including the effect on drugs that inhibit the activity of the compound). By increasing the proton motive force, the defects downstream of complex I (complexes III, IV, and V) are suppressed. It can also neutralize defects.

[0120] Compound 1 is used commercially or to reduce or inhibit the formation of lactic acid. To increase ATP availability in industrial cell lines, industrial applications, e.g., in vitro It is expected that the present invention can be used in cell culture, organ preservation, etc. Uses include:

[0121] The compounds of the present invention are useful for treating or preventing drug-induced mitochondrial-related side effects. or to therapeutically increase or decrease cellular levels of energy (ATP) or succinate. It is used to reverse direct or indirect drug-induced complications. It is used in the treatment or prevention of mitochondrial-related side effects. Treatment or prevention of acidosis, e.g., lactic acidosis induced by drug substances Used in.

[0122] The present invention also relates to the use of Compound 1 in the treatment of mitochondrial-related side effects, particularly the treatment of Complex I by drug substances. Combinations of drug substances that may induce side effects caused by direct or indirect damage Such combinations may be used as prophylactic prevention of mitochondrial-related side effects or as a treatment for side effects. may be used to reduce and / or treat mitochondrial-related side effects when This can be done.

[0123] Compound 1 has been shown to reduce drug-induced side effects, particularly those associated with direct or indirect inhibition of complex I. It is expected that the compounds will be effective in the treatment or prevention of

[0124] known to cause a defect, dysfunction, or disorder of Complex I and / or lactate acid Drug substances known to have cyclosporin as a side effect include: pain relievers containing acetaminophen and capsaicin Antianginal medications, including amiodarone and perhexiline antibiotics, including linezolid, trovafloxacin, and gentamicin quinone-containing anticancer drugs, including mitomycin C and adriamycin anticonvulsants, including valproic acid Metformin, phenformin, butylbiguanide, troglitazone, and rosiglitazo antidiabetic drugs, including methadone and pioglitazone Anti-hepatitis B drugs, including fialuridine Antihistamines Anti-Parkinson's disease drugs, including tolcapone the antipsychotic risperidone, Anti-schizophrenia drugs zotepine and clozapine Disinfectants, Quaternary Ammonium Compounds (QACs) antituberculosis drugs, including isoniazid fibrates, including clofibrate, ciprofibrate, and simvastatin Hypnotics, including propofol The immunosuppressive disease-modifying antirheumatic drug (DMARD) leflunomide Local anesthetics, including bupivacaine, diclofenac, indomethacin, and lidocaine Muscle relaxants, including dantrolene Antipsychotic neuroleptics such as chlorpromazine, fluphenazine, and haloperidol Neuroleptics, including Efavirenz, tenofovir, emtricitabine, zidovudine, lamivudine, rilpivir NRTIs (nucleotide reverse transcriptase inhibitors), including benzodiazepine, abacavir, and didanosine Nimes R NSAIDs, including sulindac, mefenamic acid, and sulindac Barbiturates.

[0125] Other drug substances known to have lactic acidosis as a side effect include β 2-agonists, epinephrine, theophylline, or other herbicides. and cocaine can also produce lactic acidosis.

[0126] Furthermore, the compounds of the present invention also have the potential to prevent lactic acidosis, even if not associated with complex I deficiency. It is envisaged that they may be effective in treatment or prevention.

[0127] (Combination of Drugs and Compounds of the Present Invention) The present invention also relates to lactic acidosis and complex I deficiency, inhibition, or dysfunction. Drug for use in the treatment and / or prevention of drug-induced side effects selected from side effects A combination of a compound of the present invention with a biological substance, i) the drug substance is used to treat a condition for which the drug substance is indicated, and ii) The compounds of the present invention are effective in preventing or suppressing side effects induced or inducible by said drug substance. is used to alleviate the side effects, wherein the side effects are caused by lactic acidosis and complex I deficiency, inhibition, or a side effect related to dysfunction, Concerning combinations.

[0128] Any combination of such drug substances with any compound of the present invention is within the scope of the present invention. Therefore, based on the disclosure herein, one skilled in the art will be able to easily understand that the gist of the present invention is as described herein. The discovery of the valuable properties of the compounds of the present invention in avoiding or reducing the side effects described above. Therefore, it will be understood that the agonist enters the cell and releases succinic acid and possibly other active moieties. 1. The administration of any of the following to a patient who has or may have the side effects described herein: The potential uses of the compounds of the present invention that can be delivered in combination with drug substances are provided by this disclosure. This is clear.

[0129] The present invention further comprises: i) a composition comprising a drug substance and a compound of the invention, wherein the drug substance is a lactic acid Potential drugs selected for side effects related to deficiency, inhibition, or dysfunction of complex I and complex II (has substance-induced side effects) ii) a composition as described in i) above, wherein the compound of the present invention is induced by the drug substance; The present invention is used for preventing or reducing side effects induced or inducible by lactic acid acid. acidosis and side effects related to complex I deficiency, inhibition, or dysfunction) Regarding.

[0130] The composition comes in two separate packages: A first package containing a drug substance or a composition containing a drug substance and a compound 1 of the present invention. a second package containing a compound or a composition containing a compound of the present invention; The composition may also be in the form of a pharmaceutical composition containing both a drug substance and a compound of the present invention. It may be a single composition containing

[0131] When the composition comprises two separate packages, the drug substance and the compound of Compound 1 of the present invention are The compounds of the present invention can be administered by different routes of administration (e.g., oral administration of the drug substance). orally or mucosally) and / or they may be administered essentially simultaneously. or the drug substance may be administered before the compound of the present invention, or vice versa. may be.

[0132] (kit) The present invention provides i) lactic acidosis and side effects related to complex I deficiency, inhibition, or dysfunction a first container containing a drug substance having a potential drug-induced side effect to be selected; and ii) side effects induced or inducible by the drug substance (wherein the side effects are lactic acid acidosis and side effects related to complex I deficiency, inhibition, or dysfunction) a second container containing a compound of the present invention, Compound 1, which may prevent or alleviate Also provided is a kit comprising:

[0133] (Treatment / prevention of side effects) The present invention also relates to lactic acidosis and complex I deficiency, inhibition, or dysfunction. 1. A method of treating a subject suffering from a drug-induced side effect selected from the group consisting of: and administering to said subject an effective amount of a compound of formula I, as well as a method for treating lactic acidosis. and side effects selected from side effects associated with defects, inhibition, or dysfunction of complex I. and Complex Lactic Acidosis in Subjects Suffering from Diseases Treated with Drug Substances That Induce Lactic Acidosis - Patent application and predicting drug-induced side effects selected from side effects associated with deficiency, inhibition, or dysfunction of the body's immune system. A method for preventing or alleviating the effects of the drug substance, comprising administering an effective amount of a compound of Compound 1 of the present invention to said drug substance. administering to the subject before, during, or after treatment.

[0134] (Metformin) Metformin is an antidiabetic drug that belongs to the biguanide class. It is the first-line treatment for type 2 diabetes, which accounts for approximately 90% of diabetes cases. The biological effect of insulin is enhanced by decreasing glucose production and increasing glucose uptake in peripheral tissues. This is attributed to increased blood flow and decreased intestinal glucose uptake, but the exact mechanism of action is unknown. Despite its advantages over other antidiabetic drugs, this It has been associated with rare cases of lactic acidosis (LA) as a side effect. It is defined as an increased blood pressure gap, an arterial lactate level above 5 mM, and a pH of 7.35.

[0135] The following list of non-limiting embodiments further illustrates the present invention: 1. Isolated methyl 3-[ (2-acetylaminoethylthio)carbonyl]propionate (Compound 1). 2. Isolated compound 1 according to embodiment 1, which is a solid product. 3. The XRPD pattern of Compound 1 Batch 12 (Figure 7) or the XRPD pattern of Compound 1 Batch 15 8) or polymorphs with positions (°2θ) at 11.2 (±0.2) and 16.9 (±0.2). The method according to any of the preceding embodiments, which is or comprises a crystalline product such as The isolated compound 1. 4. An isolated product according to any of embodiments 1-2, which is or comprises an amorphous product. Compound 1 was selected. 5. At least 20% w / w, at least 30% w / w, at least 40% w / w, at least 50% w / w, at least 60% w / w, at least 70% w / w, at least 75% w / w, at least 80% w / w, at least at least 90% w / w, at least 95% w / w, at least 97% w / w, at least 98% w / w, or at least The isolated Compound 1 according to any of the preceding embodiments, wherein both compounds have a purity of 99% w / w. 6. Less than 75% w / w, less than 70% w / w, less than 65% w / w, less than 60% w / w, less than 55% w / w, less than 50% w / w , less than 45% w / w, less than 40% w / w, less than 35% w / w, less than 30% w / w, less than 25% w / w, less than 20% w / w, Contains less than 15% w / w, less than 10% w / w, less than 5% w / w, less than 3% w / w, less than 2% w / w, or less than 1% w / w An isolated compound 1 according to any of the preceding embodiments, having a significant amount of related impurities. 7. Less than 50% w / w, less than 40% w / w, less than 30% w / w, less than 25% w / w, less than 20% w / w, less than 15% w / w , less than 10% w / w, less than 5% w / w, less than 3% w / w, less than 2% w / w, or less than 1% w / w An isolated compound 1 according to any of the preceding embodiments, having a precursor. 8. An isolated compound 1 according to any of the preceding embodiments, having sufficient purity for pharmaceutical use. . 9. Isolated Compound 1 according to any of the preceding embodiments, in free form. 10. Isolated compound 1 according to any of embodiments 1-8, which is a salt. 11. Hydrochloride, hydrobromide, acetate, citrate, lactate, maleate, or malonate The isolated compound 1 according to embodiment 10, which is a salt. 12. Isolated compound 1 according to any of embodiments 1-8, which is a hydrate, such as a monohydrate. 13. An isolated antibody according to any of the preceding embodiments for use in humans or animals. Compound 1. 14. Isolated Compound 1 according to any of the preceding embodiments for use in humans. 15. An isolated compound 1 according to any of the preceding embodiments for use in medicine. 16. The compound of any of the preceding embodiments for use as an active pharmaceutical ingredient in a pharmaceutical product. Compound 1 was isolated by 17. Metabolic diseases, diseases of mitochondrial dysfunction, and diseases related to mitochondrial dysfunction Disease, mitochondrial disorders, mitochondrial energy deficiency, drug-induced mitochondrial side effects Actions, cancer, diabetes, traumatic brain injury, cardiac arrest, hypoxia, ischemia, stroke, myocardial infarction, acute angina for the treatment of rheumatoid artery disease, acute liver injury, coronary artery blockage, atrial fibrillation, male infertility, and menopausal symptoms in women An isolated compound 1 according to any of the preceding embodiments for use in prophylaxis. 18. The mitochondrial dysfunction disease or disease associated with mitochondrial dysfunction is aging Alpers disease (progressive infantile poliodystrophy), Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), autism, Barth syndrome (fatal infantile cardiomyopathy), β-oxidation defects, bioenergetic metabolism defects, Carnitine-acyl-carnitine deficiency, Carnitine deficiency, Creatine deficiency syndrome (guanidinoacetate methyltransferase deficiency (GAMT deficiency)) , L-arginine:glycine amidinotransferase deficiency (AGAT deficiency), and SLC6A8 Related creatine transporter deficiency (SLC6A8 deficiency): including brain creatine deficiency syndrome group (CCDS), Coenzyme Q10 deficiency, Complex I deficiency (NADH dehydrogenase (NADH-CoQ reductase deficiency), Complex II deficiency (succinate dehydrogenase deficiency), Complex III deficiency (ubiquinone-cytochrome c oxidoreductase deficiency), Complex IV deficiency / COX deficiency (cytochrome c oxidase deficiency) is a defect in complex IV of the respiratory chain. caused by Complex V deficiency (ATP synthase deficiency), COX deficiency, CPEO (chronic progressive external ophthalmoplegia syndrome), CPT I deficiency, CPT II deficiency, type II diabetes, Friedreich's ataxia (FRDA or FA), Glutaric acidemia type II, KSS (Kerns-Sayre syndrome), lactic acidosis, LCAD (long-chain acyl-CoA dehydrogenase deficiency), LC-FAOD (long-chain fatty acid oxidation disorder), LCHAD, Leigh disease or Leigh syndrome (subacute necrotizing encephalomyelopathy), LHON (Leber's hereditary optic neuropathy), Luft's disease, MCAD (medium-chain acyl-CoA dehydrogenase deficiency), MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonic epilepsy and ragged red fibrosis), Methylmalonyl-CoA epimerase deficiency, Methylmalonyl-CoA mutase deficiency, mitochondrial DNA depletion syndrome 5, Mitochondrial DNA depletion syndrome 9, Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) (1 family), Maternally inherited diabetes and hearing loss, MIRAS (Mitochondrial Recessive Ataxia Syndrome), mitochondrial cytopathy, mitochondrial DNA depletion, Encephalomyopathy and cerebrospinal cord disorders, mitochondrial encephalopathies including mitochondrial myopathies, MNGIE (muscle neurogastrointestinal disorder and encephalopathy), NARP (neuropathy, ataxia, and retinitis pigmentosa), neurodegenerative disorders associated with Parkinson's disease, Alzheimer's disease, or Huntington's disease; Pearson syndrome, Parkinson's disease, progressive external ophthalmoplegia, propionic acidemia, pyruvate dehydrogenase deficiency, POLG mutation, Respiratory chain deficiency, SCAD (short-chain acyl-CoA dehydrogenase deficiency), SCHAD, VLCAD (very long-chain acyl-CoA dehydrogenase deficiency) 18. The isolated compound 1 according to embodiment 17, selected from: 19. The mitochondrial dysfunction disease or the disease associated with mitochondrial dysfunction is a Mitochondrial dysfunction is the cause of Leigh syndrome, Leber's hereditary optic neuropathy (LHON), and MELAS (mitochondrial neuropathy). Myelodysplastic syndromes (myelodysplastic syndromes, encephalomyopathy, lactic acidosis, and stroke-like episodes) and myelodysplastic syndromes (MERRF) with ragged red fibers The isolated compound 1 according to embodiment 18, wherein the compound is selected from the group consisting of oclonic epilepsy. 20. A compound according to any one of embodiments 1 to 17 for use in the treatment or prevention of metabolic dysfunction. The isolated compound 1. 21. Embodiment 20, wherein the metabolic dysfunction is diabetes (type 2 diabetes), such as a defect in insulin secretion. Compound 1 isolated by. 22. The method according to embodiment 20, wherein the metabolic dysfunction is a drug-induced side effect on mitochondria. The isolated compound 1. 23. The drug-induced side effects on mitochondria are due to metformin-induced complex I inhibition (milk acidosis), paracetamol / acetaminophen-induced complex I inhibition (hepatic failure), or The isolated compound 1 according to embodiment 22, wherein . 24. The method according to embodiment 20, wherein the metabolic dysfunction is a chemically induced side effect on mitochondria. The isolated compound 1. 25. The chemically induced side effects on mitochondria include rotenone inhibition of complex I (Parkinson et al., 2004). pesticide-induced inhibition of respiratory complexes and mitochondrial enzymes, respiratory complexes and mitochondrial enzymes Chemical warfare agent-induced inhibition of mitochondrial enzymes and the role of respiratory complexes and mitochondrial enzymes 25. An isolated compound according to embodiment 24, selected from gas poisoning, e.g., carbon monoxide poisoning. 1. 26. The isolated method according to embodiment 20, wherein the metabolic dysfunction is an inherited mitochondrial dysfunction. Compound 1. 27. The inherited mitochondrial dysfunction is a disorder characterized by reduced energy production due to a decrease in the number of mitochondria. Dysfunction of mitochondrial transcription factors, dysfunction of nuclear DNA-encoded mitochondria a protein, a large mitochondrial DNA (mtDNA)-protein complex called the nucleoid Dysfunction of transcription factors that contribute to stabilization of mitochondrial membrane proteins, energy production dysfunction, pyruvate dehydrogenase deficiency, deficiency of complex I, II, III, or IV, or Examples include enzyme deficiencies such as pyruvate dehydrogenase deficiency, enzymes involved in succinate synthesis, and Enzymes that promote the synthesis of methylmalonyl-CoA, such as propionyl-CoA carboxylase, methylmalonyl-CoA mutase, and 27. The isolated compound according to embodiment 26, wherein the compound is selected from the group consisting of a dysfunction of succinyl-CoA synthetase and a dysfunction of succinyl-CoA synthetase. Compound 1. 28. The effective amount is 1 mg to 5.0 g per day, 10 mg to 2.0 g per day, 25 mg to 1 g per day, 50mg to 500mg per day, 100mg to 1000mg per day, 250mg to 1000mg per day, or 50mg to 500mg per day In one embodiment, the compound is Compound 1 or a salt, hydrate, solvate, or complex thereof in the range of 100 mg to 500 mg. Compound 1 isolated by 27. 29. Compound 1 or a salt, hydrate, solvate, or complex thereof is administered once a day to ten times a day; or the isolated compound according to any of embodiments 15 to 28, which is administered to the subject once a day to four times a day. Compound 1. 30. The treatment or prevention is carried out after a pretreatment, for example, use before surgery, a planned procedure involving high metabolic demands, use before a medical intervention and before the subject enters a war zone or other hazardous environment; An isolated compound 1 according to any of embodiments 15 to 29. 31. An isolated compound according to any of embodiments 15 to 30, wherein the treatment or prevention is a long-term treatment. Compound 1. 32. An isolated compound according to any of embodiments 1 to 14 for non-medicinal use in humans or animals. Compound 1. 33. The composition according to embodiment 19 for use as a cosmeceutical or nutricosmetic Isolated Compound 1. 34. The method according to any of embodiments 28 to 29 for use in an energy drink or creamer. The isolated compound 1. 35. A composition comprising isolated Compound 1 according to any of the preceding embodiments. 36. A cosmeceutical comprising isolated compound 1 according to any of embodiments 1-14. 37. Nutricosmetics comprising isolated compound 1 according to any of embodiments 1 to 14. . 38. An energy drink comprising isolated compound 1 according to any of embodiments 1-14. 39. A pharmaceutical composition comprising isolated compound 1 according to any of embodiments 1 to 33. 40. A process for preparing isolated compound 1 according to any of embodiments 1 to 33, comprising: To provide isolated Compound 1, a) N-acetylcysteamine and monomethyl succinate are reacted with a coupling agent to form a A process of reacting in an organic solvent at 0°C to 100°C b) isolating compound 1 : includes, process. 41. Step a) is carried out, and independently, wherein the solvent is dichloromethane and the coupling 41. The process according to claim 40, wherein the agent is carbonyldiimidazole and the temperature is 15 to 30°C. Process. 42. Step b) comprises extracting with an aqueous acid solution (optionally 20% ammonium chloride) and then 42. The process of claim 40, further comprising extracting the organic layer with another aqueous medium (suitable brine or water). Process by either. 43. The organic layer is removed in vacuo and the residue is dissolved in an organic solvent with suitable dissolving properties for crystallization, e.g. For example, the process according to embodiment 42, wherein the hydroxybenzoate is dissolved in methyl tert-butyl ether (MTBE). 44. The solution is cooled, preferably to about 5°C, and an anti-solvent, e.g., n-heptane, is added and stirred for a period of time. Preferably, after stirring for about 24 hours, Compound 1 is recovered by filtration and washed with an anti-solvent. Process by sama42. 45. A single crystal according to any one of embodiments 1 to 3, wherein the angles (°2θ) are 11.2 (±0.2) and 16.9 (±0.2). Isolated compound 1. 46. ​​The pharmaceutical composition according to embodiment 39, which is a solid formulation. 47. The pharmaceutical composition according to embodiment 46, which is a solid formulation for reconstitution before use. 48. The pharmaceutical composition according to embodiment 46, which is an aqueous formulation. 49. The pharmaceutical composition according to embodiment 48, which is an aqueous phosphate buffered saline (PBS) formulation. 50. at least 10% w / w, at least 30% w / w, at least 50% w / w, at least 60%, or 50. A pharmaceutical composition according to any of embodiments 46 to 49, having compound 1 in a concentration of at least 70% w / w. thing. 51. For oral, subcutaneous, intravenous, parenteral, ocular, or topical administration 51. The pharmaceutical composition according to any of embodiments 46 to 50, 52. The pharmaceutical composition according to embodiment 51, which is a drink or a gel. 53. 1mg~5.0g, 10mg~2.0g, 25mg~1g, 50mg~500mg, 100mg~1000mg, 250mg~1000mg, or 50 mg to 500 mg of Compound 1 or a salt, hydrate, solvate, or complex thereof. 51. A pharmaceutical composition according to any one of claims 46 to 50. 54. The pharmaceutical composition according to any of embodiments 46-53, which is an immediate release formulation. [Example]

[0136] (Example) General methods, materials, and assays HPLC method for purity analysis (HPLC method 1) Solvent A is water + 0.1% NH4OH. Solvent B is 2.5 L acetonitrile + 130 ml H2O + 0.1% NH4OH. Gradient: T=0 min, B%=5, flow rate=1 ml / min; T=0.1 min, B%=5, flow rate=1 ml / min; T=9.5 min, B%=95, flow=1ml / min; T=10.2min, B%=95, flow=1ml / min; T=10.3min, B%=95, flow Volume=1.5ml / min; T=11.1min, B%=95, Flow rate=1.5ml / min; T=11.15min, B%=5, Flow rate=1.5m l / min; T=11.5min, B%=5, flow rate=1.5ml / min; The column is a Waters XSelect CSH C18 3.5um, 2.1mm x 50mm. Absorbance is monitored at 234 nm with a diode array detector. Sample concentration 1 mg / ml, injection volume 1 γl.

[0137] (HPLC method 2) Solvent A is water + 1.57g NH4HCO2 + 5ml formic acid. Solvent B is 2.5 L acetonitrile + 130 ml H2O + 4.5 ml formic acid. Gradient: T=0 min, B%=0, flow rate=1ml / min; T=1 min, B%=0, flow rate=1ml / min; T=9.5 min, B %=20, flow rate=1ml / min; T=10.3 min, B%=95, flow rate=1ml / min; T=10.5 min, B%=95, flow rate =1.5ml / min; T=11.0min, B%=95, flow rate=1.5ml / min; T=11.05min, B%=0, flow rate=1.5ml / min; T=11.5min, B%=0, flow rate=1.5ml / min; The column is a Waters XSelect CSH C18 3.5 um, 2.1 mm x 50 mm. Absorbance is monitored at 230 nm with a diode array detector. Sample concentration 1 mg / ml, injection volume 1 γl.

[0138] Example 1 - Methyl 3-[(2-acetylaminoethylthio)carbonyl]propionate (compound Synthesis of 1) Detailed description of the synthesis and isolation of compound 1: [ka] Compound 1 was made by three separate methods (A, B, and C below).

[0139] (Method A) 2-Aminoethanethiol hydrochloride (226 g, 2 mol), KOH (114 g, 2 mol), and NaHCO3 (168 g, 2 mol) To a solution of 100 ml of acetic anhydride (204 g, 2 mol) in water (4 L) was added dropwise. The mixture was stirred at room temperature for 45 minutes. The reaction mixture was extracted with EtOAc (8 x 2 L), dried over MgSO4, and the solvent was removed to give intermediate 1 (190 g, 80% yield) was obtained under reduced pressure as a pale yellow oil.

[0140] Dichloromethanesulfonyl 4-methoxy-4-oxobutanoic acid (209 g, 1.583 mol) and HOBT (214 g, 1.583 mol) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (304 g, 1.583 mol) was added. The mixture was stirred at room temperature for 2 hours. Intermediate 1 (189 g, 1.583 mol) was added dropwise. The mixture was stirred at room temperature for 2 hours. Triethylamine (160 g, 1.583 mol) was added dropwise. The mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (2 L) and a saturated solution of NaHCO3 (2 x 2 L). After washing with HCl, drying over Na2SO4 and concentrating under reduced pressure, crude compound 1 (350 g) was obtained as a yellow oil. The crude compound 1 was purified by silica gel column chromatography (2000 g of silica gel Purification by HPLC using a 100 / 1 to 80 / 1 mixture of CH2Cl2 / MeOH gave compound 1 (201 g, 94.9% by LCMS). The crude side cut (110 g) from the purification was purified by silica gel column chromatography. Purification by chromatography (1200 g of silica gel, eluted with CH2Cl2 / MeOH = 100 / 1 to 80 / 1) Compound 1 (40 g, 96.7% by LCMS) was obtained as a white solid.

[0141] (Method B) Acetic anhydride (7.14 g, 0.07 mol) was dissolved in 2-aminoethanethiol hydrochloride (11.3 g, 0.1 mol), KOH (5.6 The mixture was added dropwise to a solution of NaHCO3 (5.88 g, 0.07 mol) and NaHCO3 (5.88 g, 0.07 mol) in water (200 mL) at room temperature. The reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was extracted with EtOAc (8 x 200 mL), dried over MgSO4 (1 hour), and The solvent was then removed in vacuo at 50° C. to give crude intermediate 1 (7 g, 84% yield) as a pale yellow solid. Obtained as a liquid.

[0142] 1,1'-Carbonyldiimidazole (11.34 g, 0.07 mol) was dissolved in 4-methoxy-4-oxobutanoic acid (9. The mixture was stirred at room temperature for 1 hour. Intermediate 1 (7 g, 0.059 mol) was added dropwise, and the mixture was then stirred at room temperature for 3 hours. The resulting mixture was washed with HCl (1N, 3 x 150 mL) and a saturated solution of NaHCO3 (3 x 150 mL) and then evaporated over Na2SO4 After drying (1 h), the solvent was removed in vacuo at 50° C. to give 9.5 g of compound 1 as a yellow solid. Obtained as a solid.

[0143] (Method C) A solution of KOH (0.71 kg, 13.2 mol) and Na2CO3 (1.00 kg, 9.43 mol) in water (15 L) was diluted with 2-aminoethane Thiol hydrochloride (1.5 kg, 13.2 mol) was added. The resulting clear, deep purple solution was diluted with acetic anhydride. (0.96 kg, 9.43 mol) was added dropwise at +22°C, maintaining the internal temperature below +30°C during the addition. The reaction mixture was stirred at +20°C for 1 hour 35 minutes. Dichloromethane (23 L) was added and the mixture was stirred at +28±2°C for 20 minutes. The layers were separated. The aqueous phase was diluted with dichloromethane. The organic phases were combined and extracted with 2 x 15 L of solvent. was removed in vacuo. Intermediate 1 was then dried under vacuum at +40°C for 18 hours. Yield 996g and purity >97 area-% (GC). Crude intermediate 1 was obtained as a brown oil.

[0144] Distillation: using a thin layer distillation unit under the following conditions: T = +110°C, P = 1 mbar, rate 202 g / h 933 g of intermediate 1 was distilled off. Intermediate 1 was obtained as a clear, colorless oil.

[0145] A solution of 4-methoxy-4-oxobutanoic acid (1.33 kg, 10.07 mol) in DCM (10 L) was added to 1,1'-carbonyl Diimidazole (CDI) (1.63 kg, 10.07 mol) was added in small portions. During the addition, strong bubbling and Gas evolution was observed. After the addition was complete, the mixture was stirred at +20 to +25°C for 1 hour. Add a solution of Intermediate 1 (1.00 kg, 8.39 mol) in dichloromethane (5 L) while maintaining the temperature below +30°C. The reaction mixture was stirred at +20 to +25°C for 2 hours. 20% aqueous NH4Cl solution (10 L) was added, and The mixture was stirred for 20 minutes. The layers were separated. The organic phase was then diluted with 13% NaCl aqueous solution and water ( The mixture was extracted with 10 L and 5 L of distilled water, respectively. The solvent (DCM) was then replaced with MTBE by distillation. Compound 1 The MTBE (approximately 6 L) solution was gradually cooled to +5°C. When the internal temperature reached +12°C, crystallization began. To the slurry, n-heptane (15 L) was added and the mixture was stirred at 0 to +5°C for 20 hours (overnight). The slurry was filtered and the filter cake was washed with n-heptane (2 x 3 L). The product was dried by pulling it into a condenser for 42 hours. The yield was 1.26 kg (64%) and the purity was was 98.5 area-% (HPLC).

[0146] Several batches of Compound 1 were prepared by the above synthesis. These batches were synthesized using Method A. A, B, and C were purified by different purification methods.

[0147] Batch 3 (or compound 1-s3) was prepared by Method A.

[0148] Batches 12 (or compound 1-s12), 13 (or compound 1-s13), and 14 (or compound 1-s14) were Prepared by Method B.

[0149] Batches 15 (or compound 1-s15), 16, and 17 were prepared by Method C.

[0150] Example 2 - Characterization of Compound 1 from different batches [Table 1] It should be mentioned that the temperature increases during the XRPD analysis. Compound 1 has a low melting point. (and the amorphous form is believed to have a lower melting point than the crystalline form), The degree of crystallinity indicated in can be considered as a minimum value.

[0151] (Batch 3) In TGA analysis, batch 3 had a loss of 0.04 wt% between 20 and 150 °C. Figure 3 shows the spectrum obtained from the LCMS analysis of batch 3. Differential scanning calorimetry (DSC) As determined, the melting point of batch 3 was 50.4°C.

[0152] (Batch 12) Batch 12 was analyzed by the same method used to analyze Batch 3 above. The loss in TGA analysis was 0.12 wt% at temperatures between 20 and 150°C. The LCMS results are shown in Figures 4 to 6. The purity by qNMR was 96.1% and the melting point was 48.6°C.

[0153] (Batch 13) Batch 13 was analyzed by the same method used to analyze the batches above. The loss in TGA analysis was 0.18 wt% at temperatures between 20 and 150°C. Spectra obtained from LCMS The purity by qNMR was 96.3%. The melting point was 49.0°C.

[0154] (Batch 14) Batch 14 was analyzed by the same method used to analyze the batches above. The loss in TGA analysis was 0.45 wt% at temperatures between 20 and 150°C. Spectra obtained from LCMS The purity by qNMR was 91.6%. The melting point was 46.9°C.

[0155] (Batch 15) Batch 15 was analyzed by some of the same methods used to analyze the batches above. Ta. The spectra obtained from LCMS are not shown, but the results are summarized in Table 5. qNMR The purity was 98.9% by analytical method, and the melting point was 39°C.

[0156] (Comparison of batch characteristics: Batches 3, 12, 13, 14, 15, and 16) Table 5 also summarizes the purity, melting point, and visual description of solid Compound 1. One batch came out as a white, free-flowing powder, see Table 5.

[0157] Furthermore, Table 5 shows that the solubility of each batch of compound prepared was at least 366-398 mg / ml. and such formulations appear as clear, transparent or translucent solutions in water. This shows that: Table 5. Summary of results from analysis of various batches of Compound 1. [Table 2] TIFF0007827801000006.tif166170 Table 6. Summary of analysis of one batch of compound for purity and impurities (LCMS2 high pH impurity profile) ring) [Table 3]

[0158] Example 3 - Preparation of an aqueous formulation of Compound 1 (Formulation Protocol) 1. Weigh out the required amount of Compound 1, then add the required amount of vehicle (0.9% w / v saline, 100 mM PBMC) S pH 7.4, water) is added to solid Compound 1 to give the required mg / ml concentration of Compound 1 For example, for a 400 mg / ml formulation of Compound 1 in water, weigh out 400 mg of Compound 1 and add it to 0.7 ml of water. Add the following. 2. Sonicate the solution for 10 minutes, then shake for 20 minutes to ensure complete dissolution of Compound 1. Make sure that 3. If necessary, the solution can be centrifuged (13000 rpm, 10 minutes) to remove particulates. 4. If necessary, the solution can be sterile filtered. Table 7. Formulation data in water for various batches of Compound 1 prepared according to the protocol above. [Table 4]

[0159] (Formulation 50% w / v) Four batches of Compound 1 were formulated in PBS at 50% w / v.

[0160] Weigh out ~500 mg of compound into a vial and add ~500 μl of 100 mM PBS pH 7.4 The vial was sonicated for 10 minutes and then shaken for 20 minutes. The solution was diluted 1 / 2000 and the concentration was calculated by HPLC analysis. Table 8. Preparation of Compound 1 formulation in PBS at pH 7.4. Compound 1 concentration was determined by HPLC in soluble formulations. was measured. [Table 5]

[0161] (Formulation Liquid Compound 1) Compound 1 Batch 3 was heated in an oven to 60°C for 20 minutes, at which point a translucent, pale yellow liquid was formed. 100 mM PBS pH 7.4 (20% v / v) was added and the solution was mixed on a shaker for 20 minutes. After this, the solution was cooled to room temperature and remained translucent. It was left for 2 hours, after which observation confirmed that it remained a translucent solution. .

[0162] (Summary of formulations) It can be formulated in aqueous solutions such as 0.9% w / v saline, 100 mM PBS pH 7.4, or water. The amount of compound 1 that can be produced appears to have no achievable limit. This may be explained by the melting point of compound 1, which was measured to be approximately 47-50 °C in batches. When an aqueous solution is added to a solid, it disrupts the intramolecular interactions of the compound molecules. and becomes miscible with water.

[0163] Example 4 - Gel Formulation Compound 1 is formulated in a gel pack at 2.25 mg / ml.

[0164] (Experiment details) One HydroGel gel pack (clear H20 hydrogel, 8 oz. pouch, HydroGel, Portland) , ME) was taken and distributed into various experimental Falcon tubes.

[0165] First, blue food coloring was used to measure how easily the aqueous solution mixed into the gel. Two gel samples were taken, one kept at room temperature and the other in the microwave. The mixture was dissolved in 100 ml of water (1 min). Blue food coloring (1% v / v) was added and the solution was mixed. Mixing was continued until the gel is much more efficient when the dye is dissolved. The dye dissolves completely after less than 10 seconds of mixing. It can be incorporated.

[0166] The dye solution was then replaced with a solution of Compound 1.

[0167] Water was added to Compound 1 (225 mg / ml, 100x the required concentration) and sonicated for 20 minutes, followed by 30 minutes of sonication. A sample was taken for HPLC analysis to check the concentration. Table 9. Measured concentrations of Compound 1 in water stocks [Table 6]

[0168] This analysis showed that Compound 1 was completely solubilized.

[0169] Another two gels were dissolved and an aqueous solution of Compound 1 was added (1% v / v). The gel was shaken for the same length of time (10 seconds) as in Example 1. The gel was allowed to set.

[0170] Once the gel had solidified, a sample was taken for HPLC analysis to confirm the homogeneous distribution of compound 1. I checked.

[0171] (Sampling procedure) 1. A sample of gel (100 mg) was added to an Eppendorf tube and MeOH was added (0.9 ml, 1 / 10 dilution). 2. The sample was shaken on a vibrax for 30 minutes. 3. The sample was centrifuged (13,000 rpm, 10 minutes) 4. The supernatant was collected for HPLC analysis. Table 10. Measured concentrations of Compound 1 in gel samples [Table 7]

[0172] Although the concentration of Compound 1 was slightly lower than the expected 2.25 mg / ml, the two samples were sufficiently The distribution of compound 1 is consistent with the dilution factor. This suggests that...

[0173] One of the gel samples was kept at RT (room temperature) and the other at 4°C to allow for the precipitation of the compounds in the gel. The stability of Compound 1 was tested.

[0174] (Stability of gel formulation) Gels were sampled at regular time points as above to determine stability at both 4°C and RT. The data from these experiments are presented in Tables 11-12. Table 11. Concentration of Compound 1 in gel samples taken after 20 days of storage at 4°C. [Table 8] Table 12. Concentration of Compound 1 in gel samples taken after 20 days of storage at RT (approximately 20°C). [Table 9]

[0175] The general trends in the data, particularly the stability data at 230 nm, indicate that compound 1 is The AUC data suggest that the drug is stable for at least 20 days in the extraction gel formulation. Inaccuracies in weighing out the samples and possibly differences in the localized concentration of Compound 1 in the gel Therefore, it has more error.

[0176] (Protocol for preparation of gel formulation) Prepare a 100x concentrated aqueous solution of Compound 1 and add it to the gel in an amount of 1 / 100 of the gel volume. The example given is for a final concentration of 2.25 mg / ml in a 200 ml gel pack. Therefore, you need 2 ml of 100x Compound 1 (225 mg / ml) in water. It is also suggested to add the solution to the gel pack (which is the test (Provided that this does not have any adverse effects.) This allows the Compound 1 solution to be uniformly distributed throughout the gel. If food coloring is included, add the food coloring to the control gel. It is also recommended to add 1. Weigh out 500 mg of Compound 1 into a 3 ml vial (or similar). 2. Add 2 ml of water (adding 2 ml of water to 500 mg of Compound 1 corresponds to the volume of solid Compound 1, H PLC calibration curve confirmed that the concentration was 225 mg / ml), sonicated for 20 minutes, and then Add 1 ml of natural food coloring and shake for 30 minutes (the solution may remain slightly cloudy). (The food coloring helps indicate that uniform distribution has been achieved.) 3. If necessary, the solution can be sterile filtered. 4. When an unopened gel pack is heated by immersion in 70°C water for 10 minutes, the gel It becomes a fluid liquid. 5. Draw up Compound 1 solution into needle / syringe (with or without food dye). 6. Add Compound 1 solution (and food dye) to the gel pack by poking a small hole in the gel pack with a needle. Inject into the box. 7. Using tape, reclose the gel pack at the injection site. 8. Shake the gel pack vigorously for 5 minutes to obtain a uniform distribution of Compound 1 (food dye included). If so, this is evident when the injected solution is uniformly distributed by a color change in the gel. (It will become something). 9. Allow the gel to set, which takes about 45 minutes at room temperature. 10. Use the gel or seal and store at 4°C (once opened, store the gel at 4°C for up to 14 days) It is recommended to save it.) 11. Compound 1 is stable in gel at 4° C. and room temperature for at least 14 days.

[0177] (Protocol Testing) The gel formulation was prepared according to the protocol, and the exact concentration of Compound 1 was confirmed by HPLC analysis in the aqueous suspension. This has been shown to be achieved in both tonic and gel formulations. Table 13. Compound 1 concentrations in water stock solutions and gel formulations [Table 10]

[0178] 2 ml of water stock was added to 1 ml of food dye, which was diluted and analyzed by HPLC. The AUC of the diluted water stock was 0.63 times that of the undiluted water stock. This showed that Compound 1 remained soluble when diluted with water.

[0179] (Results / Conclusion) Compound 1 can be formulated at 2.25 mg / ml in an aqueous gel pack and is stable at both 4°C and RT. Stable for at least 20 days.

[0180] Example 5 - Saline formulation of Compound 1 1. Weigh out 400 mg of Compound 1 and add 0.7 ml of saline (0.9% w / v). 2. Sonicate for 20 minutes, then shake for 30 minutes or until all compounds are dissolved by eye. Can.

[0181] (Freeze / thaw stability of compound 1) method: 1. Physiological saline (0.9% w / v) was added to Compound 1 (1 mg / ml), and then the solution was stirred for 10 minutes until it was completely dissolved. The mixture was sonicated for 1 hour. 2. Samples were taken for HPLC analysis (F / T 0). 3. The solution was frozen at -80°C overnight. 4. The solution was thawed and a sample was taken for HPLC analysis (F / T 1). 5. Steps 3 and 4 were repeated for three cycles. Table 14. Purity of Compound 1 upon freeze / thaw (FT) cycling [Table 11]

[0182] The results (Table 14) showed that there was no significant change in the assay or purity of Compound 1 in saline. Therefore, compound 1 was shown to be stable for at least three freeze / thaw cycles. There are.

[0183] (RT stability of compound 1) method: 1. Physiological saline (0.9% w / v) was added to Compound 1 (1 mg / ml), and then the solution was stirred for 10 minutes until completely dissolved. The mixture was sonicated for 1 minute. 2. A sample was taken for HPLC analysis (T=0). 3. The solution was stored at RT. 4. Samples were taken periodically for HPLC analysis for stability.

[0184] result: The results showed that there was no significant change in the assay or purity of Compound 1 in saline (data not shown). (no change), thus demonstrating that compound 1 is stable at room temperature for at least 14 days.

[0185] (Compound 1 200-500mg / ml formulation) method: 1. Saline (0.9% w / v) was added to Compound 1 batch 11 in various amounts, followed by ultrasonication for 10 minutes. Processed - the sample remained slightly cloudy. 2. The sample was shaken for 30 minutes, at which point the solution became translucent. 3. The solution was diluted for HPLC analysis.

[0186] result: Table 15. Purity of Compound 1 at Increasing Concentrations in Saline Solution [Table 12] The results (Table 15) show that Compound 1 can reach over 500 mg / ml in saline solution. This shows that:

[0187] (Transition Protocol (400mg / ml formulation)) 3. Weigh out 400 mg of Compound 1 Batch 11 and add 0.7 ml of saline (0.9% w / v). 4. Sonicate for 20 minutes, then shake for 30 minutes or until all compounds are dissolved by eye. Can.

[0188] (Results / Conclusion) (Freeze / thaw stability of compound 1) Compound 1 is stable for at least three freeze / thaw cycles.

[0189] (RT stability of compound 1) Compound 1 is stable at room temperature for at least 14 days (data collection is expected to continue). (There are.)

[0190] (Compound 1 400mg / ml formulation) Compound 1 concentrations of over 500 mg / ml in saline can be reached.

[0191] Example 6 - Stability of Compound 1 in Water and DMSO Compound 1 was dissolved in water and DMSO at a concentration of 1 mg / ml, respectively, and analyzed for stability over 40 days. The mixture was then stored at RT, 37°C, and 65°C. Table 16. Compound 1 in water (concentration 1 mg / ml) in the dark at RT with purity determination [Table 13]

[0192] Little loss of purity and assay was observed for Compound 1 in water at room temperature over a period of 38 days. It can be seen. Table 17. Compound 1 in water (concentration 1 mg / ml) in the dark at 37°C with purity determination [Table 14]

[0193] Loss of purity and assay observed for Compound 1 in water at 37°C over 38 days The assay losses are significantly greater than those observed in water at room temperature. Table 18. Compound 1 (concentration 1 mg / ml) in water at 65°C in the dark with purity determination [Table 15]

[0194] Loss of purity and assay is observed for Compound 1 in water over a 29 day period. The loss in the assay is significantly greater than that observed in water at 37°C. Table 19. Compound 1 in DMSO (concentration 1 mg / ml) in the dark at 37°C with purity determination [Table 16]

[0195] No significant loss of purity or assay was observed after 37 days of compound storage in DMSO at 37°C. Item 1 is not acceptable. Table 20. Compound 1 in DMSO (concentration 1 mg / ml) in the dark at 65°C with purity determination [Table 17]

[0196] No significant loss of purity or assay was observed after 29 days of incubation of the compound in DMSO at 65°C. Item 1 is not acceptable.

[0197] Example 7 - Analysis of Compound 1 The material from Example 1, Method C (Batch 15) was analyzed by XRPD. The data is shown in Figure 12. This indicates a crystalline material.

[0198] Material from Method A (Batch 12) was also analyzed by XRPD and showed crystalline material with the same polymorph. It appeared that the

[0199] Example 8 - Comparison of Solubility of Compound 1 with Other Succinic Acid Prodrugs By dissolving the solid material in an aqueous formulation and measuring the amount in solution by HPLC(-MS) The solubility of Compound 1 in aqueous formulations was evaluated in comparison with other succinic acid prodrugs. Substance 1 was found to be present at concentrations above 350 mg / mL in water, 190 mg / mL in PBS (pH 7.4), and 0.9 mg / mL in water above 500 mg / mL. % solubility in saline, whereas other succinic acid prodrugs evaluated had much lower solubility. In many cases, the maximum solubility of other prodrugs was For example, the solubility data of other succinic acid prodrugs in PBS pH 7.4 were See Table 21 for example data. Table 21: Solubility of exemplary succinic acid prodrugs [Table 18]

[0200] Example 9 - Comparison of the bioavailability of Compound 1 with other succinic acid prodrugs The cell permeability and oral bioavailability potential of compound 1 were evaluated in standard Caco-2 cells. The iodine availability was tested using an in vitro assay (briefly, 24-well C orning Costar Transwell format confluent Caco-2 cells (L1, AP, 1992; Grass, G. M. et al., 1992; Volpe, D. A. et al., 2001) are published in In Vitro Technology. The apical chamber was provided by IVT, Baltimore, Md., USA. Basal balanced buffer solution (HBBS) pH 7.4, containing 1% DMSO and 0.1 mM Lucifer Yellow. The chamber contained 0.6 mL HBBS pH 7.4, 1% DMSO. Control and test articles were placed in a humidified The mixture was incubated in an incubator at 37°C and shaken at 130 rpm for 1 hour. W penetrates only via the paracellular (tight junction to tight junction) pathway However, high apparent permeability (Papp) of Lucifer Yellow indicates cell damage during the assay. All such wells were rejected. (good passive transmission without to role (attenuated by active efflux by P-glycoprotein) The compound (0.01 mM) was added to the apical chamber. Compounds can be tested in unidirectional and bidirectional formats by applying them to the basal chamber or the basal chamber. The compounds in the apical or basal chambers were analyzed by HPLC-MS. The apparent difference in the activity of succinic acid prodrugs compared to other succinic acid prodrugs, including those from WO2015 / 155231, is The data are presented in Table 22 below and are expressed as permeability Papp (nm / s). The highest migration from the basolateral side to the basolateral side was observed for Compound 1, indicating cell permeability and This shows improved iodine availability, which was confirmed by in vivo pharmacokinetic studies. In this study, Compound 1 also had high oral bioavailability and was significantly higher than other compounds tested. Unlike the prodrug, it has been shown to be brain penetrant. Table 22. Caco-2 bioavailability of Compound 1 compared to other succinic acid prodrugs [Table 19] TIFF0007827801000024.tif111170

[0201] Example 10 - Comparison of Thermodynamic Solubility of Different Batches of Compound 1 Two batches of Compound 1 were made with varying degrees of crystallinity. Batch 2 had a higher degree of non-crystallinity. It has a higher degree of crystallinity than batch 3, which is considered to have crystalline Compound 1 - and therefore Batch 2 is considered to be the more crystalline batch, while batch 3 is considered to be the more amorphous batch. The method used is discussed in this document. The solution was prepared using NaCl (8 g / L), KCl (0.2 g / L), anhydrous disodium hydrogen phosphate (1.42 g / L), and Add potassium dihydrogen phosphate (0.24 g / L) to 250 mL of deionized water until all solids are dissolved. The mixture was stirred until the pH of the solution was adjusted to pH 7.0 using HCl (1M) or NaOH (1M) as needed. adjusted to 4).

[0202] A sample of the more amorphous Compound 1 Batch 3 was added to PBS or water to a final concentration of 258 mg / mL. The mixture was sonicated for 10 minutes, then shaken for 30 minutes. The solid material was removed by centrifugation. Subsequent analysis revealed that it had reached a concentration of 258 mg / mL.

[0203] A sample of Compound 1 Batch 2, the more crystalline Compound 1, was diluted with HPLC-grade water to a final concentration of 30 mg / mL. (Fisher), sonicated for 10 minutes, and then shaken for 30 minutes. After removing the material, analysis revealed that a concentration of 17 mg / mL had been reached.

[0204] A sample of Compound 1 Batch 2, a more crystalline version of Compound 1, was diluted with HPLC-grade water to a final concentration of 52 mg / mL. (Fisher), sonicated for 20 minutes, and then shaken for 1 hour. After removing the material, analysis revealed that a concentration of 52 mg / mL had been reached.

[0205] As can be seen from the data presented - the more amorphous the material, the more crystalline the material. It has a much higher dynamic solubility than the material.

[0206] A sample of the more crystalline Compound 1 Batch 2 was diluted with HPLC grade water (Fisher) to a final concentration of 2000 mg / mL. ), sonicated for 20 minutes, and then shaken for 1.5 hours. After removal, analysis revealed that a concentration of 850 mg / mL had been reached. The more crystalline compound has a water solubility of at least 850 mg / ml, i.e., Although it has high aqueous solubility, the dynamic solubility is higher for the more amorphous compound 1. This shows that...

[0207] Example 11 - Comparison of the stability of Compound 1 in purified or non-purified water Stability of Compound 1 in "purified" HPLC-grade water (Fisher Scientific) and "unpurified" tap water Briefly, a 1 mg / mL solution of Compound 1 was prepared using "purified" HPLC grade These were prepared in water (Fisher Scientific) and "unpurified" tap water. They were stored at room temperature for up to 10 days. The concentration and purity of Compound 1 were monitored over time by HPLC compared to standards. The calculated concentration was evaluated by AUC of the 8.21 RT peak at 230 nm and purity analysis. is the AUC of the compound 1 peak versus the impurity). Data presented are the average of two samples. Table 23: Compound 1 Batch 3 dissolved in tap water at 1 mg / ml and stored at room temperature for several days. There are [Table 20] Table 24: Compounds dissolved at 1 mg / ml in HPLC grade water (Fisher Scientific) and stored at room temperature for several days. Item 1 Batch 3 is listed on the table [Table 21]

[0208] Significant degradation of Compound 1, as evidenced by loss of purity and assay, occurred after 6 days of storage at room temperature. This is observed in samples dissolved in (unpurified) tap water after being purified with (purified) HPLC grade water (F Similar data were not observed for samples dissolved in HCl (Isher Scientific). This was also seen in two independent samples of the same batch.

[0209] Example 12 - HP-Cyclodextrin Formulation of Compound 1 (Preparation of excipients) Kleptose Hydroxypropyl β-Cyclodextrin (25% w / v), Anhydrous Sodium Dihydrogen Phosphate sodium diphosphate anhydrous (0.295% w / v), and calcium diphosphate Sodium EDTA (0.5% w / v) was added to 100 mL of deionized water. The mixture was sonicated for 20 minutes. The mixture was then stirred until all solids had dissolved, after which the pH was adjusted to 7.4 with HCl (1M).

[0210] (Formulation Protocol) 1. Weigh out the required amount of Compound 1, then add the required amount of prepared excipients to the solid Compound 1. to produce the required mg / ml concentration of Compound 1 (maximum amount tested: 25 mg / ml). For example, for a 20 mg / ml formulation of Compound 1, weigh out 20 mg of Compound 1 and add 1 ml of the prepared excipient. Add. 2. Sonicate the solution for 10 minutes, then shake for 20 minutes to ensure complete dissolution of Compound 1. Make sure that 3. If necessary, the solution can be centrifuged (13000 rpm, 10 minutes) to remove particulates. 4. If necessary, the solution can be sterile filtered.

[0211] Example 13 - Infusion of Compound 1 provides succinic acid and increases succinic acid metabolism in pigs (reduces blood lactate levels) Infusion of Compound 1 increased plasma succinate levels and stimulated the conversion of succinate to fumarate in tissues. Increases acid metabolism and reduces blood lactate levels. See Figure 7.

[0212] Yorkshire Landrace crossbred pigs were anesthetized and injected with Compound 1 or vehicle (PBS). Two animals were given escalating doses of the compound. Drug 1 (2-6 mg / kg / min) was administered over 2.5 hours, with the dose increased by 1 mg / kg / min every 30 minutes. One animal was infused at a constant rate of 2 mg / kg / min. Control animals were infused with PBS. Blood samples were taken at 30-minute intervals and plasma was separated by centrifugation. The samples were cryopreserved and then analyzed using a Thermo Vanquish UPLC + Thermo Quantis triple-pole MS instrument and a guard Acquity UPLC HSS C18 (100 × 2.1 mm, 1.8 μm) column equipped with a filter and gradient elution; Succinic acid was analyzed by LC / MS using 0.1% formic acid and acetonitrile. [13C]- Labeled succinic acid was used as an internal standard.

[0213] Plasma succinate concentrations increased proportionally with the time of Compound 1 infusion (Figure 7A), and succinate from Compound 1 At the end of the test, succinic acid, the primary metabolite of succinic acid in the TCA cycle, was released. Fumaric acid, which is present in the steroid hormone, has high metabolic activity in the retina, brain, and heart of the target animal. The data were therefore consistent with previous data from animals receiving Compound 1. Compound 1 provides metabolizable succinic acid to these tissues and has the ability to cross the blood-brain barrier. This suggests that there is.

[0214] Combined blood lactate data from the three animals were expressed as a percentage of the initial value and were taken at the time of sampling. The results were plotted as a function of cumulative dose at the time of administration (Figure 7C).

[0215] Lactate decreased after intravenous injection of Compound 1 compared to the initial value, indicating that Compound 1 It supplies succinic acid to complex 2, increasing the supply of electrons to the mitochondrial electron transport chain and producing ATP It has been suggested that this increases the production of lactic acid and reduces the need for glycolytic conversion of pyruvate to lactate. Ta.

[0216] Example 14 - Porcine model of rotenone-induced mitochondrial complex 1 dysfunction Infusion of Compound 1 restored succinate levels in organs depleted by rotenone and increased succinate levels in the brain. Reduces rotenone-induced lactate in mice. See Figure 8.

[0217] To examine the effects of rotenone-mediated inhibition of complex 1, Yorkshire Landrace crosses The piglets were anesthetized and intravenous catheters were inserted for the co-infusion of rotenone and Compound 1 or vehicle (PBS). Rotenone (7.1 mg / h) was infused for 1.5 hours. Compound 1 was administered at 2 mg / kg for 2.5 hours. The animals were infused at a constant rate of 1000 mg / min. Control animals were infused with PBS. Blood samples were taken at 30-minute intervals. The plasma was separated by centrifugation. Microdialysates were collected and analyzed for lactate using an ISCUS device (MDialysis). At the end of the study, animals were euthanized and terminal blood and organ samples were collected. Plasma and tissue samples were frozen. The samples were then stored and analyzed using a Thermo Vanquish UPLC + Thermo Quantis triple quadrupole MS instrument. Acquity UPLC HSS C18 (100 × 2.1 mm, 1.8 μm) column with a filter and gradient elution Succinic acid was analyzed by LC / MS using A = 0.1% formic acid and B = acetonitrile. ]-labeled succinic acid was used as an internal standard. Lactate data were obtained after the start of rotenone infusion. The results were expressed as a percentage of the baseline value.

[0218] Rotenone infusion reduced tissue concentrations of succinate to subquantitative levels (<2 μM), resulting in the formation of complexes. The administration of Compound 1 increased the availability of succinate, which compensated for the decrease in electron transport from the body. Tissue succinate concentrations were restored to detectable levels, demonstrating that compound 1 provided succinate. This suggests that the increase in succinate utilization exceeds that caused by complex 1 inhibition. Administration of compound 1 counteracted the rotenone-induced increase in brain lactate and reduced the supply of succinate to the brain. This confirmed the reduction in the need for glycolytic conversion of pyruvate to lactate by feeding.

[0219] Example 15 - Mouse genetic Ndufs4 knockdown model of complex 1 dysfunction Administration of Compound 1 in drinking water (1 mg / mL) from weaning (day 21) significantly increased body weight in the high-dose group. and a trend towards increased survival. See Figure 9.

[0220] The complex I gene Ndufs4 (Quintana et al., Proceedings of the National Academy of Sciences C57BL / 6 mice with genetic ablation of the genotype 1 (Gibberish, 1996-11001) were cultured from weaning. Compound 1 (1 mg / mL) in drinking water or normal drinking water was administered to the rats. Body weight development was monitored every 10 days. Compound 1 was administered daily for the first 10 days after administration (Figure 9A) and the animals' health was monitored daily (Figure 9B). During this time, the administration of 100 mg / kg ... The therapeutic effect of succinic acid supplementation in the form of Compound 1 was investigated in mitochondria with characteristics of Leigh syndrome. These results suggest that this may be achieved in genetic models of complex I dysfunction.

[0221] Example 16 - Rat Model of Rotenone-Induced Motor Dysfunction and Lactic Acidosis Compound 1 administered in drinking water prevents exercise dysfunction and reduces blood lactate levels See Figure 10.

[0222] Rotenone-induced rat Parkinson's disease model (Cannon et al., Neurobiol Dis. 2009 M ay;34(2):279-90) to investigate the motor and metabolic dysfunction caused by complex 1 inhibition. The effect of oral administration of Compound 1 on

[0223] Twelve-week-old Lewis rats (6 animals per group) received an intraperitoneal injection of rotenone (0.25–0.75 mg / kg). The mice were given IV injections daily for 4 days. Compound 1 was dissolved in drinking water at concentrations of 0.25 and 0.75 mg / mL. Testing and lactate measurements were performed on day 4. The animals were placed in clear glass outer tubes (height = 30 cm; diameter = 18 cm). Rearing was measured by placing the subject in a tubing for 5 minutes. The legs are raised above shoulder height and one or both front legs are in contact with the wall of the tube. You should.

[0224] Postural instability was measured using P-120 sandpaper, marked with lines and numbers every centimeter. Measurements were taken on a table surface covered with a cloth (see below). The animal was placed at an angle of approximately 90° to the surface. The animal is held in a vertical position (like a "wheelbarrow") with one forelimb lightly pressed against the animal's body. The animal's center of gravity was then moved forward with one forelimb on the ground, and the This induced Ayumu to "catch up" and regain his balance. The distance required to induce a catch-up step of the unattached forelimb was recorded. Blood lactate (Figure 10C) was measured using VetScan iSTAT- 1 Measured using Analyser.

[0225] Rotenone treatment resulted in a decrease in rearing activity. Compound 1 (0.75 mg / mL) in drinking water Administration of 100 mg / kg of ethanol resulted in a significant increase in rearing (Fig. 10A) and posture compared to water-treated animals. Therefore, this data indicates that compound 1 is orally bioavailable. It is possible to treat motor dysfunction caused by mitochondrial complex 1 dysfunction. This suggests that the whole can be improved.

[0226] Blood lactate concentrations were significantly increased in animals treated with rotenone. There was a tendency for blood lactate concentrations to decrease from compound 1 at a concentration of 0.5 mg / mL to a higher concentration (0.75 mg / mL). This data demonstrates that succinic acid provided by Compound 1 can be effectively administered intermittently in drinking water. When given orally, metabolic compensation at the level of glycolysis and conversion of pyruvate to lactate is enhanced. This suggests that conversion can be achieved, implying suitability as an oral treatment.

[0227] Example 17 - Succinic Acid Release Data Briefly, a stock of Compound 1 Batch 12 was prepared in 50 / 50 DMSO / MeCN (200 mM, x200). This mixture was then diluted with KHPO (Sigma Aldrich, 13.9 g / L) dissolved in HPLC grade water. , anhydrous), KH2PO4 (Sigma Aldrich, 2.72g / L, anhydrous), MgCl2.6H2O (Fisher, 1.02g / L), and 10:1 microsome buffer (20 mM, ×20) containing EDTA (Sigma Aldrich, 0.375 g / L) A 200 mM malonic acid (Sigma Aldrich) stock was then diluted to 1:1 with the microsome buffer. A 20 mM NADPH stock was also prepared in microsome buffer (20 mM Microsome stock (Sekisui XenoTech, 0.625 mg / ml) was prepared in a 7 ml bottle. Samples were prepared for each time point (T = 0, 5, 15, 60 min) as follows: Prepared: 80 μL of microsome stock (final concentration of 0.5 mg / mL), 5 μL of compound stock (2 5 μL of malonic acid stock (10 mM final concentration), add 100 μL MeOH The T=0 sample was quenched by addition of 10 μL NADPH stock (2 mM final concentration). The reaction was initiated at all time points by adding 100 μL MeOH at each time point. The reaction was stopped by shaking the samples for 1 minute, placing them on ice for 10 minutes, and then centrifuging them at 3000 rpm for 10 minutes. The supernatant was then analyzed by LCMS. Table 25 [Table 22]

[0228] As can be seen from the data, compound 1, when incubated with microsomes, , slowly releasing succinic acid.

[0229] Example 18 - Mineral Instability Compound 1 batch 14 (2-3 mg) was dissolved in tap water (to distinguish the effect of cations or anions). Various sources of minerals commonly found in water (including various associated counterions that can The solution was dissolved in room temperature water for injection (WFI) (1 mg / ml) containing 100 mg of ethanol and the samples were then collected for HPLC analysis at various time intervals. It was collected at.

[0230] Mineral sources used in the form of inorganic salts: CuCl2, CaCl2, NiSO4, CoCl2, NH4Cl, MnCl2, NaF, NaNO3, CuSO4, Ca(NO3)2, AlSO4, Ca CO3, (NH4)2CO3. Table 26 [Table 23]

[0231] As can be seen from the data, compound 1 is more readily absorbed when in aqueous solution containing carbonate ions. Decomposes quickly.

[0232] Example 19 - Carbonate Instability Compound 1 batch 14 (2-3 mg) was diluted with various sources (two concentrations for each source, pH recorded). The samples were dissolved in room temperature HPLC grade water containing calcium and carbonate ions (1 mg / ml) and analyzed by HPLC. Samples were taken at various time intervals for analysis.

[0233] Sources of calcium and carbonate used in the form of inorganic salts: CaCl2, Ca(NO3)2, CaCO3, (NH4)2CO3 Table 27 [Table 24]

[0234] As can be seen from the data, compound 1 can sometimes be found in aqueous solutions containing carbonate ions. Decomposes quickly.

[0235] Example 19 - Carbonate concentration dependence Compound 1 batch 14 (2-3 mg) was dissolved in HPLC grade water containing different concentrations of calcium carbonate (1 mg / ml ) and samples were taken at different time intervals for HPLC analysis. Table 28: [Table 25]

[0236] Example 20 - Dynamic Solubility One batch of solid compounds (s3, s12–17) (~80 mg) was added to the wells of a clear, flat-bottom 96-well plate. Addition of 5°C PBS gave a final concentration of 460 mg / ml of O1-354 for all batches. After adding PBS, the plate was agitated for 10 seconds and then immediately assayed for turbidity at 620 nm using Eppendorf. The samples were analyzed in real time for 3 minutes using a Microplate Spectrophotometer (BioTek). The rate constant of the solution was calculated from an exponential decay fit of the recorded data.

[0237] Table 29: [Table 26]

[0238] (General method for evaluating crystallinity) X-ray powder diffraction studies were carried out using a Bruker AXS D8 Discover HTS. Anode: 40kV and 4mV Cu anode; Gobel mirror and line optics Detector: Linear detector (LYNXEYE XE) with a receiver slit of 2.95°C Measurement: Scan range 2 to 45°C 2θ, 1 s / step, 0.005°C / step Data collection software: Diffrac.Commander v7.3.3.0.0 Data analysis software: Diffrac Eva v4.2.1

[0239] No background correction or smoothing was applied. Data were analyzed using peak 2θ angles and The total peaks defined are reported as the crystallinity and the intensity. The combined area was divided by the total area under the curve and expressed as a percentage.

[0240] (Peak list) The list below details the peaks returned after XRPD for several crystal batches: The underlined peaks are common to most batches. Those with an asterisk may be peaks that are common or unique to different polymorphic forms. Peak List NV354-s3-Batch3 [Table 27] TIFF0007827801000033.tif152170 Peak List NV354-s12-Batch 18 [Table 28] Peak List NV354-s13-Batch 13 [Table 29] TIFF0007827801000036.tif235170 Peak List NV354-s14-Batch 14 [Table 30] TIFF0007827801000038.tif54170 Peak List NV354-s15-Batch 19 [Table 31] Peak List NV354-s16-Batch 16 [Table 32] TIFF0007827801000041.tif136170 Peak List NV354-s17-Batch 17 [Table 33] TIFF0007827801000043.tif187170 The present application provides the following aspects of the invention. (Aspect 1) Methyl 3-[(2-acetylaminoethylthio)carbonyl]propionate isolated in solid form nate (Compound 1). (Aspect 2) 2. The compound according to embodiment 1, in free form or in the form of a salt, hydrate, solvate, or complex thereof. Isolated compound 1. (Aspect 3) 2. The isolated compound 1 of embodiment 1, having a melting point or melting range in the range of 35 to 55°C. (Aspect 4) Any one of embodiments 1 to 3, wherein the product is a crystalline product or an amorphous product, or a mixture thereof. The isolated compound 1 described in paragraph 1. (Aspect 5) At least 20% w / w, at least 30% w / w, at least 40% w / w, at least 50% w / w, at least 60% w / w, at least 70% w / w, at least 75% w / w, at least 80% w / w, at least at least 90% w / w, at least 95% w / w, at least 97% w / w, at least 98% w / w, or at least 5. The isolated Compound 1 according to any one of embodiments 1 to 4, wherein both compounds have a purity of 99% w / w. (Aspect 6) 6. The isolated compound of any one of embodiments 1 to 5, having an aqueous solubility at room temperature of at least 300 mg / mL. Compound 1 was synthesized. (Aspect 7) The isolated compound according to aspect 6, wherein the aqueous solubility at room temperature is in the range of 300 mg / mL to 900 mg / mL. Compound 1. (Aspect 8) 8. The method according to any one of aspects 1 to 7, wherein the crystallinity ranges from 0 to 100%, for example, from 50 to 100%. The isolated compound 1 described above. (Aspect 9) 0.005~0.2s -1 Any of Aspects 1 to 8, having a dynamic aqueous solubility corresponding to a rate constant in the range of 10. The isolated compound 1 according to claim 1. (Aspect 10) X-rays with one or more signals at 21.4, 22.2, 22.8, 23.1, and 23.3 (±0.2 degrees, 2-theta value) 10. Isolated Compound 1 according to any one of embodiments 1 to 9, having a powder diffraction pattern: (Aspect 11) 10.9, 13.1, 14.9, 16.2, 20.1, 24.0, 24.8, 26.1 (±0.2 degrees, 2-theta value) 11. The isolated compound according to any one of embodiments 1 to 10, having an X-ray powder diffraction pattern having Compound 1. (Aspect 12) 12. Isolated compound 1 according to any one of embodiments 1 to 11 for use in medicine. (Aspect 13) 13. A method for producing a compound according to any one of aspects 1 to 12, for use as an active pharmaceutical ingredient in a pharmaceutical product. Isolated compound 1. (Aspect 14) Metabolic diseases, diseases of mitochondrial dysfunction, and diseases related to mitochondrial dysfunction , mitochondrial disorders, mitochondrial energy deficiency, drug-induced mitochondrial side effects for use in the treatment or prevention of cancer, diabetes, traumatic brain injury, acute liver injury, and atrial fibrillation 14. The isolated compound 1 according to any one of embodiments 1 to 13, for use in treating a patient suffering from atopic dermatitis. (Aspect 15) 15. The method according to any one of embodiments 1 to 14, for use in treating or preventing metabolic dysfunction. The isolated compound 1. (Aspect 16) Leigh syndrome, LHON, MELAS, MERRF (myoclonic epilepsy with ragged-red fibers), and For use in the treatment or prevention of other diseases / disorders associated with mitochondrial complex I deficiency 16. The isolated compound 1 according to any one of embodiments 1 to 15. (Aspect 17) 12. The isolated compound according to any one of aspects 1 to 11, for non-pharmaceutical use in humans or animals. Compound 1 was selected. (Aspect 18) 20. The isolated compound according to embodiment 17 for use as a cosmeceutical or nutricosmetic. Compound 1 was selected. (Aspect 19) 12. A cosmeceutical comprising isolated compound 1 according to any one of embodiments 1 to 11. (Aspect 20) 12. Nutricosmetics comprising isolated compound 1 according to any one of embodiments 1 to 11. (Aspect 21) 12. An energy drink comprising isolated compound 1 according to any one of embodiments 1 to 11. (Aspect 22) A pharmaceutical composition comprising isolated compound 1 according to any one of aspects 1 to 16. (Aspect 23) A process for preparing isolated compound 1 according to any one of embodiments 1 to 16, comprising: To provide compound 1, a) N-acetylcysteamine and monomethyl succinate are reacted with a coupling agent to form a A process of reacting in an organic solvent at 0°C to 100°C b) isolating compound 1 The process comprising: (Aspect 24) Its form has an X-ray powder diffraction pattern with signals at 11.2, 16.9 (±0.2 degrees, 2-θ values) Form I. The compound of any one of Embodiments 1 to 16 in the form of a crystalline polymorph. (Aspect 25) 25. A process for the preparation of Compound 1 in the form of its Form I crystalline polymorph according to embodiment 24, comprising the formula The process further comprises a step of crystallizing the compound of formula (I).

Claims

1. Isolated methyl 3-[(2-acetylaminoethylthio)carbonyl]propionate (Compound 1) in solid form, having a purity of at least 80% w / w.

2. 2. The isolated compound 1 of claim 1, having a purity of at least 90% w / w.

3. 2. The isolated compound 1 of claim 1, having a purity of at least 95% w / w.

4. 2. The isolated compound 1 of claim 1, having a purity of at least 97% w / w.

5. 2. The isolated compound 1 of claim 1, having a purity of at least 98% w / w.

6. 2. The isolated compound 1 of claim 1, having a purity of at least 99% w / w.

7. 7. The isolated compound 1 of any one of claims 1 to 6, in free form or in the form of a salt, hydrate, solvate, or complex thereof.

8. 8. The isolated compound 1 of any one of claims 1 to 7, having a melting point or melting range in the range of 35 to 55°C.

9. 9. The isolated compound 1 of any one of claims 1 to 8, which is a crystalline or amorphous product, or a mixture thereof.

10. 10. The isolated compound 1 of any one of claims 1 to 9, having an aqueous solubility at room temperature of at least 300 mg / mL.

11. 11. The isolated compound 1 of claim 10, wherein the aqueous solubility at room temperature is in the range of 300 mg / mL to 900 mg / mL.

12. 12. The isolated compound 1 of any one of claims 1 to 11, having a crystallinity ranging from 0 to 100%.

13. 13. The isolated compound 1 of any one of claims 1 to 12, having a crystallinity ranging from 50 to 100%.

14. 0.005 to 0.2 seconds -1 14. The isolated compound 1 of any one of claims 1 to 13, having a dynamic aqueous solubility corresponding to a rate constant in the range of

15. 15. The isolated compound 1 of any one of claims 1 to 14, having an X-ray powder diffraction pattern with one or more signals at 21.4, 22.2, 22.8, 23.1, and 23.3 (±0.2 degrees, 2-theta value).

16. 16. The isolated compound 1 of any one of claims 1 to 15, having an X-ray powder diffraction pattern with one or more signals at 10.9, 13.1, 14.9, 16.2, 20.1, 24.0, 24.8, 26.1 (±0.2 degrees, 2-theta values).

17. A pharmaceutical composition comprising the isolated compound 1 of any one of claims 1 to 16.

18. 18. A pharmaceutical composition according to claim 17 for use in medicine.

19. 19. The pharmaceutical composition of claim 17 or 18, comprising the isolated compound 1 as an active pharmaceutical ingredient.

20. 20. The pharmaceutical composition of any one of claims 17 to 19 for use in the treatment or prevention of metabolic diseases, diseases of mitochondrial dysfunction, diseases associated with mitochondrial dysfunction, mitochondrial disorders, mitochondrial energy deficiency, drug-induced mitochondrial side effects, cancer, diabetes, traumatic brain injury, acute liver injury, and atrial fibrillation.

21. 20. A pharmaceutical composition according to any one of claims 17 to 19 for use in the treatment or prevention of metabolic dysfunction.

22. 20. The pharmaceutical composition of claim 19 for use in the treatment or prevention of Leigh's syndrome, LHON, MELAS and MERRF (myoclonic epilepsy with ragged-red fibers).

23. Use of isolated compound 1 according to any one of claims 1 to 16 for the manufacture of a composition for non-pharmaceutical use in humans or animals.

24. 17. A cosmeceutical comprising isolated compound 1 according to any one of claims 1 to 16.

25. A nutricosmetics product comprising the isolated compound 1 according to any one of claims 1 to 16.

26. 17. An energy drink comprising the isolated compound 1 of any one of claims 1 to 16.

27. 17. The compound according to any one of claims 1 to 16 in the form of its Form I crystalline polymorph having an X-ray powder diffraction pattern with signals at 11.2, 16.9 (±0.2 degrees, 2-theta values).

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