Alpha-lipoic acid prodrug

Abstract

The present invention relates to compounds represented by formula (I), or pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof, tautomers thereof, stereoisomers thereof, enantiomers thereof, polymorphs thereof, and / or N-oxides thereof. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention, and their therapeutic use. [Formula 1] JPEG2026513964000034.jpg79169

Description

Detailed description of the invention

[0001] [Field of Invention] This invention relates to a prodrug of alpha-lipoic acid and its use in therapy.

[0002] 〔background〕 The formal name of R-α-lipoic acid is 1,2-dithiolane-3-pentanoic acid; it is also known as thioctic acid. It is a naturally occurring organosulfur compound found in all prokaryotic and eukaryotic cells (Reed, 2001; Carreau, 1979). It is an essential cofactor for several important mitochondrial polyenzyme complexes involved in energy and amino acid metabolism. In addition to the physiological functions of protein-bound R-α-lipoic acid, there is growing scientific and medical evidence supporting the use of free (unbound) R-α-lipoic acid as a therapeutic agent for diseases, disorders, and conditions in humans and animals (Smith et al., 2004; Salehi et al., 2019).

[0003] Dihydro-R-α-lipoic acid (DHLA) contains two thiol groups and is produced by the in vivo reduction of the dithiolane ring present in lipoic acid. DHLA can be reoxidized back to the dithiolane ring. Therefore, a redox "equilibrium" exists between these two chemical species. Lipoic acid also contains a stereocenter at its C-3 carbon atom. The naturally occurring enantiomer, R-α-lipoic acid, exhibits a superior pharmacokinetic (PK) profile compared to the S-enantiomer (Streeper et al., 1997; Loffelhardt et al., 1995).

[0004] [ka]

[0005] (R-α-lipoic acid) (DHLA) This is the R-enantiomer of naturally occurring α-lipoic acid. It is synthesized in trace amounts by plants and animals (including humans) (Smith et al., 2004).

[0006] In addition to its direct free radical scavenging activity, the LA / DHLA redox pair appears to be able to regenerate other antioxidants. Considering that the redox potential of the LA / DHLA pair is 0.32V compared to the redox potential of the oxidized / reduced glutathione (GSH / GSSG) pair (0.24V), DHLA can directly reduce GSSG to GSH (Jocelyn, 1967).

[0007] R-α-lipoic acid functions as a cofactor for several enzymes. Three α-keto acid dehydrogenases exist in mitochondria that mediate the oxidative decarboxylation of specific substrates: (i) pyruvate dehydrogenase complex (PDC), (ii) branched-chain α-keto acid dehydrogenase complex (BCKDC), and (iii) α-ketoglutarate dehydrogenase complex (Yeaman, 1989; Hutson, 1988; Harris et al., 1990). Each of these complexes consists of three subunits: α-keto acid dehydrogenase (E1), E2, and dihydrolipoamide dehydrogenase (E3). E1, containing thiamine diphosphate, functions as a cofactor to mediate the dehydrogenation (decarboxylation) of each α-keto acid. E2, containing R-α-lipoic acid as a cofactor, undergoes electron transfer, followed by the transfer of the acyl group of the lipoamide to coenzyme A, producing acyl-CoA. The reduced lipoyl group of E2 then becomes FAD as a cofactor. + It transfers its electrons to the E3 component containing it. As a result, FADH becomes NAD + It reduces to NADH. The E3 component is used in common in all three α-keto acid dehydrogenase complexes. The substrate specificity of the α-keto acid dehydrogenase complexes depends on the reaction rate characteristics of the E1 and E2 subunits of each enzyme complex.

[0008] In addition to its role in the α-keto acid dehydrogenase complex, R-α-lipoic acid also functions as a cofactor for glycine cleavage enzymes, which cleave the amino group of a specific lysine residue in the dihydrolipoamide acyltransferase (E2) subunit. Glycine cleavage enzymes consist of four enzyme components (P, H, T, and L components) (Hiraga and Kikuchi, 1982). The P component is very similar to E1 of the α-keto acid dehydrogenase complex, but contains pyridoxal phosphate instead of thiamine diphosphate. The H component contains R-α-lipoic acid as a cofactor similar to E2 of the α-keto acid dehydrogenase complex. In the H component of glycine cleavage enzymes, aminomethylated R-α-lipoic acid mediates the transfer of the aminomethyl group to methylenetetrahydrofolate (THF), forming N5,N10-CH2-THF in the T component. The T component is an aminomethyltransferase that is not present in the α-keto acid dehydrogenase complex. After the deamination reaction, the electrons on the H component become FAD, which is similar to E3 of the α-keto acid dehydrogenase complex. + It is transferred to the contained L component.

[0009] (Antioxidant activity) R-α-lipoic acid and DHLA have antioxidant effects by scavenging free radicals associated with both reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS are usually produced in limited amounts in the body and are important compounds involved in the regulation of processes including maintaining cellular homeostasis and functions (such as signal transduction, gene expression, and receptor activation) (Pizzino et al., 2017; Halliwell and Gutteridge, 2015). Oxidative stress refers to a state in which ROS are overproduced in cells and tissues and the antioxidant system cannot neutralize them. When the balance of this defense mechanism is disrupted, cellular molecules (such as DNA, proteins, and lipids) can be damaged (Durackova, 2010; Halliwell and Gutteridge, 2015). The production of reactive oxygen species occurs by both enzymatic and non-enzymatic reactions. Enzymatic reactions that can generate ROS involve the respiratory chain, prostaglandin synthesis, phagocytosis, and the cytochrome P450 system (Halliwell and Gutteridge, 2015).

[0010] Superoxide radical (O2 ·- ) is generated by NADPH oxidase, xanthine oxidase, and peroxidase. Once formed, they react via several pathways to form various toxic compounds (such as hydrogen peroxide (H2O2), hydroxyl radical (OH · ), peroxynitrite (ONOO - ), hypochlorous acid (HOCl), etc.). H2O2 (non-radical) is produced by multiple oxidase enzymes (such as amino acid oxidase and xanthine oxidase). Hydroxyl radical (OH · ) is the most reactive among all free radical species in vivo and is generated by the reaction of O2 2+ or Cu + with H2O2 using Fe ·- as a reaction catalyst (Fenton reaction). Nitric oxide radical (NO ·Arginine plays several physiological roles and is synthesized by the enzyme nitric oxide synthase (NOS) through the oxidation of arginine to form citrulline (Halliwell and Gutteridge, 2015; Garthwaite, 2018).

[0011] Non-enzymatic reactions also produce free radicals. These include reactions occurring within living organisms (such as reactions between oxygen and organic compounds, and mitochondrial respiration (Lobo et al., 2010)), and the activation of immune cells, inflammation, ischemia, infection, cancer, excessive exercise, mental stress, and aging all contribute to endogenous free radical production. Exogenous free radical production can occur as a result of exposure to environmental pollutants, ionizing radiation, heavy metals (such as Cd, Hg, Pb, Fe, and As), certain drugs (such as cyclosporine, tacrolimus, gentamicin, and bleomycin), chemical solvents, cooking (smoked meat, used oil, and fat), cigarette smoke, and alcohol (Halliwell and Gutteridge, 2015).

[0012] Under hypoxic conditions, nitric oxide (NO) can be produced during respiratory chain reactions. RNS further leads to the production of reactive chemical species (such as reactive aldehydes, malondialdehyde, and 4-hydroxynonenal). The main targets of oxidative and nitrosation stress are proteins, lipids, and DNA / RNA, and modifications to these molecules can increase the risk of mutagenesis. Overproduction of ROS / RNS (especially over long periods) can cause damage to cell structure and function, inducing somatic mutations, as well as precancerous and cancerous changes. Therefore, ROS produced in excess within cells and tissues will be harmful unless rapidly removed. In fact, excessive ROS / RNS production can cause irreversible damage to cells, leading to cell death through processes of necrosis and apoptosis (Halliwell and Gutteridge, 2015).

[0013] High concentrations of ROS / RNS have also been reported to initiate inflammatory processes that trigger the synthesis and secretion of inflammatory cytokines. For example, activation of nuclear factor-κB / active protein-1 (NF-κB / AP-1) and Toll-like receptors, as well as the production of tumor necrosis factor-α (TNF-α), have been recorded as playing a significant role in inflammatory processes that cause several conditions (Kim et al., 2009; Nie et al., 2018).

[0014] Alpha-lipoic acid supplements (including those used in clinical trials to evaluate therapeutic efficacy) often contain both R-alpha-lipoic acid and S-(alpha)-lipoic acid in a 50:50 ratio (racemic mixture).

[0015] When a racemic mixture (a 50:50 mixture of R-α-lipoic acid and S-α-lipoic acid) was orally administered to rats, R-α-lipoic acid showed higher plasma concentrations than S-α-lipoic acid, and the area under the plasma concentration-time curve (AUC) from time zero to the final time point was significantly higher than that of S-α-lipoic acid. However, when the racemic mixture was administered intravenously, the pharmacokinetic profiles of the stereoisomers and the initial concentration (C) were not as clear. O No significant differences were observed in ), AUC, or half-life (T1 / 2). This data is consistent with R-α-lipoic acid, which has better absorption than S-α-lipoic acid (Hermann et al., 2014; Uchida et al., 2015). Furthermore, in a study of 12 human volunteers, the effect of food on the bioavailability of R-α-lipoic acid was greater than that on the bioavailability of S-α-lipoic acid (Gleiter et al., 1996).

[0016] R-α-lipoic acid (pKa, 4.7) can exert its effects in both aqueous and lipid-soluble environments. The solubility of the free acid in water is very low (2.24 x 10⁻¹⁰). -1 Despite the concentration (g / L), under physiological conditions, the conjugated base form of R-α-lipoic acid is more dominant.

[0017] R-(α)-lipoic acid has an extremely negative redox potential of -0.32V (against a standard hydrogen electrode) (Moini et al., 2002). Under physiological conditions, both lipophilic (α-lipoic acid) and reduced dihydrolipoic acid (DHLA) exist and can function both inside and outside cells, so this R-α-lipoic acid / DHLA redox pair is called a "universal antioxidant" (Kagan et al., 1992). Both can directly remove both reactive oxygen species (ROS) and reactive nitrogen species (RNS). Furthermore, R-α-lipoic acid is oxidized nicotinamide adenine (NADP). + It can reduce DHLA, restoring both reduced and oxidized glutathione, and both forms function as antioxidants. Maintaining a GSH-dominant (GSH / GSSG) ratio is important for increasing the expression of antioxidant enzymes such as glutathione reductase, which reduce DHLA (Jocelyn, PC, 1967; Solmonson et al., 2018; Zitka et al., 2012), and for involvement in the recycling of vitamins C and E. They also repair oxidative damage to macromolecules (Biewenga et al., 1996; Biewenga et al., 1997; Packer et al., 1995).

[0018] DHLA has been shown to enhance whole-cell responses mediated by N-methyl-D-aspartate (NMDA) receptors in cultured neurons. This enhancing effect was readily reversed by the oxidizing agent 5,5'-dithio-bis-(2-nitro-benzoic acid). Single-channel recording revealed that DHLA increases the opening frequency of NMDA channels, but does not alter single-channel conductance or opening time. In contrast, α-lipoic acid reversed the dithiothreitol-induced enhancement of NMDA-induced responses (Tang and Aizenman, 1993). Glutamate is an agonist in NMDA receptor channels, and increased concentrations of this excitatory amino acid cause cell death (excitotoxicity), which is blocked by α-lipoic acid (Park et al., 2019).

[0019] R-α-lipoic acid is an antioxidant and free Fe 3+ It functions as a binder and also reduces neuroinflammation and glutamate-induced neurodegeneration (Park et al., 2019). Furthermore, R-α-lipoic acid promotes glucose uptake and modulates the activity of various cellular signaling molecules and transcription factors (Akbari et al., 2018).

[0020] Many complications caused by diabetes (such as polyneuropathy and cataract formation) appear to be mediated by ROS production. Diabetic patients have higher serum concentrations of thiobarbiturate-reactive substances (a common method for measuring lipid peroxidation products), F2-isoprostane, and 8-OH-guanosine (all indicators of oxidative stress) compared with non-diabetic patients (Stephens et al., 2008).

[0021] Furthermore, oxidative stress has been proposed as an early event in the pathology of diabetes and may influence the onset and progression of later complications. In a cross-sectional study of 107 diabetic patients, Borcea et al. showed that patients who took alpha-lipoic acid (600 mg / day, >3 months), regardless of poor glycemic control or the presence of albuminuria, had reduced oxidative stress compared to patients who did not receive alpha-lipoic acid treatment. The authors assessed oxidative stress by measuring plasma lipid peroxides (ROOHs) and evaluated the balance between oxidative stress and antioxidant defense as measured by the ROOH / (alpha-tocopherol / cholesterol) ratio. In addition, nuclear factor κB (NF-κB), a redox-sensitive transcription factor, is known to be involved in the later complications of diabetes. In this context, Hofmann et al. have reported alpha-lipoic acid-dependent downregulation of NF-κB in monocytes of diabetic patients receiving alpha-lipoic acid therapy.

[0022] In addition, oxidative stress causes endothelial cell damage and vascular dysfunction (Foarstermann 2008). In this regard, Morcos et al. conducted a prospective, open-label, non-randomized trial involving 84 diabetic patients. In this study, 49 patients served as a control group without antioxidant treatment. The remaining 35 patients received alpha-lipoic acid therapy (600 mg / day for 18 months). After 18 months of follow-up, the progression of endothelial cell damage, based on plasma thrombomodulin measurements, significantly increased in the control group and decreased in the alpha-lipoic acid therapy group. However, the progression of diabetic nephropathy, as assessed by urinary albumin concentration, significantly progressed in the control group but showed no change in the treatment group.

[0023] Furthermore, lipid peroxidation of nerve membranes has been suggested as a mechanism by which peripheral nerve ischemia and hypoxia cause neuropathy. In this regard, Androne et al. investigated the degree of oxidative stress in 10 patients with diabetic neuropathy by measuring serum ceruloplasmin and lipid peroxide concentrations around 70 days into alpha-lipoic acid therapy (600 mg / day). Alpha-lipoic acid was administered intravenously (iv) once daily for the first 10 days, and orally for the following 50 days. Serum ceruloplasmin concentration, which is suggested to be associated with antioxidant protection, was significantly higher in diabetic patients compared to healthy subjects. Furthermore, serum lipid peroxide concentration was significantly higher in diabetic patients compared to healthy subjects and significantly decreased in diabetic patients after alpha-lipoic acid treatment, but serum ceruloplasmin concentration did not change. Overall, alpha-lipoic acid therapy appears to prevent oxidative stress-induced changes in diabetic patients.

[0024] Racemic α-lipoic acid has been shown to reduce oxidative damage and inflammation caused by insecticides, and also to mitigate methylmercury-induced neurotoxicity (Astiz et al., 2012; Yang et al., 2015). It has also been shown to reduce damage from ischemia-reperfusion, Alzheimer's disease, and Parkinson's disease, which are closely related to oxidative stress in pathological conditions (Melli et al., 2008; Shay et al., 2009; Rocamonde et al., 2013).

[0025] R-α-lipoic acid and its reduced form (DHLA) are not only direct ROS scavengers, but also bind to redox-active metals in vitro and in vivo. Both the oxidized and reduced forms bind to multiple metal ions, but their properties differ depending on the metal they bind to. In in vitro studies, R-α-lipoic acid has been shown to bind to Cu 2+ Zn 2+ , and Pb 2+ It preferentially forms a complex with Fe 3+ It was shown that it cannot form a complex with Cu. On the other hand, DHLA is Cu 2+ Zn 2+Pb 2+ Hg 2+ Fe 3+ It forms a complex with (Ou et al., 1995).

[0026] (Anti-inflammatory and immunomodulatory effects) Inflammation is a clinical condition closely associated with oxidative and nitrosation stress, occurring in many diseases, disorders, and conditions. Inflammation is often mediated through the activation of nuclear factor-κB / active protein-1 (NF-κB / AP-1) and the production of tumor necrosis factor-α (TNF-α) (Moura et al., 2015). Furthermore, alpha-lipoic acid is not only a potent antioxidant but also possesses remarkable anti-inflammatory properties (Rochette et al., 2015; Moura et al., 2015). There is also evidence suggesting that alpha-lipoic acid has immunomodulatory effects (Liu et al., 2019).

[0027] Alpha-lipoic acid has also been shown to reduce the gene expression of Toll-like receptors (TLRs) (Guo et al., 2016); TLRs are highly specialized recognition receptors that help modulate the innate immune response to various foreign substances and are a cause of insulin resistance (Ghanim et al., 2009). More recently, alpha-lipoic acid has also been shown to inhibit both insulin sensitivity and cognitive function changes induced by Toll-like receptor 2 (TLR2) agonists (Ahuja et al., 2019).

[0028] (Clinical utility and safety profile) Multiple clinical trials in humans have provided sufficient data to demonstrate the beneficial effects of racemic (R,S)-α-lipoic acid in the treatment of many human diseases, disorders, and conditions (Moura et al., 2015; Tibullo et al., 2017; Salehi et al., 2019). Furthermore, a meta-analysis of randomized controlled trials showed that α-lipoic acid administration improved glucose homeostasis parameters and lipid profiles (Akbari et al., 2018).

[0029] The binding of insulin to the insulin receptor triggers autophosphorylation of multiple tyrosine residues on the insulin receptor. This activated insulin receptor stimulates a protein phosphorylation cascade, increasing the translocation of glucose transporter (GLUT4) to the cell membrane and intracellular glucose uptake (Smith et al., 2004; Konrad, 2005). Alpha-lipoic acid has been shown to promote GLUT4 translocation to the cell membrane and increase glucose uptake in cultured adipocytes and muscle cells (Estrada et al., 1996; Yaworsky et al., 2000). Therefore, alpha-lipoic acid appears to be involved in the insulin signaling pathway, thereby increasing glucose uptake into muscle and adipocytes. For this reason, alpha-lipoic acid is called an insulin mimetic agent. In particular, the insulin receptor is a characteristic feature of type 2 diabetes. Since skeletal muscle tissue is the body's primary storage site for postprandial glucose, drugs that promote glucose uptake by skeletal muscle may be useful for the long-term treatment of type 2 diabetes.

[0030] Multiple clinical studies have suggested that alpha-lipoic acid has beneficial effects on systemic glucose metabolism in patients with type 2 diabetes. These studies evaluated glucose metabolism and insulin sensitivity using the euglycemic-hyperinsulinaemic clamp method. Jacobs et al. investigated, for the first time in a clinical setting, whether alpha-lipoic acid supplementation increases insulin-mediated glucose processing in non-insulin-dependent diabetes. Thirteen patients with similar age, body mass index, and duration of diabetes, and similar baseline insulin resistance levels, were included in the glucose clamp test. They received either alpha-lipoic acid (1000 mg / 500 mL NaCl, n=7) or Vehicle alone (500 mL NaCl, n=6). Following acute non-enteral administration of alpha-lipoic acid, glucose infusion rate increased by 47% (P<0.05), metabolic clearance rate increased by 55% (P<0.05), and insulin sensitivity increased by 57% (P<0.05), while no significant changes were observed in the control group. Therefore, this was the first clinical study demonstrating that alpha-lipoic acid increases insulin-stimulated glucose processing in non-insulin-dependent diabetes mellitus. Subsequently, the same group of authors reported in an uncontrolled pilot study involving 20 patients with type 2 diabetes that intravenous administration of racemic alpha-lipoic acid (500 mg / day, 10 days) improved insulin sensitivity measured 24 hours after the final dose (Jacob et al., 1996). If the increases in metabolic clearance rate and insulin sensitivity are sustained by continued alpha-lipoic acid therapy, its effect can be evaluated as comparable to metformin, a drug widely prescribed to enhance insulin sensitivity and glucose utilization.

[0031] In fact, alpha-lipoic acid has been prescribed in Germany for over 50 years as a treatment for diabetic neuropathy (Biewenga G et al., 1997; Ziegler et al., 1997; Ziegler et al., 1999).

[0032] Alpha-lipoic acid is generally considered a safe drug with few or no side effects, typically associated with mild symptoms (such as nausea, rash, or itching). While there is no established upper limit for the intake of racemic alpha-lipoic acid in humans, safe levels for acute oral ingestion of racemic alpha-lipoic acid have been defined in animals, with significant differences between species. For dogs, LD 50 The reported dose is 400-500 mg / kg (body weight), but rats appear to have a higher tolerance to alpha-lipoic acid, and the acute LD50 in this species is low. 50 The recommended daily intake is >2000 mg / kg (body weight) (Shay et al., 2009).

[0033] Several clinical trials using racemic alpha-lipoic acid have been conducted in humans, and health effects on participants have been evaluated. No adverse effects were reported compared to placebo at doses up to 2400 mg / day. Furthermore, intravenous administration of racemic alpha-lipoic acid at a dose of 600 mg / day for 3 weeks showed no evidence of serious side effects. Oral administration of 1800 mg (600 mg three times daily) of racemic alpha-lipoic acid for 6 months did not result in significant adverse effects compared to placebo. In addition, racemic alpha-lipoic acid has been used in Germany for over 50 years as a treatment for diabetic neuropathy and diabetic retinopathy (Shay et al., 2009).

[0034] Generally, free radicals are recognized as playing a major role in the development of chronic and degenerative conditions; therefore, free radical scavengers or antioxidants can play an important role in improving these conditions. R-α-lipoic acid acts as a free radical scavenger, chelating / binding redox-active metal ions and restoring the reduced levels of other antioxidants, thereby exerting protective effects under a variety of physiological and pathophysiological conditions.

[0035] The diseases treated with alpha-lipoic acid include: chemotherapy-induced tissue injury, heavy metal poisoning, radiation injury, cardiovascular diseases (heart disease, as well as ischemic stroke and hemorrhagic stroke); brain diseases, disorders and conditions (Alzheimer's disease, Parkinson's disease, motor neuron disease, Huntington's disease, Lewy body dementia, multiple ischemic dementia, frontotemporal lobar degeneration, Pick's disease, Jakob-Creutzfeldt disease, prion diseases, traumatic brain injury, traumatic spinal cord injury, multiple sclerosis, obesity, schizophrenia, psychosis, depression, bipolar disorder, anxiety, etc.), autoimmune diseases (multiple sclerosis and psoriasis, etc.), eye diseases (retinopathy, presbyopia, glaucoma, age-related macular degeneration, and optic neuritis, etc.), metabolic syndrome, traumatic brain injury, traumatic spinal cord injury, skin diseases (acne, etc.), diabetes, and glucose. Diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, muscle diseases, nephropathy, arthritis, asthma, rheumatoid arthritis, inflammatory bowel disease, transplant rejection, ischemia-reperfusion injury (e.g., intestinal reperfusion after myocardial ischemia or hemorrhagic shock), restenosis, ileitis, Crohn's disease, thrombosis, colitis (including ulcerative colitis), lupus, frostbite injury, acute leukocytosis-mediated lung injury (e.g., adult respiratory distress syndrome), traumatic shock, septic shock Shock, nephritis, psoriasis, cholecystitis, cirrhosis, diverticulitis, fulminant hepatitis, gastritis, gastric and duodenal ulcers, hepatorenal syndrome, irritable bowel syndrome, jaundice, pancreatitis, ulcerative colitis, human granulocytic ehrlichiosis, Wiscott-Aldrich syndrome, T-cell activation, AIDS; infections caused by viruses, bacteria, protozoa, and parasites (including post-infection syndromes), tumors and cancer, neurodevelopmental disorders (such as autism and Rett syndrome), congenital metabolic disorders causing lipoic acid deficiency, genetic disorders (including chromosomal abnormalities (such as Down syndrome, Klinefelter syndrome, triple X syndrome, Turner syndrome, trisomy 18, trisomy 13)), diseases caused by mutations in a single gene (such as Kabuki syndrome, spinocerebellar degeneration, neurofibromatosis type 1, fragile X syndrome), and DNA repair disorders (such as xeroderma pigmentosum, ataxia telangiectasia, and Cockayne syndrome).The aforementioned cancers may include leukemia, lymphoma, melanoma, adenoma, sarcoma, solid tissue carcinoma, prostate, testis, mammary gland, pancreas, cervix, uterus, kidney, lung, rectum, breast, stomach, thyroid, cervix, cervix, intestine, salivary gland, bile duct, pelvis, mediastinum, urethra, bronchogenic, bladder (bladder cancer, etc.), esophagus, small intestine, oral cavity (oral cancer, etc.), colon, liver, stomach, sarcoma (Kaposi's sarcoma, etc.), adenomatous polyp, and brain tumors (medulloblastoma, glioma, craniopharyngioma, ependymoma, germ cell tumor, pineal blastoma, brainstem glioma, choroid plexus carcinoma, germ cell tumor, astrocytoma, pituitary adenoma, acoustic neuroma, meningioma, oligodendroglioma, etc.).

[0036] A double-blind, placebo-controlled trial demonstrated that administration of racemic alpha-lipoic acid significantly improved diabetes-related polyneuropathy. Racemic alpha-lipoic acid is used to treat diabetes and its neurological symptoms (including peripheral neuropathy such as burning, pain, and numbness in the hands and feet). In some countries, high doses of around 600 mg of racemic alpha-lipoic acid are approved for the treatment of these symptoms. It has also been reported that racemic alpha-lipoic acid can be used as an adjunctive therapy to prevent vision loss in diabetic patients. Here, racemic alpha-lipoic acid prevents damage to microvessels and macrovessels by normalizing the overproduction of reactive oxygen species in mitochondria, and thus maintains pericyte coverage of retinal capillaries (Salehi et al., 2019; Park et al., 2019; Shay et al., 2009).

[0037] Alpha-lipoic acid has been shown to have neuroprotective / neurorepairing effects in a variety of in vitro and in vivo experimental models (Molz et al. 2017 & Dieter et al. 2022). These include stroke models (Choi et al. 2015; Dong et al. 2015; & Ding et al. 2021), hyperthyroidism models (Khadrawy et al. 2022), optic neuritis models (Dietrich et al. 2018), and MS models (Li et al. 2018; Xie et al. 2022; Yadav et al. 2010; Spain et al. 2017; & Loy et al. 2018).

[0038] In mouse studies, racemic alpha-lipoic acid was found to effectively inhibit autoimmune responses associated with experimental autoimmune encephalomyelitis, a model of multiple sclerosis. This suggests that administering racemic alpha-lipoic acid to patients could be a potential treatment for multiple sclerosis (Morini et al., 2004). An initial study in a two-year clinical trial involving 51 patients with secondary progressive multiple sclerosis showed that administration of racemic alpha-lipoic acid (1.2 g / day) reduced the annual rate of change in brain volume by 68%. In this clinical study, racemic alpha-lipoic acid also improved walking function, particularly in patients with low baseline disability.

[0039] The use of R-α-lipoic acid has been hindered by its low absorption rate, chemical instability, and rapid metabolism. Therefore, formulations containing α-lipoic acid in a form that ensures stability, extends plasma half-life, and improves bioavailability have important pharmaceutical applications (Koufaki, 2014).

[0040] Alpha-lipoic acid has low water solubility, at 0.24 mg / mL ("Sur l'acide dithionique et ses sels" Recueil des Travaux Chimiques des Pays-Bas 45 (4), 237-244, 1926). It has also been reported to be unstable to heat and light, and to have a sulfide-like odor and a pungent taste (Takahashi et al., 2011).

[0041] Prodrug design has been proven to contribute to improving the physicochemical and biological properties, as well as the target selectivity, of many pharmacologically active compounds or drugs. Currently, 5-7% of drugs approved worldwide can be classified as prodrugs, and approximately 15% of all new drugs approved each year are prodrugs (Rautio et al., 2008).

[0042] To date, alpha-lipoic acid ester prodrugs have been reported to be either oily (US 2007 / 0055070 A1 and US2016 / 0354340A1) or unstable molecules that produce potentially toxic and pharmaceutically unacceptable chemical species (such as formaldehyde and acetaldehyde) (US 2011 / 0212954 A1). Synthesizing crystalline prodrugs of R-α-lipoic acid provides a substance that is more readily incorporated into various pharmaceutical formulations (including tablets, capsules, suppositories, and solutions). Such derivatives also enhance the feasibility of manufacturing sustained-release pharmaceutical formulations in which R-α-lipoic acid derivatives are administered alone or in combination with other pharmacologically active substances. The superior physicochemical properties of prodrugs enable the design of solid and liquid formulations incorporating various pharmacologically inert excipients, thereby facilitating post-administration prodrug delivery to the patient at various dosages designed to meet specific therapeutic functions.

[0043] The pharmacokinetic characteristics of R-α-lipoic acid (absorption time course, bioavailability, distribution, metabolism, and excretion) are considered insufficient for assessing its therapeutic efficacy as a drug. After oral administration, R-α-lipoic acid has a low absorption rate (bioavailability <25%) and is rapidly metabolized and excreted. Furthermore, plasma R-α-lipoic acid concentrations typically peak within 15 minutes after administration and then rapidly decline. The half-life is approximately 30 minutes (Hermann et al., 2014; Teichert et al., 2003; Carlson et al., 2007).

[0044] After oral administration, R-α-lipoic acid has been found to have a slightly higher absorption rate than the naturally occurring S-α-isomer. The bioavailability of the R-isomer is 24%, while that of the S-isomer is 19% (Hermann et al., 2014).

[0045] [Brief explanation of the drawing] [Figure 1] Figures 1A to 1F are graphs showing the conversion from Example 3 to R-α-lipoic acid over time in the plasma of rats, dogs, and humans.

[0046] [Figure 2] Figure 2 is a graph showing the plasma concentration of R-α-lipoic acid in rats orally administered with Example 3.

[0047] [Disclosure of the Invention] The applicant unexpectedly discovered that the compound represented by formula (I) is useful as a prodrug for R-α-lipoic acid. The compound represented by formula (I) can release α-lipoic acid via ester hydrolysis, which includes hydrolysis mediated by enzymatic activity (including carboxylesterase, acetylcholinesterase, and butyrylcholinesterase) (Yang et al., 2011).

[0048] The prodrugs of the present invention possess improved chemical and pharmaceutical properties compared to R-α-lipoic acid (acidic pKa = 4.7). Due to the relative chemical stability of the ester bond under acidic and neutral conditions, as well as the good distribution characteristics of the derivatives, these drugs are expected to survive at higher concentrations and for longer periods than when R-α-lipoic acid is administered directly.

[0049] The prodrug of the present invention is chemically neutral at physiological pH, exhibits a favorable octane-water partition coefficient (Log P), and has sufficient solubility in aqueous media or possesses moisture that can contribute to permeability through active transport. Improved permeability leads to good absorption by epithelial cells along the gastrointestinal tract (GIT) and other biological tissues. Therefore, the compound of the present invention is expected to be better absorbed in the GIT than negatively charged R-α-lipoic acid, leading to improved bioavailability. After enzymatic hydrolysis, an increase in blood R-α-lipoic acid concentration is predicted with the compound of the present invention compared to direct administration of R-α-lipoic acid. Furthermore, the dithiolane ring in the compound of the present invention is thought to possess antioxidant, anti-inflammatory, and anti-nitrosation effects due to its ability to interconvert between oxidized disulfide and reduced bissulfhydryl forms. This ability to readily undergo one-electron oxidation or reduction also promotes chelation of transition metals (such as iron and copper). Such electrochemical mechanisms are known to generate highly toxic chemical species and are involved in the progression of several degenerative diseases and disorders.

[0050] The quantitative production of R-α-lipoic acid by enzymatic hydrolysis of the compound of the present invention is expected to occur primarily in the blood. This will enhance the antioxidant capacity and strengthen the immune system in patients with degenerative diseases and cancer. It may also yield beneficial effects whether administered alone or in combination with existing treatments.

[0051] According to a first aspect of the present invention, Equation (I)

[0052] [ka]

[0053] Compounds represented by, Or, a pharmaceutically acceptable salt thereof, its solvate, its hydrate, its tautomer, its stereoisomer, its enantiomer, its polymorph, and / or its N-oxide, In formula (I), Z 1 and Z 2 These are independently -SH or -S(O)H; or Z 1 and Z 2 These atoms, together with the atoms to which they bond, form a dithiolane ring, where one of the sulfur atoms in the dithiolane ring may be substituted by an oxo group; A and Y are each independently C1-C6 alkylene chains, where the C1-C6 alkylene chains are hydroxyl, halo, -CN, -NH2, -NO2, C1-C6 alkoxy, and -NHR. 1 , -NR 1 R 1 ,-NHC(O)R 1 , -NR 1 C(O)R 1 , -C(O)R 1 -CO2H, -C(O)NH2, and -CO2R 1 Optionally substituted by one or more substituents selected from the group consisting of; X is H, -CH3, -OH, -OR 1 -NH2, -NHC(O)R 1 , -NR 1 C(O)R 1 ,-NHC(O)NHR 1 -NHC(O)NH2, -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 , -NHS(O)2R 1 , -NR 1 S(O)2R 1 , -NHS(O)2NHR 1 , -NHS(O)2NR 1 R1 , -NR 1 S(O)2NR 1 R 1 -NHCH2CO2H, -NHCH2CO2R 1 , NHCH2CH2CO2H, -NHCH2CH2CO2R 1 , and selected from the group consisting of optionally substituted 3- to 8-membered heterocycles, where the 3- to 8-membered heterocycle is aromatic or non-aromatic, monocyclic or dicyclic, where one or more of the ring constituent atoms are N, O, or S, and the ring is bonded to the rest of the molecule via a C atom or an N atom; and, R 1 Each of these independently provides a compound selected from the group consisting of optionally substituted C1-C4 alkyls, optionally substituted C2-C4 alkenyls, and optionally substituted C2-C4 alkynyls, or a pharmaceutically acceptable salt thereof, its solvate, its hydrate, its tautomer, its stereoisomer, its enantiomer, its polymorph, and / or its N-oxide.

[0054] Alternatively, A and X together form a known pharmaceutical product.

[0055] As used herein, the term "alkylene chain" refers to a divalent saturated hydrocarbon chain. The alkylene chain may be linear or branched.

[0056] Preferably, Z 1 and Z 2 These are either -SH or Z 1 and Z 2 These, together with the atoms to which they bond, form a dithiolane ring. More preferably, Z 1 and Z 2 These atoms, together with the atoms to which they bond, form a dithiolane ring.

[0057] In a preferred embodiment of the present invention, the compound represented by formula (I) is formula (Ia)

[0058] [ka]

[0059] The compound represented by , or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, enantiomer, polymorph, and / or N-oxide.

[0060] In the compounds of the present invention, Y is preferably an unsubstituted C1-C6 alkylene chain, and more preferably butylene.

[0061] In a preferred embodiment of the present invention, the compound represented by formula (I) is a compound represented by formula (Ib)

[0062] [ka]

[0063] It is a compound represented by [formula].

[0064] In the compounds of the present invention, X is preferably H, -CH3, -OH, or -OR 1 -NH2, -NHC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 -NHCH2CO2H, -NHCH2CO2R 1 , -NHCH2CH2CO2H, -NHCH2CH2CO2R 1 , and selected from the group consisting of optionally substituted 3- to 8-membered heterorings, more preferably H, -CH3, -NH2, -NHC(O)R 1 The group is selected from -NHC(O)NH2, -NHCH2CO2H, -NHCH2CH2CO2H, and any substituted 3- to 8-membered heterocycles.

[0065] Preferably, A is -CO2H, -C(O)NH2, and -CO2R 1A C1-C6 alkylene chain optionally substituted with one or more substituents selected from the group consisting of, more preferably, A is -CO2H, -C(O)NH2, and -CO2R 1 A is a C1-C4 alkylene chain optionally substituted with one or more substituents selected from the group consisting of the above, more preferably A is a C1-C4 alkylene chain optionally substituted with -CO2H or -C(O)NH2.

[0066] Preferably, each R 1 Each R is independently and optionally substituted C1-C4 alkyl group, preferably each R 1 It is -CH3.

[0067] In a preferred embodiment of the present invention, A is an unsubstituted C2-C3 alkylene chain, and X is an optionally substituted 3-8 member heterocycle; or, A is a C1-C4 alkylene chain, and X is H, -CH3, -NH2, -NHC(O)NH2, -NHC(O)R 1 The C1-C4 alkylene chain is either -NHCH2CO2H or -NHCH2CH2CO2H, where the C1-C4 alkylene chain is optionally substituted with -CO2H or -C(O)NH2.

[0068] In a more preferred embodiment of the present invention, A is an unsubstituted C2-C3 alkylene chain and X is an optionally substituted 3-8 membered heterocycle; or, A is a C1-C4 alkylene chain, and X is H, -CH3, or -NH2, where the C1-C4 alkylene chain is optionally substituted with -CO2H or -C(O)NH2; or A is a C2-C3 alkylene chain, and X is -NHC(O)NH2, -NHC(O)R 1 The C2-C3 alkylene chain is either -NHCH2CO2H or -NHCH2CH2CO2H, where the C2-C3 alkylene chain is optionally substituted with -CO2H or -C(O)NH2.

[0069] In the compound of the present invention, the optionally substituted 3- to 8-membered heterocycle is an optionally substituted 5 or 6-membered heterocycle, more preferably, one or two ring constituent atoms in the 5 or 6-membered heterocycle are independently N, O, or S, and the remaining ring constituent atoms are C.

[0070] Preferably, the 3-8 membered heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of oxo, C1-C3 alkyl, and hydroxyl, preferably from the group consisting of oxo, methyl, and hydroxyl.

[0071] Preferably, the 3- to 8-membered heterocycle is 2,5-dioxopyrrolidine-1-yl;pyrrolidine-2-on-1-yl;1,3-oxazolidine-2-on-3-yl;2,6-dioxopiperidine-1-yl;2,5-dihydro-1H-pyrrole-2,5-dione-1-yl;pyrrolidine-2,4-dione-1-yl;1,1-dioxothiomorpholin-4-yl;4-oxopiperidine-1-yl;4-hydroxypyrrolidin Selected from the group consisting of n-2-on-1-yl; morpholine-4-yl; 4-methylpiperidine-1-yl; pyrrolidine-3-on-1-yl; 1-methylpyrrolidine-2-yl; 1-methyl-1H-imidazole-2-yl; piperidine-4-yl; 1-methyl-piperidine-4-yl; 1H-imidazole-1-yl; 2,5-dioxopiperazine-1-yl; and pyrrolidine-1-yl; piperazine-2-yl.

[0072] In a preferred embodiment of the present invention, the compound represented by formula (I) is the following compound

[0073] [ka] JPEG2026513964000007.jpg225169JPEG2026513964000008.jpg241169JPEG2026513964000009.jpg21216 9JPEG2026513964000010.jpg249169JPEG2026513964000011.jpg234169JPEG2026513964000012.jpg93169

[0074] It is one of the following, or a pharmaceutically acceptable salt thereof, its solvate, its hydrate, its tautomer, its stereoisomer, its enantiomer, its polymorph, and / or its N-oxide.

[0075] A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the present invention, as well as a pharmaceutically acceptable carrier, excipient, and / or diluent.

[0076] Preferably, the pharmaceutical composition further comprises a known pharmaceutical.

[0077] According to a third aspect of the present invention, a compound or pharmaceutical composition for therapeutic use is provided.

[0078] According to a fourth aspect of the present invention, compounds or pharmaceutical compositions described in the present invention are provided for use in the treatment or prevention of diseases, disorders, or conditions related to one or more of the following: neurodegeneration, oxidative stress, nitrosation stress, excitotoxicity, immune dysfunction, metabolic dysfunction, mitochondrial dysfunction, vascular dysfunction, inflammation (including neuroinflammation), and glucose metabolism.

[0079] More preferably, the disease, disorder, or condition is selected from the group consisting of: chemotherapy-induced tissue injury, heavy metal poisoning, radiation injury, cardiovascular disease (heart disease, as well as ischemic stroke and hemorrhagic stroke); brain diseases, disorders, and conditions (Alzheimer's disease, Parkinson's disease, motor neuron disease, Huntington's disease, Lewy body dementia, multiple cerebral infarction dementia, frontotemporal lobar degeneration, Pick's disease, Jakob-Creutzfeldt disease, prion disease, traumatic brain injury, traumatic spinal cord injury, multiple sclerosis, obesity, schizophrenia, psychosis, depression, bipolar disorder, anxiety, etc.), autoimmune diseases (multiple sclerosis and psoriasis, etc.), eye diseases (retinopathy, presbyopia, glaucoma, age-related macular degeneration, and optic neuritis, etc.), metabolic syndrome, traumatic brain injury, traumatic spinal cord injury, skin diseases (acne, etc.), diabetes, sugar Diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, muscle diseases, nephropathy, arthritis, asthma, rheumatoid arthritis, inflammatory bowel disease, transplant rejection, ischemia-reperfusion injury (e.g., intestinal reperfusion after myocardial ischemia or hemorrhagic shock), restenosis, ileitis, Crohn's disease, thrombosis, colitis (including ulcerative colitis), lupus, frostbite injury, acute leukocytosis-mediated lung injury (e.g., adult respiratory distress syndrome), traumatic shock, septic shock Shock, nephritis, psoriasis, cholecystitis, cirrhosis, diverticulitis, fulminant hepatitis, gastritis, gastric and duodenal ulcers, hepatorenal syndrome, irritable bowel syndrome, jaundice, pancreatitis, ulcerative colitis, human granulocytic ehrlichiosis, Wiscott-Aldrich syndrome, T-cell activation, AIDS; infections caused by viruses, bacteria, protozoa, and parasites (including post-infection syndromes), tumors and cancer, neurodevelopmental disorders (such as autism and Rett syndrome), congenital metabolic disorders causing lipoic acid deficiency, genetic disorders (including chromosomal abnormalities (such as Down syndrome, Klinefelter syndrome, triple X syndrome, Turner syndrome, trisomy 18, trisomy 13)), diseases caused by mutations in a single gene (such as Kabuki syndrome, spinocerebellar degeneration, neurofibromatosis type 1, fragile X syndrome), and DNA repair disorders (such as xeroderma pigmentosum, ataxia telangiectasia, and Cockayne syndrome).

[0080] In some embodiments, the disease, disorder, or condition may be selected from the group consisting of: chemotherapy-induced tissue injury, heavy metal poisoning, radiation injury, cardiovascular disease (heart disease, as well as ischemic stroke and hemorrhagic stroke); brain diseases, disorders, and conditions (Alzheimer's disease, Parkinson's disease, motor neuron disease, Huntington's disease, Lewy body dementia, multiple cerebral infarction dementia). Frontotemporal dementia, Pick's disease, Jacob-Creutzfeldt disease, prion diseases, traumatic brain injury, traumatic spinal cord injury, multiple sclerosis, obesity, schizophrenia, psychosis, depression, bipolar disorder, anxiety, etc.), autoimmune diseases (multiple sclerosis and psoriasis, etc.), eye diseases (retinopathy, presbyopia, glaucoma, age-related macular degeneration, and optic neuritis, etc.), metabolic syndrome, traumatic brain injury, traumatic spinal cord injury, skin diseases (acne, etc.), diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, muscle diseases, nephropathy, arthritis, asthma, rheumatoid arthritis, inflammatory bowel disease, transplant rejection, ischemia-reperfusion injury (examples) For example, myocardial ischemia or intestinal reperfusion after hemorrhagic shock), restenosis, ileitis, Crohn's disease, thrombosis, colitis (including ulcerative colitis), lupus, frostbite injury, acute leukocytosis-mediated lung injury (such as adult respiratory distress syndrome), traumatic shock, septic shock, nephritis, psoriasis, cholecystitis, cirrhosis, diverticulitis, fulminant hepatitis, gastritis, gastric and duodenal ulcers, hepatorenal syndrome, irritable bowel syndrome, jaundice, pancreatitis, ulcerative colitis, human granulocytic ehrlichiosis, Wiscott-Aldrich syndrome, T-cell activation, AIDS; infections caused by viruses, bacteria, protozoa, and parasites (including post-infection syndromes), tumors, and cancer.

[0081] Preferably, the cancer is selected from leukemia, lymphoma, melanoma, adenoma, sarcoma, solid tissue carcinoma, prostate, testis, mammary gland, pancreas, cervix, uterus, kidney, lung, rectum, breast, stomach, thyroid, cervix, intestine, salivary gland, bile duct, pelvis, mediastinum, urethra, bronchogenic, bladder (bladder cancer, etc.), esophagus, small intestine, oral cavity (oral cancer, etc.), colon, liver, stomach, sarcoma (Kaposi's sarcoma, etc.), adenomatous polyp, and brain tumors (medulloblastoma, glioma, craniopharyngioma, ependymoma, germ cell tumor, pineal blastoma, brainstem glioma, choroid plexus carcinoma, germ cell tumor, astrocytoma, pituitary adenoma, acoustic neuroma, meningioma, oligodendroglioma, etc.).

[0082] According to a fifth aspect of the present invention, there is provided a compound or pharmaceutical composition according to the present invention for use in the treatment of side effects caused by the administration of other medicaments.

[0083] According to a sixth aspect of the present invention, there is provided a method of treating one of the above-mentioned diseases. The method includes administering a therapeutically effective amount of a compound or pharmaceutical composition of the present invention to a subject in need of treatment.

[0084] The compounds of the present invention may include isotopically labeled forms and / or isotopically enriched forms of the compounds. As used herein, a compound of the present invention may include an isotopic abundance ratio different from the natural abundance ratio of atoms in one or more of the atoms constituting such a compound. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine ( 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl, etc.).

[0085] (Pharmaceutical composition) The compounds of the present invention are often used in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, where appropriate, pharmaceutically acceptable base addition salts and acid addition salts (e.g., metal salts such as alkali metal salts and alkaline earth metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and sulfonates). Acid addition salts include inorganic acid addition salts (e.g., hydrochlorides, sulfates, and phosphates) and organic acid addition salts (e.g., alkyl sulfonates, aryl sulfonates, acetates, maleates, fumarates, tartrates, citrates, and lactates). Examples of metal salts include alkali metal salts (e.g., lithium salts, sodium salts, and potassium salts), alkaline earth metal salts (e.g., magnesium salts, and calcium salts), aluminum salts, and zinc salts. Examples of ammonium salts include ammonium salts and tetramethylammonium salt. Examples of organic amine addition salts include salts with morpholine and piperidine. Examples of amino acid addition salts include salts with glycine, phenylalanine, glutamic acid, and lysine. Sulfonates include mesylates, tosylates, and benzenesulfonates.

[0086] The pharmaceutical compositions of the present invention are suitable for administration to warm-blooded animals such as humans (or including cells or cell lines derived from warm-blooded animals (such as human cells)) and are intended for the treatment of diseases that respond to inhibition of sodium channel activity, or, in another aspect of the present invention, for the prevention thereof (also called a preventive method). The pharmaceutical compositions may comprise a compound of the present invention that is effective in the inhibition thereof, and at least one pharmaceutically acceptable carrier.

[0087] The pharmaceutical compositions of the present invention may be articles for enteral administration (such as intranasal, rectal, oral, sublingual, or buccal mucosal administration) and non-enteral administration (such as intramuscular, subcutaneous, or intravenous administration) to warm-blooded animals (including humans, for example). These contain an effective dose of the pharmacologically active ingredient, either alone or with a substantial amount of a pharmaceutically acceptable carrier. The dosage of the active ingredient is determined by the species, weight, age, and individual condition of the warm-blooded animal, individual pharmacokinetic data, the disease being treated, and the method of administration.

[0088] The dosage of the compound of the present invention for warm-blooded animals (e.g., a human weighing approximately 70 kg) is, for example, approximately 3 mg to approximately 10 g / person / day, approximately 10 mg to approximately 1.5 g / person / day, or approximately 100 mg to approximately 1000 mg / person / day, and may be divided into 1 to 3 single doses (for example, the same amount). Typically, half the adult dose is administered to children.

[0089] The dosage of the compound of the present invention for administration to a warm-blooded animal (for example, a human weighing approximately 70 kg) is, for example, 50 μg to approximately 2000 mg, and optionally 50 μg to approximately 1000 mg.

[0090] The pharmaceutical composition forms, for example, about 1% to about 95%, or about 20% to about 90% of the active ingredient. The pharmaceutical composition according to the present invention may be in the form of a single dose (ampoule, vial, suppository, sugar-coated tablet (dragee), tablet, capsule, or solution, etc.).

[0091] The pharmaceutical compositions of the present invention are prepared by known methods (conventional processes such as dissolution, freeze-drying, mixing, granulation, or formulation).

[0092] Solutions and suspensions of the active ingredient, particularly isotonic aqueous solutions or suspensions, are used. For example, in the case of lyophilized compositions containing only the active ingredient or together with a carrier (such as mannitol), these solutions or suspensions can be prepared before use. The pharmaceutical composition may be sterilized and / or may contain excipients (such as preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for osmotic pressure adjustment, and / or buffers). The pharmaceutical composition is prepared by known methods (such as conventional dissolution or lyophilization processes). The solution or suspension may contain thickeners (such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatin).

[0093] The suspension in oil may contain as an oil component vegetable oil, synthetic oil, or semi-synthetic oil commonly used for injection purposes. Examples include liquid fatty acid esters containing long-chain fatty acids with 8 to 22 or 12 to 22 carbon atoms as an acid component. Specifically, examples include lauric acid, tridecyl acid, myristic acid, pentadecyl acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or corresponding unsaturated acids (e.g., oleic acid, elaidic acid, erucic acid, brazidic acid, linoleic acid, etc.). If necessary, antioxidants (such as vitamin E, β-carotene, or 3,5-di-tert-butyl-4-hydroxytoluene) may be added. The alcohol components of these fatty acid esters have up to six carbon atoms and are monovalent or polyvalent hydroxy compounds (e.g., monovalent, divalent, or trivalent alcohols such as methanol, ethanol, propanol, butanol, or pentanol, or their isomers, but especially glycols and glycerols)). Therefore, examples of fatty acid esters include: ethyl oleate, isopropyl myristate, isopropyl palmitate, Labrafil M2375, polyoxyethylene glyceryl trioleate, Gattefosse, Miglyol 812 (triglycerides, which are saturated fatty acids with chain lengths of C8-C12), especially vegetable oils (cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, and especially peanut oil).

[0094] Compounds with a cLogP value of 3 or higher (such as compounds 8, 9, and 26) can be incorporated into lipids such as polyunsaturated fatty acids (PUFAs) at least one of each. Suitable PUFAs include, but are not limited to, omega-3 and omega-6 fatty acids. Appropriate omega-3 fatty acids include alpha-linolenic acid (octadeca-9,12,15-trienoic acid), stearidonic acid (octadeca-3,6,9,12,15-tetraenoic acid), eicosapentaenoic acid (eicosa-5,8,11,14,17-pentaenoic acid), docosapentaenoic acid (docosa-7,10,13,16,19-pentaenoic acid), eicosatetraenoic acid (eicosa-8,11,14,17-tetraenoic acid), and docosahexaenoic acid (docosa-4,7,10,13,16,19-hexaenoic acid). Appropriate omega-6 fatty acids include linoleic acid (9,12-octadecadienoic acid), gamma-linolenic acid (6,9,12-octadecatrienoic acid), eicosadienoic acid (11,14-eicosadienoic acid), dihomo-gamma-linolenic acid (8,11,14-eicosatrienoic acid), arachidonic acid (5,8,11,14-eicosatetraenoic acid), docosadienoic acid (13,16-docosadienoic acid), adrenaline (7,10,13,16-docosatetraenoic acid), docosapentaenoic acid (4,7,10,13,16-docosapentaenoic acid), and calendic acid (8E,10E,12Z-octadecatrienoic acid).

[0095] The injectable composition is prepared under sterile conditions by conventional methods. This also applies to filling the composition into ampoules or vials and sealing the containers.

[0096] Pharmaceutical compositions for oral administration are obtained by mixing an active ingredient with a solid carrier, granulating the resulting mixture as needed, and then, if necessary or desirable, adding appropriate excipients, and finally processing the mixture into tablets, sugar-coated tablets, capsules, pills, or liquids. It is also possible to incorporate the active ingredient into a plastic carrier that allows for diffusion or release in fixed amounts.

[0097] Suitable carriers include fillers (sugars, e.g., lactose, sucrose, mannitol or sorbitol, cellulose preparations, and / or calcium phosphate (e.g., tricalcium triphosphate or calcium hydrogen phosphate)), binders (starch paste (e.g., made from corn, wheat, rice, or potato starch), gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, etc.), and / or, if necessary, disintegrants (the starches mentioned above, and / or carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts (e.g., sodium alginate)). Excipients are particularly fluid modifiers and lubricants (silicic acid, talc, stearic acid or its salts (e.g., magnesium stearate or calcium stearate), and / or polyethylene glycol, etc.). The core of the sugar-coated tablet is coated with an appropriate, optionally enteric coating. The coating may be prepared using a concentrated sugar solution (which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide), or a coating solution in a suitable organic solvent. Alternatively, for the preparation of enteric coatings, a solution of a suitable cellulose preparation (such as ethylcellulose phthalate or hydroxypropyl methylcellulose phthalate) may be used. The capsules are dry-filled capsules made from gelatin, and flexible sealed capsules made from gelatin and a plasticizer (such as glycerol or sorbitol). The dry-filled capsules may contain the active ingredient in granular form with a filler such as lactose; a binder such as starch; a lubricant such as talc or magnesium stearate, and, if necessary, a stabilizer. The active ingredient in the flexible capsule is preferably dissolved or suspended in a suitable oily excipient (such as fatty oil, paraffin oil, or liquid polyethylene glycol). Stabilizers and / or antimicrobial agents may also be added. Dyes or pigments may be added to the tablet or sugar-coated tablet coating, or to the capsule shell, for identification purposes or to indicate differences in the dosage of the active ingredient.

[0098] A pharmaceutical composition generally contains an effective dose of the compound of the present invention. As used herein, “effective dose” means the amount of the two active ingredients (either the compound of the present invention and another known agent in combination, or in embodiments where AX in formula (I) is a known agent) and is different from the optimal amount of the ingredients when administered in a therapeutic regimen that does not contain the other active ingredient. The effective dose of the pharmaceutical composition, when administered to a subject, prevents or improves the symptoms of a disease, disorder, or condition and reduces side effects compared to these symptoms in a control group (where the subject is administered the compound of the present invention and another active ingredient alone). Those skilled in the art can easily determine the effective dose of each ingredient in the combination. The objective of the methods and compositions herein is that, in the presence of or in combination with another active ingredient, the effective dose of the compound of the present invention is reduced compared to the effective dose in the absence of the other known agent, due to the increased efficacy when these compounds are administered in combination. The ratio of the compound of the present invention to the second active ingredient in a single dosage form may vary. In some cases, an “effective” dose of one or both of the two drugs can be achieved by using one or more tablets or capsules. Useful combinations include combining the compound of the present invention (which possesses both antioxidant and free radical scavenging properties by generating R-α-lipoic acid under physiological conditions) with another agent to reduce or prevent side effects such as tissue damage. Under certain conditions, the generation of R-α-lipoic acid from the compound of the present invention, when combined with other known agents, may have a synergistic effect in preventing or alleviating diseases, disorders, or conditions. Therefore, the pharmaceutical composition may contain an effective dose of the compound of the present invention that can obtain a therapeutic effect equivalent to that obtained by administering R-α-lipoic acid alone to the subject, but at a lower dose.

[0099] The present invention may be implemented in other specific forms without departing from its spirit or essential features. Therefore, the embodiments described herein should be considered illustrative and not limiting in all respects to the invention described herein. Accordingly, the scope of the invention is not defined by the foregoing description but by the appended claims, and therefore, all modifications within the meaning and equivalents of those claims are intended to be encompassed within the scope of the invention.

[0100] Throughout this disclosure, references and citations are made to other documents (patents, patent applications, patent publications, journals, books, articles, web content, etc.). All of these documents are incorporated in their entirety by reference herein for any purpose.

[0101] [Examples] [Example 1] (2-(2,5-dioxopyrrolidine-1-yl)ethyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoic acid)

[0102] [ka]

[0103] (R)-α-lipoic acid (10.0 g, 0.048 mol) and N,N-dimethylaminopyridine (0.592 g, 0.005 mol) were dissolved in MTBE (131 ml) at room temperature. ({[3-(dimethylamino)propyl]imino]methylidene)(ethyl)amine, EDC) (10.3 ml, 0.058 mol) was added dropwise for 5 minutes, and the mixture was stirred for a further 30 minutes at room temperature. 1-(2-hydroxyethyl)pyrrolidine-2,5-dione (7.632 g, 0.053 mol) was added as a solid. After another hour, the reaction was confirmed to be complete by LC-MS. MTBE (20 ml) was added to the reaction mixture, and the mixture was washed with saturated sodium bicarbonate solution (10 ml), 1 M aqueous HCl solution (10 ml), and saline solution (5 ml). The organic layer was dried and filtered. The solvent was evaporated under reduced pressure using a water bath set to room temperature. During evaporation, the solvent was replaced with n-heptane (150 ml). The resulting yellow oily substance (12.300 g, 0.037 mol) crystallized after being stored at -20°C for 16 hours. LC-MS: m / z 349.1 (M+NH4) + ; 1 H-NMR(400MHz,DMSO):δ 4.12(t,J=5.5Hz,2H),3.67-3.55(m,3H),3.24-3.05(m,2H),2.63(s,4H),2.47-2.35(m,1H),2. 24(t,J=7.3Hz,2H),1.94-1.81(m,1H),1.73-1.60(m,2H),1.59-1.44(m,2H),1.43-1.27(m,2H); 13 C-NMR (100MHz, DMSO): δ 178.0,173.2,60.8,56.5,40.4,38.6,37.6,34.5,33.6,34.5,33.6,28.5,28.4,27.3,24.4.

[0104] [Example 2] (2-Acetamidoethyl 5-[(3R)-1,2-Dithiolan-3-yl]pentanoic acid)

[0105] [ka]

[0106] (R)-α-lipoic acid (10.0 g, 0.048 mol) and N,N-dimethylaminopyridine (1.776 g, 0.015 mol) were dissolved in MTBE (131 ml) at room temperature, and EDC (10.3 ml, 0.058 mol) was added dropwise for 5 minutes, followed by stirring for a further 30 minutes. 2-hydroxyethyl)acetamide (5.498 g, 0.053 mol) was added, and after 2 hours, the reaction mixture was passed through a silica plug, and the silica was washed with MTBE (100 mL). The integrated organic fraction was removed by distillation under reduced pressure at room temperature using a water bath (water batch) to obtain the crude product (20 g). The crude product was purified by silica gel chromatography (ethyl acetate / isohexane, gradient 0:1 to 1:0), the solvent was evaporated, and the mixture was stored at -20°C for 16 hours to obtain a crystalline yellow solid (7.7 g, 0.026 mol). LC-MS: m / z 292.1 (M+H) + ; 1 H-NMR(400MHz,DMSO):δ 7.96(br s,1H),4.00(t,J=5.8Hz,2H),3.68-3.56(m,1H),3.26(q,J=5.8Hz,2H),3.23-3.09(m,2H),2.48-2.36(m,1H),2 .31(t,J=7.3Hz,2H),1.94-1.82(m,1H),1.81(s,3H),1.73-1.64(m,1H),1.60-1.51(m,3H),1.42-1.36(m,2H); 13 C-NMR (100MHz, DMSO): δ 173.2, 169.9, 63.0, 56.6, 38.6, 38.1, 34.5, 33.7, 28.6, 24.6, 23.0.

[0107] [Example 3] (2-(carbamoylamino)ethyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoic acid)

[0108] [ka]

[0109] (R)-α-Lipoic acid (15.0 g, 0.073 mol) and N,N-dimethylaminopyridine (2.665 g, 0.022 mol) were dissolved in MTBE (196.5 ml) at room temperature. EDC (13.5 g, 0.087 mol) was added dropwise over 5 minutes, and the mixture was further stirred for 30 minutes. 2-Hydroxyethyl)urea (8.326 g, 0.080 mol) was added, and after 2.5 hours, the reaction mixture was filtered through a plug of silica. The reaction mixture was washed with MTBE (100 mL) and then with DCM (100 ml). The DCM fraction was evaporated under reduced pressure at room temperature, and the yellow residue was purified by silica gel chromatography (ethyl acetate / hexane, gradient 0:1 to 1:0). After evaporation of the solvent, it was stored at -20 °C for 16 hours to obtain a crystalline yellow solid (8.0 g, 0.027 mol). LC-MS: m / z 293.1 (M+H) + ; 1 1H-NMR (400 MHz, DMSO): δ 6.04 (t, 1H), 5.49 (s, 2H), 3.97 (t, J = 5.7 Hz, 2H), 3.68 - 3.57 (m, 1H), 3.25 - 3.15 (m, 3H), 3.18 - 3.07 (m, 1H), 2.42 (dt, J = 20, 8 Hz, 1H), 2.31 (t, J = 7.4 Hz, 2H), 1.88 (dt, J = 20, 8 Hz, 1H), 1.75 - 1.62 (m, 1H), 1.62 - 1.49 (m, 3H), 1.42 - 1.33 (m, 2H); 13 13C-NMR (100 MHz, DMSO): δ 173.2, 159.0, 63.9, 56.5, 40.4, 38.7, 38.6, 34.5, 33.8, 28.6, 24.6.

[0110] [Example 4] (2-(Morpholin-4-yl)ethyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate)

[0111] [Chemical formula]

[0112] (R)-α-lipoic acid (10.0 g, 0.048 mol) and N,N-dimethylaminopyridine (1.776 g, 0.015 mol) were dissolved in MTBE (131 ml) at room temperature, and EDC (9.029 g, 0.058 mol) was added dropwise for 5 minutes, followed by stirring for a further 30 minutes. 2-(morpholine-4-yl)ethane-1-ol (6.994 g, 0.053 mol) was added, and after 2 hours, the reaction mixture was passed through a silica plug, and the silica was washed with MTBE (100 mL). The integrated organic fraction was removed by distillation under reduced pressure at room temperature using a water bath (water batch) to obtain the crude product (16.5 g). The crude product was purified by silica gel chromatography (ethyl acetate / isohexane, gradient 0:1~7:3), and after evaporation of the solvent, a yellow viscous oil (9.636 g, 0.029 mol) was obtained. LC-MS: m / z 320.2 (M+H) + ; 1 H-NMR(400MHz, CDCl3):δ 4.14(t,J=5.9Hz,2H),3.65-3.63(m,4H),3.54-3.47(m,1H),3.16-2.99(m,2H),2.56(t,J=5.9Hz ),2.45-2.39(m,5H),2.27(t,J=7.4Hz),1.89-1.78(m,1H),1.71-1.51(m,5H,1.51-1.32(m,2H); 13 C-NMR (100MHz, CDCl3): δ 173.4,67.0,61.4,57.2,56.4,53.9,40.3,38.5,34.6,34.1,28.8,24.7.

[0113] [Example 5] (3-(morpholine-4-yl)propyl-5-[(3R)-1,2-dithiolan-3-yl]pentanoic acid)

[0114] [ka]

[0115] (R)-α-lipoic acid (15.0 g, 0.073 mol) and N,N-dimethylaminopyridine (2.665 g, 0.022 mol) were dissolved in MTBE (196.5 ml) at room temperature, and EDC (13.54 g, 0.087 mol) was added dropwise for 5 minutes, followed by stirring for another 30 minutes. 3-(morpholin-4-yl)propan-1-ol (11.61 g, 0.080 mol) was added, and after 2 hours, the reaction mixture was passed through a silica plug, and the silica was washed with MTBE (100 mL). The integrated organic fraction was removed by distillation under reduced pressure at room temperature using a water bath (water batch) to obtain the crude product (32.4 g). The crude product was purified by silica gel chromatography (DCM / ethyl acetate, gradient 1:0 to 3:8), and after evaporation of the solvent, a yellow viscous oil (14.80 g, 0.044 mol) was obtained. LC-MS: m / z 334.2 (M+H) + ; 1 H-NMR(400MHz, CDCl3):δ 4.06(t,J=6.6Hz,2H),3.67-3.61(m,4H),3.56-3.44(m,1H),3.17-2.99(m,2H),2.46-2.30(m,7H), 2.25(t,J=7.4Hz,2H),1.91-1.80(m,1H),1.80-1.70(m,2H),1.70-1.51(m,4H),1.51-1.31(m,2H); 13 C-NMR (100MHz, CDCl3): δ 173.5,67.0,62.7,56.4,55.4,53.7,40.2,38.5,34.6,34.1,28.8,25.9,24.7.

[0116] The following examples can be synthesized by a method similar to that of the above examples.

[0117] [ka] JPEG2026513964000019.jpg255166JPEG2026513964000020.jpg253169JPEG2026513964000021.jpg241169

[0118] 〔data〕 Table 1 below lists the calculated cLogP values ​​for the example compounds. These calculations were performed using Molinspiration software (https: / / www.molinspiration.com / cgi-bin / properties).

[0119] [Table 1]

[0120] Examples 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 24, 25, 26, 27, 37, 38, 42, and 43 are either free bases or pharmaceutically acceptable salts. The latter substances include hydrochlorides, tartrates, citrates, succinates, maleates, malons, fumarates, acetates, and sulfates.

[0121] The calculated octanol-water partition coefficient (LogP) of R-α-lipoic acid is 2.25 (Molinspiration software). This value is in the range of 0 to 3, which is generally considered optimal for gastrointestinal absorption. However, since R-α-lipoic acid is a weak acid (pKa 4.7), most of the substance becomes negatively charged when it is excreted from the stomach and moves through the intestinal tract (pH 5.5 to 7.5). This negative charge is expected to result in low absorption of R-α-lipoic acid. The LogD value of the anionic form under small and large intestinal conditions was calculated to be less than -0.46, indicating low passive diffusivity across the plasma membrane and the possibility of transporter enzyme-dependent transport along the human intestinal tract (Vadlapudi et al., 2012). Furthermore, it has been reported that medium-chain fatty acids significantly inhibit the transport of R-α-lipoic acid, suggesting that proton-coupled monocarboxylic acid transporters may also be involved in the intestinal transport of R-α-lipoic acid (Takaishi et al., 2007). This phenomenon is not expected to occur in the case of the compound of the present invention.

[0122] Unlike R-α-lipoic acid (pKa 4.7), Examples 1-3, 6, 7, 8, 11, 16, 19, 20, 28, 32, 33, 34, 36, and 41 are expected to be neutral at all physiological pH values ​​(pH approximately 5-7.5) encountered in the small and large intestines. Therefore, the absorption of these prodrugs is pH independent and unlikely to be inhibited by pH changes in the gastrointestinal tract. After leaving the stomach and entering the gastrointestinal tract, R-α-lipoic acid becomes partially or completely negatively charged. The chemical species expected to cross the plasma membrane via passive diffusion is neutral R-α-lipoic acid, not the corresponding anion.

[0123] Based on the LogP values ​​of Examples 1-43 (see Table 1 above), it is presumed that most derivatives exhibit improved gastrointestinal absorption due to passive diffusion permeability compared to simple alkyl or aryl esters of R-α-lipoic acid, which show high LogP values.

[0124] Examples 4, 5, 9, 10, 12, 13, 14, 15, 17, 18, 21, 22, 23, 24, 25, 26, 27, 37, 38, 42, and 43 contain aliphatic amino groups. The pKa values ​​of these compounds have not been measured, but are expected to be around 5-11. Therefore, these compounds are expected to become partially positively charged in the gastrointestinal tract, resulting in improved solubility and good absorption.

[0125] The pKa values ​​of imidazole derivatives 10 and 14 are expected to be approximately 7.0, with both neutral and cationic forms present in high proportions along the pH gradient of the gastrointestinal tract. The partition coefficients are also within the optimal range, promoting good absorption of these derivatives.

[0126] Examples 1-43 are expected to show delayed but sustained release of R-α-lipoic acid over a long period compared to direct administration of R-α-lipoic acid. Furthermore, these compounds may exhibit some resistance to rapid metabolism and excretion, which may result in higher concentrations of R-α-lipoic acid functioning as an essential cofactor in mitochondrial oxidative metabolism.

[0127] Since dithiolanmoyety remains in the example compounds, similar to R-α-lipoic acid, it may maintain antioxidant activity and capture metal ions in the bloodstream through its ability to interconvert between the oxidized disulfide (α-lipoic acid) form and the reduced bissulfhydryl (DHLA) form. These may be involved in reactions (such as ROS scavenging or chelation of oxidation-induced metal cations) either alone or when R-α-lipoic acid is released by hydrolysis. Because there may be differences in the hydrolysis of these derivatives at the application site, we plan to test administration methods other than oral administration (intravenous, subcutaneous, intramuscular, topical, ophthalmic, and suppository administration, etc.).

[0128] Table 2 below lists the physicochemical properties of R-α-lipoic acid, which possesses all the characteristics that make it a promising central nervous system (CNS) drug.

[0129] Based on an analysis of the physicochemical properties of approved drugs and clinical candidates, Christopher Lipinski proposed that his "rule of five" can predict the likelihood that certain small molecules will cross biological membranes and expose their molecular targets after oral administration (Lipinski, 2004).

[0130] This guideline prioritizes compounds with a molecular weight of less than 500 daltons, a cLOGP of less than 5, 5 or fewer hydrogen bond donors, and 10 or fewer hydrogen bond acceptors.

[0131] [Table 2]

[0132] In addition to the data described above, therapeutic efficacy data from both experimental animal models of brain diseases and patients with brain diseases (as previously stated herein) indicate that R-α-lipoic acid produced from the compound of the present invention exerts its therapeutic effect by crossing the blood-CNS barrier and entering brain and spinal cord tissue.

[0133] For Example 3 at 5 μM, kinetic analysis of preliminary enzymatic cleavage in rat plasma, canine plasma, and human plasma confirmed rapid ester cleavage and R-α-lipoic acid production over time (shown in Figures 1A-1F). Figures 1A, 1B, and 1C show the time-dependent retention rates of the compound in rat plasma, canine plasma, and human plasma, respectively. Figures 1D, 1E, and 1F show the time-dependent increase in R-α-lipoic acid in rat plasma, canine plasma, and human plasma, respectively. The half-lives in rats, dogs, and humans were approximately 10 minutes, 45 minutes, and 7 minutes, respectively. R-α-lipoic acid concentration was measured using validated liquid chromatography-tandem mass spectrometry.

[0134] One of the prodrugs (Example 3) has been shown to generate R-α-lipoic acid in rat plasma after oral administration (Figure 2). This indicates that the prodrug is efficiently absorbed from the gastrointestinal tract and generates R-α-lipoic acid by rapid hydrolysis. Figure 2 shows the plasma concentrations of R-α-lipoic acid in rats orally administered Example 3 (75 mg / kg). The initial Cmax (t=5 min) may be related to the use of a solution formulation that allows for rapid absorption in the stomach. Preferably, the compound is administered as an enteric-coated capsule to avoid instability and absorption in the stomach. The second Cmax (t=2 hours) likely reflects absorption in the intestinal tract.

[0135] Table 3 below shows the LD50 of R-α-lipoic acid and the alcohol promoyety produced by hydrolysis of the example compounds. 50 This indicates.

[0136] [Table 3]

[0137] The data in Table 3 strongly suggests that hydrolysis of the prodrug produces two products (lipoic acid and alcohol), both of which are expected to be relatively low in toxicity.

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[0139] [Figure 1] Figures 1A-1F are graphs showing the conversion from Example 3 to R-α-lipoic acid over time in the plasma of rats, dogs, and humans. [Figure 2] Figure 2 is a graph showing the plasma concentration of R-α-lipoic acid in rats orally administered with Example 3.

Claims

1. Equation (I) 【Chemistry 1】 Compounds represented by, Or, a pharmaceutically acceptable salt thereof, its solvate, its hydrate, its tautomer, its stereoisomer, its enantiomer, its polymorph, and / or its N-oxide, In formula (I), Z １ and Z ２ These are, independently, -SH or -S(O)H; or Z １ and Z ２ These, together with the atoms to which they are bonded, form a dithiolane ring, where one of the sulfur atoms in the dithiolane ring may be substituted by an oxo group; A and Y are each independently C １ ~C ６ an alkylene chain, where the C １ ~C ６ alkylene chain is optionally substituted by one or more substituents selected from the group consisting of hydroxy, halo, -CN, -NH ２ , -NO ２ , C １ ~C ６ alkoxy, -NHR １ , -NR １ R １ , -NHC(O)R １ , -NR １ C(O)R １ , -C(O)R １ , -CO ２ H, -C(O)NH ２ , and, -CO ２ R １ and is optionally substituted by one or more substituents selected from the group consisting of; X is H, -CH ３ -OH, -OR １ , -NH ２ ,-NHC(O)R １ , -NR １ C(O)R １ , -NHC(O)NHR １ , -NHC(O)NH ２ , -NR １ C(O)NHR １ , -NR １ C(O)NR １ R １ , -NHS(O) ２ R １ , -NR １ S(O) ２ R １ , -NHS(O) ２ NHR １ , -NHS(O) ２ NR １ R １ , -NR １ S(O) ２ NR １ R １ , - NHCH ２ CO ２ H, -NHCH ２ CO ２ R １ , NHCH ２ CH ２ CO ２ H, -NHCH ２ CH ２ CO ２ R １ , and selected from the group consisting of optionally substituted 3- to 8-membered heterocycles, wherein the 3- to 8-membered heterocycle is aromatic or non-aromatic, monocyclic or dicyclic, wherein one or more of the ring constituent atoms are N, O, or S, and the ring is bonded to the rest of the molecule via a C atom or an N atom; and, R １ Each of these is an arbitrarily substituted C, independently of the others. １ ~C ４ Alkyl, optionally substituted C ２ ~C ４ Alkenyls and optionally substituted C ２ ~C ４ Selected from the group consisting of alkynnyls; Alternatively, A and X together form a compound, or a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a tautomer thereof, a stereoisomer thereof, a enantiomer thereof, a polymorph thereof, and / or its N-oxide.

2. Z １ and Z ２ Each is either -SH or Z １ and Z ２ These, together with the atoms to which they bond, form a dithiolane ring, preferably Z １ and Z ２ The compound according to claim 1, wherein the atoms they bond to together form a dithiolane ring.

3. The compound represented by formula (I) is given by formula (Ia) 【Chemistry 2】 A compound represented by, or its pharmaceutically acceptable salt, its solvate, its hydrate, its tautomer, its stereoisomer, its enantiomer, its polymorph, and / or its N-oxide, The compound according to claim 2.

4. Y is the unsubstituted C １ ~C ６ The compound according to any one of claims 1 to 3, wherein the compound is an alkylene chain, preferably butylene.

5. X is H, -CH ３ , -OH, -OR １ , -NH ２ , -NHC(O)R １ , -NHOC(0)NH ２ , -NHOC(0)NHR １ , -NHCH ２ CO ２ H, -NHCH ２ CO ２ R １ , -NHCH ２ CH ２ CO ２ H, -NHCH ２ CH ２ CO ２ R １ , and is selected from the group consisting of optionally substituted 3- to 8-membered heterocyclic rings, preferably H, -CH ３ , -NH ２ , -NHC(O)R １ , -NHOC(0)NH ２ , -NHCH ２ CO ２ H, -NHCH ２ CH ２ CO ２ H, and is selected from the group consisting of optionally substituted 3- to 8-membered heterocyclic rings, the compound according to any one of claims 1 to 4.

6. A is -CO ２ H, -C(O)NH ２ , and, -CO ２ R １ C, which is optionally substituted with one or more substituents selected from the group consisting of １ ~C ６ It is an alkylene chain, preferably A is -CO ２ H, -C(O)NH ２ , and, -CO ２ R １ C, which is optionally substituted with one or more substituents selected from the group consisting of １ ~C ４ It is an alkylene chain, and more preferably, A is -CO ２ H or -C(O)NH ２ C arbitrarily substituted by １ ~C ４ A compound according to any one of claims 1 to 5, wherein the compound is an alkylene chain.

7. Each R １ This is an independently and arbitrarily substituted C １ ~C ４ They are alkyl groups, preferably each R １ ha-CH ３ The compound according to any one of claims 1 to 6.

8. A is not replaced by C ２ ~C ３ It is an alkylene chain, and X is an arbitrarily substituted 3- to 8-membered heterocycle; or, A is C １ ~C ４ It is an alkylene chain, and X is H, -CH ３ , -NH ２ , -NHC(O)NH ２ ,-NHC(O)R １ , - NHCH ２ CO ２ H, or -NHCH ２ CH ２ CO ２ H is, and here, C １ ~C ４ Alkylene chains are -CO ２ H or -C(O)NH ２ It is arbitrarily replaced by The compound according to any one of claims 1 to 7.

9. A is not replaced by C ２ ~C ３ It is an alkylene chain, and X is an arbitrarily substituted 3- to 8-membered heterocycle; or A is C １ ~C ４ It is an alkylene chain, and X is H, -CH ３ , or -NH ２ And here, C １ ~C ４ Alkylene chains are -CO ２ H or -C(O)NH ２ Whether it is arbitrarily replaced by; or A is C ２ ~C ３ It is an alkylene chain, and X is -NHC(O)NH ２ ,-NHC(O)R １ , - NHCH ２ CO ２ H, or -NHCH ２ CH ２ CO ２ H is, and here, C ２ ~C ３ Alkylene chains are -CO ２ H or -C(O)NH ２ It is arbitrarily replaced by The compound according to any one of claims 1 to 8.

10. The compound according to any one of claims 1 to 9, wherein the arbitrarily substituted 3 to 8-membered heterocycle is an arbitrarily substituted 5 or 6-membered heterocycle, preferably, one or two ring constituent atoms in the 5 or 6-membered heterocycle are independently N, O, or S, and the remaining ring constituent atoms are C.

11. The aforementioned 3- to 8-membered heterocycles are oxo, C １ ~C ３ The compound according to any one of claims 1 to 10, which is optionally substituted with one or more substituents independently selected from the group consisting of alkyl and hydroxyl, preferably from the group consisting of oxo, methyl and hydroxyl.

12. The aforementioned 3- to 8-membered heterocycles are 2,5-dioxopyrrolidine-1-yl; pyrrolidine-2-on-1-yl; 1,3-oxazolidine-2-on-3-yl; 2,6-Dioxopiperidine-1-yl; 2,5-dihydro-1H-pyrrole-2,5-dione-1-yl; pyrrolidine-2,4-dione-1-yl; 1,1-Dioxothiomorpholin-4-yl; 4-oxopiperidine-1-yl; 4-Hydroxypyrrolidine-2-on-1-yl; Morpholine-4-yl; 4-methylpiperidine-1-yl; pyrrolidine-3-on-1-yl; 1-Methylpyrrolidine-2-yl; 1-methyl-1H-imidazole-2-yl; Piperidine-4-yl; A compound according to any one of claims 1 to 11, selected from the group consisting of 1-methyl-piperidine-4-yl; 1H-imidazole-1-yl; 2,5-dioxo-piperazine-1-yl; pyrrolidine-1-yl; and piperazine-2-yl.

13. The aforementioned compound is equivalent to the following compounds 【Transformation 3】 【change】 【change】 【change】 【change】 【change】 【change】 A compound according to any one of claims 1 to 12, which is one of the following, or a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a tautomer thereof, a stereoisomer thereof, a enantiomer thereof, a polymorph thereof, and / or an N-oxide thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, and a pharmaceutically acceptable carrier, excipient, and / or diluent, preferably further comprising a known pharmaceutical.

15. A compound according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14, for use in treatment.

16. A compound according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14, for use in the treatment or prevention of a disease, disorder, or condition relating to one or more of the following: neurodegeneration, oxidative stress, nitrosation stress, excitotoxicity, immune dysfunction, metabolic dysfunction, mitochondrial dysfunction, vascular dysfunction, inflammation (including neuroinflammation), and glucose metabolism.

17. The aforementioned diseases are selected from the following group: Chemotherapy-induced tissue injury, heavy metal poisoning, radiation injury, cardiovascular diseases (heart disease, as well as ischemic stroke and hemorrhagic stroke, etc.); brain diseases, disorders and conditions (Alzheimer's disease, Parkinson's disease, motor neuron disease, Huntington's disease, Lewy body dementia, multiple ischemic dementia, frontotemporal lobar degeneration, Pick's disease, Jakob-Creutzfeldt disease, prion diseases, traumatic brain injury, traumatic spinal cord injury, multiple sclerosis, obesity, schizophrenia, psychosis, depression, bipolar disorder, anxiety, etc.), autoimmune diseases (multiple sclerosis and psoriasis, etc.), eye diseases (retinopathy, presbyopia, glaucoma, age-related macular degeneration, and optic neuritis, etc.), metabolic syndrome, traumatic brain injury, traumatic spinal cord injury, skin diseases (acne, etc.), diabetes, sugar Diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, muscle diseases, nephropathy, arthritis, asthma, rheumatoid arthritis, inflammatory bowel disease, transplant rejection, ischemia-reperfusion injury (e.g., intestinal reperfusion after myocardial ischemia or hemorrhagic shock), restenosis, ileitis, Crohn's disease, thrombosis, colitis (including ulcerative colitis), lupus, frostbite injury, acute leukocytosis-mediated lung injury (e.g., adult respiratory distress syndrome), traumatic shock, septic shock Shock, nephritis, psoriasis, cholecystitis, cirrhosis, diverticulitis, fulminant hepatitis, gastritis, gastric and duodenal ulcers, hepatorenal syndrome, irritable bowel syndrome, jaundice, pancreatitis, ulcerative colitis, human granulocytic ehrlichiosis, Wiscott-Aldrich syndrome, T-cell activation, AIDS; infections caused by viruses, bacteria, protozoa, and parasites (including post-infection syndromes), tumors and cancers, neurodevelopmental disorders (such as autism and Rett syndrome), congenital metabolic disorders causing lipoic acid deficiency, genetic disorders (including chromosomal abnormalities (such as Down syndrome, Klinefelter syndrome, triple X syndrome, Turner syndrome, trisomy 18, trisomy 13)), diseases caused by single gene mutations (such as Kabuki syndrome, spinocerebellar degeneration, neurofibromatosis type 1, fragile X syndrome), and DNA repair disorders (such as xeroderma pigmentosum, ataxia telangiectasia, and Cockayne syndrome); Preferably, the cancer is selected from leukemia, lymphoma, melanoma, adenoma, sarcoma, solid tissue carcinoma, prostate, testis, mammary gland, pancreas, cervix, uterus, kidney, lung, rectum, breast, stomach, thyroid, cervix, intestine, salivary gland, bile duct, pelvis, mediastinum, urethra, bronchogenic, bladder (bladder cancer, etc.), esophagus, small intestine, oral cavity (oral cancer, etc.), colon, liver, stomach, sarcoma (Kaposi's sarcoma, etc.), adenomatous polyp, and brain tumors (medulloblastoma, glioma, craniopharyngioma, ependymoma, germ cell tumor, pineal blastoma, brainstem glioma, choroid plexus carcinoma, germ cell tumor, astrocytoma, pituitary adenoma, acoustic neuroma, meningioma, oligodendroglioma, etc.). A compound or pharmaceutical composition for use according to claim 16.

18. A compound according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14, for use in treating side effects caused by the administration of other pharmaceuticals.

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