WO2024209214A1 - Prodrugs of alpha lipoic acids - Google Patents

Abstract

The present invention relates to compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, enantiomer, polymorph, and/or N-oxide thereof. The present invention also relates to pharmaceutical compositions comprising the compounds of the invention, and to their use in therapy.

Description

PRODRUGS OF ALPHA LIPOIC ACIDS

FIELD OF THE INVENTION

The invention relates to prodrugs of alpha-lipoic acid and their use in therapy.

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 organosulphur compound, present in all prokaryotic and eukaryotic cells (Reed, 2001 ; Carreau, 1979). It is an essential cofactor for several important mitochondrial multienzyme complexes involved in energy and amino acid metabolism. In addition to its physiological functions of protein-bound R-α-lipoic acid, there is increasing scientific and medical evidence to support the use of free (unbound) R-α-lipoic acid as a therapeutic agent to treat human and animal diseases, disorders and conditions (Smith et al., 2004; Salehi et al., 2019).

Di-hydro-R-α-lipoic acid (DHLA) contains two thiol groups and is produced by reduction in vivo of the dithiolane ring present in lipoic acid. DHLA can be reoxidised back to the dithiolane ring. Thus, there exists a redox ‘equilibrium’ between the two species. Lipoic acid also contains a stereogenic centre at its C- 3 carbon atom; R-α-lipoic acid, the naturally occurring enantiomer, has a superior pharmacokinetic (PK) profile to that of the S-enantiomer (Streeper et al., 1997; Loffelhardt et al., 1995).

(R-α-lipoic acid) (DHLA) It is the R-enantiomer of α-lipoic acid that occurs naturally. It is synthesized in small amounts by plants and animals, including humans (Smith et al. ,2004).

In addition to direct free radical scavenging activity, LA/DHLA redox couple appears to be able to regenerate other antioxidants. Considering a redox potential of 0.32 V for the LA/DHLA redox couple compared to that of the oxidised/reduced glutathione (GSH/GSSG) couple (0.24 V), DHLA is able to directly reduce GSSG to GSH (Jocelyn, 1967).

R- α-lipoic acid serves as a cofactor for several enzymes. There are three α- ketoacid dehydrogenases that mediate the oxidative decarboxylation of their specific substrate in the mitochondria: (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-ketoacid dehydrogenase (E1), E2, and dihydrolipoamide dehydrogenase (E3). E1 , which contains thiamine pyrophosphate, serves as a cofactor and mediates the dehydrogenation (decarboxylation) of each α-ketoacid. E2, which contains R-α- lipoic acid as a cofactor, transfers the electron and subsequently the acyl group of lipoamide is transferred to coenzyme A to produce acyl-CoA. The reduced lipoyl group of E2 then transfers its electron to the E3 component, which contains FAD⁺ as a cofactor, resulting in FADH reducing NAD⁺ to NADH. E3 components are commonly used in all three α-ketoacid dehydrogenase complexes. The substrate specificity of α-ketoacid dehydrogenase complexes depends on the kinetic properties of the E1 and E2 subunit of each enzyme complex.

In addition to its role in α-ketoacid dehydrogenase complexes, R- α-lipoic acid also serves as a cofactor for glycine cleavage enzyme, which cleaves the amino group of specific lysine residues of the dihydrolipoamide acyltransferase (E2) subunits. Glycine cleavage enzyme consists of four enzyme components (P, H, T, and L components) (Hiraga and Kikuchi, 1982). P-components are very similar to E1 of the α-ketoacid dehydrogenase complex, but it contains a pyridoxal phosphate rather than a thiamine pyrophosphate. H-components contain R-α-lipoic acid as a cofactor similar to E2 of the α-keto acid dehydrogenase complex. The aminomethylated R- α-lipoic acid in the H-component of glycine cleavage enzyme mediates the transfer of the aminomethyl group to methylenetetrahydrofolate (THF), forming N5, N10 -CH2 -THF of the T-component. The T-component is an aminomethyltransferase not found in the α-ketoacid dehydrogenase complexes. After a deamination reaction, the electrons on the H-component are transferred to the FAD⁺ containing L-component similar to E3 of the α-ketoacid dehydrogenase complexes.

Antioxidant activity

R-α-lipoic acid and DHLA have antioxidant effects by quenching free radicals associated with both reactive oxygen (ROS) and reactive nitrogen species (RNS). ROS are normally produced within the body in limited quantity and are important compounds involved in the regulation of processes involving the maintaining of cell homeostasis and functions such as signal transduction, gene expression, and activation of receptors (Pizzino et al., 2017; Halliwell and Gutteridge, 2015). Oxidative stress refers to the excessive production of ROS in the cells and tissues and antioxidant system is not able to counteract them. Imbalance in this protective mechanism can lead to the damage of cellular molecules such as DNA, proteins, and lipids (Durackova, 2010; Halliwell and Gutteridge, 2015). The production of ROS occurs by both enzymatic and nonenzymatic reactions. Enzymatic reactions able to generate ROS are those involved in respiratory chain, prostaglandin synthesis, phagocytosis, and cytochrome P450 system (Halliwell and Gutteridge, 2015).

Superoxide radicals (O₂-) are generated by NADPH oxidase, xanthine oxidase, and peroxidases. Once formed, they react in several ways to form a variety of toxic compounds, such as hydrogen peroxide (H₂O₂), hydroxyl radicals (OH‘), peroxynitrite (ONOO“), hypochlorous acid (HOCI), and so on. H₂O₂ (a nonradical) is produced by multiple oxidase enzymes, such as amino acid oxidase and xanthine oxidase. Hydroxyl radical (OH^.), the most reactive among all the free radical species in vivo, is generated by reaction of O₂ ” with H₂O₂ with Fe²⁺ or Cu⁺ as a reaction catalyst (the Fenton reaction). Nitric oxide radical (NO‘) plays several physiological roles and is synthesized from the oxidation of arginine to form citrulline by the enzyme nitric oxide synthase (NOS) (Halliwell and Gutteridge, 2015; Garthwaite, 2018).

Nonenzymatic reactions also produce free radicals. This includes reactions occurring within an organism such as the reaction of oxygen with organic compounds and mitochondrial respiration (Lobo et al., 2010) immune cell activation, inflammation, ischaemia, infection, cancer, excessive exercise, mental stress, and aging are all responsible for endogenous free radical production. Exogenous free radical production can occur as a result from exposure to environmental pollutants, ionizing radiations, heavy metals (e.g. Cd, Hg, Pb, Fe, and As), certain drugs (e.g. cyclosporine, tacrolimus, gentamycin, and bleomycin), chemical solvents, cooking (smoked meat, used oil, and fat), cigarette smoke, and alcohol (Halliwell and Gutteridge, 2015).

In hypoxic conditions, nitric oxide (NO) may also be produced during the respiratory chain reaction. RNS may further lead to the production of reactive species such as reactive aldehydes, malondialdehyde, and 4-hydroxynonenal. The major targets of oxidative and nitrosative stress are proteins, lipids, and DNA/RNA, and modifications in these molecules may increase the chances of mutagenesis. ROS/RNS overproduction notably over a prolonged period of time can cause damage of the cellular structure and functions and may induce somatic mutations and preneoplastic and neoplastic transformations. Then, excessive production of ROS in cells and tissues may be deleterious if not removed quickly. Indeed, excessive ROS/RNS production may cause irreversible damage to cells resulting in cell death by the necrotic and apoptotic processes (Halliwell and Gutteridge, 2015).

High concentrations of ROS/RNS have also been reported to initiate the inflammatory process resulting in synthesis and secretion of proinflammatory cytokines. Activation of nuclear factor kappa B/active protein-1 (NF-KB/AP-1 ) and toll-like receptors, along with the production of tumour necrosis factor-alpha (TNF- a) have been for instance documented to play critical role in the inflammatory process resulting in several conditions (Kim et al., 2009; Nie et al., 2018). cc-lipoic acid supplements (including some used in clinical trials to assess therapeutic efficacy) often contain both R-α-lipoic acid and S-(a)-lipoic acid in a 50:50 ratio (a racemic mixture).

After oral administration of the racemic mixture (R-α-lipoic acid and S-α-lipoic acid mixed at the ratio of 50:50) to rats, R-α-lipoic acid showed higher plasma concentration than S-α-lipoic acid, and its area under the plasma concentrationtime curve from time zero to the last (AUC) was significantly higher than that of S- α-lipoic acid. However, after intravenous administration of the racemic mixture, the pharmacokinetic profiles, initial concentration (C_o), AUC, and half-life (T 1/2) of the stereoisomers were not significantly different. This data is consistent with R-a- lipoic acid being absorbed better than S-α-lipoic acid (Hermann et al., 2014; Uchida et al., 2015). In addition, in a study of 12 human volunteers, there is an effect of food on the bioavailability of R-α-l ipoic acid was greater than the effect of food on the bioavailability of S-α-lipoic acid (Gleiter et al., 1996).

R-α-lipoic acid (pKa, 4.7) can produce its effects in both aqueous and lipophilic environments. Despite the very low solubility of the free acid in water (2.24 x 10'¹ g/L), its conjugate base is the more prevalent form of R-α-lipoic acid under physiological conditions.

R-(a)-lipoic acid has a highly negative redox potential of -0.32 V (vs. Normal Hydrogen Electrode) (Moini et al., 2002). With both fat-soluble (α-lipoic acid) and the reduced form dihydrolipoic acid (DHLA) present under physiological conditions, this R-α-lipoic acid/DHLA redox couple has been called a "universal antioxidant" since it can function both intracellularly and extracellularly (Kagan et al., 1992). Together, they can directly scavenge both reactive oxygen species (ROS) and reactive nitrogen species (RNS). In addition, R-α-lipoic acid can reduce the oxidized form of nicotinamide adenine (NADP⁺), to restore the reduced/oxidized glutathione, and both forms act as antioxidants. It is important (GSH/GSSG) ratio, in favour of GSH, to increase the expression of antioxidant enzymes such as glutathione reductase and reduced to DHLA (Jocelyn, P. C., 1967; Solmonson et al., 2018; Zitka et al., 2012) as well as to participate in the recycling of vitamins C and E. They also repair oxidative damage of macromolecules (Biewenga et al., 1996; Biewenga et al., 1997; Packer et al., 1995).

DHLA has been shown to potentiate N-methyl-D-aspartate (NMDA) receptor- mediated whole-cell responses in cultured neurons. This potentiation was readily reversed by the oxidizing agent 5,5'-dithio-bis-(2-nitro-benzoic acid. Singlechannel recordings revealed that DHLA produced an increase in NMDA channel open frequency, with no change in single-channel conductance or open time. In contrast, α-lipoic acid reversed the potentiation of NMDA-evoked responses produced by dithiothreitol (Tang and Aizenman, 1993). Glutamate is an agonist at the NMDA receptor channel and elevated concentrations of this excitatory amino acid cause cell death (excitotoxicity) that is blocked by α-lipoic acid (Park et al., 2019).

R-α-lipoic acid also serves as an antioxidant and binder of free Fe³⁺ that also reduces both neuroinflammation and glutamate-induced neurodegeneration (Park et al., 2019). In addition, it enhances glucose uptake and modulates the activity of various cell-signalling molecules and transcription factors (Akbari et al., 2018).

Many of the complications induced by diabetes, including polyneuropathy and cataract formation, appear to be mediated by ROS generation. Diabetic patients have elevated serum concentrations of thiobarbituric acid reactive substances (a common way to measure lipid peroxidation products), F2 isoprostanes, and 8-OH- guanosine (both measures of oxidative stress) compared to non-diabetics (Stephens et al., 2008).

In addition, oxidative stress is proposed to be an early event in the pathology of diabetes and may influence the onset and progression of late complications. Borcea et al. demonstrated in a cross-sectional study of 107 diabetic patients that those taking α-lipoic acid (600 mg/day for >3 months) had decreased oxidative stress compared with those without α-lipoic acid treatment, irrespective of their poor glycaemic control and albuminuria. These authors assessed oxidative stress by measuring plasma lipid hydroperoxide (ROOHs), and on the balance between oxidative stress and antioxidant defence, as measured by the ratio ROOH/(alphα- tocopherol/cholesterol). Additionally, the redox-sensitive transcription factor nuclear factor-kappa B (NF-kappa B) is known to contribute to late diabetic complications. In this context, Hofmann et al. reported that α-lipoic acid - dependent downregulation of NF-kappa B is evident in the monocytes of diabetic patients receiving α-lipoic acid therapy.

Additionally, oxidative stress leads to endothelial cell damage and vascular dysfunction (Forstermann 2008). In this regard, Morcos et al. conducted a prospective, open, and non-randomized study in 84 diabetic patients. In this study, 49 patients had no antioxidant treatment and served as controls. The 35 remaining patients underwent α-lipoic acid therapy (600 mg/day for 18 months). The progression of endothelial cell damage in terms of the measurement of plasma thrombomodulin was significantly increased in the control group and decreased in the α-lipoic acid therapy group after 18 months of follow-up. However, the course of diabetic nephropathy, as assessed by urinary albumin concentration, was significantly increased in controls, but was unchanged in the treated group.

Furthermore, lipid peroxidation of nerve membranes has been suggested as a mechanism by which peripheral nerve ischemia and hypoxia could cause neuropathy. In this regard, Androne et al. investigated the magnitude of oxidative stress in terms of the measurement of serum ceruloplasmin and lipid peroxide levels in 10 patients with diabetic neuropathy before and after 70 days of α-lipoic acid treatment (600 mg/day). α-lipoic acid was administered intravenously (i.v.) once daily for the first 10 days and orally for the next 50 days. Serum ceruloplasmin levels were significantly higher in diabetic patients compared to healthy subjects, probably related to antioxidant defence. Furthermore, serum lipid peroxide levels were significantly higher in diabetics compared with healthy subjects and were significantly decreased in diabetics after α-lipoic acid treatment with no change in serum ceruloplasmin levels. Overall, α-lipoic acid treatment appears to prevent oxidative stress-induced changes in diabetic patents. Racemic α-Lipoic acid has been shown to reduce the oxidative damage and inflammation caused by pesticides and reduces methyl-mercury-induced neurotoxicity (Astiz et al., 2012; Yang et al., 2015) and to attenuate damage from ischemia-reperfusion, Alzheimer’s disease, and Parkinson’s disease, which are all closely related to oxidative stress under pathological circumstances (Meili et al., 2008; Shay et al., 2009; Rocamonde et al., 2013).

In addition to being direct ROS scavengers, both R- α-lipoic acid and the reduced form (DHL.A) bind to redox-active metals in vitro and in vivo. The oxidized and reduced forms bind several metal ions, but with different properties depending on the metal bound, in vitro studies show that R- α-lipoic acid preferentially forms complexes with Cu²\ ZrP' and Pb²*, but cannot form a complex with Fe³⁺, whereas DHLA forms complexes with Cu²⁺, Zn²⁺, Pb²⁺, Hg²⁺ and Fe³⁺ (Ou et al., 1995).

Anti-inflammatory activity and immune modulation

Inflammation, a clinical state closely related to oxidative and nitrosative stress, occurs in many diseases, disorders and conditions, often mediated through activation of nuclear factor kappa B/active protein-1 (NF-KB/AP-1 ) and production of tumour necrosis factor-alpha (TNF-a) (Moura et al., 2015). In addition, to being a potent antioxidant, α-lipoic acid also has a substantial anti-inflammatory property (Rochette et al., 2015; Moura et al., 2015). There is also evidence to indicate α- lipoic acid has an immunomodulatory effect (Liu et al., 2019). α-Lipoic acid has also been shown to reduce the gene expression of Toll-like receptors (TLRs) (Guo et al., 2016); TLRs are highly specialised recognition receptors that help coordinate the innate inflammatory response to various foreign substances and are responsible for insulin resistance (Ghanim et al., 2009). α- Lipoic acid was also recently shown to block toll-like receptor 2 (TLR2) agonist- induced changes in both insulin sensitivity and cognitive function (Ahuja et al., 2019). Clinical utility and safety profile

There is substantial data from a number of clinical trials in humans to indicate that racemic (R, S)-α-lipoic acid has a beneficial effect in the treatment of a number of human diseases, disorders and conditions (Moura et al. , 2015; Tibullo et al. , 2017; Salehi et al., 2019). In addition, a metanalysis of randomized controlled trials showed that α-lipoic acid administration improves glucose homeostasis parameters and lipid profiles (Akbari et al., 2018).

The binding of insulin to the insulin receptor triggers the auto phosphorylation of several tyrosine residues on the insulin receptor. Activation of the insulin receptor in this manner stimulates a cascade of protein phosphorylations, resulting in the translocation of glucose transporters (GLUT4) to the cell membrane and increased cellular glucose uptake (Smith et al., 2004; Konrad, 2005). α-lipoic acid has been found to increase GLUT4 translocation to cell membranes and to increase glucose uptake in cultured adipose (fat) and muscle cells (Estrada et al., 1996; Yaworsky et al., 2000). Thus, α-lipoic acid appears to engage the insulinsignalling pathway, thereby increasing glucose uptake into muscle and fat cells. Because of this, α-lipoic acid is referred to as an insulin mimetic agent. Notably, insulin receptor is the hallmark feature of type-2 diabetes. As skeletal muscle tissue is the major sink in the body for glucose following a meal, agents that enhance glucose uptake by skeletal muscle are potentially useful in the long-term treatment of type-2 diabetes.

Several clinical studies point to a beneficial effect of α-lipoic acid on whole-body glucose metabolism in patients with type-2 diabetes. In these studies, glucose metabolism and insulin sensitivity were assessed using the euglycemic- hyperinsulinaemic clamp. Jacobs et al tested for the first time in a clinical setting if α-lipoic acid supplementation augments insulin-mediated glucose disposal in non-insulin dependent diabetes. Thirteen patients comparable in age, body-mass index, duration of diabetes, and with a similar degree of insulin resistance at baseline received either α-lipoic acid (1000 mg/500 mL NaCI, n = 7) or vehicle only (500 mL NaCI, n ~ 6) during a glucose-clamp study. After acute parenteral administration of α-lipoic acid, the glucose infusion rate increased 47% (P < 0.05), metabolic clearance rate increased 55% (P < 0.05), and insulin sensitivity increased 57% (P < 0.05), whereas the control group did not show any significant change. Thus, this was the first clinical study to show that α-lipoic acid increases insulin-stimulated glucose disposal in non-insulin dependent diabetes. Subsequently, the same group of authors reported in an uncontrolled pilot study of 20 patients with type-2 diabetes that i.v. infusion of 500 mg/day of racemic α- lipoic acid for 10 days improved insulin sensitivity measured 24 h after the last infusion (Jacob et al., 1996). If these increases in metabolic clearance rate and insulin sensitivity were to persist with continued α-lipoic acid therapy, then its effect can be compared favourably with metformin, a widely prescribed medication that increases insulin sensitivity and glucose utilization.

Indeed, α-lipoic acid has been prescribed in Germany for over fifty years for the treatment of diabetes-induced neuropathy (Biewenga G et al., 1997; Ziegler et al., 1997; Ziegler et al., 1999). α-Lipoic is normally considered as a safe drug substance with little to no side effects, related to mild symptoms, such as nausea, rashes, or itching. While no upper limit for racemic-α-lipoic acid consumption in humans has been established, safe levels for acute oral racemic-α-lipoic acid intake have been defined in animals, with marked differences depending on the species. For dogs, a LD₅o of 400-500 mg /kg b.w. has been reported, but rats appear to be more tolerant of α- lipoic acid, as the acute LD₅o for this species is >2000 mg/kg b.w (Shay et al., 2009).

For humans, several clinical trials using racemic-α-lipoic acid have been undertaken which also assessed adverse health effects in the participants. There were no reported adverse effects versus placebo of up to 2400 mg/day. Racemic- α-lipoic acid has also been administered intravenously in doses of 600 mg/day for three weeks with no evidence of serious side-effects. Oral doses of 1800 mg racemic-α-lipoic acid (600 mg t.i.d.) for 6 months did not elicit significant adverse effects compared to placebo. In addition, racemic-α-lipoic acid has been used in Germany for over 50 years as a therapy for diabetic neuropathy and retinopathy (Shay et al., 2009).

It is generally accepted that free radicals play a major role in the development of chronic and degenerative conditions so that free radical quenching substances or antioxidants can play an important part in ameliorating such conditions. R-α-li poic acid exerts its protective effects by acting as a free radical scavenger, chelating/binding redox active metal ions, and restoring reduced levels of other antioxidants under various physiological and pathophysiological conditions.

Conditions subject to treatment by α-lipoic acid are: chemotherapy-induced tissue damage, heavy metal poisoning, radiation damage, cardiovascular disease (such as heart disease and both ischaemic and haemorrhagic stroke), brain diseases, disorders and conditions (such as Alzheimer’s disease, Parkinson’s disease, motor neuron disease, Huntington’s disease, Lewy body disease, multi-infarct 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), autoimmune disorders (such as multiple sclerosis and psoriasis), eye disorders (such as retinopathy, presbyopia, glaucoma, age-related macular degeneration and optic neuritis), metabolic syndrome, traumatic brain injury, traumatic spinal cord injury, skin disorders (such as acne), diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiopathy, myopathy, nephropathy, arthrosclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, transplant rejection, ischaemia reperfusion injury (e.g. myocardial ischaemia, intestinal reperfusion e.g. after haemorrhagic shock), restenosis, ileitis, Chrohn’s disease, thrombosis, colitis including for example ulcerative colitis, lupus, frostbite injury, acute leucocyte mediated lung injury (e.g. 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 granulocyte ehrlichiosis, Wiskott-Aldrich syndrome, T-cell activation, AIDS, infection with viruses, bacteria, protozoa and parasites (including post-infection syndromes), tumours and cancer, neurodevelopmental disorders (such as autism and Rett syndrome), inborn errors of metabolism causing lipoic acid deficiencies, genetic disorders, including chromosomal disorders (such as Down syndrome, Klinefelter syndrome, triple X syndrome, Turner syndrome, Trisomy 18 and Trisomy 13), and disorders caused by mutations in single-genes (such as Kabuki syndrome, spinocerebellar ataxia, neurofibromatosis type 1 , fragile X syndrome) and DNA repair disorders (such as xeroderma pigmentosum, ataxia telangiectasia, and Cockayne syndrome). The cancer may be leukaemias, lymphomas, melanomas, adenomas, sarcomas, carcinomas of solid tissues, prostrate, testicular, mammary, pancreatic, cervical, uterine, kidney, lung, rectum, breast, gastric, thyroid, neck, cervix, bowel, salivary gland, bile duct, pelvis, mediastinum, urethra, bronchogenic, bladder (e.g. bladder carcinoma), oesophagus, small intestine, oral cavity (e.g. oral cavity carcinomas), colon, liver, stomach, sarcomas (e.g. Kaposi’s sarcoma), adenomatous polyps, and brain tumours (such as medulloblastomas, gliomas, craniopharyngiomas, ependymomas, embryonal tumours, pineoblastomas, brainstem gliomas, choroid plexus carcinomas, germ-cell tumours, astrocytomas, pituitary adenomas, acoustic neuromas, meningiomas, and oligodendrogliomas).

Double blind, placebo-controlled trials have shown that racemic α-lipoic acid administration significantly ameliorates polyneuropathies associated with diabetes. Racemic α-lipoic acid is indicated for treating diabetes and nerve-related symptoms of diabetes, including burning, pain, and numbness in the legs and arms, including peripheral neuropathy. High doses of the order of 600 mg of racemic α-lipoic acid are approved in some countries for the treatment of these symptoms. It has also been reported that racemic α-lipoic acid can be used as adjunct therapy to avert vision loss in diabetic patients by preventing micro- and macrovascular damage through normalization of mitochondrial overproduction of reactive oxygen species, thus preserving pericyte coverage of retinal capillaries (Salehi et al., 2019; Park et al., 2019; Shay et al., 2009). α-Lipoic acid has been shown to have neuroprotective/neurorestorative efficacy in many diverse experimental models, both in vitro and in vivo (Molz et al. 2017 & Dieter et al. 2022). This includes models of stroke (Choi et al. 2015; Dong et al. 2015; & Ding et al. 2021), hyperthroidism (Khadrawy et al. 2022), optic neuritis (Dietrich et al. 2018) and MS (Li et al. 2018; Xie et al. 2022; Yadav et al. 2010; Spain et al. 2017; & Loy et al. 2018).

In a mouse study racemic α-lipoic acid was found to effectively interfere with the autoimmune reaction associated with experimental autoimmune encephalomyelitis, a model of multiple sclerosis, indicating that the administration of racemic α-lipoic acid to patients could be a potential therapy for multiple sclerosis (Morini et al., 2004). Initial studies, involving multiple sclerosis patients in a two-year clinical trial of 51 people with secondary progressive multiple sclerosis, racemic α-lipoic acid administered, at 1.2 g/day, has demonstrated a 68% reduction in annualized percent change brain volume. In this clinical study racemic α-lipoic acid also improved walking performance, particularly in those with lower baseline disability.

The use of R-α-lipoic acid has been hampered by its poor absorption, chemical instability and its rapid metabolism. Thus, formulations containing α-lipoic acid, in a form ensuring its stability, extending its plasma half-life, and improving its bioavailability, can have important applications as medicaments (Koufaki, 2014). α-Lipoic acid has low aqueous solubility of 0.24 mg/mL ("Sur I'acide dithionique et ses seis" 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 has a sulphide-smell and an irritating taste (Takahashi et al., 2011).

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

Ester prodrugs of α-lipoic acid that have been reported to date are either oils (US 2007/0055070 A1 and US2016/0354340A1) or unstable molecules that generate potentially toxic and pharmaceutically unacceptable species such as formaldehyde and acetaldehyde (US 2011/0212954 A1). The synthesis of crystalline prodrugs of R-α-lipoic acid can provide substances that are potentially easier to incorporate in a variety of drug products including tablet, capsule, suppository and solution. Such derivatives also increase the possibility of producing a slow-release drug product where the R-α-lipoic acid derivative is either administered alone or co-administered with other pharmacologically active drug substances. Favourable physico-chemical properties of the prodrugs may also allow the design of solid and liquid formulations which incorporate a variety of pharmaceutically inactive excipients that will facilitate the delivery of the prodrugs, following the administration to patients in a variety of dosages, designed to meet a specific therapeutic function.

The pharmacokinetic characteristics of R-α-lipoic acid (time course of absorption, bioavailability, distribution, metabolism, and excretion) are considered to be inadequate for the therapeutic efficacy of a drug substance. Following oral ingestion, R-α-lipoic acid is poorly absorbed (bioavailability <25%), rapidly metabolised and excreted. Moreover, plasma R-α-lipoic acid concentrations generally peak within 15 minutes or less of drug administration and decline rapidly, with a half-life of about 30 minutes (Hermann et al., 2014: Teichert et al., 2003; Carlson et al., 2007).

Following oral administration, R-α-l ipoic acid has been found to be slightly better absorbed than the unnatural S-α-isomer. The R-isomer has a bioavailability of 24% and the S-isomer has a bioavailability of 19% (Hermann et al., 2014).

BRIEF DESCRIPTION OF FIGURES

Figures 1A to 1 F are graphs showing the conversion of example 3 to R-α-lipoic acid over time in rat, dog, and human plasma.

Figure 2 is a graph depicting the plasma concentration of R-α-lipoic acid in a rat following po administration of example 3. DISCLOSURE OF THE INVENTION

The applicant has surprisingly found that compounds of Formula (I) are useful as prodrugs of R-α-lipoic acid. The compounds of Formula (I) are able to release α- lipoic acid via ester hydrolysis, including via the activity of enzymes including carboxylesterase, acetylcholinesterase and butyrylcholinesterase (Yang et al., 2011).

The prodrugs of the invention are endowed with improved chemical and pharmaceutical properties, relative to R-α-lipoic acid (acidic pKa = 4.7). The relative chemical stability of the ester linkage under acidic and neutral conditions and favourable partition characteristics of the derivatives should allow the longer- term survival of these drug substances in higher quantities than when R-α-lipoic acid is administered directly.

The prodrugs of the invention are either chemically neutral under physiological pH, a property that gives them a favourable octanol-water partition coefficient (Log P), and adequate solubility in aqueous media, or they possess a moiety that can contribute to permeability via active transport. The enhanced permeability results in good absorption by the epithelial cells along the gastrointestinal tract (GIT) and other biological tissues. The compounds of the invention are therefore expected to be better absorbed in the GIT than the negatively charged R-α-lipoic acid resulting in improved bioavailability. Following enzymatic hydrolysis an increase in the concentration of R-α-lipoic acid in the blood is expected with compounds of the invention compared to the direct administration of R-α-lipoic acid. It is also envisaged that the dithiolane ring in the compounds of the invention will possess antioxidant, anti-inflammatory and anti-nitrosative activity due to the ability to undergo interconversion between oxidized disulphide and the reduced bis- sul phydry I form. This ability to undergo facile 1 -electron oxidation or reduction also facilities the chelation of transition metals, such as iron and copper. Mechanisms involving such electrochemistry result in highly toxic species and are known to play a role in the progression of several degenerative diseases and disorders. Enzymatic hydrolysis of the compounds of the invention to quantitatively produce R-α-lipoic acid will be expected to largely take place in the blood, serving to increase antioxidant capacity and strengthen the immune system of patients suffering from degenerative diseases and cancer, and may have beneficial effects either when administered alone or in combination with current treatments.

According to a first aspect of the invention, there is provided a compound of Formula (I)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, enantiomer, polymorph, and/or N-oxide thereof; wherein

Z¹ and Z² are each independently -SH or -S(O)H; or Z¹ and Z² are taken together with the atoms to which they are attached to form a dithiolane ring, wherein one of the sulphur atoms in the dithiolane ring may be substituted with an oxo group; each of A and Y is independently a Ci-Ce alkylene chain, wherein the Ci-Ce alkylene chain is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, -CN, -NH₂, -NO₂, Ci-Ce alkoxy, -NHR¹, -NR¹R¹, -NHC(O)R¹, -NR¹C(O)R¹, -C(O)R¹, -CO₂H, -C(O)NH₂, and -CO₂R¹;

X is selected from the group consisting of H, -CH₃, -OH, -OR¹, -NH₂, -NHC(O)R¹, -NR¹C(O)R¹, -NHC(O)NHR¹, -NHC(O)NH₂, -NR¹C(O)NHR¹, -NR¹C(O)NR¹R¹, -NHS(O)₂R¹, -NR¹S(O)₂R¹, -NHS(O)₂NHR¹, -NHS(O)₂NR¹R¹, -NR¹S(O)₂NR¹R¹, -NHCH2CO₂H, -NHCH2CO₂R¹, NHCH2CH2CO₂H, -NHCH2CH2CO₂R¹, and an optionally substituted 3 to 8-membered heterocyclic ring, wherein the 3 to 8-membered heterocyclic ring is an aromatic or non-aromatic, monocyclic or bicyclic ring, wherein one or more of the ring atoms are N, O, or S and the ring is attached to the remainder of the molecule via a C or N atom; and each R¹ is independently selected from the group consisting of optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl.

Alternatively, A and X are taken together to form a known medicament.

As used herein, the term “alkylene chain” refers to a divalent saturated hydrocarbon chain. The alkylene chain may be straight or branched.

Preferably, Z¹ and Z² are each -SH or Z¹ and Z² are taken together with the atoms to which they are attached to form a dithiolane ring. More preferably, Z¹ and Z² are taken together with the atoms to which they are attached to form a dithiolane ring.

In a preferred aspect of the invention, the compound of Formula (I) is a compound of Formula (la)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, enantiomer, polymorph, and/or N-oxide thereof.

In the compounds of the invention, Y is preferably an unsubstituted Ci-Ce alkylene chain, more preferably butylene.

In a preferred aspect of the invention, the compound of Formula (I) is therefore a compound of Formula (lb)

In compounds of the present invention, X is preferably selected from the group consisting of H, -CH₃, -OH, -OR¹, -NH₂, -NHC(O)R¹, -NHC(O)NH₂, -NHC(O)NHR¹, -NHCH₂CO₂H, -NHCH₂CO₂R¹, -NHCH₂CH₂CO₂H, -NHCH₂CH₂CO₂R¹, and an optionally substituted 3 to 8-membered heterocyclic ring, more preferably H, -CH₃, -NH₂, -NHC(O)R¹, -NHC(O)NH₂, -NHCH₂CO₂H, -NHCH₂CH₂CO₂H, and an optionally substituted 3 to 8-membered heterocyclic ring.

Preferably, A is a Ci-Ce alkylene chain optionally substituted with one or more substituents selected from the group consisting of -CO₂H, -C(O)NH₂, and -CO₂R¹, more preferably A is a C1-C4 alkylene chain optionally substituted with one or more substituents selected from the group consisting of -CO₂H, -C(O)NH₂, and -CO₂R¹, more preferably A is a C1-C4 alkylene chain optionally substituted with -CO₂H or , -C(O)NH₂.

Preferably, each R¹ is independently an optionally substituted C1-C4 alkyl group, preferably each R¹ is -CH₃.

In a preferred aspect of the invention, A is an unsubstituted C₂-C₃ alkylene chain and X is an optionally substituted 3 to 8-membered heterocyclic ring; or

A is a C1-C4 alkylene chain and X is H, -CH₃, -NH₂, -NHC(O)NH₂, -NHC(O)R¹, -NHCH₂CO₂H, or -NHCH₂CH₂CO₂H, wherein the C₂-C4 alkylene chain is optionally substituted with -CO₂H or -C(O)NH₂.

In a more preferred aspect of the invention, A is an unsubstituted C₂-C₃ alkylene chain and X is an optionally substituted 3 to 8-membered heterocyclic ring; or A is a C1-C4 alkylene chain and X is H, -CH₃, or -NH₂, wherein the C1-C4 alkylene chain is substituted with -CO₂H or -C(O)NH₂; or

A is a C₂-C₃ alkylene chain and X is -NHC(O)NH₂, - NHC(O)R¹, -NHCH₂CO₂H, or -NHCH₂CH₂CO₂H, wherein the C₂-C₃ alkylene chain is optionally substituted with -CO₂H or -C(O)NH₂.

In the compounds of the invention, the optionally substituted 3 to 8-membered heterocyclic ring is an optionally substituted 5- or 6-membered heterocyclic ring, more preferably one or two ring atoms in the 5- or 6-membered heterocyclic ring are independently N, O, or S, and the remaining ring atoms are C.

Preferably, the 3 to 8-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of oxo, Ci-C₃ alkyl, and hydroxy, preferably oxo, methyl, and hydroxy.

Preferably, the 3 to 8-membered heterocyclic ring is selected from the group consisting of 2,5-dioxopyrrolidin-1 -yl; pyrrolidin-2-one-1 -yl; 1 ,3-oxazolidine-2-one- 3-yl; 2,6-dioxopiperidin-1 -yl; 2,5-dihydro-1 H-pyrrole-2,5-dione-1 -yl; pyrrolidin-2,4- di-one-1 -yl; 1 ,1 -dioxothiomorpholin-4-yl; 4-oxopiperidin-1 -yl; 4-hydroxypyrrolidin- 2-one-1 -yl; morpholin-4-yl; 4-methylpiperizin-1 -yl; pyrrolidin-3-one-1 -yl; 1 - methylpyrrolidin-2-yl; 1 -methyl-1 H-imidazol-2-yl; piperidin-4-yl; 1 -methyl- piperidin-4-yl; 1 H-imidazol-1 -yl; 2,5-dioxo-piperazin-1 -yl; and pyrrolidin-1 -yl; pipererazin-2-yl.

In a preferred aspect of the invention, the compound of Formula (I) is one of the following compounds or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, enantiomer, polymorph, and/or N-oxide thereof

15

According to a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the invention and a pharmaceutically acceptable carrier, excipient, and/or diluent.

Preferably, the pharmaceutical composition further comprises a known medicament.

According to a third aspect of the invention, there is provided a compound or pharmaceutical composition according to the invention for use in therapy.

According to a fourth aspect of the invention, there is provided a compound or pharmaceutical composition according to the invention, for use in the treatment or prevention of a disease, disorder, or condition that is associated with one or more of neurodegeneration, oxidative stress, nitrosative stress, excitotoxicity, immune dysfunction, metabolic dysfunction, mitochondrial dysfunction, vascular dysfunction, inflammation (including neuroinflammation), and glucose metabolism.

More preferably the disease, disorder or condition is selected from the group consisting of: chemotherapy-induced tissue damage, heavy metal poisoning, radiation damage, cardiovascular disease (such as heart disease and both ischaemic and haemorrhagic stroke), brain diseases, disorders and conditions (such as Alzheimer’s disease, Parkinson’s disease, motor neuron disease, Huntington’s disease, Lewy body disease, multi-infarct 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), autoimmune disorders (such as multiple sclerosis and psoriasis), eye disorders (such as retinopathy, presbyopia, glaucoma, age-related macular degeneration and optic neuritis), metabolic syndrome, traumatic brain injury, traumatic spinal cord injury, skin disorders (such as acne), diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiopathy, myopathy, nephropathy, arthrosclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, transplant rejection, ischaemia reperfusion injury (e.g. myocardial ischaemia, intestinal reperfusion e.g. after haemorrhagic shock), restenosis, ileitis, Chrohn’s disease, thrombosis, colitis including for example ulcerative colitis, lupus, frostbite injury, acute leucocyte mediated lung injury (e.g. 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 granulocyte ehrlichiosis, Wiskott-Aldrich syndrome, T-cell activation, AIDS, infection with viruses, bacteria, protozoa and parasites (including post-infection syndromes), tumours and cancer, neurodevelopmental disorders (such as autism and Rett syndrome), inborn errors of metabolism causing lipoic acid deficiencies, genetic disorders, including chromosomal disorders (such as Down syndrome, Klinefelter syndrome, triple X syndrome, Turner syndrome, Trisomy 18 and Trisomy 13), and disorders caused by mutations in single-genes (such as Kabuki syndrome, spinocerebellar ataxia, neurofibromatosis type 1 , fragile X syndrome) and DNA repair disorders (such as xeroderma pigmentosum, ataxia telangiectasia, and Cockayne syndrome).

In some embodiments, the disease, disorder or condition may be selected from the group consisting of: chemotherapy-induced tissue damage, heavy metal poisoning, radiation damage, cardiovascular disease (such as heart disease and both ischaemic and haemorrhagic stroke), brain diseases, disorders and conditions (such as Alzheimer’s disease, Parkinson’s disease, motor neuron disease, Huntington’s disease, Lewy body disease, multi-infarct 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), autoimmune disorders (such as multiple sclerosis and psoriasis), eye disorders (such as retinopathy, presbyopia, glaucoma, age-related macular degeneration and optic neuritis), metabolic syndrome, traumatic brain injury, traumatic spinal cord injury, skin disorders (such as acne) diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiopathy, myopathy, nephropathy, arthrosclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, transplant rejection, ischaemia reperfusion injury (e.g. myocardial ischaemia, intestinal reperfusion e.g. after haemorrhagic shock), restenosis, ileitis, Chrohn’s disease, thrombosis, colitis including for example ulcerative colitis, lupus, frostbite injury, acute leucocyte mediated lung injury (e.g. 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 granulocyte ehrlichiosis, Wiskott-Aldrich syndrome, T-cell activation, AIDS, infection with viruses, bacteria, protozoa and parasites (including post-infection syndromes), tumours and cancer.

Preferably, the cancer is selected from leukaemias, lymphomas, melanomas, adenomas, sarcomas, carcinomas of solid tissues, prostrate, testicular, mammary, pancreatic, cervical, uterine, kidney, lung, rectum, breast, gastric, thyroid, neck, cervix, bowel, salivary gland, bile duct, pelvis, mediastinum, urethra, bronchogenic, bladder (e.g. bladder carcinoma), oesophagus, small intestine, oral cavity (e.g. oral cavity carcinomas), colon, liver, stomach, sarcomas (e.g. Kaposi’s sarcoma), adenomatous polyps, and brain tumours (such as medulloblastomas, gliomas, craniopharyngiomas, ependymomas, embryonal tumours, pineoblastomas, brainstem gliomas, choroid plexus carcinomas, germ-cell tumours, astrocytomas, pituitary adenomas, acoustic neuromas, meningiomas, and oligodendrogliomas). According to a fifth aspect of the invention, there is provided a compound or pharmaceutical composition according to the invention, for use in the treatment of side effects caused by the administration of another medicament.

According to a sixth aspect of the invention, there is provided a method of treating one of the above-mentioned diseases comprising administering a therapeutically effective amount of the compound or pharmaceutical composition of the invention to a subject in need thereof.

The compounds of the invention may include isotopically-labelled and/or isotopically-enriched forms of the compounds. The compounds of the invention herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, 15Q 17Q 32p 35g 18p 36Q|

Pharmaceutical Compositions

The compounds of the invention are often used in the form ofa pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, when appropriate, pharmaceutically acceptable base addition salts and acid addition salts, for example, metal salts, such as alkali and alkaline earth metal salts, ammonium salts organic amine addition salts, and amino acid addition salts, and sulphonate salts. Acid addition salts include inorganic acid addition salts such as hydrochloride, sulphate and phosphate, and organic acid addition salts such as alkyl sulphonate, aryl-sulphonate, acetate, maleate, fumarate, tartrate, citrate and lactate. Examples of metal salts are alkali metal salts, such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminium salt, and zinc salt. Examples of ammonium salts are ammonium salt and tetramethylammonium salt. Examples of organic amine addition salts are salts with morpholine and piperidine. Examples of amino acid addition salts are salts with glycine, phenylalanine, glutamic acid and lysine. Sulphonate salts include mesylate, tosylate and benzene sulphonic acid salts. The pharmaceutical compositions of the invention are suitable for administration to a warm-blooded animal, including, for example, a human (orto cells orcell lines derived from a warm-blooded animal, including for example, a human cell), for the treatment or, in another aspect of the invention, prevention of (also referred to as prophylaxis against) a disease that responds to inhibition of sodium channel activity. The pharmaceutical compositions may comprise a compound of the present invention, which is effective for this inhibition, together with at least one pharmaceutically acceptable carrier.

The pharmaceutical compositions of the invention may be those for enteral, such as nasal or rectal or oral or sublingual or buccal and parenteral, such as intramuscular or subcutaneous or intravenous, administration to warm-blooded animals (including, for example, a human), that comprise an effective dose of the pharmacologically active ingredient, alone or together with a significant amount ofa pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species ofwarm-blooded animal, the body weight, the age and the individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.

The dose of a compound of the invention to be administered to warm-blooded animals, for example humans of approximately 70 kg body weight, is for example, from approximately 3 mg to approximately 10 g, from approximately 10 mg to approximately 1.5 g, from about 100 mg to about 1000 mg/person/day, divided into 1-3 single doses which may, for example, be of the same size. Usually, children receive half of the adult dose.

The dose of the compounds of the invention to be administered to warm-blooded animals, for example humans of approximately 70 kg body weight, may be from 50 p.g up to about 2000 mg, optionally from 50 p.g up to about 1000 mg.

The pharmaceutical compositions form approximately, for example, 1 % to approximately 95%, or from approximately 20% to approximately 90%, active ingredients. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets, capsules or solutions.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional dissolving, lyophilizing, mixing, granulating or confectioning processes.

Solutions of the active ingredients, and also suspensions, and especially isotonic aqueous solutions or suspensions, are used, it being possible, for example in the case of lyophilized compositions that have the active ingredient alone or together with a carrier, for example mannitol, for such solutions or suspensions to be produced priorto use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting and/or emulsifying agents, solubilizers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilizing processes. The solutions or suspensions may have viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil may comprise as the oil component the vegetable, synthetic orsemi-syntheticoils customary for injection purposes. There may be mentioned, for example, liquid fatty acid esters that contain as the acid component a long- chained fatty acid having from 8-22, or from 12-22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, forexample oleicacid, elaidicacid, erucic acid, brasidicacid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, beta. -carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydroxy, for example a mono-, di- or tri-hydroxy, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol. The following examples of fatty acid esters are therefore to be mentioned: ethyl oleate, iso-propyl myristate, isopropyl palmitate, Labrafil M 2375, polyoxyethylene glycerol trioleate, Gattefosse, Miglyol 812 (triglyceride of saturated fatty acids with a chain length of C8 to C12), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.

Compounds with cLogP values of 3 or higher (e.g., compounds 8, 9 and 26) can be formulated in lipids, such as at least one polyunsaturated fatty acid (PUFA). Suitable PUFA include, but are not limited to, omegα-3 fatty acids and omegα-6 fatty acids. Suitable omegα-3 fatty acids include, for example, α-linolenic acid (octadecα-9,12,15-trienoic acid), stearidonic acid (octadecα-3,6,9,12,15- tetraenoic acid), eicosapentaenoic acid (eicosα-5,8,11 ,14,17- pentaenoic acid), docosapentaenoic acid (docosα-7,10,13,16,19-pentaenoic acid), eicosatetraenoic acid (eicosα-8,11 ,14,17-tetraenoic acid), and docosahexaenoic acid (docosα-4,7,10,13,16,19-hexaenoic acid. Suitable omegα-6 fatty acids include, for example, linoleic acid (9,12-octadecadienoic acid ), y-linolenic acid (6,9,12-octade catrienoic acid), eicosadienoic acid (11 ,14-eicosadienoic acid), dihomo-y-linolenic acid (8,11 ,14-eicosatrienoic acid), arachidonic acid (5,8,11 ,14-eicosatetraenoic acid), docosadienoic acid (13,16-docosadienoic acid), adrenic acid (7,10,13,16-docosatetraenoic acid), docosapentaenoic acid (4,7,10,13,16-docosapentaenoic acid), and calendic acid (8E, 10E, 12Z- octadecatrienoic acid).

The injection compositions are prepared in customary manner under sterile conditions; the same applies also to introducing the compositions into ampoules orvials and sealing the containers.

Pharmaceutical compositions for oral administration can be obtained by combining the active ingredients with solid carriers, if desired granulating a resulting mixture and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragees capsules, pills, and liquids. It is also possible for them to be incorporated into plastics carriers that allow the active ingredients to diffuse or be released in measured amounts. Suitable carriers are for example, fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes using for example com, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, and/or carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or poly- ethylene glycol. Dragee cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic sol- vents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Capsules are dry-filled capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The dry-filled capsules may comprise the active ingredients in the form of granules, for example with fillers, such as lactose; binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired with stabilizers. In soft capsules the active ingredients are preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilizers and/or antibacterial agents to be added. Dyes or pigments may be added to the tablets or dragee coatings or the capsule casings, for example for identification purposes or to indicate different doses of active ingredient.

The pharmaceutical compositions generally include an effective dose of a compound of the invention. As used herein, an “effective dose” means an amount of two active components (a compound of the invention and another known medicament, either co-administered or an embodiment wherein AX in Formula (I) is a known medicament) that is different from an optimal amount of that component if administered in a therapeutic regimen absent of the other active component. An effective dose of the pharmaceutical composition when administered to a subject, prevents or ameliorates the symptoms of a disease, disorder or condition also produces fewer side effects compared to these symptoms in a control subject administered a compound of the invention and another active component alone. One of ordinary skill in the art can readily determine an effective amount of each component in the combination. It is an object of the methods and compositions herein that in the presence orco-administration of another active component, an effective dose of a compound of the invention is reduced compared to an effective dose in the absence of another known medicament, due to increased efficacy of these compounds when given together. The ratio between the compound of the invention and the second active component in the single dosage form can vary, and at times the ‘effective’ dose of one or both of the two drug substances can be reached using more than one tablet or capsule. A useful combination is one involving the inclusion of the compound of the invention (which has both antioxidant and free-radical scavenging properties due to the generation of R-a- lipoic acid under physiological conditions) with another drug to decrease or to prevent side effects, such as tissue damage. Under certain conditions, the generation of R-α-lipoic acid from the compound of the invention may have a synergistic effect in combination with another known medicament in preventing or ameliorating a disease or disorder or condition. Thus, the pharmaceutical composition includes an effective dose which is a lesser amount of the compound of the invention, compared to administering to the subject R-α-lipoic acid alone, to obtain a comparable therapeutic effect.

The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

EXAMPLES

Example 1

2-(2,5-Dioxopyrrolidin-1-yl)ethyl 5-[(3/?)-1,2-dithiolan-3-yl]pentanoate

(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 over 5 minutes, then stirred for an additional 30 minutes at room temperature. 1-(2-hydroxyethyl)pyrrolidine-2, 5-dione (7.632 g, 0.053 mol) was added as a solid. After a further 1 h, LCMS indicated the reaction was complete. MTBE (20ml) was added to the reaction, which was washed with saturated sodium hydrogen carbonate solution (10ml), 1 M aqueous HCI (10 ml) and brine (5 ml). The organic layer was dried (Na₂SO₄), filtered and the solvents evaporated under reduced pressure with the water bath set at room temperature. During the evaporation the solvent was replaced with n-heptane (150ml). The resulting yellow oil (12.300 g, 0.037 mol) crystallised after storing at -20°C for 16h. LC-MS: m/z 349.1 (M+NH₄)⁺; ¹H-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, 1 H), 2.24 (t, J=7.3Hz, 2H), 1.94-1.81 (m, 1 H), 1.73-1.60 (m, 2H), 1.59-1.44 (m, 2H), 1.43-1.27 (m, 2H); ¹³C-NMR (100 MHz, 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. Example 2

2 -Acetamidoethyl 5-[(3/?)-1 ,2-dithiolan-3-yl]pentanoate

(R)-α-Lipoic acid (10.0 g, 0.048 mol) and N,N-dimethylaminopyridine (1.776 g, 0.015 mol) were dissolved in MTBE (131ml) and EDC (10.3 ml, 0.058 mol) added dropwise over 5 min then stirred for an additional 30 minutes at room temperature. N-(2-hydroxyethyl)acetamide (5.498 g, 0.053 mol) was added and after 2h the reaction mixture was passed through a plug of silica and the silica washed with MTBE (100 ml). The combined organic fractions were evaporated under reduced pressure with the water batch at room temperature, to provide the crude product (20 g), which was purified by silica gel chromatography (ethyl acetate/iso-hexane gradient 0:1 to 1 :0) to provide a crystalline yellow solid (7.7 g, 0.026 mol) after evaporation of the solvents and storage at -20°C for 16h. LC-MS: m/z 292.1 (M+H)⁺; ¹H-NMR (400MHz, DMSO): δ 7.96 (br s, 1 H), 4.00 (t, J=5.8 Hz, 2H), 3.68- 3.56 (m, 1 H), 3.26 (q, J=5.8 Hz, 2H), 3.23-3.09 (m, 2H), 2.48-2.36 (m, 1 H), 2.31 (t, J=7.3 Hz, 2H), 1.94-1.82 (m, 1 H), 1.81 (s, 3H), 1.73-1.64 (m, 1 H), 1.60-1.51 (m, 3H), 1.42-1.36 (m, 2H); ¹³C-NMR (100 MHz, DMSO): δ 173.2, 169.9, 63.0, 56.6, 38.6, 38.1 , 34.5, 33.7, 28.6, 24.6, 23.0.

Example 3 2-(Carbamoylamino)ethyl 5-[(3/?)-1 ,2-dithiolan-3-yl]pentanoate

(R)-α-Lipoic acid (15.0 g, 0.07 3mol) and N,N-dimethylaminopyridine (2.665 g, 0.022 mol) were dissolved in MTBE (196.5ml) and EDC (13.5 g, 0.087 mol) added dropwise over 5 min then stirred for an additional 30 minutes at room temperature. 2-Hydroxyethyl)urea (8.326 g, 0.080 mol) was added After 2.5h the reaction was filtered through a plug of silica, which was washed with MTBE (100ml) followed by DCM (100 ml). The DCM fraction was evaporated under reduced pressure at room temperature and the yellow residue purified by silica gel chromatography (ethyl acetate/hexane gradient 0:1 to 1 :0) to provide a yellow crystalline solid (8.0g, 0.027mol) after evaporation of the solvents and storage at -20°C for 16h. LC-MS: m/z 293.1 (M+H)⁺; ¹H-NMR (400MHz, DMSO): δ 6.04 (t, 1 H), 5.49 (s, 2H), 3.97 (t, J=5.7 Hz, 2H), 3.68-3.57 (m, 1 H), 3.25-3.15 (m, 3H), 3.18-3.07 (m, 1 H), 2.42 (dt, J=20, 8 Hz, 1 H), 2.31 (t, J=7.4 Hz, 2H), 1.88 (dt, J=20, 8 Hz, 1 H), 1.75- 1.62 (m, 1 H), 1.62-1.49 (m, 3H), 1.42-1.33 (m, 2H); ¹³C-NMR (100 MHz, DMSO): 5 173.2, 159.0, 63.9, 56.5, 40.4, 38.7, 38.6, 34.5, 33.8, 28.6, 24.6.

Example 4

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

(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) and EDC (9.029g, 0.058mol) added dropwise over 5 min then stirred for an additional 30 minutes at room temperature. 2-(Morpholin-4-yl)ethan-1-ol (6.994 g, 0.053 mol) was added and after 2h the reaction mixture was passed through a plug of silica and the silica washed with MTBE (100ml). The combined organic fractions were evaporated under reduced pressure with the water batch at room temperature, to provide the crude product (16.5g), which was purified by silica gel chromatography (ethyl acetate/iso-hexane gradient 0:1 to 7:3) to provide a yellow viscous oil (9.636 g, 0.029 mol) after evaporation of the solvents. LC-MS: m/z 320.2 (M+H)⁺; ¹H-NMR (400MHz, CDCI₃): 6 4.14 (t, J=5.9 Hz, 2H), 3.65-3.63 (m, 4H), 3.54-3.47 (m, 1 H), 3.16-2.99 (m, 2H), 2.56 (t, J=5.9 Hz), 2.45-2.39 (m, 5H), 2.27 (t, J=7.4 Hz), 1.89-1.78 (m, 1 H), 1.71-1.51 (m, 5H, 1.51-1.32 (m, 2H); ¹³C-NMR (100 MHz, CDCI3): 6 173.4, 67.0, 61.4, 57.2, 56.4, 53.9, 40.3, 38.5, 34.6, 34.1 , 28.8, 24.7. Example 5 3-(Morpholin-4-yl)propyl-5-[(3/?)-1,2-dithiolan-3-yl]pentanoate

(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) and EDC (13.54g, 0.087mol) added dropwise over 5 min then stirred for an additional 30 minutes at room temperature. 3-(Morpholin-4-yl)propan-1-ol (11.61 g, 0.080 mol) was added and after 2h the reaction mixture was passed through a plug of silica and the silica washed with MTBE (100 ml). The combined organic fractions were evaporated under reduced pressure with the water batch at room temperature, to provide the crude product (32.4 g), which was purified by silica gel chromatography (DCM/ethyl acetate gradient 1 :0 to 3:8) to provide a yellow viscous oil (14.80 g, 0.044 mol) after evaporation of the solvents. LC-MS: m/z 334.2 (M+H)⁺; ¹H-NMR (400MHz, CDCI₃): 6 4.06 (t, J=6.6 Hz, 2H), 3.67-3.61 (m, 4H), 3.56-3.44 (m, 1 H), 3.17-2.99 (m, 2H), 2.46-2.30 (m, 7H), 2.25 (t, J=7.4 Hz, 2H), 1.91-1.80 (m, 1 H), 1.80-1.70 (m, 2H), 1.70-1.51 (m, 4H), 1.51-1.31 (m, 2H); ¹³C-NMR (100 MHz, CDCI3): 6 173.5, 67.0, 62.7, 56.4, 55.4, 53.7, 40.2, 38.5, 34.6, 34.1 , 28.8, 25.9, 24.7.

The following examples can be synthesised in an analogous manner to the examples above.

Data Table 1 below lists the calculated cLogP values of the example compounds.

These calculations were carried out using Molinspiration software (https://www.molinspiration.com/cgi-bin/properties).

Table 1 : CLogP of example compounds

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 the free base or a pharmaceutically acceptable salt. The latter substances include hydrochloride, tartrate, citrate, succinate, maleate, malonate, fumarate, acetate and sulphate. R-α-lipoic acid has a calculated octanol-water partition coefficient (LogP) of 2.25 (Molinspiration software). Although this value is within the range 0 to 3, generally considered as optimal for gastrointestinal absorption, it is a weak acid (pKa 4.7) so that a large proportion of this substance will be negatively charged as it exits the stomach and transits the intestinal tract (pH 5.5 to 7.5). Due to its negative charge R-α-lipoic acid is expected to have low absorption. The LogD value of the anionic form under the conditions of the small and large intestines is calculated to be < -0.46, indicating low passive diffusion across the plasma membrane, and the possible necessity for transport depending on transporter enzymes along the human intestine (Vadlapudi et al., 2012). It has also been reported that mediumchain fatty acids significantly inhibit the transport of R-α-lipoic acid, suggesting that a proton-linked monocarboxylic acid transporter may also be involved in its intestinal transport (Takaishi et al., 2007). This phenomenon is not expected to occur in the case of the compounds of the invention.

Unlike R-α-lipoic acid (pKa 4.7), Examples 1 to 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 encountered in the small and large intestines (pHs from about 5 to 7.5). Thus, absorption of these prodrugs will not be pH-dependent and will likely not be hampered by changes in the pH of the GIT. R-α-lipoic acid is partially or wholly negatively charged after it leaves the stomach and enters the digestive tract. Neutral R-α-lipoic acid, and not the corresponding anion is the species that will be expected to cross the plasma membrane, via passive diffusion.

The LogP values of examples 1-43 (see Table 1 above) suggest that most of the derivatives should have improved gastrointestinal absorption by passive diffusion permeability, when compared with the simple alkyl or aryl esters of R-α-lipoic acid, possessing higher LogP values.

Examples 4, 5, 9, 10, 12, 13, 14, 15, 17, 18, 21 , 22, 23, 24, 25, 26, 27, 37, 38, 42 and 43 contain an aliphatic amino group; pKa values of these compounds have not been measured but are expected to be of the order of 5 to 11. These compounds are therefore expected to be partially positively charged in the gastrointestinal tract, resulting in enhanced solubility and good absorption.

The pKa values of the imidazole derivatives 10 and 14 are expected to be about 7.0 which will lead to a high proportion of both the neutral and the cationic form along the pH gradient of the gastrointestinal tract. The partition coefficient is also within the optimal range and will favour good absorption of these derivatives.

Examples 1 to 43 are expected to exhibit a delayed but steady release of R-α- lipoic acid over a longer period compared to the direct administration of R-α-lipoic acid. These compounds may also show some resistance to rapid metabolism and elimination, allowing a higher concentration of R-α-lipoic acid to exercise its function as an essential cofactor for mitochondrial oxidative metabolism.

The dithiolane moiety in the example compounds is still intact so that, in the same manner as R-α-lipoic acid, they may still both retain antioxidant activity and trap metal ions in the blood circulation, due to their ability to undergo interconversion between oxidized disulphide (α-lipoic acid) and the reduced bis-sulphydryl (DHLA) forms. They may be involved in reactions such as quenching ROS or chelation of pro-oxidant metal cations, either on their own or when hydrolysed to release R-α- lipoic acid. Modes of delivery, besides oral, such as intravenous, subcutaneous, intramuscular, topical, ocular and suppository administration will be tested due to possible differences in the hydrolysis of these derivatives at different sites of application.

Table 2 below lists the physiochemical properties of R-α-lipoic acid, which has all the attributes of a successful central nervous system (CNS) drug.

Based on an analysis of the physicochemical characteristics of approved drugs and clinical candidates, Christopher Lipinski proposed that his ‘rule of 5’ could predict the likelihood that a given small molecule will cross biological membranes to gain exposure to its molecular target following oral administration (Lipinski, 2004). This guideline prioritized compounds that have molecular masses of less than 500 Daltons, clogPs of less than 5, five or fewer hydrogen bond donors, and ten or fewer hydrogen bond acceptors. Table 2: Physiochemical properties of R-α-lipoic acid

* Pajouhesh et al. 2005.

** Minimal hydrophobicity The data above, along with therapeutic efficacy data in both experimental animal models of brain disease and in people with brain disease (described earlier in this specification), demonstrates that R-α-lipoic acid produced from the compounds of the invention will cross the blood-CNS barrier and thus enter the tissues of the brain and spinal cord to produce therapeutic benefit.

Preliminary enzymatic cleavage kinetics of 5 pM example 3 in rat, dog and human plasma showed rapid ester cleavage and production of R-α-lipoic acid over time, as shown in Figures 1A to 1 F. Figures 1A, 1 B, and 1C show the percentage of the compound remaining over time in rat, dog, and human plasma respectively. Figures 1 D, 1 E, and 1 F show the corresponding increase in R-α-lipoic acid over time in rat, dog, and human plasma respectively. The half-life in rat, dog and human was about 10, 45 and 7 min, respectively. R-α-lipoic acid concentrations were determined using a validated liquid chromatograpy-mass spectrometry/mass spectrometry method.

One of the prodrugs (Example 3) has been shown to produce R-α-lipoic acid in rat plasma following oral dosing (Fig. 2). This shows that the prodrug is efficiently absorbed from the gastrointestinal tract and is rapidly hydrolysed to produce R-α- lipoic acid. Figure 2 shows plasma concentrations of R-α-lipoic acid in a rat following po administration of 75 mg/kg Example 3. The initial Cmax (t = 5 min) may be related to the solution formulation used, which permits rapid absorption in the stomach. Preferably, the compound is administered as enteric-coated capsules to avoid instability and absorption in the stomach. The second Cmax (t = 2 hours) probably reflects absorption in the intestine.

Table 3 below shows the LD₅o for R-α-lipoic acid and alcohol pro-moieties generated from the hydrolysis of example compounds.

Table 3: In vivo toxicity of R-α-lipoic acid and alcohols produced from the enzymatic hydrolysis of Examples 2-5

*The LD₅o is the amount of an administered compound that is required to kill 50% of the population of test animals (data obtained from published, peer-reviewed manuscripts). The data in Table 3 strongly indicates that the hydrolysis of the prodrugs produces two products (lipoic acid and an alcohol), both of which are expected to be relatively non-toxic.

Therefore, the LD50 data in Table 3 above demonstrates that the compounds of the invention are expected to show a good safety profile.

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Claims

1. A compound of Formula (I)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, enantiomer, polymorph, and/or N-oxide thereof; wherein

Z¹ and Z² are each independently -SH or -S(O)H; or Z¹ and Z² are taken together with the atoms to which they are attached to form a dithiolane ring, wherein one of the sulphur atoms in the dithiolane ring may be substituted with an oxo group; each of A and Y is independently a Ci-Ce alkylene chain, wherein the Ci-Ce alkylene chain is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, -CN, -NH₂, -NO₂, Ci-Ce alkoxy, -NHR¹, -NR¹R¹, -NHC(O)R¹, -NR¹C(O)R¹, -C(O)R¹, -CO₂H, -C(O)NH₂, and -CO₂R¹;

X is selected from the group consisting of H, -CH₃, -OH, -OR¹, -NH₂, -NHC(O)R¹, -NR¹C(O)R¹, -NHC(O)NHR¹, -NHC(O)NH₂, -NR¹C(O)NHR¹, -NR¹C(O)NR¹R¹, -NHS(O)₂R¹, -NR¹S(O)₂R¹, -NHS(O)₂NHR¹, -NHS(O)₂NR¹R¹, -NR¹S(O)₂NR¹R¹, -NHCH2CO₂H, -NHCH2CO₂R¹, NHCH2CH2CO₂H, -NHCH2CH2CO₂R¹, and an optionally substituted 3 to 8-membered heterocyclic ring, wherein the 3 to 8-membered heterocyclic ring is an aromatic or non-aromatic, monocyclic or bicyclic ring, wherein one or more of the ring atoms are N, O, or S and the ring is attached to the remainder of the molecule via a C or N atom; and each R¹ is independently selected from the group consisting of optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, and optionally substituted C2-C4 alkynyl; or A and X are taken together to form a known medicament.

2. The compound according to claim 1 , wherein Z¹ and Z² are each -SH or Z¹ and Z² are taken together with the atoms to which they are attached to form a dithiolane ring, preferably Z¹ and Z² are taken together with the atoms to which they are attached to form a dithiolane ring.

3. The compound according to claim 2, wherein the compound of Formula (I) is a compound of Formula (la)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, enantiomer, polymorph, and/or N-oxide thereof.

4. The compound according to any preceding claim, wherein Y is an unsubstituted Ci-Ce alkylene chain, preferably butylene.

5. The compound according to any preceding claim, wherein X is selected from the group consisting of H, -CH₃, -OH, -OR¹, -NH₂, -NHC(O)R¹, - NHC(O)NH₂, -NHC(O)NHR¹, -NHCH₂CO₂H, -NHCH₂CO₂R¹, -NHCH₂CH₂CO₂H, - NHCH₂CH₂CO₂R¹, and an optionally substituted 3 to 8-membered heterocyclic ring, preferably H, -CH₃, -NH₂, -NHC(O)R¹, -NHC(O)NH₂, -NHCH₂CO₂H, - NHCH₂CH₂CO₂H, and an optionally substituted 3 to 8-membered heterocyclic ring.

6. The compound according to any preceding claim, wherein A is a Ci-Ce alkylene chain optionally substituted with one or more substituents selected from the group consisting of -CO₂H, -C(O)NH₂, and -CO₂R¹, preferably A is a C1-C4 alkylene chain optionally substituted with one or more substituents selected from the group consisting of -CO₂H, -C(O)NH₂, and -CO₂R¹, more preferably A is a C1- C4 alkylene chain optionally substituted with -CO₂H or -C(O)NH₂.

7. The compound according to any preceding claim, wherein each R¹ is independently an optionally substituted C1-C4 alkyl group, preferably each R¹ is -CH₃.

8. The compound according to any preceding claim, wherein A is an unsubstituted C2-C3 alkylene chain and X is an optionally substituted 3 to 8-membered heterocyclic ring; or

A is a C1-C4 alkylene chain and X is H, -CH₃, -NH₂, -NHC(O)NH₂, - NHC(O)R¹, -NHCH2CO₂H, or -NHCH₂CH₂CO₂H, wherein the C1-C4 alkylene chain is optionally substituted with -CO₂H or -C(O)NH₂.

9. The compound according to any preceding claim, wherein A is an unsubstituted C2-C₃ alkylene chain and X is an optionally substituted 3 to 8-membered heterocyclic ring; or

A is a C1-C4 alkylene chain and X is H, -CH₃, or -NH₂, wherein the C1-C4 alkylene chain is substituted with -CO₂H or -C(O)NH₂; or

A is a C₂-C₃ alkylene chain and X is -NHC(O)NH₂, - NHC(O)R¹, -NHCH2CO₂H, or -NHCH₂CH₂CO₂H, wherein the C₂-C₃ alkylene chain is optionally substituted with -CO₂H or -C(O)NH₂.

10. The compound according to any preceding claim, wherein the optionally substituted 3 to 8-membered heterocyclic ring is an optionally substituted 5- or 6-membered heterocyclic ring, preferably one or two ring atoms in the 5- or 6-membered heterocyclic ring are independently N, O, or S, and the remaining ring atoms are C.

11. The compound according to any preceding claim, wherein the 3 to 8-membered heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of oxo, C1-C3 alkyl, and hydroxy, preferably oxo, methyl, and hydroxy.

12. The compound according to any preceding claim, wherein the 3 to 8-membered heterocyclic ring is selected from the group consisting of 2,5- dioxopyrrolidin-1 -yl; pyrrolidin-2 -one-1 -yl; 1 ,3-oxazolidine-2-one-3-yl; 2,6- dioxopiperidin-1 -yl; 2,5-dihydro-1 H-pyrrole-2,5-dione-1 -yl; pyrrolidin-2, 4-di-one-1 - yl; 1 ,1-dioxothiomorpholin-4-yl; 4-oxopiperidin-1 -yl; 4-hydroxypyrrolidin-2-one-1- yl; morpholin-4-yl; 4-methylpiperizin-1-yl; pyrrolidin-3-one-1 -yl; 1 -methylpyrrolidin- 2-yl; 1-methyl-1 H-imidazol-2-yl; piperidin-4-yl; 1-methyl-piperidin-4-yl; 1 H- imidazol-1 -yl; 2,5-dioxo-piperazin-1-yl; pyrrolidin-1 -yl; and pipererazin-2-yl.

13. The compound according to any preceding claim, wherein the compound is one of the following compounds or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, enantiomer, polymorph, and/or N-oxide thereof

Ċ

10

15

14. A pharmaceutical composition comprising a compound according to any preceding claim and a pharmaceutically acceptable carrier, excipient, and/or diluent, preferably the pharmaceutical composition further comprises a known medicament.

15. The compound according to any one of claims 1 to 13, or the pharmaceutical composition of claim 14, for use in therapy.

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

17. The compound or pharmaceutical composition for use according to claim

16, wherein the disease is selected from the group consisting of: chemotherapy- induced tissue damage, heavy metal poisoning, radiation damage, cardiovascular disease (such as heart disease and both ischaemic and haemorrhagic stroke), brain diseases, disorders and conditions (such as Alzheimer’s disease, Parkinson’s disease, motor neuron disease, Huntington’s disease, Lewy body disease, multi-infarct 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), autoimmune disorders (such as multiple sclerosis and psoriasis), eye disorders (such as retinopathy, presbyopia, glaucoma, age-related macular degeneration and optic neuritis), metabolic syndrome, traumatic brain injury, traumatic spinal cord injury, skin disorders (such as acne), diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiopathy, myopathy, nephropathy, arthrosclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, transplant rejection, ischaemia reperfusion injury (e.g. myocardial ischaemia, intestinal reperfusion e.g. after haemorrhagic shock), restenosis, ileitis, Chrohn’s disease, thrombosis, colitis including for example ulcerative colitis, lupus, frostbite injury, acute leucocyte mediated lung injury (e.g. 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 granulocyte ehrlichiosis, Wiskott-Aldrich syndrome, T-cell activation, AIDS, infection with viruses, bacteria, protozoa and parasites (including post-infection syndromes), tumours and cancer, neurodevelopmental disorders (such as autism and Rett syndrome), inborn errors of metabolism causing lipoic acid deficiencies, genetic disorders, including chromosomal disorders (such as Down syndrome, Klinefelter syndrome, triple X syndrome, T urner syndrome, T risomy 18 and T risomy 13), and disorders caused by mutations in single-genes (such as Kabuki syndrome, spinocerebellar ataxia, 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 leukaemias, lymphomas, melanomas, adenomas, sarcomas, carcinomas of solid tissues, prostrate, testicular, mammary, pancreatic, cervical, uterine, kidney, lung, rectum, breast, gastric, thyroid, neck, cervix, bowel, salivary gland, bile duct, pelvis, mediastinum, urethra, bronchogenic, bladder (e.g. bladder carcinoma), oesophagus, small intestine, oral cavity (e.g. oral cavity carcinomas), colon, liver, stomach, sarcomas (e.g. Kaposi’s sarcoma), adenomatous polyps, and brain tumours (such as medulloblastomas, gliomas, craniopharyngiomas, ependymomas, embryonal tumours, pineoblastomas, brainstem gliomas, choroid plexus carcinomas, germ-cell tumours, astrocytomas, pituitary adenomas, acoustic neuromas, meningiomas, and oligodendrogliomas).

18. The compound according to any one of claims 1 to 13, or the pharmaceutical composition of claim 14, for use in the treatment of side effects caused by the administration of another medicament.