Nucleic acid precursor

Abstract

The present invention provides a compound for treating or preventing reduced intracellular ATP levels.　The present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical composition that contains the compound or the pharmaceutically acceptable salt or solvate thereof. [In the formula, X and Y are the same or different and are each selected from among substituent group A, which is groups represented by formula 1: -O-R1 (in the formula, R1 is selected from among hydrogen, C1–8 alkyl groups, C1–3 alkyl aryl groups, CH3OCH2-, CH3OCH2CH2-, ester groups, phenyl groups, pyridyl groups, benzyl groups, indolyl groups, and naphthyl groups, and any aromatic rings or heterocyclic rings may be substituted with one to three functional groups) when the atom connected to the phosphorus atom is O, or substituent group B, which is groups represented by formula 2: -R2-R3 (in the formula, R2 is a residue generally described as an amino carboxylic acid, and R3 is a substituent bonded to the carboxylic acid portion of the amino carboxylic acid of R2) when the atom connected to the phosphorus atom is N.]

Description

nucleic acid precursor

[0001] This patent application claims priority under the Paris Convention to and the benefit of Japanese Patent Application No. 2022-128175 (filed August 10, 2022), the entire contents of which are incorporated herein by reference.

[0002] The present invention generally relates to nucleic acid precursors and pharmaceutical compositions containing the same, and specifically to prodrug-formed ATP and pharmaceutical compositions containing the same.

[0003] All living organisms, from single-celled organisms to humans, survive by performing metabolism within their cells. The energy source for this metabolism is adenosine triphosphate (ATP), and all living organisms commonly use ATP as the intracellular energy currency. Recently, in addition to its role as an intracellular energy currency, ATP has been attracting attention for its ability to dissolve proteins at high concentrations within cells and to dissolve intracellular droplets (Non-Patent Document 1).

[0004] ATP is sometimes administered intravenously as a medicine for pulmonary hypertension, blood pressure during anesthesia and surgery, lung cancer, multiple organ failure, weight loss associated with cancer, acute renal failure, cystic fibrosis, ischemia, and cardiac stress testing. ATP deficiency is one of the main causes of delayed healing of chronic diabetic wounds (Non-Patent Document 2). Aging leads to a decline in cellular energy metabolism, leading to aging, a decline in physical function. It has been reported that the decline in energy metabolism and intracellular ATP levels are correlated with aging. In other words, the amount of intracellular ATP decreases with age, and the resulting decline in cellular stress resistance leads to various age-related diseases.

[0005] Adenosine derivatives such as ATP have a half-life of about 10 seconds in the blood, making them extremely unstable in the blood, and their administration is inefficient. Furthermore, because ATP has a negative charge, it is not permeable to cell membranes and hardly enters cells when applied extracellularly.

[0006] A. Patel et al., Science, 356, 753-756 (2017)J. Drug Targeting, 2015, 23, 580-596

[0007] ATP alone has low cell membrane permeability, and even when added to cells, it has almost no effect as ATP. Therefore, currently, ATP delivery methods have been reported in which ATP is encapsulated in lipid bilayer membranes (liposomes) or nanoparticles and introduced into cells. However, the effect is limited and does not reach the level where ATP can be used as a medicine, and there is currently little data to suggest that intracellular ATP concentrations can be increased.

[0008] Under these circumstances, we have conducted extensive research to increase intracellular ATP levels. In the present invention, we have discovered that prodrugs of ATP, such as phosphoramidate-modified AMP (ATP prodrugs), are highly hydrophobic and therefore can penetrate cell membranes, unlike ATP, which cannot. We have discovered that these compounds are prodrugs that are converted from AMP to ATP through intracellular metabolism, thereby increasing intracellular ATP levels, leading to the completion of this invention.

[0009] Therefore, the present invention includes the following aspects: <Compound> [1] Formula (I): [In the formula, X and Y are the same or different and are each a substituent selected from Substituent Group A shown below, Substituent Group B shown below, and Substituent Group C shown below, provided that neither X nor Y is a substituent selected from Substituent Group A. Substituent group A: When the atom connected to the phosphorus atom is O, the group represented by formula 1: -O-R1 (wherein R1 is selected from hydrogen, a C1-C8 alkyl group, a C1-C3 alkylaryl group, CHOCH-, CHOCHCH-, an ester group, a phenyl group, a pyridyl group, a benzyl group, an indolyl group, and a naphthyl group, and these aromatic rings or heterocyclic rings are optionally substituted with 1 to 3 of the following functional groups: halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, C1-C6 halogenated alkoxy, phenyl, hydroxyC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, carboxyC e -C ealkyl, hydroxy group, amino group, cyano group, nitro group, trimethylsilyl group); Substituent group B: when the atom connected to the phosphorus atom is N, a group represented by formula 2: -R2-R3 (wherein R2 is a residue collectively known as aminocarboxylic acid, preferably an amino acid residue, more preferably an L-amino acid residue, and even more preferably an amino acid residue selected from alanine, glycine, isoleucine, leucine, proline, methionine, phenylglycine, phenylalanine, valine, and asparagine, R3 is a substituent bonded to the carboxylic acid moiety of the aminocarboxylic acid in R2, and is preferably a linear C1-C6 alkyl group or a branched or cyclic C3-C6 alkyl group, and is preferably, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a sec-pentyl group, a tert-pentyl group, a neopentyl group, a 1-methylpentyl group, an n-hexyl group, an isohexyl group, a sec-hexyl group, a tert-hexyl group, a neohexyl group, etc.; a C4-C8 cycloalkyl group optionally substituted with a C1-C8 alkyl group; a tetrahydropyranyl group; a benzyl group optionally substituted with a halogen, a C1-C8 alkyl group, or a C1-C6 alkoxy group; a 2-phenylethyl group optionally substituted with a halogenated phenyl group; or an indole group). Substituent group C: When the atom connected to the phosphorus atom is N, it may be a heterocycle, such as a C3-C5 heterocycle, a morpholino ring, a piperazine ring, a thiomorpholine ring, or a ring represented by formula 3: (wherein R4 is hydrogen, a C1-C8 alkyl group optionally substituted with a C3-C6 cycloalkyl group; a C4-C8 cycloalkyl group; a tetrahydropyranyl group; a benzyl group optionally substituted with a halogen, a C1-C8 alkyl group, or a C1-C6 alkylalkoxy group; a 2-phenylethyl group optionally substituted with a halogenated phenyl group, or an indole group), or a pharmaceutically acceptable salt or solvate thereof.

[0010] [2] The compound according to [1], or a pharmaceutically acceptable salt or solvate thereof, wherein Substituent Group A is a phenyl group optionally substituted by halogen, a C1-C8 alkyl group, or a C1-C6 alkoxy group. [3] The compound according to [1], or a pharmaceutically acceptable salt or solvate thereof, wherein Substituent Group B is a group represented by Formula 2: -R2-R3 (wherein R2 is an amino acid residue selected from alanine, glycine, isoleucine, leucine, proline, methionine, phenylglycine, phenylalanine, valine, and asparagine). [4] The compound according to [1], wherein Substituent group B is a group represented by formula 2: -R2-R3 (wherein R3 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, 1-methylpentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, and neohexyl), or a pharmaceutically acceptable salt or solvate thereof. [5] The compound according to [1], wherein Substituent group B is a group represented by formula 2: -R2-R3 (wherein R3 is a linear or branched C4-C6 alkyl group), or a pharmaceutically acceptable salt or solvate thereof. [6] The compound according to formula (II) or Formula (III): The compound according to [1], or a pharmaceutically acceptable salt or solvate thereof,

[0011] <Pharmaceutical Compositions> [7] A pharmaceutical composition comprising the compound according to any one of [1] to [6], or a pharmaceutically acceptable salt or solvate thereof. [8] The pharmaceutical composition according to [7], for treating or preventing a state of reduced intracellular ATP levels. [9] The pharmaceutical composition according to [8], wherein the state of reduced intracellular ATP levels is associated with aging, non-alcoholic fatty liver disease and / or hepatitis.

[10] The pharmaceutical composition according to [8], wherein the state of reduced intracellular ATP levels is associated with mitochondrial disease, hypoxic conditions due to cancer or insufficient blood flow, or areas of tissue regeneration accompanied by inflammation.

[11] The pharmaceutical composition according to [8], wherein the state of reduced intracellular ATP levels is a neurodegenerative disease.

[12] The pharmaceutical composition according to

[11] , wherein the neurodegenerative disease is selected from Parkinson's disease, Alzheimer's disease, and ALS.

[0012] The phosphoramidate-modified AMP of the present invention is highly hydrophobic and therefore can permeate cell membranes. This compound exerts its effect by being converted from AMP to ATP through intracellular metabolism, thereby increasing the intracellular ATP concentration.

[0013] FIG. 1 is a chart of the NMR spectrum (400 MHz, 400 MHz) of (S)-2-ethylbutyl 2-(((S)-(((2R,3S4R,5R)-5-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3.4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate prepared in Example 1-1. 1 1 H NMR, MeOD). FIG. 2 is a chart of the NMR spectrum of the phosphoramidate-modified AMP (ATP prodrug) prepared in Example 1 (400 MHz, 1 1H NMR, MeOD). FIG. 3 is a chart of the FAB MS spectrum of the ATP prodrug. FIG. 4 is a chart of the NMR spectrum (400 MHz, 1 1 H NMR, MeOD). Figure 5 is a graph showing the effect of ATP prodrugs on intracellular ATP concentration. In the figure, "proATP" means ATP prodrug.

[0014] Figure 6 is a graph showing the effects of adenosine, AMP, ATP, and ATP prodrugs on intracellular ATP concentrations. In the graph, "proATP" refers to the ATP prodrug. Figure 7 is a graph showing the effect of an ATP prodrug on intracellular ATP concentrations in normal cells. In the graph, "proATP" refers to the ATP prodrug. Figure 8 is a graph showing the effect of an ATP prodrug on increasing ATP levels in senescent cells and the effect on stress load. Figure 8(A) is a graph showing the effect of an ATP prodrug on young and senescent cells, and Figure 8(B) is a graph showing the effect of an ATP prodrug on oxidative stress load in senescent cells. The vertical axis of Figure 8(B) represents the percentage of cell counts, with the number of cells in the absence of both hydrogen peroxide and proATP being 100%. In the graph, "proATP" refers to the ATP prodrug. Figure 9 is a graph showing the cytotoxicity of an ATP prodrug using LDH release as an indicator. In the graph, "proATP" refers to the ATP prodrug. Figure 10 is a graph showing the effect of an ATP prodrug on intracellular ATP levels in two types of liver cell lines (established cells and primary cells). In the figure, "proATP" means an ATP prodrug.

[0015] Figure 11 is a graph showing the effect of an AMPK inhibitor on the amount of intracellular ATP induced by an ATP prodrug. In the figure, "proATP" refers to an ATP prodrug. Figure 12 is a graph showing the lifespan extension effect of an ATP prodrug on nematodes. In the figure, "proATP" refers to an ATP prodrug. Figure 13 is a graph showing the change in the amount of ATP induced by an ATP prodrug on nematodes. In the figure, "proATP" refers to an ATP prodrug. Figure 14 is a graph showing the effect of an ATP prodrug-neo on the intracellular ATP concentration. Figure 15 is a graph showing the lifespan extension effect of an ATP prodrug-neo on nematodes. In the figure, "proATP-neo" refers to an ATP prodrug-neo.

[0016] He invented a precursor to adenosine triphosphate (ATP), which is known as the intracellular energy currency of all living organisms. This compound does not have ATP activity outside the cell, but once it penetrates the cell membrane and enters the cell, it is converted into ATP through enzymatic reactions and hydrolysis, thereby functioning as the energy currency.

[0017] <Compound> In one aspect, the present invention provides a compound represented by formula (I): [In the formula, X and Y are the same or different and are each a substituent selected from Substituent Group A shown below, Substituent Group B shown below, and Substituent Group C shown below, provided that neither X nor Y is a substituent selected from Substituent Group A. Substituent group A: When the atom connected to the phosphorus atom is O, the group represented by formula 1: -O-R1 (wherein R1 is selected from hydrogen, a C1-C8 alkyl group, a C1-C3 alkylaryl group, CHOCH-, CHOCHCH-, an ester group, a phenyl group, a pyridyl group, a benzyl group, an indolyl group, and a naphthyl group, and these aromatic rings or heterocyclic rings are optionally substituted with 1 to 3 of the following functional groups: halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, C1-C6 halogenated alkoxy, phenyl, hydroxyC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, carboxyC e -C ealkyl, hydroxy group, amino group, cyano group, nitro group, trimethylsilyl group); Substituent group B: when the atom connected to the phosphorus atom is N, a group represented by formula 2: -R2-R3 (wherein R2 is a residue collectively known as aminocarboxylic acid, preferably an amino acid residue. This is preferred from the viewpoint of cytotoxicity after hydrolysis. Furthermore, from the viewpoint of metabolic efficiency, it is particularly preferred that it is an L-form. More preferably, from the viewpoint of hydrolysis, it is an amino acid residue selected from alanine, glycine, isoleucine, leucine, proline, methionine, phenylglycine, phenylalanine, valine, and asparagine, R3 is a substituent bonded to the carboxylic acid moiety of the aminocarboxylic acid in R2, and is preferably a linear C1-C6 alkyl group or a branched or cyclic C3-C6 alkyl group from the viewpoint of membrane permeability of the drug, and is preferably, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a sec-pentyl group, a tert-pentyl group, a neopentyl group, a 1-methylpentyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-pentyl group, a neopentyl group, a 1-methylpentyl group, an ethyl group, an n-butyl group, an isopentyl group, a sec-pentyl group, a tert-pentyl group, a neopentyl group, a 1-methylpentyl group, an ethyl group, an ethyl group, an isopentyl group, a sec-pentyl group, a tert-pentyl group, a neopentyl group, a 1-methylpentyl group, an ethyl group, an ethyl group, an isopentyl group, a sec-pentyl group, a tert-pentyl group, a neopentyl group, a 1-methylpentyl group, an ethyl group, an isopentyl group, a tert-pentyl group, a methyl group, an ethyl group, an isopentyl group, a tert- ...methyl group, an isopentyl group, a tert-pentyl group, a methyl Examples of such groups include a C4-C8 cycloalkyl group optionally substituted with a C1-C8 alkyl group, an n-hexyl group, an isohexyl group, a sec-hexyl group, a tert-hexyl group, a neohexyl group, etc.; a C4-C8 cycloalkyl group optionally substituted with a C1-C8 alkyl group; a tetrahydropyranyl group; a benzyl group optionally substituted with a halogen, a C1-C8 alkyl group, or a C1-C6 alkoxy group; a 2-phenylethyl group optionally substituted with a halogenated phenyl group; and an indole group. Among these, a linear or branched C4-C6 alkyl group is preferred. Substituent group C: When the atom connected to the phosphorus atom is N, the group may be a heterocycle, for example, a C3-C5 heterocycle, a morpholino ring, a piperazine ring, a thiomorpholine ring, or a group represented by formula 3: (wherein R4 is hydrogen, a C1-C8 alkyl group optionally substituted with a C3-C6 cycloalkyl group; a C4-C8 cycloalkyl group; a tetrahydropyranyl group; a benzyl group optionally substituted with a halogen, a C1-C8 alkyl group, or a C1-C6 alkylalkoxy group; a 2-phenylethyl group optionally substituted with a halogenated phenyl group, or an indole group), or a pharmaceutically acceptable salt or solvate thereof.

[0018] In formula (I), X and Y are the same or different and are substituents selected from substituent group A, substituent group B and substituent group C, respectively, with the proviso that neither X nor Y is a substituent selected from substituent group A. Therefore, options for the substituent groups for X and Y are as follows: X and Y = substituents in substituent group A and substituents in substituent group B X and Y = substituents in substituent group A and substituents in substituent group C X and Y = substituents in substituent group B and substituents in substituent group A X and Y = substituents in substituent group B and substituents in substituent group B X and Y = substituents in substituent group B and substituents in substituent group C X and Y = substituents in substituent group C and substituent group A X and Y = substituents in substituent group C and substituent group B X and Y = substituents in substituent group C and substituent group C

[0019] As used herein, the term "C1-C8 alkyl group" means a straight or branched hydrocarbon chain group consisting of the designated number of carbon and hydrogen atoms, containing no unsaturation, and connected to the remainder of the molecule by a single bond. Examples include, but are not limited to, alkyl groups such as methyl, ethyl, n-propyl, isopropyl, isobutyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 3,3-dimethyl-1-butyl, t-butyl, pentyl, isopentyl, and hexyl.

[0020] As used herein, the term "C1-C3 alkylaryl group" refers to an aryl group substituted with an alkyl having the indicated number of carbon atoms and hydrogen atoms. The term "aryl" is a general term for the remaining atoms after removing one hydrogen atom from an aromatic ring of an aromatic hydrocarbon. In one embodiment of the present invention, aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0021] In this specification, the term "ester group" refers to a bond, -COO-, formed by dehydration condensation between a hydroxyl group and an acid.

[0022] As used herein, the term "C1-C6 alkoxy group" refers to an -O-alkyl group in alkyl as defined above. C1-C6 alkoxy groups include, but are not limited to, lower alkylalkoxy, lower cycloalkylalkoxy, and lower bicycloalkoxy.

[0023] In this specification, the term "residues generally known as aminocarboxylic acids" is not particularly limited as long as it has a structure having an amino group and a carboxylic acid, but is typically an amino acid residue.

[0024] As used herein, the term "amino acid residue" refers to natural or unnatural α-amino acid and β-amino acid residues. The term "α-amino acid residue" refers to the group -CHR-NH- in the formula -C(O)-CHR-NH-, and includes natural and unnatural amino acids in either the D- or L-configuration. "α-amino acid" includes α-amino acids having the D-, L-, or racemic (D,L) configuration. In the present invention, amino acid residues have the conventional amino acid configuration, and each amino acid residue moiety can independently exist in the "L" or "D" stereoisomeric form. Examples of natural and unnatural amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0025] As used herein, the term "halogen" means chloro, bromo, iodo or fluoro.

[0026] In each of the above definitions, "optionally substituted" means that the substituent may be further substituted with one or more substituents at any substitutable position (including carbon atoms and heteroatoms).

[0027] The compounds of the present invention may be in the form of a salt, preferably a pharmaceutically acceptable salt, or a solvate.

[0028] The term "pharmaceutically acceptable salt" refers to a salt that, when administered to a subject, can provide (directly or indirectly) a compound described herein. Salt preparation can be carried out by methods known in the art. Preferably, a "pharmaceutically acceptable salt" provides a molecular moiety that is physiologically tolerated and typically does not cause an allergic or similar adverse reaction (e.g., upset stomach, dizziness, etc.) when administered to a human.

[0029] For example, pharmaceutically acceptable salts of the compounds provided herein are synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Typically, such salts are prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid, for example, in water or an organic solvent, or a mixture of the two. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. Examples of acid addition salts include mineral acid addition salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate), and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts (e.g., sodium, potassium, calcium, ammonium, magnesium, aluminum, and lithium salts), and organic alkali salts (e.g., salts of ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, glucamine, and basic amino acids).

[0030] According to the present invention, the term "solvate" should be understood to mean any form of the active compound of the present invention in which another molecule (most likely a polar solvent) is attached via a non-covalent bond. Examples of such solvates include hydrates and alcoholates, such as methanolates.

[0031] The compounds of the present invention may be in crystalline form, either as free compounds or as solvates (e.g., hydrates), and both forms are intended to be within the scope of the present invention.Solvation methods are generally known in the art.Suitable solvates are pharmaceutically acceptable solvates.In a specific embodiment, the solvate is a hydrate.

[0032] The term "prodrug," as used herein, refers to a chemical compound that has undergone chemical derivatization, such as substitution or addition of additional chemical groups, to alter any of its physicochemical properties, e.g., solubility or bioavailability, for pharmaceutical use. Examples include ester and ether derivatives of an active compound that, after administration to a subject, yield the active compound itself. Examples of well-known methods for producing prodrugs of a given active compound are known to those skilled in the art and can be found, for example, in Krogsgaard-Larsen et al., Textbook of Drug design and Discovery, Taylor & Francis (April 2002).

[0033] The preparation of salts, solvates and prodrugs can be carried out by methodology known in the art. It will be appreciated that non-pharmaceutically acceptable salts, solvates or prodrugs also fall within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts, solvates or prodrugs.

[0034] As mentioned above, the phosphoramidate-modified AMP (ATP prodrug) developed in this study is a prodrug that exerts its effect by converting AMP to ATP through intracellular metabolism, thereby increasing intracellular ATP concentrations. Various prodrugs have been reported to exert their therapeutic effects through similar intracellular metabolism. For example, remdesivir (GS 5734), an antiviral treatment for Ebola virus infection and coronavirus infection, exerts its therapeutic effect by being triphosphorylated in cells (inhibiting viral replication) (ACS Cent. Sci. 2020, 6, 5, 672-683).

[0035] The expected effects of drugs (prodrugs) that can increase intracellular ATP levels are as follows: 1. By compensating for the age-related decline in ATP levels, they can have an anti-aging effect on cells, tissues, organs, and individuals. It has been reported that intracellular ATP levels decrease with age (PNAS, 2006, 103, 1727). Replenishing ATP may reduce oxidative stress damage to cells.

[0036] 2. Therapeutic drugs for neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, ALS, etc.) In Parkinson's disease, ATP reduction due to mitochondrial dysfunction is thought to be related to the disease (EBioMedicine, 2017, 22, 225). ATP supplementation may be an effective therapeutic drug, and may be effective in treating ALS, which is caused by abnormalities in intracellular fluid-liquid phase separation.

[0037] 3. Effect of replenishing ATP deficiency caused by hypoxia on maintaining cell viability and function in 3D cultures. When oxygen is deficient, ATP production decreases significantly, leading to cell necrosis, and ATP replenishment may be able to prevent this.

[0038] 4. ATP Supplementation Effect in Tissue Regeneration There have been reports of encapsulating and delivering ATP in liposomes (The American Journal of Surgery (2010) 199, 823-832). It is possible that replenishing ATP in areas of skin or other tissue defects could promote tissue regeneration. As mentioned above, ATP can be artificially replenished, and if its effectiveness can be confirmed, various applications are expected. This invention proposes a new ATP therapy.

[0039] 5. Therapeutic Effects on Non-Alcoholic Fatty Liver Disease and / or Hepatitis: Mitochondrial damage to liver cells in non-alcoholic fatty liver disease and / or hepatitis (NAFLD and / or NASH) has been reported, resulting in a decrease in intracellular ATP levels and a worsening of the disease. If the decreased ATP levels in these liver diseases can be improved, this could potentially be applied to the prevention and treatment of NAFLD and / or NASH.

[0040] 6. AMPK Activation Effect Small molecule drugs known as anti-aging drugs have been reported to activate AMPK. Examples include metformin (B. Onken et al., PLOS ONE, 2010) and resveratrol (JG Wood et al., Nature, 2004). The ATP prodrug of the present invention has been shown to function as an AMP-activated protein kinase (AMPK) activator. Therefore, the compound of the present invention activates AMPK, increases intracellular ATP levels, and exhibits anti-aging effects.

[0041] <Pharmaceutical Composition> In another aspect, the present invention relates to a pharmaceutical composition containing a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of this aspect, the present invention relates to a pharmaceutical composition containing a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof. Specifically, the pharmaceutical composition is for treating or preventing a condition with reduced intracellular ATP levels.

[0042] As used herein, the term "treat," unless otherwise specified, means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. In one embodiment, the term "treatment" refers to the administration of a compound or composition of the present invention to alleviate or eliminate the symptoms of a condition with reduced intracellular ATP levels and / or to reduce a condition with reduced intracellular ATP levels in an individual. Treatment may be administered before the onset of a disease or condition as a preventative measure, or alternatively, treatment may be administered after the onset of a disease.

[0043] "Preventing" refers to any treatment of a disease or condition that prevents the clinical symptoms of the disease or condition from occurring. The term "prevention" also encompasses the administration of a therapeutically effective amount of a compound or composition according to the present invention to prevent the onset of disease symptoms and / or to prevent the reaching of a state in which intracellular ATP levels are reduced (e.g., pre-exposure prophylaxis).

[0044] In the present invention, the pharmaceutical composition generally means a drug for treating or preventing a disease, or for testing or diagnosing a disease.

[0045] The pharmaceutical compositions of the present invention can be formulated by methods known to those skilled in the art. For example, they can be used orally or parenterally in the form of a sterile solution or suspension in water or other pharmaceutically acceptable liquid, or parenterally in the form of an injection. For example, they can be formulated by appropriately combining them with pharmacologically acceptable carriers or vehicles, specifically, sterile water, physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives, binders, etc., and blending them into unit dosage forms required for generally accepted pharmaceutical practice. The amount of active ingredient in these formulations is set so that an appropriate volume within the specified range is obtained.

[0046] Sterile compositions for injection can be formulated according to conventional formulations using vehicles such as distilled water for injection.

[0047] Examples of aqueous solutions for injection include isotonic solutions containing physiological saline, glucose, or other adjuvants (e.g., D-sorbitol, D-mannose, D-mannitol, sodium chloride).Appropriate solubilizing agents, such as alcohol (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants (e.g., Polysorbate 80™, HCO-50), may be used in combination.

[0048] Oily liquids include sesame oil and soybean oil, and may contain benzyl benzoate and / or benzyl alcohol as solubilizers. They may also contain buffers (e.g., phosphate buffer and sodium acetate buffer), soothing agents (e.g., procaine hydrochloride), stabilizers (e.g., benzyl alcohol and phenol), and antioxidants. The prepared injection solution is usually filled into suitable ampoules.

[0049] The pharmaceutical composition of the present invention can be administered orally or parenterally. For example, it can be an injection, intranasal, pulmonary, or transdermal composition. For example, it can be administered systemically or locally by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, or the like.

[0050] The administration method can be selected appropriately depending on the patient's age and symptoms. The dosage of the pharmaceutical composition can be set, for example, in the range of 0.0001 mg to 1,000 mg per kg of body weight per administration. Alternatively, the dosage can be set, for example, in the range of 0.001 to 100,000 mg per patient, although the present invention is not necessarily limited to these numerical values. The dosage and administration method vary depending on the patient's weight, age, symptoms, etc., but one skilled in the art can determine an appropriate dosage and administration method taking these conditions into consideration.

[0051] In another aspect, the present invention relates to a method for treating or preventing conditions with reduced intracellular ATP levels, such as aging, non-alcoholic fatty liver disease and / or hepatitis, mitochondrial diseases, hypoxic conditions due to cancer or insufficient blood flow, tissue regeneration associated with inflammation, or neurodegenerative diseases, comprising administering a compound of the present invention to a subject in need of such treatment, preferably a method comprising administering an effective amount of a compound of the present invention to such a subject. In yet another aspect, the present invention relates to a compound of the present invention for treating or preventing conditions with reduced intracellular ATP levels, such as aging, non-alcoholic fatty liver disease and / or hepatitis, mitochondrial diseases, hypoxic conditions due to cancer or insufficient blood flow, tissue regeneration associated with inflammation, or neurodegenerative diseases. In yet another aspect, the present invention relates to the use of a compound of the present invention for the manufacture of a medicament for treating or preventing conditions with reduced intracellular ATP levels, such as aging, mitochondrial diseases, hypoxic conditions due to cancer or insufficient blood flow, tissue regeneration associated with inflammation, or neurodegenerative diseases.

[0052] The present invention will be described in detail below with reference to examples. However, it should be noted that these examples do not limit the scope of the present invention and are merely illustrative.

[0053] Example 1 Phosphoramidate AMP (ATP prodrug)

[0054] Example 1-1: (S)-2-Ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3.4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

[0055] 2-Ethylbutyl (2s)-2-([(s)-(4-nitrophenoxy)(phenoxy)phosphoryl]amino)propanoate (1.8 g, 4 mmol) obtained from Combi-Blocks and 2',3'-O-isopropylideneadenosine (1.0 g, 3.3 mmol) obtained from Tokyo Chemical Industry Co., Ltd. were reacted in acetonitrile (20 mL) in the presence of magnesium chloride and N,N-diisopropylethylamine at 50 °C. After purification on a silica gel column, the title compound (1.9 g, 92%) was obtained.

[0056] The NMR spectrum chart of the obtained compound is shown in FIG.

[0057] Example 1-2: Phosphoramidite AMP (ATP prodrug) (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate The compound prepared in Example 1-1 (1.2 g, 2 mmol) was reacted with 2 ml of 37% hydrochloric acid in THF (10 mL) at 0°C, and the mixture was purified using a silica gel column to obtain the title compound (1.5 g, 75%, melting point 129.9°C).

[0058] The NMR spectrum chart and FAB MS spectrum of the resulting compound are shown in FIG. 2 and FIG. 3, respectively.

[0059] Example 2 Phosphoramidate-modified AMP (ATP prodrug-neo) Example 2-1 4-Nitrophenyl phosphorodichloridate (1.3 g, 5.1 mmol) purchased from MERCK and L-alanine neopentyl ester hydrochloride (2.0 g, 10.2 mmol) purchased from ACROTEIN were reacted in dichloromethane in the presence of triethylamine at room temperature. After purification on a silica gel column, the desired compound (0.8 g, 30%) was obtained.

[0060] Example 2-2 The compound synthesized in Example 2-1 (0.6 g, 1.2 mmol) was reacted with 2',3'-O-isopropylidene adenosine (1.0 g, 3.3 mmol) purchased from Tokyo Chemical Industry Co., Ltd. in acetonitrile (20 mL) in the presence of magnesium chloride and N,N-diisopropylethylamine at 50°C. After purification with a silica gel column, the target compound (0.5 g, 79%) was obtained.

[0061] Example 2-3 The compound prepared in Example 2-2 (0.53 g, 0.79 mmol) was reacted with 2 ml of 37% hydrochloric acid in THF (5 mL) at 0°C, and the mixture was purified using a silica gel column to obtain the desired compound (0.1 g, 22%).

[0062] The NMR spectrum chart of the obtained compound is shown in FIG.

[0063] Test Example 1: Effect of ATP Prodrug on Intracellular ATP Concentration. MCF7 (human breast cancer cells) (RIKEN BRC) cells were seeded at 5,000 cells / well (DMEM low glucose, 10% FBS, 1% penicillin / streptomycin). After 3 hours, solutions of the ATP prodrug prepared in Example 1 dissolved in DMSO at varying concentrations were added. After 1, 2, and 3 days, DNA content was measured using Picogreen and converted to cell count using a separately prepared calibration curve. ATP content was quantified using an ATP measurement kit (Dojindo Laboratories), and the amount of ATP per cell was calculated. The results are shown in Figure 5. Figure 5 shows that intracellular ATP content increased in a concentration-dependent manner with the ATP prodrug, reaching approximately 2.5-fold higher than the control after 3 days (when 100 μM ATP prodrug was added). Thus, the conversion of ATP to a prodrug was able to increase intracellular ATP concentration.

[0064] Test Example 2: Effect of ATP Analogues on Intracellular ATP Concentration Adenosine, AMP, ATP, and ATP prodrugs were added to the medium of MCF7 cells (5000 cells / well) at 100 μM. ATP levels were measured one and two days later and normalized by DNA content. The results are shown in Figure 6. Figure 6 shows that intracellular ATP levels increased only when ATP prodrugs were added.

[0065] Test Example 3: Effect on Intracellular ATP Concentration Using Normal Cells. NHDF (human fibroblasts) (Takara Bio) were seeded at 5,000 cells / well (DMEM low glucose, 10% FBS, 1% penicillin / streptomycin). After 3 hours, solutions of the ATP prodrug prepared in Example 1 dissolved in DMSO at varying concentrations were added. One day later, DNA content was measured using picogreen and converted to cell count using a separately prepared calibration curve. ATP content was quantified using an ATP measurement kit (Dojindo Laboratories), and the amount of ATP per cell was calculated. The results are shown in Figure 7. Figure 7 shows that the addition of ATP prodrug also increased intracellular ATP content in normal NHDF cells in a concentration-dependent manner, with the ATP prodrug (200 μM) increasing ATP content by 1.7-fold compared to the control (0 μM).

[0066] Experimental Example 4: Effect of ATP Increase on Senescent Cells and Stress Loading. HDFs (human dermal cells) (Toyobo) derived from 75-year-old and 29-year-old humans were seeded at 5,000 cells / well (DMEM low glucose, 10% FBS, 1% penicillin / streptomycin). After three hours, 0 or 50 μM of ATP prodrug dissolved in DMSO was added. (A) The cells were incubated for 24 hours. DNA content was measured using Picogreen and converted to cell count using a separately prepared calibration curve. ATP content was quantified using an ATP measurement kit (Dojindo Laboratories), and the amount of ATP per cell was calculated. (B) 75 μM ATP prodrug was added to HDFs derived from a 75-year-old human. After 24 hours, the medium was replaced with serum-free medium containing 200 μM hydrogen peroxide and incubated for 6 hours. After 6 hours, the cells were washed, and cell counts were compared using a WST-8 kit.

[0067] The results are shown in Figure 8. Figure 8(A) shows that the addition of an ATP prodrug increased intracellular ATP levels in cells derived from 29- and 75-year-olds. Figure 8(B) shows that in cells derived from 75-year-olds, stress-induced cell number decreased in the absence of an ATP prodrug, but that the addition of 75 μM of an ATP prodrug prevented this decrease. These results suggest that stress tolerance was improved even in aged cells due to the increase in intracellular ATP levels resulting from the addition of an ATP prodrug.

[0068] Test Example 5 Cytotoxicity of ATP Prodrug NHDF (normal human dermal fibroblasts) were seeded at 5,000 cells / well (DMEM / F12, 10% FBS, 1% penicillin / streptomycin), and after 3 hours, solutions of the ATP prodrug prepared in Example 1 dissolved in DMSO at varying concentrations were added. After 24 hours, the amount of LDH (lactate dehydrogenase) released, which serves as an indicator of cytotoxicity, was quantified using an LDH assay kit (Dojindo Laboratories), and the cytotoxicity was calculated.

[0069] The results are shown in Figure 9. Figure 9 shows that even when the ATP prodrug was added at a high concentration (256 μM), the amount of LDH released was low. Thus, it was confirmed that the ATP prodrug has low cytotoxicity.

[0070] Test Example 6: Effect of ATP Prodrug on Hepatocytes Human hepatoma cells (HepG2) were seeded at 5,000 cells / well (DMEM, 10% FBS, 1% penicillin / streptomycin). After 3 hours, solutions of the ATP prodrug prepared in Example 1 dissolved in DMSO at varying concentrations were added. After 24 hours, the DNA content was measured using picogreen and converted to cell number using a separately prepared calibration curve. The ATP content was quantified using an ATP measurement kit (Dojindo Laboratories) to calculate the ATP content per cell.

[0071] Separately, normal porcine hepatocytes were seeded at 5,000 cells / well (Hepatocyte Differentiation Environment Hepatp-STIM, 1 μg / 100 mL EGF, 1% penicillin / streptomycin). After 3 hours, varying concentrations of ATP prodrugs dissolved in DMSO were added. After 24 hours, DNA content was measured using Picogreen. ATP content was quantified using an ATP assay kit (Dojindo Laboratories).

[0072] The results obtained are shown in Figure 10. An increase in the intracellular ATP level due to the ATP prodrug was confirmed in two types of liver cells (established cell line and primary cells).

[0073] Test Example 7: Evaluation of intracellular ATP levels using an AMPK inhibitor 100 μL of serum-containing medium (DMEM / F12, 10% FBS) was added to a 96-well plate, and preconditioning was performed in an incubator for 1 hour. Then, normal human dermal fibroblasts were seeded (cell seeding number: 5 × 10 3 Three hours after seeding, the ATP prodrug prepared in Example 1 (final concentration: 100 μM) and the AMP-activated protein kinase (AMPK) inhibitor dorsomorphin (final concentration: 0 or 12.5 μM) were added to each well, and the plates were cultured at 37°C for 24 hours. 100 μL of the detection reagent included in the ATP measurement kit was added to each well, and a color reaction was carried out for 30 minutes at room temperature in the dark. Then, 50 μL of reaction stop solution was added to each well, and the absorbance at 490 nm was measured using a microplate reader.

[0074] The results are shown in Figure 11. Addition of the AMPK inhibitor dorsomorphin partially inhibited ATP production by the ATP prodrug. These results suggest that the ATP prodrug activates AMPK, increases intracellular ATP levels, and exerts anti-aging effects.

[0075] Test Example 8: Confirmation of Lifespan Extension Effect Using Model Animals (Nematodes): Part 1: Preparation of Substrates. ATP prodrug-containing NGM plates were prepared by adding the ATP prodrug prepared in Example 1 dissolved in DMSO to a final concentration of 100 μM in sterilized liquid nematode growth medium (NGM) maintained at 60°C. The final DMSO concentration in NGM was adjusted to 1%. DMSO was also added to NGM plates without ATP prodrugs to a final DMSO concentration of 1%. Immediately before use in survival analysis, Escherichia coli OP50 (Escherichia coli strain OP50) stirred in M9 buffer was applied to the surface of the NGM plates as nematode food.

[0076] After age synchronization, 35 nematodes were transferred to NGM plates. The nematodes were transferred to new NGM plates daily from the first day of adulthood (day 3) until day 7, and every two days from day 8 until death. The number of live and dead nematodes was recorded. Nematodes were determined to be alive or dead by their lack of reaction to touch. The average lifespan was calculated from the results, and the lifespan extension rate was calculated by comparing the average lifespans. This experiment was repeated four times to confirm reproducibility (n = 114, both with and without proATP).

[0077] The results are shown in Figure 12. Figure 12 shows that the average lifespan of nematodes cultured on NGM plates containing ATP prodrugs was extended by approximately 33% compared to the control. Thus, adding ATP prodrugs to nematodes extended their average lifespan.

[0078] For reference, the table below shows a comparison with other drugs known to extend the lifespan of nematodes. Comparison of ATP levels in the body of a model organism (nematode). C. elegans were cultured and treated with ATP prodrugs under the same conditions as those used for survival analysis. Five nematodes on day 7 of culture (25 nematodes total per condition) were collected in a 24-well plate containing PBS and sonicated (1 minute) on ice. The homogenates were then collected in a microtube and centrifuged (15,000 rpm, 30 minutes, 4°C), after which the supernatant was collected. The amount of ATP in the supernatant was quantified using an ATP measurement kit (Dojindo Laboratories), and the amount of ATP per nematode was calculated.

[0079] The results are shown in Figure 13. Figure 13 shows that the ATP content in each worm cultured on an NGM plate containing an ATP prodrug was increased by approximately 23% compared to the control. Thus, adding an ATP prodrug to worms increased the ATP content in the worms.

[0080] Test Example 9: Effect of ATP Prodrug-neo on Intracellular ATP Concentration. HDF75 (human dermal fibroblasts derived from a 75-year-old) (Cell Applications, Inc.) were seeded at 5,000 cells / well (human dermal fibroblast growth medium). After 3 hours, solutions of ATP prodrug-neo prepared in Example 2 dissolved in DMSO at varying concentrations were added. After 24 hours, DNA content was measured using picogreen and converted to cell number using a separately prepared calibration curve. ATP content was quantified using an ATP measurement kit (Dojindo Laboratories), and the amount of ATP per cell was calculated.

[0081] The results are shown in Figure 14. Figure 14 shows that the amount of intracellular ATP increased with the ATP prodrug-neo. As described above, the ATP prodrug, which has a different structure from the ATP prodrug of Example 1, was also able to increase the intracellular ATP concentration.

[0082] Test Example 10: Confirmation of Lifespan Extension Effect Using Model Animals (Nematodes) Part 2: Substrate Preparation. ATP prodrug-neo-containing NGM plates were prepared by adding ATP prodrug-neo, prepared in Example 2 and dissolved in DMSO, to a final concentration of 200 μM in sterilized liquid nematode growth medium (NGM) maintained at 60°C. The final DMSO concentration in NGM was adjusted to 1%. DMSO was also added to NGM plates without ATP prodrug-neo to a final DMSO concentration of 1%. Immediately before use in survival analysis, Escherichia coli OP50 (Escherichia coli strain OP50) stirred in M9 buffer was applied to the surface of the NGM plates as nematode food.

[0083] Survival Analysis After age synchronization, 35 nematodes were transferred to NGM plates. The nematodes were transferred to new NGM plates daily from the first day of adulthood (day 3) until day 7, and every two days from day 8 until death. The number of live and dead nematodes was recorded. Nematodes were determined to be alive or dead by their lack of reaction to touch. The mean lifespan was calculated from the results, and the lifespan extension rate was calculated by comparing the mean lifespans. This experiment was repeated four times to confirm reproducibility. The results are shown in Figure 15. Figure 15 shows that nematodes cultured on NGM plates containing ATP prodrug-neo had a mean lifespan extended by approximately 26% compared to the control. Thus, adding proATP-neo to nematodes extended their mean lifespan.

[0084] As described above, the ATP prodrug of the present invention is a groundbreaking substance that can artificially increase intracellular ATP. To date, no ATP precursor capable of increasing ATP concentration has been reported. Furthermore, ATP is an energy currency commonly present in all living organisms. The impact of the present invention, which can control ATP concentration, and its potential for pharmaceutical application are extremely high.

Claims

1. Phosphoamidated AMP, and formula (I): 【Chemistry 1】 [In the formula, In the sugar moiety of a five-membered ring, the stereochemistry between the hydroxyl group at position 2 and the hydroxyl group at position 3 is cis. X and Y are either the same or different substituents selected from substituent group A, substituent group B, and substituent group C, respectively. However, neither X nor Y are substituents selected from substituent group A. Substituent group A: When the atom connected to the phosphorus atom is O, Equation 1: -O-R 1 (wherein, R 1 is hydrogen, C 1 - C 8 alkyl group, C 1 - C 3 alkylaryl group, CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, ester group, phenyl group, pyridyl group, benzyl group, indolyl group, and naphthyl group, and these aromatic rings or heterocyclic rings may be substituted by 1 to 3 functional groups shown below; halogen, C 1 - C 6 alkyl, C 2 - C 6 alkenyl, C 1 - C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 - C 6 haloalkoxy, phenyl, hydroxy C 1 - C 6 alkyl, C 3 - C 6 cycloalkyl, C 1 - C 6 alkylcarbonyl, C 3 - C 6 cycloalkylcarbonyl, carboxy C1 - C6 alkyl, hydroxy group, amino group, cyano group, nitro group, trimethylsilyl group) The base indicated by; Substituent group B: When the atom connected to the phosphorus atom is N, Equation 2: -R 2 -R 3 (In the formula, R 2 These are residues collectively referred to as aminocarboxylic acids, R 3 R 2 Linear C bonded to the carboxylic acid portion of aminocarboxylic acid in the above. 1 ~C 6 Alkyl, branched or cyclic C 3 ~C 6 Alkyl group; C 1 ~C 8 C may be substituted with an alkyl group. 4 ~C 8 Cycloalkyl groups; tetrahydropyranyl groups; halogens, C 1 ~C 8 Alkyl alkyl group, or C 1 ~C 6 (These include benzyl groups that may be substituted with alkoxy groups; 2-phenylethyl groups that may be substituted with halogenated phenyl groups; and indole groups.) The base indicated by; Substituent group C: When the atom connected to the phosphorus atom is N, C 3 ~C 5 Heterocyclic ring, morpholino ring, piperazine ring, thiomorphyl ring, or formula 3: 【Chemistry 2】 (In the formula, R 4 is hydrogen, C 3 ~C 6 C may be substituted with a cycloalkyl group. 1 ~C 8 Alkyl group: C 4 ~C 8 Cycloalkyl group: Tetrahydropyranyl group: Halogen, C 1 ~C 8 Alkyl alkyl group, or C 1 ~C 6 Benzyl groups that may be substituted with alkylalkoxy groups: 2-phenylethyl groups or indole groups that may be substituted with halogenated phenyl groups. [The ring structure shown by] The compound indicated by, or a pharmaceutically acceptable salt or solvate thereof.

2. X or Y is a substituent selected from substituent group A, and R1 is a halogen, C 1 ~C 8 Alkyl or C 1 -C 6 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the phenyl group may be substituted with an alkoxy group.

3. At least one of X and Y is a substituent selected from substituent group B, and formula 2: -R 2 -R 3 (In the formula, R 2 This is an amino acid residue selected from alanine, glycine, isoleucine, leucine, proline, methionine, phenylglycine, phenylalanine, valine, and asparagine. (R 3 has the same meaning as defined in claim 1) The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is a group represented by .

4. At least one of X and Y is a substituent selected from substituent group B, and formula 2: -R 2 -R 3 (In the formula, R 2 has the same meaning as defined in claim 1, R 3 (The group is selected from among methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, sec-pentyl group, tert-pentyl group, neopentyl group, 1-methylpentyl group, n-hexyl group, isohexyl group, sec-hexyl group, tert-hexyl group, and neohexyl group.) The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is a group represented by .

5. At least one of X and Y is a substituent selected from substituent group B, and formula 2: -R 2 -R 3 (In the formula, R 2 has the same meaning as defined in claim 1, R 3 C is linear or branched 4 ~C 6 (It is an alkyl group.) The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is a group represented by .

6. Formula (II) 【Transformation 3】 or Formula (III): 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, as shown by [the formula].

7. A pharmaceutical composition containing a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof.

8. A pharmaceutical composition according to claim 7 for treating or preventing a state of decreased intracellular ATP levels.

9. The pharmaceutical composition according to claim 8, wherein a state of decreased intracellular ATP levels is associated with the state of aging, as well as non-alcoholic fatty liver disease and / or hepatitis.

10. The pharmaceutical composition according to claim 8, wherein the state of decreased intracellular ATP levels is a mitochondrial disease, a hypoxic state due to cancer or insufficient blood flow, or a tissue regeneration area accompanied by inflammation.

11. The pharmaceutical composition according to claim 8, wherein the state of decreased intracellular ATP levels is a neurodegenerative disease.

12. The pharmaceutical composition according to claim 11, wherein the neurodegenerative disease is selected from Parkinson's disease, Alzheimer's disease, and ALS.

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