Succinate prodrug, compositions containing succinate prodrug 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 THEINVENTION 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. Concerning cell-permeable precursors. [Background technology]

[0002] BACKGROUND OF THEINVENTION Mitochondria are the cellular supplier of adenosine triphosphate (ATP), which is used as an energy source. Mitochondria are the eukaryotic organelles that generate the majority of our nutrients. It is 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 cycle function. 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 is a contributing factor in a wide variety of diseases, and mitochondrial or 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 treatment available that can cure pituitary disease.

[0004] The oxidation of nutrients to produce usable chemical energy in the form of ATP is Most of the reactions occur in mitochondria through a series of chemical reactions in the phosphorylation cycle and electron transport chain. The 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 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 Maintenance or restoration of normal mitochondrial function or cellular energy production (ATP) in Given the recognized importance of enhancing the ability of the cellular permeability, intracellular succinate or succinate The ability to liberate precursors, the low toxicity of the compounds and by-products released within the cells, and There is a need for compounds that have physicochemical properties that are compatible with administration to animals or patients. .

[0006] Succinic acid compounds have been prepared as prodrugs of other active agents, see, for example, WO 200 No. 2 / 28345 contains succinic acid bis(2,2-dimethylpropionyloxymethyl) ester, succinic acid 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] In a paper by Murli et al. (Appl. Environ. Microbiol. 71:2005:4503-4509), the bacterium 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)carbamate 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 the treatment of diseases caused by mitochondrial dysfunction or for metabolism There is a need for new effective and safe therapeutic options to enhance metabolism. A new method for stimulating energy in a subject and for acting as an antioxidant. The need for nutritional supplements, nutricosmetics, cosmeceuticals, and cosmetics There are also new treatments, nutritional supplements, nutricosmetics, Cosmeceuticals and cosmetics contain 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 In preferred cases, the active ingredient is one that has high blood-brain barrier permeability and / or low lactic acid production. Bringing you new treatments, nutritional supplements, nutricosmetics, There is a need for cosmeceuticals and cosmetic products. Summary of the Invention

[0012] (Summary of the invention) In a first aspect, the present invention provides an isolated methyl 3-[(2-acetylamino)phenyl]phenylacetamide in solid form. ethylthio)carbonyl]propionate (Compound 1), which may be used in 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] has.

[0014] It has now been surprisingly discovered that the cell-permeable compound 1 possesses a remarkable and advantageous combination of 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 It is stable, reduces lactate production, and restores succinate levels. At the same time, Compound 1: It has a remarkably high solubility in water and aqueous systems. Solubility evaluation indicates a solubility of ~2.1M. The extremely high aqueous solubility of Compound 1 was due to its low melting point ( (less than 55°C) when an aqueous solvent is added, which is miscible with the aqueous solvent. This allows for extremely concentrated aqueous formulations and actually reduces the amount of substrate for metabolism. This allows for high oral administration of the compound that serves as the prodrug.

[0015] In certain embodiments, isolated Compound 1 has a melting point or melting viscosity in the range of about 35° C. to about 55° C. In a preferred embodiment, the isolated compound 1 is a solid product having a range of at least 80% w / w, e.g. at least 85% w / w, at least 90% w / w, e.g. at least Although the purity of the cellulose derivative is generally 95% w / w, it is understood that the cellulose derivative 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 at least 60% w / w, at least 65% w / w, at least 70% w / w, or at least 75% w / w. Depending on the preparation 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, any of Compound 1, including mixtures of two or more forms of Compound 1, is contemplated. is within the scope of this application. Thus, the term "Compound 1" refers to the solid form of formula 1 wherein the compound is in a crystalline form, an amorphous form, a polymorphic form, or the like. The present invention is not limited to the above-mentioned examples, and may be in the form of a solid, a powder, or a mixture thereof.

[0017] In particular, compound 1 has been shown to have several solid forms with different properties. For example, as an amorphous solid or a predominantly amorphous solid, this may result in 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 highly crystalline. The purity can affect the properties of the preparation. In particular, it has a low melting point, close to body temperature, and is affected by the presence of impurities. The stability of preparations of compound 1 was also evaluated for 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 a nutricosmetics composition 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 in the presence of a coupling agent. A process in which the reaction is carried out 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 the present invention, Compound 1, 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] In addition, 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, longer plasma half-life, and Short life, excellent oral bioavailability, reduced toxicity, increased mitochondrial activity For therapeutic, energy-releasing and nutritional supplement and cosmetic uses Improved properties for the preparation of pharmaceutical compositions as well as improved formulations, e.g., due to improved solubility in water. Indicates characteristics.

[0025] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of 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 a liquid, such as an aqueous solution, including, for example, an aqueous phosphate buffered 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 arthritis.

[0029] In one aspect, the present invention provides a process for preparing a pharmaceutical composition comprising Compound 1. provide. [Brief description 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. [Diagram 2] Figure 2. LCMS analysis of compound 1 batch 3 showing total ion counts on a normalized scale versus time using HPLC method 2. [Diagram 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 showing absorbance units (AU) versus time using HPLC method 2. [Diagram 5] Figure 5. LCMS analysis of compound 1 batch 12 showing total ion counts on a normalized scale versus time using HPLC method 2. [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 succinate concentration in plasma versus infusion time (A) and fumarate concentration in tissues (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 concentration in tissue at the end of the infusion (A) and lactate concentration 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] FIG. 10. Treatment of rotenone-injected rats with Compound 1 in the 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. [Diagram 25] Figure 25. XRPD analysis of compound 1 batch 17. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Description of the Invention In a first aspect, the present invention provides an isolated methyl 3-[(2-acetylamino)phenyl]phenylacetamide in solid form. ethylthio)carbonyl]propionate (Compound 1), which may be used in 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] has.

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

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

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

[0036] In certain embodiments, isolated Compound 1 has a melting point or melting viscosity in the range of 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, the melting points are in the range of 39 to 51° C., for example, 39° C., and 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. It has a purity of at least 30% w / w, but it may have a lower purity, for example at least 40% w / w. 0%w / w, at least 45%w / w, at least 50%w / w, at least 55%w / w, at least 60%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 may be in a state where the crystals are ... The compound may include non-crystalline, such as amorphous forms of Compound 1, and mixtures thereof. As can be seen from the examples in the paper, all of the methods used produce 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 in the present specification, 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 may 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 about 900 mg / mL.

[0039] The kinetic solubility has also been determined, with the kinetic solubility 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 100 to 200 nm. It depends on various factors such as the degree of crystallinity, the content of amorphous material, etc.

[0040] Regarding the crystallinity of compound 1, this can be 0% to 100%, for example, 10% to 100%, 20% to 100%. %, 30%-100%, 40%-100%, 50%-100%, 60%-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 were also obtained at 10.9, 13.1, 14.9, 16.2, 20.1, 24.0, 24.8, 26.1, 1 or more. 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 had sigma within these degrees (±0.2 degrees, 2-θ 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 polymorphism ( It is assumed that the crystals of compound 1 are related to form 1). Therefore, the crystals of compound 1 are related to the above signal. One or more of these may be supplemented or otherwise scaled to 11.1 and 16.9 (±0.2 degrees, 2-θ 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. It is advantageous, although less certain, that compound 1 is not in the form of an oil. In the manufacture of pharmaceutical / cosmeceutical compositions, compound 1 is easy to process (e.g., powder). Second, the crystalline form is usually the most stable form. Over time, amorphous (less ordered) materials change morphology to crystalline (more ordered, more elastic). The tendency is to convert the energy of the organism into something that has less energy.

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

[0046] The term "purity" as used herein with respect to Compound 1 refers to the degree to which a 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] in relation to the total amount of precursor 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 the compound 1 used to prepare the composition may be 95% w / w or 50% w / w, respectively. Purity can be measured by a number of methods, including qNMR, HPLC, etc. In qNMR, a known amount of analyte is mixed with a known amount of an internal standard. Dissolve in 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, in addition to 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 the purity (in w / w%). In HPLC, purity is determined by the curve of an 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 "nutrices" 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 the inside out to promote healthy skin, hair, and nails from the inside out.

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

[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 with The term refers to both therapeutic treatment and prophylactic or preventive 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 new discoveries, which have led to the discovery that Compound I has several therapeutic and non-therapeutic uses. It has been shown to have an unexpected and advantageous combination of properties that make it suitable for therapeutic use. Additionally, surprising discoveries have been made surrounding the advantages of certain forms and formulations of Compound I.

[0053] General Uses of the Compounds of the Invention The mesylate or methacrylate copolymers described herein in free form or in the form of salts, hydrates, solvates, or complexes thereof. Thiol 3-[(2-acetylaminoethylthio)carbonyl]propionate (Compound 1) is used in medicine. In particular, in the medical treatment or prevention of a mitochondrial-related disease, condition, or disorder. 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 manufacture of a cosmetic composition. The hydrates, solvates, or complexes are useful in the treatment of conditions where it is desired to enhance or restore energy production (ATP). It can be used in any situation, for example in the medical treatment of a disease. Treatment may be for a metabolic disorder or disease 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 in which the anaplerotic effect or signaling properties of cyclic acid are useful The present invention may be directed to treating or suppressing mitochondrial disorders. Compound 1 has potential applications in stimulating mitochondrial energy production and in treating, for example, sensitization. Neuropathic hearing loss or tinnitus (a side effect of certain antibiotics due to mitochondrial toxicity), Poisoning due to chemicals or gases that affect endorheic 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, anti-diabetic, anti-inflammatory and anti-inflammatory properties in a variety of conditions, including cancer, diabetes, acute starvation, endotoxemia, sepsis, systemic inflammatory response syndrome, and multi-organ 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 treating the condition.

[0054] The compounds of the present invention, Compound 1, are capable of inhibiting cell permeability of components of the Krebs cycle and, optionally, the glycolytic pathway. After entering the cell, it is expected that the β-lactamases will provide functional precursors that can be converted to β-lactamases by enzymatic or chemical hydrolysis. Succinic acid is expected to be liberated by the reaction. Since the released thiol group has reducing properties, This hydrolysis of compound 1 is also considered to be particularly advantageous. Many diseases are thought to be caused by the and has undesirable oxidative stress components that can lead to damage to cellular function. Oxidative stress is thought to play a role in the aging process. Components that can act to scavenge free radicals or reduce oxygen reactive species. The release of is important in both medical, nutricosmetic and cosmetic applications. 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 oxygen reactive species associated with mitochondrial dysfunction. Disorders or diseases having a component of deficiency of succinic acid or succinic acid derivatives and / or energy (ATP) deficiency or diseases associated with a decreased level of functional activity of succinic acid, or anaplerotic anaplasia of succinic acid In the prevention or treatment of diseases in which the drug's agonistic effect or its signaling properties are beneficial. It is possible.

[0056] Enhancement of energy production may be useful, for example, in treating patients suffering from mitochondrial defects, disorders, or diseases. Mitochondrial diseases are caused by a special mitochondrial protein that is present in all cells of the body except red blood cells. This is due to the dysfunction of mitochondria, which are the compartments that are converted into proteins. When this occurs, the energy produced within the cell decreases, resulting in cell injury or death.

[0057] Mitochondrial diseases most often affect the retina, cochlea, brain, heart, liver, skeletal muscles, 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 disorders, 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 By spontaneous mutations that result in a change in the function of a normally occurring protein or RNA molecule Many diseases are due to deficiencies of complexes I, II, III, or IV or, for example, It has been linked to mitochondrial defects, such as enzyme deficiencies, such as deficiency of pyruvate dehydrogenase. 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 alleviate symptoms and reduce the severity of the disease. It 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 effect of the cell-permeable compound 1, a thioester prodrug of succinic acid, on the production of erythrocytes. This is very important as it shows beneficial effects.

[0060] In addition, known succinic acid prodrugs (such as those mentioned in WO 97 / 47584) may be used. In comparison with the above, the isolated compound 1 of the present invention has superior 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 In some cases, the isolated compound of Compound 1 is It is also orally bioavailable, allowing for easier administration.

[0061] Thus, advantageous properties of the isolated compounds of the invention include one or more of the following: One or more of the following may be mentioned: -Increased cell permeability -Enhanced 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 a compound having pharmacological activity, such as a pharmaceutical, in the treatment of cellular energy (ATP) deficiency, 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 / or dysfunction of glucose or complex I-related substance transport. , can be used in the treatment of Complex I disorders.

[0064] The present invention relates to, but is not limited to, Leigh syndrome, Leber's hereditary optic neuropathy (LHON), MELAS (mitochondrial sarcoma 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 The present invention also provides a method for treating a patient suffering from atopic dermatitis, the method comprising administering to the 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. There is also provided the use of a compound of the invention for the manufacture of a medicament for

[0066] Isolated compound 1 may be useful in any condition where additional energy production is potentially beneficial, such as 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. 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 formation 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 produces reduced flavin adenine dinucleotide (FADH2) from fatty acid dinucleotide (FAD). (the tricarboxylic acid cycle, or Krebs cycle), during which NADH and FADH2 are converted to NAD + and FAD This includes oxidative phosphorylation, in which phospholipid is oxidized to .

[0068] The electrons released by the oxidation of NADH are transported through a series of pathways known as the electron transport chain or respiratory chain. The protein complexes (Complex I, Complex II, Complex III, and Complex IV) are inherited. The oxidation of succinate occurs in complex II (succinate dehydrogenase complex), and FAD is converted to succinate dehydrogenase. It is the prosthetic group in the enzyme complex called hydrogenase (complex II). It is embedded in the inner membrane of mitochondria. Complex IV at the end of this chain transfers electrons to oxygen. These electrons are released as they pass through the complex, which reduces them to water. Energy is used to generate a proton gradient across the inner membrane of 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 driven by an 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 is converted into It is completely oxidized to CO2 and H2O by oxidative phosphorylation (the entire process is The complete oxidation of two molecules of pyruvate to carbon dioxide and water is called aerobic respiration. In addition to the two molecules of ATP produced by the conversion of glucose to two molecules of pyruvate, When oxygen is not available, a pyruvate molecule produces 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 powers, directly or indirectly, almost every other biochemical reaction in the cell. Therefore, the additional phosphorylation that occurs during aerobic respiration is a contributing factor. An additional (approximately) 28 or 29 molecules of ATP are crucial for the proper functioning of cells. The lack of oxygen prevents aerobic respiration and ultimately causes 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. The accumulation of lactic acid prevents oxygen from being delivered to muscle cells. It is believed to be the cause of muscle fatigue during periods of intense activity when the body is unable to re-use oxygen. Once available, lactate is converted into protease inhibitors 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 in 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 a tissue, When people have defective mitochondria, symptoms of tissue or organ dysfunction can occur. Any organization may be affected, and the extent to which different organizations are involved may vary widely. symptoms may be present.

[0073] Use of the Compounds of the Invention The compounds of the present invention are useful in any situation in which 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 cerebral function, e.g. or chemically induced mitochondrial dysfunction or succinate levels or Lactic acidosis state associated with decreased functional activity of succinate, anaplerosis of succinate amelioration of diseases in which the drug's blocking effect or signaling properties 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, inter alia, for the treatment of mitochondrial-related diseases, conditions, or disorders. or in preventive medicine, in nutricosmetics or in cosmetics It can be used in the following cases.

[0075] Mitochondrial dysfunction is a risk factor for renal tubular acidosis; motor neuron disease; and other neurological disorders. diseases; epilepsy; genetic diseases; 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-associated disorders or diseases The compound according to the present invention is useful for the prevention or treatment of a mitochondrial-associated disease 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 deficiency, bioenergetic metabolic deficiency, 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 of the respiratory chain) caused by a collapse), 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 deafness, ·MIRAS (Mitochondrial recessive ataxia syndrome), Mitochondrial cytopathy, Mitochondrial DNA depletion, Mitochondrial encephalopathies, including encephalomyopathy and cerebrospinal fluid disorders, mitochondrial myopathy, MNGIE (Muscle Neurogastrointestinal Disorder and Encephalopathy, NARP (Neuropathy, Ataxia, and Retinitis Pigmentosa), Neurodegenerative disorders associated with Parkinson's, Alzheimer's, 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 epilepsy, rheumatoid arthritis, and other disorders / diseases related to complex I deficiency. be.

[0078] Use of the compounds of the invention in cosmetics The compounds according to the invention can be used in cosmetic products for: Improves the 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 distribution to tissues 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 pharma- ceutically 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, For example, but not limited to, this can be parenterally, orally, topically (mucosal, 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 by intravenous infusion. It is also possible.

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

[0084] The formulations may conveniently be presented 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 methods described above. The formulation generally comprises the step of bringing into association the compound (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 together and then, if necessary, shaping the product.

[0085] The compounds of the present invention are typically administered intravenously, orally, or by any parenteral route, and are effective in treating or preventing the onset of symptoms. 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, are all dependent upon the individual. Depending on the route, the composition can be administered in various dosages.

[0086] Pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, 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 selected from the group consisting of hexane, hexane diluent, hexane tetrahydrofuran ...

[0087] For example, the compounds of the present invention may be used as flavoring or coloring agents for immediate, delayed, or controlled release applications. The agent may be included in a tablet, capsule, ovule, elixir, gel, solution, ema They may also be administered orally, bucally, or sublingually in the form of a suspension or infusion.

[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 an aqueous liquid 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 pill. It can also be presented as a post.

[0089] Solutions or suspensions of the compounds of the invention suitable for oral administration may be prepared by mixing 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 is , Phosphatidylcholine, Soybean Fatty Acids, Ethanol, Mono / Diglycerides, Propylene The formulation according to the present invention may also contain glyceryl stearate, ... and ascorbyl palmitate. 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 in an oil-in-water emulsion. The oil may be, for example, soybean oil, safflower oil, or the like. Ligylcerides, such as medium chain triglycerides (MCT oils), such as coconut oil, palm oil, etc. It may be any oil substance, or a combination thereof.

[0090] Tablets may contain pharma- ceutically acceptable excipients, such as fillers, binders, dispersants, disintegrants, lubricants, etc. The composition may contain additives, pH adjusters, stabilizers, flavoring agents, etc. Specific examples include microcrystalline cellulose. Lactose (e.g., lactose monohydrate or anhydrous lactose), sodium citrate calcium carbonate, dibasic calcium phosphate, and glycine, butylated hydroxyl ruene (E321), crospovidone, hypromellose, disintegrants such as starch (preferably (corn, potato, or tapioca starch), sodium starch glycolate , croscarmellose sodium, and certain complex silicates, as well as granulation binders, For example, polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), HPC, macrogol 8000, sucrose, gelatin, and arabic Additionally, magnesium stearate, stearic acid, glyceryl behenate, Lubricating agents such as glycolic acid, ethylhexyl ether, and talc may be included.

[0091] Tablets are made by compression or molding, optionally with one or more pharma- ceutically acceptable excipients. Compressed tablets can be made using, optionally, binders (e.g., povidone, gelatin, hyaluronan, etc.). hydroxypropyl methylcellulose), 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 sugar, surfactant, or dispersing agent. The ingredients can be prepared by compressing in a suitable machine. Molded tablets can be made 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 can be optionally coated or scored, e.g. Hydroxypropyl methylcellulose in various ratios 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. The compounds of the present invention can be used in combination with various sweeteners or flavorings, coloring substances or pigments, emulsifiers and and / or suspending agents, such as water, ethanol, propylene glycol, and glycerin. and combinations thereof.

[0093] Formulations suitable for topical administration in the mouth include flavored bases, 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 as well as 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. 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 the penetration of the drug, emollients in creams or ointments. They 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. More typically, these may form up to about 80% of the composition. By way of example only, a cream or ointment may comprise about 5 to 10 A sufficient amount of hydrophilic material containing 10% by weight of the compound and water is added to form a cream having a desired consistency. The composition is prepared by mixing sufficient quantities of the active ingredient(s) to produce 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 extended periods of time. It may be presented as a separate patch that is intended to remain in place. For example, 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 may 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 solvent may include, but is not limited to, water, alcohol, polyol, glycerin, and vegetable oil. The active ingredient is prepared in a 100% aqueous solution, preferably water, depending on the vehicle and concentration used. It is either colloidal, suspended, or dissolved in the vehicle. In preparing the solutions, the active ingredient can be dissolved in water for injection and then sterilized by, for example, filtration. After sterilization by, suitable vials or ampoules can be filled 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, free The mixture can be frozen by freeze-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 prior to use. can supply iar.

[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 efficiently 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 the compound 1, one or more pharma- ceutically acceptable excipients or pharma- ceutically acceptable carriers. Such pharmaceutical compositions have the same or better bioavailability as conventional eye drops. The present invention provides a method for overcoming intraocular drug delivery barriers and providing improved intraocular bioavailability. Such compositions having a long shelf life 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 the vehicle rather than dissolved. Prepared in substantially the same manner as a solution, except that the addition of the solvent cannot be accomplished by filtration. The active ingredient is sterilized by exposure to ethylene oxide and then suspended in a sterile vehicle. Advantageously, a surfactant or wetting agent can be used to promote uniform distribution of the active ingredient. In order to achieve this, it is included in the composition.

[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. It 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 include flavorings. It should be understood that the formulation may include a medicament. Those skilled in the art will appreciate how to select a suitable formulation. 1. Those skilled in the art will know the methods and procedures for preparing the same (see, for example, Remington's Pharmaceutical Sciences, 1999). (See, for example, John Wiley & Sons, Pharmaceutical Sciences, 18th Edition or later). Those skilled in the art will recognize 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, to obtain the pharmaceutical composition, the process 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 in 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 degree, form, route, and site of administration, as well as the age and condition of the particular subject being treated. 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 determined as frequently as appropriate. If side effects occur, the amount and / or frequency of administration may be adjusted according to normal clinical practice. The amount of the charge can be changed or reduced according to the following:

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

[0108] Nutricosmetic Compositions Comprising the Compounds of the Invention Nutricosmetics are products for oral administration. The present invention contains the compound Compound 1. The nutricosmetic composition also includes a nutricosmetic composition comprising: Compound 1 or a salt thereof in free form, water, together with the orally acceptable diluent or carrier described above. The nutricosmetic composition includes 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 the compounds of the present invention Cosmeceutical compositions are usually administered to the skin or mucosa. Sometimes this is by injection. The present invention also provides a cosmeceutical composition comprising the compound of Compound 1. Cosmeceutical compositions include compositions in free form together with one or more orally acceptable diluents or carriers. The present invention includes Compound 1 in the form of a salt, hydrate, solvate, or complex thereof.

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

[0112] Other Aspects of the Invention The present invention relates to a compound of formula (I) as defined above (e.g. for the treatment of mitochondrial dysfunction). Compound or a pharma- ceutically acceptable form thereof Quinone derivatives, e.g., 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 peptides, elamipretide, and elamipretide analogues Creatine Benzodiazepines PGC-1α modulators AMPK modulators 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 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. This means that.

[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 invention is a compound of formula 1 which is capable of inhibiting the activation of the agonist ... 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 activation of 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 further For drugs that affect the transport or levels of glucose or other complex I-related substrates The present invention provides prevention or treatment of a disease (such as a pulmonary function disorder).

[0115] Drug-induced mitochondrial toxicity may be part of the desired therapeutic effect. In most cases, however, the cause is drug-induced mitochondrial toxicity. The mitochondrial toxicity induced thereby is an undesirable effect. significantly increased glycolysis and reduced 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 by liver disease, diabetes, cancer, and inborn errors of metabolism (e.g. It is associated with systemic disorders such as mitochondrial genetic defects.

[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 may be induced The present invention provides methods that can be used to avoid or reduce the negative mitochondrial effects caused by There is a need to identify or develop new drugs to treat 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 formula 1 for use in the prevention or treatment of allergic side effects, Succinic acid prodrugs inhibit mitochondrial drug-induced activation of complex I or its upstream mitochondrial pathway The present invention relates to 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 The acid prodrug is provided.

[0118] As mentioned above, increased plasma levels of lactate may be associated with the administration of drugs that may have mitochondrial-related side effects. This is often observed in patients treated with metformin (the first-line treatment for type 2 diabetes). is the treatment of choice and is associated with lactic acidosis as a rare side effect) Human endocannabinoids 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 relates to 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 partial inhibition or defects in complex I or its upstream. Since the compound according to the present invention is based on the mitochondrial pathway, it is believed that the compound inhibits the mitochondrial pathway in complex I or its upstream. It is envisaged that the compound 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-transferase to complex I). Action of any drug that limits the supply of ADH, e.g., Krebs cycle, glycolysis, β-oxidation, pyruvate It affects acid metabolism and, in turn, the levels of glucose or other complex I-related substrates. The compound will neutralize the indirect inhibition of complex I, including the effect on drugs that inhibit the By increasing the proton motive force, the deletion of the downstream complexes (complexes III, IV, and V) of complex I is 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, in industrial applications, e.g. in vitro Examples include cell culture, organ preservation, etc. Examples of uses include:

[0121] The compounds according to the 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. In combination with mitochondrial therapy or prevention of side effects associated with lactose intolerance. Treatment or prevention of acid acidosis, e.g. lactic acidosis induced by drug substances Used in.

[0122] The present invention also relates to the use of Compound 1 to inhibit mitochondrial-related side effects, particularly the inhibition 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 to prevent or alleviate 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 related to the 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 deficiency, dysfunction, or impairment of Complex I and / or lactate acetate Drug substances known to have hyphema as a side effect are: Painkillers containing acetaminophen or capsaicin Antianginal drugs, 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, butyl biguanide, troglitazone, and rosiglitazone Antidiabetic drugs, including cyclosporine and pioglitazone Anti-hepatitis B drugs, including fiaruridine Antihistamines Anti-Parkinson's drugs, including tolcapone The antipsychotic risperidone, Antischizophrenia drugs zotepine, clozapine Disinfectants, Quaternary Ammonium Compounds (QACs) Antituberculosis drugs, including isoniazid Fibrates, including clofibrate, ciprofibrate, and simvastatin Hypnotics, including propofol Leflunomide, an immunosuppressant disease-modifying antirheumatic drug (DMARD) 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 abacavir, didanosine, and abacavir NSAIDs, including nimesulfide, 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. Alcohol and cocaine can also produce lactic acidosis.

[0126] Furthermore, the compounds of the present invention also have the potential to prevent lactic acidosis even in the setting of a complex I deficiency. It is envisaged that it may be effective in the treatment or prevention.

[0127] Combination of Drugs and Compounds of the 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 invention with a biological substance, i) the drug substance is used to treat a disease for which the drug substance is indicated, and ii) The compounds of the present invention are effective in preventing or preventing side effects induced or inducible by said drug substance. is used to alleviate, wherein the side effects are caused by lactic acidosis and complex I deficiency, inhibition, or a side effect associated with 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 can 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 which avoid or reduce the side effects described herein. Therefore, it will be understood that the agonist enters the cell and releases succinic acid and possibly other active moieties. 2. Administer the drug to any patient who has or may have the side effects described herein. Potential uses of the compounds of the invention that can be delivered in combination with drug substances are disclosed herein. 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 from those with side effects related to deficiency, inhibition, or dysfunction of complex I and (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. acidosis and side effects related to deficiency, inhibition, or dysfunction of Complex I) Regarding.

[0130] The composition is 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 comprising both a drug substance and a compound of the invention, Compound 1. The composition may be a single composition comprising:

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

[0132] (kit) The present invention relates to i) lactic acidosis and side effects related to deficiency, inhibition, or dysfunction of complex I 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 deficiency, inhibition, or dysfunction of Complex I) A second container containing a compound of the present invention, Compound 1, which may prevent or reduce Also provided is a kit comprising:

[0133] (Methods for treating / preventing side effects) The present invention also relates to lactic acidosis and complex I deficiency, inhibition, or dysfunction. 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 1, as well as a method for treating lactic acidosis. and side effects selected from side effects associated with a defect, 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 The present invention provides a method for predicting drug-induced side effects selected from side effects associated with a defect, inhibition, or dysfunction of the A method for preventing or alleviating the effects of the drug substance, comprising administering an effective amount of a compound of the present invention, 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 improved by decreasing glucose production and increasing glucose uptake in peripheral tissues. This has been attributed to increased splenic circulation and decreased intestinal glucose uptake, but the exact mechanism of action remains unclear. Despite its advantages over other antidiabetic drugs, it is It has been associated with rare cases of lactic acidosis (LA) as a side effect. is defined as an increased vasodilatory rate, an arterial lactate level greater than 5 mM, and a pH ≦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. The 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 The isolated Compound 1 according to any of the preceding embodiments, both having 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. An isolated compound 1 according to any of the preceding embodiments, in free form. 10. An 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. An 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 according to 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 Effects, cancer, diabetes, traumatic brain injury, cardiac arrest, hypoxia, ischemia, stroke, myocardial infarction, acute angina for the treatment of acute hepatitis, acute liver injury, coronary artery blockage, atrial fibrillation, male infertility, and menopausal symptoms in women; The 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, aging Alpers disease (progressive infantile poliodystrophy), Alzheimer's disease, Amyotrophic lateral sclerosis (ALS) Autism, Barth syndrome (fatal infantile cardiomyopathy), β-oxidation deficiency, bioenergetic metabolism deficiency, 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 deafness, MIRAS (Mitochondrial Recessive Ataxia Syndrome), Mitochondrial cytopathy, mitochondrial DNA depletion, Encephalomyopathy and cerebrospinal cord disorders, mitochondrial encephalopathies including mitochondrial myopathy, 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) The isolated compound 1 according to embodiment 17, selected from: 19. The mitochondrial dysfunction disease or the disease associated with mitochondrial dysfunction is Caused by deficiency of fusion I, Leigh syndrome, Leber's hereditary optic neuropathy (LHON), and MELAS (mitochondrial schizophrenia). Myelodysplastic syndrome (MYOS), lactic acidosis, and stroke-like episodes, and MERRF (MYOS ​​with ragged red fibers). The isolated compound 1 according to embodiment 18, wherein the compound is selected from the group consisting of oclonus epilepsy. 20. A method according to any one of embodiments 1 to 17 for use in the treatment or prevention of metabolic dysfunction. The isolated compound 1. 21. The metabolic dysfunction is diabetes (type 2 diabetes), such as a defect in insulin secretion, embodiment 20. 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 (lactamase inhibitor). acidosis), paracetamol / acetaminophen-induced complex I inhibition (liver 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. Chemically induced side effects on mitochondria include rotenone inhibition of complex I (Parkinson et al., 2013). pesticide-induced inhibition of respiratory complexes and mitochondrial enzymes; Chemical warfare agent-induced inhibition of mitochondrial enzymes and of respiratory complexes and mitochondrial enzymes. 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 decrease in the number of mitochondria, resulting in reduced energy production. Dysfunction of mitochondrial transcription factors, and mitochondrial 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 complexes I, II, III, or IV, or Examples include enzyme deficiencies such as pyruvate dehydrogenase deficiency, and Enzymes that can be used to convert methylmalonyl-CoA to carboxylase, methylmalonyl-CoA mutase, and The isolated compound according to embodiment 26, selected from the group consisting of 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, or 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 in the range of 1 mg to 500 mg of Compound 1 or a salt, hydrate, solvate, or complex thereof. Compound 1 isolated by . 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 intended to be a pretreatment, e.g., use before surgery, or a planned procedure involving high metabolic demands. use prior to any prescribed 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 composition according to any one of embodiments 28 to 29 for use as an energy drink or cream. The isolated compound 1. 35. A composition comprising isolated compound 1 according to any of the preceding embodiments. 36. A cosmeceutical comprising an isolated compound 1 according to any of embodiments 1 to 14. 37. Nutricosmetics comprising isolated compound 1 according to any one 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 an isolated compound 1 according to any of embodiments 1 to 33. 40. A process for preparing an isolated compound 1 according to any one of embodiments 1 to 33, comprising: To provide isolated Compound 1, a) N-acetylcysteamine and monomethyl succinate are reacted in the presence of a coupling agent. A process in which the reaction is carried out in an organic solvent at 0°C to 100°C. b) isolating compound 1 : includes, process. 41. Step a) is carried out, and independently, the solvent is dichloromethane, and the coupling The process according to embodiment 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 according to any one of embodiments 40 to 41, comprising extracting the organic layer with another aqueous medium (suitably brine or water). A process by either. 43. The organic layer is removed in vacuo and the residue is dissolved in an organic solvent with suitable solubility properties for crystallization, e.g. For example, the process according to embodiment 42, wherein the carboxylic acid 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 allowed to stand 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 positions (°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 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. A pharmaceutical composition according to any of embodiments 46-53, which is an immediate release formulation. EXAMPLES

[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) were added. 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 min. The reaction mixture was extracted with EtOAc (8×2 L), dried over MgSO4, and the solvent was removed to give intermediate 1. (190 g, 80% yield) was obtained as a pale yellow oil under reduced pressure.

[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 500 mL of 1000 mM NaCl, 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 eluted with CH2Cl2 / MeOH = 100 / 1 to 80 / 1) to give compound 1 (201 g, 94.9% by LCMS). The crude side cut from the purification (110 g) was purified by silica gel column chromatography. The product was purified 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 g, 0.1 mol) and NaHCO3 (5.88 g, 0.07 mol) in water (200 mL) at room temperature. The mixture was The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was extracted with EtOAc (8×200 mL), dried over MgSO4 (1 h). After that, the solvent was removed in vacuum 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 h. 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, 3x150 mL) and a saturated solution of NaHCO3 (3x150 mL) and concentrated over Na2SO4 After drying (1 h), the solvent was then removed in vacuum 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 (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 min. The layers were separated. The aqueous phase was diluted with dichloromethane. The organic phases were combined and extracted with ethanol (2 x 15 L) and the internal temperature was adjusted to +28 ± 2°C during the extraction. was removed in vacuum. Intermediate 1 was then dried under vacuum at +40° C. for 18 hours. Yield 996 g 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 portions. During the addition, vigorous 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% NH4Cl aqueous solution (10 L) was added and The mixture was stirred for 20 min. The layers were separated. The organic phase was then washed with 13% NaCl aqueous solution and water (solubility The mixture was extracted with 10 L and 5 L, respectively. The solvent (DCM) was then exchanged for 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 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. Since the amorphous form is believed to have a lower melting point than the crystalline form (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 the TGA analysis, batch 3 had a loss of 0.04% by weight at temperatures 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 the 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 mass spectrometry 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 solubilities of all the batches of compounds prepared were at least 366-398 mg / ml. and such preparations appear as clear, transparent or translucent solutions in water. This shows that: Table 5. Summary of results from analysis of different batches of compound 1. [Table 2] TIFF2025004155000007.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, followed by 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 min) 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 ~500mg of compound into a vial and add ~500μl of 100mM PBS pH 7.4 The vials were then sonicated for 10 minutes and then shaken for 20 minutes. The samples were then removed and The solution was diluted 1 / 2000 and the concentration was calculated by HPLC analysis. Table 8. Preparation of Compound 1 formulation in PBS 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 obtained. 100 mM PBS pH 7.4 (20% v / v) was added and the solution was mixed on a shaker for 20 min. After this, the solution was cooled to room temperature and remained translucent. The solution was then stored at 4°C for 7 It was left for 2 hours. Observation after this time 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 around 47-50 °C in batches. When an aqueous solution is added to a solid, it disrupts the intramolecular interactions of the compound. and becomes miscible with water.

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

[0164] (Experiment details) 1 HydroGel Gel Pack (Clear H20 Hydrogel, 8 oz. Pouch, HydroGel, Portland , ME) and distributed into Falcon tubes for various experiments.

[0165] First, blue food coloring was used to determine 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 50 mL of 10 ... is much more efficient when the dye is melted. 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 that compound 1 was uniformly distributed. I checked.

[0171] (Sampling procedure) 1. Gel sample (100 mg) was added to an Eppendorf 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 (13000 rpm, 10 min) 4. The supernatant was collected for HPLC analysis. Table 10. Measured concentrations of Compound 1 in gel samples [Table 7]

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

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

[0174] (Stability of gel formulations) 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, especially 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. Inaccuracies in weighing out samples and possibly differences in localized concentrations of Compound 1 in the gel For , it has more error.

[0176] (Protocol for preparation of gel formulations) Prepare a 100x concentrated aqueous solution of compound 1 and add it to the gel in 1 / 100th the volume of the gel. The example given is for a final concentration of 2.25 mg / ml in a 200 ml gel pack. Therefore, you will need 2 ml of 100x Compound 1 (225 mg / ml) in water. It is also suggested to add 100 mg of 10 ... (Provided that this does not have any detrimental effect). This allows the compound 1 solution to be distributed uniformly throughout the gel. If food coloring is included, add 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 confirms that the concentration is 225mg / ml), sonicated for 20 minutes, and then After that, shake for 30 minutes (the solution may remain a little cloudy). Add 1 ml of natural food coloring. (The food coloring helps to show that even 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 stock. 7. Using tape, reclose the gel pack over the injection site. 8. Shake the gel pack vigorously for 5 minutes to obtain a uniform distribution of Compound 1 (contains food dye). If so, it is evident when the injected solution is uniformly distributed by a color change in the gel. (It will be something like that.) 9. Allow the gel to set, this takes approximately 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 at 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 in water by HPLC analysis. This has been shown to be achieved in tocque and gel formulations. Table 13. Compound 1 concentrations in water stock solutions and gel formulations [Table 10]

[0178] 2 ml of the water stock was added to 1 ml of food dye, which was then diluted and analyzed by HPLC. The AUC of the water stock diluted with food coloring was 0.63 times that of the water stock before dilution. This demonstrated 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 compound is 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 mixture was left for 10 minutes until it was completely dissolved. The mixture was sonicated for 1 h. 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) cycles. [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 it was completely dissolved. The mixture was sonicated for 1 min. 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). ), thus indicating 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 in various amounts to batch 11 of compound 1, followed by ultrasonication for 10 min. The processed sample remained slightly hazy. 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 compound is 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 can reach over 500 mg / ml in saline.

[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 a 40-day period. The cultures were then stored at RT, 37°C, and 65°C. Table 16. Compound 1 in water at RT in the dark (concentration 1 mg / ml) 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 at 37°C in the dark (concentration 1 mg / ml) 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 in water at 65°C in the dark (concentration 1 mg / ml) with purity determination [Table 15]

[0194] Loss of purity and assay is observed for Compound 1 in water over a 29 day period. The losses in the assay are significantly greater than those 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 incubation of compound in DMSO at 37°C for 37 days. 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 incubation of compound in DMSO at 65°C for 29 days. 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 FIG. This indicates a crystalline material.

[0198] Material from Method A (Batch 12) was also analyzed by XRPD and showed crystalline material with the same polymorphism. This appeared to be the case (Figure 11).

[0199] Example 8 - Comparison of the 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 at 350 mg / mL in water, 190 mg / mL in PBS (pH 7.4), and 0.9 mg / mL in PBS (pH 7.4). % saline solubility, 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 See Table 21 for example data. Table 21: Solubility of exemplary succinic acid prodrugs [Table 18]

[0200] Example 9 - Comparison of Bioavailability of Compound 1 with Other Succinic Acid Prodrugs The cell permeability and oral bioavailability of compound 1 were evaluated in standard Caco-2 mice. The ioavailability was tested using an in vitro assay (briefly, 24-well C orning Confluent Caco-2 cells in Costar Transwell format (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 filled with 0.15 mL of hamster endothelial cell suspension (IVT, Baltimore, Md., USA). Basal balanced buffer solution (HBBS) pH 7.4, 1% DMSO, 0.1 mM Lucifer Yellow. The chamber contained 0.6 mL HBBS pH 7.4, 1% DMSO. Controls and test articles were placed in a humidified The mixture was incubated in a 37°C incubator with shaking at 130 rpm for 1 hour. Lucifer Yellow W permeates 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 permeation) and acebutalol (weakened 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 to the basal chamber. Compounds in the apical or basal chambers were analyzed by HPLC-MS. The apparent solubility of the succinic acid prodrugs compared to other succinic acid prodrugs, including those from WO2015 / 155231, is The data are presented in Table 22 below, which shows the permeability from the apical side to the Compound 1 showed the highest basolateral to basolateral migration, indicating that it has cell permeability and This shows improved ioavailability, which was confirmed by in vivo pharmacokinetic studies. In this study, compound 1 also had high oral bioavailability and was more potent than the 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] TIFF2025004155000025.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, whereas batch 3 is considered to be the more amorphous batch. The method used is discussed in this document. PBS is The aqueous solutions were prepared using NaCl (8 g / L), KCl (0.2 g / L), anhydrous disodium dihydrogen 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 and 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 the more crystalline Compound 1, Compound 1 Batch 2, was diluted with HPLC grade water to a final concentration of 30 mg / mL. (Fisher), sonicated for 10 minutes, 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 the more crystalline Compound 1, Compound 1 Batch 2, was diluted with HPLC grade water to a final concentration of 52 mg / mL. (Fisher), sonicated for 20 minutes, 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 presented data - the more amorphous the material, the more crystalline the material. It has a much higher dynamic solubility than the material.

[0206] The more crystalline sample of Compound 1 Batch 2 was diluted with HPLC grade water (Fisher) to a final concentration of 2000 mg / mL. ), sonicated for 20 minutes, then shaken for 1.5 hours. Centrifugation was performed to remove solid material. After removal, analysis revealed that it had reached a concentration of 850 mg / mL. 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 Water (Fisher Scientific) and "non-purified" tap water were prepared and stored at room temperature for up to 10 days. The concentration and purity of Compound 1 was monitored over time by HPLC in comparison 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 compound 1 peak vs. impurities). Data presented are the average of two samples. Table 23: Compound 1 batch 3 dissolved at 1 mg / ml in tap water 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 was observed in samples that were dissolved in (non-purified) tap water after being purified with (purified) HPLC grade water (F Similar data were not observed for samples dissolved in 100% ethanol (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), Sodium Dihydrogen Phosphate Anhydrous thorium (0.048% w / v), anhydrous disodium dihydrogen phosphate (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 min. 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 is 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 prepared vehicle. 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 min) 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 reduced 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 administered increasing 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-min intervals and plasma was separated by centrifugation. The samples were frozen and then analyzed using a Thermo Vanquish UPLC + Thermo Quantis triple-pole MS instrument and a guard frame. 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 A = 0.1% formic acid, B = acetonitrile. [13C]- Labeled succinic acid was used as an internal standard.

[0213] Plasma succinate concentrations increased proportionally with time of Compound 1 infusion (Figure 7A), indicating that succinate from Compound 1 At the end of the study, the release of succinic acid, the primary metabolite of succinic acid in the TCA cycle, was observed. Fumaric acid, which is a stimulant for the production of stimulants, has high metabolic activity in the vehicle animals, especially in the retina, brain, and heart. The IL-10 expression was greater in tissues from animals administered Compound 1 than in tissues from animals administered Compound 1. Therefore, this data Compound 1 provides metabolizable succinic acid to these tissues and has the ability to cross the blood-brain barrier. This suggests that

[0214] Combined blood lactate data from the three animals were expressed as a percentage of the initial value and were taken at 1 h after sampling. The results were plotted as a function of cumulative dose at the time of collection (FIG. 7C).

[0215] Lactic acid decreased after intravenous injection of Compound 1 compared to the initial value, indicating that Compound 1 is a 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 glucose production 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 an intravenous catheter was inserted for the co-infusion of rotenone and Compound 1 or vehicle (PBS). Rotenone (7.1 mg / h) was infused for 1.5 h. Compound 1 was administered at 2 mg / kg for 2.5 h. The animals were infused with PBS at a constant rate of 1000 mg / min. Blood samples were taken at 30 min intervals. The plasma was separated by centrifugation. Microdialysates were collected and analyzed for lactate using an ISCUS instrument (MDialysis). At the end of the study, animals were euthanized and terminal blood and organ samples were collected. Plasma and tissue samples were frozen and stored. The samples were then stored and analyzed using a Thermo Vanquish UPLC + Thermo Quantis triple quadrupole MS instrument. An 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, B=acetonitrile. [13C ]-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 baseline values.

[0218] Rotenone infusion reduced tissue concentrations of succinate to subquantitative levels (<2 μM) and Compound 1 administration increased the availability of succinate, which offset the decrease in electron transport from the body. The tissue succinate concentration was restored to detectable levels, indicating that compound 1 provided succinate. These results suggest that the increase in succinate utilization is greater than that caused by inhibition of complex 1. 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-concentration 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 a genetic deletion of the chromosome 111 gene (sciences. 107, 24(2010), 10996-11001) were incubated 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 the administration of 100 mg / kg ... During the study, the treatment increased body weight gain (p<0.05) and survival rate (p=0.0697). The therapeutic effect of succinic acid supplementation in the form of compound 1 was evaluated in mitochondria with characteristics of Leigh syndrome. These results suggest that apoptosis can 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 concentrations See Figure 10.

[0222] Rotenone-induced Parkinson's disease model in rats (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 (six animals per group) were treated with an intraperitoneal injection of rotenone (0.25–0.75 mg / kg). 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 cylinders (height = 30 cm; diameter = 18 cm). Rearing was measured by placing the subject in a 5-minute bath. The legs are raised above shoulder height and either one or both front legs are in contact with the wall of the tube. should be done.

[0224] Postural instability was measured using P-120 sandpaper marked with lines and numbers every centimeter. Measurements were taken on a table covered with a cloth (see below). The animal was placed at an approximately 90° angle 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 was then held firmly in place. The center of gravity of the animal was then moved forward on one of its forelimbs, which was on the ground, and the animal was then held in its forelimb position for 2 This induced Ayumu to "catch up" and regained his balance. The distance required to induce a catch-up step of the unaffected forelimb was recorded. Blood lactate (FIG. 10C) was analyzed using VetScan iSTAT- 1 Measured using an Analyser.

[0225] Rotenone treatment resulted in a decrease in rearing activity. Compound 1 in drinking water (0.75 mg / mL) Administration of 100 mg / kg / day 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. The present study is aimed at preventing motor dysfunction caused by mitochondrial complex 1 dysfunction. This suggests that the overall picture can be improved.

[0226] Blood lactate concentrations were significantly increased in animals treated with rotenone. There was a tendency for blood lactate concentration to decrease from compound 1 at a concentration of 0.5 mg / mL to a higher concentration (0.75 mg / mL). The data indicate that succinic acid provided by compound 1 can be effectively administered intermittently in drinking water. When administered orally, it promoted metabolic compensation at the level of glycolysis and conversion of pyruvate to lactate. These results suggest that exchange 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, ×200). This mixture was then diluted with K2HPO4 (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 The microsomes were diluted in 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 1:1 with 100 mM ethanol. A 20 mM NADPH stock was also prepared in microsome buffer (20 mM Microsome stock (Sekisui XenoTech, 0.625mg / ml) was prepared in 7ml buffer. 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), and 100 μL MeOH. T=0 samples were quenched by addition of 10 μL NADPH stock (2 mM final concentration). The reaction was started at all time points by addition of 100 μL MeOH. The reaction was stopped by shaking the samples for 1 min, placing them on ice for 10 min, and then centrifuging them at 3000 rpm for 10 min. 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 samples were dissolved in room temperature water for injection (WFI) (1 mg / ml) containing 100 mL of ... The samples were taken 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 - Carbonic acid instability Compound 1 batch 14 (2-3 mg) was diluted with 100% ethanol from 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 be dissolved 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 460mg / ml 01-354 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 plates were analyzed in real time for 3 minutes using a Microplate Spectrophotometer (BioTek). The rate constants of the solution were calculated from exponential decay fits 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 receiver slit of 2.95°C Measurement: Scan range 2~45℃ 2θ, 1s / step, 0.005℃ / 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 following list details the peaks returned after XRPD for several crystal batches: The underlined peaks are common to most batches. Those with asterisks may be peaks shared or unique depending on the polymorphic form. Peak list NV354-s3-batch3 [Table 27] TIFF2025004155000034.tif152170 Peak List NV354-s12-Batch 18 [Table 28] Peak list NV354-s13-batch 13 [Table 29] TIFF2025004155000037.tif235170 Peak List NV354-s14-Batch 14 [Table 30] TIFF2025004155000039.tif54170 Peak List NV354-s15-Batch 19 [Table 31] Peak list NV354-s16-batch 16 [Table 32] TIFF2025004155000042.tif136170 Peak List NV354-s17-Batch 17 [Table 33] TIFF2025004155000044.tif187170

Claims

1. Methyl 3-[(2-acetylaminoethylthio)carbonyl]propionate isolated in solid form nate (Compound 1).

2. 2. The compound according to claim 1, in free form or in the form of a salt, hydrate, solvate or complex thereof. Isolated Compound 1.

3. 2. The isolated compound 1 of claim 1, having a melting point or melting range in the range of 35 to 55°C.

4. Any of claims 1 to 3, which is a crystalline or amorphous product or a mixture thereof.

1. Isolated compound 1 according to claim 1.

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 The isolated compound 1 according to any one of claims 1 to 4, wherein both have a purity of 99% w / w.

6. The single compound according to any one of claims 1 to 5, having a water solubility at room temperature of at least 300 mg / mL. Isolated compound 1.

7. The isolated compound according to claim 6, wherein the aqueous solubility at room temperature is in the range of 300 mg / mL to 900 mg / mL. Compound 1.

8. Any one of claims 1 to 7 having a crystallinity ranging from 0 to 100%, for example from 50 to 100%. The isolated compound 1 described herein.

9. 0.005 to 0.2 s -1 Any of claims 1 to 8 has a dynamic water solubility corresponding to a rate constant in the range of 2. The isolated compound 1 according to claim 1.

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. The isolated compound 1 according to any one of claims 1 to 9, having a powder diffraction pattern.

11. 10.9, 13.1, 14.9, 16.2, 20.1, 24.0, 24.8, 26.1 (±0.2 degrees, 2-θ value) with 1 or more signals The isolated compound according to any one of claims 1 to 10, having an X-ray powder diffraction pattern having Compound 1.

12. 12. The isolated compound 1 according to any one of claims 1 to 11 for use in medicine.

13. A composition according to any one of claims 1 to 12 for use as an active pharmaceutical ingredient in a pharmaceutical product. Isolated Compound 1.

14. Metabolic diseases, diseases of mitochondrial dysfunction, diseases associated with mitochondrial dysfunction , mitochondrial disorder, 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 The isolated compound 1 according to any one of claims 1 to 13 for use in treating a patient suffering from atopic dermatitis.

15. A compound according to any one of claims 1 to 14 for use in the treatment or prevention of metabolic dysfunction. The isolated compound 1 described above.

16. Leigh syndrome, LHON, MELAS, MERRF (myoclonic epilepsy with ragged red fibers), and For use in the treatment or prevention of other diseases / diseases associated with mitochondrial complex I deficiency The isolated compound 1 according to any one of claims 1 to 15.

17. The isolated compound according to any one of claims 1 to 11 for non-medicinal use in humans or animals. Compound 1 was synthesized.

18. The isolated composition according to claim 17 for use as a cosmeceutical or nutricosmetic. Compound 1 was synthesized.

19. A cosmeceutical comprising the isolated compound 1 according to any one of claims 1 to 11.

20. Nutricosmetics comprising the isolated compound 1 according to any one of claims 1 to 11. 。

21. 12. An energy drink comprising the isolated compound 1 according to any one of claims 1 to 11.

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

23. A process for preparing the isolated compound 1 according to any one of claims 1 to 16, comprising the steps of: To provide isolated Compound 1, a) N-acetylcysteamine and monomethyl succinate are reacted in the presence of a coupling agent. A process in which the reaction is carried out in an organic solvent at 0°C to 100°C. b) isolating compound 1 The process comprising:

24. Its form has an X-ray powder diffraction pattern with signals at 11.2, 16.9 (±0.2 degrees, 2-θ values).

17. The compound according to any one of claims 1 to 16 in the form of the Form I crystalline polymorph.

25. 25. A process for the preparation of Compound 1 in the form of its Form I crystalline polymorph according to claim 24, comprising: The process further comprising the step of crystallizing the compound of formula (I).

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