Ferroptosis inhibitors

Abstract

This invention relates to quinones for use in inhibiting ferroptosis.

Description

[Technical Field]

[0001] This invention relates to quinones for use in inhibiting ferroptosis. [Background technology]

[0002] Ferroptosis is a controlled, non-apoptotic form of cell death. Ferroptotic cell death is characterized by excessive iron-dependent lipid peroxidation and can be a cause of certain degenerative diseases (1). Cells use system x to prevent death by ferroptosis. C - Numerous ferroptosis inhibitory mechanisms are formed, including the / glutathione / GPX4 system (2), the FSP1-ubiquinol system (3, 4), the GCH1 / tetrahydrobiopterin / DHFR system (5, 6), the DHODH / ubiquinol system (7), and the FSP1 / vitamin-K system (8). All of these inhibitory modules convert lipid peroxides back to their non-lethal alcoholic form, thereby counteracting ferroptotic cell death. Ferroptosis is caused by system x C - It can be chemically induced by inhibiting (e.g., elastin or IKE), or by directly inhibiting GPX4 (e.g., (1S,3R)-RSL3 or ML210), or by directly inhibiting FIN56 and FINO2, which together have a combined effect in inducing ferroptosis (9). On the other hand, numerous radical-scavenging antioxidants (RTAs), such as ferrostatin-1, riproxstatin-1, and vitamin E, can suppress lipid peroxidation (2, 9), thereby inhibiting ferroptosis. Despite the availability of many ferroptosis-modulating compounds, most of them are either not suitable in vivo or are still in preclinical development (10), thus highlighting the need for further strategies to develop ferroptosis-based medicines.

[0003] Studies in the past few years have revealed that ferroptosis occurs in organ injuries and degenerative diseases such as the brain, kidneys, and heart. Therefore, it is considered that ferroptosis inhibition has been demonstrated to be therapeutically beneficial for treating the above diseases.

Summary of the Invention

[0004] The present invention is directed to quinones for use in the inhibition of ferroptosis.

[0005] Furthermore, the present invention is directed to the quinones described for use in the treatment of diseases that can be treated or prevented by inhibiting ferroptosis, and in particular, the diseases are selected from the group consisting of amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), COPD, hepatic, renal, intestinal, and pulmonary ischemia-reperfusion injury (IRI), myocardial infarction, cardiomyopathy, stroke, traumatic brain injury, renal degeneration, and retinal degeneration (2, 10, 11).

[0006] The present invention is directed to quinones, and in one embodiment, the quinones for use in the above treatment are selected from the quinones specified in one of general formulas (I) or (II).

Chemical formula

Chemical formula

[0007] Furthermore, the quinones of the present invention include pharmaceutically acceptable salts, solvates, enantiomers, or hydrates thereof.

[0008] The present invention further relates to a quinone in formula (III), [ka] R 16 and R 17 These are independently selected from the group consisting of H and -OH, R 18 H, -(C1-C 30 ) Selected from the group consisting of alkyl and trifluoromethyl, R 19 teeth, [ka] And, D is N, E is a bond, (C1-C8)alkylene, or (C2-C8)alkenneene. R 20 It is selected from the group consisting of H, -COOH, -CONH2, and -COO(C1-C6)alkyl. R 21 , R 22 , R 23 , R 24 , R 25 These are independently selected from the group consisting of H, (C1-C4)alkyl, -O(C1-C4)alkyl, -OH, halogen, -CF3, -CO(C1-C4)alkyl, COOH, -COO(C1-C6)alkyl, -CONH2, -NH2, -NHCO(C1-C4)alkyl, -NH(C1-C4)alkyl, and -N((C1-C4)alkyl)2, preferably H, -(C1-C4)alkyl, -O(C1-C4)alkyl, -OH, Cl, F, -CF3, -CO(C1-C4)alkyl, and COOH, more preferably H, -(C1-C4)alkyl, -O(C1-C4)alkyl, -OH, Cl, -CO(C1-C4)alkyl, and COOH. -(C1-C 30 In alkyl groups, one or more hydrogen atoms are optionally and independently -OH, -O(C1-C 10 )alkyl, (C1-C 10 )alkyl, -C(O)(C1-C 10 )alkyl, -COO(C1-C 10 )alkyl, -CONH2, -COOH, -(C6-C 12 ) Substituted by a substituent selected from the group consisting of aryls, Conditions (i) and (ii) do not exist in the same molecule. (i) E is a bond, R 20 H is (ii)R 18 H is a quinone, Or relating to pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, racemates, or hydrates thereof. [Brief explanation of the drawing]

[0009] [Figure 1]Figure 1 shows that seratrodust inhibits ferroptosis by suppressing lipid peroxidation. (A) shows the chemical structure of seratrodust. (B) shows that seratrodust (Sera) dose-dependently suppresses ferroptosis induced for 18 hours by 100 nM RSL3 or 1.5 μM IKE. Plotted data are mean ± SD (n=4). (C) shows that seratrodust does not inhibit necroptosis. T+zV+L=20 ng / ml TNFα + 10 μM Z-VAD-FMK + 10 μM LCL161 for 18 hours, 10 μM necrostatin-1 (Nec-1), 6 μM seratrodust, ****p ≤ 0.0001 (one-way ANOVA), plotted data are mean ± SD (n=3). (D) shows that seratrodust does not inhibit apoptosis. (E) shows that seratrodust inhibits ferroptosis induced by RSL3, IKE, FINO2, and FIN56 to a degree comparable to that of ferrostatin-1. Cell viability was normalized to DMSO-treated cells for 18 hours with 1 μM staurosporine (Stauro), 50 μM Z-VAD-FMK, and 6 μM seratrodust. Plotted data are mean ± SD (n=3). (E) shows that seratrodust inhibits ferroptosis induced by RSL3, IKE, FINO2, and FIN56 to a degree comparable to that of ferrostatin-1. Cell viability was normalized to DMSO-treated cells for 18 hours with 2 μM Fer-1 and 6 μM seratrodust. Plotted data are mean ± SEM (n=4). (F) shows that seratrodust inhibits ferroptosis in a 3D spheroid model. Representative images of spheroids (n=8 per condition) are shown for 48 hours with 200 nM RSL3, 2 μM Fer-1, and 6 μM seratrodust. The roundness of spheroids was quantified (n=8). ****p ≤ 0.0001 (one-way ANOVA). (G) indicates that TXA2 receptor antagonists without a quinone moiety cannot inhibit ferroptosis. 200 nM RSL3 and the indicated antagonist concentration range for 18 hours. Plotted data are mean ± SD (n=3).(H) shows that seratrodust exhibits antioxidant effects in an oxidative cell-free BODIPY-C11 assay treated with 7.5 mM 2,2'-azobis(2-methyl-propanimidoamide) dihydrochloride (AAPH), which generates free radicals. A significant decrease in oxidative fluorescence was observed. 25 μM Fer-1, 25 μM seratrodust, p ≤ 0.0001 (one-way ANOVA), plotted data are mean ± SD (n=3). (I) shows that seratrodust reduces RSL3-induced malondialdehyde (MDA), a product of lipid peroxidation. 250 nM RSL3, 2 μM Fer-1, 6 μM seratrodust for 2.5 hours, p ≤ 0.05 (one-way ANOVA), plotted data are mean ± SD (n=3). (J) shows that seratrodust suppresses RSL3-mediated oxidation of the lipid peroxidation sensor BODIPY-C11. 200 nM RSL3, 2 μM Fer-1, 6 μM seratrodust for 2.5 hours. A representative histogram is shown. Quantification of the biological replicas for n=3 is shown. ****p ≤ 0.0001 (one-way ANOVA). Plotted data are mean ± SD (n=3). (K) shows that seratrodust reduces RSL3-induced 4-hydroxynonenal (4-HNE), a product of lipid peroxidation. 300 nM RSL3, 2 μM Fer-1, 6 μM seratrodust for 2 hours. A representative histogram is shown. Quantification of the replicas for n=3 is shown. ***p ≤ 0.001 (one-way ANOVA). Plotted data are mean ± SD (n=3). [Modes for carrying out the invention]

[0010] This invention provides a small molecule having a quinone moiety that may inhibit ferroptosis.

[0011] definition It should be noted that, as used herein, the singular forms "a," "an," and "the" also include the plural form unless the context makes it clear. Therefore, for example, "reagent" includes one or more such various reagents, and "method" includes equivalent steps and methods known to those skilled in the art, which may be modified or substituted for the methods described herein.

[0012] The term “at least” preceding a set of components is understood to refer to all of those components unless otherwise specified. Those skilled in the art will recognize, or grasp by conventional experimentation alone, numerous equivalents of the particular embodiments of the invention described herein. Such equivalents are intended to be encompassed within the invention.

[0013] As used in any part of this specification, the terms “and / or” include the meanings of “and,” “or,” and “all of the components connected by the term, or any other combination thereof.”

[0014] In this specification and the following claims, unless required by context, the word “including,” and variations such as “including (third person)” and “including,” are understood to mean encompassing the described component or step or group of components or steps, and not to exclude any other component or step or group of components or steps. As used herein, the term “including” is interchangeable with the terms “containing” or “inclusion,” and, where applicable, with the term “having.” As used herein, “consisting of” excludes any component, step, or factor not specified.

[0015] The term "alkyl" refers to a monoradical of a saturated linear or branched hydrocarbon. Preferably, an alkyl group contains 1 to 30 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms, more preferably 1 to 10 carbon atoms, for example 1 to 6 or 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,2-dimethylpropyl, isoamyl, n-hexyl, isohexyl, sec-hexyl, n-heptyl, isoheptyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.

[0016] The term "alkylene" refers to a diradical of a saturated linear or branched hydrocarbon. Preferably, alkylenes contain 1 to 8 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, preferably 1 to 6 or 1 to 4 carbon atoms. Examples of alkylene groups include methylene, ethylene (i.e., 1,1-ethylene, 1,2-ethylene), propylene (i.e., 1,1-propylene, 1,2-propylene (-CH(CH3)CH2-), 2,2-propylene (-C(CH3)2-), and 1,3-propylene), butylene isomers (e.g., 1,1-butylene, 1,2-butylene, 2,2-butylene, 1,3-butylene, 2,3-butylene (cis or trans or mixtures thereof), 1,4-butylene, 1,1-isobutylene, This includes 1,2-isobutylene and 1,3-isobutylene), pentylene isomers (e.g., 1,1-pentylene, 1,2-pentylene, 1,3-pentylene, 1,4-pentylene, 1,5-pentylene, 1,1-isopentylene, 1,1-sec-pentyl, 1,1-neopentyl), and hexylene isomers (e.g., 1,1-hexylene, 1,2-hexylene, 1,3-hexylene, 1,4-hexylene, 1,5-hexylene, 1,6-hexylene, and 1,1-isohexylene), etc.

[0017] The term "alkenyl" refers to a monoradical of an unsaturated linear or branched hydrocarbon having at least one carbon-carbon double bond. Generally, the maximum number of carbon-carbon double bonds in an alkenyl group can be equal to an integer calculated by dividing the number of carbon atoms in the alkenyl group by 2, and rounding the result to the next integer if the number of carbon atoms in the alkenyl group is odd. For example, in an alkenyl group with 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenyl group has 1 to 4 carbon atoms, i.e., 1, 2, 3, or 4 carbon-carbon double bonds. Preferably, the alkenyl group contains 2 to 10 carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably 2 to 8 carbon atoms, for example, 2 to 6 carbon atoms or 2 to 4 carbon atoms. Therefore, in a preferred embodiment, the alkenyl group comprises 2 to 10 carbon atoms and 1, 2, 3, 4, or 5 carbon-carbon double bonds, more preferably 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, for example, 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds, or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bonds may be in a cis (Z) or trans (E) configuration. Examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl (i.e., allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methylpent-2-enyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, This includes 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, and 9-decenyl, etc. When an alkenyl group is bonded to a nitrogen atom, the double bond cannot be the alpha bond of the nitrogen atom.

[0018] The term "alkenylene" refers to a diradical of an unsaturated linear or branched hydrocarbon having at least one carbon-carbon double bond. Generally, the maximum number of carbon-carbon double bonds in an alkenylene group can be equal to an integer calculated by dividing the number of carbon atoms in the alkenylene group by 2 and rounding the result to the next integer if the number of carbon atoms in the alkenylene group is odd. For example, in an alkenylene group with 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenylene group has 1 to 4 carbon atoms, i.e., 1, 2, 3, or 4 carbon-carbon double bonds. Preferably, the alkenylene group contains 2 to 10 carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably 2 to 8 carbon atoms, for example, 2 to 6 carbon atoms or 2 to 4 carbon atoms. Therefore, in a preferred embodiment, the alkenylene group comprises 2 to 10 carbon atoms and 1, 2, 3, 4, or 5 carbon-carbon double bonds, more preferably 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, for example, 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds, or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bonds may be in a cis (Z) or trans (E) configuration. Examples of alkenylene groups include ethene-1,2-diyl, vinylidene, 1-propene-1,2-diyl, 1-propene-1,3-diyl, 1-propene-2,3-diyl, alilidene, 1-butene-1,2-diyl, 1-butene-1,3-diyl, 1-butene-1,4-diyl, 1-butene-2,3-diyl, 1-butene-2,4-diyl, 1-butene-3,4-diyl, 2-butene-1,2-diyl, 2-butene-1,3-diyl, 2-butene-1,4-diyl, 2-butene-2,3-diyl, 2-butene-2,4-diyl, and 2-butene-3,4-diyl. When an alkenylene group is bonded to a nitrogen atom, the double bond cannot be the alpha bond of the nitrogen atom.

[0019] "Pharmacologically acceptable salt" is intended to mean a salt that retains the biological efficacy of the free acids and bases of a particular compound, and is also desirable biologically or otherwise. The compounds of the present invention have functional groups that are sufficiently acidic, sufficiently basic, or both, and can therefore react with many inorganic or organic bases as well as inorganic and organic acids to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with inorganic or organic acids or inorganic bases, such as sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propions, decanoates, caprylates, acrylates, formates, isobutyrates, capronates, heptanes, propiolates, oxalates, malons, succinates, suberates, sebacinates, fumarates, and more. Salts containing leate, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulfonate, phenyl acetate, phenylpropionate, phenyl butyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0020] "Isomers" are compounds that have the same molecular formula but different structures ("structural isomers"), or compounds that have different geometric positions of functional groups and / or atoms ("stereoisomers"). "Enantiomers" are a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A "racemic mixture" or "racemate" contains equal amounts of a pair of enantiomers and is indicated by the prefix (±).

[0021] Diastereomers are stereoisomers, which are mirror images of each other and cannot be superimposed. Tautomers are structural isomers of the same chemical substance that can spontaneously interconvert to each other even in their pure form.

[0022] The term "solvate," as used herein, refers to an addition complex of a substance dissolved in a solvent (e.g., organic solvents (e.g., aliphatic alcohols (e.g., methanol, ethanol, n-propanol, isopropanol), acetone, acetonitrile, and ether, etc.), water, or a mixture of two or more of these liquids), where the addition complex exists in the form of crystals or mixed crystals. The amount of solvent contained in the addition complex may be stoichiometric or non-stoichiometric. "Hydrate" is a solvate in which the solvent is water.

[0023] compound The present invention comprises a quinone, which is selected from quinones specified in one of general formulas (I) or (II). [ka] [ka]

[0024] R 1 and R 2 These are independently selected from the group consisting of H and -OH.

[0025] R 3 H, -(C1-C 30 )alkyl, -(C2-C 12 ) Alkenyl, -OH, Cl, -O(C1-C 10 ) Selected from the group consisting of alkyl and trifluoromethyl.

[0026] Preferably, R 3 The group is selected from H, -(C1-C5)alkyl, -O(C1-C5)alkyl, -OH, trifluoromethyl, and Cl.

[0027] More preferably, R 3 is selected from the group consisting of H, -CH3, -OH, -OMe, trifluoromethyl, and Cl.

[0028] Most preferably, R 3 is selected from the group consisting of H, -CH3, -OH, trifluoromethyl, and Cl.

[0029] R 4 is independently -(C1-C 30 ) alkyl, -(C2-C 12 ) alkenyl, -NH(C1-C 10 ) alkyl, -NH(C6-C 12 ) aryl, and

Chemical formula

[0030] R 5 is selected from the group consisting of H, -(C1-C 30 ) alkyl, -(C2-C 12 ) alkenyl, -OH, Cl, and -O(C1-C 10 ) alkyl, trifluoromethyl.

[0031] Preferably, R 5H, -(C1-C 10 )alkyl, -O(C1-C 10 ) Selected from the group consisting of alkyl groups.

[0032] Comfortable, R 5 The group is selected from the group consisting of H, -CH3, and -OCH3.

[0033] Most preferably, R 5 The group is selected from the group consisting of -CH3 and -OCH3.

[0034] R 6 Independently, -(C1-C 30 )alkyl, -(C2-C 12 ) Alkenyl, -NH(C1-C 10 ) alkyl, -NH(C6-C 12 ) Aryl, and, [ka] Selected from a group, -(C1-C 30 )alkyl, -(C2-C 12 ) Alkenyl, -NH(C1-C 10 )alkyl and -NH(C6-C 12 In aryl groups, one or more hydrogen atoms are optionally and independently -OH, -O(C1-C) 10 )alkyl, -(C1-C 10 )alkyl, -C(O)(C1-C 10 )alkyl, -COO(C1-C 10 )alkyl, -CONH2, -(C5-C 10 )aryl, -COOH, (C6-C 12 ) Substituted by a substituent selected from the group consisting of aryl atoms.

[0035] R 7 H, -(C1-C 30 )alkyl, -(C2-C 12 ) Alkenyl, -OH, -Cl, -O(C1-C 10 ) Selected from the group consisting of alkyl and trifluoromethyl.

[0036] Preferably, R 7 The group is selected from the group consisting of H, -(C1-C5)alkyl, -O(C1-C5)alkyl, -OH, and -Cl.

[0037] Comfortable, R 7 The group is selected from the group consisting of H, -CH3, -OH, -OMe, and Cl.

[0038] Most preferably, R 7 The group is selected from the group consisting of H, -CH3, -OH, and Cl.

[0039] R 8 H, -(C1-C 30 )alkyl, -(C2-C 12 ) Alkenyl, -OH, -Cl, -O(C1-C 10 ) Selected from the group consisting of alkyl and trifluoromethyl.

[0040] Preferably, R 8 H, -(C1-C 10 )alkyl, -O(C1-C 10 ) Selected from the group consisting of alkyl groups.

[0041] Comfortable, R 8 The group is selected from the group consisting of H, -CH3, and -OCH3.

[0042] Most preferably, R 8 The group is selected from the group consisting of -CH3 and -OCH3.

[0043] A is N or CR 16 That is the case.

[0044] B is a bond, a (C1-C8)alkylene, or a (C2-C8)alkenneene.

[0045] R 10The group is selected from H, -COOH, -CONH2, and -COO(C1-C6)alkyl.

[0046] R 11 , R 12 , R 13 , R 14 , R 15 The following are independently selected from the group consisting of H, (C1-C4)alkyl, -O(C1-C4)alkyl, -OH, halogen, -CF3, -CO(C1-C4)alkyl, COOH, -COO(C1-C6)alkyl, -CONH2, -NH2, -NHCO(C1-C4)alkyl, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, preferably H, -(C1-C4)alkyl, -OCH3, -OH, Cl, F, -CF3, -CO(C1-C4)alkyl, COOH, and more preferably H, -(C1-C4)alkyl, -OCH3, -OH, Cl, F, -CO(C1-C4)alkyl, COOH.

[0047] In one embodiment, R 13 R is selected from the group consisting of -C(O)CH3, -ethyl, -methyl, -OH, and -OCH3. 11 , R 12 , R 14 , R 15 H is H.

[0048] In one embodiment, R 12 is -C(O)CH3, and R 11 , R 13 , R 14 , R 15 H is H.

[0049] In one embodiment, R 11 and R 13 is methyl, and R 12 , R 14 , R 15 H is H.

[0050] R 16 The group is H, (C1-C4) alkyl, OH, preferably H, CH3, or OH.

[0051] In one embodiment, the quinone is the quinone in formula (III), [ka] R 16 and R 17 It is independently selected from the group consisting of H and -OH, and is preferably H. R 18 H, -(C1-C 30 ) Selected from the group consisting of alkyl, trifluoromethyl, preferably H,-CH3, and trifluoromethyl, R 19 teeth, [ka] And, D is N, E is a bond, (C1-C8)alkylene, or (C2-C8)alkenne, preferably a bond, (C1-C8)alkylene, more preferably (C3-C5)alkylene. R 20 This is selected from the group consisting of H, -COOH, -CONH2, -COO(C1-C6)alkyl, preferably H, -COOH, -CONH2. R 21 , R 22 , R 23 , R 24 , R 25 These are independently selected from the group consisting of H, (C1-C4)alkyl, -O(C1-C4)alkyl, -OH, halogen, -CF3, -CO(C1-C4)alkyl, COOH, -COO(C1-C6)alkyl, -CONH2, and -N((C1-C4)alkyl)2, preferably H, -(C1-C4)alkyl, -O(C1-C4)alkyl, -OH, Cl, F, -CF3, -CO(C1-C4)alkyl, and COOH, more preferably H, -(C1-C4)alkyl, -O(C1-C4)alkyl, -OH, Cl, -CO(C1-C4)alkyl, and COOH, particularly preferably H, (C1-C4)alkyl, and -NHCO(C1-C4)alkyl. -(C1-C 30 In alkyl groups, one or more hydrogen atoms are optionally and independently -OH, -O(C1-C 10 )alkyl, (C1-C 10 )alkyl, -C(O)(C1-C 10 )alkyl, -COO(C1-C 10 )alkyl, -CONH2, -COOH, -(C6-C 12 ) Substituted by a substituent selected from the group consisting of aryls, Conditions (i) and (ii) do not exist in the same molecule. (i) E is a bond, R 20 H is (ii)R 18 H is a quinone, Alternatively, it may be a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or hydrate thereof.

[0052] In particular, the quinone is selected from the quinones in Table 1. [Table 1] JPEG2026512759000014.jpg157154JPEG2026512759000015.jpg189154JPEG2026512759000016.jpg89154

[0053] In one embodiment, quinone is, [ka] JPEG2026512759000018.jpg231164JPEG2026512759000019.jpg200141JPEG20265127590 00020.jpg160131JPEG2026512759000021.jpg194157JPEG2026512759000022.jpg103156

[0054] In a further embodiment, quinone is [ka]

[0055] In a further embodiment, the quinone is selected from the quinones in formulas (I) and (II), where the quinone in formula (II) is, [ka]

[0056] In one embodiment, the quinone is not at least one of the following: [ka] JPEG2026512759000026.jpg224152JPEG2026512759000027.jpg232161JPEG2026512759000028.jpg236151JPEG2026512759000029.jpg129141

[0057] Furthermore, the quinones of the present invention include pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, racemates, or hydrates thereof.

[0058] Some of the ingenious compounds may exist as a single stereoisomer (i.e., substantially free of other stereoisomers), a racemate, and / or a mixture of enantiomers and / or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention. Preferably, ingenious compounds that are optically active are used in an optically pure form.

[0059] As is generally understood by those skilled in the art, an optically pure compound having one chiral center (i.e., one chiral carbon atom) is substantially composed of one of two possible enantiomers (i.e., enantiomerically pure), and an optically pure compound having more than one chiral center is both diastereoisomerically pure and enantiomerically pure. Preferably, the compounds of the present invention are used in a form in which the compound contains at least 90% of other enantiomers or diastereomers, i.e., at least 90% (80% enantiomeric excess ("ee")) or diastereomeric excess ("de"), more preferably at least 95% (90% ee or de), even more preferably at least 97.5% (95% ee or de), and most preferably at least 99% (98% ee or de) of a single isomer.

[0060] Pharmaceutical use The quinone of this invention is intended for use in inhibiting ferroptosis.

[0061] In particular, the quinones of the present invention are intended for use in the treatment of diseases that can be treated or prevented by inhibiting ferroptosis.

[0062] Preferably, the disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), COPD, ischemia-reperfusion injury (IRI) of the liver, kidneys, intestines, and lungs, myocardial infarction, cardiomyopathy, stroke, traumatic brain injury, renal degeneration, and retinal degeneration (2, 10, 11).

[0063] Stockwell et al. (2) (Figure 3 and pages 2411 onwards), Conrad et al. (10), and Hadian et al. (11) have reported that ferroptosis is associated with several diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), COPD, ischemia-reperfusion injury (IRI) of the liver, kidneys, intestines, and lungs, myocardial infarction, cardiomyopathy, stroke, traumatic brain injury, renal degeneration, and retinal degeneration.

[0064] The present invention includes a pharmaceutical composition comprising a quinone for use as defined above, and a pharmaceutically acceptable carrier.

[0065] "Pharmaceutical composition" refers to one or more active ingredients, one or more inactive ingredients constituting a carrier, and any products obtained directly or indirectly from any combination, complex formation, or aggregation of any two or more components, or from the dissociation of one or more components, or from other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical composition of the present invention encompasses any composition prepared by mixing the compound of the present invention with a pharmaceutically acceptable carrier.

[0066] A "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutically acceptable carriers may be sterile solutions such as water and oil, including those of petroleum, animal, plant, or synthetic origin, and include, but are not limited to, peanut oil, soybean oil, mineral oil, and sesame oil. When a pharmaceutical composition is administered orally, water is a preferred carrier. When a pharmaceutical composition is administered intravenously, physiological saline and dextrose aqueous solutions are preferred carriers. Physiological saline solutions, dextrose aqueous solutions, and glycerol aqueous solutions are preferably used as pharmaceutically acceptable liquid carriers for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, corn syrup, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, and ethanol. Furthermore, the compositions may optionally contain small amounts of wetting or emulsifying agents or pH buffers. These compositions can take the form of liquids, suspensions, emulsions, tablets, pills, capsules, powders, and sustained-release formulations. Compositions can be formulated as suppositories with conventional binders such as triglycerides and pharmaceutically acceptable carriers. Oral formulations may contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. Examples of suitable pharmaceutically acceptable carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions may contain a therapeutically effective amount of the therapeutic agent, preferably in a purified form, along with an appropriate amount of carrier, to provide a form for appropriate administration to a patient. The formulations must be suitable for the method of administration.

[0067] Regardless of the chosen route of administration, the compounds and / or pharmaceutical compositions of the present invention, which can be used in an appropriate hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art (see, for example, Remington, “The Science and Practice of Pharmacy,” Allen, Loyd V., Jr., eds., 22nd edition, Pharmaceutical Sciences, September 2012; Ansel et al., “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7th edition, Lippincott Williams & Wilkins Publishers, 1999).

[0068] The actual dose level of the active ingredient in the pharmaceutical composition of the present invention may be varied to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response for a particular patient, composition, and method of administration without causing toxicity to the patient. The selected dose level may be determined by a variety of pharmacokinetic factors, including the activity of the particular composition of the present invention used, the route of administration, the time of administration, the excretion rate of the particular compound used, the duration of treatment, other drugs, compounds, and / or substances used in combination with the particular composition used, the age, sex, weight, condition, general health status, and medical history of the patient being treated, as well as similar factors well known in the medical technology.

[0069] A physician or veterinarian skilled in the art can easily determine and prescribe the effective dose of the required pharmaceutical composition. For example, a physician or veterinarian can start the dose of the compound of the present invention used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. Generally, an appropriate daily dose of the composition of the present invention may be the amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such an effective dose may generally be determined by the factors described above. Administration is preferably done orally, intravenously, intramuscularly, intraperitoneally, or subcutaneously, and preferably, for example, proximal to the target site. Where desired, the effective daily dose of the pharmaceutical composition may be administered as 2, 3, 4, 5, 6, or more divided doses, optionally in unit dose form, administered separately at appropriate intervals throughout the day. While the compound of the present invention can be administered alone, it is preferable to administer the compound as a pharmaceutical formulation / composition.

[0070] Generally, the amount of the active ingredient (in particular, the amount of the compound of the present invention, optionally accompanied by other therapeutic agents, if present in a pharmaceutical formulation / composition) may be in the range of about 0.01% to about 99%, preferably about 0.1% to about 70%, most preferably about 1% to about 30%, of 100% (in a pharmaceutical formulation / composition), with the remainder preferably consisting of one or more pharmaceutically acceptable excipients.

[0071] In unit dose forms, and / or when administered to an individual or used for treatment, the amount of the active ingredient, for example, the compound of the present invention, may range from about 0.1 mg to about 1000 mg per unit, dose, or treatment (e.g., about 10 mg to about 200 mg, or about 1 mg to about 500 mg). In certain embodiments, an appropriate amount of such active ingredient may be calculated using the individual's mass or body surface area, ranging from about 1 mg / kg to 10 mg / kg (e.g., about 2 mg / kg to 5 mg / kg), or about 1 mg / m². 2 ~about 400mg / m 2 (For example, about 3 mg / m²) 2 ~about 350mg / m 2Alternatively, approximately 10 mg / m² 2 ~about 200mg / m 2 This includes the amount of ).

[0072] In one embodiment, the compound or composition of the present invention may be administered by infusion, preferably by slow, continuous infusion, over a long period of time, for example, more than 24 hours, in order to minimize toxic side effects. Alternatively, administration may be carried out by continuous infusion over 2 to 24 hours, for example, 2 to 12 hours. Such regimens may be repeated once or more as needed, for example, after 6 or 12 months.

[0073] In yet another embodiment, the compound or composition of the present invention is administered as maintenance therapy once a week for a period of six months or more.

[0074] For oral administration, the pharmaceutical compositions of the present invention may take the form of tablets or capsules, prepared by conventional means, together with pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica), disintegrants (e.g., potato starch, sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). Liquid formulations for oral administration may take the form of, for example, liquids, syrups, or suspensions, or may be provided as a dried product consisting of water or another suitable vehicle before use. Such liquid formulations can be prepared by conventional means with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol, syrup, cellulose derivatives, hydrogenated edible oils), emulsifiers (e.g., lecithin, acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, fractionated vegetable oils), and preservatives (e.g., methyl or propyl-p-hydroxycarbonate, sorbic acid). The formulations may also contain buffer salts, flavorings, colorants, and sweeteners, as appropriate. Formulations for oral administration can be appropriately formulated to control the release of the pharmaceutical composition of the present invention.

[0075] Pharmaceutical compositions can be formulated as suppositories along with conventional binders and carriers such as triglycerides. Oral formulations may contain pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and other standard carriers.

[0076] In administration by inhalation, the pharmaceutical composition of the present invention can be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, nitrogen, or other suitable gas). In the case of a pressurized aerosol, the dose unit can be determined by providing a valve for delivering a fixed amount. For use in inhalers or insufflers, for example, gelatin capsules and cartridges can be formulated to contain a powder mixture of the pharmaceutical composition of the present invention and a suitable powder base material such as lactose or starch.

[0077] The pharmaceutical compositions of the present invention can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations can be provided in unit dose forms (e.g., in vials, multi-dose containers) with the addition of preservatives. The pharmaceutical compositions of the present invention can take the form of suspensions, liquids, or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending agents, stabilizers, and / or dispersing agents. Alternatively, the drug may be in powder form, which is prepared in a suitable vehicle (e.g., sterile water free of pyrogens) before use. Typically, compositions for intravenous administration are liquids in sterile isotonic aqueous buffer. If necessary, the composition may also contain solubilizers and local anesthetics such as lignocaines to relieve pain at the injection site. Generally, the components are supplied separately or mixed in unit dose forms as lyophilized powders or anhydrous concentrates in sealed containers, such as ampoules or sachets, indicating the amount of the active ingredient. When the composition is administered by infusion, it may be provided in an infusion bottle containing pharmaceutical-grade sterile water or saline solution. When the composition is administered by injection, ampoules of sterile water for injection or physiological saline can be provided so that the components can be mixed before administration.

[0078] The therapeutic / pharmaceutical compositions can be administered using medical devices known in the art. For example, in a preferred embodiment, the therapeutic / pharmaceutical compositions of the present invention can be administered with needleless subcutaneous injection devices, such as those disclosed in U.S. Patent No. 5,399,163, U.S. Patent No. 5,383,851, U.S. Patent No. 5,312,335, U.S. Patent No. 5,064,413, U.S. Patent No. 4,941,880, U.S. Patent No. 4,790,824, or U.S. Patent No. 4,596,556. Examples of well-known implants and modules useful in the present invention include those described in U.S. Patent No. 4,487,603, which discloses an implantable microinfusion pump for delivering pharmaceuticals at a controlled rate; U.S. Patent No. 4,486,194, which discloses a therapeutic device for administering pharmaceuticals through the skin; U.S. Patent No. 4,447,233, which discloses a pharmaceutical infusion pump for delivering pharmaceuticals at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow rate implantable infusion device for continuous drug delivery; U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system having multiple chamber compartments; and U.S. Patent No. 4,475,196, which discloses an osmotic drug delivery system.

[0079] Many other such implants, delivery systems, and modules are known to those skilled in the art. In certain embodiments, the compounds of the present invention can be formulated to ensure appropriate distribution in vivo. For example, the blood-brain barrier (BBB) ​​rejects many highly hydrophilic compounds. To ensure that the compounds of the present invention can reliably cross the BBB (where desired), they can be formulated, for example, in liposomes. For methods of producing liposomes, see, for example, U.S. Patent No. 4,522,811, U.S. Patent No. 5,374,548, and U.S. Patent No. 5,399,331. Since liposomes contain one or more components that are selectively delivered to specific cells or organs, they can enhance targeted drug delivery (see, for example, VVRanade (1989), J. Clin. Pharmacol. 29:685). Examples of targeted components include folic acid or biotin (see, e.g., U.S. Patent No. 5,416,016, Lou et al.), mannoside (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153:1038), antibodies (PGBloeman et al., (1995) FEBS Lett. 357:140; M. Owais et al., (1995) Antimicrob. Agents Chemother. 39:180), and surfactant protein A receptors (Briscoe et al., (1995) Am.J. Physiol. 1233:134).

[0080] In one embodiment of the present invention, the compound of the present invention is formulated in liposomes. In a more preferred embodiment, the liposomes contain a target-directed component. In the most preferred embodiment, the compound in the liposomes is delivered by bolus injection to a proximal site of a desired region. Such liposome-based compositions need to be fluid enough to be easily used with a syringe, stable under manufacturing and storage conditions, and resistant to contamination by microorganisms such as bacteria and fungi. [Examples]

[0081] 1. Example 1 1.1 Materials and Methods cell culture Cell lines: Human fibrosarcoma cell line HT-1080 and immortalized mouse embryonic fibroblasts (MEF). The MEF cells were donated by Daniel Klapman, and the HT-1080 cells were purchased from ATCC. Both cell lines were grown in Dulbecco's modified Eagle medium (Thermo Fisher Scientific, 41966-029) supplemented with 10% fetal bovine serum (FBS, Thermo Fisher Scientific), 1% penicillin-streptomycin (Thermo Fisher Scientific), and 1% non-essential amino acids (MEM NEAA, Thermo Fisher Scientific). Cells were grown at 37°C and 5% CO2.

[0082] compound For the ferroptosis assay, I purchased (1S,3R)-RSL3 (RSL3, Sigma), imidazole ketone elastin (IKE, Cayman Chemical), FIN56 (Cayman Chemical), FINO2 (Cayman Chemical), ceratrodust (Sera, Cayman Chemical), and ferrostatin-1 (Fer-1, Sigma).

[0083] For apoptosis and necrotosis assays, we purchased staurosporine (Stauro, TargetMol), Z-VAD-FMK (zVAD, TargetMol), LCL161 (MedChemExpress), tumor necrosis factor α (TNFα, biomol), and necrostatin-1 (Nec-1, BioVision).

[0084] I purchased the following TXA2 receptor antagonists: Tertroban (Sigma), Bapiprost (Santa Cruz Biotechnology), Ramatroban (BAYu 3405, Santa Cruz Biotechnology), and 15(R)-Pinantromboxane A2 (PTA2, Cayman Chemical).

[0085] Cell viability assay HT-1080 cells were seeded in 384-well plates (CulturPlates, PerkinElmer) at a density of 750 cells per well. After 24 hours of growth, the cells were treated for 18 hours with compounds at 10 or 12-point serial dilutions at the indicated concentrations. Viability was detected using CellTiter-Glo2.0 reagent (Promega) according to the manufacturer's instructions, and luminescence was read using an EnVision2104 multi-label plate reader (PerkinElmer).

[0086] To detect apoptosis, HT-1080 cells were treated with staurosporine, followed by the addition of ceratrodust or zVAD-FMK. After 18 hours, caspase-Glo3 / 7 activity was measured using the Caspase-Glo3 / 7 assay reagent (Promega) according to the manufacturer's instructions. Cells were incubated at room temperature for 45 minutes, and luminescence was measured.

[0087] To detect necroptosis, MEFs were treated with TNFα, zVAD-FMK, and LCL161, followed by the addition of seratrodust or necrostatin-1. After 18 hours, CellTiter-Glo2.0 reagent (Promega) was added according to the manufacturer's instructions, viability was measured, and luminescence was read.

[0088] Spheroid formation and imaging 2,000 HT-1080 cells were seeded per well in a 96-well round-bottom ultra-low adhesion microplate (Corning Costar 7007). Spheroids formed over 48 hours, after which they were treated with RSL3 and either ferrostatin-1 or seratrodust. After a further 48 hours, the spheroids were stained with Hoechst 33342 (Sigma) at a 1:10,000 dilution and incubated for 1 hour. Images were acquired using the Operetta High Content Imaging System (PerkinElmer) and analyzed using Columbus software (PerkinElmer). For analysis, spheroids were detected as "image regions" and morphological properties (roundness) were calculated.

[0089] Cell-free BODIPY assay Ferrostatin-1 and seratrodast were diluted in 150 μl of PBS to obtain a concentration of 25 μM. As a control, the same amount of DMSO was diluted in 150 μl of PBS. In a separate tube, BODIPY 581 / 591 C11 (Thermo Fisher Scientific) was diluted to 1.875 μM in 150 μl of PBS, and 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH, Sigma) was diluted to 7.5 mM in 150 μl of PBS. For the non-oxidation control, one sample was prepared using only DMSO without AAPH. All three solutions were equally mixed and incubated in the dark at room temperature for 30 minutes. 100 μl of each condition was transferred to a black 96-well plate (Greiner Bio-One), and fluorescence was measured at 495 nm / 520 nm using an EnVision2104 multi-label plate reader (PerkinElmer).

[0090] TBARS assay Two million HT-1080 cells were seeded in 150 mm dishes and grown for 48 hours. Ferroptosis was induced in RSL3 for 2.5 hours, and cells were co-treated with ferrostatin-1 or seratrodust. Cells were detached with 0.05% trypsin-EDTA (Thermo Fisher Scientific), and cell counts were adjusted to the sample with the lowest cell count. To measure MDA levels, a TBARS (TCA method) assay kit (Cayman Chemical, 700870) was used according to the manufacturer's instructions. Fluorescence was detected at 530 nm / 550 nm using an EnVision2104 multi-label plate reader (PerkinElmer).

[0091] Flow cytometry HT1080 cells were grown in a 6-well plate (200,000 cells per well) and incubated for 24 hours. To stain with BODIPY 581 / 591 C11 (Thermo Fisher Scientific), cells were treated with RSL3 and ferrostatin-1 or seratrodust for 2 hours, after which BODIPY was added to the wells to a final concentration of 2 μM. After incubation for 30 minutes, cells were detached using trypsin and washed twice with PBS. Between washing steps, cells were centrifuged at 500 × g for 5 minutes. After the final washing step, the cell pellet was resuspended in 300 μl of PBS, and 10,000 events per condition were analyzed on the BL-1 channel of an Attune acoustic flow cytometer (Applied Biosystems). To detect 4-hydroxynonenal (4-HNE), HT-1080 cells were induced with RSL3, co-treated with ferrostatin-1 or seratrodust for 2 hours, and then detached using trypsin. The cell pellet was incubated on ice for 30 minutes in 10% normal goat serum (Thermo Fisher Scientific). Subsequently, the cells were incubated on ice for 1 hour with anti-4-HNE antibody (1:50 dilution in 1% BSA in PBS, ab46545, Abcam). After three washing steps in PBS, the cells were resuspended in anti-rabbit Alexa488 antibody (1:200 dilution in 1% BSA in PBS, A32731, Thermo Fisher Scientific) and incubated on ice for 30 minutes. For flow cytometry, cells were collected in 300 μl of PBS, and 10,000 events per condition were analyzed using an Attune acoustic flow cytometer (Applied Biosystems) with the BL-1 channel. FlowJo v10.8.1 (BD Life Sciences) was used to create histograms and analyze fluorescence intensity.

[0092] statistics Statistical analysis was performed using GraphPad Prism version 9.4. Dose-response curves were created using two biological replicas, and each experiment was performed using two technical replicas per condition. Apoptosis and necroptosis assays were performed using technical triplicates. Spheroid experiments were performed with n=8 spheroids under all conditions. TXA2 receptor antagonist assays were performed using technical triplicates. TBARS assays, cell-free BODIPY assays, 4-HNE immunostaining, and BODIPY staining were performed in three independent biological experiments. For FACS experiments, representative histograms are shown, and all histograms were quantified for representation in bar graphs (n=3). Statistical tests are indicated in the figure captions.

[0093] 1.2 Results and Discussion The potential of small molecules with radical scavenging capabilities, which have been previously used clinically, to be used in a different application of drugs, namely ferroptosis inhibition, is a reasonable exploration. Seratrodast (Figure 1A), a studied thromboxane A2 receptor (TXA2) antagonist containing a quinone moiety (13), was investigated to see if it could inhibit ferroptosis in the model cell line HT-1080. The effects of seratrodast on various modes of cell death have been studied. Interestingly, seratrodast suppressed ferroptosis (Figure 1B) but not necroptosis (Figure 1C) and apoptosis (Figure 1D), thus demonstrating good selectivity for ferroptosis compared to the other two regulatory cell death pathways tested. Next, various ferroptosis-inducing factors (FINs) were used to understand whether seratrodast counteracts ferroptosis in general. Therefore, ferroptosis was induced by IKE (class I FIN), RSL3 (class II FIN), FIN56, and FINO2. Seratrodust was able to suppress ferroptosis induced by all four FINs (Figure 1E), and importantly, it was as potent as ferrostatin-1 (9), a reference ferroptosis inhibitor. Further analysis was conducted to determine whether seratrodust competes with ferroptotic cell death in a 3D spheroid system encompassing a more physiological context than 2D monolayer culture. Treatment of HT-1080-derived spheroids with RSL3 resulted in dissociation of 3D tissue bodies, which was quantified by a decrease in roundness (Figure 1F). Ferrostatin-1 and seratrodust adequately inhibited ferroptosis-based spheroid disruption (Figure 1F). To understand the mechanism behind seratrodast's potential ferroptosis inhibition, we tested further TXA2 receptor antagonists lacking a quinone moiety (in contrast to seratrodast) to detach radical scavenging activity from TXA2 receptor inhibition. Interestingly, all TXA2 receptor inhibitors lacking a quinone moiety were unable to compete with ferroptotic cell death, thus suggesting that seratrodast's radical scavenging activity inhibits ferroptosis (Figure 1G).To verify these findings, cell-free C11-BODIPY experiments were performed using 2,2'-azobis(2-methyl-propanimidoamide) dihydrochloride (AAPH), which generates free radicals, in conjunction with the C11-BODIPY sensor. Both ceratorodust and Fer-1 significantly reduced AAPH-induced oxidative fluorescence, again demonstrating ceratorodust's radical scavenging ability (Figure 1H). As a result, ceratorodust reduced the level of malondialdehyde (MDA), a product of lipid peroxidation induced by RSL3 treatment (Figure 1I). Similarly, the level of RSL3-mediated peroxidation in the C11-BODIPY sensor was significantly reduced by ceratorodust treatment (Figure 1J). Finally, the level of 4-hydroxynonenal (4-HNE) produced by RSL3 treatment was reduced by ceratorodust (Figure 1K). In particular, the ferroptosis inhibitory effects of seratrodust on cell viability and lipid peroxidation were similar to those of the reference molecule ferrostatin-1.

[0094] 2. Example 2 Based on the assay of Example 1, further quinones listed in Table 2 were tested. Table 2 shows the efficacy and cytotoxicity of quinones. [Table 2] JPEG2026512759000031.jpg238162JPEG2026512759000032.jpg233164JPEG2026512759000033.jpg237144JPEG2026512759000034.jpg238155JPEG2026512759000035.jpg234149JPEG2026512759000036.jpg238145JPEG2026512759000037.jpg239142JPEG2026512759000038.jpg242158JPEG2026512759000039.jpg241152JPEG2026512759000040.jpg241154JPEG2026512759000041.jpg236138JPEG2026512759000042.jpg236135

[0095] References 1. S. J. Dixon et al., Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060 - 1072 (2012). 2. B. R. Stockwell, Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 185, 2401 - 2421 (2022). 3. K. Bersuker et al., The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688 - 692 (2019). 4. S. Doll et al., FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693 - 698 (2019) 5. V. A. N. Kraft et al., GTP Cyclohydrolase 1 / Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS central science 6, 41-53 (2020). 6. M. Soula et al., Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat Chem Biol 16, 1351-1360 (2020). 7. C. Mao et al., DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 593, 586-590 (2021). 8. E. Mishima et al., A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 10.1038 / s41586-022-05022-3 (2022). 9. K. Hadian, B. R. Stockwell, SnapShot: Ferroptosis. Cell 181, 1188-1188 e1181 (2020). 10. M. Conrad, S. M. Lorenz, B. Proneth, Targeting Ferroptosis: New Hope for As-Yet-Incurable Diseases. Trends in molecular medicine 27, 113-122 (2020). 11. K. Hadian, B. R. Stockwell, A roadmap to creating ferroptosis-based medicines. Nat Chem Biol 17, 1113-1116 (2021). 12. S. Pushpakom et al., Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18, 41-58 (2019). 13. S. Terao, M. Shiraishi, T. Matsumoto, Y. Ashida, [Thromboxane A2 antagonist--discovery of seratrodast]. Yakugaku Zasshi 119, 377-390 (1999).

Claims

1. Quinones for use in inhibiting ferroptosis.

2. The quinone according to claim 1, for use in the treatment of a disease that can be treated or prevented by inhibiting ferroptosis.

3. The quinone according to claim 2, wherein the disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), COPD, stroke, traumatic brain injury, renal degeneration, acute renal failure, cardiac disorders, cardiomyopathy, acute liver failure, lung disorders, and retinal degeneration.

4. The quinone is a quinone specified in one of general formulas (I) or (II), 【Chemistry 1】 (I) 【Chemistry 2】 (II) R １ and R ２ These are independently selected from the group consisting of H and -OH, R ３ is selected from the group consisting of H, -(C １ -C ３０ ), alkyl, -(C ２ -C １２ ), alkenyl, -OH, chlorine, -O(C １ -C １０ ), alkyl, trifluoromethyl, R ４ Independently, -(C １ -C ３０ ) alkyl, -(C ２ -C １２ ) Alkenyl, -NH(C １ -C １０ ) alkyl and -NH(C ６ -C １２ ) Ariel, 【Transformation 3】 Selected from a group, - (C １ -C ３０ ) alkyl, -(C ２ -C １２ ) Alkenyl, -NH(C １ -C １０ ) alkyl and -NH(C ６ -C １２ In the aryl group, one or more hydrogen atoms may be independently -OH, -O(C) １ -C １０ ) alkyl, (C １ -C １０ ) alkyl, -C(O)(C １ -C １０ ) alkyl, -COO(C １ -C １０ ) Alkyl, -CONH ２ , -COOH, -(C ６ -C １２ ) Substituted by a substituent selected from the group consisting of aryls, R ５ H, -(C １ -C ３０ ) alkyl, -(C ２ -C １２ ) Alkenyl, -OH, and chlorine, -O(C １ -C １０ ) Selected from the group consisting of alkyl and trifluoromethyl, R ６ Independently, -(C １ -C ３０ ) alkyl, -(C ２ -C １２ ) Alkenyl, -NH(C １ -C １０ ) alkyl and -NH(C ６ -C １２ ) Ariel, 【Chemistry 4】 Selected from a group, - (C １ -C ３０ ) alkyl, -(C ２ -C １２ ) Alkenyl, -NH(C １ -C １０ ) alkyl and -NH(C ６ -C １２ In the aryl group, one or more hydrogen atoms may be independently -OH, -O(C) １ -C １０ ) alkyl, (C １ -C １０ ) alkyl, -C(O)(C １ -C １０ ) alkyl, -COO(C １ -C １０ ) Alkyl, -CONH ２ , -COOH, -(C ６ -C １２ ) Substituted by a substituent selected from the group consisting of aryls, R ７ H, -(C １ -C ３０ ) alkyl, -(C ２ -C １２ ) Alkenyl, -OH, Chlorine, -O(C １ -C １０ ) Selected from the group consisting of alkyl and trifluoromethyl, R ８ H, -(C １ -C ３０ ) alkyl, -(C ２ -C １２ ) Alkenyl, -OH, Chlorine, -O(C １ -C １０ ) Selected from the group consisting of alkyl and trifluoromethyl, A is N or CR １６ And, B is a bond, (C １ -C ８ ) alkylene, or (C ２ -C ８ ) alkenylene, and R １０ H, -COOH, -CONH ２ , -COO(C １ -C ６ ) Selected from the group consisting of alkyl groups, R １１ 、R １２ 、R １３ 、R １４ 、R １５ is independently H, (C １ -C ４ ), alkyl, -O(C １ -C ４ ), alkyl, -OH, halogen, -CF ３ 、-CO(C １ -C ４ ), alkyl, COOH, -COO(C １ -C ６ ), alkyl, -CONH ２ 、-NH ２ 、-NHCO(C １ -C ４ ), alkyl, -NH(C １ -C ４ ), alkyl, and, -N((C １ -C ４ ), alkyl) ２ 、preferably, H, -(C １ -C ４ ), alkyl, -O(C １ -C ４ ), alkyl, -OH, Cl, F, -CF ３ 、-CO(C １ -C ４ ), alkyl, and, COOH, more preferably, H, -(C １ -C ４ ), alkyl, -O(C １ -C ４ ), alkyl, -OH, Cl, -CO(C １ -C ４ ), alkyl, and, COOH selected from the group consisting of, R １６ H, (C １ -C ４ ) alkyl, OH, preferably H, CH ３ , or OH, quinone, Alternatively, a quinone according to any one of claims 1 to 3, selected from pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, racemates, or hydrates thereof.

5. The quinone is quinone (I), R ３ H, -(C １ -C ５ ) alkyl, -O(C １ -C ５ ) Selected from the group consisting of alkyl, -OH, trifluoromethyl, and Cl, Preferably, R ３ H, -CH ３ Selected from the group consisting of -OH, -OMe, trifluoromethyl, and Cl, more preferably R ３ H, -CH ３ Selected from the group consisting of -OH, trifluoromethyl, and Cl, and / or R １１ , R １２ , R １３ , R １４ , R １５ These are independently H, -(C １ -C ４ ) alkyl, -OCH ３ , -OH, Cl, F, -CF ３ , -CO(C １ -C ４ ) Selected from the group consisting of alkyl and COOH, Preferably, R １１ , R １２ , R １３ , R １４ , R １５ These are independently H, -(C １ -C ４ ) alkyl, -OCH ３ , -OH, Cl, F, -CF ３ , -CO(C １ -C ４ ) Selected from the group consisting of alkyl and COOH, more preferably R １１ , R １２ , R １３ , R １４ , R １５ These are independently H, -(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkyl, -OH, Cl, -CO(C １ -C ４ A quinone (I) selected from the group consisting of alkyl and COOH groups, or It is Quinon (II), R ５ H, -(C １ -C １０ ) Alkyl, trifluoromethyl, -O(C １ -C １０ ) Selected from the group consisting of alkyl groups, preferably R ５ H, -CH ３ , -OCH ３ Selected from the group, more preferably R ５ is, -CH ３ , -OCH ３ Selected from a group consisting of, and / or, R ７ H, -(C １ -C ５ ) alkyl, -O(C １ -C ５ ) Selected from the group consisting of alkyl, -OH, trifluoromethyl, and Cl, Preferably, R ７ H, -CH ３ Selected from the group consisting of -OH, -OMe, and Cl, More specifically, R ７ H, -CH ３ Selected from the group consisting of , -OH, and Cl, and / or R ８ H, -(C １ -C １０ ) Alkyl, trifluoromethyl, -O(C １ -C １０ ) Selected from the group consisting of alkyl groups, preferably R ８ H, -CH ３ , -OCH ３ Selected from the group, more preferably R ８ is, -CH ３ , -OCH ３ Selected from a group consisting of, and / or, R １１ , R １２ , R １３ , R １４ , R １５ These are independently H, -(C １ -C ４ ) alkyl, -OCH ３ , -OH, Cl, F, -CF ３ , -CO(C １ -C ４ ) Selected from the group consisting of alkyl and COOH, Preferably, R １１ , R １２ , R １３ , R １４ , R １５ These are independently H, -(C １ -C ４ ) alkyl, -OCH ３ , -OH, Cl, F, -CF ３ , -CO(C １ -C ４ ) Selected from the group consisting of alkyl and COOH, more preferably R １１ , R １２ , R １３ , R １４ , R １５ These are independently H, -(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkyl, -OH, Cl, -CO(C １ -C ４ A quinone according to claim 4, selected from the group consisting of alkyl and COOH, and quinone(II).

6. The quinone is quinone (I), (i) R １３ is -C(O)CH ３ -ethyl, -methyl, -OH, and -OCH ３ Selected from the following group, R １１ , R １２ , R １４ , R １５ is H, or (ii) R １２ Ha-C(O)CH ３ And R １１ , R １３ , R １４ , R １５ is H, or, (iii) R １１ and R １３ is methyl, R １２ , R １４ , R １５ A quinone according to claim 4 or 5, wherein is H, selected from quinone (I).

7. The aforementioned quinone is, 【Transformation 5】 【change】 【change】 A quinone according to any one of claims 1 to 3, selected from the group comprising the above.

8. The aforementioned quinone is, 【Transformation 6】 A quinone according to any one of claims 1 to 3, selected from the group comprising the above.

9. The aforementioned quinone is, 【Transformation 7】 A quinone according to any one of claims 1 to 3, selected from the group comprising the above.

10. The aforementioned quinone is, 【Transformation 8】 Not the quinone described in any of claims 1 to 3.

11. The quinone in formula (III), 【Chemistry 9】 R １６ and R １７ These are independently selected from the group consisting of H and -OH, R １８ H, -(C １ -C ３０ ) Selected from the group consisting of alkyl and trifluoromethyl, R １９ teeth, 【Chemistry 10】 And, D is N, E is bonded, (C １ -C ８ ) Alkilen, or (C ２ -C ８ ) are alkenylenes, R ２０ H, -COOH, -CONH ２ , -COO(C １ -C ６ ) Selected from the group consisting of alkyl groups, R ２１ , R ２２ , R ２３ , R ２４ , R ２５ H, (C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkyl, -OH, halogen, -CF ３ , -CO(C １ -C ４ ) Alkyl, COOH, -COO(C １ -C ６ ) Alkyl, -CONH ２ , -NH ２ , - NHCO (C １ -C ４ ) Alkyl, -NH(C １ -C ４ ) alkyl, and -N((C １ -C ４ )alkyl) ２ Preferably, H, -(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkyl, -OH, Cl, F, -CF ３ , -CO(C １ -C ４ ) alkyl, and COOH, more preferably H, -(C １ -C ４ ) alkyl, -O(C １ -C ４ ) Alkyl, -OH, Cl, -CO(C １ -C ４ ) Selected from the group consisting of alkyl and COOH, - (C １ -C ３０ In alkyl groups, one or more hydrogen atoms can optionally and independently form -OH, -O(C) １ -C １０ ) alkyl, (C １ -C １０ ) alkyl, -C(O)(C １ -C １０ ) alkyl, -COO(C １ -C １０ ) Alkyl, -CONH ２ , -COOH, -(C ６ -C １２ ) Substituted by a substituent selected from the group consisting of aryls, Conditions (i) and (ii) do not exist in the same molecule. (i) E is a bond, R ２０ H is (ii) R １８ H is quinone, Alternatively, a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or hydrate thereof.

12. R １６ and R １７ They are independently selected from the group consisting of H, R １８ H, -CH ３ Selected from the group consisting of trifluoromethyl, R １９ teeth, 【Chemistry 11】 And, D is N, E is bonded, (C １ -C ８ ) Alkylene, preferably (C ３ -C ５ ) is alkylene, R ２０ H, -COOH, -CONH ２ Selected from a group, R ２１ , R ２２ , R ２３ , R ２４ , R ２５ H, (C １ -C ４ ) Alkyl, -NHCO(C １ -C ４ ) Selected from the group consisting of alkyl groups, Conditions (i) and (ii) do not exist in the same molecule. (i) E is a bond, R ２０ H is (ii) R １８ H is quinone, Alternatively, the quinone according to claim 11, which is a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate, or hydrate thereof. 【Request Item 13】 【Chemistry 12】 A quinone according to claim 11 or 12, selected from the group comprising the above.

14. A pharmaceutical composition comprising a quinone according to any one of claims 1 to 13, and a pharmaceutically acceptable carrier.

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