Method and composition for inhibiting accumulation of lipid peroxides

Abstract

The present invention provides the following as individual embodiments: a method for inhibiting dysfunction caused by the accumulation of lipid peroxides in a living body or a biomaterial; a composition for inhibiting dysfunction caused by the accumulation of lipid peroxides in a living body or a biomaterial; and a low molecular compound capable of inhibiting the accumulation of lipid peroxides. The method for inhibiting dysfunction of a living body or a biomaterial includes inhibiting the accumulation of lipid peroxides in a living body or a biomaterial. Also provided are: a composition for dysfunction of a living body or a biomaterial, the composition containing a substance that inhibits the accumulation of lipid peroxides as an active ingredient; and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Description

Methods and compositions for inhibiting lipid peroxide accumulation

[0001] The present disclosure relates to a method and composition for inhibiting the accumulation of lipid peroxides. The present disclosure relates to a method for inhibiting functional damage of a living organism or biomaterial, a method for inhibiting functional damage of a living organism or biomaterial, a composition for inhibiting functional damage, a preservation method, a preservation solution, as well as a transplantation adjuvant, a pharmaceutical composition, and an agent for inhibiting the accumulation of lipid peroxides.

[0002] Ferroptosis is a type of iron-dependent programmed cell death caused by the accumulation of lipid peroxides in cells due to glutathione depletion or excessive oxidative stress. Ferroptosis is thought to be involved in various diseases, such as acute organ damage, ischemic diseases, and neurodegenerative diseases such as Parkinson's disease. Therefore, efforts have been made to develop drugs that inhibit ferroptosis. Examples of drugs that inhibit ferroptosis include low-molecular-weight lipophilic free radical scavengers such as ferrostatin-1 and liproxstatin-1, Zileuton, and 10H-phenothiazine compounds (see, for example, Patent Document 1). It has also been reported that certain spiroquinoxaline derivatives have the effect of inhibiting ferroptosis (see, for example, Patent Document 2).

[0003] Ischemia-reperfusion injury, which can occur during organ transplantation, is caused by cell death, which has traditionally been thought to be a result of two processes: apoptosis and necrosis. However, recent research has suggested that ferroptosis may also be involved. Furthermore, organs used for transplantation are cold-preserved to extend their storage life. However, when mammalian cells are stored in a low-temperature environment, cell death occurs due to the low-temperature stress caused by non-hibernating mammals such as humans, who have low cold tolerance. For this reason, the standard method for organ preservation has remained unchanged for over 20 years: cold preservation using an organ protection solution (Patent Documents 3 and 4), with the time each organ can withstand cold preservation being the upper limit of storage time. Recently, it has been reported that cold-induced cell death of human cancer cells can be suppressed by ferroptosis inhibitors, while it cannot be suppressed by inhibitors of apoptosis or necrosis (Non-Patent Document 1).

[0004] JP 2021-526157 A JP 2019-196390 A JP 2010-239963 A JP 2010-529053 A

[0005] Hattori, K., et al., EMBO Rep, 18(11), 2067-2078

[0006] Accumulation of lipid peroxides can cause functional disorders in the body, including cellular dysfunction and organ damage, various diseases such as neurodegenerative diseases, and ischemia-reperfusion injury that can occur after organ transplantation and cold injury during organ preservation. Therefore, in one aspect, the present disclosure provides a method for suppressing functional disorder in a living organism or biomaterial by suppressing the accumulation of lipid peroxides, a composition for suppressing functional disorder, a method and preservation solution for preserving a living organism or biomaterial, and a transplant adjuvant. In another aspect, the present disclosure provides a new low-molecular-weight compound capable of suppressing lipid peroxide accumulation, and a pharmaceutical composition containing, as an active ingredient, a substance that suppresses lipid peroxide accumulation.

[0007] In one aspect, the present disclosure relates to a method for suppressing functional disorder of a living organism or a biological material, which comprises suppressing accumulation of lipid peroxides in the living organism or the biological material. In another aspect, the present disclosure relates to a method for suppressing functional disorder of a living organism or a biological material, which comprises contacting the living organism or the biological material with a compound represented by the following formulas (I) to (VII) or a pharmaceutically acceptable salt thereof: In formula (I), R 1 is a C1 to C6 hydrocarbon group, and R 2 is a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group, and R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group which may have a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group. In formula (II), A is a sulfur atom or an oxygen atom, and Ar 1 is selected from the following groups: In the above group, R 11 is a hydrogen atom, a hydroxyl group, a halogen atom, an amino group, or a C1 to C6 alkylamino group, and R 4 and R 6 are each independently a hydrogen atom, a hydroxyl group, a C1-C6 alkoxy group, a halogen atom, an amino group, a C1-C6 alkylamino group, or a nitrogen-containing saturated heterocyclic group represented by the following formula: 4 and R 6 one of the groups is a nitrogen-containing saturated heterocyclic group represented by the following formula, in which x is an integer of 1 to 5: R 5 is a hydrogen atom, a hydroxyl group, a C1 to C6 alkoxy group, a halogen atom, an amino group, or a C1 to C6 alkylamino group. 7 is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a halogen atom, and Ar 2 is represented by the following group: In the above group, R 12 and R 14are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group. 8 is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a halogen atom, and Ar 3 is represented by the following group: In the above group, R 12 and R 14 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group. 9 is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a halogen atom, and Ar 4 is represented by the following group: In the above group, R 12 and R 14 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group. 5 and Ar 6 are each independently selected from the following groups: In the above group, R 15 , R 17 , and R 19 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkoxy group, a halogen atom, an amino group, or a C1 to C6 alkylamino group, and R 16 and R 18are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen atom, a nitro group, an amino group, a C1 to C6 alkylamino group, or a C1 to C6 alkylcarbonyloxy group. In formula (VII), X is a sulfur atom, an imino group (-NH-), or a methylene group (-CH2-), Y is a sulfur atom or an oxygen atom, and Ar 7 is selected from the following groups: In the above group, R 20 , R 22 , and R 23 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 21 is selected from a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, a halogen atom, or the following group: R 24 is a hydrogen atom or a C1-C6 alkyl group, In the above group, x 1 is an integer from 1 to 3, and R 25 is a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom.

[0008] In another aspect, the present disclosure relates to a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, the present disclosure relates to a pharmaceutical composition containing, as an active ingredient, a substance that inhibits the accumulation of lipid peroxides.In another aspect, the present disclosure relates to a pharmaceutical composition containing, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present disclosure relates to a composition for suppressing functional disorder of a living organism or a biomaterial, which comprises, as an active ingredient, a substance that suppresses the accumulation of lipid peroxides.In another aspect, the present disclosure relates to a composition for suppressing functional disorder of a living organism or a biomaterial, which comprises, as an active ingredient, a compound represented by any of the above formulas (I) to (VII) or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present disclosure relates to a method for preserving a living organism or a biological material, which comprises suppressing accumulation of lipid peroxides in the living organism or the biological material during preservation.In another aspect, the present disclosure relates to a method for preserving a living organism or a biological material, which comprises contacting the living organism or the biological material with a compound represented by any one of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof during preservation.

[0012] In another aspect, the present disclosure relates to a preservation solution for a living organism or a biological material, which contains, as an active ingredient, a substance that inhibits the accumulation of lipid peroxides.In another aspect, the present disclosure relates to a preservation solution for a living organism or a biological material, which contains, as an active ingredient, a compound represented by any of the above formulas (I) to (VII) or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present disclosure relates to a transplant adjuvant containing a substance that inhibits lipid peroxide accumulation as an active ingredient.In another aspect, the present disclosure relates to a transplant adjuvant containing a compound represented by any of the above formulas (I) to (VII) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014] In another aspect, the present disclosure relates to an agent for suppressing lipid peroxide accumulation, which comprises, as an active ingredient, a compound represented by any one of the above formulas (I) to (VII) or a pharmaceutically acceptable salt thereof.

[0015] In one aspect, the present disclosure can provide a method for suppressing functional impairment of a living organism or biomaterial by suppressing the accumulation of lipid peroxides, a composition for suppressing functional impairment, a method and preservation solution for preserving a living organism or biomaterial, and a transplant adjuvant.In one aspect, the present disclosure can provide a new low-molecular-weight compound capable of suppressing the accumulation of lipid peroxides, and a pharmaceutical composition containing, as an active ingredient, a substance that suppresses the accumulation of lipid peroxides.

[0016] FIG. 1 shows a graph illustrating an example of the results of evaluating the lipid peroxide accumulation inhibitory effect of Compounds 2 to 10 according to the present disclosure as an inhibitory effect on a cell-free Fenton reaction, and the associated experimental scheme. FIG. 2 shows a graph illustrating an example of the results of evaluating the lipid peroxide accumulation inhibitory effect of Compound 2 according to the present disclosure as an inhibitory effect on intracellular lipid peroxide accumulation, as well as stained images of nuclei and lipid peroxides and the associated experimental scheme. FIG. 3 shows a graph illustrating an example of the results of evaluating the inhibitory effect of Compounds 1 to 11 according to the present disclosure on functional impairment of cultured human cells, and the associated experimental scheme. FIG. 4 shows a graph illustrating an example of the pain therapeutic effect of Compound 2 according to the present disclosure when orally administered to a mouse model of low-temperature burn-induced pain, and the associated experimental scheme. FIG. 5 shows an example of the stained image of cells (calcein-positive cells) and the associated experimental scheme, illustrating the inhibitory effect of Compound 2 according to the present disclosure on erastin-induced ferroptosis. FIG. 6 shows a graph illustrating an example of the inhibitory effect of Compound 2 according to the present disclosure on erastin-induced ferroptosis, as well as the associated experimental scheme. Figure 7 shows a graph illustrating an example of blood concentration distribution after oral administration of compound 2 according to the present disclosure, and an experimental scheme thereof. Figure 8 shows a graph illustrating an example of the inhibitory effect of compound 2 according to the present disclosure on pulmonary function decline due to pulmonary ischemia-reperfusion injury, and a photograph of a left-side isogenic single lung transplant. Figure 9 shows the inhibitory effect of compound 2 according to the present disclosure on death from cerebral ischemia-reperfusion injury, and an experimental scheme thereof. Figure 10 shows a graph illustrating an example of the inhibitory effect of compound 2 according to the present disclosure on cerebral ischemia-reperfusion injury, and an experimental scheme thereof. Figure 11 shows the modified neurological severity score used to evaluate the inhibitory effect of compound 2 according to the present disclosure on cerebral ischemia-reperfusion injury.

[0017] In the course of extensive research to develop a compound capable of suppressing the accumulation of lipid peroxides, the present inventors have discovered that compounds having a structure represented by the following formulas (I) to (VII) in their skeleton, capsaicin, and N-[4-[[4-(4-methylpiperazin-1-yl)-6-[(3-methyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl]thio]phenyl]cyclopropane-1-carboxamide (Compound A: VX-680 or Tozasertib), have the effect of suppressing the accumulation of lipid peroxides and further the production of lipid peroxides by the Fenton reaction. Furthermore, the present inventors have discovered that compounds having a structure represented by the following formulas (I) to (VII) in their skeleton and Compound A can suppress cellular dysfunction during cryopreservation, and have confirmed in vivo experiments using a mouse model of acetaminophen-induced liver injury that they can suppress liver damage caused by the accumulation of lipid peroxides.

[0018] Lipid peroxides (lipid hydroperoxides, LOOH) are a general term for lipid peroxides that are generated by the addition of active oxygen to the unsaturated fatty acid moiety of phospholipids, and have a peroxide bond (-O-O-) in the molecule. In one or more embodiments, the Fenton reaction can be mentioned as a reaction that generates lipid peroxides. The Fenton reaction is a reaction in which Fe 2+ The Fenton reaction is a reaction in which electrons are donated to hydrogen peroxide (HO) using Fe(II) as a catalyst, generating hydroxyl radicals (OH·). It is believed that most hydroxyl radicals generated in living organisms are generated by the Fenton reaction. Hydroxyl radicals (OH·) generated in living organisms react with lipids (LH) present in cell membranes, etc., to generate lipid radicals (L·), which then react with dissolved oxygen to become lipid peroxyl radicals (LOO·). The lipid peroxyl radicals (LOO·) react with other lipids (LH) to abstract hydrogen from the lipids, becoming lipid peroxides, and simultaneously generating new lipid radicals (L·). As a result, lipid peroxidation reactions are repeated in a chain reaction. Therefore, by inhibiting the Fenton reaction and suppressing the generation of hydroxyl radicals, it is possible to suppress the accumulation of lipid peroxides.

[0019] In one or more embodiments, the reduction reaction of lipid peroxides may be a reduction reaction catalyzed by glutathione peroxidase 4 (GPX4). GPX4 is an antioxidant enzyme containing selenocysteine, and it reduces lipid peroxides using reduced glutathione as a cofactor (electron donor), converting them to lipid alcohols. Therefore, by activating the reduction reaction catalyzed by GPX4, the generated lipid peroxides can be reduced and eliminated, and the chain reaction of lipid oxidation can be avoided, thereby suppressing the accumulation of lipid peroxides.

[0020] In one or more embodiments, "suppressing the accumulation of lipid peroxides" in the present disclosure may include not only suppressing the accumulation of lipid peroxides themselves, but also suppressing the production of lipid peroxides, suppressing the reaction that produces lipid peroxides, and / or activating (promoting) the reduction reaction of lipid peroxides, etc. In one or more embodiments, "suppressing the accumulation of lipid peroxides" in the present disclosure may use suppression of lipid peroxide accumulation as an indicator, suppression of the Fenton reaction as an indicator, suppression of lipid peroxide accumulation resulting from the Fenton reaction as an indicator, and / or suppression of programmed cell death characterized by iron-dependent accumulation of lipid peroxides as an indicator.

[0021] In one or more embodiments, the inhibition of lipid peroxide accumulation may be measured using the amount of lipid peroxide produced or the pIC50 obtained therefrom as an indicator, or using a stained image of cells / tissues obtained by fluorescently staining lipid peroxides as an indicator. In one or more embodiments, examples of the inhibition of lipid peroxide accumulation include, when the amount of lipid peroxide produced is measured by the TBARS method (or the MDA method), the inhibition rate of lipid peroxide production is 50% or more, 55% or more, 60% or more, 65% or more, 66% or more, 67% or more, 68% or more, 69% or more, or 70% or more compared to a control (no contact with the compound). The amount of lipid peroxide produced can be measured by the method described in the Examples. In one or more embodiments, examples of the inhibition of lipid peroxide accumulation include, when the amount of lipid peroxide produced is measured by the TBARS method (or the MDA method), the pIC50 (M) is 6.5 or more, 6.6 or more, 6.7 or more, 6.8 or more, 6.9 or more, or 7 or more. The amount of lipid peroxide produced can be measured by the method described in the Examples. In one or more embodiments, examples of inhibition of lipid peroxide accumulation include, when cell nuclei and lipid peroxides are fluorescently stained, the proportion of cells stained with lipid peroxides among live cells is 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, or 10% or less. Cell staining and measurement can be performed by the method described in the Examples.

[0022] In the present disclosure, the term "functional disorder" refers to a functional disorder caused by the accumulation of lipid peroxides and / or the generation of lipid peroxy radicals, and in one or more non-limiting embodiments, may also be referred to as a functional disorder caused by ferroptosis and / or a functional disorder caused by nephrosis. In one or more embodiments, the functional disorder may include disorders in various organs and tissues, functional disorders in cells, and diseases.

[0023] Ferroptosis is a type of iron-dependent programmed cell death caused by the accumulation of lipid peroxides in cells due to glutathione depletion or excessive oxidative stress. Ferroptosis has been shown to be involved in various diseases, such as acute organ failure, ischemic diseases, and neurodegenerative diseases such as Parkinson's disease. Ferroptosis can also be induced by the accumulation of lipid peroxides due to cold stress.

[0024] NETosis is a type of cell death specific to neutrophils, and the accumulation of lipid peroxides is one of the causes of NETosis. NETs undergoing NETosis form extracellular net-like structures called neutrophil extracellular traps (NETs). NETs are formed by the neutrophil's own chromatin and facilitate phagocytosis by neutrophils and macrophages. However, because NETs contain inflammatory substances, excessive release of NETs induces tissue damage. Therefore, excessive NETosis is thought to be involved in the development of thrombosis and autoimmune diseases such as systemic lupus erythematosus (SLE).

[0025] In the present disclosure, "functional disorder caused by ferroptosis" refers to a functional disorder in which ferroptosis contributes to the onset, chronicity, and / or aggravation of the disorder, and in one or more non-limiting embodiments, refers to a functional disorder in which ferroptosis induced by the accumulation of lipid peroxides contributes to the onset, chronicity, and / or aggravation of the disorder. In the present disclosure, "functional disorder caused by netosis" refers to a functional disorder in which netosis contributes to the onset, chronicity, and / or aggravation of the disorder, and in one or more non-limiting embodiments, refers to a functional disorder in which neutrophils undergoing netosis and / or neutrophils forming Nets contribute to the onset, chronicity, and / or aggravation of the disorder.

[0026] In one or more embodiments, functional disorders include acute organ disorders, cold injury, ischemia-reperfusion injury (IRI), cancer, ischemic disease, organ fibrosis, pain, immune cell dysfunction, and neurodegenerative diseases. In one or more embodiments, ischemia-reperfusion injury includes pulmonary ischemia-reperfusion injury and cerebral ischemia-reperfusion injury. In one or more embodiments, acute organ disorders include liver disorders, kidney disorders, stroke, myocardial infarction, heart, and cerebral ischemic injury. In one or more embodiments, cancer includes hepatocellular carcinoma, sarcoma, glioma, renal cell carcinoma, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, melanoma, colon cancer, diffuse large B-cell lymphoma, leukemia, lung cancer, clear cell carcinoma, and non-small cell lung cancer. In one or more embodiments, ischemic diseases include ischemic heart diseases such as angina pectoris and myocardial infarction, and ischemic brain diseases such as cerebral infarction. In one or more embodiments, examples of organ fibrosis include pulmonary fibrosis, myocardial fibrosis, hepatic fibrosis, renal fibrosis, and systemic sclerosis, in which fibrosis (excessive deposition of intercellular components such as collagen, resulting in organ dysfunction) is observed in the lungs, heart, liver, kidneys, skin, and the like. In one or more embodiments, examples of pain include all conditions in which pain is observed, including acute and chronic pain, such as inflammatory pain, neuropathic pain, burn-induced pain, and cancer pain. In one or more embodiments, examples of immune cell dysfunction include dysfunction that can occur in some or all of immune cells due to the accumulation of lipid peroxides, and diseases accompanied by immune cell dysfunction. In one or more embodiments, examples of immune cell dysfunction include dysfunction and decreased activity of immune cells. In one or more embodiments, examples of immune cells include T cells, helper cells, and NK cells. In one or more embodiments, examples of diseases accompanied by immune cell dysfunction include primary amyloidosis.In one or a plurality of embodiments, examples of neurodegenerative diseases include Parkinson's disease, Huntington's disease, tauopathy, muscular dystrophy, Marfan syndrome, amyotrophic lateral sclerosis (ALS), cerebral ischemia, multiple sclerosis, Lewy body disease, Menkes disease, Wilson's disease, Creutzfeldt-Jakob disease, Fahr's disease, frontotemporal dementia, amyloidosis, depression, autism spectrum disorder, dementia, frontotemporal dementia, Alzheimer's disease, and HIV-associated dementia.

[0027] In one or more embodiments, dysfunctions caused by NETOS include systemic inflammatory response syndrome (SIRS); acute lung injury (ALI); acute respiratory distress syndrome (ARDS); multiple organ failure or multiple organ dysfunction syndrome (MODS) due to ARDS, hemorrhagic shock, surgery, burns, sepsis, or the like; sepsis; septic coagulopathy; trauma; multiple sclerosis; acute kidney injury (AKI); AKI-associated tubular necrosis and remote organ damage; post-traumatic surgery; hemorrhagic shock; cytokine storm induced by infection, or drugs or any agent; ischemic or hemorrhagic stroke; secondary brain injury in stroke; myocardial ischemia / infarction; atherosclerotic vulnerable plaque; atherosclerotic thrombosis; coronary artery disease; acute coronary syndrome; heart failure; reperfusion injury; comorbidities in renal dialysis patients (e.g., thrombosis and endothelial dysfunction); cerebral ischemic or drug-induced These diseases include drug-induced hemorrhagic changes, hemorrhagic encephalopathy, traumatic brain injury; anoxic brain injury; chronic kidney disease; cancer; actPMN-dependent cancers; diabetes; type 1 diabetes; type 2 diabetes; vascular disorders; vasculopathy; end-organ complications (e.g., retinopathy and diabetic nephropathy); poor wound healing of diabetic ulcers; deep vein thrombosis; cancer metastasis; systemic microthrombosis; chemotherapy-induced microthrombosis; atherosclerotic thrombosis; systemic lupus erythematosus (SLE); lupus nephritis; SLE-accelerated atherosclerosis; autoimmune diseases such as rheumatoid arthritis; COPD; cystic fibrosis; and organ fibrosis (excessive deposition of intercellular components such as collagen, resulting in organ dysfunction) in the lungs, heart, liver, kidneys, and skin; pulmonary diseases; Alzheimer's disease; sickle cell disease; inflammatory bowel disease (IBD); Crohn's disease; ulcerative colitis; and undifferentiated colitis.

[0028] In the present disclosure, "cold injury" refers to injury to cells caused by exposure of biological materials such as cells or organs to low temperatures. In one or more embodiments, cold injury in a living organism or biological material can lead to a decrease in cell viability or cell death in the living organism or biological material. In one or more embodiments, "low temperature" in the present disclosure refers to a low temperature not below 0°C, and in one or more embodiments, the temperature can be between 0°C and 4°C.

[0029] In the present disclosure, in one or more embodiments, "suppression of functional impairment" may include prevention, inhibition, prevention, reduction, etc. of functional impairment. In one or more embodiments, suppression of functional impairment may include suppression of a decrease in cell viability, suppression of cell death, etc.

[0030] In one or more embodiments, the biomaterial may be a material (biomaterial) obtained from an animal such as a human or a non-human mammal. In one or more embodiments, the biomaterial may be an organ, tissue, cell, body fluid, blood transfusion product, cell sheet, or the like. In one or more embodiments, the organ may be a heart, blood, skin, diaphragm, cornea, liver, pancreas, blood vessel, kidney, brain, eyeball, spleen, gallbladder, bile duct, ovary, uterus, lung, esophagus, duodenum, small intestine, large intestine (colon or rectum), prostate, bladder, nerve, placenta, umbilical cord, or retina. In one or more embodiments, the body fluid may be blood or semen, or the like, and in one or more embodiments, a body fluid that is sensitive to low temperatures may be platelets, or the like.

[0031] In one or more embodiments, the living body may be an animal such as a human or a non-human mammal. In one or more embodiments, the non-human mammal in the present disclosure may be a mouse, rat, guinea pig, hamster, rabbit, cat, dog, sheep, pig, cow, horse, goat, monkey, etc.

[0032] In the present disclosure, the term "hydrocarbon group" refers to a group containing carbon atoms and hydrogen atoms, and is obtained by removing a hydrogen atom from a hydrocarbon. In one or more embodiments, examples of the hydrocarbon group include an aliphatic hydrocarbon group and an aromatic hydrocarbon group. The "aliphatic hydrocarbon group" may be linear, branched, or cyclic, and may be saturated or unsaturated. The hydrocarbon group may also contain one or more ring structures. In one or more embodiments, examples of the C1 to C6 hydrocarbon group include a C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, and a C2 to C6 alkenyl group.

[0033] In the present disclosure, the term "C1 to C6 alkyl group" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. In one or more embodiments, examples of the C1 to C6 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, and a hexyl group. In one or more embodiments, examples of the butyl group include an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group. In one or more embodiments, examples of the pentyl group include an isopentyl group, a sec-pentyl group, a 3-pentyl group, and a tert-pentyl group.

[0034] In the present disclosure, a "C3 to C6 cycloalkyl group" refers to a cyclic alkyl group (saturated hydrocarbon group (ring)) having 3 to 6 carbon atoms. In one or more embodiments, examples of the C3 to C6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0035] In the present disclosure, the term "C2 to C6 alkenyl group" refers to a hydrocarbon group having at least one double bond and having 2 to 6 carbon atoms. In one or more embodiments, examples of the C2 to C6 alkenyl group include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl (homoallyl), isobutenyl, pentenyl, and hexenyl.

[0036] In the present disclosure, the term "C2 to C6 alkenyloxy group" refers to a group in which a C2 to C6 alkenyl group is bonded to an oxy group. In one or more embodiments, examples of the C2 to C6 alkenyloxy group include a vinyloxy group, a 1-propenyloxy group, an allyloxy group, an isopropenyloxy group, a 1-butenyloxy group, an isobutenyloxy group, a 3-methyl-2-butenyloxy group, a butadienyloxy group, a pentenyloxy group, an isopentenyloxy group, a pentadienyloxy group, a hexenyloxy group, an isohexenyloxy group, and a hexadienyloxy group.

[0037] In the present disclosure, the term "C1 to C6 alkoxy group" refers to a group in which a C1 to C6 alkyl group is bonded to an oxy group (-O-R: R is a C1 to C6 alkyl group). In one or more embodiments, the C1 to C6 alkoxy group includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, an isobutoxy group, and a tert-butoxy group.

[0038] In the present disclosure, the term "C1 to C6 alkylamino group" refers to an amino group that is mono- or di-substituted with an alkyl group and has 1 to 6 carbon atoms. In one or more embodiments, examples of the C1 to C6 alkylamino group include a methylamino group, a dimethylamino group, an ethylamino group, a propylamino group, and a diethylamino group.

[0039] In the present disclosure, a "C1 to C6 alkylcarbonyloxy group" refers to a carbonyloxy group having a C1 to C6 alkyl group (-C(=O)-O-R, where R is a C1 to C6 alkyl group). In one or more embodiments, examples of the C1 to C6 alkylcarbonyloxy group include a methyl ester group, an ethyl ester group, a propyl ester group, and a butyl ester group.

[0040] In one or more embodiments, the C1 to C6 hydrocarbon group, C1 to C6 alkyl group, C1 to C6 cycloalkyl group, C2 to C6 alkenyl group, C1 to C6 alkoxy group, C1 to C6 alkylamino group, C2 to C6 alkenyloxy group, and C1 to C6 alkylcarbonyloxy group may or may not have a substituent. In one or more embodiments, examples of the substituent include a halogen atom, a hydroxyl group, a nitro group, —CN, a C1 to C6 alkyl group, and a C1 to C6 alkoxy group.

[0041] In one or more embodiments, halogen atoms in the present disclosure include fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.

[0042] [Substances that suppress lipid peroxide accumulation] In one or more embodiments, examples of substances that suppress lipid peroxide accumulation in the present disclosure include substances that suppress the Fenton reaction, etc. In one or more embodiments, examples of substances that suppress lipid peroxide accumulation in the present disclosure include substances that can suppress lipid peroxide accumulation, and in one or more embodiments, examples of substances that can suppress ferroptosis, etc.

[0043] In one or more embodiments, the substance that inhibits the accumulation of lipid peroxides includes the compounds according to the present disclosure described below, i.e., the compound represented by formula (I) above or a pharmaceutically acceptable salt thereof. In one or more embodiments, other substances that inhibit the accumulation of lipid peroxides include capsaicin (N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methyl-6-nonenamide), compounds represented by formulas (II) to (VII) or pharmaceutically acceptable salts thereof, and compound A having the following structure (N-[4-[[4-(4-methylpiperazin-1-yl)-6-[(3-methyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl]thio]phenyl]cyclopropane-1-carboxamide).

[0044] [Compound represented by formula (I) according to the present disclosure] In one aspect, the present disclosure provides a compound represented by the following formula (I): or a pharmaceutically acceptable salt thereof. 1 is a C1 to C6 hydrocarbon group, and R 2 is a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group, and R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group which may have a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group.

[0045] R 1 In one or more embodiments, R is preferably a C1 to C6 alkyl group, more preferably a C1 to C5 alkyl group or a C1 to C4 alkyl group. 1 In one or more embodiments, a methyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group are preferred.

[0046] R 2 In one or more embodiments, R is preferably a halogen atom or a C1 to C6 alkoxy group. 2 In one or more embodiments, the C1 to C6 alkoxy group of R includes a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. 2 In one or more embodiments, is preferably a halogen atom or a methoxy group.

[0047] R 3 In one or more embodiments, R is preferably a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group. 3 In one or more embodiments, the C1 to C6 alkoxy group of R includes a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. 3 In one or more embodiments, the heterocyclyl group preferably contains 2 to 3 heteroatoms. In one or more embodiments, one of the heteroatoms is preferably a nitrogen atom, and R 3 The bond of R is preferably bonded to this hetero nitrogen atom. 3In one or more embodiments, the heteroatoms of the heterocyclyl group are nitrogen atoms only, or a combination of nitrogen and oxygen atoms. 3 In one or more embodiments, the heterocyclyl group of R may be a piperazinyl group, a morpholinyl group, or a triazolyl group. 3 In one or more embodiments, the substituent of the heterocyclyl group of R is a C1 to C3 alkyl group, preferably a methyl group or an ethyl group. 3 In one or more embodiments, examples of the heterocyclyl group include the following heterocyclyl groups. In the above substituents, the bond marked with * indicates the bonding site to the compound of formula (I). 3 In one or more embodiments, examples of the heterocyclyl group include a halogen atom, a C1-C3 alkoxy group, or the above-mentioned heterocyclyl group, preferably a fluorine atom, a chlorine atom, a bromine atom, a methoxy group, an ethoxy group, an isopropoxy group, or the above-mentioned heterocyclyl group, and more preferably a chlorine atom, a methoxy group, or the above-mentioned heterocyclyl group.

[0048] R 1 , R 2 and R 3 In one or more embodiments, the halogen atom in may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom, a chlorine atom, or a bromine atom, and more preferably a chlorine atom.

[0049] In one or more embodiments, R 1 is a C1 to C6 alkyl group, and / or R 2 is a halogen atom or a C1-C6 alkoxy group, and / or R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and preferably R 1 is a methyl group, an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, and / or R 2 is a chlorine atom or a methoxy group, and / or R 3is a chlorine atom or an isopropoxy group.

[0050] In one or more embodiments, the compound represented by formula (I) includes a compound represented by the following formula: In the above compound, R 1 , R 2 , and R 3 is the same as that of the compound represented by formula (I). 1 In one or more embodiments, R is preferably a C1 to C6 alkyl group, and more preferably a methyl group, an ethyl group, an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group. 2 In one or more embodiments, R is preferably a halogen atom, a C1 to C3 alkyl group, or a C1 to C6 alkoxy group, more preferably a halogen atom, a C1 to C6 alkyl group, or a C1 to C3 alkoxy group, even more preferably a halogen atom or a C1 to C3 alkoxy group, and even more preferably a chlorine atom or a methoxy group. 3 In one or more embodiments, R is preferably a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and more preferably a chlorine atom. 1 is a C1 to C6 alkyl group, and / or R 2 is a halogen atom, a C1-C3 alkyl group, or a C1-C6 alkoxy group, and / or R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and preferably R 1 is a C1 to C6 alkyl group, and / or R 2 is a halogen atom, a C1-C3 alkyl group, or a C1-C3 alkoxy group, and / or R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and more preferably, R 1 is a C1 to C6 alkyl group, and / or R 2 is a halogen atom or a C1-C3 alkoxy group, and / or R 3is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and more preferably R 1 is a methyl group, an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, and / or R 2 is a chlorine atom or a methoxy group, and / or R 3 is a chlorine atom, an isopropoxy group, or a heterocyclyl group shown below.

[0051] In one or more embodiments, the compound represented by formula (I) includes a compound represented by the following formula: In the above compound, R 1 , R 2 , and R 3 is the same as that of the compound represented by formula (I). 1 In one or more embodiments, R is preferably a C3 to C6 alkyl group, more preferably an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group. 2 In one or more embodiments, R is preferably a halogen atom or a C1 to C6 alkoxy group, more preferably a halogen atom or a C1 to C3 alkoxy group, even more preferably a chlorine atom, a methoxy group or an ethoxy group, and even more preferably a chlorine atom or a methoxy group. 3 In one or more embodiments, R is preferably a halogen atom, and more preferably a chlorine atom. 1 is a C3 to C6 alkyl group, and / or R 2 is a halogen atom or a C1-C6 alkoxy group, and / or R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and preferably R 1 is an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, and / or R 2 is a halogen atom or a C1-C3 alkoxy group, and / or R 3is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and more preferably, R 1 is an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, and / or R 2 is a chlorine atom or a methoxy group, and / or R 3 is a chlorine atom.

[0052] In one or more embodiments, the compound represented by formula (I) includes a compound represented by the following formula: In the above compound, R 1 , R 2 , and R 3 is the same as that of the compound represented by formula (I). 1 In one or more embodiments, R is preferably a C1 to C6 alkyl group, and more preferably a methyl group, an ethyl group, an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, or a C3 to C6 alkyl group. 2 In one or more embodiments, R is preferably a halogen atom or a C1 to C6 alkoxy group, and more preferably a chlorine atom or a methoxy group. 3 In one or more embodiments, R is preferably a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and more preferably a chlorine atom. 1 is a C3 to C6 alkyl group, and / or R 2 is a halogen atom or a C1-C6 alkoxy group, and / or R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and preferably R 1 is a C3 to C6 alkyl group, and / or R 2 is a halogen atom or a C1-C3 alkoxy group, and / or R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and more preferably, R 1is an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, and / or R 2 is a chlorine atom or a methoxy group, and / or R 3 is a chlorine atom, an isopropoxy group, or a heterocyclyl group shown below.

[0053] In one or more embodiments, the compound represented by formula (I) includes a compound represented by the following formula: In the above compound, R 2 and R 3 is the same as in formula (I). 2 In one or more embodiments, R is preferably a halogen atom or a C1 to C6 alkoxy group, and more preferably a chlorine atom or a methoxy group. 3 In one or more embodiments, is preferably a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, more preferably a chlorine atom.

[0054] In one or more embodiments of the above formula, R 2 is a halogen atom or a C1-C6 alkoxy group, and / or R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and preferably R 2 is a chlorine atom or a methoxy group, and / or R 3 is a chlorine atom, an isopropoxy group, or a heterocyclyl group shown below, More preferably, R 2 is a chlorine atom or a methoxy group, and / or R 3 is a chlorine atom.

[0055] In one or more embodiments, the compound represented by formula (I) includes a compound represented by the following formula: In the following compound, R 2 and R 3 is the same as formula (I). In the above compound, R 2 and R 3is the same as in formula (I). 2 In one or more embodiments, R is preferably a halogen atom or a C1 to C6 alkoxy group, and more preferably a chlorine atom or a methoxy group. 3 In one or more embodiments, is preferably a chlorine atom.

[0056] In one or more embodiments of the above formula, R 2 is a halogen atom or a C1-C6 alkoxy group, and / or R 3 is a halogen atom, and preferably, R 2 is a chlorine atom or a methoxy group, and / or R 3 is a chlorine atom.

[0057] In one or more embodiments, the compound represented by formula (I) includes a compound represented by the following formula: In the above compound, R 2 and R 3 is the same as in formula (I). 2 In one or more embodiments, R is preferably a halogen atom or a C1 to C6 alkoxy group, and more preferably a chlorine atom or a methoxy group. 3 In one or more embodiments, is preferably a chlorine atom.

[0058] In one or more embodiments of the above formula, R 2 is a halogen atom or a C1-C6 alkoxy group, and / or R 3 is a halogen atom, and preferably, R 2 is a chlorine atom or a methoxy group, and / or R 3 is a chlorine atom.

[0059] In one or more embodiments, the compound represented by formula (I) includes the following compounds.

[0060] [Compound Represented by Formula (II)] In one or more embodiments, the substance that inhibits the accumulation of lipid peroxides includes a compound represented by formula (II). A is a sulfur atom or an oxygen atom, and Ar1 is selected from the following groups: R 4 and R 6 are each independently a hydrogen atom, a hydroxyl group, a C1-C6 alkoxy group, a halogen atom, an amino group, a C1-C6 alkylamino group, or a nitrogen-containing saturated heterocyclic group represented by the following formula: 4 and R 6 one of R is a nitrogen-containing saturated heterocyclic group represented by the following formula: 5 is a hydrogen atom, a hydroxyl group, a C1 to C6 alkoxy group, a halogen atom, an amino group, or a C1 to C6 alkylamino group. In the above group, R 11 is a hydrogen atom, a hydroxyl group, a halogen atom, an amino group, or a C1 to C6 alkylamino group, and x is an integer of 1 to 5. In the above substituents, the bond marked with * indicates the bonding site to the compound of formula (II).

[0061] In formula (II), the C1 to C6 alkoxy group, halogen atom, and C1 to C6 alkylamino group are as defined above.

[0062] The compound represented by formula (II) includes a compound represented by the following formula: 1 , R 4 , R 5 , R 6 and x are the same as in formula (II).

[0063] In one or more embodiments of the above formula, A is a sulfur atom, and / or Ar 1 is selected from the following groups (wherein R 11 is a hydrogen atom, a hydroxyl group, a halogen atom, an amino group, or a methyl group), and / or R 4 and R 6 is a hydrogen atom or an amino group, and / or R 5 is a halogen atom, and / or x is 2, 3, or 4. In the above substituents, the bond marked with * indicates the bonding site to the compound of formula (II).

[0064] The compound represented by formula (II) includes a compound represented by the following formula: 4 , R 5 , R 11 and x are the same as in formula (II).

[0065] In one or more embodiments of the above formula, R 4 is a hydrogen atom or an amino group, and / or R 5 is a fluorine atom, a chlorine atom, or a bromine atom, and / or x is 2, 3, or 4, and / or R 11 is a hydrogen atom, a hydroxyl group, a halogen atom, an amino group, or a methyl group, and preferably R 4 is a hydrogen atom or an amino group, and / or R 5 is a fluorine atom, and / or x is 3 or 4, and / or R 11 is a hydrogen atom.

[0066] In one or more embodiments, the compound represented by formula (II) includes a compound represented by the following formula: 4 and R 5 is the same as formula (II).

[0067] In one or more embodiments of the above formula, R 4 is a hydrogen atom or an amino group, and / or R 5 is a fluorine atom, a chlorine atom, or a bromine atom, and preferably R 4 is a hydrogen atom or an amino group, and / or R 5 is a fluorine atom.

[0068] In one or more embodiments, the compound represented by formula (II) includes the following compounds.

[0069] [Compound Represented by Formula (III)] In one or more embodiments, the substance that inhibits the accumulation of lipid peroxides includes a compound represented by formula (III). R7 is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a halogen atom, and Ar 2 is represented by the following group. In the above group, R 12 and R 14 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group.

[0070] In formula (III), the C1-C6 alkyl group, C2-C6 alkenyl group, halogen atom, C1-C6 alkoxy group, C1-C6 alkoxy group, C2-C6 alkenyloxy group, and C1-C6 alkylamino group are as defined above. In the above substituents, the bond marked with * indicates the bonding site to the compound of formula (III).

[0071] In one or more embodiments, the compound represented by formula (III) includes a compound represented by the following formula: 7 , R 12 , R 13 , and R 14 is the same as formula (III).

[0072] In one or more embodiments of the above formula, R 7 is a hydrogen atom or a C1 to C6 alkyl group, and / or R 12 is a hydrogen atom, a hydroxyl group, or a C1 to C6 alkoxy group, and / or R 13 is a hydroxyl group, and / or R 14 is a hydrogen atom, a C2-C6 alkenyl group, or a C1-C6 alkoxy group. 7 is a hydrogen atom, a methyl group, a propyl group, or a pentyl group, and / or R 12 is a hydrogen atom, a methoxy group, an ethoxy group, or a propoxy group, and / or R 13 is a hydroxyl group, and / or R 14is an ethenyl group, a propenyl group, a butenyl group, a methoxy group, an ethoxy group, or a propoxy group. 7 is a hydrogen atom or a 3-pentyl group, and / or R 12 is a hydrogen atom or a methoxy group, and / or R 13 is a hydroxyl group, and / or R 14 is a propenyl group or an ethoxy group.

[0073] In the above formula, R 12 is a hydrogen atom, in one or more embodiments, R 14 is a C1 to C6 alkoxy group, preferably a methoxy group, an ethoxy group, or a propoxy group. 12 is a C1-C6 alkoxy group, in one or more embodiments, R 14 is a hydrogen atom or a C2 to C6 alkenyl group, preferably a C2 to C6 alkenyl group, more preferably an ethenyl group, a propenyl group, or a butenyl group.

[0074] In one or more embodiments, the compound represented by formula (III) includes the following compounds.

[0075] [Compound Represented by Formula (IV)] In one or more embodiments, the substance that inhibits the accumulation of lipid peroxides includes a compound represented by formula (IV). Ar 3 is represented by the following group, and R 8 is a hydrogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, or a halogen atom. In the above group, R 12 and R 14 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group.

[0076] In formula (IV), the C1-C6 alkoxy group, halogen atom, and C1-C6 alkylamino group are as defined above. In the above substituents, the bond marked with * indicates the bonding site to the compound of formula (IV).

[0077] In one or more embodiments, the compound represented by formula (IV) includes a compound represented by the following formula: In the following formula, R 8 , R 12 , R 13 , and R 14 is the same as formula (IV).

[0078] [Compound Represented by Formula (V)] In one or more embodiments, the substance that inhibits the accumulation of lipid peroxides includes a compound represented by formula (V). Ar 4 is represented by the following group, and R 9 is a hydrogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, or a halogen atom. In the above group, R 12 and R 14 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group.

[0079] In formula (V), the C1-C6 alkoxy group, halogen atom, and C1-C6 alkylamino group are as defined above. In the above substituents, the bond marked with * indicates the bonding site to the compound of formula (V).

[0080] In one or more embodiments, the compound represented by formula (V) includes a compound represented by the following formula: In the following formula, R 9 , R 12 , R 13 , and R 14 is the same as formula (V).

[0081] [Compound Represented by Formula (VI)] In one or more embodiments, the substance that inhibits the accumulation of lipid peroxides includes a compound represented by formula (VI). Ar 5 and Ar 6 are each independently selected from the following groups: In the above group, R 15 , R 17 , and R 19 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkoxy group, a halogen atom, an amino group, or a C1 to C6 alkylamino group, and R 16 and R 18 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen atom, a nitro group, an amino group, a C1 to C6 alkylamino group, or a C1 to C6 alkylcarbonyloxy group.

[0082] In formula (VI), the halogen atom, C1-C6 alkylamino group, C1-C6 alkyl group, C1-C6 alkoxy group, and C1-C6 alkylcarbonyloxy group are as defined above. In the above substituents, the bond marked with * indicates the bonding site to the compound of formula (VI).

[0083] In one or more embodiments, the compound represented by formula (VI) includes a compound represented by the following formula: 15 , R 16 , R 17 , R 18 , and R 19 is the same as in formula (VI). 15' , R 16' , R 17' , and R 18' are R 15 , R 16 , R 17 , and R 18 Corresponds to.

[0084] In one or more embodiments, the compound represented by formula (VI) includes a compound represented by the following formula: 15 , R 16, R 17 , R 18 , and R 19 is the same as in formula (VI). 15' , R 16' , R 17' , and R 18' are R 15 , R 16 , R 17 , and R 18 Corresponds to.

[0085] In one or more embodiments of the above formula, R 15 , R 16 , and R 17 are each independently a hydrogen atom, a methyl group, or a halogen atom, and / or R 15' , R 16' , R 17' , and R 18' are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkoxy group, a halogen atom, a nitro group, a methyl group, or a C1 to C6 alkylcarbonyloxy group, and preferably, R 15 , R 16 , and R 17 are each independently a hydrogen atom, a methyl group, a fluorine atom, a bromine atom, an iodine atom, or a chlorine atom, and / or R 15' , R 16' , R 17' , and R 18' are each independently a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, a halogen atom, a nitro group, a methyl group, or an ethoxycarbonyloxy group.

[0086] In one or more embodiments of the above formula, R 15 is a hydrogen atom or a halogen atom, and / or R 16 is a hydrogen atom, a methyl group, or a halogen atom, and / or R 17 is a hydrogen atom or a halogen atom, and / or R 15' is a hydrogen atom or a C1-C6 alkoxy group, and / or R 16'is a hydrogen atom, a C1-C6 alkoxy group, or a C1-C6 alkyl group, and / or R 17' is a hydrogen atom, a hydroxyl group, a C1-C6 alkoxy group, a halogen atom, or a C1-C6 alkylcarbonyloxy group, and / or R 18' is a hydrogen atom, a nitro group, or a C1 to C6 alkoxy group, and preferably R 15 is a hydrogen atom or a bromine atom, and / or R 16 is a hydrogen atom, a methyl group, an iodine atom, a fluorine atom, or a chlorine atom, and / or R 17 is a hydrogen atom or a chlorine atom, and / or R 15' is a hydrogen atom or a methoxy group, and / or R 16' is a hydrogen atom, a methoxy group, a chlorine atom, or a methyl group, and / or R 17' is a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, or an ethoxycarbonyloxy group, and R 18' is a hydrogen atom, a nitro group, a methoxy group, or an ethoxy group.

[0087] In one or more embodiments of the above formula, R 15 , R 16 , and R 17 are each independently a hydrogen atom, a methyl group, or a halogen atom, and / or R 19 is a hydrogen atom, a hydroxyl group, a C1 to C6 alkoxy group, a halogen atom, or a methyl group, and preferably R 15 , R 16 , and R 17 is a hydrogen atom, and / or R 19 are each independently a hydrogen atom, a hydroxyl group, a methoxy group, a halogen atom, a nitro group, or a methyl group.

[0088] In one or more embodiments, the compound represented by formula (VI) includes the following compounds.

[0089] [Compound Represented by Formula (VII)] In one or more embodiments, the substance that inhibits the accumulation of lipid peroxides includes a compound represented by formula (VII). X is a sulfur atom, an imino group (-NH-), or a methylene group (-CH2-), Y is a sulfur atom or an oxygen atom, and Ar 7 is selected from the following groups: In the above group, R 20 , R 22 , and R 23 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 21 is selected from a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, a halogen atom, or the following substituents, and R 24 is a hydrogen atom or a C1-C6 alkyl group. In the above groups, the bond marked with * indicates the bonding site to the compound of formula (VII). In the above substituents, x 1 is an integer from 1 to 3, and R 25 is a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom. In the above substituents, a bond marked with * indicates the bonding site to the above group.

[0090] In formula (VII), the C1 to C6 alkyl group, the C2 to C6 alkenyl group, the C1 to C6 alkoxy group, the C2 to C6 alkenyloxy group, and the halogen atom are as defined above.

[0091] In one or more embodiments, X is a sulfur atom or an imino group (—NH—), and / or Y is a sulfur atom, and / or Ar 7 is selected from the following groups: 22 and R 23 may be the same or different. In one or more embodiments of the above group, R20 is a hydrogen atom, a hydroxyl group, a methyl group, a methoxy group, or a halogen atom, and / or R 21 is a hydrogen atom, a hydroxyl group, a methyl group, a methoxy group, a halogen atom, or a pyrrolidinyl group, and / or R 22 and R 23 are each independently a hydrogen atom or a methyl group, and / or R 24 is a hydrogen atom, a methyl group, or an ethyl group. In the above groups, the bond marked with * indicates the bonding site to the compound of formula (VII).

[0092] In one or more embodiments, the compound represented by formula (VII) includes a compound represented by the following formula: 20 , R 21 , R 22 , R 23 , and R 24 is the same as in formula (VII). 20 and R 21 may be the same or different. 22 and R 23 may be the same or different.

[0093] In one or more embodiments of the above formula, R 20 is a hydroxyl group, a methyl group, a methoxy group, or a halogen atom, and / or R 21 is a hydroxyl group, a methyl group, a methoxy group, a halogen atom, or a pyrrolidinyl group, and / or R 22 is a hydrogen atom or a methyl group, and / or R 23 is a hydrogen atom or a methyl group, and / or R 24 is a hydrogen atom, a methyl group, or an ethyl group.

[0094] R 20 and R 21 In one or more embodiments, examples of the combination include a methoxy group and a methoxy group, a methoxy group and a hydroxyl group, a methoxy group and a halogen atom, a halogen atom and a hydroxyl group, and a halogen atom and a pyrrolidinyl group.

[0095] In one or more embodiments, the compound represented by formula (VII) includes the following compounds.

[0096] In one or more embodiments, when the compounds represented by formulas (I) to (VII) have asymmetric carbon atoms and / or stereoisomers, the compounds are a mixture of isomers or isolated isomers. In one or more embodiments, stereoisomers include cis-trans isomers, but are not limited thereto.

[0097] In the present disclosure, a "pharmaceutically acceptable salt" refers to a pharmacologically and / or pharmaceutically acceptable salt, and includes inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acidic amino acid salts, basic amino acid salts, etc. In one or more embodiments, inorganic acid salts include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc. In one or more embodiments, organic acid salts include acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, p-toluenesulfonate, etc. In one or more embodiments, inorganic base salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, and ammonium salt. In one or more embodiments, organic base salts include diethylamine salt, diethanolamine salt, meglumine salt, N,N'-dibenzylethylenediamine salt, etc. In one or more embodiments, examples of the acidic amino acid salt include aspartate and glutamate. In one or more embodiments, examples of the basic amino acid salt include arginine salt, lysine salt, and ornithine salt.

[0098] Pharmaceutically acceptable salts of the compounds of the present disclosure may include hydrates. In addition, in the present disclosure, "salts of compounds" may also include solvates that may be formed when the compounds absorb other types of solvents.

[0099] The compounds of the present disclosure, their pharmaceutically acceptable salts, or solvates thereof may exist in various isomers, such as geometric isomers such as cis- and trans-isomers, tautomers, rotational isomers, optical isomers (enantiomers) such as d- and l-isomers, and diastereomers, depending on the types and combinations of substituents. Unless otherwise specified, the compounds of the present disclosure encompass all isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio. Mixtures of these isomers can be separated by known resolution methods.

[0100] In one or more embodiments, the compounds of the present disclosure may be labeled, i.e., one or more atoms of the compound may be isotoped (e.g., 2 H. 3 H. 13 C. 14 C, and 35 Also included are compounds substituted with aryl groups such as S.

[0101] Compounds that are converted into the compounds represented by formulae (I) to (VII), which are active ingredients of the pharmaceutical compositions of the present invention, by reactions catalyzed by enzymes, gastric acid, or the like under physiological conditions in vivo, i.e., compounds that are converted into the compounds represented by formulae (I) to (VII) by enzymatic oxidation, reduction, hydrolysis, or the like, or compounds that are converted into the compounds represented by formulae (I) to (VII) by hydrolysis, or the like, by gastric acid, or the like, are encompassed in the present disclosure as "pharmaceutically acceptable prodrug compounds." In one or more embodiments, a prodrug is a compound having a group that can be converted into an amino group, hydroxyl group, carboxyl group, or the like of a compound by hydrolysis or under physiological conditions, and examples of groups that form such prodrugs include those described in Prog. Med., Vol. 5, pp. 2157-2161, 1985, and the like.

[0102] In one or more embodiments, the compound represented by formula (I) can be synthesized by taking into consideration the synthesis methods described below and / or the methods described in the Examples.

[0103] [Method for synthesizing a compound represented by formula (I)] A representative method for producing a compound represented by formula (I) will be described below. In one or more embodiments, the compound of the present disclosure can be produced by the following method. 1 , R 2 and R 3 is the same as the above formula (I). The production methods shown below are examples, and the present disclosure should not be construed as being limited thereto.

[0104] Step (1) is a step of acetylating compound (a) to obtain compound (b). t Step (1) can be carried out using BuOK (potassium tert-butoxide) and ethyl acetate under the following conditions: Reaction temperature: 25°C Reaction time: 20 hours

[0105] Step (2) is a step of introducing chlorine into the active methylene of compound (b) to obtain compound (c). The introduction of chlorine can be carried out using TMS-Cl (Trimethylchlorosilane) and NCS (N-chlorosuccinimide). Step (2) can be carried out under the following conditions: Reaction temperature: 0°C to 15°C Reaction time: 2 to 6 hours

[0106] Step (3) is a step of reacting compound (d) with sodium nitrite to obtain compound (e). Step (3) can be carried out under acidic conditions under the following conditions: Reaction temperature: 0°C to 15°C Reaction time: 1 hour to 2 hours

[0107] Step (4) is a step in which compound (c), which is the chloride prepared in step (2), is reacted with compound (e), which is the diazonium salt prepared in step (3), in the presence of pyridine to obtain compound (f), which is a hydrazone compound. Step (4) can be carried out under the following conditions: Reaction temperature: 0°C to 25°C Reaction time: 2 to 4 hours

[0108] Steps (5-1) and (5-2) are steps in which compound (g) and triethylamine are added to compound (f) obtained in step (4) at 0°C to undergo a cyclization reaction to obtain a compound represented by formula (I). Steps (5-1) and (5-2) can be carried out under the following conditions. Conditions for steps (5-1) and (5-2): Reaction temperature: 25°C; Reaction time: 6 to 12 hours

[0109] [Pharmaceutical Composition] In one aspect, the present disclosure relates to a pharmaceutical composition (pharmaceutical composition according to the present disclosure) containing, as an active ingredient, a substance that inhibits the accumulation of lipid peroxides. The substance that inhibits the accumulation of lipid peroxides is as described above, and in one or more embodiments, a compound represented by formulas (I) to (VII) or a pharmaceutically acceptable salt thereof can be preferably used. Thus, in one aspect, the present disclosure relates to a pharmaceutical composition containing, as an active ingredient, a compound represented by formulas (I) to (VII) or a pharmaceutically acceptable salt thereof. The compounds represented by formulas (I) to (VII) are as described above.

[0110] The compounds represented by formulas (I) to (VII) have the effect of inhibiting the accumulation of lipid peroxides. Thus, in one or more embodiments, the pharmaceutical composition of the present disclosure can prevent, improve, treat, or inhibit functional disorders caused by the accumulation of lipid peroxides and / or the generation of lipid peroxy radicals. Thus, in one or more embodiments, the pharmaceutical composition of the present disclosure can be used to prevent, improve, treat, and / or inhibit functional disorders of living organisms or biomaterials. The functional disorders are as described above. Furthermore, in one or more embodiments, the pharmaceutical composition of the present disclosure can also be used in cancer immunotherapy.

[0111] In one or more embodiments, the pharmaceutical composition of the present disclosure comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and may further comprise a pharmaceutically acceptable carrier, preservative, diluent, excipient, or other pharmaceutically acceptable ingredient. In one or more embodiments, the pharmaceutical composition of the present disclosure may contain no other active ingredient having a therapeutic effect, or may further comprise one or more active ingredients.

[0112] In one or more embodiments, the content of the compound or pharmaceutically acceptable salt of the present disclosure, which is the active ingredient, in the pharmaceutical composition of the present disclosure, can be appropriately determined depending on the dosage form, administration method, carrier, etc. In one or more embodiments, the pharmaceutical composition of the present disclosure can be produced according to a conventional method by adding the compound of the present disclosure in a ratio of 0.01 to 100% (w / w) or 0.1 to 95% (w / w) relative to the total amount of the formulation.

[0113] In one or more embodiments, the pharmaceutical composition of the present disclosure can be prepared into a dosage form suitable for the administration mode by applying well-known formulation techniques. In one or more embodiments, the administration mode can be oral administration, parenteral administration, etc. In one or more embodiments, formulations for oral administration can include dosage forms such as tablets, capsules, granules, powders, pills, lozenges, syrups, and liquids (e.g., solutions and suspensions). In one or more embodiments, formulations for parenteral administration can include injections, aerosols, etc. In one or more embodiments, these formulations can be prepared by well-known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavorings, and diluents.

[0114] In one or more embodiments, excipients include starches such as potato starch and corn starch, lactose, crystalline cellulose, and calcium hydrogen phosphate. In one or more embodiments, lubricants include ethyl cellulose, shellac, talc, carnauba wax, and paraffin. In one or more embodiments, binders include polyvinylpyrrolidone, macrogol, hydroxypropyl cellulose, and hydroxypropylmethylcellulose. In one or more embodiments, disintegrants include chemically modified starches and celluloses such as croscarmellose sodium, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone. In one or more embodiments, stabilizers include parahydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. In one or more embodiments, the flavoring agent may include commonly used sweeteners, acidulants, fragrances, and the like.

[0115] In one or more embodiments, a solvent such as ethanol, phenol, chlorocresol, purified water, or distilled water can be used to prepare the liquid formulation, and a surfactant, preservative, isotonicity agent, pH adjuster, and / or emulsifier can also be used as needed. In one or more embodiments, the liquid formulation for oral administration may further contain a solubilizer, a wetting agent, a suspending agent, a sweetener, a flavoring agent, a fragrance, and / or a preservative. Examples of surfactants or emulsifiers include, but are not limited to, polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.

[0116] Injectables for parenteral administration may be sterile aqueous or non-aqueous solutions, suspensions, or emulsions. In one or more embodiments, aqueous solvents for injections may be distilled water or physiological saline. In one or more embodiments, non-aqueous solvents for injections may include vegetable oils, alcohols, and polysorbate 80 (pharmacopoeia name). Examples of vegetable oils include propylene glycol, polyethylene glycol, and olive oil. Examples of alcohols include ethanol. In one or more embodiments, the injections may further contain an isotonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, and / or a solubilizer. In one or more embodiments, these formulations may be sterilized by filtration through a bacteria-retaining filter, addition of a disinfectant, or irradiation. Alternatively, these formulations may be prepared by dissolving or suspending a sterile solid composition in sterile water or an injection solvent before use.

[0117] The method of use of the pharmaceutical composition according to the present disclosure may vary depending on symptoms, age, administration method, etc. The method of use is not limited thereto, but an effective amount of the compound according to the present disclosure, which is the active ingredient, can be administered intermittently or continuously, orally, transdermally, submucosally, subcutaneously, intramuscularly, intravascularly, intracerebrally, and / or intraperitoneally. Alternatively, the compound according to the present disclosure, which is the active ingredient, can be administered intermittently or continuously, orally, transdermally, submucosally, subcutaneously, intramuscularly, intravascularly, intracerebrally, or intraperitoneally so that the intracellular concentration of the compound according to the present disclosure is anywhere between 100 nM and 1 mM. Non-limiting examples of oral administration include a dose of 0.01 mg (preferably 0.1 mg) per day to a subject (an adult human) in terms of the compound according to the present disclosure, with a lower limit of 0.01 mg and an upper limit of 2000 mg (preferably 500 mg, more preferably 100 mg), administered once or in divided doses depending on symptoms. In a non-limiting embodiment, in the case of intravenous administration, a lower limit of 0.001 mg (preferably 0.01 mg) and an upper limit of 500 mg (preferably 50 mg) may be administered to a subject (an adult human) per day, in a single dose or in divided doses, depending on the symptoms. In the present disclosure, an effective amount, in one or more embodiments, includes an amount that can improve, inhibit the progression of, and / or treat a disease or the like in a subject.

[0118] In another aspect, the present disclosure relates to a method for preventing, ameliorating, treating, or suppressing a functional disorder caused by accumulation of lipid peroxides and / or generation of lipid peroxy radicals, comprising administering an effective amount of a pharmaceutical composition according to the present disclosure to a subject. In one or more embodiments, the subject includes a patient in need of treatment, amelioration, or the like of a functional disorder caused by accumulation of lipid peroxides, generation of lipid peroxy radicals, and / or ferroptosis.

[0119] [Method for Suppressing Functional Damage] In one aspect, the present disclosure relates to a method for suppressing functional damage in a living organism or biomaterial (the method for suppressing functional damage according to the present disclosure), which comprises suppressing the accumulation of lipid peroxides in the living organism or biomaterial. In one or more embodiments, the method for suppressing functional damage according to the present disclosure can suppress functional damage caused by the accumulation of lipid peroxides and / or the generation of lipid peroxy radicals, which may occur in the living organism or biomaterial. In one or more embodiments, the method for suppressing functional damage according to the present disclosure can suppress a decrease in cell viability, cell death, etc., which may occur during cryopreservation of the living organism or biomaterial. The method for suppressing functional damage according to the present disclosure can suppress deterioration of the state of the biomaterial due to functional damage during cryopreservation, thereby enabling cryopreservation for a longer period of time and maintaining the freshness of the biomaterial for a longer period of time. In one or more embodiments, the method for suppressing functional damage according to the present disclosure can be applied to a living organism and / or a biomaterial that may or has experienced functional damage at low temperatures.

[0120] In one or more embodiments, the inhibition of lipid peroxide accumulation comprises contacting a living organism or a biomaterial with a substance that inhibits lipid peroxide accumulation. In one or more embodiments, the substance that inhibits lipid peroxide accumulation includes a compound represented by formula (I) to (VII) or a pharmaceutically acceptable salt thereof. Thus, in another aspect, the present disclosure relates to a method for inhibiting functional impairment of a living organism or a biomaterial, comprising contacting a living organism or a biomaterial with a compound represented by formula (I) to (VII) or a pharmaceutically acceptable salt thereof.

[0121] In one or more non-limiting embodiments, the method of the present disclosure may comprise contacting an effective amount of a compound represented by any one of Formulas (I) to (VII) or a pharmaceutically acceptable salt thereof with a living body or a biological material for a predetermined period of time, which may be, in one or more embodiments, 1 minute or more, 5 minutes or more, 10 minutes or more, 30 minutes or more, or 1 hour or more.

[0122] In one or more embodiments, contact between a living body and a substance that inhibits lipid peroxide accumulation may be achieved by administration, and administration routes include oral, transdermal, submucosal, subcutaneous, intramuscular, intravascular, intracerebral, or intraperitoneal administration.

[0123] In one or more embodiments, the contact between the biomaterial and the substance that inhibits lipid peroxide accumulation may be carried out by immersing the biomaterial in a solution containing the substance that inhibits lipid peroxide accumulation, or by applying, adding, dripping, or spraying the solution onto the biomaterial. In one or more embodiments, the solution may contain, in addition to the substance that inhibits lipid peroxide accumulation as an active ingredient, physiological saline, cell culture medium, buffer solution, infusion fluid, or a preservation or perfusion fluid for organs, etc. In one or more embodiments, when the biomaterial is an organ or tissue, the method for inhibiting functional impairment of the present disclosure may include perfusion, immersion, rinsing, injection, or a combination thereof, with a preservation or perfusion fluid containing the substance that inhibits lipid peroxide accumulation.

[0124] In one or more embodiments, the method for suppressing functional impairment according to the present disclosure may include cryopreserving a living organism or biomaterial. In one or more embodiments, cryopreservation may include storage at a low temperature not lower than 0° C., preferably at 0° C. to 4° C. In one or more embodiments, the storage period may be 1 day or more, 2 days or more, 3 days or more, 5 days or more, 10 days or more, 11 days or more, 12 days or more, 13 days or more, 14 days or more, 15 days or more, 16 days or more, 17 days or more, 18 days or more, 19 days or more, 20 days or more, 1 month or more, 6 months or more, 8 months or more, 10 months or more, 12 months or more, or 15 months or more.

[0125] In one or more embodiments, the timing for suppressing the accumulation of lipid peroxides may be before the start of cryopreservation, simultaneously with the start of cryopreservation, or during cryopreservation.

[0126] [Composition for Suppressing Functional Damage] In one aspect, the present disclosure relates to a composition for suppressing functional damage in a living organism or biological material (a composition for suppressing functional damage according to the present disclosure), which comprises as an active ingredient a substance that suppresses lipid peroxide accumulation. In one or more embodiments, the composition for suppressing functional damage according to the present disclosure can suppress functional damage that may occur during cryopreservation of a living organism or biological material. The composition for suppressing functional damage according to the present disclosure can suppress deterioration of the condition of a biological material due to functional damage during cryopreservation, thereby enabling cryopreservation for a longer period of time and maintaining the freshness of the biological material for a longer period of time. In one or more embodiments, the composition for suppressing cold damage according to the present disclosure can be used as a preservation solution or perfusion solution for a biological material, such as an organ, used for transplantation. The substance that suppresses lipid peroxide accumulation, the living organism, and the biological material are as described above.

[0127] In one or more embodiments, the composition for functional disorders according to the present disclosure may contain, in addition to the active ingredient, a substance that suppresses lipid peroxide accumulation, physiological saline, cell culture medium, buffer solution, infusion fluid, and preservation or perfusion fluid for organs, etc.

[0128] In one or more embodiments, the substance that inhibits the accumulation of lipid peroxides includes a compound represented by formula (I) to (VII) or a pharmaceutically acceptable salt thereof. Thus, in another aspect, the present disclosure relates to a composition for inhibiting dysfunction of a living organism or biomaterial, which comprises a compound represented by formula (I) to (VII) or a pharmaceutically acceptable salt thereof as an active ingredient. The compound represented by formula (I) to (VII) is as described above.

[0129] [Preservation Method] In one aspect, the present disclosure relates to a method for preserving a living organism or a biological material (the preservation method according to the present disclosure), which includes suppressing the accumulation of lipid peroxides in the living organism or the biological material during preservation. According to the preservation method of the present disclosure, in one or more embodiments, the biological material can be cryopreserved while suppressing functional impairment. According to the preservation method of the present disclosure, the biological material can be preserved at low temperature for a longer period of time, thereby maintaining the freshness of the biological material for a longer period of time. Therefore, in one or more embodiments, the preservation method of the present disclosure can be preferably applied to the preservation of biological materials that will undergo functional impairment when stored at low temperature, biological materials that are not suitable for cryopreservation, or biological materials that can be stored at low temperature but are difficult to store for long periods of time. In one or more embodiments, the preservation method of the present disclosure can be used for the preservation of biological materials such as organs used for transplantation. The suppression of lipid peroxide accumulation, the living organism, and the biological material are as described above.

[0130] In the present disclosure, the term "long-term" refers to a period of time longer than the storage time possible with conventional cryopreservation methods, and in one or more non-limiting embodiments, refers to a period of time that is 1.5 times or more, 2 times or more, or 3 times or more the storage time possible with conventional cryopreservation methods. In one or more embodiments, long-term storage can include cryopreservation for 1 month or more, 3 months or more, 6 months or more, 12 months or more, 15 months or more, 20 months or more, 24 months or more, 30 months or more, or 36 months or more. In one or more non-limiting embodiments, long-term storage in the present disclosure can include continuous cryopreservation for 1 month or more, 3 months or more, 6 months or more, 12 months or more, 15 months or more, 20 months or more, 24 months or more, 30 months or more, or 36 months or more.

[0131] In one or more embodiments, the preservation method of the present disclosure comprises suppressing the accumulation of lipid peroxides in a living organism or a biological material by contacting the living organism or the biological material with a substance that suppresses the accumulation of lipid peroxides. In one or more embodiments, the substance that suppresses the accumulation of lipid peroxides includes the compounds represented by formulas (I) to (VII) above or pharmaceutically acceptable salts thereof. Thus, in another aspect, the present disclosure relates to a method for preserving a living organism or a biological material, comprising contacting the living organism or the biological material with the compounds represented by formulas (I) to (VII) above or pharmaceutically acceptable salts thereof.

[0132] In one or more embodiments, contact between a living organism or a biomaterial and a substance that inhibits lipid peroxide accumulation may be achieved by immersing the living organism or biomaterial in a solution containing the substance that inhibits lipid peroxide accumulation, or by applying, adding, dripping, or spraying the solution onto the living organism or biomaterial. When the biomaterial is an organ or part of a living body, in one or more embodiments, contact between the biomaterial and a substance that inhibits lipid peroxide accumulation may be achieved by perfusion, immersion, rinsing, injection, or a combination thereof with a preservation solution or perfusion solution containing the substance that inhibits lipid peroxide accumulation.

[0133] In one or more embodiments, the preservation method according to the present disclosure may include storing a living organism or biomaterial that has been contacted with a substance that suppresses lipid peroxide accumulation at a low temperature. In one or more embodiments, the low temperature may be a temperature not lower than 0° C., such as 0° C. to 4° C. In one or more embodiments, the storage period may be 5 days or more, 10 days or more, 11 days or more, 12 days or more, 13 days or more, 14 days or more, 15 days or more, 16 days or more, 17 days or more, 18 days or more, 19 days or more, 20 days or more, 1 month or more, 6 months or more, 8 months or more, 10 months or more, 12 months or more, 15 months or more, 20 months or more, 25 months or more, or 27 months or more.

[0134] In the preservation method of the present disclosure, the concentration of the substance that suppresses lipid peroxide accumulation to be brought into contact with a living organism or biomaterial (e.g., the concentration of the compound represented by Formulae (I) to (VII)) may be any concentration that can suppress lipid peroxide accumulation, and in one or more embodiments, examples thereof include, but are not limited to, 0.001 μM to 150 μM, 0.01 μM to 100 μM, or 0.1 μM to 100 μM. In one or more other embodiments, the concentration of the substance that suppresses lipid peroxide accumulation to be brought into contact with a living organism or biomaterial may be, for example, 0.01 mM to 100 mM.

[0135] In one or more embodiments, contact of a living body or biomaterial with a substance that inhibits lipid peroxide accumulation may be carried out prior to or simultaneously with the initiation of low-temperature storage, in order to sufficiently inhibit functional impairment and enable storage at low temperatures for a longer period of time.

[0136] In one or more embodiments, the preservation method of the present disclosure may include preserving a living organism or biological material in a solution (preservation solution) containing a substance that inhibits lipid peroxide accumulation at a concentration capable of inhibiting lipid peroxide accumulation. The concentration of the substance that inhibits lipid peroxide accumulation in the solution (preservation solution) (e.g., the concentration of a compound represented by Formulas (I) to (VII)) may be any concentration capable of inhibiting lipid peroxide accumulation, and in one or more embodiments, the concentration may be, but is not limited to, 0.001 μM to 150 μM, 0.01 μM to 100 μM, or 0.1 μM to 100 μM. In one or more other embodiments, the concentration of the substance that inhibits lipid peroxide accumulation in the solution (preservation solution) may be, for example, 0.01 mM to 100 mM.

[0137] In one or more embodiments, the preservation method according to the present disclosure may include preserving a living organism or a biological material at a low temperature while contacting the living organism or biological material with a substance that inhibits the accumulation of lipid peroxides. The preservation temperature is not limited, but a low temperature, such as 0°C to 4°C, is preferable.

[0138] [Preservation Solution] In one aspect, the present disclosure relates to a preservation solution for a living organism or a biological material (the preservation solution according to the present disclosure) containing, as an active ingredient, a substance that inhibits lipid peroxide accumulation. In one or more embodiments, the preservation solution according to the present disclosure is intended for use in the preservation method according to the present disclosure. The substance that inhibits lipid peroxide accumulation, the living organism, and the biological material are as described above. The preservation solution according to the present disclosure may contain, in addition to the substance that inhibits lipid peroxide accumulation as an active ingredient, physiological saline, cell culture medium, buffer solution, infusion solution, and a preservation solution or perfusion solution for organs, etc.

[0139] In one or more embodiments, the substance that inhibits the accumulation of lipid peroxides includes a compound represented by formula (I) to (VII) or a pharmaceutically acceptable salt thereof. Therefore, in another aspect, the present disclosure relates to a preservation solution for a living organism or biological material, which contains a compound represented by formula (I) to (VII) or a pharmaceutically acceptable salt thereof as an active ingredient. The compound represented by formula (I) to (VII) is as described above.

[0140] The concentration of the substance that suppresses lipid peroxide accumulation (e.g., a compound represented by Formulae (I) to (VII)), which is an active ingredient in the preservation solution of the present disclosure, may be any concentration that can suppress lipid peroxide accumulation, and in one or more embodiments, examples thereof include, but are not limited to, 0.001 μM to 150 μM, 0.01 μM to 100 μM, or 0.1 μM to 100 μM. In one or more other embodiments, the concentration of the substance that suppresses lipid peroxide accumulation, which is an active ingredient in the preservation solution of the present disclosure, may be 0.01 mM to 100 mM, etc.

[0141] [Transplantation Adjuvant] In one aspect, the present disclosure relates to a transplantation adjuvant (transplantation adjuvant according to the present disclosure) containing, as an active ingredient, a substance that inhibits lipid peroxide accumulation. Examples of substances that inhibit lipid peroxide accumulation are as described above. Accordingly, in another aspect, the present disclosure relates to a transplantation adjuvant containing, as an active ingredient, a compound represented by formula (I) to (VII) or a pharmaceutically acceptable salt thereof. The compounds represented by formula (I) to (VII) are as described above. In one or more embodiments, the transplantation adjuvant according to the present disclosure can improve the survival rate, colonization rate, and / or survival rate of the transplanted biomaterial or cells in the transplant recipient after transplantation. Thus, in one or more embodiments, the transplantation adjuvant according to the present disclosure can be used for organ, tissue, or cell transplantation for regenerative medicine.

[0142] In one or more embodiments, "transplantation" in the present disclosure refers to transplanting a biomaterial or cells into a specific site of a transplant subject (recipient) and allowing them to take root (settle) in the transplanted site and / or surrounding sites, and / or allowing them to differentiate appropriately in response to the surrounding environment.

[0143] In one or more embodiments, "aiding transplantation" in the present disclosure includes promoting the engraftment of transplanted biomaterials or cells after transplantation, and improving the survival rate, fixation rate, and / or survival rate of transplanted biomaterials or cells after transplantation.

[0144] In one or more embodiments, specific sites to be transplanted include the nervous system, the central nervous system (for example, the brain and spinal cord), the peripheral nervous system, or tissues thereof.

[0145] The transplantation adjuvant according to the present disclosure can be administered to a recipient before, simultaneously with, or after transplantation, or can be added to cells or biomaterials to be transplanted before transplantation.

[0146] The recipient may be a human or a non-human animal, such as a mammal. The biomaterial to be transplanted may also be a biomaterial from a human or a non-human animal as described above. The species of the recipient and the transplanted cells may be the same or different.

[0147] The dosage of the transplant adjuvant according to the present disclosure varies depending on the purpose of administration, the method of administration, and the condition of the recipient (sex, age, body weight, medical condition, etc.), but when administered to humans, in one or more embodiments, the active ingredient may be administered in an amount of 10 mg to 1200 mg, or 100 mg to 1200 mg, per day.

[0148] The transplantation adjuvant according to the present disclosure can be administered via direct contact with the transplant site or transplanted cells, or via oral, transdermal, submucosal, subcutaneous, intramuscular, intravascular, intracerebral, or intraperitoneal administration. In one or more embodiments, commonly used dosage forms include solutions, tablets, capsules, granules, fine granules, powders, sublingual tablets, syrups, and suspensions. A liquid transplantation adjuvant may also be administered parenterally as an injection. The above dosage forms can be prepared by blending the active ingredient according to the present disclosure with an acceptable carrier, excipient, binder, and / or stabilizer. When the transplantation adjuvant according to the present disclosure is used as an injection, an acceptable buffer, solubilizer, isotonicity agent, etc. may also be added.

[0149] [Agent for Inhibiting Lipid Peroxide Accumulation] In one aspect, the present disclosure relates to an agent for inhibiting lipid peroxide accumulation (the agent for inhibiting lipid peroxide accumulation according to the present disclosure), which comprises, as an active ingredient, a compound represented by any one of Formulas (I) to (VII) or a pharmaceutically acceptable salt thereof. In one or more embodiments, the agent for inhibiting lipid peroxide accumulation according to the present disclosure can be used for preventing, treating, ameliorating, and / or inhibiting functional disorders of living organisms or biomaterials, cryopreserving living organisms or biomaterials, and assisting in transplantation.

[0150] That is, the present disclosure may relate to one or more of the following embodiments: [1] A method for suppressing functional impairment of a living organism or biomaterial, comprising suppressing accumulation of lipid peroxides in the living organism or biomaterial. [2] The method for suppressing functional impairment according to [1], wherein the suppression of lipid peroxide accumulation comprises contacting the living organism or biomaterial with a substance that suppresses lipid peroxide accumulation. [3] The method for suppressing functional impairment according to [2], wherein the substance that suppresses lipid peroxide accumulation is a substance that suppresses the Fenton reaction. [4] A method for suppressing functional impairment of a living organism or biomaterial, comprising contacting the living organism or biomaterial with a compound represented by the following formulas (I) to (VII) or a pharmaceutically acceptable salt thereof. In formula (I), R 1 is a C1 to C6 hydrocarbon group, and R 2 is a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group, and R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group which may have a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group. In formula (II), A is a sulfur atom or an oxygen atom, and Ar 1 is selected from the following groups: In the above group, R 11 is a hydrogen atom, a hydroxyl group, a halogen atom, an amino group, or a C1 to C6 alkylamino group, and R 4 and R 6 are each independently a hydrogen atom, a hydroxyl group, a C1-C6 alkoxy group, a halogen atom, an amino group, a C1-C6 alkylamino group, or a nitrogen-containing saturated heterocyclic group represented by the following formula: 4 and R 6 one of the groups is a nitrogen-containing saturated heterocyclic group represented by the following formula, in which x is an integer of 1 to 5: R 5 is a hydrogen atom, a hydroxyl group, a C1 to C6 alkoxy group, a halogen atom, an amino group, or a C1 to C6 alkylamino group. 7 is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a halogen atom, and Ar2 is represented by the following group: In the above group, R 12 and R 14 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group. 8 is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a halogen atom, and Ar 3 is represented by the following group: In the above group, R 12 and R 14 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group. 9 is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a halogen atom, and Ar 4 is represented by the following group: In the above group, R 12 and R 14 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group. 5 and Ar 6 are each independently selected from the following groups: In the above group, R 15 , R 17 , and R 19 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkoxy group, a halogen atom, an amino group, or a C1 to C6 alkylamino group, and R 16 and R 18are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen atom, a nitro group, an amino group, a C1 to C6 alkylamino group, or a C1 to C6 alkylcarbonyloxy group. In formula (VII), X is a sulfur atom, an imino group (-NH-), or a methylene group (-CH2-), Y is a sulfur atom or an oxygen atom, and Ar 7 is selected from the following groups: In the above group, R 20 , R 22 , and R 23 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom; R 21 is selected from a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, a halogen atom, or the following group: R 24 is a hydrogen atom or a C1-C6 alkyl group, In the above group, x 1 is an integer from 1 to 3, and R 25 is a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C2-C6 alkenyloxy group, or a halogen atom. [5] A method for suppressing dysfunction of a living organism or a biomaterial, comprising contacting a living organism or a biomaterial with a compound represented by formula (I) defined in [4] or a pharmaceutically acceptable salt thereof. [6] In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 is a halogen atom, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group which may have a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group. or a pharmaceutically acceptable salt thereof. 1 is a C1 to C6 hydrocarbon group, and R 2is a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group, and R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group which may have a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group. [8] R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and the substituent is a halogen atom or a C1-C6 alkyl group. [9] A pharmaceutical composition comprising, as an active ingredient, a substance that inhibits the accumulation of lipid peroxides.

[10] The pharmaceutical composition according to [9], wherein the substance that inhibits the accumulation of lipid peroxides is a substance that inhibits the Fenton reaction.

[11] A pharmaceutical composition comprising, as an active ingredient, a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: In formula (I), R 1 is a C1 to C6 hydrocarbon group, and R 2 is a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group, and R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group which may have a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group.

[12] R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3is a halogen atom, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group optionally having a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group.

[13] The pharmaceutical composition according to any one of [9] to

[12] , for treating, preventing, ameliorating, and / or suppressing dysfunction of a living organism or a biomaterial.

[14] The pharmaceutical composition according to

[13] , wherein the dysfunction is dysfunction caused by ferroptosis and / or nephrosis.

[15] A composition for suppressing dysfunction of a living organism or a biomaterial, comprising, as an active ingredient, a substance that suppresses the accumulation of lipid peroxides.

[16] A composition for suppressing dysfunction of a living organism or a biomaterial, comprising, as an active ingredient, a compound represented by formula (I) to (VII) defined in [4] or a pharmaceutically acceptable salt thereof.

[17] A composition for suppressing dysfunction of a living organism or a biomaterial, comprising, as an active ingredient, a compound represented by formula (I) defined in [7] or a pharmaceutically acceptable salt thereof.

[18] In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 is a halogen atom, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group optionally having a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group.

[19] An agent for suppressing lipid peroxide accumulation, comprising, as an active ingredient, a compound represented by formula (I) to (VII) defined in [4] or a pharmaceutically acceptable salt thereof.

[20] An agent for suppressing lipid peroxide accumulation, comprising, as an active ingredient, a compound represented by formula (I) defined in [7] or a pharmaceutically acceptable salt thereof.

[21] In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3is a halogen atom, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group optionally having a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group.

[22] A method for preserving a living organism or a biomaterial, comprising suppressing accumulation of lipid peroxides in the living organism or biomaterial during preservation.

[23] The method for preservation according to

[22] , wherein the suppression of lipid peroxide accumulation comprises contacting the living organism or biomaterial with a substance that suppresses lipid peroxide accumulation.

[24] The method for preservation according to

[23] , wherein the substance that suppresses lipid peroxide accumulation is a substance that suppresses the Fenton reaction.

[25] A method for preserving a living organism or a biomaterial, comprising contacting a living organism or a biomaterial with a compound represented by formula (I) to (VII) defined in [4] or a pharmaceutically acceptable salt thereof during preservation.

[26] A method for preserving a living organism or a biomaterial, comprising contacting a living organism or a biomaterial with a compound represented by formula (I) defined in [7] or a pharmaceutically acceptable salt thereof during preservation.

[27] In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 is a halogen atom, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group optionally having a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group.

[28] The preservation method according to any one of

[22] to

[27] , wherein the preservation is cryopreservation.

[29] A preservation solution for a living organism or a biomaterial, comprising, as an active ingredient, a substance that inhibits the accumulation of lipid peroxides.

[30] The preservation solution according to

[29] , wherein the substance that inhibits the accumulation of lipid peroxides is a substance that inhibits the Fenton reaction.

[31] A preservation solution for a living organism or a biomaterial, comprising, as an active ingredient, a compound represented by formula (I) to (VII) defined in [4] or a pharmaceutically acceptable salt thereof.

[32] A preservation solution for a living organism or a biomaterial, comprising, as an active ingredient, a compound represented by formula (I) defined in [7] or a pharmaceutically acceptable salt thereof.

[33] In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3is a halogen atom, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group optionally having a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group.

[34] The preservation solution according to any one of

[29] to

[33] , which is for cryopreservation.

[35] A transplantation adjuvant comprising, as an active ingredient, a substance that inhibits lipid peroxide accumulation.

[36] The transplantation adjuvant according to

[35] , wherein the substance that inhibits lipid peroxide accumulation is a substance that inhibits the Fenton reaction.

[37] A transplantation adjuvant comprising, as an active ingredient, a compound represented by formula (I) to (VII) defined in [4] or a pharmaceutically acceptable salt thereof.

[38] A transplantation adjuvant comprising, as an active ingredient, a compound represented by formula (I) defined in [7] or a pharmaceutically acceptable salt thereof.

[39] In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3

[38] The transplant adjuvant according to

[38] , wherein R is a halogen atom, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group which may have a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group.

[0151] The present disclosure will be described in more detail below with reference to examples, but these are merely illustrative and the present disclosure is not limited to these examples. All references cited in this disclosure are incorporated herein by reference.

[0152] [Synthesis of Compound 2] Compound 2 was synthesized according to the following scheme.

[0153] 1. Acetylation of 2-hexanone to iPrO2 at 0°C tBuOK was added, and then 2-hexanone in ethyl acetate was added dropwise. After stirring at room temperature for 20 hours, water was added at 0°C and the mixture was extracted with 1N NaOH aqueous solution. The resulting aqueous phase was acidified with 6N hydrochloric acid and extracted with EtO. The organic phase was washed with water and dried over saturated saline and sodium sulfate. After concentration under reduced pressure, the target product was obtained as a crude product by distillation. 2. Introduction of chlorine into activated methylene. To a dichloromethane solution of the mixture obtained in 1, TMS-Cl diluted with dichloromethane was added at 0°C and stirred at 0°C for 30 minutes. To this was then slowly added dropwise NCS in dichloromethane at 0°C. After stirring at 0°C for 1 hour and 30 minutes, the mixture was heated to 15°C. The reaction mixture was washed twice with 2N hydrochloric acid and twice with water. The organic phase was removed and dried over saturated saline and sodium sulfate, and the solvent was removed under reduced pressure to obtain the target product as a crude product. 3. Preparation of Diazonium Salt and Condensation: 6N hydrochloric acid and water were added to 4-chloroaniline at 0°C and stirred for 15 minutes. An aqueous solution of sodium nitrite was added dropwise at 0°C and stirred at 0°C for 1 hour to prepare the diazonium salt. Water and pyridine were added to the chloride obtained in 2 at 0°C, and the previously prepared diazonium salt solution was added dropwise. The mixture was slowly brought to room temperature and stirred for 2 hours. Ethyl acetate was added for extraction, and the organic phase was washed twice with 2N hydrochloric acid and dried over saturated saline and sodium sulfate. After removing the solvent under reduced pressure, methanol was added and the mixture was heated to reflux. The hydrazone was then recrystallized from hexane and ethanol to obtain the hydrazone. 4. Synthesis of Compound 2: The hydrazone obtained in 3 was dissolved in ethanol, and 4-chloro-2-fluoroaniline and triethylamine were added at 0°C. After stirring at room temperature for 6 hours, the solvent was removed under reduced pressure. The reaction mixture was dissolved in ethyl acetate, and water was added to wash the organic phase. After drying over saturated saline and sodium sulfate, the solvent was removed under reduced pressure. The residue was dissolved in cyclohexane again and stirred for 48 hours at 40° C. After removing the solvent under reduced pressure, the residue was recrystallized from cyclohexane and ethanol to obtain the target compound 2.

[0154] Compounds 1 and 3 to 11 were also synthesized by a similar method with reference to the above scheme and the synthesis method of compound 2. The structural formulas and physical science data of compounds 1 to 11 are shown in Table 1 below. Compounds 12 to 15 shown in the above scheme can also be synthesized with reference to the above scheme and the synthesis method of compound 2. Compounds 1 to 15 are compounds represented by formula (I).

[0155]

[0156] Example 2: Inhibition of Lipid Peroxide Accumulation (1) Evaluation of the Effect of Inhibiting Lipid Peroxide Production Reaction in a Cell-Free System We confirmed whether the target compounds (the compound represented by Formula (I) and known compounds) could inhibit the production of lipid peroxides via the Fenton reaction. The following methods were used for the lipid peroxide production system and lipid peroxide measurement system. Lipid peroxide production system: A liposome solution (L-α-phosphatidylcholine:stearylamine:cholesterol = 7:2:1) containing the target compound (10 μM) was added with ascorbic acid and iron sulfide, and the mixture was incubated in a 10 mM hydrochloric acid solution at 37°C for 2 hours to induce lipid peroxidation via the Fenton reaction and generate lipid peroxides (Giovanni Miotto et al., Redox Biology. 2019). Lipid peroxide measurement system: The liposome suspension obtained in the lipid peroxide generation system was mixed with thiobarbituric acid (TBA). Malondialdehyde (MDA), a decomposition product of lipid peroxides, was reacted with TBA, and the fluorescence of the product in the liposome suspension was measured. MDA is a major marker of lipid peroxides. Measurements were performed using a lipid peroxidation measurement kit (trade name: TBARS Microplate Assay Kit, Oxford Biomedical Research, Inc.) according to the method described in the kit. Fluorescence was measured using an ARVO X5 multilabel plate reader (PerkinElmer).

[0157] The degree of inhibition of lipid peroxide production was evaluated based on the %DMSO obtained by the following formula: %DMSO = ([[compound sample] - [compound fenton(-)]]) / ([DMSO sample] - [DMSO fenton(-)]) x 100 [compound sample]: Fluorescence intensity when lipid peroxidation was carried out in the "lipid peroxide production system" with the addition of the target compound. [compound fenton(-)]: Fluorescence intensity obtained in the same manner as the compound sample, except that the "lipid peroxide production system" was incubated without the Fenton reaction, i.e., without the addition of ascorbic acid or iron sulfide. [DMSO sample]: Fluorescence intensity obtained in the same manner as the compound sample, except that DMSO was used instead of the target compound in the "lipid peroxide production system." [DMSO fenton(-)]: Fluorescence intensity obtained in the same manner as the DMSO sample, except that the "lipid peroxide production system" was incubated without the Fenton reaction, i.e., without the addition of ascorbic acid or iron sulfide.

[0158] Evaluation Results of Known Compounds Among the known compounds evaluated, 30 compounds that inhibited lipid peroxide production by 50% or more are shown in Table 2 below. The "Amount of Lipid Peroxide Production" in Table 2 below is the % DMSO calculated using the above formula. For example, capsaicin, which produced 30.5% lipid peroxide, can be said to have inhibited lipid peroxide production by 69.5%. Among the compounds in Table 2, all except ferrostatin-1, capsaicin, and N-[4-[[4-(4-methylpiperazin-1-yl)-6-[(3-methyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl]thio]phenyl]cyclopropane-1-carboxamide are compounds represented by any of formulas (II) to (VII).

[0159]

[0160] Evaluation results for synthesized compounds 2 to 10 (compounds represented by formula (I)) For the synthesized compounds, the compound concentration (M) at % DMSO = 50% was defined as IC50, and the pIC50 (M) was calculated. The higher the pIC50 value, the stronger the compound's inhibitory effect on lipid peroxide production. The results for compounds 2 to 10 are shown in Figure 1. In Figure 1, phenoxazine (Phe) is a known compound reported to have lipid oxidation inhibitory effect (Cell Chem Biol. 2019. PMID: 31564533) and was used as a positive control. In Figure 1, Necrostatin-1 (Nec1: methyl-thiohydantoin-tryptophan) is a known necroptosis inhibitor that has been reported to inhibit receptor-interaction protein kinase 1 (RIPK1) and indoleamine 2,3-dioxygenase (IDO) (Nat Chem Biol. 2008. PMID 18408713, Cell Death Differ. 2013. PMID 23197295). It was used as a negative control. In Figure 1, TY52156 (TY: N-(4-chlorophenyl)-3,3-dimethyl-2-oxobutanimidic 2-(4-chlorophenyl)hydrazide) is a known compound that has been reported to suppress organ dysfunction (Kanemitsu et al., PMID: 36347491). As shown in FIG. 1, Compounds 2 to 10, which are compounds represented by formula (I), inhibited the Fenton reaction, and Compounds 2 to 10 were found to have a concentration-dependent inhibitory effect on lipid peroxide production.

[0161] Example 3: Inhibition of Lipid Peroxide Accumulation (2) Evaluation of Inhibitory Effect on Intracellular Lipid Peroxide Accumulation Using a system in which lipid peroxide accumulation is induced in cultured cells with RSL3 ((1S,3R)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1-[4-(methoxycarbonyl)phenyl]-1H-pyrido[3,4-b]indole-3-carboxylic acid, methyl ester, a GPX4 inhibitor), we confirmed whether the compound could inhibit lipid peroxide accumulation. As shown in the scheme in Figure 2, airway epithelial cells BEAS-2B were seeded at 10,000 cells / well in a 96-well plate and cultured at 37°C for 24 hours. After adding 1 µM of compound 2 and 3 µM of RSL3, the cells were further cultured at 37°C for 4 hours, stained, and observed under a fluorescent microscope (Figure 2). Cell nuclei were stained with Hoechst 33342, and lipid peroxides were stained with C11BODIPY581 / 591. Images were captured using an All-One fluorescence microscope (model: BZ-X800, KEYENCE), and the number of cells with fluorescence intensity above a threshold was counted using the attached analysis application. The results are shown in Figure 2. The graph in Figure 2 shows the percentage of cells stained with C11BODIPY581 / 591 (lipid ROS positive) among the Hoechst 33342-stained cells in the stained image. As shown in the graph and the lipid peroxide stained image in Figure 2, the addition of compound 2 (C2) inhibited the accumulation of lipid peroxides.

[0162] Example 4: Evaluation of functional impairment inhibitory effect The cell death inhibitory effect was evaluated when the human vascular endothelial cell line HUEhT-2 was cultured at low temperature in the presence of compounds 1 to 11. HUEhT-2 cells were seeded in MCDB131 medium and cultured overnight at 37°C. After that, the medium was replaced with 4°C medium to which a compound of any concentration had been added, and the cells were cultured at 4°C in a low-temperature incubator for 96 hours. After the 96-hour low-temperature culture, the cells were rewarmed in medium (MCDB131 medium) preheated to 37°C and cultured at 37°C for 24 hours. After the culture, alamarBlue (登録商標)The reducing power of viable cells was quantitatively measured by adding 100% of the compound. Cell viability was measured at each compound concentration, with the value measured immediately before low-temperature incubation considered to be 100%. Under conditions where viability was less than 5% without compound treatment, the compound concentration (M) at which viability was 50% was defined as EC50, and pEC50(M) was calculated. An example of the results is shown in Figure 3. In Figure 3, TY is a known compound, TY52156, which has been reported to have organ damage inhibitory effects (Kanemitsu et al., PMID: 36347491).

[0163] As shown in Figure 3, the decrease in cell viability during cryopreservation was improved by cryopreservation in the presence of compounds 1 to 11. Thus, compounds 1 to 11 were able to suppress cellular dysfunction caused by the accumulation of lipid peroxides during cryopreservation.

[0164] Example 5: Evaluation of Pain Therapeutic Effect The pain therapeutic effect of compound 2 was evaluated when orally administered to a mouse model of low-temperature burn-induced pain. Low-temperature burns were induced by pressing the sole of the left hind paw of 8- to 12-week-old C57BL / 6J male mice (n = 6 or 7) against an aluminum block heated to 52.5°C for 25 seconds, and then compound 2 was orally administered at a dose of 10 mg / kg / day. Five, seven, and nine days after the low-temperature burn, mechanical stimulation was administered to the sole of the paw using an electronic von Frey device, and the threshold for the withdrawal reflex behavior of the hind paw was measured (von Frey test). The administration solution of compound 2 was prepared by crushing compound 2 with stainless steel beads using a bead crusher, and suspending the powder in distilled water containing 0.1% DMSO and 0.01% Cremophor EL (vehicle) (vehicle: 0.1% DMSO, 0.01% Cremophor EL).

[0165] As shown in FIG. 4, oral administration of Compound 2 significantly increased the threshold for mechanical stimulation after 7 and 9 days, demonstrating a therapeutic effect on pain.

[0166] Example 6: Evaluation of Erastin-Induced Ferroptosis Inhibitory Effect. Ferroptosis was induced in human vascular endothelial cells (HUEhT-2 cells) by adding erastin to the culture medium. HUEhT-2 cells were seeded into a 96-well culture plate containing 0.1 ml of MCDB131 medium and cultured at 37°C in a CO2 incubator for 1 day. The medium was then replaced with prewarmed medium containing the test compounds Ferrostatin 1 (Fer-1), TY52156, or Compound 2 (C2), 0.1% DMSO, 0.01% Cremophor EL, 20 mM HEPES, pH 7.5, and 20 μM elastin. After incubation at 37°C for 2 days, the medium containing the test compounds was removed from the plate and washed with HBSS(+). Cells were stained using a viability / cytotoxicity assay kit for animal live and dead cells (Biotium) according to the manufacturer's instructions. Nuclei were visualized by Hoechst 33342 staining. After 30 minutes of incubation at room temperature, the stained cells were imaged using a fluorescence microscope BZ-X800 system (KEYENCE), and nine field sets were collected from each well. Hoechst-positive, calcein-positive, and EthD-III-negative cells were counted as live cells using an image cytometer module (KEYENCE). The measurements were analyzed using GraphPad Prism software. The results are shown in Figures 5 and 6. As shown in Figures 5 and 6, compound 2 significantly suppressed erastin-induced cell death in HUEhT-2 cells, demonstrating its inhibitory effect on ferroptosis.

[0167] Example 7: Blood Concentration Distribution of Orally Administered Compounds. Compound 2, Ferrostatin-1 (Fer-1), or TY52156 dissolved in water containing 5% DMSO and 0.01% Cremophor EL was orally administered once to 7-week-old male mice (C57BL / 6, 21-26 g) at a dose of 10 μmol / kg. Blood samples were collected from the inferior vena cava of mice anesthetized with isoflurane using a syringe attached to a 25G needle containing EDTA. After collection, the blood samples were transferred to new collection tubes and centrifuged to remove clots. The supernatant was used as a plasma sample. To deproteinize the plasma samples, 40 μl of plasma sample was mixed with 10 μl of an internal standard (20 μM in 20% acetonitrile) and 150 μl of acetonitrile. The samples were vortexed for 30 seconds and centrifuged at high speed for 5 minutes. Next, 100 μl of the supernatant and 300 μl of 10 mM ammonium formate were thoroughly mixed and centrifuged at high speed for 5 minutes. The supernatant was centrifuged and filtered through a 0.2 μm pore size Cosmos Spin Filter (Nacalai Tesque), and the filtrate was injected into an LC-MS / MS system for multiple reaction monitoring (MRM) analysis. The samples were measured under MRM conditions, and a calibration curve was created. Based on the results, the detection limit and lower limit of quantification for each compound were calculated, and the blood concentration of each compound was determined from the calibration curve. Figure 7 shows the blood concentration of each compound 30 minutes after oral administration. The detection limit (LOD) and lower limit of quantification (LOQ) for each compound are as follows: Fer-1, LOD = 40 nM, LOQ = 40 nM TY52156, LOD = 200 nM, LOQ = 200 nM Compound 2, LOD = 200 nM, LOQ = 200 nM As shown in Figure 7, compound 2 (C2) had a significantly higher blood concentration 30 minutes after oral administration than Ferrostatin-1 (Fer-1), suggesting that it has a high blood penetration rate.

[0168] Example 8: Evaluation of the effect of suppressing the decline in pulmonary function due to pulmonary ischemia-reperfusion injury Compound 2 suppresses the decline in pulmonary function due to pulmonary ischemia-reperfusion injury A rat lung transplantation model of ischemia-reperfusion injury was created using Lewis rats (male, weighing 300-340 g). Seventeen rats were randomly assigned to three groups. In the Sham group (n=5), the chest was opened and closed without lung transplantation, and then an artificial respirator was attached. In the Vehicle group (n=6), donor lungs were preserved in an organ preservation solution (Perfadex) already used in clinical lung transplantation. (登録商標) , XVIVO) flush with 20ml and Perfadex (登録商標) The donor lung was then transferred to a left isogeneic lung transplant (the arrow in the photograph indicates the transplanted lung). (登録商標) Flushed in solution and Perfadex containing compound 2 (登録商標) After storage in the solution at 4°C for 6 hours, left-sided syngeneic lung transplantation was performed. (登録商標) The solution was prepared by dissolving Compound 2 in DMSO and preserving it in an organ preservation solution (Perfadex (登録商標) ) and adjusted to a final concentration of 2 μM (final DMSO concentration: 0.02%). Recipient rats were placed on a ventilator for 2 hours after reperfusion. Two hours after reperfusion, oxygenation and respiratory function were measured. Pulmonary arterial blood oxygen tension was measured by clamping the right hilum and collecting blood gases from the ascending aorta. Respiratory function was evaluated by measuring airway pressure and dynamic lung compliance using a FlexiVent (Scireq Inc.). The lower lung tissue was then used to measure wet-to-dry weight ratio. Animals were anesthetized with isoflurane during the experiment. The results are shown in Figure 8. As shown in Figure 8, pulmonary arterial blood oxygen tension and respiratory function at 2 hours after reperfusion were significantly improved in the Compound 2 group compared to the vehicle group in terms of pulmonary arterial blood oxygen tension, maximum airway pressure, and dynamic lung compliance, and the wet-to-dry lung weight ratio was also significantly reduced. This suggests that the addition of Compound 2 to the preservation solution in a rat lung transplantation model suppresses the decline in pulmonary function and pulmonary edema caused by ischemia-reperfusion injury.

[0169] Example 9: Suppression of Cerebral Ischemia-Reperfusion Injury Death. Compound 2 suppresses cerebral ischemia-reperfusion injury death. C57BL / 6 mice (male, 8-12 weeks old) were anesthetized with isoflurane and administered vehicle (0.1% DMSO, 0.01% Cremophor EL) or Compound 2 (C2) intracerebroventricularly (ICV). Subsequently, local cerebral ischemia and reperfusion were performed by middle cerebral artery (MCA) occlusion (MCAO). Specifically, mice were placed on their side, and the skin was incised between the left eyeball and the left external auditory canal. The left salivary gland and a portion of the temporal muscle were resected, and a burr hole was created in the skull to visualize the MCA through the skull. The MCA was then isolated and occluded with nylon suture for 90 minutes. The nylon suture was then removed to restore blood flow through the MCA. Rectal temperature was controlled at 36.0-37.2°C using a heating pad during surgery. The experimental scheme and results are shown in Figure 9. By day 14 after ischemia-reperfusion, all four mice in the vehicle group had died, but half of the four mice in the Compound 2 group survived. This suggests that administration of Compound 2 reduces the mortality rate due to cerebral ischemia-reperfusion injury caused by middle cerebral artery occlusion.

[0170] Example 10: Suppression of Cerebral Ischemia-Reperfusion Injury Compound 2 Suppresses Cerebral Ischemia-Reperfusion Injury. C57BL / 6 mice (male, 8-12 weeks old) underwent focal cerebral ischemia and reperfusion via middle cerebral artery (MCA) occlusion (MCAO) under isoflurane anesthesia. Subsequently, vehicle (0.1% DMSO, 0.01% Cremophor EL) or Compound 2 (C2) was administered intracerebroventricularly. Motor function was assessed over time using the modified neurological severity score. The evaluation criteria for the modified neurological severity score are shown in Figure 11. Specifically, mice were placed on their side, and the skin was incised between the left eyeball and the left external auditory canal. The left salivary gland and a portion of the temporal muscle were resected, and a burr hole was created in the skull to visualize the middle cerebral artery through the skull. The middle cerebral artery was then isolated and occluded with nylon suture for 60 minutes. The nylon suture was then removed to restore blood flow through the middle cerebral artery. Furthermore, one day after focal cerebral ischemia and reperfusion, vehicle or compound 2 was administered intracerebroventricularly. The experimental scheme and results are shown in Figure 10. As shown in Figure 10, motor function was evaluated using the modified neurological severity score 1, 7, and 14 days after ischemia and reperfusion. A decrease in the mean modified neurological severity score was observed in the vehicle group (control), while the mean value was maintained in the compound 2-administered group. This suggests that administration of compound 2 reduces motor dysfunction due to cerebral ischemia-reperfusion injury caused by middle cerebral artery occlusion.

Claims

1. A method for inhibiting functional impairment of a biomaterial, comprising inhibiting accumulation of lipid peroxides in the biomaterial.

2. The method for inhibiting functional impairment according to claim 1, wherein the inhibition of the accumulation of lipid peroxides comprises contacting the biomaterial with a substance that inhibits the accumulation of lipid peroxides.

3. The method for inhibiting functional disorders according to claim 2, wherein the substance that inhibits the accumulation of lipid peroxides is a substance that inhibits the Fenton reaction.

4. A method for suppressing functional impairment of a biological material, which comprises contacting the biological material with a compound represented by any one of the following formulas (I) to (VII) or a pharmaceutically acceptable salt thereof: In formula (I), R 1 is a C1 to C6 hydrocarbon group, and R 2 is a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group, and R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group which may have a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group. In formula (II), A is a sulfur atom or an oxygen atom, and Ar 1 is selected from the following groups: In the above group, R 11 is a hydrogen atom, a hydroxyl group, a halogen atom, an amino group, or a C1 to C6 alkylamino group, and R 4 and R 6 are each independently a hydrogen atom, a hydroxyl group, a C1-C6 alkoxy group, a halogen atom, an amino group, a C1-C6 alkylamino group, or a nitrogen-containing saturated heterocyclic group represented by the following formula: 4 and R 6 one of the groups is a nitrogen-containing saturated heterocyclic group represented by the following formula, in which x is an integer of 1 to 5: R 5 is a hydrogen atom, a hydroxyl group, a C1 to C6 alkoxy group, a halogen atom, an amino group, or a C1 to C6 alkylamino group. 7 is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a halogen atom, and Ar 2 is represented by the following group: In the above group, R 12 and R 14 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom, and R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group. 8 is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a halogen atom, and Ar 3 is represented by the following group: In the above group, R 12 and R 14 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom, and R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group. 9 is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a halogen atom, and Ar 4 is represented by the following group: In the above group, R 12 and R 14 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom, and R 13 is a hydroxyl group, an amino group, or a C1 to C6 alkylamino group. 5 and Ar 6 are each independently selected from the following groups: In the above group, R 15 , R 17 , and R 19 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkoxy group, a halogen atom, an amino group, or a C1 to C6 alkylamino group, and R 16 and R 18 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen atom, a nitro group, an amino group, a C1 to C6 alkylamino group, or a C1 to C6 alkylcarbonyloxy group. In formula (VII), X is a sulfur atom, an imino group (-NH-), or a methylene group (-CH2-), Y is a sulfur atom or an oxygen atom, and Ar 7 is selected from the following groups: In the above group, R 20 , R 22 , and R 23 are each independently a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom, and R 21 is selected from a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, a halogen atom, or the following group: R 24 is a hydrogen atom or a C1-C6 alkyl group, In the above group, x 1 is an integer from 1 to 3, and R 25 is a hydrogen atom, a hydroxyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxy group, or a halogen atom.

5. A method for inhibiting functional impairment of a biological material, which comprises contacting the biological material with a compound represented by formula (I) as defined in claim 4 or a pharmaceutically acceptable salt thereof.

6. In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and the substituent is a halogen atom or a C1-C6 alkyl group.

7. Formula (I): or a pharmaceutically acceptable salt thereof. 1 is a C1 to C6 hydrocarbon group, and R 2 is a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group, and R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group which may have a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group.

8. R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and the substituent is a halogen atom or a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition containing, as an active ingredient, a substance that inhibits the accumulation of lipid peroxides.

10. The pharmaceutical composition according to claim 9, wherein the substance that inhibits the accumulation of lipid peroxides is a substance that inhibits the Fenton reaction.

11. A pharmaceutical composition comprising, as an active ingredient, a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: In formula (I), R 1 is a C1 to C6 hydrocarbon group, and R 2 is a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group, and R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group which may have a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group.

12. R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and the substituent is a halogen atom or a C1-C6 alkyl group.

13. A pharmaceutical composition according to any one of claims 9 to 12 for treating, preventing, ameliorating and / or suppressing dysfunction of a living organism or biomaterial.

14. The pharmaceutical composition according to claim 13, wherein the dysfunction is a dysfunction caused by ferroptosis and / or nephrosis.

15. A composition for suppressing functional disorders of a living organism or biomaterial, comprising as an active ingredient a substance that suppresses the accumulation of lipid peroxides.

16. A composition for suppressing dysfunction of a living organism or a biological material, comprising as an active ingredient a compound represented by formula (I) to (VII) defined in claim 4 or a pharmaceutically acceptable salt thereof.

17. A composition for suppressing dysfunction of a living organism or biological material, comprising as an active ingredient a compound represented by formula (I) defined in claim 7 or a pharmaceutically acceptable salt thereof.

18. In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and the substituent is a halogen atom or a C1-C6 alkyl group.

19. An agent for suppressing lipid peroxide accumulation, comprising as an active ingredient a compound represented by formula (I) to (VII) defined in claim 4 or a pharmaceutically acceptable salt thereof.

20. An agent for suppressing the accumulation of lipid peroxides, comprising as an active ingredient a compound represented by formula (I) defined in claim 7 or a pharmaceutically acceptable salt thereof.

21. In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and the substituent is a halogen atom or a C1-C6 alkyl group.

22. A method for preserving a biomaterial, comprising inhibiting lipid peroxide accumulation in the biomaterial during storage.

23. The method of preservation according to claim 22, wherein the inhibition of the accumulation of lipid peroxides comprises contacting the biological material with a substance that inhibits the accumulation of lipid peroxides.

24. The method for preservation according to claim 23, wherein the substance that inhibits the accumulation of lipid peroxides is a substance that inhibits the Fenton reaction.

25. A method for preserving a biological material, comprising contacting the biological material with a compound of formula (I) to (VII) as defined in claim 4 or a pharmaceutically acceptable salt thereof during preservation.

26. A method for preserving a biological material, comprising contacting the biological material with a compound of formula (I) as defined in claim 7 or a pharmaceutically acceptable salt thereof during preservation.

27. In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and the substituent is a halogen atom or a C1-C6 alkyl group.

28. A method of preservation according to any one of claims 22 to 27, wherein the preservation is cryopreservation.

29. A preservation solution for living organisms or biological materials containing, as an active ingredient, a substance that inhibits the accumulation of lipid peroxides.

30. The preservation solution according to claim 29, wherein the substance that inhibits the accumulation of lipid peroxides is a substance that inhibits the Fenton reaction.

31. A preservation solution for a living organism or a biological material, containing as an active ingredient a compound represented by formula (I) to (VII) defined in claim 4 or a pharmaceutically acceptable salt thereof.

32. A preservation solution for a living organism or a biological material, containing as an active ingredient a compound represented by formula (I) defined in claim 7 or a pharmaceutically acceptable salt thereof.

33. In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 The preservative solution according to claim 32, wherein is a halogen atom, a C1-C6 alkoxy group, or an optionally substituted 4- to 6-membered heterocyclyl group, and the substituent is a halogen atom or a C1-C6 alkyl group.

34. A preservation solution according to any one of claims 29 to 33, for cryopreservation.

35. A transplant adjuvant containing as an active ingredient a substance that inhibits the accumulation of lipid peroxides.

36. The transplant adjuvant according to claim 35, wherein the substance that inhibits the accumulation of lipid peroxides is a substance that inhibits the Fenton reaction.

37. A transplantation adjuvant containing, as an active ingredient, a compound represented by formula (I) to (VII) defined in claim 4 or a pharmaceutically acceptable salt thereof.

38. A transplantation adjuvant containing, as an active ingredient, a compound represented by formula (I) defined in claim 7 or a pharmaceutically acceptable salt thereof.

39. In formula (I), R 1 is a C3 to C6 alkyl group, and R 2 is a halogen atom or a C1-C3 alkoxy group, and R 3 The transplantation adjuvant according to claim 38, wherein is a halogen atom, a C1-C6 alkoxy group, or a 4- to 6-membered heterocyclyl group which may have a substituent, and the substituent is a halogen atom or a C1-C6 alkyl group.

40. A method for inhibiting a functional disorder of a living organism, comprising inhibiting accumulation of lipid peroxides in the organism.

41. The method for suppressing functional impairment according to claim 40, wherein the suppression of the accumulation of lipid peroxides comprises contacting the living body with a substance that suppresses the accumulation of lipid peroxides.

42. The method for inhibiting functional disorders according to claim 41, wherein the substance that inhibits the accumulation of lipid peroxides is a substance that inhibits the Fenton reaction.

43. A method for suppressing functional disorders in a living organism, which comprises contacting the living organism with a compound represented by formula (I) to (VII) defined in claim 4 or a pharmaceutically acceptable salt thereof.

44. A method for preserving a living organism, comprising inhibiting accumulation of lipid peroxides in the living organism during preservation.

45. The method for preservation according to claim 44, wherein the inhibition of the accumulation of lipid peroxides comprises contacting the living body with a substance that inhibits the accumulation of lipid peroxides.

46. ​​The method for preservation according to claim 45, wherein the substance that inhibits the accumulation of lipid peroxides is a substance that inhibits the Fenton reaction.

47. A method for preserving a living organism, comprising contacting the living organism with a compound represented by formula (I) to (VII) as defined in claim 4 or a pharmaceutically acceptable salt thereof during preservation.

48. A method of preservation according to any one of claims 45 to 47, wherein the preservation is cryopreservation.

Images