(S)-tianeptine and use in treating disorders and conditions associated with peroxisome proliferator-activated receptors

Abstract

The present disclosure provides (S)-enantiomers of 7-(3-chloro-6-methyl-5, 5-dioxo-6, 11-dihydrodibenzo [c, f] [1, 2] thiaza-11-ylamino) heptanoic acid ((S)-tianeptine) and (S)-enantiomers of deuterated tianeptine (11-D-(S)-tianeptine), both of which are characterized by comprising no more than 2%, or no more than about 0.1%, of the corresponding (R)-enantiomer. The present disclosure also provides salts, amides, esters, co-crystals, crystals, analogs, and pharmaceutical compositions thereof, and the use of (S)-enantiomers and those compounds and compositions for the treatment of diseases, disorders or conditions of CNS as well as diseases, disorders and disorders associated with, aggravated by, or modulated by altered activity of peroxisome proliferator-activated receptors (PPAR-beta / delta) and / or PPAR-gamma, and at the same time minimizes or eliminates the likelihood of opioid abuse. The present disclosure also provides methods of making the (S)-enantiomers and 11-D-(S)-enantiomers of the present disclosure, as well as related compounds.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and interest in U.S. Provisional Application No. 63 / 454,958, filed March 27, 2023; U.S. Provisional Application No. 63 / 463,299, filed May 1, 2023; U.S. Provisional Application No. 63 / 466,999, filed May 16, 2023; U.S. Provisional Application No. 63 / 468,221, filed May 22, 2023; and U.S. Provisional Application No. 63 / 528,631, filed July 24, 2023. The contents of each of the foregoing applications are hereby incorporated, in their entirety, by reference. Technical Field

[0003] This disclosure relates to the (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-ylamino)heptanoic acid ((S)-tiaponectin) and the (S)-enantiomer of deuterated tiaponectin (11-D-(S)-tiaponectin), both characterized by comprising no more than about 2% or no more than about 0.1% of the corresponding (R)-enantiomer. This disclosure also provides its salts, amides, esters, cocrystals, crystals, analogs, and pharmaceutical compositions, as well as methods for using the (S)-enantiomers and those compounds and compositions to treat diseases, disorders, or conditions of the CNS and diseases, conditions, and disorders associated with, exacerbated by, or regulated by altered activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, while minimizing or eliminating the possibility of opioid abuse. These diseases, disorders, and conditions are CNS disorders (e.g., major depressive disorder, age-related cognitive impairment, and neurodegenerative diseases), asthma, and primary biliary cholangitis. This disclosure also provides methods for preparing the (S)-enantiomers and 11-D-(S)-enantiomers of this disclosure, as well as related compounds.

[0004] background

[0005] Tinapril, the racemic mixture of 7-[(3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][2,1]benzothiazol-11-yl)amino]heptanoic acid, is an antidepressant with neuroprotective and cognitive-restorative effects. Researchers have reported that tianapordine can be used to treat post-traumatic stress disorder (PTSD) (Onder E et al., Eur Psychiatry. 2005), attention deficit hyperactivity disorder (ADHD) (Niederhofer H., Neuropsychobiology. 2004), Alzheimer's disease (García-Alberca JM et al., J Alzheimers Dis. 2022), asthma (Lechin F et al., Methods Find Exp Clin Pharmacol. 2004), and fibromyalgia (ISRCTN16400909). Although tianapordine shares structural similarities with classic tricyclic antidepressants, its pharmacological behavior is unique. The U.S. Food and Drug Administration (FDA) has not approved any drugs containing tiannaphthol for any indication. However, tiannaphthol is currently available as the active ingredient in approved products and is marketed, particularly under the trade names Stablon®, Coaxil®, Tatinol, Tianeurax®, and Salymbra, for the treatment of depression throughout Europe, Asia, and Latin America. For example, France first approved tiannaphthol (e.g., Stablon®) as an antidepressant in 1989, at a dose of 12.5 mg three times daily. Products containing tiannaphthol are also available as over-the-counter food supplements or investigational chemicals in certain regions of the United States.

[0006] Racemic tiannaptine has been reported to affect serotonin reuptake, regulate glutamatergic activity, and recently, has been reported to weakly activate µ-opioid receptors. In animal studies involving severe stress exposure, tiannaptine has been reported to restore neuroplasticity through synaptic processes by exerting biological effects on neurons and glial cells, increasing dendritic branching of dendrites in key hippocampal circuits to restore hippocampal neurogenesis, and reversing stress-induced impairment in synaptic glutamate neurotransmission (McEwen BS et al., Mol Psychiatry. 2010). Furthermore, tiannaptine has been shown to increase brain-derived neurotrophic factor (BNDF) in the amygdala of rats (Reagan LP et al., Eur J Pharmacol. 2007; Della FP et al., Behav Brain Res. 2012). However, these mechanistic studies are difficult to interpret because many studies are based on measurements using a 50:50 mixture (racemic) of the (R)- and (S)-enantiomers of tiannaptine.

[0007] Furthermore, the U.S. Centers for Disease Control and Prevention (CDC) published its Morbidity and Mortality Weekly Report (MMWR) in August 2018, describing the incidence of tiannapritine overdose from over-the-counter products, which is associated with the potential for abuse due to tiannapritine's opioid effects, and issued a public health risk warning. In fact, Georgia revoked its marketing authorization in June 2010, and tiannapritine was included on the list of psychotropic drugs in Russia, Ukraine, and Armenia due to its abuse by "drug addicts" via intravenous injection. As a result of these actions and reports of abuse, in September 2012, tiannapritine was added to List I of drugs with special status for prescription and dispensing conditions in France. Other common adverse events associated with tiannapritine include anorexia, nightmares, insomnia, somnolence, dizziness, headache, tachycardia, dyspnea, gastrointestinal upset, myalgia, and weakness.

[0008] Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors belonging to the nuclear receptor superfamily, involved in the regulation of inflammatory responses and lipid metabolism in both the peripheral and central nervous systems (CNS). The PPAR subfamily comprises three isoforms: PPAR-α, PPAR-γ, and PPAR-β / δ. Research has focused on the activation of PPAR-α and PPAR-γ in the regulation of neuroinflammation, mitochondrial alterations, and memory impairment. PPAR-γ has also been shown to play a role in depression, neurogenesis, and the expression of brain-derived neurotrophic factor (BDNF) (Nicolakakis N et al., J Neurosci. 2008; Heneka MT et al., Brain. 2005; Gold PW. Int J Mol Sci. 2021). PPAR-γ modulation has also been used to treat diabetes, for example, through agonists of the “thiazolidinediones” (“TZDs”) class, commonly referred to as “glitazones,” including rosiglitazone (Avandia®) and pioglitazone (Actos®). Alzheimer's disease is referred to as "type 3 diabetes" to reflect the concept that it may be a metabolic disorder of glucose metabolism in the central nervous system, similar to how type 1 and type 2 diabetes are metabolic disorders of peripheral glucose metabolism (de la Monte SM, Wands JR. J Diabetes Sci Technol. 2008). Downregulation of PPAR-β / δ is also associated with depressive behavior, while activation of PPAR-β / δ has been shown to improve the clinical symptoms of CNS conditions by modulating oxidative stress and inflammatory responses (Chen F et al., Int J Neuropsychopharmacol. 2019; Strosznajder AK, Neuromolecular Med. 2021; Espinosa-Jiménez T et al. Front Pharmacol. 2022). PPAR-β / δ activation is also currently being investigated in a phase 3 trial for the treatment of primary biliary cholangitis using MBX-8025 (Seladelpar®) from CymaBay Therapeutics.

[0009] Major depressive disorder (MDD) is a mood disorder lasting two weeks or more and is a leading cause of disability worldwide. MDD affects how a person feels, thinks, and processes daily activities and can significantly impair all aspects of life because patients exhibit persistent sadness or anxiety, irritability, anhedonia, significant weight changes, appetite disturbances, sleep disturbances, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness, impaired thinking or attention, indecisiveness, pain without a clear physical cause, or recurrent thoughts of death or suicide. In 2020, an estimated 21 million adults in the United States (approximately 8.4% of all adults (18 years or older) experienced at least one major depressive episode. The annual prevalence of major depressive episodes is higher in adult women (e.g., approximately 10.5%) than in men (e.g., approximately 6.2%). Furthermore, the annual prevalence of major depressive episodes is highest in individuals aged 18–25 years (e.g., approximately 17.0%). Human and animal studies have shown that depression is associated with a reduction in the size of brain regions believed to regulate mood and cognition, including the prefrontal cortex and hippocampus. Furthermore, these brain regions exhibit reduced neuronal synapses in depression (MacQueen G, Frodl T. Mol Psychiatry. 2011; Price JL, Drevets WC. Neuropsychopharmacology. 2010).

[0010] The current pillars of pharmacological treatment for MDD include the use of selective serotonin reuptake inhibitors (SSRIs) (Fava et al., Int J Neuropsychopharmacol. 2007), serotonin-norepinephrine reuptake inhibitors (SNRIs) (Stahl et al., CNS Spectr. 2005), and tricyclic antidepressants (TCAs). However, these therapies are not effective in all patients and are often associated with undesirable side effects such as weight gain and sexual dysfunction. Moreover, even with repeated treatments, only a small percentage of patients achieve an asymptomatic state, i.e., remission (Rush, Am J Psychiatry. 2007). Many patients who do not respond adequately to therapy with SSRIs, SNRIs, and TCAs receive intensified therapy with mood stabilizers or antipsychotics (Strawbridge R et al., Br J Psychiatry. 2019), and other such patients sometimes receive off-label opioids and narcotic analgesics (e.g., oxycodone, hydrocodone, fentanyl, and tramadol) in the absence of reliable experimental evidence. Using opioids to treat MDD is associated with an increased risk of long-term use, abuse (e.g., parenteral, transmucosal, intranasal, or oral drug abuse), and addiction.

[0011] Depression is also associated with impaired neuroplasticity and cellular resilience. Traditional antidepressants work in part by normalizing this damage and restoring neuronal connections. For example, ketamine—an N-methyl-D-aspartate (NMDA) receptor antagonist—has been found to produce a rapid (within hours) antidepressant response in patients with treatment-resistant depression and rapidly induces BDNF-dependent synapsis in animal models, reversing synaptic defects caused by chronic stress by activating the mammalian target of rapamycin (mTOR) signaling pathway (Duman RS, Aghajanian GK. Science. 2012). Intranasal S-ketamine (Spravato®) is approved by the FDA for the acute treatment of depression. Dextromethorphan—another NMDA receptor antagonist—is also FDA-approved for the treatment of depression in combination with bupropion (Auvelity®), a fixed-dose oral product. However, ketamine, S-ketamine, dextromethorphan, and other ligands of the NMDA receptor exhibit dissociative effects, which limit their use. Another proposed method for inducing synapse formation is 5-HT. 2A The receptor agonist selocillin was used, but this method is limited by hallucinations, which are a side effect of pseudopsychosis.

[0012] Therefore, there exists a long-standing, unmet need for the safe treatment of MDD and various other CNS disorders and conditions, as well as a range of disorders and conditions associated with or regulated by alterations in PPAR-β / δ and / or PPAR-γ activity. These disorders and conditions include stress (psychological, environmental, chemical, radiation, oxidative, hormonal, vascular, and traumatic), depression, aging, and chronic diseases, each of which is associated with reduced neuronal connectivity.

[0013] As described in various embodiments of this disclosure, the (S)-enantiomer of tiannaphthol, its zwitterion, its cocrystal, its ester, amide, and any of the deuterated analogs of the latter or pharmaceutically acceptable salts of the (S)-enantiomer, their crystalline forms, and compositions thereof, as well as various analogs of the two tiannaphthol enantiomers and their compositions thereof, and methods of using these compositions to meet the unmet need and improve the treatment of various CNS disorders and conditions (including MDD) and disorders and conditions associated with or regulated by alterations in the activity of PPAR-β / δ and / or PPAR-γ, while minimizing or eliminating the possibility of opioid abuse. Invention Overview

[0015] Some implementation schemes for the content of this disclosure are as follows:

[0016] 1. The (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazide-11-ylamino)heptanoic acid of general formula (Ia) (the (S)-enantiomer of tianapordine), a pharmaceutically acceptable salt of the zwitterion or (S)-enantiomer of formula (Ib), or a mixture of two or more of these substances, wherein the (S)-enantiomer, zwitterion, or pharmaceutically acceptable salt is characterized by comprising ≤ about 2% of the (R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of its (R)-enantiomer:

[0017] .

[0018] 2. The (S)-enantiomer according to embodiment 1, wherein the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the (R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof.

[0019] 3. A pharmaceutically acceptable salt of the (S)-enantiomer according to embodiment 1 or 2, wherein the pharmaceutically acceptable salt is (S)-tiaponectin benzenesulfonate (1:1), (S)-tiaponectin fumarate (1:1), (S)-tiaponectin fumarate (2:1), (S)-tiaponectin hippurate (1:1), (S)-tiaponectin maleate (1:1), (S)-tiaponectin maleate (2:1), (S)-tiaponectin p-toluenesulfonate (1:1), (S)-tiaponectin orotate (1:1), (S)-tiaponectin camphorsulfonate (1:1), (S)-tiaponectin N-acetyl-L-tyrosine salt (1:1), (S)-tiaponectin polisterix, (S)-tiaponectin:L-DBTA (2:1), (S)-tiaponectin sodium, (S)-tiaponectin oxalate or (S)-tiaponectin hemioxalate (2:1).

[0020] 4. A pharmaceutically acceptable salt of the (S)-enantiomer according to embodiment 3, wherein the pharmaceutically acceptable salt is (S)-tiaponectin benzyl sulfonate (1:1), (S)-tiaponectin fumarate (1:1), (S)-tiaponectin fumarate (2:1), (S)-tiaponectin hippurate (1:1), (S)-tiaponectin maleate (1:1), (S)-tiaponectin maleate (2:1), (S)-tiaponectin p-toluenesulfonate (1:1), or (S)-tiaponectin orotate (1:1).

[0021] 5. A pharmaceutically acceptable salt of the (S)-enantiomer according to embodiment 3, wherein the pharmaceutically acceptable salt is (S)-tiaponectin camphor sulfonate (1:1), (S)-tiaponectin N-acetyl-L-tyrosine salt (1:1), or (S)-tiaponectin polisterix.

[0022] 6. A pharmaceutically acceptable salt of the (S)-enantiomer according to embodiment 3, wherein the pharmaceutically acceptable salt is (S)-tiaponectin hemioxalate (2:1).

[0023] 7. A zwitterion comprising the zwitterion of the (S)-enantiomer according to embodiment 1 or 2.

[0024] 8. A cocrystal of the (S)-enantiomer according to embodiment 1 or 2, wherein the (S)-enantiomer or its zwitterion forms a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid.

[0025] 9. The eutectic according to embodiment 8, wherein the complex comprises the (S)-enantiomer or its zwitterion in a ratio of 1:1, 1:2, or 2:1 with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid.

[0026] 10. The eutectic according to embodiment 8 or 9, wherein the eutectic comprises the inorganic monocarboxylic acid salt of the (S)-enantiomer and the zwitterion of the L-amino acid.

[0027] 11. The eutectic according to embodiment 8 or 9, wherein the eutectic comprises an inorganic monocarboxylic acid salt of the L-amino acid and a zwitterion of the (S)-enantiomer.

[0028] 12. The eutectic according to embodiment 10 or 11, wherein the inorganic monocarboxylic acid is hydrochloric acid (HCl).

[0029] 13. An ester of the (S)-enantiomer according to embodiment 1 or 2, wherein the ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof.

[0030] 14. The ester of the (S)-enantiomer according to embodiment 13, wherein the ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof.

[0031] 15. An ester of the (S)-enantiomer according to embodiment 13 or 14, wherein the ester of the (S)-enantiomer is a methyl ester of the (S)-enantiomer, an ethyl ester of the (S)-enantiomer, or another C1-C6 alkyl ester of the (S)-enantiomer, or a pharmaceutically acceptable salt of any of them.

[0032] 16. An amide of the (S)-enantiomer according to embodiment 1 or 2, wherein the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the (R)-enantiomer amide or a pharmaceutically acceptable salt thereof.

[0033] 17. The (S)-enantiomer amide according to embodiment 16, wherein the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the (R)-enantiomer amide or a pharmaceutically acceptable salt thereof.

[0034] 18. An amide of the (S)-enantiomer according to embodiment 13 or 14, wherein the amide of the (S)-enantiomer is a simple amide or a C1-C6 alkyl amide optionally substituted with at least one hydroxyl group or a pharmaceutically acceptable salt of either.

[0035] 19. The (S)-enantiomer of 7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-yl-11-d)amino)heptanoic acid of general formula (IIa) (the 11-D-(S)-enantiomer of tianapordine), or a pharmaceutically acceptable salt of its zwitterion or 11-D-(S)-enantiomer of formula (IIb), or a mixture of two or more of these substances, wherein deuterium substitutes for the hydrogen at the 11-position, and wherein said 11-D-(S)-enantiomer or its zwitterion or pharmaceutically acceptable salt is characterized by comprising ≤ about 2% of the 11-D-(R)-enantiomer of tianapordine or its zwitterion or pharmaceutically acceptable salt of 11-D-(R)-enantiomer:

[0036] .

[0037] 20. The (S)-enantiomer according to embodiment 19, wherein the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of a 11-D-(R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof.

[0038] 21. The (S)-enantiomer according to embodiment 19 or 20, wherein the 11-D-(S)-enantiomer or the zwitterion or pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is characterized by reduced racemization at position 11 compared to the (S)-enantiomer of tinaptrine or the zwitterion or pharmaceutically acceptable salt of the enantiomer.

[0039] 22. The (S)-enantiomer according to any one of embodiments 19-21, wherein the 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is further deuterated at at least one of the 3' positions, and optionally deuterated at other positions on the aminoheptanoic acid side chain.

[0040] 23. The (S)-enantiomer according to embodiment 22, wherein the 11-D-(S)-enantiomer is the (S)-enantiomer of 3',3',4',4',11-pentadeuterated thiazonaprotin of formula (IIIa) or its zwitterion of formula (IIIb); or the 2',2',3',3',4',4',5',5',6',6',7',7',11-tweldeuterated thiazonaprotin of general formula (IVa). The (S)-enantiomer of naproxen or its zwitterion of formula (IVb); the 3', 3', 4', 4' of formula (Va), the (S)-enantiomer of tetradeuterated tiaponectin or its zwitterion of formula (Vb); or the 2', 2', 3', 3', 4', 4', 5', 5', 6', 6', 7', 7' of general formula (VIa), the (S)-enantiomer of dodeuterated tiaponectin or its zwitterion of formula (VIb).

[0041]

[0042]

[0043] 24. A pharmaceutically acceptable salt of the 11-D-(S)-enantiomer according to any one of embodiments 19-23, wherein the pharmaceutically acceptable salt is 11-D-(S)-thiazopridine benzylsulfonate (1:1), 11-D-(S)-thiazopridine fumarate (1:1), 11-D-(S)-thiazopridine fumarate (2:1), 11-D-(S)-thiazopridine hippurate (1:1), 11-D-(S)-thiazopridine maleate (1:1). 1) 11-D-(S)-Tiaponectin maleate (2:1), 11-D-(S)-Tiaponectin p-toluenesulfonate (1:1), 11-D-(S)-Tiaponectin orotate (1:1), 11-D-(S)-Tiaponectin camphorsulfonate (1:1), 11-D-(S)-Tiaponectin N-acetyl-L-tyrosine (1:1), 11-D-(S)-Tiaponectin polisterix, 11-D-(S)-Tiaponectin:L-DBTA (2:1), 11-D-(S)-Tiaponectin sodium, 11-D-(S)-Tiaponectin oxalate or 11-D-(S)-Tiaponectin hemioxalate (2:1).

[0044] 25. A pharmaceutically acceptable salt of the 11-D-(S)-enantiomer according to embodiment 24, wherein the pharmaceutically acceptable salt is 11-D-(S)-tiaponectin benzylsulfonate (1:1), 11-D-(S)-tiaponectin fumarate (1:1), 11-D-(S)-tiaponectin fumarate (2:1), 11-D-(S)-tiaponectin hippurate (1:1), 11-D-(S)-tiaponectin maleate (1:1), 11-D-(S)-tiaponectin maleate (2:1), 11-D-(S)-tiaponectin p-toluenesulfonate (1:1), or 11-D-(S)-tiaponectin orotate (1:1).

[0045] 26. A pharmaceutically acceptable salt of the 11-D-(S)-enantiomer according to embodiment 24, wherein the pharmaceutically acceptable salt is 11-D-(S)-thiazopridine camphor sulfonate (1:1), 11-D-(S)-thiazopridine N-acetyl-L-tyrosine salt (1:1), or 11-D-(S)-thiazopridine polisterix.

[0046] 27. A pharmaceutically acceptable salt of the 11-D-(S)-enantiomer according to embodiment 24, wherein the pharmaceutically acceptable salt is 11-D-(S)-tiaponectin hemioxalate (2:1).

[0047] 28. A zwitterion comprising the zwitterion of the 11-D-(S)-enantiomer according to any one of embodiments 19-23.

[0048] 29. A eutectic of the 11-D-(S)-enantiomer according to any one of embodiments 19-23 or 26, wherein the 11-D-(S)-enantiomer or its zwitterion forms a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid.

[0049] 30. The eutectic according to embodiment 29, wherein the complex comprises the 11-D-(S)-enantiomer or its zwitterion in a ratio of 1:1, 1:2, or 2:1 with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid.

[0050] 31. The eutectic according to embodiment 29 or 30, wherein the eutectic comprises the inorganic monocarboxylic acid salt of the 11-D-(S)-enantiomer and the zwitterion of the L-amino acid.

[0051] 32. The eutectic according to embodiment 29 or 30, wherein the eutectic comprises an inorganic monocarboxylic acid salt of the L-amino acid and a zwitterion of the 11-D-(S)-enantiomer.

[0052] 33. The eutectic according to embodiment 31 or 32, wherein the inorganic monocarboxylic acid is hydrochloric acid (HCl).

[0053] 34. An ester of the (S)-enantiomer according to any one of embodiments 19-23, wherein the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

[0054] 35. The ester of the (S)-enantiomer according to embodiment 34, wherein the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

[0055] 36. An ester of the (S)-enantiomer according to embodiment 34 or 35, wherein the ester of the 11-D-(S)-enantiomer is a methyl ester of the 11-D-(S)-enantiomer, an ethyl ester of the 11-D-(S)-enantiomer, or another C1-C6 alkyl ester of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof.

[0056] 37. An amide of the (S)-enantiomer according to any one of embodiments 19-23, wherein the amide of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

[0057] 38. The amide of the (S)-enantiomer according to embodiment 37, wherein the amide of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

[0058] 39. An amide of the (S)-enantiomer according to embodiment 37 or 38, wherein the amide of the (S)-enantiomer is a simple amide or a C1-C6 alkyl amide optionally substituted with at least one hydroxyl group or a pharmaceutically acceptable salt of either.

[0059] 40. A pharmaceutically acceptable acid salt of the (S)-enantiomer or the 11-D-(S)-enantiomer according to any one of embodiments 1, 2 or 19-23, wherein the nitrogen atom in the side chain attached to carbon-11 (C-11) is 100% protonated, and the 100% protonated salt in solid or solution form is less sensitive to air oxidation than the (S)-enantiomer, the 11-D-(S)-enantiomer, the zwitterion of any of them or the sodium salt of any of them.

[0060] 41. A pharmaceutical composition comprising the (S)-enantiomer of tiannaphthol according to any one of embodiments 1-12, its zwitterion or a pharmaceutically acceptable salt of said (S)-enantiomer, or a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer according to any one of embodiments 13-15 or a pharmaceutically acceptable salt of said ester, or an amide of the (S)-enantiomer according to any one of embodiments 16-18 or a pharmaceutically acceptable salt of said amide, and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises ≤ about 2% of the (R)-enantiomer of tiannaphthol, its zwitterion or a pharmaceutically acceptable salt of said (R)-enantiomer, or a cocrystal of said (R)-enantiomer or its zwitterion, or an ester of said (R)-enantiomer or a pharmaceutically acceptable salt of said (R)-enantiomer, or an amide of said (R)-enantiomer or a pharmaceutically acceptable salt of said amide.

[0061] 42. The pharmaceutical composition of claim 41, wherein the pharmaceutical composition comprises ≤ about 0.1% of the (R)-enantiomer of tianapordine, its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer, or a eutectic of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt of the (R)-enantiomer, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt of the (R)-enantiomer.

[0062] 43. A pharmaceutical composition comprising the 11-D-(S)-enantiomer of tianapordine according to any one of embodiments 19-33, its zwitterion or a pharmaceutically acceptable salt of said 11-D-(S)-enantiomer, or a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer according to any one of embodiments 34-36 or a pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer according to any one of embodiments 37-39. The composition comprises ≤2% of the 11-D-(R)-enantiomer of tianapordine, its zwitterion or a pharmaceutically acceptable salt thereof, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

[0063] 44. The pharmaceutical composition according to embodiment 43, wherein the pharmaceutical composition comprises ≤ about 0.1% of the 11-D-(R)-enantiomer of tianapordine, its zwitterion or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer or an amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer.

[0064] 45. The pharmaceutical composition according to any one of embodiments 41-44, wherein the composition is in the form of tablets, films, powders, capsules, soft gels, suppositories, nasal sprays, oral sprays, or lung sprays.

[0065] 46. ​​The pharmaceutical composition according to any one of embodiments 41-45, wherein the composition is formulated for immediate, controlled, sustained, prolonged, or slow release of the (S)-enantiomer or the 11-D-(S)-enantiomer, or either of the zwitterion or ester or amide, or a pharmaceutically acceptable salt of either of the zwitterion, or a cocrystal of the (S)-enantiomer or the 11-D-(S)-enantiomer or either of the zwitterion.

[0066] 47. The pharmaceutical composition according to embodiment 46, wherein the composition is formulated for the controlled release of a cocrystallization of the (S)-enantiomer or the 11-D-(S)-enantiomer, or either of the zwitterion or ester or amide, or either of the pharmaceutically acceptable salts, or either of the (S)-enantiomer or the 11-D-(S)-enantiomer or either of the zwitterion.

[0067] 48. A pharmaceutical composition comprising a mixture of two or more pharmaceutically acceptable salts or cocrystals of the (S)-enantiomer or the 11-D-(S)-enantiomer according to any one of embodiments 41-47, wherein the mixture is characterized by enhanced prolonged release upon oral administration compared to administration of a composition comprising a single pharmaceutically acceptable salt or cocrystal of the (S)-enantiomer or the 11-D-(S)-enantiomer according to any one of embodiments 41-47.

[0068] 49. A method for treating diseases, disorders, or conditions and one or more associated symptoms of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ whose activity is modulated, exacerbated, or associated with them, comprising administering to a subject in need or at risk a therapeutically effective amount of any of the embodiments 1-18, a zwitterion thereof, or a pharmaceutically acceptable salt of said (S)-enantiomer, or a cocrystal of said (S)-enantiomer or its zwitterion, or an ester of said (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of said (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any of embodiments 41, 42, or 45-48.

[0069] 50. A method for treating diseases, disorders, or conditions and one or more associated symptoms of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ whose activity is modulated, exacerbated, or associated with them, comprising administering to a subject in need or at risk a therapeutically effective amount of any one of the following embodiments: 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of said 11-D-(S)-enantiomer, or a cocrystal of said 11-D-(S)-enantiomer or its zwitterion, or an ester of said 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of said (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 43-48.

[0070] 51. The method according to embodiment 49 or 50, wherein the disease, disorder or condition is selected from the group consisting of central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infectious diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopausal and chronic overlapping pain syndrome (COPC), and psychological, physiological, metabolic or hormonal stress and COPC.

[0071] 52. The method according to embodiment 51, wherein the disease, disorder or symptom is a CNS disorder.

[0072] 53. The method according to embodiment 52, wherein the CNS disorder is selected from the group consisting of mood disorders, trauma and stress-related disorders, anxiety disorders, obsessive-compulsive disorder, neurodegenerative or neuroinflammatory disorders, neurodevelopmental disorders, leukodystrophy, and CNS oxidative stress.

[0073] 54. The method according to implementation plan 53, wherein the mood disorder is a depressive disorder, bipolar disorder, or a substance-induced disorder.

[0074] 55. The method according to embodiment 54, wherein the depressive disorder is major depressive disorder (MDD).

[0075] 56. The method according to embodiment 53, wherein the trauma- and stress-related disorder is post-traumatic stress disorder (PTSD), acute stress disorder (ASD), adjustment disorder, or reactive attachment disorder.

[0076] 57. The method according to embodiment 53, wherein the anxiety disorder is panic disorder, generalized anxiety disorder (GAD), specific phobia, agoraphobia, or social phobia.

[0077] 58. The method according to embodiment 53, wherein the neurodegenerative or neuroinflammatory disorder is mild cognitive impairment, Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, neuromyelitis optica, myasthenia gravis, autoimmune encephalitis, prions, transverse myelitis, childhood autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), vanishing white matter disease, childhood ataxia with CNS myelination insufficiency, Kreutzfeldt-Jacob disease, Gerstmann-Straussler-Scharinkel disease, kuru disease, or dementia.

[0078] 59. The method according to embodiment 53, wherein the neurodevelopmental disorder is attention deficit hyperactivity disorder (ADHD), schizophrenia, Prad-Willi syndrome (including overeating and other symptoms such as depression and anxiety) or autism.

[0079] 60. The method according to embodiment 53, wherein the leukodystrophy is leukoencephalopathy, insufficient myelination or demyelinating disease, intellectual disability syndrome, cognitive impairment, glial cell dysfunction or brain injury.

[0080] 61. The method according to embodiment 60, wherein the cognitive impairment is age-related cognitive impairment, age-related cognitive decline (ARCD), age-related memory impairment (AAMI), cognitive impairment associated with mild cognitive impairment, prodromal Alzheimer's disease or Alzheimer's disease, prodromal frontotemporal dementia (FTD) or FTD, prodromal posterior cortical atrophy (PCA) or PCA, cognitive impairment associated with schizophrenia, drug-induced cognitive impairment, radiation-induced cognitive impairment, cognitive decline associated with space travel, or cognitive deficits and neuropathic pain associated with diabetes.

[0081] 62. The method of embodiment 60, wherein the drug-induced cognitive impairment is corticosteroid-induced cognitive impairment, doxorubicin-induced cognitive impairment, chemotherapy-induced cognitive impairment, alcohol-induced cognitive impairment, or substance-induced cognitive impairment.

[0082] 63. The method according to embodiment 60, wherein the brain injury is traumatic brain injury, hypoxia-induced brain injury, toxin-induced brain injury, or reperfusion injury following stroke or ischemic stroke.

[0083] 64. The method according to embodiment 51, wherein the inflammatory disease is asthma, postoperative cognitive impairment, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis.

[0084] 65. The method according to embodiment 51, wherein the autoimmune disease is achalasia, Addison's disease, adult-onset Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy. (AMAN), Barlow's disease, Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, Kassman's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Schulchström syndrome (CSS) or eosinophilic granuloma (EGPA), cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, Coxsackievirus myocarditis, CREST syndrome, Crohn's disease, herpetic dermatitis, dermatomyositis, Dervec disease (neuromyelitis optica), discoid lupus, Dressler's syndrome Eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, primary mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpassuia syndrome, granulomatous polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, and Henoch-Schonleinpurpura. Herpes gestationis (HSP), pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (acne paradox), hypogammaglobulinemia, IgA nephropathy, IgG4-associated sclerosis, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eton syndrome, leukocytic clotting vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer.ulcer), Muhammad-Haydner disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parsonage-Ross syndrome, ciliary body plaque inflammation (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, peripheral encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, type I polyglandular syndrome, type II polyglandular syndrome Polyglandular syndrome, Polyglandular syndrome type III, Polymyalgia rheumatica, Polymyositis, Post-myocardial infarction syndrome, Post-pericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosa, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjögren's syndrome, Sperm and testis autoimmunity, Stiff-person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome Sympathetic ophthalmitis (SO), hyperaorticitis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunter syndrome (THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, or Wechsler granulomatosis (or granulomatous polyangiitis (GPA)).

[0085] 66. The method according to embodiment 51, wherein the infectious disease is a viral infection or postviral disease.

[0086] 67. The method according to embodiment 51, wherein the hearing loss condition is mitochondrial nonsyndromic hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic / inherited hearing loss, hearing loss experienced due to ototoxic exposure, hearing loss caused by disease, or hearing loss caused by trauma.

[0087] 68. The method according to embodiment 51, wherein the eye disease is cataract, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy.

[0088] 69. The method according to embodiment 51, wherein the musculoskeletal disease is muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinal bulbar muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, painful spastic fasciculations, Friedrich's ataxia, muscle wasting disorder, inclusion body myopathy, motor neuron disease, or paralysis.

[0089] 70. The method according to embodiment 51, wherein the metabolic disease is non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes, phenylketonuria, proliferative retinopathy, and Karns-Sell disease.

[0090] 71. The method according to embodiment 51, wherein the mitochondrial disease is Bath syndrome, chronic progressive extraocular muscle palsy (cPEO), Karns-Sell syndrome (KSS), Leigh syndrome, mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with broken red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber hereditary optic neuropathy (LHON), and Pearson syndrome.

[0091] 72. The method according to embodiment 51, wherein the cancer is glioblastoma or glioma.

[0092] 73. A method for treating a subject who has experienced high stress, including diseases, disorders, or conditions and one or more related symptoms caused by or exacerbated by alterations in the activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, comprising administering to the subject a therapeutically effective amount of the (S)-enantiomer, zwitterion, or pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 41, 42, or 45-48.

[0093] 74. A method for treating a subject who has experienced high stress with a disease, disorder, or condition and one or more associated symptoms of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ whose activity is modulated, exacerbated, or associated therewith, is affected by or exacerbated by such alterations, comprising administering to the subject a therapeutically effective amount of any one of embodiments 19-39, a zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 43-48.

[0094] 75. The method according to implementation scheme 73 or 74, wherein the stress is caused by adversity in early life or by childhood trauma.

[0095] 76. A method for treating diseases, disorders, or conditions and one or more associated symptoms caused by altered activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, which are exacerbated or associated with them, while reducing µ-opioid receptor agonism associated with treatment with racemic tianapordine, the method comprising administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 41, 42, or 45-48.

[0096] 77. A method for treating diseases, disorders, or conditions and one or more associated symptoms caused by altered activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, which are exacerbated or associated with them, while reducing µ-opioid receptor agonism associated with treatment with racemic tianapordine, the method comprising administering to a subject in need or at risk a therapeutically effective amount of any one of the following embodiments: 11-D-(S)-enantiomer or a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 43-48.

[0097] 78. The method according to any one of embodiments 49-77 or 104-124, wherein the (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the (S)-enantiomer, a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or the pharmaceutical composition thereof, is administered once or more daily.

[0098] 79. The method according to embodiment 78, wherein the (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the (S)-enantiomer, a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or the pharmaceutical composition thereof, is administered once daily.

[0099] 80. The method according to any one of embodiments 49-77 or 104-124, wherein the (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the (S)-enantiomer, a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the (S)-enantiomer, is administered parenterally, or orally, sublingually, sublingually, by inhalation, palatally, transdermally, rectally, or vaginally. The 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

[0100] 81. The method according to embodiment 80, wherein the (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the (S)-enantiomer, a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or the pharmaceutical composition is administered orally.

[0101] 82. The method according to embodiment 80, wherein the (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the (S)-enantiomer, a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or the pharmaceutical composition is administered by inhalation.

[0102] 83. The method according to any one of embodiments 49-82 or 104-124, wherein the (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the (S)-enantiomer, a eutectic of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, ... The 11-D-(S)-enantiomer or a zwitterion thereof, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition administered sequentially or concurrently with one or more other therapeutic agents selected from the group consisting of: antidepressants, anticonvulsants, anxiolytics, antipsychotics, cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, 5HT2 modulators, corticosteroids, antiamyloid agents, anti-tau agents, and chemotherapeutic agents.

[0103] 84. The method according to any one of embodiments 49-82 or 104-124, wherein the (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the (S)-enantiomer, a eutectic of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or the pharmaceutical composition is administered as part of a treatment regimen that also includes a psychotherapeutic intervention.

[0104] 85. A method for reducing the potential racemization of the (S)-enantiomer, its zwitterion, a pharmaceutically acceptable salt of the (S)-enantiomer, a eutectic of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, according to any one of embodiments 1-19, comprising the step of deuterating the (S)-enantiomer, its zwitterion, a pharmaceutically acceptable salt of the (S)-enantiomer, a eutectic of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt at the C-11 position.

[0105] 86. A method for preparing the (S)-enantiomer of thiazoline according to embodiment 1 or 2, the method comprising the following steps:

[0106] (i) A racemic mixture or other mixture of the (S)- and (R)-enantiomers of a chiral amine thianaptine intermediate is resolved by enantioselective crystallization in a solvent mixture using a conformational isomer selective to the (S)-enantiomer, the mixture being characterized by ≥0.1% of the (R)-enantiomer of the chiral amine thianaptine intermediate to produce (S)-amine thianaptine intermediate:(S)-enantiomer selective conformational isomer, the (S)-amine thianaptine intermediate:(S)-enantiomer selective conformational isomer crystallizing from the solvent mixture, and characterized in that it comprises ≤2% of the (R)-amine thianaptine intermediate:(R)-enantiomer selective conformational isomer;

[0107] (ii) Reacting the (S)-amine thiaponectin intermediate: (S)-enantiomer selective conformation isomer with alkyl 7-bromoheptanoate to produce the (S)-thiaponectin alkyl ester intermediate: (S)-enantiomer selective conformation isomer;

[0108] (iii) Reacting the (S)-thiazoprine alkyl ester intermediate: the (S)-enantiomer-selective conformational isomer with a base to produce the (S)-thiazoprine alkyl ester intermediate; and

[0109] (iv) Saponify the (S)-thiaponectin alkyl ester intermediate to produce the (S)-enantiomer of thiaponectin, which contains ≤2% of the (R) enantiomer of thiaponectin.

[0110] 87. The method according to embodiment 86, wherein the (S)-enantiomer of tiannaphthol is characterized by ≤0.1% of the (R)-enantiomer of tiannaphthol.

[0111] 88. The method according to embodiment 86, wherein the chiral amine thiazoprine intermediate is 3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][1,2]benzothiazazon-11-amine, and the (S)-amine thiazoprine intermediate: the (S)-enantiomer selective conformational isomer is (11S)-3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][1,2] ... ] Benzothiaza-11-amine: (S)-enantiomer selective conformation isomer, and the (S)-thiazoprine ester intermediate: (S)-enantiomer selective conformation isomer is 7-[[(11S)-3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][1,2]benzothiaza-11-yl]amino]heptanate ethyl ester: (S)-enantiomer selective conformation isomer.

[0112] 89. A method for preparing 11-D-(S)-thiazopridine according to embodiment 19 or 20, the method comprising the following steps:

[0113] (i) A racemic mixture or other mixture of the (S)- and (R)-enantiomers of the chiral amine 11-D-thianaptine intermediate is resolved by enantioselective crystallization of the (S)-enantiomer in a solvent mixture, the mixture being characterized by ≥0.1% of the (R)-enantiomer of the chiral amine 11-D-thianaptine intermediate to produce the (S)-amine 11-D-thianaptine intermediate:(S)-enantiomer selective conformational isomer, the (S)-amine 11-D-thianaptine intermediate:(S)-enantiomer selective conformational isomer crystallizing from the solvent mixture, and characterized in that it comprises ≤2% of the (R)-amine 11-D-thianaptine intermediate:(R)-enantiomer selective conformational isomer;

[0114] (ii) Reacting the (S)-amine 11-D-thiaponectin intermediate: (S)-enantiomer selective conformation isomer with alkyl 7-bromoheptanoate to produce 11-D-(S)-thiaponectin alkyl ester intermediate: (S)-enantiomer selective conformation isomer;

[0115] (iii) Reacting the 11-D-(S)-thiazoprine alkyl ester intermediate: the (S)-enantiomer-selective conformational isomer with a base to produce the 11-D-(S)-thiazoprine alkyl ester intermediate; and

[0116] (iv) Saponify the 11-D-(S)-thiaponectin alkyl ester intermediate to produce the 11-D-(S)-enantiomer of thiaponectin, which comprises ≤2% of the (R) enantiomer of 11-D-thiaponectin.

[0117] 90. The method according to embodiment 89, wherein the (S)-enantiomer of 11-D-tianaphthol is characterized by ≤0.1% of the (R)-enantiomer of 11-D-tianaphthol.

[0118] 91. The method according to embodiment 89, wherein the chiral amine 11-D-thianaptine intermediate is 11-amino-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazaza 5,5-dioxide 11-d, and the (S)-amine 11-D-thianaptine intermediate: the (S)-enantiomer selective conformational isomer is (S)-11-amino-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiaza 5,5-dioxide 11-d. 2] Thiazido-5,5-dioxide-11-d:(S)-enantiomer selective conformation isomer, and the 11-D-(S)-thiazolinone alkyl ester intermediate:(S)-enantiomer selective conformation isomer is (S)-7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazo-11-yl-11-d)amino)heptaate ethyl ester:(S)-enantiomer selective conformation isomer.

[0119] 92. A method for preparing the (S)-enantiomer of thiazoline according to embodiment 1 or 2, or its zwitterion, the method comprising the following steps:

[0120] (i) A racemic mixture or other mixture of (S)- and (R)-enantiomers of thiazoline alkyl esters is separated by enantioselective crystallization in a solvent mixture using a conformational isomer selective for (R)-enantiomers, the mixture being characterized by ≥0.1% of the (R)-enantiomer of thiazoline alkyl esters to produce (R)-thiazoline alkyl ester:(R)-enantiomer selective conformational isomer and (S)-thiazoline alkyl ester:(R)-enantiomer selective conformational isomer, causing the (R)-thiazoline alkyl ester to crystallize and separate from the solvent mixture, the (S)-thiazoline alkyl ester remaining in the solvent mixture and characterized in that it comprises ≤2% of the (R)-thiazoline alkyl ester;

[0121] (ii) Hydrolyzing the (S)-thiazoliptin alkyl ester:(R)-enantiomer selective conformation isomer with a strong acid to produce a (S)-thiazoliptin acid salt comprising ≤2% (R)-thiazoliptin acid salt; and

[0122] (iii) Neutralize the (S)-thiazoprine acid salt with a base to produce a zwitterion of the (S)-enantiomer of thiazoprine.

[0123] 93. A method for preparing the 11-D-(S)-enantiomer or zwitterion according to embodiment 19 or 20, the method comprising the following steps:

[0124] (i) A racemic mixture or other mixture of (S)- and (R)-enantiomers of 11-D-thianaphthyl alkyl ester is separated by enantioselective crystallization in a solvent mixture using a conformational isomer selective for (R)-enantiomers, the mixture being characterized by ≥0.1% of the (R)-enantiomer of 11-D-thianaphthyl alkyl ester to produce 11-D-(R)-thianaphthyl alkyl ester:(R)-enantiomer selective conformational isomer and 11-D-(S)-thianaphthyl alkyl ester:(R)-enantiomer selective conformational isomer, causing the 11-D-(R)-thianaphthyl alkyl ester to crystallize and separate from the solvent mixture, the 11-D-(S)-thianaphthyl alkyl ester remaining in the solvent mixture and characterized in that it comprises ≤2% of the 11-D-(R)-thianaphthyl alkyl ester;

[0125] (ii) Hydrolyzing the 11-D-(S)-thianaptine alkyl ester:(R)-enantiomer-selective conformational isomer with a strong acid to produce a 11-D-(S)-thianaptine acid salt comprising ≤2% of 11-D-(R)-thianaptine acid salt; and

[0126] (iii) Neutralize the 11-D-(S)-thiaponectin acid salt with a base to produce a zwitterion of the 11-D-(S)-enantiomer of thiaponectin.

[0127] 94. The method according to any one of embodiments 86, 89, 92 or 93, wherein the thiazoprine alkyl ester is a methyl ester, an ethyl ester or any other C1-C6 alkyl ester.

[0128] 95. The method according to any one of embodiments 86, 89, 92 or 93, wherein the enantioselective crystallization comprises using a conformational isomer selected from the group consisting of: L-dibenzoyl tartaric acid (DBTA), D-DBTA, di-o-toluyl-L-tartaric acid (LD(2-Me)BTA), DD(2-Me)BTA, other DBTA derivatives, (S)-1,1′-bi-2-naphthalene Phenol-2,2′-dimethylhydrogen phosphate, (R)-1,1′-bi-2-naphthol-2,2′-dimethylhydrogen phosphate, (S)-(R)-mandelic acid, (R)-(S)-mandelic acid, (S)-(S)-α-methoxy-α-trifluoromethylphenylacetic acid, (R)-(S)-α-methoxy-α-trifluoromethylphenylacetic acid, (1S)-(R)-10-camphorsulfonic acid and (1R)-(R)-10-camphorsulfonic acid.

[0129] 96. The method according to any one of embodiments 86, 89, 92 or 93, wherein the solvent comprises a mixture of benzene, acetone and chloroform.

[0130] 97. The method according to embodiment 96, wherein the solvent comprises benzene, acetone and chloroform in a ratio of 2:1:1.

[0131] 98. The method according to any one of embodiments 86, 89, 92 or 93, wherein the enantioselective crystallization of the (S)-amine thiaponectin intermediate: (S)-enantiomer selective conformational isomer, the (S)-amine 11-D-thiaponectin intermediate: (S)-enantiomer selective conformational isomer, the (R)-thiaponectin alkyl ester: (R)-enantiomer selective conformational isomer or the 11-D-(R)-thiaponectin alkyl ester: (R)-enantiomer selective conformational isomer comprises the step of slowly evaporating the solvent mixture.

[0132] 99. The method according to any one of embodiments 86, 89, 92 or 93, wherein the enantioselective crystallization is repeated to improve the enantiomeric or chiral purity of the separated (S)-amine thiazoprine intermediate, (S)-amine 11-D-thiazoprine intermediate, (S)-thiazoprine methyl ester or 11-D-(S)-thiazoprine methyl ester.

[0133] 100. The method according to embodiment 92 or 93, wherein the strong acid is selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid.

[0134] 101. The method according to any one of embodiments 86, 89, 92 or 93, wherein the base is sodium bicarbonate, sodium carbonate, potassium bicarbonate or sodium hydroxide.

[0135] 102. The method according to any one of embodiments 86, 89, 92 or 93, wherein the separation of the racemic mixture or other mixture is performed using high performance liquid chromatography (HPLC).

[0136] 103. The method according to any one of embodiments 86, 89, 92 or 93, wherein the separation of the racemic mixture or other mixture is performed using supercritical fluid chromatography with a chiral column.

[0137] 104. A method for treating a disease, disorder, or condition selected from the group consisting of central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infectious diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopausal and chronic overlapping pain syndrome (COPC), and psychological, physiological, metabolic, or hormonal stress and COPC, the method comprising administering to a subject in need or at risk a therapeutically effective amount of any one of embodiments 1-18, or a eutectic of said (S)-enantiomer or its zwitterion, or an ester of said (S)-enantiomer or its pharmaceutically acceptable form. The subject may receive a therapeutically effective amount of the 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or a pharmaceutically acceptable composition according to any one of embodiments 43-48.

[0138] 105. The method according to embodiment 104, wherein the CNS disorder is selected from the group consisting of mood disorders, trauma and stress-related disorders, anxiety disorders, obsessive-compulsive disorder, neurodegenerative or neuroinflammatory disorders, neurodevelopmental disorders, leukodystrophy, and CNS oxidative stress.

[0139] 106. The method according to embodiment 105, wherein the mood disorder is a depressive disorder, bipolar disorder, or a substance-induced disorder.

[0140] 107. The method according to embodiment 106, wherein the depressive disorder is major depressive disorder (MDD).

[0141] 108. The method according to embodiment 105, wherein the trauma- and stress-related disorder is post-traumatic stress disorder (PTSD), acute stress disorder (ASD), adjustment disorder, or reactive attachment disorder.

[0142] 109. The method according to embodiment 105, wherein the anxiety disorder is panic disorder, generalized anxiety disorder (GAD), specific phobia, agoraphobia, or social phobia.

[0143] 110. The method according to embodiment 105, wherein the neurodegenerative or neuroinflammatory disorder is mild cognitive impairment, Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, neuromyelitis optica, myasthenia gravis, autoimmune encephalitis, prions, transverse myelitis, childhood autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), vanishing leukoencephalopathy, childhood ataxia with CNS myelination insufficiency, Kreutzfeldt-Jacob disease, Gerstmann-Straussler-Scharinkel disease, kuru disease, or dementia.

[0144] 111. The method according to embodiment 105, wherein the neurodevelopmental disorder is attention deficit hyperactivity disorder (ADHD), schizophrenia, Prad-Willi syndrome (including overeating and other symptoms such as depression and anxiety) or autism.

[0145] 112. The method according to implementation plan 105, wherein the leukodystrophy is leukoencephalopathy, insufficient myelination or demyelinating disease, intellectual disability syndrome, cognitive impairment, glial cell dysfunction or brain injury.

[0146] 113. The method according to embodiment 112, wherein the cognitive impairment is age-related cognitive impairment, age-related cognitive decline (ARCD), age-related memory impairment (AAMI), cognitive impairment associated with mild cognitive impairment, prodromal Alzheimer's disease or Alzheimer's disease, prodromal frontotemporal dementia (FTD) or FTD, prodromal posterior cortical atrophy (PCA) or PCA, cognitive impairment associated with schizophrenia, drug-induced cognitive impairment, radiation-induced cognitive impairment, cognitive decline associated with space travel, or cognitive deficits and neuropathic pain associated with diabetes.

[0147] 114. The method as described in embodiment 113, wherein the drug-induced cognitive impairment is corticosteroid-induced cognitive impairment, doxorubicin-induced cognitive impairment, chemotherapy-induced cognitive impairment, alcohol-induced cognitive impairment, or substance-induced cognitive impairment.

[0148] 115. The method according to embodiment 112, wherein the brain injury is traumatic brain injury, hypoxia-induced brain injury, toxin-induced brain injury, or reperfusion injury following stroke or ischemic stroke.

[0149] 116. The method according to embodiment 104, wherein the inflammatory disease is asthma, postoperative cognitive impairment, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis.

[0150] 117. The method according to embodiment 104, wherein the autoimmune disease is achalasia, Addison's disease, adult-onset Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, or other autoimmune diseases. Immune urticaria, axononeuropathy (AMAN), Barlow's disease, Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, Kassman's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Schulchström syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, Coxsackievirus myocarditis, CREST syndrome, Crohn's disease, herpetic dermatitis, dermatomyositis, Dermoid disease (optic nerve) (e.g., myelitis), discoid lupus, Desleser syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, primary mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpassuu syndrome, granulomatous polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, allergic purpura (HSP), herpes gestationis or pemphigoid of pregnancy (PG), hidradenitis suppurativa (HS) (acne paradox), low gamma glomerulonephritis Globulinemia, IgA nephropathy, IgG4-associated sclerotic disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eton syndrome, leukocytic clotting vasculitis, lichen planus, sclerosing lichen, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer.ulcer), Muhammad-Haydner disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parsonage-Ross syndrome, paroxysmal uveitis, Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, peripheral encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, jaundice Ketoacidosis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrene, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testis autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Sussac syndrome, sympathetic ophthalmia (SO), high-stress arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunter syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, or Wechsler granulomatosis (or granulomatous polyangiitis (GPA)).

[0151] 118. The method according to embodiment 104, wherein the infectious disease is a viral infection or postviral disease.

[0152] 119. The method according to embodiment 104, wherein the hearing loss condition is mitochondrial nonsyndromic hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic / inherited hearing loss, hearing loss experienced due to ototoxic exposure, hearing loss caused by disease, or hearing loss caused by trauma.

[0153] 120. The method according to embodiment 104, wherein the eye disease is cataract, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy.

[0154] 121. The method according to embodiment 104, wherein the musculoskeletal disease is muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinal bulbar muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, painful spastic fasciculations, Friedreich ataxia, muscle wasting disorder, inclusion body myopathy, motor neuron disease, or paralysis.

[0155] 122. The method according to embodiment 104, wherein the metabolic disease is non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes, phenylketonuria, proliferative retinopathy, and Karns-Sell disease.

[0156] 123. The method according to embodiment 104, wherein the mitochondrial disease is Bath syndrome, chronic progressive extraocular muscle palsy (cPEO), Karns-Sell syndrome (KSS), Leigh syndrome, mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with broken red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber hereditary optic neuropathy (LHON), and Pearson syndrome.

[0157] 124. The method according to embodiment 104, wherein the cancer is glioblastoma or glioma.

[0158] 125. A method for enhancing neurite growth, comprising administering to a subject in need a (S)-enantiomer according to any one of embodiments 1-18, or a cocrystal of said (S)-enantiomer or its zwitterion, or an ester of said (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of said (S)-enantiomer or its pharmaceutically acceptable salt, or a pharmaceutical composition according to any one of embodiments 41, 42 or 45-48, or administering to said subject a therapeutically effective... The amount of the 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 43-48.

[0159] 126. The method according to embodiment 125, wherein the neurite growth is observed in glutamatergic neurons.

[0160] 127. A method for treating a disease, disorder, or condition regulated, aggravated, or associated with an excessive level of metal ions in circulation, comprising administering to a subject in need or at risk a therapeutically effective amount of any one of embodiments 1-18, or a eutectic of said (S)-enantiomer or its zwitterion, or an ester of said (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of said (S)-enantiomer or a pharmaceutically acceptable salt thereof, or any one of embodiments 41, 42, or 45-48. The pharmaceutical composition, or administered to the subject a therapeutically effective amount of any one of embodiments 19-39, the zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of embodiments 43-48.

[0161] 128. The method according to claim 127, wherein the metal ion is iron or copper.

[0162] 129. The method according to embodiment 127 or 128, wherein the disease, disorder or condition is selected from the group consisting of central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infectious diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopausal and chronic overlapping pain conditions (COPC), and psychological, physiological, metabolic or hormonal stress and COPC.

[0163] 130. The method according to embodiment 129, wherein the CNS disorder is selected from the group consisting of mood disorders, trauma and stress-related disorders, anxiety disorders, obsessive-compulsive disorder, neurodegenerative or neuroinflammatory disorders, neurodevelopmental disorders, leukodystrophy, and CNS oxidative stress.

[0164] 131. A method for reducing violence or aggression associated with CNS disorders, comprising administering to a subject in need or at risk a therapeutically effective amount of any of embodiments 1-18, or a cocrystal of said (S)-enantiomer or its zwitterion, or an ester of said (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of said (S)-enantiomer or its pharmaceutically acceptable salt, or a pharmaceutical composition according to any of embodiments 41, 42 or 45-48, or to a subject who requires or is at risk of such behavior, a therapeutically effective amount of a ... a pharmaceutical composition according to any of embodiments 41, 42 or 45-48, or a pharmaceutical composition according to any of embodiments 41, 42 or 45-48, or a pharmaceutical composition according to any of embodiments 41, 42 or 45-48, or a pharmaceutical composition according to any of embodiments 41, 42 or 45-48, or a pharmaceutical composition according to any of embodiments 41, 42 or 45-48, or a pharmaceutical composition according to any of embodiments 41, 42 or 45- The subject is given a therapeutically effective amount of any one of the embodiments 19-39, the zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 43-48.

[0165] 132. A method for reducing the likelihood of admission to a psychiatric hospital or incarceration due to behaviors or actions associated with CNS disorders, comprising administering to a subject in need or at risk a therapeutically effective amount of any one of embodiments 1-18, or a eutectic of said (S)-enantiomer or its zwitterion, or an ester of said (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of said (S)-enantiomer or a pharmaceutically acceptable salt thereof, or any one of embodiments 41, 42, or 45-48. The pharmaceutical composition, or administered to the subject a therapeutically effective amount of any one of embodiments 19-39, the zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of embodiments 43-48.

[0166] 133. A method for treating a disease, disorder, or condition regulated, exacerbated, or associated with high levels of S-nitrosylation of PPAR-β / δ and / or PPAR-γ, comprising administering to a subject in need or at risk a therapeutically effective amount of any one of embodiments 1-18, or a cocrystal of said (S)-enantiomer or its zwitterion, or an ester of said (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of said (S)-enantiomer or a pharmaceutically acceptable salt thereof, or according to embodiments 41, 42, or 45- The pharmaceutical composition of any one of embodiments 48, or administered to the subject a therapeutically effective amount of any one of embodiments 19-39, the zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of embodiments 43-48.

[0167] 134. The method according to embodiment 133, wherein the disease, disorder or condition is selected from the group consisting of central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infectious diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopausal and chronic overlapping pain conditions (COPC), and psychological, physiological, metabolic or hormonal stress and COPC.

[0168] 135. The method according to embodiment 134, wherein the CNS disorder is selected from the group consisting of mood disorders, trauma and stress-related disorders, anxiety disorders, obsessive-compulsive disorder, neurodegenerative or neuroinflammatory disorders, neurodevelopmental disorders, leukodystrophy, and CNS oxidative stress.

[0169] 136. N-hydroxy-tiaponectin of formula (XV) or a pharmaceutically acceptable salt thereof:

[0170]

[0171] Formula (XV).

[0172] 137. The (S)-enantiomer of N-hydroxy-tianapril of formula (XVI) (N-hydroxy-(S)-tianapril) or a pharmaceutically acceptable salt thereof, wherein the (S)-enantiomer of N-hydroxy-tianapril or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the (R)-enantiomer of N-hydroxy-tianapril or a pharmaceutically acceptable salt thereof:

[0173]

[0174] Formula (XVI).

[0175] 138. The (S)-enantiomer of N-hydroxy-tianaphthol according to embodiment 137, wherein the (S)-enantiomer or a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxy-tianaphthol is characterized by comprising ≤ about 0.1% of the (R)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of the enantiomer.

[0176] 139. The (R)-enantiomer of N-hydroxy-(R)-tiaponectin of formula (XVII) (N-hydroxy-(R)-tiaponectin) or a pharmaceutically acceptable salt thereof, wherein the (R)-enantiomer of N-hydroxy-tiaponectin or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the (S)-enantiomer of N-hydroxy-tiaponectin or a pharmaceutically acceptable salt thereof:

[0177]

[0178] Formula (XVII).

[0179] 140. The (R)-enantiomer of N-hydroxy-tianaphthol according to embodiment 139, wherein the (R)-enantiomer or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy-tianaphthol is characterized by comprising ≤ about 0.1% of the (S)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of the enantiomer.

[0180] 141. N-nitroso-thiaponectin of formula (XVIII) or a pharmaceutically acceptable salt thereof:

[0181]

[0182] Formula (XVIII).

[0183] 142. The (S)-enantiomer of N-nitroso-tianapril of formula (XIX) (N-nitroso-(S)-tianapril) or a pharmaceutically acceptable salt thereof, wherein the (S)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the (R)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof:

[0184]

[0185] Formula (XIX).

[0186] 143. The (S)-enantiomer of N-nitroso-tianaphthol according to embodiment 142, wherein the (S)-enantiomer or a pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-tianaphthol is characterized by comprising ≤ about 0.1% of the (R)-enantiomer of N-nitroso-tianaphthol or a pharmaceutically acceptable salt of the enantiomer.

[0187] 144. The (R)-enantiomer of N-nitroso-tianapril of formula (XX) (N-nitroso-(R)-tianapril) or a pharmaceutically acceptable salt thereof, wherein the (R)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the (S)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof:

[0188]

[0189] Formula (XX).

[0190] 145. The (R)-enantiomer of N-nitroso-tianaphthol according to embodiment 144, wherein the (R)-enantiomer or a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso-tianaphthol is characterized by comprising ≤ about 0.1% of the (S)-enantiomer of N-nitroso-tianaphthol or a pharmaceutically acceptable salt of the enantiomer.

[0191] 146. An aryl-substituted thiazoprine analogue or a pharmaceutically acceptable salt thereof.

[0192] 147. The aryl-substituted thiazoprine analog according to embodiment 146, wherein the aryl-substituted thiazoprine derivative is 7-((3-(furan-2-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-yl)amino)heptanoic acid of formula (XXI) or 7-((3-(furan-3-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-yl)amino)heptanoic acid of formula (XXII). 2] Thiazido-11-yl)amino)heptanoic acid, 7-((6-methyl-5,5-dioxy-3-(thiophen-3-yl)-6,11-dihydrodibenzo[c,f][1,2]thazido-11-yl)amino)heptanoic acid of formula (XXIII) or 2-(4-(((3-chloro-6-methyl-5,5-dioxy-6,11-dihydrodibenzo[c,f][1,2]thazido-11-yl)amino)methyl)-2-methylphenoxy)acetic acid of formula (XXIV).

[0193]

[0194]

[0195] 148. A pharmaceutical composition comprising N-hydroxy-tiaponectin or a pharmaceutically acceptable salt thereof according to embodiment 136, or N-nitroso-tiaponectin or a pharmaceutically acceptable salt thereof according to embodiment 141, or an aryl-substituted tiaponectin analogue or a pharmaceutically acceptable salt thereof according to embodiment 146 or 147, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0196] 149. A pharmaceutical composition comprising the (S)-enantiomer of N-hydroxy-tianaphthol according to embodiment 137 or 138, or the (S)-enantiomer of N-nitroso-tianaphthol according to embodiment 142 or 143, or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises ≤ about 2% or ≤ about 0.1% of the (R)-enantiomer of N-hydroxy-tianaphthol or the (R)-enantiomer of N-hydroxy-tianaphthol or the pharmaceutically acceptable salt thereof.

[0197] 150. A pharmaceutical composition comprising the (R)-enantiomer of N-hydroxy-tiaponectin according to embodiment 139 or 140, or the (R)-enantiomer of N-nitroso-tiaponectin according to embodiment 144 or 145, or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises ≤ about 2% or ≤ about 0.1% of the (S)-enantiomer of N-hydroxy-tiaponectin or the (S)-enantiomer of N-hydroxy-tiaponectin or the pharmaceutically acceptable salt thereof.

[0198] 151. The pharmaceutical composition according to any one of embodiments 148-150, wherein the composition is in the form of tablets, films, powders, capsules, soft gels, suppositories, nasal sprays, oral sprays, or lung sprays.

[0199] 152. The pharmaceutical composition according to any one of embodiments 148-150, wherein the composition is formulated for the immediate release, controlled release, sustained release, prolonged release, or slow release of N-hydroxy-tiaponectin, the (S)-enantiomer of N-hydroxy-tiaponectin, the (R)-enantiomer of N-hydroxy-tiaponectin, N-nitroso-tiaponectin, the (S)-enantiomer of N-nitroso-tiaponectin, the (R)-enantiomer of N-nitroso-tiaponectin, or an aryl-substituted tiaponectin analog or a pharmaceutically acceptable salt thereof.

[0200] 153. A method for treating diseases, disorders, or conditions and one or more associated symptoms caused by altered activity regulation of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, exacerbated by or associated with such alterations, comprising administering to a subject in need or at risk a therapeutically effective amount of N-hydroxy-tiaponectin, the (S)-enantiomer of N-hydroxy-tiaponectin, or the (R)-enantiomer of N-hydroxy-tiaponectin according to any one of embodiments 136-140. Or a pharmaceutically acceptable salt of any of them, or N-nitroso-tiaponectin, the (S)-enantiomer of N-nitroso-tiaponectin, or the (R)-enantiomer of N-nitroso-tiaponectin, or a pharmaceutically acceptable salt of any of them, or an aryl-substituted tiaponectin analogue or a pharmaceutically acceptable salt thereof as described in embodiments 146 or 147, or a pharmaceutical composition as described in any of embodiments 148-152.

[0201] 154. The method according to embodiment 153, wherein the disease, disorder or condition is selected from the group consisting of central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infectious diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopausal and chronic overlapping pain conditions (COPC), and psychological, physiological, metabolic or hormonal stress and COPC.

[0202] 155. The method according to embodiment 154, wherein the CNS disorder is selected from the group consisting of mood disorders, trauma and stress-related disorders, anxiety disorders, obsessive-compulsive disorder, neurodegenerative or neuroinflammatory disorders, neurodevelopmental disorders, leukodystrophy, and CNS oxidative stress.

[0203] 156. The method according to implementation plan 155, wherein the mood disorder is a depressive disorder, bipolar disorder, or a substance-induced disorder.

[0204] 157. The method according to embodiment 156, wherein the depressive disorder is major depressive disorder (MDD).

[0205] 158. The method according to embodiment 155, wherein the trauma- and stress-related disorder is post-traumatic stress disorder (PTSD), acute stress disorder (ASD), adjustment disorder, or reactive attachment disorder.

[0206] 159. The method according to embodiment 155, wherein the anxiety disorder is panic disorder, generalized anxiety disorder (GAD), specific phobia, agoraphobia, or social phobia.

[0207] 160. The method according to embodiment 155, wherein the neurodegenerative or neuroinflammatory disorder is mild cognitive impairment, Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, neuromyelitis optica, myasthenia gravis, autoimmune encephalitis, prions, transverse myelitis, childhood autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), vanishing leukoencephalopathy, childhood ataxia with CNS myelination insufficiency, Kreutzfeld-Jacob disease, Gerstmann-Straussler-Scharinkel disease, kuru disease, or dementia.

[0208] 161. The method according to embodiment 155, wherein the neurodevelopmental disorder is attention deficit hyperactivity disorder (ADHD), schizophrenia, Prad-Willi syndrome (including overeating and other symptoms such as depression and anxiety) or autism.

[0209] 162. The method according to embodiment 155, wherein the leukodystrophy is leukoencephalopathy, insufficient myelination or demyelinating disease, intellectual disability syndrome, cognitive impairment, glial cell dysfunction or brain injury.

[0210] 163. The method according to embodiment 162, wherein the cognitive impairment is age-related cognitive impairment, age-related cognitive decline (ARCD), age-related memory impairment (AAMI), cognitive impairment associated with mild cognitive impairment, prodromal Alzheimer's disease or Alzheimer's disease, prodromal frontotemporal dementia (FTD) or FTD, prodromal posterior cortical atrophy (PCA) or PCA, cognitive impairment associated with schizophrenia, drug-induced cognitive impairment, radiation-induced cognitive impairment, cognitive decline associated with space travel, or cognitive deficits and neuropathic pain associated with diabetes.

[0211] 164. The method as described in embodiment 163, wherein the drug-induced cognitive impairment is corticosteroid-induced cognitive impairment, doxorubicin-induced cognitive impairment, chemotherapy-induced cognitive impairment, alcohol-induced cognitive impairment, or substance-induced cognitive impairment.

[0212] 165. The method according to embodiment 162, wherein the brain injury is traumatic brain injury, hypoxia-induced brain injury, toxin-induced brain injury, or reperfusion injury following stroke or ischemic stroke.

[0213] 166. The method according to embodiment 154, wherein the inflammatory disease is asthma, postoperative cognitive impairment, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis.

[0214] 167. The method according to embodiment 154, wherein the autoimmune disease is achalasia, Addison's disease, adult-onset Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, or other autoimmune diseases. Immune urticaria, axononeuropathy (AMAN), Barlow's disease, Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, Kassman's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Schulchström syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, Coxsackievirus myocarditis, CREST syndrome, Crohn's disease, herpetic dermatitis, dermatomyositis, Dermoid disease (optic nerve) (e.g., myelitis), discoid lupus, Desleser syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, primary mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpassuu syndrome, granulomatous polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, allergic purpura (HSP), herpes gestationis or pemphigoid of pregnancy (PG), hidradenitis suppurativa (HS) (acne paradox), low gamma glomerulonephritis Globulinemia, IgA nephropathy, IgG4-associated sclerotic disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eton syndrome, leukocytic clotting vasculitis, lichen planus, sclerosing lichen, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer.ulcer), Muhammad-Haydner disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parsonage-Ross syndrome, paroxysmal uveitis, Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, peripheral encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, jaundice Ketoacidosis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrene, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testis autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Sussac syndrome, sympathetic ophthalmia (SO), high-stress arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunter syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, or Wechsler granulomatosis (or granulomatous polyangiitis (GPA)).

[0215] 168. The method according to embodiment 154, wherein the infectious disease is a viral infection or postviral disease.

[0216] 169. The method according to embodiment 154, wherein the hearing loss condition is mitochondrial nonsyndromic hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic / inherited hearing loss, hearing loss experienced due to ototoxic exposure, hearing loss caused by disease, or hearing loss caused by trauma.

[0217] 170. The method according to embodiment 154, wherein the eye disease is cataract, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy.

[0218] 171. The method according to embodiment 154, wherein the musculoskeletal disease is muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinal bulbar muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, painful spastic fasciculations, Friedreich ataxia, muscle wasting disorder, inclusion body myopathy, motor neuron disease, or paralysis.

[0219] 172. The method according to embodiment 154, wherein the metabolic disease is non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes, phenylketonuria, proliferative retinopathy, and Karns-Sell disease.

[0220] 173. The method according to embodiment 154, wherein the mitochondrial disease is Bath syndrome, chronic progressive extraocular muscle palsy (cPEO), Karns-Sell syndrome (KSS), Leigh syndrome, mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with broken red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber hereditary optic neuropathy (LHON), and Pearson syndrome.

[0221] 174. The method according to embodiment 154, wherein the cancer is glioblastoma or glioma.

[0222] 175. A method for treating a subject experiencing high stress with a disease, disorder, or condition and one or more associated symptoms of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ whose activity is modulated, exacerbated, or associated therewith, is affected by or exacerbated by such alterations, comprising administering to the subject a therapeutically effective amount of N-hydroxy-tiaponectin, the (S)-enantiomer of N-hydroxy-tiaponectin, or the (R)-enantiomer of N-hydroxy-tiaponectin according to any one of embodiments 136-140. The composition, or a pharmaceutically acceptable salt thereof, or N-nitroso-tiaponectin, the (S)-enantiomer of N-nitroso-tiaponectin, or the (R)-enantiomer of N-nitroso-tiaponectin, or a pharmaceutically acceptable salt thereof, or an aryl-substituted tiaponectin analogue or a pharmaceutically acceptable salt thereof, as described in embodiments 146 or 147, or a pharmaceutical composition, as described in any one of embodiments 148-152.

[0223] 176. The method according to embodiment 175, wherein the stress is caused by adversity in early life or by childhood trauma.

[0224] 177. A method for treating diseases, disorders, or conditions and one or more associated symptoms caused by altered activity regulation of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, exacerbated by or associated with such diseases, disorders, or conditions, while reducing µ-opioid receptor agonism associated with treatment with racemic tiannaphthol, said method comprising administering to a subject in need or at risk a therapeutically effective amount of N-hydroxy-tiannaphthol, the (S)-enantiomer of N-hydroxy-tiannaphthol, or N-hydroxy- The (R)-enantiomer of nitro-tiaponectin, or a pharmaceutically acceptable salt thereof, or N-nitroso-tiaponectin, the (S)-enantiomer of N-nitroso-tiaponectin, or the (R)-enantiomer of N-nitroso-tiaponectin, or a pharmaceutically acceptable salt thereof, or an aryl-substituted tiaponectin analogue or a pharmaceutically acceptable salt thereof, as described in embodiments 146 or 147, or a pharmaceutical composition according to any one of embodiments 148-152.

[0225] 178. A method for treating a disease, disorder, or condition selected from the group consisting of central nervous system (CNS) disorders, asthma, primary biliary cholangitis, hypertriglyceridemia, cardiomegaly, fibromyalgia, cancer, infectious diseases, COVID-19, prolonged COVID, menopausal and chronic overlapping pain syndrome (COPC), psychological, physiological, metabolic or hormonal stress, and COPC, and obesity, comprising administering to the subject a therapeutically effective amount of N-hydroxy-tiaponectin, N-hydroxy-tiaponectin (S)- The pharmaceutical composition according to any one of the following embodiments: enantiomers, (R)-enantiomers of N-hydroxy-tiaphrine, or pharmaceutically acceptable salts thereof; N-nitroso-tiaphrine, (S)-enantiomers of N-nitroso-tiaphrine, or (R)-enantiomers of N-nitroso-tiaphrine, or pharmaceutically acceptable salts thereof; aryl-substituted tiaphrine analogs according to embodiments 146 or 147, or pharmaceutical compositions according to any one of embodiments 148-152.

[0226] 179. The method according to any one of embodiments 153-178, wherein the N-hydroxy-tiaponectin, the (S)-enantiomer of N-hydroxy-tiaponectin, the (R)-enantiomer of N-hydroxy-tiaponectin, N-nitroso-tiaponectin, the (S)-enantiomer of N-nitroso-tiaponectin, the (R)-enantiomer of N-nitroso-tiaponectin, or an aryl-substituted tiaponectin analog, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, is administered once or more daily.

[0227] 180. The method according to embodiment 179, wherein the N-hydroxy-tiaponectin, the (S)-enantiomer of N-hydroxy-tiaponectin, the (R)-enantiomer of N-hydroxy-tiaponectin, N-nitroso-tiaponectin, the (S)-enantiomer of N-nitroso-tiaponectin, the (R)-enantiomer of N-nitroso-tiaponectin, or an aryl-substituted tiaponectin analog, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, is administered once daily.

[0228] 181. The method according to any one of embodiments 153-180, wherein the N-hydroxy-tiaponectin, the (S)-enantiomer of N-hydroxy-tiaponectin, the (R)-enantiomer of N-hydroxy-tiaponectin, N-nitroso-tiaponectin, the (S)-enantiomer of N-nitroso-tiaponectin, the (R)-enantiomer of N-nitroso-tiaponectin, or an aryl-substituted tiaponectin analogue, or a pharmaceutically acceptable salt of any of the above, or the pharmaceutical composition thereof, is administered parenterally, or orally, sublingually, sublingually, sublingually, sublingually, transdermally, transrectally, or vaginally.

[0229] 182. The method according to embodiments 153-181, wherein the N-hydroxy-tiaponectin, the (S)-enantiomer of N-hydroxy-tiaponectin, the (R)-enantiomer of N-hydroxy-tiaponectin, N-nitroso-tiaponectin, the (S)-enantiomer of N-nitroso-tiaponectin, the (R)-enantiomer of N-nitroso-tiaponectin, or an aryl-substituted tiaponectin analogue, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, is administered sequentially or concurrently with one or more other therapeutic agents selected from the group consisting of: antidepressants, anticonvulsants, anxiolytics, antipsychotics, cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, 5HT2 modulators, corticosteroids, antiamyloid agents, anti-tau agents, and chemotherapeutic agents.

[0230] 183. The method according to embodiments 153-181, wherein the N-hydroxy-tiaponectin, the (S)-enantiomer of N-hydroxy-tiaponectin, the (R)-enantiomer of N-hydroxy-tiaponectin, N-nitroso-tiaponectin, the (S)-enantiomer of N-nitroso-tiaponectin, the (R)-enantiomer of N-nitroso-tiaponectin, or an aryl-substituted tiaponectin analog, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, is administered as part of a treatment regimen that also includes a psychotherapeutic intervention.

[0231] 184. A crystalline hemioxalate of (S)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-ylamino)heptanoic acid 5,5-dioxide ((S)-tiaponectin), wherein the salt exhibits an X-ray diffraction (XRPD) pattern containing at least one peak selected from 8.5, 20.6, 21.0, and 24.2 degrees 2θ ± 0.3 degrees 2θ.

[0232] 185. The crystalline (S)-thiazopridine hemioxalate according to embodiment 184, wherein the salt exhibits an XRPD spectrum comprising at least one peak selected from the group consisting of 12.1, 13.3, 16.1, 18.9, 19.1, 22.0 and 22.4 degrees 2θ ± 0.3 degrees 2θ.

[0233] 186. A crystalline free acid / base of the (S)-enantiomer of tianapordine according to embodiment 1, wherein the crystalline tianapordine (S)-enantiomer exhibits an X-ray diffraction (XRPD) pattern containing at least one peak selected from 10.6, 13.0, 21.1 and 23.7 degrees 2θ ± 0.3 degrees 2θ.

[0234] 187. The crystalline free acid / free base of the (S)-enantiomer of tianapordine according to embodiment 186, wherein the crystalline free acid / free base of the (S)-enantiomer of tianapordine exhibits an XRPD spectrum comprising at least one peak selected from the group consisting of 8.7, 9.1, 12.6, 18.1, 20.4, 23.0 and 26.1 degrees 2θ ± 0.3 degrees 2θ. Brief description of the attached diagram

[0235] Figure 1 This is a graph showing the separation of a mixture of zwitterionic enantiomers of tinaptrine derived from a racemic mixture of tinaptrine oxalate enantiomers by direct-phase preparative high-performance liquid chromatography (HPLC) at a wavelength of 220 nm. AU = absorbance unit.

[0236] Figure 2A and2B The crystal structure of the enantiomer of thiaponectin complexed with L-dibenzoyl tartaric acid (DBTA) (which, as a sodium salt, has (-) optical rotation) is shown. Figure 2A The crystal structure of salt (S)-thiazoprine:0.5 L-DBTA is shown. Figure 2B The different crystalline isomers of (S)-tiaponectin enantiomers and L-DBTA ((S)-tiaponectin: 0.5 L-DBTA) are shown.

[0237] Figures 3A-3B This shows the use of different concentrations of [D-Ala] 2 , NMe-Phe 4 Gly-ol 5 Graphs of cAMP inhibition at the µ-opioid receptor by dAMGO, racemic tinaptine, and 99.0%–99.35% pure (S)-tinaptine oxalate or 98.5%–99.35% pure (R)-tinaptine oxalate. Figure 3A shows the graph of cAMP inhibition at steady state. Figure 3B shows the graph of the initial rate of cAMP inhibition. NFU is normalized fluorescence unit.

[0238] Figures 4A-4B Figure 4A shows the concentration-response curves at the µ-opioid receptor using different concentrations of DAMGO, racemic tinaptine, and 99.0%–99.35% pure (S)-tinaptine oxalate or 98.5%–99.35% pure (R)-tinaptine oxalate, illustrating the average repressor protein recruitment. Figure 4B shows the repressor protein recruitment response at steady state. Figure 4B shows the initial rate analysis of repressor protein recruitment.

[0239] Figures 5A-5B Concentration-response graphs of cAMP inhibition % at µ-opioid receptors are shown, illustrating different logarithmic concentrations (M) of DAMGO, racemic tinaptine, and 99.35% pure (S)-tinaptine sodium or (R)-tinaptine sodium. The graphs also show the initial rate analysis of cAMP inhibition % (Figure 5A) and the maximum effect analysis of cAMP inhibition % (Figure 5B).

[0240] Figures 6A-6B The graphs show concentration-response curves of cAMP inhibition % at the µ-opioid receptor using different logarithmic concentrations (M) of DAMGO, racemic tinaptine, racemic tinaptine sodium, and 99.0%–99.35% pure (S)-tinaptine sodium or 98.5%–99.35% pure (R)-tinaptine sodium. The graphs show the initial rate analysis of cAMP inhibition % (Figure 6A) and the maximum effect analysis of cAMP inhibition % (Figure 6B).

[0241] Figures 7A-7B The graphs show concentration-response curves of mean repressor protein recruitment at the µ-opioid receptor using different logarithmic concentrations (M) of DAMGO, tionapril, racemic tionapril sodium, and 99.9% pure (S)-tionapril sodium or (R)-tionapril sodium. The graphs show the initial rate analysis of repressor protein recruitment (Fig. 7A) and repressor protein recruitment normalized to baseline (Fig. 7B).

[0242] Figures 8A-8B The graphs depict the agonistic effects of tiannaptine at the µ-opioid receptor using different logarithmic concentrations (M) of DAMGO and 99.9% pure (S)-tiannaptine sodium or (R)-tiannaptine sodium. The graphs show peak cAMP inhibition (Fig. 8A) and peak inhibition protein recruitment (Fig. 8B).

[0243] Figures 9A-9D show graphs depicting the activities of racemic tinaptine, racemic tinaptine oxalate, (S)-tinaptine and (R)-tinaptine (99.9% chiral purity), the PPAR-β / δ agonist positive control GW0742, the PPAR-β / δ agonist seladelpar and dimethyl sulfoxide (DMSO, negative control), and the peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ). Figures 9B and 9D show magnified views of activation by (S)-tinaptine at ~3 µM PPAR-β / δ.

[0244] Figure 10A and 10B The diagram depicts the activities of racemic tinaptine, racemic tinaptine oxalate, (S)-tinaptine and (R)-tinaptine (99.9% chiral purity), the PPAR-γ agonist positive control rosiglitazone, the PPAR-β / δ agonist sradpa and DMSO (negative control), and peroxisome proliferator-activated receptor-γ (PPAR-γ).

[0245] Figure 11A and 11B Charts depicting the activities of racemic tiannaphthol, racemic tiannaphthol oxalate, (S)-tiannaphthol and (R)-tiannaphthol (99.9% chiral purity), the PPAR-α agonist positive control GW7647, the PPAR-β / δ agonists sradpa and DMSO (negative control), and peroxisome proliferator-activated receptor-α (PPAR-α).

[0246] Figure 12The crystal structure of PPAR-δ / β in the complex with ligand GW2331 is depicted, and the calculated models of PPAR-δ / β in the complex with (S)-tiaponectin and the complex with (R)-tiaponectin are superimposed.

[0247] Figure 13A and 13B This demonstrates the effect of (S)-tinaptol in accessing PPAR-δ / β. Figure 13A ) and (R)-tiaponectin in PPAR-δ / β Figure 13B Computational modeling was used to depict the formation of a covalent carbon-sulfur (CS) bond between (S)-tinaphthol and cysteine ​​285 of PPAR-δ / β. The bond length between (S)-tinaphthol and Cys285 of PPAR-δ / β is 5.00 Å. Figure 13A ), and the bond length between (R)-tiaponectin and PPAR-δ / β Cys285 is 7.92 Å ( Figure 13B ).

[0248] Figure 14A-14F A graph depicting the effects of (S)-tiaponectin and (R)-tiaponectin zwitterions (99.9% chiral purity) on neurite growth in cultured glutamatergic neurons is shown. Figure 14A and 14B Depicting 24 hours after treatment ( Figure 14A ) and 72 hours ( Figure 14B The average neurite length (µm) at that time. Figure 14C and 14D The total neurite length (µm) was depicted 5 days after treatment with (S)-tinaptrine zwitterion (99.9% chiral purity). Figure 14C ) and average neurite width (nm) Figure 14D ). Figure 14E and 14F The total neurite length (µm) was depicted 5 days after treatment with (R)-tiaponectin zwitterion (99.9% chiral purity). Figure 14E ) and average neurite width (nm) Figure 14F Data were normalized to the 1% PBS control and compared using strictly standardized mean difference (SSMD). P-value: *p<0.05.

[0249] Figures 15A-15D A graph depicting the effects of (S)-tiaponectin and (R)-tiaponectin zwitterions (99.9% chiral purity) on mitochondrial staining (MitoTracker) in glutamatergic neurons cultured 5 days after treatment is shown. Figure 15A and 15BThe cell bodies (Cells) treated with (S)-tiaponectin zwitterion (99.9% chiral purity) were described. Figure 15A ) and neural spurs ( Figure 15B Mitochondrial staining in ). Figure 15C and 15D The cell bodies (Cells) treated with (R)-thiazoprine zwitterion (99.9% chiral purity) were described. Figure 15C ) and neural spurs ( Figure 15D Mitochondrial staining in [data missing]. Data were normalized to 1% PBS control and compared using strictly normalized mean difference (SSMD). p-value: *p<0.05. RFU = relative fluorescence unit.

[0250] Figures 16A-16C The image depicts racemic thiazoline sodium ( Figure 16A (S)-Tiaponectin sodium (99.9% chiral purity) Figure 16B (R)-Tiaponectin sodium (99.9% chiral purity) Figure 16C A graph showing the performance in the Novel Object Recognition (NOR) test. ANOVA p-values: ***p<0.001, **p<0.1, *p<0.05.

[0251] Figure 17A-17F The image depicts racemic thiazoline sodium ( Figures 17A-17B (R)-Tiaponectin sodium (99.9% chiral purity) Figure 17C-17D (S)-Tiazoprid sodium (99.9% chiral purity) and (S)-Tiazoprid sodium Figure 17E-17F A graph showing the effect of the test in the Forced Swimming Test (FST). Figure 17A , 17C Figure 17E shows a timeline of stationary time spent within 6 minutes. Figure 17B , 17D Figure 17F shows the total stationary time spent during the 6-minute test. ANOVA p-values: ***p<0.001, *p<0.05.

[0252] Figures 18A-18D The image depicts the crystallization of (S)-thiazoprine ( Figure 18A ), crystalline (S)-thiazoline hemioxalate ( Figure 18B Amorphous (S)-Tiaponectin sodium ( Figure 18C XRPD spectra of the three XRPDs and a comparison of the XRPDs of these three XRPDs with those of racemic thiazoline hemioxalate. Figure 18D (Charts)

[0253] Detailed Explanation

[0254] In some embodiments, this disclosure provides the (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-ylamino)heptanoic acid ((S)-tiaponectin), its zwitterion, ester or amide, or a pharmaceutically acceptable salt of the (S)-enantiomer or its crystalline form, or a pharmaceutically acceptable salt of its ester or amide, or a cocrystal of the (S)-enantiomer or its zwitterion. In other embodiments, this disclosure provides the (S)-enantiomer of deuterated tianapordine (11-D-(S)-tianapordine), its zwitterion, ester or amide, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or its crystalline form, or a pharmaceutically acceptable salt of its ester or amide, or a cocrystal of the 11-D-(S)-enantiomer or its zwitterion. In two embodiments, the (S)-enantiomer, zwitterion, cocrystal, ester, amide and salt are characterized by comprising ≤2% of the corresponding (R)-enantiomer, its zwitterion, ester, amide or salt. In two embodiments, the (S)-enantiomer, zwitterion, ester, amide and salt are characterized by comprising ≤0.1% of the corresponding (R)-enantiomer, its zwitterion, ester, amide or salt.

[0255] In other embodiments, this disclosure provides thiazoliptin analogues, including N-hydroxy-thiazoliptin, (S)- and (R)-enantiomers of N-hydroxy-thiazoliptin (i.e., N-hydroxy-(S)-thiazoliptin or N-hydroxy-(R)-thiazoliptin), N-nitroso-thiazoliptin, (S)- and (R)-enantiomers of N-nitroso-thiazoliptin (i.e., N-nitroso-(S)-thiazoliptin or N-nitroso-(R)-thiazoliptin), aryl-substituted thiazoliptin analogues, and pharmaceutically acceptable salts thereof. In some embodiments, the (S)-enantiomers of N-hydroxy-thiazoliptin or N-nitroso-thiazoliptin are characterized by comprising ≤2% of the corresponding (R)-enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxy-tiaponectin or N-nitroso-tiaponectin is characterized by containing ≤0.1% of the corresponding (R)-enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxy-tiaponectin or N-nitroso-tiaponectin is characterized by containing ≤2% of the corresponding (S)-enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxy-tiaponectin or N-nitroso-tiaponectin is characterized by containing ≤0.1% of the corresponding (S)-enantiomer.

[0256] In some embodiments, this disclosure provides pharmaceutical compositions comprising one or more of the (S)-enantiomers of this disclosure or their crystalline forms, zwitterions, cocrystals, esters, amides, analogs, or salts, said compositions comprising ≤2% of the corresponding (R)-enantiomer. In some embodiments, said pharmaceutical compositions comprise ≤0.1% of the corresponding (R)-enantiomer.

[0257] In some embodiments, this disclosure provides methods for treating diseases, disorders, or conditions and related symptoms selected from the group consisting of: central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infectious diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopausal and chronic overlapping pain syndromes (COPC), and psychological, physiological, metabolic or hormonal stress and COPC, said methods being carried out by administering the (S)-enantiomer of this disclosure (i.e., the (S)-enantiomer of tianapordine and / or the 11-D-(S)-enantiomer of tianapordine) or its crystalline form, zwitterion, ester, amide, salt, analogue and composition thereof. In some embodiments, the disease, disorder or condition is regulated, exacerbated or associated with altered activity of PPAR-β / δ and / or PPAR-γ. In some embodiments, the disease, disorder, or condition is regulated, exacerbated, or associated with high levels of S-nitrosylation of PPAR-β / δ and / or PPAR-γ. In some embodiments, the disease, disorder, or condition is regulated, exacerbated, or associated with excessive levels of metal ions in circulation. In some embodiments, the disease, disorder, or condition is regulated, exacerbated, or associated with stress.

[0258] In some embodiments, the method minimizes the likelihood of opioid abuse by administering the (S)-enantiomer of this disclosure (i.e., the (S)-enantiomer of tianapordine and / or the 11-D-(S)-enantiomer of tianapordine) or its crystalline form, its zwitterion, ester, amide, analog or pharmaceutically acceptable salt, or a composition comprising them.

[0259] In other embodiments, this disclosure provides methods for preparing the (S)-enantiomer of tiannaphthol and / or the 11-D-(S)-enantiomer of tiannaphthol of this disclosure.

[0260] Unless otherwise stated, the methods of the various embodiments disclosed herein are implemented using conventional techniques within the scope of the art in molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA, and related fields. These techniques are well explained in the literature.

[0261] definition

[0262] The term "this paper" refers to the entire application.

[0263] Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. In the event of any conflict, this specification (including the definitions) shall prevail.

[0264] It should be understood that, unless explicitly waived or inappropriate, any of the embodiments described herein, including those described in different aspects and parts of this disclosure (including those described only in the embodiments), can be combined with one or more other embodiments of this disclosure, and are thus disclosed as embodiments of this disclosure. The combination of embodiments is not limited to those specific combinations described in the various dependent embodiments of this disclosure.

[0265] All publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In the event of any conflict, this specification (including its specific definitions) shall prevail.

[0266] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising”, which are synonymous with “including,” “containing,” or “characterized by,” are inclusive or open-ended and do not exclude additional, unlisted elements or methodological steps.

[0267] Any instances (or instances) following the terms "e.g." or "for example" are not intended to be exhaustive or restrictive.

[0268] The terms "including" or "includes" are used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

[0269] Unless the context otherwise requires, singular terms should include plural terms and plural terms should include singular terms.

[0270] The articles “a / an” and “the” used in this article refer to one or more (i.e., at least one) grammatical objects of the article.

[0271] As used herein, the meaning of the term "about" depends on the context in which it is used. When used with respect to the amount, parameter, calculation, or measurement of a component in a composition used in a method modifying this disclosure, it refers to a variation in a numerical quantity that can occur, for example, by ordinary measurement and liquid handling procedures used in the preparation of the compounds or pharmaceutical compositions of this disclosure in the real world; by unintentional errors in these procedures; by differences in the preparation, source, or purity of the enantiomers or compositions of this disclosure or the components used to carry out the method; and any amount or use of ordinary + / - that does not materially affect the chemical or physical properties of the compounds, compositions, or methods of this disclosure. Such variations are typically within 10% of a given value or range, more typically within 5%. In some embodiments, the variation may be within 1%. The term "about" also covers amounts that differ due to different equilibrium conditions of the composition obtained from a particular initial mixture. Whether or not a paragraph is modified by the term "about," it includes equivalent schemes of the amount. References to a value or parameter of "about" herein include (and describe) embodiments relating to that value or parameter itself. For example, a description referring to "about X" includes the description of "X". Numerical ranges include the numbers that define the range. When used concerning the location of a peak in an X-ray powder diffraction (XRPD) pattern, the term "about" includes peaks within a relevant tolerance of ±0.3 degrees 2θ. For example, as used herein, an XRPD peak at "about 10.0 degrees 2θ" means that the peak appears between 9.7 and 10.3 degrees 2θ. When referring to the location of a peak in a solid state... 13 When using the position of a peak on a C NMR spectrum, the term "about" includes peaks within ±0.2 ppm of said position. For example, as used herein, "about 100.0 ppm" refers to peaks at that position. 13 The C NMR spectrum peaks indicate that the peaks appear in the range of 99.8 to 100.2 ppm.

[0272] As used herein, the term "substantially" for XRPD spectra refers to a spectrum having at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 common peaks (amplitudes may differ) with a reference spectrum; or a spectrum with a tolerance of ±0.3 degrees 2θ within the reference peak. For NMR spectra, "substantially" refers to a spectrum having at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 common peaks (amplitudes may differ) with a reference spectrum; or a spectrum with a tolerance of ±0.2 ppm within the reference peak. For FT-IR spectra, "substantially" refers to a spectrum having at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 common peaks (amplitudes may differ) with a reference spectrum; or a spectrum with a tolerance of ±0.5 cm⁻¹ within the reference peak. -1 The tolerance chart.

[0273] Unless the context clearly indicates otherwise, the term “or” as used herein should be understood to mean “and / or”.

[0274] Although the disclosed numerical ranges and parameters are approximate, the values ​​described in specific examples are reported as precisely as possible. However, any numerical value inherently contains a certain degree of error, which is necessarily caused by the standard deviation present in its corresponding test measurement. Furthermore, all ranges disclosed herein should be understood to encompass any and all subranges contained therein. For example, the range “1 to 10” should be considered as including any and all subranges between the minimum value of 1 and the maximum value of 10 (and including the endpoints); that is, all subranges begin with a minimum value of 1 or greater (e.g., 1 to 6.1) and end with a maximum value of 10 or less (e.g., 5.5 to 10).

[0275] Where aspects or implementations are described in terms of Markush groups or other alternative groupings, this application covers not only the entire group listed as a whole, but also each member of a separate group and all possible subgroups of the main group, as well as one or more non-existent main groups among the group members, although such individuals and subgroups are not specifically mentioned in this disclosure.

[0276] This document describes exemplary methods and materials, but similar or equivalent methods and materials may also be used in the implementation or testing of various aspects and embodiments. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0277] To facilitate a clearer understanding of this disclosure, certain terms are first defined. These definitions should be interpreted in accordance with the remainder of this disclosure as would be understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Further definitions are set forth throughout the detailed description.

[0278] As used herein, the term “treatment” and its cognates refer to a complete or partial improvement or regulation of a disease, disorder, or condition, particularly a symptom or pathology that can be achieved using the compounds and compositions of this disclosure, and may include, but is not limited to, even the smallest change or improvement in one or more measurable markers of the treated disease, disorder, or condition. “Treatment” also means delaying the onset of a disease, disorder, or condition to which the term applies, or one or more symptoms of such a disease, disorder, or condition, to halt or reverse its progression, to reduce its severity, or to alleviate or prevent one or more symptoms of a disease, disorder, or condition to which the term applies, such as, and not limited to, delaying or reducing the rate of cognitive decline in age-related cognitive decline.

[0279] "Treating cognitive impairment" refers to taking steps to improve the cognitive function of a subject with cognitive impairment, such that the subject's performance on one or more cognitive tests improves to any detectable level or prevents further decline or slows the rate of such decline. Preferably, after treating cognitive impairment, the subject's cognitive function more closely resembles that of a normal, unimpaired subject. Treatment of cognitive impairment can improve cognitive function to any detectable level, but preferably sufficiently improves it to allow the impaired subject to perform normal daily activities with a similar level of proficiency as a normal, unimpaired subject. In some cases, "treating cognitive impairment" refers to taking steps to improve the cognitive function of a subject with cognitive impairment, such that the subject's performance on one or more cognitive tests improves to any detectable level, prevents further decline, or slows the rate of such decline. Preferably, after treating cognitive impairment, the subject's cognitive function more closely resembles that of a normal, unimpaired subject. In some cases, "treating cognitive impairment" in subjects affected by age-related cognitive impairment refers to taking steps to improve the subject's cognitive function so that, after treatment, the subject's cognitive function more closely resembles that of age-matched normal, unimpaired subjects or younger adult subjects. In other cases, "treating cognitive impairment" in subjects refers to taking steps to delay or slow the progression of cognitive impairment in subjects with cognitive impairment. In still other cases, "treating cognitive impairment" in subjects refers to taking steps to reduce the rate of cognitive decline in subjects with cognitive impairment.

[0280] As used herein, the terms “subject,” “patient,” or “individual” are used interchangeably and include both human and non-human mammals. Non-human mammals include cattle, sheep, pigs, horses, dogs, cats, and rodents (e.g., rats, mice, guinea pigs, and rabbits). Preferably, the subject is a human.

[0281] As used herein, the term “(S)-enantiomer of tianapordine” refers to the (S)-enantiomer of tianapordine or its crystalline form, its zwitterion, a pharmaceutically acceptable salt of the (S)-enantiomer or its crystalline form, a cocrystal of the (S)-enantiomer or its zwitterion, an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or 11-D-(S)-enantiomer, its crystalline form, its zwitterion, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, an ester of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt.

[0282] As used herein, the term "therapeuticly effective amount" of the (S)-enantiomer of tiannaphthol of this disclosure or the composition of this disclosure refers to an amount for treating, preventing, or alleviating one or more symptoms of a disease or disorder of this disclosure. In some embodiments, the disease or disorder or one or more symptoms of a disease or disorder are modulated, exacerbated, or associated with altered activity of PPAR-β / δ and / or PPAR-γ. In some embodiments, some of the disease or disorder are associated with stress or the presence of excess metal ions. Those skilled in the art can readily determine the therapeutically effective amount of the (S)-enantiomer of tiannaphthol of this disclosure (i.e., the (S)-enantiomer or 11-D-(S)-enantiomer), the zwitterion of the (S)-enantiomer of this disclosure, or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure by taking into account factors such as the size, weight, age, and sex of the subject, the extent of disease penetration or persistence, the severity of symptoms, and the route of administration. Typically, the therapeutically effective amount of the (S)-enantiomer of tianapordine of this disclosure (i.e., the (S)-enantiomer or the 11-D-(S)-enantiomer), the zwitterion of the (S)-enantiomer of this disclosure, or a pharmaceutically acceptable salt thereof, administered to a subject is about 1 mg / day to about 5000 mg / day, about 1 mg / day to about 4000 mg / day, about 1 mg / day to about 3000 mg / day, about 1 mg / day to about 2000 mg / day, about 1 mg / day to about 1000 mg / day, about 2 mg / day to about 600 mg / day, about 10 mg / day to about 400 mg / day, or about 25 mg / day to 300 mg / day. Higher or lower doses are also contemplated.

[0283] As used herein, a "pharmaceuticalally acceptable carrier" refers to any diluent or excipient that is compatible with the other components of the formulation and is harmless to the recipient. A pharmaceutically acceptable carrier may be selected based on the desired route of administration and in accordance with standard pharmaceutical practice.

[0284] As used herein, “enantiomer” refers to each of two non-overlapping isomers of a compound having at least one chiral / asymmetric atom. Each enantiomer is optically active in terms of its optical rotation. Individual enantiomers are named according to the Cahn-Ingold-Prelog system, a well-known set of priority rules for ordering the four groups attached to the asymmetric carbon. See, for example, March, Advanced Organic Chemist, 4th edition, (1992), page 109, the entire disclosure of which is incorporated herein by reference.

[0285] As used herein, “optical activity” refers to the property of a material to rotate the plane of plane-polarized light. Optically active isomers or enantiomers are not superimposed on their mirror images. As used herein, the property that an object is not superimposed on its mirror image is called “chirality.” The most common structural feature that produces chirality is an asymmetric carbon atom, that is, a carbon atom with four distinct groups attached to it.

[0286] As used herein, “racemate” or “racemic compound” refers to a 50-50 mixture of two enantiomers such that the mixture does not rotate plane-polarized light and, in many cases, can be separated into two peaks of equal weight by various methods, including chromatography.

[0287] As used herein, the terms “substantially pure” or “pure” mean that the enantiomer or composition comprising it comprises no more than 2% of the corresponding enantiomer. In some embodiments, the substantially pure (S)-enantiomer of tiannaphthol of this disclosure (i.e., the (S)-enantiomer or 11-D-(S)-enantiomer), its zwitterion, a pharmaceutically acceptable salt of the (S)-enantiomer, or the composition of this disclosure comprises no more than about 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the (R)-enantiomer of tiannaphthol (i.e., the (R)-enantiomer or 11-D-(R)-enantiomer), the zwitterion of the (R)-enantiomer, or a pharmaceutically acceptable salt of the (R)-enantiomer.

[0288] As used herein, the term "chiral purity" refers to the degree to which a mixture of enantiomers contains one enantiomer relative to another.

[0289] As used herein, the term "eutectic" is distinct from salt and refers to a solid crystalline supramolecular complex consisting of two or more components within the same lattice, where the components are in a neutral state and interact via nonionic interactions. The ability of an active pharmaceutical ingredient (API) and a co-former to form a eutectic can be predicted by determining the ΔpKa value. When the ΔpKa of the API and the co-former is negative (<0), no proton transfer occurs, indicating that the system will form a eutectic; in contrast, when the ΔpKa is above 3, complete proton transfer occurs, indicating that the system forms a salt. Typically, the ΔpKa is between 0 and 3, where only partial proton transfer occurs, and therefore the system is often referred to as a salt eutectic (Nugrahani and Jessica. Molecules. 2021).

[0290] As used herein, the terms “µ-opioid receptor assay” or “MOR assay” refer to a method for analyzing the activity of G protein-coupled receptor signaling pathways in response to ligand binding at µ-opioid receptors.

[0291] As used in this article, the term "Gi" refers to the Gi subunit in the G protein-coupled receptor signaling pathway.

[0292] As used in this article, the term "Gs" refers to the Gs subunit in the G protein-coupled receptor signaling pathway.

[0293] As used herein, the terms “β-inhibitory protein” and “inhibitory protein” are used interchangeably.

[0294] As used in this article, the term "m / z" refers to the mass-to-charge ratio.

[0295] As used in this article, the term "t" R "Retention time" or "retention time" refers to the interval between sample injection and detection of the substance in the sample.

[0296] As used in this article, the term "neurite growth" refers to the process by which developing neurons produce new protrusions (called neurites) in response to guiding factors.

[0297] As used herein, the term "aryl" refers to any functional group or substituent derived from an aromatic ring having 5 to 7 ring atoms, including 1 to 4 heteroatoms selected from the group consisting of carbon, nitrogen, sulfur, or oxygen. The aryl group may be added at any possible position of (S)- or (R)-tiaponectin in this disclosure.

[0298] As used herein, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group of any length from one to six carbon atoms (C1-C6), wherein the alkyl group may optionally be independently substituted by one or more substituents.

[0299] As used herein, the term "analyte" refers to a compound that is related to tiannaphthol but has a modified chemical structure. For example, tiannaphthol analogs may contain additional functional groups, including hydroxyl, nitroso, or aryl groups. The tiannaphthol analogs of this disclosure include N-hydroxy-tiannaphthol, its (S)- and (R)-enantiomers, N-nitroso-tiannaphthol, its (S)- and (R)-enantiomers, aryl-substituted tiannaphthol analogs, or pharmaceutically acceptable salts thereof.

[0300] (S)-Tiazoprine enantiomer

[0301] In some aspects, this disclosure provides the (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-ylamino)heptanoic acid (the (S)-enantiomer of tianapordine) or its zwitterion or a pharmaceutically acceptable salt of the (S)-enantiomer, or a mixture of two or more of these substances, wherein the (S)-enantiomer, zwitterion or pharmaceutically acceptable salt is characterized by comprising no more than about 2% (i.e., ≤ about 2%) of the (R)-enantiomer or its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by containing no more than about 1% (i.e., ≤ about 1%) of the (R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by containing no more than about 0.9% (i.e., ≤ about 0.9%) of the (R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by containing no more than about 0.8% (i.e., ≤ about 0.8%) of the (R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by containing no more than about 0.7% (i.e., ≤ about 0.7%) of the (R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by containing no more than about 0.6% (i.e., ≤ about 0.6%) of the (R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by containing no more than about 0.5% (i.e., ≤ about 0.5%) of the (R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.4% (i.e., ≤ about 0.4%) of the (R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof.In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.3% (i.e., ≤ about 0.3%) of the (R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.2% (i.e., ≤ about 0.2%) of the (R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by containing no more than about 0.1% (i.e., ≤ about 0.1%) of the (R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof.

[0302] In some embodiments, the (S)-enantiomer of this disclosure is in the form of its pharmaceutically acceptable salt or crystalline form. In some embodiments, the (S)-tiaponectin of this disclosure is in a zwitterionic form.

[0303] In some aspects, this disclosure provides the (S)-enantiomer of 7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-yl-11-d)amino)heptanoic acid (the 11-D-(S)-enantiomer of tianapordine), its zwitterion or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a mixture of two or more of these substances, wherein the 11-D-(S)-enantiomer, zwitterion or pharmaceutically acceptable salt is characterized by comprising no more than about 2% (i.e., ≤ about 2%) of the 11-D-(R)-enantiomer or its zwitterion or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer. In some embodiments, the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 1% (i.e., ≤ about 1%) of the 11-D-(R)-enantiomer of tianapordine, or its zwitterion, or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.9% (i.e., ≤ about 0.9%) of the 11-D-(R)-enantiomer of tianapordine, or its zwitterion, or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.8% (i.e., ≤ about 0.8%) of the 11-D-(R)-enantiomer of tianapordine, or its zwitterion, or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.7% (i.e., ≤ about 0.7%) of the 11-D-(R)-enantiomer of tianapordine, or its zwitterion, or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.6% (i.e., ≤ about 0.6%) of the 11-D-(R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.5% (i.e., ≤ about 0.5%) of the 11-D-(R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof.In some embodiments, the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.4% (i.e., ≤ about 0.4%) of the 11-D-(R)-enantiomer of tianapordine, or its zwitterion, or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.3% (i.e., ≤ about 0.3%) of the 11-D-(R)-enantiomer of tianapordine, or its zwitterion, or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.2% (i.e., ≤ about 0.2%) of the 11-D-(R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.1% (i.e., ≤ about 0.1%) of the 11-D-(R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt thereof. In some embodiments, 11-D-(S)-tiaponectin, its zwitterion, or any pharmaceutically acceptable salt thereof is characterized by reduced racemization at the 11 position compared to 11-D-(S)-tiaponectin, its zwitterion, or any pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the 11-D-(S)-tiaponectin of this disclosure is in the form of its pharmaceutically acceptable salt or crystalline form. In some embodiments, the 11-D-(S)-tiaponectin of this disclosure is in the form of a zwitterionic ion.

[0305] In some embodiments, the 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is deuterated at both 3' positions, and optionally at other positions on the aminoheptanoic acid side chain. In some embodiments, the 11-D-(S)-enantiomer is 3',3',4',4',11-pentadeuterated tiaponectin of formula (IIIa) or its zwitterion of formula (IIIb); 2',2',3',3',4',4',5',5',6',6',7',7',11-tweldeuterated tiaponectin of formula (IVa) or its zwitterion of formula (IVb); 3',3',4',4',tetradeuterated tiaponectin of formula (Va) or its zwitterion of formula (Vb); or 2',2',3',3',4',4',5',5',6',6',7',7',dodecadeuterated tiaponectin of formula (VIa) or its zwitterion of formula (VIb). In some embodiments, the 11-D-(S)-enantiomer is 3',3',4',4',11-pentadeuterated tiaponectin of formula (IIIa) or its zwitterion (IIIb). In some embodiments, the 11-D-(S)-enantiomer is 2',2',3',3',4',4',5',5',6',6',7',7',11-tweldeuterated tiaponectin of formula (IVa) or its zwitterion (IVb). In some embodiments, the 11-D-(S)-enantiomer is 3',3',4',4',tetradeuterated tiaponectin of formula (Va) or its zwitterion (Vb). In some embodiments, the 11-D-(S)-enantiomer is 2',2',3',3',4',4',5',5',6',6',7',7' of general formula (VIa), dodeuterated thiaponectin, or its zwitterion of general formula (VIb).

[0306]

[0307] Methods for preparing pharmaceutically acceptable salts of the (S)-enantiomers of this disclosure from the compounds described herein are well known to those skilled in the art. For example, salts can be prepared from free bases using conventional methods that typically involve reaction with a suitable acid. Suitable acids for preparing acid addition salts include, but are not limited to, both organic acids (e.g., acetic acid, propionic acid, glycolic acid, gluconic acid, glucuronic acid, glutamic acid, pyruvic acid, oxalic acid, lactic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, formic acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, salicylic acid, orotic acid, hippuric acid, anthranilic acid, mesylate, 4-hydroxybenzoic acid, 2-hydroxyethanesulfonic acid, phenylacetic acid, mandelic acid, p-aminobenzenesulfonic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, camphorsulfonic acid, galactopyric acid, and galacturonic acid) and inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid). Conversely, the preparation of basic salts of the S-enantiomers described herein can be carried out in a similar manner using pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base addition salts of the (S)-enantiomers of this disclosure include metal salts made from calcium, magnesium, potassium, sodium, ammonium, and zinc, or organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), procaine, and trimethylamine.

[0308] In some embodiments, the pharmaceutically acceptable salts of the (S)-enantiomers of this disclosure and their crystalline forms are (S)-tiaponectin benzenesulfonate (1:1), (S)-tiaponectin fumarate (1:1), (S)-tiaponectin fumarate (2:1), (S)-tiaponectin hippurate (1:1), (S)-tiaponectin maleate (1:1), (S)-tiaponectin maleate (2:1), (S)-tiaponectin p-toluenesulfonate (1:1), (S)-tiaponectin orotate (1:1), (S)-tiaponectin camphorsulfonate (1:1), (S)-tiaponectin N-acetyl-L-tyrosine salt (1:1), (S)-tiaponectin polisterix, and (S)-tiaponectin:L-DBTA. (2:1), (S)-tinaptine sodium, (S)-tinaptine oxalate, or (S)-tinaptine oxalate (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tinaptine benzylsulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tinaptine fumarate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tinaptine fumarate (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tinaptine hippurate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tinaptine maleate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tinaptrine maleate (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tinaptrine p-toluenesulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tinaptrine orotate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tinaptrine camphorsulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tinaptrine N-acetyl-L-tyrosine salt (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tinaptrine polisterix. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tiaponectin:L-DBTA (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tiaponectin sodium. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tiaponectin oxalate.In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tiaponectin oxalate (2:1) (i.e., (S)-tiaponectin hemioxalate). In some embodiments, the hemioxalate is in crystalline form.

[0309] In some embodiments, the pharmaceutically acceptable salts of the 11-D-(S)-enantiomer of this disclosure and their crystalline forms are 11-D-(S)-tiaponectin benzylsulfonate (1:1), 11-D-(S)-tiaponectin fumarate (1:1), 11-D-(S)-tiaponectin fumarate (2:1), 11-D-(S)-tiaponectin hippurate (1:1), 11-D-(S)-tiaponectin maleate (1:1), 11-D-( 11-D-(S)-Tiaponectin maleate (2:1), 11-D-(S)-Tiaponectin p-toluenesulfonate (1:1), 11-D-(S)-Tiaponectin orotate (1:1), 11-D-(S)-Tiaponectin camphorsulfonate (1:1), 11-D-(S)-Tiaponectin N-acetyl-L-tyrosine (1:1), 11-D-(S)-Tiaponectin polisterix, 11-D-(S)-Tiaponectin:L-DBTA (2:1), 11-D-(S)-Tiaponectin sodium, 11-D-(S)-Tiaponectin oxalate, or 11-D-(S)-Tiaponectin oxalate (2:1). In some embodiments, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-Tiaponectin benzenesulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tiaponectin fumarate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tiaponectin fumarate (2:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tiaponectin hippurate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tiaponectin maleate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tiaponectin maleate (2:1). In some embodiments, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tinaptrine p-toluenesulfonate (1:1). In some embodiments, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tinaptrine orotate (1:1). In some embodiments, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tinaptrine camphorsulfonate (1:1). In some embodiments, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tinaptrine N-acetyl-L-tyrosine salt (1:1).In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tiaponectin polisterix. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is 11-D-(S)-tiaponectin:L-DBTA (2:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tiaponectin sodium. In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tiaponectin oxalate. In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tiaponectin oxalate (2:1) (i.e., 11-D-(S)-tiaponectin hemioxalate). In some embodiments, the hemioxalate is in crystalline form.

[0310] In some embodiments, for example, fumaric acid and maleic acid act as monoanions or dianions, resulting in different salt stoichiometry (i.e., a thiazoprine to fumaric acid / maleic acid ratio of 1:1 or 2:1). These salts may also contain additional deuterium substitution at one or more sites on the aminoheptanoic acid side chain.

[0311] In some embodiments, a pharmaceutically acceptable salt or crystalline form of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt or crystalline form of the 11-D-(S)-enantiomer of this disclosure is formed from benzenesulfonic acid, fumaric acid, hippuric acid, maleic acid, or p-toluenesulfonic acid in acetone and 2-propanol. In some embodiments, a pharmaceutically acceptable salt or crystalline form of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt or crystalline form of the 11-D-(S)-enantiomer of this disclosure is formed from orotic acid in 58% water / 42% tetrahydrofuran (THF).

[0312] In some aspects, this disclosure provides a cocrystal of the (S)-enantiomer of this disclosure, wherein the (S)-enantiomer or its zwitterion forms a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid. In some embodiments, the (S)-enantiomer or its zwitterion forms a complex with L-tyrosine. In some embodiments, the (S)-enantiomer or its zwitterion forms a complex with L-tryptophan. In some embodiments, the (S)-enantiomer or its zwitterion forms a complex with L-phenylalanine. In some embodiments, the (S)-enantiomer or its zwitterion forms a complex with another L-amino acid. In some embodiments, the ratio of the (S)-enantiomer or its zwitterion to the L-amino acid is 1:1, 1:2, or 2:1. In some embodiments, the ratio of the (S)-enantiomer or its zwitterion to the L-amino acid is 1:1. In some embodiments, the ratio of the (S)-enantiomer or its zwitterion to the L-amino acid is 1:2. In some embodiments, the ratio of the (S)-enantiomer or its zwitterion to the L-amino acid is 2:1. In some embodiments, the eutectic comprises an inorganic monocarboxylic acid salt of the (S)-enantiomer and a zwitterion of the L-amino acid. In some embodiments, the eutectic comprises an inorganic monocarboxylic acid salt of the L-amino acid and a zwitterion of the (S)-enantiomer. In some embodiments, the inorganic monocarboxylic acid is hydrochloric acid (HCl).

[0313] In some aspects, this disclosure provides cocrystals of the 11-D-(S)-enantiomer of this disclosure (and 11-D-(S)-enantiomers having at least one deuterium substitution on the aminoheptanoic acid side chain), wherein the (S)-enantiomer or its zwitterion forms a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid. In some embodiments, the 11-D-(S)-enantiomer or its zwitterion forms a complex with L-tyrosine. In some embodiments, the 11-D-(S)-enantiomer or its zwitterion forms a complex with L-tryptophan. In some embodiments, the 11-D-(S)-enantiomer or its zwitterion forms a complex with L-phenylalanine. In some embodiments, the 11-D-(S)-enantiomer or its zwitterion forms a complex with another L-amino acid. In some embodiments, the ratio of the 11-D-(S)-enantiomer or its zwitterion to the L-amino acid is 1:1, 1:2, or 2:1. In some embodiments, the ratio of the 11-D-(S)-enantiomer or its zwitterion to the L-amino acid is 1:1. In some embodiments, the ratio of the 11-D-(S)-enantiomer or its zwitterion to the L-amino acid is 1:2. In some embodiments, the ratio of the 11-D-(S)-enantiomer or its zwitterion to the L-amino acid is 2:1. In some embodiments, the eutectic comprises an inorganic monocarboxylic acid salt of the 11-D-(S)-enantiomer and a zwitterion of the L-amino acid. In some embodiments, the eutectic comprises an inorganic monocarboxylic acid salt of the L-amino acid and a zwitterion of the 11-D-(S)-enantiomer. In some embodiments, the inorganic monocarboxylic acid is hydrochloric acid (HCl).

[0314] In some aspects, this disclosure provides esters of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, wherein the (S)-enantiomers or pharmaceutically acceptable salts thereof are characterized by comprising ≤ about 2% of the (R)-enantiomers or pharmaceutically acceptable salts thereof. In some embodiments, the (S)-enantiomers or pharmaceutically acceptable salts thereof are characterized by comprising ≤ about 1% of the (R)-enantiomers or pharmaceutically acceptable salts thereof. In some embodiments, the (S)-enantiomers or pharmaceutically acceptable salts thereof are characterized by comprising ≤ about 0.9% of the (R)-enantiomers or pharmaceutically acceptable salts thereof. In some embodiments, the (S)-enantiomers or pharmaceutically acceptable salts thereof are characterized by comprising ≤ about 0.8% of the (R)-enantiomers or pharmaceutically acceptable salts thereof. In some embodiments, the (S)-enantiomer ester or its pharmaceutically acceptable salt is characterized by containing ≤ about 0.7% of the (R)-enantiomer ester or its pharmaceutically acceptable salt. In some embodiments, the (S)-enantiomer ester or its pharmaceutically acceptable salt is characterized by containing ≤ about 0.6% of the (R)-enantiomer ester or its pharmaceutically acceptable salt. In some embodiments, the (S)-enantiomer ester or its pharmaceutically acceptable salt is characterized by containing ≤ about 0.5% of the (R)-enantiomer ester or its pharmaceutically acceptable salt. In some embodiments, the (S)-enantiomer ester or its pharmaceutically acceptable salt is characterized by containing ≤ about 0.4% of the (R)-enantiomer ester or its pharmaceutically acceptable salt. In some embodiments, the (S)-enantiomer ester or its pharmaceutically acceptable salt is characterized by containing ≤ about 0.3% of the (R)-enantiomer ester or its pharmaceutically acceptable salt. In some embodiments, the (S)-enantiomer ester or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.2% of the (R)-enantiomer ester or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer ester or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the (R)-enantiomer ester or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, this disclosure provides esters of the 11-D-(S)-enantiomer of this disclosure (and 11-D-(S)-enantiomers having at least one deuterium substitution on the aminoheptanoic acid side chain) or pharmaceutically acceptable salts thereof, wherein the esters of the 11-D-(S)-enantiomers or pharmaceutically acceptable salts thereof are characterized by comprising ≤ about 2% of the esters of the 11-D-(R)-enantiomers or pharmaceutically acceptable salts thereof. In some embodiments, the esters of the 11-D-(S)-enantiomers or pharmaceutically acceptable salts thereof are characterized by comprising ≤ about 1% of the esters of the 11-D-(R)-enantiomers or pharmaceutically acceptable salts thereof. In some embodiments, the esters of the 11-D-(S)-enantiomers or pharmaceutically acceptable salts thereof are characterized by comprising ≤ about 0.9% of the esters of the 11-D-(R)-enantiomers or pharmaceutically acceptable salts thereof. In some embodiments, the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.8% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.7% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.6% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.5% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.4% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.3% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.2% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.1% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the ester includes C1-C6 alkyl, C3-C6 branched alkyl, C3-C6 cycloalkyl, and pivaloyloxyethyl esters. Where it is not desirable to be bound by theory, the ester is designed such that the salt of the ester dissolves sufficiently slowly to provide a slow release of the ester, and such that the ester can undergo enzymatic cleavage in the intestine, serum, and / or brain to form the active (S)-enantiomer or the 11-D-(S)-enantiomer at a rate that provides a slow release of the (S)-enantiomer or the 11-D-(S)-enantiomer, allowing for once-daily administration of the ester salt.

[0317] Exemplary esters include 3',3',4',4',tetradeuterated-(S)-thiazoliptin methyl oxalate 1:1 of formula (VII), 2',2',3',3',4',4',5',5',6',6',7',7'-dodecadeuterated-(S)-thiazoliptin isopropyl ester p-toluenesulfonate of formula (VIII), 3',3',4',4',11-pentadeuterated-(S)-thiazoliptin pentazoliptin tervaline ethyl ester benzoate of formula (IX), and (S)-thiazoliptin ethyl ester orotate of formula (X).

[0318]

[0319]

[0320]

[0321]

[0322] In some aspects, this disclosure provides an (S)-enantiomer of the amide or a pharmaceutically acceptable salt thereof, wherein the (S)-enantiomer of the amide or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of an (R)-enantiomer of the amide or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of the amide or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 1% of an (R)-enantiomer of the amide or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of the amide or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.9% of an (R)-enantiomer of the amide or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of the amide or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.8% of an (R)-enantiomer of the amide or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.7% of the (R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.6% of the (R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.5% of the (R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.4% of the (R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.3% of the (R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of the amide or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.2% of the (R)-enantiomer of the amide or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of the amide or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the (R)-enantiomer of the amide or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, this disclosure provides amides of the 11-D-(S)-enantiomer of this disclosure (and 11-D-(S)-enantiomers having at least one deuterium-substituted side chain on an aminoheptanoic acid), wherein the 11-D-(S)-enantiomer amide or its pharmaceutically acceptable salt is characterized by comprising ≤ about 2% of the 11-D-(R)-enantiomer amide or its pharmaceutically acceptable salt. In some embodiments, the 11-D-(S)-enantiomer amide or its pharmaceutically acceptable salt is characterized by comprising ≤ about 1% of the 11-D-(R)-enantiomer amide or its pharmaceutically acceptable salt. In some embodiments, the 11-D-(S)-enantiomer amide or its pharmaceutically acceptable salt is characterized by comprising ≤ about 0.9% of the 11-D-(R)-enantiomer amide or its pharmaceutically acceptable salt. In some embodiments, the 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.8% of the 11-D-(R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.7% of the 11-D-(R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.6% of the 11-D-(R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.5% of the 11-D-(R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.4% of the 11-D-(R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.3% of the 11-D-(R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.2% of the 11-D-(R)-enantiomer amide or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.1% of the 11-D-(R)-enantiomer amide or a pharmaceutically acceptable salt thereof.

[0324] In some embodiments, the amide includes simple amides, C1-C6 alkyl, C3-C6 branched alkyl, and C3-C6 cycloalkyl amides optionally substituted with at least one hydroxyl group. Where it is not desired to be bound by theory, the amide is designed such that the salt of the amide provides the advantages of: improved crystallinity compared to the (S)-enantiomer or 11-D-(S)-enantiomer of tinaptol, selective delivery to the CNS due to metabolism by brain-specific fatty acid amide hydrolases (FAAHs), and cannabinoid activity through the binding of the fatty acid amide to cannabinoid receptors, which may contribute to pain reduction and antidepressant activity.

[0325] Exemplary amides include (S)-N-(7-amino-7-oxoheptyl-4,4,5,5-d4)-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-ammonium 5,5-dioxide oxalate 1:1 of formula (XI) and (S)-3-chloro-N-(7-(isopropylamino)-7-oxoheptyl-1,1,2,2,3,3,4,4,5,5,6,6-d12)-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-ammonium 5,5-dioxide oxalate of formula (XII). The compounds are p-toluenesulfonate, (11S)-3-chloro-6-methyl-N-(7-oxo-7-((1-p-pentamidoethyl)amino)heptyl-4,4,5,5-d4)-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-d-11-ammonium 5,5-dioxide benzoate of formula (XIII), and (S)-3-chloro-N-(7-(ethylamino)-7-oxoheptyl)-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-ammonium 5,5-dioxide orotate of formula (XIV).

[0326]

[0327]

[0328]

[0329]

[0330] In some embodiments, this disclosure provides pharmaceutically acceptable acid salts of the (S)-enantiomers of this disclosure (e.g., (S)-enantiomers or 11-D-(S)-enantiomers), wherein the nitrogen atom in the side chain attached to carbon-11 (C-11) is 100% protonated, and the 100% protonated salts in solid or solution form are less sensitive to air oxidation compared to the (S)-enantiomers, 11-D-(S)-enantiomers, zwitterions of either, or sodium salts of either.

[0331] In some aspects, this disclosure provides a crystalline hemioxalate of (S)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-ylamino)heptanoic acid 5,5-dioxide ((S)-tinaptine). In some embodiments, the crystalline (S)-tinaptine hemioxalate of this disclosure exhibits an X-ray diffraction (XRPD) pattern comprising at least one peak selected from 8.5, 20.6, 21.0, and 24.2 degrees 2θ ± 0.3 degrees 2θ. In some embodiments, the crystalline (S)-tinaptine hemioxalate also exhibits an XRPD pattern comprising at least one peak further comprising the group consisting of 12.1, 13.3, 16.1, 18.9, 19.1, 22.0, and 22.4 degrees 2θ ± 0.3 degrees 2θ.

[0332] In some aspects, this disclosure provides crystalline free acid / free base of the (S)-enantiomer of tiannaphthol. In some embodiments, the crystalline (S)-enantiomer of tiannaphthol exhibits an X-ray diffraction (XRPD) pattern comprising at least one peak selected from 10.6, 13.0, 21.1, and 23.7 degrees 2θ ± 0.3 degrees 2θ. In some embodiments, the crystalline (S)-enantiomer of tiannaphthol exhibits an X-ray diffraction (XRPD) pattern further comprising at least one peak selected from the group consisting of 8.7, 9.1, 12.6, 18.1, 20.4, 23.0, and 26.1 degrees 2θ ± 0.3 degrees 2θ.

[0333] (S)-Tiazoprine analogues

[0334] In some aspects, this disclosure provides the compound N-hydroxy-tianapontine or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure provides the (S)-enantiomer of N-hydroxy-tianapontine (i.e., N-hydroxy-(S)-tianapontine) or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure provides the (R)-enantiomer of N-hydroxy-tianapontine (i.e., N-hydroxy-(R)-tianapontine) or a pharmaceutically acceptable salt thereof. Without wishing to be bound by theory, N-hydroxy-tianapontine does not exhibit µ-opioid receptor (MOR) agonist activity and acts as a potent PPAR-β / δ and / or PPAR-γ agonist.

[0335] In some embodiments, the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 2% (i.e., ≤ about 2%) of the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 1% (i.e., ≤ about 1%) of the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.9% (i.e., ≤ about 0.9%) of the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.8% (i.e., ≤ about 0.8%) of the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.7% (i.e., ≤ about 0.7%) of the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.6% (i.e., ≤ about 0.6%) of the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.5% (i.e., ≤ about 0.5%) of the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.4% (i.e., ≤ about 0.4%) of the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.3% (i.e., ≤ about 0.3%) of the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof.In some embodiments, the (S)-enantiomer of N-hydroxy-tianaphthylamine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.2% (i.e., ≤ about 0.2%) of the (R)-enantiomer of N-hydroxy-tianaphthylamine or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-hydroxy-tianaphthylamine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.1% (i.e., ≤ about 0.1%) of the (R)-enantiomer of N-hydroxy-tianaphthylamine or a pharmaceutically acceptable salt thereof.

[0336] In some embodiments, the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 2% (i.e., ≤ about 2%) of the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 1% (i.e., ≤ about 1%) of the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.9% (i.e., ≤ about 0.9%) of the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.8% (i.e., ≤ about 0.8%) of the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.7% (i.e., ≤ about 0.7%) of the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.6% (i.e., ≤ about 0.6%) of the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.5% (i.e., ≤ about 0.5%) of the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.4% (i.e., ≤ about 0.4%) of the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.3% (i.e., ≤ about 0.3%) of the (S)-enantiomer of N-hydroxy-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.2% (i.e., ≤ about 0.2%) of the (S)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt thereof.In some embodiments, the (R)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.1% (i.e., ≤ about 0.1%) of the (S)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 2% (i.e., ≤ about 2%) of the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 1% (i.e., ≤ about 1%) of the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.9% (i.e., ≤ about 0.9%) of the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.8% (i.e., ≤ about 0.8%) of the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.7% (i.e., ≤ about 0.7%) of the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.6% (i.e., ≤ about 0.6%) of the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.5% (i.e., ≤ about 0.5%) of the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.4% (i.e., ≤ about 0.4%) of the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-nitroso-tianaphthol or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.3% (i.e., ≤ about 0.3%) of the (R)-enantiomer of N-nitroso-tianaphthol or a pharmaceutically acceptable salt thereof.In some embodiments, the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.2% (i.e., ≤ about 0.2%) of the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.1% (i.e., ≤ about 0.1%) of the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof.

[0338] In some embodiments, the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 2% (i.e., ≤ about 2%) of the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 1% (i.e., ≤ about 1%) of the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.9% (i.e., ≤ about 0.9%) of the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.8% (i.e., ≤ about 0.8%) of the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.7% (i.e., ≤ about 0.7%) of the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.6% (i.e., ≤ about 0.6%) of the (S)-enantiomer of N-nitroso-tianaphthylpropionate or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.5% (i.e., ≤ about 0.5%) of the (S)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.4% (i.e., ≤ about 0.4%) of the (S)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianaphthol or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.3% (i.e., ≤ about 0.3%) of the (S)-enantiomer of N-nitroso-tianaphthol or a pharmaceutically acceptable salt thereof.In some embodiments, the (R)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.2% (i.e., ≤ about 0.2%) of the (S)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.1% (i.e., ≤ about 0.1%) of the (S)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof.

[0339] In some aspects, this disclosure provides the compound N-nitroso-tiaponectin or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure provides the (S)-enantiomer of N-nitroso-tiaponectin (i.e., N-nitroso-(S)-tiaponectin) or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure provides the (R)-enantiomer of N-nitroso-tiaponectin (i.e., N-nitroso-(R)-tiaponectin) or a pharmaceutically acceptable salt thereof. Without wishing to be bound by theory, N-hydroxy-tiaponectin does not exhibit µ-opioid receptor (MOR) agonist activity and acts as a potent PPAR-β / δ and / or PPAR-γ agonist.

[0340] In some aspects, this disclosure provides aryl-substituted thiazoprine derivatives. Exemplary derivatives include 7-((3-(furan-2-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-yl)amino)heptanoic acid of formula (XXI), 7-((3-(furan-3-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-yl)amino)heptanoic acid of formula (XXII), and so on. (XXIII) 7-((6-methyl-5,5-dioxide-3-(thien-3-yl)-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-yl)amino)heptanoic acid and (XXIV) 2-(4-(((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-yl)amino)methyl)-2-methylphenoxy)acetic acid. Without being bound by theory, aryl-substituted tiannaptine derivatives exhibit increased membrane permeability compared to tiannaptine due to the aromatic ring, and the (R)-enantiomers and racemic mixtures of aryl-substituted tiannaptine derivatives exhibit reduced MOR activating activity compared to (R)-tiannaptine and racemic tiannaptine due to the molecular shape.

[0341]

[0342] Pharmaceutical Composition

[0343] The compounds described herein may be applied as the (S)-enantiomer or 11-D-(S)-enantiomer of this disclosure, or, if desired, as a zwitterion, salt (including crystalline salt), ester, ester salt, amide, amide salt, or cocrystal of this disclosure, provided that the zwitterion, salt, ester, ester salt, amide, amide salt, or cocrystal is pharmacologically suitable, for example, effective in one or more of the methods of this application. The zwitterion, salt, ester, ester salt, or cocrystal of the (S)-enantiomer or 11-D-(S)-enantiomer of this disclosure may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry.

[0344] In some embodiments, this disclosure provides pharmaceutical compositions comprising one or more of the (S)-enantiomers of this disclosure, namely, zwitterions or pharmaceutically acceptable salts of the (S)-enantiomers of this disclosure, or cocrystals of the (S)-enantiomers of this disclosure (including crystalline salts thereof) or zwitterions thereof, or esters of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, or amides of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents, or excipients, wherein the composition comprises not more than about 2% (i.e., ≤ about 2%) of the (R)-enantiomer, its zwitterion, or pharmaceutically acceptable salts of the (R)-enantiomer, or cocrystals of the (R)-enantiomer or its zwitterion, or esters of the (R)-enantiomer or pharmaceutically acceptable salts thereof, or amides of the (R)-enantiomer or pharmaceutically acceptable salts thereof.

[0345] In some embodiments, this disclosure provides pharmaceutical compositions comprising the (S)-enantiomer of tianapordine of this disclosure, its zwitterion, or a pharmaceutically acceptable salt (including crystalline salts) of the (S)-enantiomer of this disclosure, or a cocrystal of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this disclosure or thereof. Pharmaceutically acceptable salts and pharmaceutically acceptable carriers, diluents, or excipients, wherein the composition comprises not more than about 2% (i.e., ≤ about 2%) of the (R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (R)-enantiomer of this disclosure or its pharmaceutically acceptable salt. In some embodiments, the composition comprises not more than about 1% (i.e., ≤ about 1%) of the (R)-enantiomer of tianapordine of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.9% (i.e., ≤ about 0.9%) of the (R)-enantiomer of tianapordine of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.8% (i.e., ≤ about 0.8%) of the (R)-enantiomer of tianapordine of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.7% (i.e., ≤ about 0.7%) of the (R)-enantiomer of tinaptrine of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a eutectic of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt of the (R)-enantiomer, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt of the (R)-enantiomer.In some embodiments, the composition comprises no more than about 0.6% (i.e., ≤ about 0.6%) of the (R)-enantiomer of tiannaphthol of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.5% (i.e., ≤ about 0.5%) of the (R)-enantiomer of tiannaphthol of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.4% (i.e., ≤ about 0.4%) of the (R)-enantiomer of tiannaphthol of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.3% (i.e., ≤ about 0.3%) of the (R)-enantiomer of tiannaphthol of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.2% (i.e., ≤ about 0.2%) of the (R)-enantiomer of tianapordine of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments of this disclosure, the composition comprises no more than about 0.1% (i.e., ≤ about 0.1%) of the (R)-enantiomer of tianapordine of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (R)-enantiomer or its pharmaceutically acceptable salt.

[0346] In some embodiments, the pharmaceutical composition of this disclosure comprises the (S)-enantiomer of tianapordine of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt (including crystalline salts thereof) of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable cocrystal of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a zwitterion of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises an ester of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of an ester of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises an amide of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of an amide of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient.

[0347] In some embodiments, this disclosure provides pharmaceutical compositions comprising the 11-D-(S)-enantiomer of tianapordine of this disclosure (and the 11-D-(S)-enantiomer having at least one deuterium substitution on the aminoheptanoic acid side chain), its zwitterion, or a pharmaceutically acceptable salt (including its crystalline salt) of the 11-D-(S)-enantiomer of this disclosure, or a cocrystal of the 11-D-(S)-enantiomer of this disclosure or its zwitterion, or an ester of the 11-D-(S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer of this disclosure. The composition comprises an amide of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition contains not more than about 2% (i.e., ≤ about 2%) of the 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 1% (i.e., ≤ about 1%) of the 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.9% (i.e., ≤ about 0.9%) of the 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.8% (i.e., ≤ about 0.8%) of the 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt.In some embodiments, the composition comprises no more than about 0.7% (i.e., ≤ about 0.7%) of the 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.6% (i.e., ≤ about 0.6%) of the 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.5% (i.e., ≤ about 0.5%) of the 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.4% (i.e., ≤ about 0.4%) of the 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.3% (i.e., ≤ about 0.3%) of the 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt. In some embodiments, the composition comprises no more than about 0.2% (i.e., ≤ about 0.2%) of the 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt.In some embodiments of this disclosure, the composition comprises no more than about 0.1% (i.e., ≤ about 0.1%) of the 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(R)-enantiomer or its pharmaceutically acceptable salt.

[0348] In some embodiments, the pharmaceutical compositions of this disclosure comprise the 11-D-(S)-enantiomer of tianapordine of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions comprise a pharmaceutically acceptable salt (including its crystalline salt) of the 11-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions comprise a pharmaceutically acceptable cocrystal of the 11-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions comprise a zwitterion of the 11-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions comprise an ester of the 11-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of an ester of the 11-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises an amide of the 11-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of an amide of the 11-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient.

[0349] In some embodiments, the composition comprises a mixture of pharmaceutically acceptable salts (including crystalline salts thereof) or cocrystals of two or more (S)-enantiomers or 11-D-(S)-enantiomers (and 11-D-(S)-enantiomers having at least one deuterium substitution on the aminoheptanoic acid side chain), wherein the mixture of pharmaceutically acceptable salts or cocrystals is characterized by enhanced prolonged release upon oral administration compared to administration of a composition comprising a single pharmaceutically acceptable salt or cocrystal of the (S)-enantiomer or 11-D-(S)-enantiomer of the present disclosure. In some embodiments, without being bound by theory, the enhanced prolonged release of the mixture of pharmaceutically acceptable salts or cocrystals is due to the different dissolution rates of each of the salt or cocrystal forms in the intestine.

[0350] In some embodiments, the pharmaceutical compositions of this disclosure comprise one or more of the following: thiazoliptin analogues of this disclosure, namely, N-hydroxy-thiazoliptin, (S)-enantiomers of N-hydroxy-thiazoliptin, (R)-enantiomers of N-hydroxy-thiazoliptin, N-nitroso-thiazoliptin, (S)-enantiomers of N-nitroso-thiazoliptin, (R)-enantiomers of N-nitroso-thiazoliptin, or aryl-substituted analogues of thiazoliptin of this disclosure, or pharmaceutically acceptable salts of any of them; and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise N-hydroxy-thiazoliptin of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise a pharmaceutically acceptable salt of the N-hydroxy-tianaphthylpropionate of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise the (S)-enantiomer of the N-hydroxy-tianaphthylpropionate of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise a pharmaceutically acceptable salt of the (S)-enantiomer of the N-hydroxy-tianaphthylpropionate of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise the (R)-enantiomer of the N-hydroxy-tianaphthylpropionate of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise a pharmaceutically acceptable salt of the (R)-enantiomer of the N-hydroxy-tianaphthylpropionate of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise the N-nitroso-tiaponectin of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise a pharmaceutically acceptable salt of the N-nitroso-tiaponectin of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise the (S)-enantiomer of the N-nitroso-tiaponectin of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise a pharmaceutically acceptable salt of the (S)-enantiomer of the N-nitroso-tiaponectin of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise the (R)-enantiomer of the N-nitroso-tiaponectin of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient.In some embodiments, the pharmaceutical compositions of this disclosure comprise a pharmaceutically acceptable salt of the (R)-enantiomer of the N-nitroso-tianapordine of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise an aryl-substituted analog of tianapordine of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical compositions of this disclosure comprise a pharmaceutically acceptable salt of an aryl-substituted analog of tianapordine of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient.

[0351] In some embodiments, this disclosure provides pharmaceutical compositions comprising the (S)-enantiomer of N-hydroxy-tianapril of this disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises not more than about 2% (i.e., ≤ about 2%) of the (R)-enantiomer of N-hydroxy-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 1% (i.e., ≤ about 1%) of the (R)-enantiomer of N-hydroxy-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 0.9% (i.e., ≤ about 0.9%) of the (R)-enantiomer of N-hydroxy-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 0.8% (i.e., ≤ about 0.8%) of the (R)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of such enantiomer. In some embodiments, the composition comprises not more than about 0.7% (i.e., ≤ about 0.7%) of the (R)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of such enantiomer. In some embodiments, the composition comprises not more than about 0.6% (i.e., ≤ about 0.6%) of the (R)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of such enantiomer. In some embodiments, the composition comprises not more than about 0.5% (i.e., ≤ about 0.5%) of the (R)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of such enantiomer. In some embodiments, the composition comprises no more than about 0.4% (i.e., ≤ about 0.4%) of the (R)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of such enantiomer. In some embodiments, the composition comprises no more than about 0.3% (i.e., ≤ about 0.3%) of the (R)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of such enantiomer. In some embodiments, the composition comprises no more than about 0.2% (i.e., ≤ about 0.2%) of the (R)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of such enantiomer. In some embodiments, the composition comprises no more than about 0.1% (i.e., ≤ about 0.1%) of the (R)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of such enantiomer.

[0352] In some embodiments, this disclosure provides pharmaceutical compositions comprising the (R)-enantiomer of N-hydroxy-tianapril of this disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises not more than about 2% (i.e., ≤ about 2%) of the (S)-enantiomer of N-hydroxy-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 1% (i.e., ≤ about 1%) of the (S)-enantiomer of N-hydroxy-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 0.9% (i.e., ≤ about 0.9%) of the (S)-enantiomer of N-hydroxy-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 0.8% (i.e., ≤ about 0.8%) of the (S)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.7% (i.e., ≤ about 0.7%) of the (S)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.6% (i.e., ≤ about 0.6%) of the (S)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.5% (i.e., ≤ about 0.5%) of the (S)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.4% (i.e., ≤ about 0.4%) of the (S)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.3% (i.e., ≤ about 0.3%) of the (S)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.2% (i.e., ≤ about 0.2%) of the (S)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.1% (i.e., ≤ about 0.1%) of the (S)-enantiomer of N-hydroxy-tianaphthol or a pharmaceutically acceptable salt of the enantiomer.

[0353] In some embodiments, this disclosure provides pharmaceutical compositions comprising the (S)-enantiomer of N-nitroso-tianapril of this disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises not more than about 2% (i.e., ≤ about 2%) of the (R)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 1% (i.e., ≤ about 1%) of the (R)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 0.9% (i.e., ≤ about 0.9%) of the (R)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 0.8% (i.e., ≤ about 0.8%) of the (R)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.7% (i.e., ≤ about 0.7%) of the (R)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.6% (i.e., ≤ about 0.6%) of the (R)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.5% (i.e., ≤ about 0.5%) of the (R)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises no more than about 0.4% (i.e., ≤ about 0.4%) of the (R)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises no more than about 0.3% (i.e., ≤ about 0.3%) of the (R)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises no more than about 0.2% (i.e., ≤ about 0.2%) of the (R)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises no more than about 0.1% (i.e., ≤ about 0.1%) of the (R)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer.

[0354] In some embodiments, this disclosure provides pharmaceutical compositions comprising the (R)-enantiomer of N-nitroso-tianapril of this disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises not more than about 2% (i.e., ≤ about 2%) of the (S)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 1% (i.e., ≤ about 1%) of the (S)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 0.9% (i.e., ≤ about 0.9%) of the (S)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises not more than about 0.8% (i.e., ≤ about 0.8%) of the (S)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.7% (i.e., ≤ about 0.7%) of the (S)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.6% (i.e., ≤ about 0.6%) of the (S)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises not more than about 0.5% (i.e., ≤ about 0.5%) of the (S)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises no more than about 0.4% (i.e., ≤ about 0.4%) of the (S)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises no more than about 0.3% (i.e., ≤ about 0.3%) of the (S)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises no more than about 0.2% (i.e., ≤ about 0.2%) of the (S)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises no more than about 0.1% (i.e., ≤ about 0.1%) of the (S)-enantiomer of N-nitroso-tianapriptine or a pharmaceutically acceptable salt of the enantiomer.

[0355] Dosage form and administration method

[0356] The (S)-enantiomers (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), zwitterions, pharmaceutically acceptable salts, cocrystals, esters and pharmaceutically acceptable salts of such esters, amides and pharmaceutically acceptable salts of such amides, and analogs of the tiannaphthol of this disclosure (i.e., N-hydroxy-tiannaphthol, its (S)- and (R)-enantiomers, N-nitroso-tiannaphthol, its (S)- and (R)-enantiomers or aryl-substituted tiannaphthol analogs, or pharmaceutically acceptable salts thereof) and pharmaceutical compositions thereof may be administered by any suitable route of administration. The present disclosure includes the (S)-enantiomer of tialapril, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer of the present disclosure and its crystalline form, or a cocrystal of the (S)-enantiomer of the present disclosure or its zwitterion, or an ester of the (S)-enantiomer of the present disclosure or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer of the present disclosure or its pharmaceutically acceptable salt, or the present disclosure includes the 11-D-(S)-enantiomer of tialapril, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the present disclosure and its crystalline form, or the present disclosure includes the 11-D-(S)-enantiomer of the present disclosure. Exemplary routes of administration for the pharmaceutical compositions thereof or the pharmaceutical compositions thereof include, but are not limited to, parenteral, oral, sublingual, sublingual, inhalation, palatal, transdermal, rectal, and vaginal administration of the enantiomers or zwitterions thereof, or esters of the 11-D-(S)-enantiomers of this disclosure, or amides of the 11-D-(S)-enantiomers thereof, or analogs of tiaponectin of this disclosure (i.e., N-hydroxy-tiaponectin, its (S)- and (R)-enantiomers, N-nitroso-tiaponectin, its (S)- and (R)-enantiomers, or aryl-substituted tiaponectin analogs) or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof or pharmaceutical compositions thereof.

[0357] In some embodiments, the dosage forms available for administration of the (S)-enantiomers of tiannaphthol of this disclosure (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), zwitterions, pharmaceutically acceptable salts, cocrystals, esters and pharmaceutically acceptable salts of such esters, amides, or analogs of tiannaphthol (i.e., N-hydroxy-tiannaphthol, its (S)- and (R)-enantiomers, N-nitroso-tiannaphthol, its (S)- and (R)-enantiomers, or aryl-substituted tiannaphthol analogs and their pharmaceutically acceptable salts) and pharmaceutical compositions of this disclosure may include, but are not limited to, tablets (such as scored tablets, coated tablets, small tablets, chewable tablets, orally dispersible tablets, or soluble tablets); films; powders (e.g., lung powders or dry powder inhalers); capsule tablets; capsules (e.g., hard gelatin capsules); soft gels; suppositories; nasal and other forms of inhalation sprays. In some embodiments, the dosage form is a tablet. In some embodiments, the dosage form is a film. In some embodiments, the dosage form is a powder. In some embodiments, the dosage form is a capsule tablet. In some embodiments, the dosage form is a capsule. In some embodiments, the dosage form is a suppository. In some embodiments, the dosage form is an inhalation spray. In some embodiments, the spray is a nasal spray. In some embodiments, the spray is an oral spray.

[0358] In some embodiments, the dosage form of this disclosure for parenteral administration may be in the form of an aqueous or non-aqueous solution, a dispersion, a suspension, or an emulsion. For example, in preparing a dosage form of the present disclosure for parenteral administration, at least one of the following is mixed with a suitable pharmaceutically acceptable carrier (such as water, oil (especially vegetable oil), ethanol, saline solution (e.g., physiological saline), dextran (glucose) aqueous solution and related sugar solution, glycerol, or glycol (such as propylene glycol or polyethylene glycol)): the (S)-enantiomer of tianapordine of the present disclosure (i.e., (S)-enantiomer or 11-D-(S)-enantiomer), zwitterion, eutectic, ester or pharmaceutically acceptable salt, amide, or analogue of tianapordine (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers or aryl-substituted tianapordine analogues) or a pharmaceutically acceptable salt thereof. For parenteral administration, these dosage forms preferably contain a water-soluble salt of at least one of the following: the (S)-enantiomer of tiannaphthol of this disclosure (i.e., the (S)-enantiomer or the 11-D-(S)-enantiomer), zwitterion, eutectic, ester, amide, N-hydroxy-tiannaphthol, its (S)- or (R)-enantiomer, or analogs of tiannaphthol (i.e., N-hydroxy-tiannaphthol, its (S)- and (R)-enantiomers, N-nitroso-tiannaphthol, its (S)- and (R)-enantiomers, or aryl-substituted tiannaphthol analogs) or pharmaceutically acceptable salts thereof. Stabilizers, antioxidants, and preservatives may also be added to the parenteral dosage forms. Suitable antioxidants include sulfites, ascorbic acid, citric acid and its salts, and sodium EDTA. Suitable preservatives include benzalkonium chloride, methylparaben or propylparaben and chlorobutanol.

[0359] For oral administration, in some embodiments, the dosage form of this disclosure comprises at least one of the following: (S)-enantiomers of tianapordine of this disclosure (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), zwitterions, cocrystals, esters, amides, or analogs of tianapordine (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogs), and salts, combined with one or more solid or liquid inactive ingredients to form tablets, capsules, pills, powders, or other suitable oral dosage forms. For example, at least one of the following: (S)-enantiomers of tianapordine of this disclosure (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), zwitterions, esters, amides, salts or cocrystals, or analogs of tianapordine (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers or aryl-substituted tianapordine analogs) and salts, may be combined with at least one pharmaceutically acceptable carrier (such as a solvent, filler, binder, wetting agent, disintegrant, solution retarder, absorption enhancer, wetting absorbent or lubricant). In one embodiment, at least one of the following: (S)-enantiomers of tiannaphthol of the present disclosure (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), zwitterions, esters, amides, salts or cocrystals or analogs of tiannaphthol (i.e., N-hydroxy-tiannaphthol, its (S)- and (R)-enantiomers, N-nitroso-tiannaphthol, its (S)- and (R)-enantiomers or aryl-substituted tiannaphthol analogs) and salts, is combined with calcium carboxymethyl cellulose, magnesium stearate, mannitol and starch, and tablets are formed by conventional tableting methods. In one embodiment, the (S)-enantiomer of tiannaphthol of this disclosure (i.e., the (S)-enantiomer or 11-D-(S)-enantiomer), zwitterion, ester, amide, salt or cocrystal or analogue of tiannaphthol (i.e., N-hydroxy-tiannaphthol, its (S)- and (R)-enantiomers, N-nitroso-tiannaphthol, its (S)- and (R)-enantiomers or aryl-substituted tiannaphthol analogues) and salt are formulated into tablets comprising cellulose and calcium salts, as described in U.S. Patent No. 5,888,542, the entire disclosure of which is incorporated herein by reference.

[0360] In some embodiments, dosage forms of the (S)-enantiomer or 11-D-(S)-enantiomer of this disclosure, its zwitterion, salt, cocrystal, ester or amide, or analogues of tianapordine (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers or aryl-substituted tianapordine analogues) and salts are formulated for immediate release, controlled release, sustained release, extended release, or slow release. In some embodiments, the dosage forms of this disclosure are formulated for the immediate release of the (S)-enantiomer of this disclosure, its zwitterion, salt, ester, amide, or cocrystal, or analogs of tianapordine (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogs) and their salts. In some embodiments, the dosage forms of this disclosure are formulated for the immediate release of the 11-D-(S)-enantiomer of this disclosure, its zwitterion, salt, ester, amide, or cocrystal. In some embodiments, the dosage forms of this disclosure are formulated for the immediate release of tianapordine analogs of this disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogs or pharmaceutically acceptable salts thereof). In some embodiments, the dosage forms of this disclosure are formulated for the controlled release of the (S)-enantiomer of this disclosure, its zwitterion, salt, ester, amide, or cocrystal. In some embodiments, the dosage forms of this disclosure are formulated for the controlled release of the 11-D-(S)-enantiomer of this disclosure, its zwitterion, salt, ester, amide, or cocrystal. In some embodiments, the dosage forms of this disclosure are formulated for the controlled release of tiannaphthol analogues of this disclosure (i.e., N-hydroxy-tiannaphthol, its (S)- and (R)-enantiomers, N-nitroso-tiannaphthol, its (S)- and (R)-enantiomers, or aryl-substituted tiannaphthol analogues or pharmaceutically acceptable salts thereof). In some embodiments, the compositions of this disclosure are formulated for the sustained release of the (S)-enantiomer of this disclosure, its zwitterion, salt, ester, amide, or cocrystal. In some embodiments, the dosage forms of this disclosure are formulated for the sustained release of the 11-D-(S)-enantiomer of this disclosure, its zwitterion, salt, ester, amide, or cocrystal. In some embodiments, the dosage forms of this disclosure are formulated for the sustained release of analogues of tiannaphthol of this disclosure (i.e., N-hydroxy-tiannaphthol, its (S)- and (R)-enantiomers, N-nitroso-tiannaphthol, its (S)- and (R)-enantiomers, or aryl-substituted tiannaphthol analogues or pharmaceutically acceptable salts thereof).In some embodiments, the dosage forms of this disclosure are formulated for the prolonged release of the (S)-enantiomer, its zwitterion, salt, ester, amide, or cocrystal of this disclosure. In some embodiments, the dosage forms of this disclosure are formulated for the prolonged release of the 11-D-(S)-enantiomer, its zwitterion, salt, ester, amide, or cocrystal of this disclosure. In some embodiments, the dosage forms of this disclosure are formulated for the prolonged release of tianaporptine analogs of this disclosure (i.e., N-hydroxy-tianaporptine, its (S)- and (R)-enantiomers, N-nitroso-tianaporptine, its (S)- and (R)-enantiomers, or aryl-substituted tianaporptine analogs or pharmaceutically acceptable salts). In some embodiments, the dosage forms of this disclosure are formulated for the slow release of the (S)-enantiomer, its zwitterion, salt, ester, amide, or cocrystal of this disclosure. In some embodiments, the dosage forms of this disclosure are formulated for the slow release of the 11-D-(S)-enantiomer of this disclosure, its zwitterion, salt, ester, amide, or cocrystal. In some embodiments, the dosage forms of this disclosure are formulated for the slow release of analogues of tianapordine of this disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogues or pharmaceutically acceptable salts thereof).

[0361] Preferably, the controlled-release formulations of this disclosure enable the release of at least one of the (S)-enantiomers of tiannaphthol (i.e., the (S)-enantiomer or the 11-D-(S)-enantiomer), its zwitterions, esters, amides, salts, or cocrystals, or analogs of tiannaphthol (i.e., N-hydroxy-tiannaphthol, its (S)- and (R)-enantiomers, N-nitroso-tiannaphthol, its (S)- and (R)-enantiomers, or aryl-substituted tiannaphthol analogs or pharmaceutically acceptable salts thereof) at a desired rate into a subject, thereby maintaining substantially constant pharmacological activity over a given time period. The formulation of the controlled-release pharmaceutical compositions of the present invention is within the scope of the art. Controlled-release formulations suitable for use in this invention are described, for example, in U.S. Patent No. 5,674,533 (liquid dosage form), U.S. Patent No. 5,591,767 (liquid reservoir transdermal patch), U.S. Patent No. 5,120,548 (device comprising a swellable polymer), U.S. Patent No. 5,073,543 (ganglioside-liposome mediator), and U.S. Patent No. 5,639,476 (stable solid dosage form coated with a hydrophobic acrylic polymer), the entire disclosure of which is incorporated herein by reference.

[0362] Biodegradable microparticles may also be used to formulate controlled-release formulations of the present disclosure, for example, as described in U.S. Patent Nos. 5,354,556 and 5,733,566, the entire disclosure of which is incorporated herein by reference.

[0363] In one embodiment, the controlled-release dosage form of this disclosure comprises at least one of the following: a (S)-enantiomer of tiannaphthol (i.e., (S)-enantiomer or 11-D-(S)-enantiomer), a zwitterion thereof, a pharmaceutically acceptable salt of the (S)-enantiomer, a eutectic of the (S)-enantiomer or its zwitterion, an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or an analogue of tiannaphthol (i.e., N-hydroxy-tiannaphthol, its (S)- and (R)-enantiomers, N-nitroso-tiannaphthol, its (S)- and (R)-enantiomers, or an aryl-substituted tiannaphthol analogue or its pharmaceutically acceptable salt), and a controlled-release component. As used herein, a “controlled release component” is a compound, such as a polymer, polymer matrix, gel, permeable membrane, liposome, and / or microsphere, which, upon exposure to a physiological compound or condition, induces the controlled release of at least one of the (S)-enantiomers, zwitterions, cocrystals, esters, amides, and salts of this disclosure into a subject. For example, a controlled release component may be biodegradable and activated by exposure to a certain pH or temperature, by exposure to an aqueous environment, or by exposure to an enzyme. An example of a controlled release component activated by exposure to a certain temperature is a sol-gel. In this embodiment, at least one of the following is incorporated into a sol-gel matrix that is solid at room temperature: the (S)-enantiomer of thiazoline of the present disclosure (i.e., the (S)-enantiomer or 11-D-(S)-enantiomer), its zwitterion, a pharmaceutically acceptable salt of the (S)-enantiomer, a eutectic of the (S)-enantiomer or its zwitterion, an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer, N-hydroxy-thiazoline, its (S)- or (R)-enantiomer, or an analogue of thiazoline (i.e., N-hydroxy-thiazoline, its (S)- and (R)-enantiomers, N-nitroso-thiazoline, its (S)- and (R)-enantiomers, or an aryl-substituted thiazoline analogue or a pharmaceutically acceptable salt thereof). When the sol-gel matrix is ​​implanted in a subject with a sufficiently high body temperature to induce gel formation of the sol-gel matrix, tinaptine is released into the subject.

[0364] Exemplary obstacles to this disclosure

[0365] The diseases, disorders, or conditions covered in this disclosure include, but are not limited to, central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infectious diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia (e.g., statin-resistant hypertriglyceridemia, mixed hypertriglyceridemia, and familial hypertriglyceridemia), cancers (e.g., glioblastoma or glioma), menopausal and chronic overlapping pain syndromes (COPC), as well as psychological, physiological, metabolic, or hormonal stress and COPC.

[0366] The CNS disorders disclosed herein include, but are not limited to, mood disorders (e.g., major depressive disorder (MDD), bipolar disorder, or substance-induced disorders), trauma and stress-related disorders (e.g., post-traumatic stress disorder (PTSD), acute stress disorder (ASD), adjustment disorder, or reactive attachment disorder), anxiety disorders (e.g., panic disorder, generalized anxiety disorder (GAD), specific phobias, agoraphobia, or social phobia), obsessive-compulsive disorder, and neurodegenerative or neuroinflammatory disorders (e.g., mild cognitive impairment, Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, multiple sclerosis). (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, neuromyelitis optica, myasthenia gravis, autoimmune encephalitis, prions, transverse myelitis, or childhood autoimmune neuropsychiatric disorders (PANDAS) associated with streptococcal infection, neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder (ADHD), schizophrenia, Prad-Willi syndrome (including overeating and other symptoms such as depression and anxiety) or autism), leukodystrophy (e.g., leukoencephalopathy, myelination insufficiency or demyelinating disease), intellectual disability syndromes (e.g., Fragile X syndrome). (Combined symptoms), cognitive impairment (e.g., cognitive impairment associated with disease, disorder, or condition (e.g., mild cognitive impairment, prodromal Alzheimer's disease or Alzheimer's disease, prodromal frontotemporal dementia (FTD) or FTD, prodromal postcortical atrophy (PCA) or PCA, cognitive impairment associated with schizophrenia, drug-induced cognitive impairment – ​​such as corticosteroid-induced cognitive impairment, doxorubicin-induced cognitive impairment, chemotherapy-induced cognitive impairment, alcohol-induced cognitive impairment, or substance-induced cognitive impairment, radiation-induced cognitive impairment, and cognitive impairment associated with space). Travel-related cognitive decline (e.g., space-related neuro-eye syndrome (SANS) or cognitive decline associated with increased space radiation exposure, or cognitive deficits and neuropathic pain associated with diabetes), age-related cognitive impairment (e.g., age-related cognitive impairment, age-related cognitive decline (ARCD), age-related memory impairment (AAMI)), glial cell dysfunction, or brain injury (e.g., traumatic brain injury, hypoxia-induced brain injury, toxin-induced brain injury, reperfusion injury after stroke or ischemic stroke), and CNS oxidative stress.

[0367] Inflammatory diseases covered by this disclosure include, but are not limited to, postoperative cognitive impairment, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile diabetes or type 1 diabetes), Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0368] The autoimmune diseases disclosed herein include, but are not limited to, achalasia, Addison's disease, adult-onset Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and... Aneurysmal neuron disease (AMAN), Barlow's disease, Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, Kassman's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Schulchström syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, Coxsackievirus myocarditis, CREST syndrome, Crohn's disease, herpetic dermatitis, dermatomyositis, Dervex disease (neuromyelitis optica). Discoid lupus, Desleser syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, primary mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpassuu syndrome, granulomatous polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, allergic purpura (HSP), herpes gestationis or pemphigoid of pregnancy (PG), hidradenitis suppurativa (HS) (acne paradox), hypogammaglobulin Blood disorders, IgA nephropathy, IgG4-associated sclerotic diseases, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eton syndrome, leukocytic clotting vasculitis, lichen planus, sclerosing lichen, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcerulcer), Muhammad-Haydner disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parsonage-Ross syndrome, paroxysmal plaque inflammation (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, peripheral encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, jaundice Ketoacidosis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrene, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testis autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Sussac syndrome, sympathetic ophthalmia (SO), high-stress arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunter syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wechsler granulomatosis (or granulomatous polyangiitis (GPA)).

[0369] Infectious diseases covered by this disclosure include, but are not limited to, viral infections (e.g., COVID-19, influenza, human immunodeficiency virus (HIV), and herpes) or postviral conditions (e.g., long COVID).

[0370] The hearing loss conditions disclosed herein include, but are not limited to, mitochondrial nonsyndromic hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic / inherited hearing loss, hearing loss experienced due to ototoxic exposure, hearing loss caused by disease, and hearing loss caused by trauma.

[0371] The eye diseases covered by this disclosure include, but are not limited to, cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), and diabetic retinopathy.

[0372] The musculoskeletal disorders disclosed herein include, but are not limited to, muscular dystrophy (e.g., Dichené muscular dystrophy, Beck muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emory-Dreyfus muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy type 1, or myotonic dystrophy type 2), multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, painful spastic fasciculations, Friedreich ataxia, muscle wasting disorders (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease, and paralysis.

[0373] The metabolic diseases covered by this disclosure include, but are not limited to, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity (e.g., diet-induced obesity), heart disease (e.g., cardiomegaly), atherosclerosis, arthritis, cystinosis, diabetes (e.g., type I diabetes, type II diabetes, or gestational diabetes), phenylketonuria, proliferative retinopathy, and Karns-Sell disease.

[0374] Mitochondrial diseases covered by this disclosure include, but are not limited to, Bass syndrome, chronic progressive extraocular muscle palsy (cPEO), Karns-Sell syndrome (KSS), Leigh syndrome (e.g., MILS, or maternally inherited Leigh syndrome), mitochondrial DNA depletion syndromes (MDDS, e.g., Alpert syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, hyperlactatemia, and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with broken red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leigh inherited optic neuropathy (LHON), and Pearson syndrome.

[0375] In some embodiments, the diseases, disorders, or conditions illustrated in this disclosure are regulated, aggravated, or associated with altered activity of PPAR-β / δ and / or PPAR-γ. In some embodiments, the diseases, disorders, or conditions illustrated in this disclosure are regulated, aggravated, or associated with high levels of S-nitrosylation of PPAR-β / δ and / or PPAR-γ. In some embodiments, the diseases, disorders, or conditions illustrated in this disclosure are regulated, aggravated, or associated with excessive levels of circulating metal ions (e.g., iron or copper).

[0376] CNS disorders

[0377] Exemplary clinical symptoms of CNS disorders, diseases, and conditions include, but are not limited to, cognitive impairments, including age-related cognitive decline (which is similar to or less robust than age-matched controls), changes in attention and memory; difficulties with speech, comprehension, reading, or writing; inability to process thoughts; anxiety; irritability or aggression; muscle fatigue; muscle wasting; difficulty walking; headache; hearing loss; seizures; spasms; speech and swallowing difficulties; tremor; paralysis; blindness; and sensory loss.

[0378] Major depressive disorder

[0379] Major depressive disorder (MDD), also known as "clinical depression," is a mood disorder in which symptoms affecting how a person feels, thinks, and deals with daily activities are present almost daily and last for at least two weeks. Symptoms associated with MDD include: (1) persistent sadness, anxiety, or “emptiness”; (2) feelings of hopelessness or pessimism; (3) irritability; (4) feelings of guilt, worthlessness, or helplessness; (5) loss of interest in or pleasure from hobbies and activities (e.g., anhedonia); (6) reduced energy or fatigue; (7) slower movement or speech; (8) psychomotor agitation or retardation; (9) restlessness or difficulty sitting still; (10) difficulty concentrating, remembering, or making decisions; (11) difficulty sleeping, early awakening, or excessive sleep (e.g., insomnia or hypersomnia); (12) changes in appetite and / or weight (e.g., more than 5% weight change in one month); (13) recurrent thoughts of death or suicide; (14) suicide attempts; and (15) pain (ache / pain), headache, cramps, or digestive problems that are not relieved by treatment and have no clear physical cause.

[0380] MDD can be diagnosed based on the following: (1) physical examination; (2) laboratory tests (e.g., blood tests for complete blood count and / or assessment of thyroid function); (3) psychiatric evaluation (e.g., health professionals asking about symptoms, thoughts, feelings, and behavioral patterns and / or patients completing questionnaires such as the Hospital Anxiety and Depression Scale (HADS), Hamilton Depression Rating Scale (HDRS, HAM-D), and Montgomery-Essenberg Depression Rating Scale (MADRS)); and (4) Diagnostic and Statistical Manual of Mental Disorders (e.g., DSM-5 lists the criteria for depression published by the American Psychiatric Association).

[0381] The DSM-5 criteria for diagnosing MDD include at least five symptoms present during the same two-week time period, at least one of which is diminished interest or pleasure or depressed mood. Symptoms associated with the DSM-5 criteria for MDD include (1) depressed mood (which may also be irritability in children and adolescents); (2) diminished interest in almost all activities or loss of pleasure (e.g., anhedonia); (3) significant weight changes or appetite disturbances (which may be failure to achieve expected weight gain in children); (4) sleep disturbances (e.g., insomnia or hypersomnia); (5) psychomotor agitation or retardation; (6) fatigue or loss of energy; (7) feelings of worthlessness; (8) diminished ability to think or pay attention; indecisiveness; and (9) recurrent thoughts of death, recurrent unplanned suicidal ideation, or suicidal attempts or specific plans of suicide.

[0382] Age-related cognitive impairment

[0383] Age-related cognitive impairment refers to cognitive impairment in older subjects where their cognitive function is not as robust as expected in age-matched healthy subjects or in younger adult subjects. In some cases, cognitive function is reduced by approximately 5%, 10%, 30%, or more compared to expected cognitive function in age-matched healthy subjects. In other cases, cognitive function is the same as expected in age-matched healthy subjects, but is reduced by approximately 5%, 10%, 30%, 50%, or more compared to expected cognitive function in younger adult subjects. Age-related cognitive impairment can be associated with mild cognitive impairment (MCI) (including amnestic and non-amnestic MCI), age-related memory impairment (AAMI), and age-related cognitive decline (ARCD).

[0384] Age-related memory impairment (AAMI) refers to memory decline due to aging. A patient can be considered to have AAMI if he or she is at least 50 years old and meets all of the following criteria: a) the patient has noticed a decline in memory performance; b) the patient performs worse on standard memory tests compared to younger adults; and c) all other apparent causes of memory decline other than normal aging have been ruled out (in other words, memory decline cannot be attributed to other causes such as a recent heart attack or head injury, depression, adverse reactions to medications, Alzheimer's disease, etc.).

[0385] Age-related cognitive decline (ARCD) refers to the decline in memory and cognitive abilities as a normal consequence of aging in humans (e.g., Craik and Salthouse, 1992). This is also true in almost all mammalian species. Age-related memory impairment refers to an objective decline in memory relative to one's younger years, but with normal cognitive function relative to one's peers (Crook et al., 1986). Age-consistent memory decline is a less derogatory label, emphasizing that these are normal developmental changes (Crook, 1993; Larrabee, 1996), not pathophysiological changes (Smith et al., 1991), and rarely progress to overt dementia (Youngjohn and Crook, 1993). The DSM-IV (1994) codified the diagnostic classification of ARCD, which was continued in the DSM-5 (2013) as ARCD code 780.9.

[0386] Drug-induced cognitive impairment

[0387] Corticosteroid-induced cognitive impairment

[0388] Due to their anti-inflammatory properties, corticosteroids are used to treat a variety of diseases and conditions, including asthma, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, nephritis syndrome, cancer, organ transplantation, autoimmune hepatitis, hypersensitivity reactions, cardiogenic and septic shock, glucocorticoid deficiency disorders (Addison's disease and panhypopituitarism), and multiple sclerosis. When the body experiences stress, the adrenal glands release corticosteroids, such as cortisol. Synthetic corticosteroids work by mimicking steroid hormones naturally produced by the adrenal glands. Once released into the body's circulatory system, these hormones help regulate inflammation and the body's immune response. Common synthetic corticosteroids include prednisone, cortisone, hydrocortisone, and methylprednisone. Replenishing the body's normal hormone levels with synthetic corticosteroids induces a genomic cascade that reduces inflammation and suppresses the immune response. This genomic cascade is triggered by the binding of steroids to the intracellular glucocorticoid receptor (GR) (Datson, NA et al., European Journal of Neuroscience. 2001).

[0389] Despite their widespread use and therapeutic benefits, synthetic corticosteroids commonly cause a number of adverse psychological, metabolic, and physical side effects (Warrington TP et al., Mayo Clinic Proceedings. 2006). Examples of such physical side effects include hypertension, accelerated atherosclerosis, acne, hair loss, hirsutism, striae, skin atrophy, purpura, obesity, diabetes, adrenal-pituitary axis suppression, hyperlipidemia, fluid and sodium retention, loss of potassium, calcium, and nitrogen, delayed growth, pseudotumor cerebri, peptic ulcer disease, pancreatitis, fatty liver, leukocytosis, neutrophilia, lymphophenia, oral candidiasis, increased risk of systemic infections, myopathy, osteoporosis, ischemic necrosis, cataracts, and glaucoma. Psychological side effects include mood and anxiety disorders, behavioral disorders, cognitive impairment, and psychosis.

[0390] Cognitive impairment, anxiety, and mood disorders are the most common psychological side effects of corticosteroid use. These effects lead to a decline in quality of life, especially for patients requiring long-term steroid treatment. For example, it has been reported that 33% of individuals taking corticosteroids (approximately 13 million people) exhibit deficits in work or short-term memory, declarative memory, attention span and focus (academic and occupational performance), and executive function (Stoudemire A et al., Gen Hosp Psychiatry. 1984). In extreme cases, steroids can even induce delirium, dementia (persistent memory impairment), and mania (Varney NR et al., Am J Psychiatry. 1984). Currently, there are no FDA-approved drugs specified for the treatment of cognitive impairment and similar mental disorders (such as anxiety and mood disorders) associated with corticosteroid use. Furthermore, there are no alternatives to corticosteroids for the treatment of inflammatory disorders—corticosteroids must be used.

[0391] Chemotherapy-induced cognitive impairment

[0392] Chemotherapy-associated cognitive impairment, also known as chemotherapy-associated cognitive impairment, chemotherapy fog, or chemotherapy brain, refers to a decline in various neuropsychological tasks following chemotherapy or other anticancer treatments (such as radiation therapy or surgery) in patients with non-central nervous system cancers. The areas most impaired after chemotherapy are memory, processing speed, attention, and executive function (Lange M, et al., Ann Oncol. 2019).

[0393] asthma

[0394] Asthma is a chronic inflammatory disease of the lung airways caused by a combination of genetic and environmental factors, including exposure to air pollution and allergens. Other potential triggers include medications such as aspirin and beta-blockers. Eosinophilic inflammatory events in the airways, particularly in patients with asthma, have been reported. The pathophysiology of the disease is characterized by variable airflow obstruction, airway inflammation, excessive mucus production, and subepithelial fibrosis. Clinically, patients may present with cough, wheezing, and shortness of breath.

[0395] Primary biliary cholangitis

[0396] Primary biliary cholangitis (PBC) is an organ-specific autoimmune disease characterized by chronic, progressive destruction of the small bile ducts in the liver, accompanied by inflammation of the portal areas. The destruction of the bile ducts leads to the accumulation of bile and other toxins within the liver, resulting in scarring, fibrosis, and eventually cirrhosis. PBC is a relatively rare disease, affecting up to one in 3,000–4,000 people, but primarily affects middle-aged women. Early symptoms of PBC include fatigue and itchy skin, while symptoms of late-stage disease include dry eyes and mouth, right upper quadrant pain, splenomegaly, musculoskeletal pain, edema, ascites, fatty deposits on the skin (xanthoma), jaundice, hyperpigmentation, osteoporosis, high cholesterol, diarrhea, and hypothyroidism (Boonstra K et al., J Hepatol. 2012).

[0397] Hypertriglyceridemia

[0398] Hypertriglyceridemia (HTG) is a common metabolic disorder characterized by elevated plasma triglyceride levels (i.e., levels exceeding 150 mg / dL), which increases the risk of cardiovascular disease. While most patients with hypertriglyceridemia are asymptomatic, those with severe HTG may develop xanthomas. Severe HTG (i.e., levels exceeding 500 mg / dL) is also associated with an increased risk of pancreatitis. Both genetic and lifestyle factors play important roles in the pathophysiology of HTG. Medications, including corticosteroids, thiazides, nonselective beta-blockers, estrogens, tamoxifen, bile acid sequestrants, cyclophosphamide, antiretroviral drugs, and second-generation antipsychotics, can also elevate TG levels. The initial and most valuable approach to treating HTG is to modulate the lifestyle factors that contribute to it, including diet, weight, and management of non-TG components of metabolic syndrome; however, these approaches are often unreliable due to poor patient adherence. Medications such as fibrates (e.g., fenofibrate (PPAR-α agonist), prescription omega-3 fatty acids (e.g., Vascepa® (icosapentaenoic acid ethyl ester, IPE)) and statins are also used to treat TG, but are associated with side effects such as musculoskeletal pain, general weakness, edema, headache, drowsiness, rash, constipation, and altered libido (Santos-Baez LS and Ginsberg HN. Front Endocrinol. 2020).

[0399] Fibromyalgia, prolonged COVID, menopausal and chronic overlapping pain syndrome (COPC)

[0400] Fibromyalgia is a condition characterized by widespread pain, fatigue, sleep disturbances, and cognitive impairment, or “brain fog.” It is a member of a group of conditions originally called “overlapping chronic pain syndrome” (OCPC), but is now more commonly referred to as “chronic overlapping pain syndrome” (COPC), which also includes temporomandibular joint disorder (TMD), irritable bowel syndrome (IBS), vulvar pain, myalgic encephalomyelitis / chronic fatigue syndrome, interstitial cystitis / bladder pain syndrome, endometriosis, chronic tension headache, migraine, and chronic lower back pain. Epidemiological studies estimate the prevalence of COPC in individuals to range from approximately 4 million (myalgic encephalomyelitis / chronic fatigue syndrome) to 44 million (IBS). Many COPCs are defined as idiopathic, occurring spontaneously without a specific cause. However, central sensitization is currently believed to contribute to these conditions (Maixner W, et al., JPain. 2016). Exemplary clinical symptoms of fibromyalgia and other COPCs include, but are not limited to, widespread pain, fatigue, sleep disturbances, and cognitive impairment.

[0401] Acute post-SARS-CoV-2 sequelae (PASC) (commonly known as “long COVID”) is a term used to describe a group of symptoms experienced by individuals with a history of possible or confirmed SARS-CoV-2 infection, typically occurring 3 months after the onset of COVID-19 infection, with symptoms lasting at least 2 months and not explainable by an alternative diagnosis. PASC symptoms span multiple organ systems, may occur within symptom clusters (i.e., neurological, non-neurological, and systemic symptoms), and may fluctuate or recur over time (Davis et al., *Ecological Medicine*. 2021; Crook et al., *BMJ*. 2021; Bierle et al., *JPrim Care Community Health*. 2021, WHO 2021). The lack of a standardized definition for PASC makes it difficult to determine the exact epidemiological, morbid, and disease impact on long-term disability. A conservative estimate based on data collected from many countries is that, on average, 30% of people with COVID-19 will experience PASC (Nalbandian et al., *Nat Med*. 2021).

[0402] PASC is a multifaceted condition affecting multiple bodily systems. Symptoms of PASC can be new onset after recovery from an acute or even mild COVID-19 illness (e.g., new onset of pain) or persistent from the initial illness. While PASC symptoms vary, pain, fatigue, and sleep disturbances have been found to be major symptoms affecting quality of life and the ability to return to full-time work (Alonso-Matielo et al. Front Physiol. 2021, Davis et al. EclinicalMedicine. 2021, Sahin et al. Eur Neurol. 2021).

[0403] Exemplary clinical symptoms of prolonged COVID include, but are not limited to, fatigue, muscle weakness, sweating, myalgia, arthralgia, chills, edema of the extremities, dizziness, weakness after exercise, cognitive impairment, respiratory symptoms (rapid breathing, chest pain, cough, sputum, sore throat), cardiovascular abnormalities, hair loss, olfactory abnormalities, neurocognitive difficulties (including memory and attention problems), psychological symptoms such as sleep difficulties, depression, anxiety, feelings of inferiority, and a generally worse quality of life.

[0404] Menopause is the period after a normal ovulatory cycle ceases, during which normal menstruation stops. This period is characterized by a decrease in hormone production in the ovaries (e.g., estradiol (E2)), leading to changes in the body's hormonal balance, which typically causes a variety of symptoms associated with menopause. Perimenopause, also known as premenopause or climacteric, is the period before menopause, during which normal ovulatory cycles gradually give way to the cessation of menstruation. Symptoms during perimenopause, menopause, and postmenopause include physical symptoms such as hot flashes, chills, and sweating secondary to vasomotor instability. In addition, the onset of menopause may be accompanied by psychological and mood symptoms such as fatigue, irritability, insomnia, difficulty concentrating, depression, memory loss, headaches, anxiety, and tension. Other symptoms may include intermittent dizziness, paresthesia, palpitations and tachycardia, as well as nausea, constipation, diarrhea, joint pain, muscle pain, cold hands and feet, and weight gain. In addition, with the onset of menopause, there are changes in the reproductive organs, urinary incontinence, vaginal dryness, loss of pelvic muscle tone, an increased risk of cardiovascular disease, and an increased risk of osteoporosis.

[0405] obesity

[0406] Obesity, defined by the U.S. Centers for Disease Control and Prevention (CDC) as an excess of body fat or adipose tissue relative to lean body mass, is now a global epidemic and one of the most serious contributing factors to increased morbidity and mortality. Obesity is associated with leading causes of death, including those from diabetes, heart disease, stroke, and some types of cancer.

[0407] In some embodiments, the (S)-enantiomer of this disclosure (i.e., (S)-tiaponectin or 11-D-(S)-tiaponectin) is used to treat obesity and weight gain, particularly in individuals who tend to gain weight and fat content despite not overeating and on a medium- or low-fat diet. In some embodiments, the (S)-enantiomer of this disclosure (i.e., (S)-tiaponectin or 11-D-(S)-tiaponectin) or analogues of tiaponectin (i.e., N-hydroxy-tiaponectin, its (S)- and (R)-enantiomers, N-nitroso-tiaponectin, its (S)- and (R)-enantiomers, or aryl-substituted tiaponectin analogues or pharmaceutically acceptable salts thereof) is used to treat obesity and weight gain in individuals with low levels of PPAR-β / δ and / or PPAR-γ expression and / or neuronal activity.

[0408] Treatment

[0409] In some aspects, this disclosure provides methods for treating diseases, disorders, or conditions exacerbated or associated with alterations in the activity regulation of peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ) and / or PPAR-γ, including administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or 11-D-(S)- Enantiomers, zwitterions thereof, or pharmaceutically acceptable salts of the 11-D-(S)-enantiomer of this disclosure, or eutectics of the 11-D-(S)-enantiomer of this disclosure or its zwitterions, or esters of the 11-D-(S)-enantiomer of this disclosure or their pharmaceutically acceptable salts, or amides of the 11-D-(S)-enantiomer of this disclosure or their pharmaceutically acceptable salts, or analogs of tianapordine of this disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogs or their pharmaceutically acceptable salts), or pharmaceutical compositions of this disclosure comprising one or more of these.

[0410] In some embodiments, a method of treating a disease, disorder, or condition that modulates PPAR-β / δ and / or PPAR-γ includes administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt (including its crystalline form), or a eutectic of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating a disease, disorder, or condition that modulates PPAR-β / δ and / or PPAR-γ includes administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer of this disclosure. In some embodiments, a method of treating a disease, disorder, or condition regulated by PPAR-β / δ and / or PPAR-γ includes administering a therapeutically effective amount of the zwitterion of the (S)-enantiomer of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition regulated by PPAR-β / δ and / or PPAR-γ includes administering a therapeutically effective amount of a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition regulated by PPAR-β / δ and / or PPAR-γ includes administering a therapeutically effective amount of a pharmaceutically acceptable cocrystal of the (S)-enantiomer of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition regulated by PPAR-β / δ and / or PPAR-γ includes administering a therapeutically effective amount of a pharmaceutically acceptable cocrystal of the zwitterion of the (S)-enantiomer of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition of PPAR-β / δ and / or PPAR-γ regulation includes administering a therapeutically effective amount of an ester of the (S)-enantiomer of this disclosure to a subject who needs or is at risk of such a disease. In some embodiments, a method of treating a disease, disorder, or condition of PPAR-β / δ and / or PPAR-γ regulation includes administering a therapeutically effective amount of a pharmaceutically acceptable salt of an ester of the (S)-enantiomer of this disclosure to a subject who needs or is at risk of such a disease. In some embodiments, a method of treating a disease, disorder, or condition of PPAR-β / δ and / or PPAR-γ regulation includes administering a therapeutically effective amount of an amide of the (S)-enantiomer of this disclosure to a subject who needs or is at risk of such a disease.In some embodiments, methods of treating diseases, disorders, or conditions that regulate PPAR-β / δ and / or PPAR-γ include administering a therapeutically effective amount of a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure of an amide to a subject who needs or is at risk of such treatment.

[0411] In some embodiments, a method of treating a disease, disorder, or condition that modulates PPAR-β / δ and / or PPAR-γ includes administering to a subject in need or at risk a therapeutically effective amount of the 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of this disclosure, or a eutectic of the 11-D-(S)-enantiomer of this disclosure or its zwitterion, or an ester of the 11-D-(S)-enantiomer of this disclosure, or an amide of the 11-D-(S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating a disease, disorder, or condition that modulates PPAR-β / δ and / or PPAR-γ includes administering to a subject in need or at risk a therapeutically effective amount of the 11-D-(S)-enantiomer of this disclosure. In some embodiments, a method of treating a disease, disorder, or condition regulated by PPAR-β / δ and / or PPAR-γ includes administering a therapeutically effective amount of a zwitterion of the 11-D-(S)-enantiomer of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition regulated by PPAR-β / δ and / or PPAR-γ includes administering a therapeutically effective amount of a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition regulated by PPAR-β / δ and / or PPAR-γ includes administering a therapeutically effective amount of a pharmaceutically acceptable eutectic of the 11-D-(S)-enantiomer of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition that regulates PPAR-β / δ and / or PPAR-γ includes administering a therapeutically effective amount of a pharmaceutically acceptable cocrystal of the zwitterion of the 11-D-(S)-enantiomer of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition that regulates PPAR-β / δ and / or PPAR-γ includes administering a therapeutically effective amount of an ester of the 11-D-(S)-enantiomer of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition that regulates PPAR-β / δ and / or PPAR-γ includes administering a therapeutically effective amount of a pharmaceutically acceptable salt of an ester of the 11-D-(S)-enantiomer of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, methods of treating diseases, disorders, or conditions that regulate PPAR-β / δ and / or PPAR-γ include administering a therapeutically effective amount of the 11-D-(S)-enantiomer of this disclosure to a subject who needs or is at risk of such treatment.In some embodiments, methods of treating diseases, disorders, or conditions that regulate PPAR-β / δ and / or PPAR-γ include administering a therapeutically effective amount of a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of this disclosure to a subject who needs or is at risk of such treatment.

[0412] In some embodiments, methods of treating diseases, disorders, or conditions involving PPAR-β / δ and / or PPAR-γ regulation include administering a therapeutically effective amount of N-hydroxy-tiaponectin, its (S)-enantiomer, (R)-enantiomer, or N-nitroso-tiaponectin, its (S)-enantiomer, or (R)-enantiomer, or a pharmaceutically acceptable salt thereof, to a subject who needs or is at risk of such disease, disorder, or condition. In some embodiments, methods of treating diseases, disorders, or conditions involving PPAR-β / δ and / or PPAR-γ regulation include administering a therapeutically effective amount of the N-hydroxy-tiaponectin of this disclosure to a subject who needs or is at risk of such disease, disorder, or condition. In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of the N-hydroxy-tiaponectin of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation comprises administering a therapeutically effective amount of a (S)-enantiomer of the N-hydroxy-tiaponectin of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of a (S)-enantiomer of the N-hydroxy-tiaponectin of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation includes administering a therapeutically effective amount of the (R)-enantiomer of N-hydroxy-tiaponectin of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation includes administering a therapeutically effective amount of a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy-tiaponectin of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation includes administering a therapeutically effective amount of N-nitroso-tiaponectin of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, methods of treating diseases, disorders, or conditions that regulate PPAR-β / δ and / or PPAR-γ include administering a therapeutically effective amount of a pharmaceutically acceptable salt of N-nitroso-thiaponectin of this disclosure to a subject who needs or is at risk of such treatment.In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation includes administering a therapeutically effective amount of the (S)-enantiomer of N-nitroso-tiaponectin of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation includes administering a therapeutically effective amount of a pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-tiaponectin of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation includes administering a therapeutically effective amount of the (R)-enantiomer of N-nitroso-tiaponectin of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso-tianaporptine of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation comprises administering a therapeutically effective amount of an aryl-substituted tianaporptine analog of this disclosure to a subject who needs or is at risk of such a condition. In some embodiments, a method of treating a disease, disorder, or condition involving PPAR-β / δ and / or PPAR-γ regulation comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt of an aryl-substituted tianaporptine analog of this disclosure to a subject who needs or is at risk of such a condition.

[0413] In some embodiments, a method of treating diseases, disorders, or conditions that regulate PPAR-β / δ and / or PPAR-γ includes administering a therapeutically effective amount of the pharmaceutical composition of this disclosure to a subject who needs or is at risk of such treatment.

[0414] In some aspects, this disclosure provides methods for treating diseases, disorders, or conditions and one or more associated symptoms in subjects who have experienced high stress. In some embodiments, the disease, disorder, or condition is caused by prenatal or early life adversity or childhood trauma, and in some embodiments manifests as subsequent violent behavior. In some embodiments, the disease, disorder, or condition in subjects who have experienced high stress is regulated, exacerbated, or associated with altered activity of peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ) and / or PPAR-γ. Without wishing to be bound by theory, prolonged stress (prenatal, postnatal, or both) leads to increased free radical production, particularly in the brain. The (S)-enantiomer of this disclosure (i.e., (S)-tiaponectin or 11-D-(S)-tiaponectin) is activated in the presence of a free radical to form a tiaponectin C11-radical intermediate (which can be delocalized at 13 carbon atoms, 2 nitrogen atoms, 2 oxygen atoms, and 1 sulfur atom), which can covalently interact with PPAR-δ / β and / or PPAR-γ and irreversibly activate them. These free radicals can be formed when the (S)-tiaponectin enantiomer binds to a PPAR ligand binding site (LBS), whereby (S)-tiaponectin preferentially covalently bonds to the PPAR LBS due to the chiral geometry of the site.

[0415] In some aspects, this disclosure provides methods for treating diseases, disorders, or conditions regulated, exacerbated, or associated with high levels of receptor S-nitrosylation. In some aspects, this disclosure provides methods for treating diseases, disorders, or conditions regulated, exacerbated, or associated with high levels of PPAR-β / δ and / or PPAR-γ S-nitrosylation, comprising administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or the (S)-enantiomer of this disclosure. 11-D-(S)-enantiomers of the present disclosure, amides thereof or pharmaceutically acceptable salts thereof, or 11-D-(S)-enantiomers of the present disclosure, zwitterions thereof, or pharmaceutically acceptable salts thereof, or eutectics of 11-D-(S)-enantiomers of the present disclosure or zwitterions thereof, or esters thereof, or pharmaceutically acceptable salts thereof, or amides thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising one or more of these. Without wishing to be bound by theory, the (S)-enantiomer of this disclosure (i.e., (S)-tiaponectin or 11-D-(S)-tiaponectin) reacts with S-nitroso-PPAR-β / δ and / or S-nitroso-PPAR-γ to form S-nitroso-(S)-enantiomers and non-nitrosolated PPAR-β / δ and / or PPAR-γ.

[0416] In some respects, the treatment of diseases, disorders, or conditions caused by, or associated with altered activity of peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ) and / or PPAR-γ is improved by methods using racemic mixtures of enantiomers of tiannaptine, their zwitterions, salts, cocrystals, and esters, because the methods of the present disclosure result in reduced agonist activity of µ-opioid receptors. The reduced µ-opioid receptor agonist activity of the (S)-enantiomers of the present disclosure (i.e., (S)-tiannaptine or 11-D-(S)-tiannaptine) minimizes the likelihood of opioid abuse, opioid toxicity, or opioid overdose (e.g., opioid-induced respiratory depression (OIRD)) compared to racemic mixtures of enantiomers of tiannaptine.

[0417] In some aspects, this disclosure provides methods for treating diseases, disorders, or conditions selected from central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infectious diseases, hearing loss disorders, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopausal and chronic overlapping pain disorders (COPC), and the group consisting of psychological, physiological, metabolic or hormonal stress and COPC, comprising administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or the (S)-enantiomer of this disclosure. The 11-D-(S)-enantiomer of the present disclosure, an amide thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a eutectic of the 11-D-(S)-enantiomer of the present disclosure or a zwitterion thereof, or an ester thereof or a pharmaceutically acceptable salt thereof, or an amide thereof, or an analogue of 11-D-(S)-enantiomer of the present disclosure (i.e., N-hydroxy-tiaponectin, its (S)- and (R)-enantiomers, N-nitroso-tiaponectin, its (S)- and (R)-enantiomers or aryl-substituted tiaponectin analogues or pharmaceutically acceptable salts thereof), or a pharmaceutical composition comprising one or more of these.

[0418] In some aspects, this disclosure provides methods for treating diseases, disorders, or conditions regulated, exacerbated, or associated with excessive levels of metal ions in circulation, comprising administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a eutectic of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or 11-D-(S)-enantiomer of this disclosure, its zwitterion, or the present disclosure. The metal ion may be a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the present disclosure, or a eutectic of the 11-D-(S)-enantiomer of the present disclosure or its zwitterion, or an ester of the 11-D-(S)-enantiomer of the present disclosure or its pharmaceutically acceptable salt, or an amide of the 11-D-(S)-enantiomer of the present disclosure, or an analogue of tianapordine of the present disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogues or their pharmaceutically acceptable salts), or a pharmaceutical composition comprising one or more of these. In some embodiments, the metal ion is iron or copper. In some embodiments, the (S)-enantiomer of this disclosure (i.e., (S)-tiaponectin or 11-D-(S)-tiaponectin) or an analogue of tiaponectin (i.e., N-hydroxy-tiaponectin, its (S)- and (R)-enantiomers, N-nitroso-tiaponectin, its (S)- and (R)-enantiomers, or aryl-substituted tiaponectin analogues or pharmaceutically acceptable salts) is administered to a subject having elevated iron or copper ion levels as determined by blood tests or cerebrospinal fluid (CSF) tests. Without wishing to be bound by theory, the (S)-enantiomers of this disclosure (i.e., (S)-tiaponectin or 11-D-(S)-tiaponectin) or analogs of tiaponectin (i.e., N-hydroxy-tiaponectin, its (S)- and (R)-enantiomers, N-nitroso-tiaponectin, its (S)- and (R)-enantiomers, or aryl-substituted tiaponectin analogs or pharmaceutically acceptable salts thereof) are activated in the presence of free radicals (e.g., hydroxyl radicals) generated by the reaction of free iron or copper with oxygen and hydrogen peroxide to form a tiaponectin C11-radical intermediate (which can be delocalized on 13 carbon atoms, 2 nitrogen atoms, 2 oxygen atoms, and 1 sulfur atom), which is capable of covalently interacting with PPAR-δ / β and / or PPAR-γ and irreversibly activating them.These free radicals can be formed when the (S)-tinaphthol enantiomer binds to the PPAR ligand binding site (LBS), whereby (S)-tinaphthol preferentially covalently binds to the PPAR LBS due to the chiral geometry of the site. In some embodiments, diseases, disorders, or conditions regulated, aggravated, or associated with excess levels of circulating metal ions are regulated, aggravated, or associated with altered activity of peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ) and / or PPAR-γ.

[0419] In some respects, this disclosure provides methods for reducing violence or aggression associated with CNS disorders, comprising administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or 11-D-(S)-enantiomer of this disclosure, its zwitterion, or 11-D-(S)-enantiomer of this disclosure. Pharmaceutically acceptable salts of the enantiomers, or eutectic crystals of the 11-D-(S)-enantiomers of this disclosure or their zwitterions, or esters of the 11-D-(S)-enantiomers of this disclosure or their pharmaceutically acceptable salts, or amides of the 11-D-(S)-enantiomers of this disclosure or their pharmaceutically acceptable salts, or analogs of tianapordine of this disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogs or their pharmaceutically acceptable salts), or pharmaceutical compositions of this disclosure comprising one or more of them.

[0420] In some respects, this disclosure provides methods for reducing the likelihood of admission to a psychiatric hospital or incarceration due to behaviors or actions associated with CNS disorders, including administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a eutectic of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or 11-D-(S)-enantiomer of this disclosure, its zwitterion, or 11-D-(S)-enantiomer of this disclosure. Pharmaceutically acceptable salts of the -D-(S)-enantiomers of this disclosure, or eutectic crystals of the 11-D-(S)-enantiomers of this disclosure or their zwitterions, or esters of the 11-D-(S)-enantiomers of this disclosure or their pharmaceutically acceptable salts, or amides of the 11-D-(S)-enantiomers of this disclosure or their pharmaceutically acceptable salts, or analogs of tialapril of this disclosure (i.e., N-hydroxy-tialapril, its (S)- and (R)-enantiomers, N-nitroso-tialapril, its (S)- and (R)-enantiomers, or aryl-substituted tialapril analogs or their pharmaceutically acceptable salts), or pharmaceutical compositions of this disclosure comprising one or more of them.

[0421] In some embodiments, the treatment methods of this disclosure include once or more daily administration of the (S)-enantiomer of tiannaphthol of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or a cocrystal of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer of this disclosure or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer of tiannaphthol of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of this disclosure. An acceptable salt, or a eutectic of the 11-D-(S)-enantiomer of this disclosure or its zwitterion, or an ester of the 11-D-(S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an analogue of tianapordine of this disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers or aryl-substituted tianapordine analogues or their pharmaceutically acceptable salts), or a pharmaceutical composition of this disclosure comprising one or more of these. In some embodiments, the treatment methods of this disclosure include once-daily administration of the (S)-enantiomer of tiannaphthol of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or a cocrystal of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer of this disclosure or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer of tiannaphthol of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of this disclosure. Salts of the present disclosure, or eutectic of the 11-D-(S)-enantiomer of the present disclosure or its zwitterion, or esters of the 11-D-(S)-enantiomer of the present disclosure or pharmaceutically acceptable salts thereof, or amides of the 11-D-(S)-enantiomer of the present disclosure or pharmaceutically acceptable salts thereof, or analogs of tianapordine of the present disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers or aryl-substituted tianapordine analogs or pharmaceutically acceptable salts thereof), or pharmaceutical compositions of the present disclosure comprising one or more of these.

[0422] In some embodiments, the treatment methods of this disclosure include the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt, or a cocrystal of the (S)-enantiomer of this disclosure, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an analogue of tinaphthol of this disclosure (i.e., N-hydroxy-tinaphthol, its (S)- and (R)-enantiomers, N-nitroso-tinaphthol). The pharmaceutical compositions comprising tialastin, its (S)- and (R)-enantiomers or aryl-substituted tialastin analogs or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for administration in combination or in combination with one or more additional therapeutic agents selected from the group consisting of: antidepressants, anticonvulsants, anxiolytics, antipsychotics, cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, 5-HT2 modulators, corticosteroids, antiamyloid agents, antitau agents, and chemotherapeutic agents. In some embodiments, the treatment methods of this disclosure include sequential administration of the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt thereof, or a cocrystal of the (S)-enantiomer of this disclosure, or an ester of the (S)-enantiomer of this disclosure, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an analogue of tianapordine of this disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogues or pharmaceutically acceptable salts thereof), or a pharmaceutical composition of this disclosure comprising them, with one or more additional therapeutic agents. In some embodiments, the treatment methods of this disclosure include concurrent administration of the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt, or a cocrystal of the (S)-enantiomer of this disclosure, or an ester of the (S)-enantiomer of this disclosure, or an amide of the (S)-enantiomer of this disclosure, or a pharmaceutically acceptable salt thereof, or an analogue of tianapordine of this disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogues or their pharmaceutically acceptable salts), or a pharmaceutical composition comprising them, with one or more additional therapeutic agents. Exemplary antidepressants include, but are not limited to, citalopram, fluoxetine, paroxetine, trazodone, or sertraline. Exemplary anticonvulsants include, but are not limited to, carbamazepine, divalproic acid, or dextromethorphan. Exemplary anxiolytics include, but are not limited to, lorazepam, oxazepam, or buspirone.Exemplary antipsychotics include, but are not limited to, quetiapine, promethazine, aripiprazole, ziprasidone, olanzapine, or risperidone. Exemplary cholinesterase inhibitors include, but are not limited to, donepezil, rivastigmine, galantamine, or tacrine. Exemplary NMDA receptor antagonists include, but are not limited to, amantadine or memantine. Exemplary 5-HT2 modulators include, but are not limited to, pimovanzerin or cyclobenzaline. Exemplary corticosteroids include, but are not limited to, prednisone, methylprednisolone, and dexamethasone. Exemplary antiamyloid agents include, but are not limited to, aducanumab (Aduhelm®), bapineuzumab, solanezumab, or verubecestat. In some embodiments, the antiamyloid agent and / or anti-tau agent is one or more of the pharmaceutical agents described by Cummings et al., which are incorporated herein by reference (Cummings et al., Alzheimers Dement (NY), 2017). Exemplary chemotherapeutic agents include, but are not limited to, temozolomide, carmustine, bevacizumab, or lomustine.

[0423] In some embodiments of the combination of the present disclosure, the (S)-enantiomer of the present disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer of the present disclosure, or a eutectic of the (S)-enantiomer of the present disclosure or its zwitterion, or an ester of the (S)-enantiomer of the present disclosure or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer of the present disclosure or its pharmaceutically acceptable salt, or an analogue of tianapordine of the present disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogues) or its pharmaceutically acceptable salt, or a pharmaceutical composition of the present disclosure comprising them, and one or more other therapeutic agents are formulated individually. In some embodiments of the combination of the present disclosure, the (S)-enantiomer of the present disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer of the present disclosure, or a eutectic of the (S)-enantiomer of the present disclosure or its zwitterion, or an ester of the (S)-enantiomer of the present disclosure or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer of the present disclosure or its pharmaceutically acceptable salt, or an analogue of tianapordine of the present disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogues) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure comprising them, is formulated together with one or more other therapeutic agents. In some such embodiments, the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or a eutectic of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an analogue of tianapordine of this disclosure (i.e., N-hydroxy-tianapordine, its (S)- and (R)-enantiomers, N-nitroso-tianapordine, its (S)- and (R)-enantiomers, or aryl-substituted tianapordine analogues) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure comprising them, is packaged together with one or more other therapeutic agents.In some of these embodiments, the (S)-enantiomer of this disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or a eutectic of the (S)-enantiomer of this disclosure or its zwitterion, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or ...

Claims

1. The (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-ylamino)heptanoic acid of general formula (Ia) (the (S)-enantiomer of tianapordine), the zwitterion of formula (Ib) or a pharmaceutically acceptable salt of said (S)-enantiomer, or a mixture of two or more of these substances, wherein said (S)-enantiomer, zwitterion or pharmaceutically acceptable salt is characterized by comprising ≤ about 2% of the (R)-enantiomer of tianapordine, its zwitterion or a pharmaceutically acceptable salt of said (R)-enantiomer: 。 2. The (S)-enantiomer according to claim 1, wherein the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the (R)-enantiomer of the tianapordine, or its zwitterion or a pharmaceutically acceptable salt thereof.

3. A pharmaceutically acceptable salt of the (S)-enantiomer according to claim 1 or 2, wherein the pharmaceutically acceptable salt is (S)-tiaponectin benzenesulfonate (1:1), (S)-tiaponectin fumarate (1:1), (S)-tiaponectin fumarate (2:1), (S)-tiaponectin hippurate (1:1), (S)-tiaponectin maleate (1:1), (S)-tiaponectin maleate (2:1), (S)-tiaponectin p-toluenesulfonate (1:1), (S)-tiaponectin orotate (1:1), (S)-tiaponectin camphorsulfonate (1:1), (S)-tiaponectin N-acetyl-L-tyrosine salt (1:1), (S)-tiaponectin polisterix, (S)-tiaponectin:L-DBTA (2:1), (S)-tiaponectin sodium, (S)-tiaponectin oxalate or (S)-tiaponectin hemioxalate (2:1).

4. The pharmaceutically acceptable salt of the (S)-enantiomer according to claim 3, wherein the pharmaceutically acceptable salt is (S)-tiaponectin hemioxalate (2:1).

5. A zwitterion comprising the zwitterion of the (S)-enantiomer according to claim 1 or 2.

6. A eutectic of the (S)-enantiomer according to claim 1 or 2, wherein the (S)-enantiomer or its zwitterion forms a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid.

7. An ester of the (S)-enantiomer according to claim 1 or 2, wherein the ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof.

8. The ester of the (S)-enantiomer according to claim 7, wherein the ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof.

9. An amide of the (S)-enantiomer according to claim 1 or 2, wherein the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the (R)-enantiomer amide or a pharmaceutically acceptable salt thereof.

10. The (S)-enantiomer amide according to claim 9, wherein the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the (R)-enantiomer amide or a pharmaceutically acceptable salt thereof.

11. The (S)-enantiomer of 7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-yl-11-d)amino)heptanoic acid of general formula (IIa) (the 11-D-(S)-enantiomer of tianapordine), or a zwitterion or a pharmaceutically acceptable salt of the zwitterion or 11-D-(S)-enantiomer of formula (IIb), or a mixture of two or more of these substances, wherein deuterium substitutes for the hydrogen at the 11-position, and wherein the 11-D-(S)-enantiomer or its zwitterion or pharmaceutically acceptable salt is characterized by comprising ≤ about 2% of the 11-D-(R)-enantiomer of tianapordine or its zwitterion or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer: 。 12. The (S)-enantiomer of claim 11, wherein the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the 11-D-(R)-enantiomer of the tianapordine, or its zwitterion, or a pharmaceutically acceptable salt thereof.

13. The (S)-enantiomer according to claim 11 or 12, wherein the 11-D-(S)-enantiomer or the zwitterion or pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is characterized by reduced racemization at position 11 compared to the (S)-enantiomer of tinaptrine or the zwitterion or pharmaceutically acceptable salt of the enantiomer.

14. A pharmaceutically acceptable salt of the 11-D-(S)-enantiomer according to any one of claims 11-13, wherein the pharmaceutically acceptable salt is 11-D-(S)-tiaponectin benzylsulfonate (1:1), 11-D-(S)-tiaponectin fumarate (1:1), 11-D-(S)-tiaponectin fumarate (2:1), 11-D-(S)-tiaponectin hippurate (1:1), or 11-D-(S)-tiaponectin maleate (1:1). 11-D-(S)-Tianaphthylpropionate maleate (2:1), 11-D-(S)-Tianaphthylpropionate p-toluenesulfonate (1:1), 11-D-(S)-Tianaphthylpropionate orotate (1:1), 11-D-(S)-Tianaphthylpropionate camphorsulfonate (1:1), 11-D-(S)-Tianaphthylpropionate N-acetyl-L-tyrosine (1:1), 11-D-(S)-Tianaphthylpropionate polisterix, 11-D-(S)-Tianaphthylpropionate:L-DBTA (2:1), 11-D-(S)-Tianaphthylpropionate sodium, 11-D-(S)-Tianaphthylpropionate oxalate or 11-D-(S)-Tianaphthylpropionate hemioxalate (2:1).

15. The pharmaceutically acceptable salt of the 11-D-(S)-enantiomer according to claim 14, wherein the pharmaceutically acceptable salt is 11-D-(S)-tiaponectin hemioxalate (2:1).

16. A zwitterion comprising the zwitterion of the 11-D-(S)-enantiomer according to any one of claims 11-13.

17. A eutectic of the 11-D-(S)-enantiomer according to any one of claims 11-13, wherein the 11-D-(S)-enantiomer or its zwitterion forms a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid.

18. An ester of the (S)-enantiomer according to any one of claims 11-13, wherein the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

19. The ester of the (S)-enantiomer according to claim 18, wherein the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

20. An amide of the (S)-enantiomer according to any one of claims 11-13, wherein the amide of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

21. The amide of the (S)-enantiomer according to claim 20, wherein the amide of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 0.1% of the amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

22. A pharmaceutically acceptable acid salt of the (S)-enantiomer or the 11-D-(S)-enantiomer according to any one of claims 1, 2 or 11-13, wherein the nitrogen atom in the side chain attached to carbon-11 (C-11) is 100% protonated, and the 100% protonated salt in solid or solution form is less sensitive to air oxidation than the (S)-enantiomer, the 11-D-(S)-enantiomer, the zwitterion of any of them or the sodium salt of any of them.

23. A pharmaceutical composition comprising the (S)-enantiomer of tiannaphthol according to any one of claims 1-6, its zwitterion or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer according to claim 7 or 8 or a pharmaceutically acceptable salt of the (S)-enantiomer, or an amide of the (S)-enantiomer according to claim 9 or 10 or a pharmaceutically acceptable salt of the (S)-enantiomer, and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises ≤ about 2% of the (R)-enantiomer of tiannaphthol, its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt of the (R)-enantiomer, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt of the (R)-enantiomer.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition comprises ≤ about 0.1% of the (R)-enantiomer of the tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a eutectic of the (R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt of the (R)-enantiomer, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt of the (R)-enantiomer.

25. A pharmaceutical composition comprising the 11-D-(S)-enantiomer of tianapordine according to any one of claims 11-17, its zwitterion or a pharmaceutically acceptable salt of said 11-D-(S)-enantiomer, or a eutectic of said 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer according to claim 18 or 19 or a pharmaceutically acceptable salt thereof, or an acyl group of the 11-D-(S)-enantiomer according to claim 20 or 21. An amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient thereof, wherein the composition comprises ≤2% of 11-D-(R)-enantiomer of tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition comprises ≤ about 0.1% of the 11-D-(R)-enantiomer of the tianapordine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a eutectic of the 11-D-(R)-enantiomer or its zwitterion, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

27. The pharmaceutical composition according to any one of claims 23-26, wherein the composition is in the form of tablets, films, powders, capsules, soft gels, suppositories, nasal sprays, oral sprays, or lung sprays.

28. The pharmaceutical composition according to any one of claims 23-26, wherein the composition is formulated for immediate, controlled, sustained, prolonged, or slow release of the (S)-enantiomer or the 11-D-(S)-enantiomer, or any of the zwitterions, esters or amides, or pharmaceutically acceptable salts of any of the zwitterions, or a cocrystal of the (S)-enantiomer or the 11-D-(S)-enantiomer or any of the zwitterions.

29. A pharmaceutical composition comprising a mixture of two or more pharmaceutically acceptable salts or cocrystals of the (S)-enantiomer or the 11-D-(S)-enantiomer according to any one of claims 23-26, wherein the mixture is characterized by enhanced prolonged release upon oral administration compared to administration of a composition comprising a single pharmaceutically acceptable salt or cocrystal of the (S)-enantiomer or the 11-D-(S)-enantiomer according to any one of claims 23-26.

30. A method for treating diseases, disorders, or conditions and one or more associated symptoms of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ whose activity is modulated, exacerbated, or associated with them, comprising administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer, zwitterion, or pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 23, 24, and 27-29.

31. A method for treating diseases, disorders, or conditions and one or more associated symptoms of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ whose activity is modulated, exacerbated, or associated with such alterations, comprising administering to a subject in need or at risk a therapeutically effective amount of any of the following: an 11-D-(S)-enantiomer, a zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any of the following claims:

32. The method of claim 30 or 31, wherein the disease, disorder, or condition is selected from the group consisting of central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infectious diseases, hearing loss disorders, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopausal and chronic overlapping pain disorders (COPC), and psychological, physiological, metabolic or hormonal stress and COPC.

33. The method of claim 32, wherein the CNS disorder is selected from the group consisting of mood disorders, trauma and stress-related disorders, anxiety disorders, obsessive-compulsive disorder, neurodegenerative or neuroinflammatory disorders, neurodevelopmental disorders, leukodystrophy, and CNS oxidative stress.

34. The method of claim 33, wherein the mood disorder is a depressive disorder, bipolar disorder, or a substance-induced disorder.

35. The method of claim 34, wherein the depressive disorder is major depressive disorder (MDD).

36. A method for treating a subject who has experienced high stress with a disease, disorder, or condition and one or more associated symptoms of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ whose activity is modulated, exacerbated, or associated therewith, is affected by or exacerbated by such alterations, comprising administering to the subject a therapeutically effective amount of the (S)-enantiomer, zwitterion, or pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 23, 24, or 27-29.

37. A method for treating a subject who has experienced high stress, including diseases, disorders, or conditions and one or more related symptoms, caused by or exacerbated by alterations in the activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, comprising administering to the subject a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 25-29.

38. The method of claim 36 or 37, wherein the stress is caused by adversity in early life or by childhood trauma.

39. A method for treating diseases, disorders, or conditions and one or more associated symptoms caused by altered activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, which are exacerbated or associated with them, while reducing µ-opioid receptor agonism associated with treatment with racemic tianapordine, the method comprising administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 23, 24, and 27-29.

40. A method for treating diseases, disorders, or conditions and one or more associated symptoms of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ whose activity is modulated, exacerbated, or associated with them, while reducing µ-opioid receptor agonism associated with treatment with racemic tianapordine, the method comprising administering to a subject in need or at risk a therapeutically effective amount of the 11-D-(S)-enantiomer of any one of claims 11-22 or a cocrystal of the 11-D-(S)-enantiomer or a zwitterion thereof, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 25-29.

41. The method according to any one of claims 30-40 or 59, wherein the (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the (S)-enantiomer, a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or the pharmaceutical composition thereof, is administered once or more daily.

42. The method according to any one of claims 30-40 or 59, wherein the (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the (S)-enantiomer, a eutectic of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or the (S)-enantiomer of the zwitterion, is administered parenterally, or orally, sublingually, sublingually, sublingually, by inhalation, transpalatally, transdermally, transrectally, or vaginally. The amide or a pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

43. The method according to any one of claims 30-42 or 59, wherein the (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the (S)-enantiomer, a eutectic of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or the 11-D-(S)-enantiomer... The pharmaceutical composition may be administered sequentially or concurrently with one or more other therapeutic agents selected from the group consisting of: antidepressants, anticonvulsants, anxiolytics, antipsychotics, cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, 5HT2 modulators, corticosteroids, antiamyloid agents, anti-tau agents, and chemotherapeutic agents.

44. The method according to any one of claims 30-42 or 59, wherein the (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the (S)-enantiomer, a eutectic of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or the pharmaceutical composition is administered as part of a treatment regimen that also includes a psychotherapeutic intervention.

45. A method for reducing the potential racemization of the (S)-enantiomer, its zwitterion, a pharmaceutically acceptable salt of the (S)-enantiomer, a eutectic of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, according to any one of claims 1-10 and 22, comprising the step of deuterating the (S)-enantiomer, its zwitterion, a pharmaceutically acceptable salt of the (S)-enantiomer, a eutectic of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt at the C-11 position.

46. ​​A method for preparing the (S)-enantiomer of thiazoline according to claim 1 or 2, the method comprising the following steps: (i) A racemic mixture or other mixture of the (S)- and (R)-enantiomers of a chiral amine thianaptine intermediate is resolved by enantioselective crystallization in a solvent mixture using a conformational isomer selective to the (S)-enantiomer, the mixture being characterized by ≥0.1% of the (R)-enantiomer of the chiral amine thianaptine intermediate to produce (S)-amine thianaptine intermediate:(S)-enantiomer selective conformational isomer, the (S)-amine thianaptine intermediate:(S)-enantiomer selective conformational isomer crystallizing from the solvent mixture, and characterized in that it comprises ≤2% of the (R)-amine thianaptine intermediate:(R)-enantiomer selective conformational isomer; (ii) Reacting the (S)-amine thiaponectin intermediate: (S)-enantiomer selective conformation isomer with alkyl 7-bromoheptanoate to produce the (S)-thiaponectin alkyl ester intermediate: (S)-enantiomer selective conformation isomer; (iii) Reacting the (S)-thiazoprine alkyl ester intermediate: the (S)-enantiomer-selective conformational isomer with a base to produce the (S)-thiazoprine alkyl ester intermediate; and (iv) Saponify the (S)-thiazoprine alkyl ester intermediate to produce the (S)-enantiomer of thiazoprine, which contains ≤2% of the (R) enantiomer of thiazoprine.

47. The method according to embodiment 46, wherein the (S)-enantiomer of thiazoline is characterized by ≤0.1% of the (R)-enantiomer of thiazoline.

48. A method for preparing 11-D-(S)-thiazopridine according to claim 11 or 12, the method comprising the following steps: (i) A racemic mixture or other mixture of the (S)- and (R)-enantiomers of the chiral amine 11-D-thianaptine intermediate is resolved by enantioselective crystallization of the (S)-enantiomer in a solvent mixture, the mixture being characterized by ≥0.1% of the (R)-enantiomer of the chiral amine 11-D-thianaptine intermediate to produce the (S)-amine 11-D-thianaptine intermediate:(S)-enantiomer selective conformational isomer, the (S)-amine 11-D-thianaptine intermediate:(S)-enantiomer selective conformational isomer crystallizing from the solvent mixture, and characterized in that it comprises ≤2% of the (R)-amine 11-D-thianaptine intermediate:(R)-enantiomer selective conformational isomer; (ii) Reacting the (S)-amine 11-D-thiaponectin intermediate: (S)-enantiomer selective conformation isomer with alkyl 7-bromoheptanoate to produce 11-D-(S)-thiaponectin alkyl ester intermediate: (S)-enantiomer selective conformation isomer; (iii) Reacting the 11-D-(S)-thiazoprine alkyl ester intermediate: the (S)-enantiomer-selective conformational isomer with a base to produce the 11-D-(S)-thiazoprine alkyl ester intermediate; and (iv) Saponify the 11-D-(S)-thianaptine alkyl ester intermediate to produce the 11-D-(S)-enantiomer of thianaptine, which comprises ≤2% of the (R) enantiomer of 11-D-thianaptine.

49. The method of claim 48, wherein the (S)-enantiomer of 11-D-tianaphthol is characterized by ≤0.1% of the (R)-enantiomer of 11-D-tianaphthol.

50. A method for preparing the (S)-enantiomer of thiazoline according to claim 1 or 2, or its zwitterion, the method comprising the following steps: (i) A racemic mixture or other mixture of (S)- and (R)-enantiomers of thiazoline alkyl esters is separated by enantioselective crystallization in a solvent mixture using a conformational isomer selective for (R)-enantiomers, the mixture being characterized by ≥0.1% of the (R)-enantiomer of thiazoline alkyl esters to produce (R)-thiazoline alkyl ester:(R)-enantiomer selective conformational isomer and (S)-thiazoline alkyl ester:(R)-enantiomer selective conformational isomer, causing the (R)-thiazoline alkyl ester to crystallize and separate from the solvent mixture, the (S)-thiazoline alkyl ester remaining in the solvent mixture and characterized in that it comprises ≤2% of the (R)-thiazoline alkyl ester; (ii) Hydrolyzing the (S)-thiazoliptin alkyl ester:(R)-enantiomer selective conformation isomer with a strong acid to produce a (S)-thiazoliptin acid salt comprising ≤2% (R)-thiazoliptin acid salt; and (iii) Neutralize the (S)-thiazopritine acid salt with a base to produce a zwitterion of the (S)-enantiomer of the thiazopritine.

51. A method for preparing the 11-D-(S)-enantiomer or its zwitterion according to claim 11 or 12, the method comprising the following steps: (i) A racemic mixture or other mixture of (S)- and (R)-enantiomers of 11-D-thianaphthyl alkyl ester is separated by enantioselective crystallization in a solvent mixture using a conformational isomer selective for (R)-enantiomers, the mixture being characterized by ≥0.1% of the (R)-enantiomer of 11-D-thianaphthyl alkyl ester to produce 11-D-(R)-thianaphthyl alkyl ester:(R)-enantiomer selective conformational isomer and 11-D-(S)-thianaphthyl alkyl ester:(R)-enantiomer selective conformational isomer, causing the 11-D-(R)-thianaphthyl alkyl ester to crystallize and separate from the solvent mixture, the 11-D-(S)-thianaphthyl alkyl ester remaining in the solvent mixture and characterized in that it comprises ≤2% of the 11-D-(R)-thianaphthyl alkyl ester; (ii) Hydrolyzing the 11-D-(S)-thianaptine alkyl ester:(R)-enantiomer-selective conformational isomer with a strong acid to produce a 11-D-(S)-thianaptine acid salt comprising ≤2% of 11-D-(R)-thianaptine acid salt; and (iii) Neutralize the 11-D-(S)-thiaponectin acid salt with a base to produce a zwitterion of the 11-D-(S)-enantiomer of the thiaponectin.

52. The method according to any one of claims 46-51, wherein the thiazoprine alkyl ester is a methyl ester, an ethyl ester, or any other C1-C6 alkyl ester.

53. The method according to any one of claims 46-51, wherein the enantioselective crystallization comprises using a conformational isomer selected from the group consisting of: L-dibenzoyl tartaric acid (DBTA), D-DBTA, di-o-toluyl-L-tartaric acid (LD(2-Me)BTA), DD(2-Me)BTA, other DBTA derivatives, (S)-1,1′-bi-2-naphthol-2,2′-dimethyl phosphate, (R)-1,1′-bi-2-naphthol-2,2′-dimethyl phosphate, (S)-(R)-mandelic acid, (R)-(S)-α-methoxy-α-trifluoromethylphenylacetic acid, (R)-(S)-α-methoxy-α-trifluoromethylphenylacetic acid, (1S)-(R)-10-camphorsulfonic acid and (1R)-(R)-10-camphorsulfonic acid.

54. The method according to any one of claims 46-51, wherein the solvent comprises a mixture of benzene, acetone and chloroform.

55. The method according to any one of claims 46-51, wherein the enantioselective crystallization of the (S)-amine thiaponectin intermediate: (S)-enantiomer-selective conformational isomer, the (S)-amine 11-D-thiaponectin intermediate: (S)-enantiomer-selective conformational isomer, the (R)-thiaponectin alkyl ester: (R)-enantiomer-selective conformational isomer, or the 11-D-(R)-thiaponectin alkyl ester: (R)-enantiomer-selective conformational isomer comprises the step of slowly evaporating the solvent mixture.

56. The method according to any one of claims 46-55, wherein the enantioselective crystallization is repeated to improve the enantiomeric or chiral purity of the separated (S)-amine thiazoliptin intermediate, (S)-amine 11-D-thiazoliptin intermediate, (S)-thiazoliptin methyl ester or 11-D-(S)-thiazoliptin methyl ester.

57. The method according to any one of claims 46-51, wherein the separation of the racemic mixture or other mixture is performed using high performance liquid chromatography (HPLC).

58. The method according to any one of claims 46-51, wherein the separation of the racemic mixture or other mixture is performed using supercritical fluid chromatography with a chiral column.

59. A method for treating a disease, disorder, or condition selected from the group consisting of central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infectious diseases, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopausal and chronic overlapping pain syndrome (COPC), and psychological, physiological, metabolic, or hormonal stress and COPC, the method comprising administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer according to any one of claims 1-10 and 22, or a eutectic of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or its pharmaceutically acceptable form. An acceptable salt, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 23, 24, or 27-29, or administration to the subject a therapeutically effective amount of the 11-D-(S)-enantiomer according to any one of claims 11-22, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 25-29.

60. A method for enhancing neurite growth, comprising administering to a subject in need an (S)-enantiomer according to any one of claims 1-10 and 22, or a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 23, 24, or 27-29, or administering to the subject a therapeutically effective amount of 11-D-(S)-enantiomer according to any one of claims 11-22, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 25-29.

61. A method for treating a disease, disorder, or condition regulated, aggravated, or associated with an excessive level of metal ions in circulation, comprising administering to a subject in need or at risk a therapeutically effective amount of the (S)-enantiomer according to any one of claims 1-10 and 22, or a eutectic of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the substance according to any one of claims 23, 24, or 27-29. The pharmaceutical composition described herein, or administered to the subject a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or the pharmaceutical composition according to any one of claims 25-29.

62. A method for reducing violence or aggression associated with CNS disorders, comprising administering to a subject in need or at risk a therapeutically effective amount of any of the following: the (S)-enantiomer of any one of claims 1-10 and 22, or a cocrystal of the (S)-enantiomer or its zwitterion, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 23, 24, or 27-29, or The subject is given a therapeutically effective amount of the 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 25-29.

63. A method for reducing the likelihood of admission to a psychiatric hospital or incarceration due to behaviors or actions associated with CNS disorders, comprising administering to a subject in need or at risk a therapeutically effective amount of any of the following: the (S)-enantiomer according to any one of claims 1-10 and 22; or a eutectic of the (S)-enantiomer or its zwitterion; or an ester of the (S)-enantiomer or its pharmaceutically acceptable salt; or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt; or any of the following: claims 23, 24, or 27-29. The pharmaceutical composition described herein, or administered to the subject a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or the pharmaceutical composition according to any one of claims 25-29.

64. A method for treating a disease, disorder, or condition regulated, exacerbated, or associated with high levels of S-nitrosylation of PPAR-β / δ and / or PPAR-γ, comprising administering to a subject in need or at risk a therapeutically effective amount of any of claims 1-10 and 22, or a eutectic of said (S)-enantiomer or its zwitterion, or an ester of said (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of said (S)-enantiomer or a pharmaceutically acceptable salt thereof, or according to claim 23, 24, or 27. The pharmaceutical composition of any one of claims 29, or administered to the subject a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a eutectic of the 11-D-(S)-enantiomer or its zwitterion, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 25-29.

65. N-hydroxy-tiaponectin of formula (XV) or a pharmaceutically acceptable salt thereof: Formula (XV).

66. The (S)-enantiomer of N-hydroxy-tianapril of formula (XVI) (N-hydroxy-(S)-tianapril) or a pharmaceutically acceptable salt thereof, wherein the (S)-enantiomer of N-hydroxy-tianapril or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the (R)-enantiomer of N-hydroxy-tianapril or a pharmaceutically acceptable salt thereof: Formula (XVI).

67. The (R)-enantiomer of N-hydroxy-(R)-thiazopritine of formula (XVII) (N-hydroxy-(R)-thiazopritine) or a pharmaceutically acceptable salt thereof, wherein the (R)-enantiomer of N-hydroxy-thiazopritine or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the (S)-enantiomer of N-hydroxy-thiazopritine or a pharmaceutically acceptable salt thereof: Formula (XVII).

68. N-nitroso-thiaponectin of formula (XVIII) or a pharmaceutically acceptable salt thereof: Formula (XVIII).

69. The (S)-enantiomer of N-nitroso-tianapril of formula (XIX) (N-nitroso-(S)-tianapril) or a pharmaceutically acceptable salt thereof, wherein the (S)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the (R)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof: Formula (XIX).

70. The (R)-enantiomer of N-nitroso-tianapril of formula (XX) (N-nitroso-(R)-tianapril) or a pharmaceutically acceptable salt thereof, wherein the (R)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof is characterized by comprising ≤ about 2% of the (S)-enantiomer of N-nitroso-tianapril or a pharmaceutically acceptable salt thereof: Formula (XX).

71. An aryl-substituted thiazoprine analogue or a pharmaceutically acceptable salt thereof.

72. The aryl-substituted thiazoliptin analogue according to claim 71, wherein the aryl-substituted thiazoliptin derivative is 7-((3-(furan-2-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-yl)amino)heptanoic acid of formula (XXI) or 7-((3-(furan-3-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-yl)amino)heptanoic acid of formula (XXII) Thiazido-11-yl)amino)heptanoic acid, formula (XXIII) of 7-((6-methyl-5,5-dioxide-3-(thiophen-3-yl)-6,11-dihydrodibenzo[c,f][1,2]thiazo-11-yl)amino)heptanoic acid, or formula (XXIV) of 2-(4-(((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazo-11-yl)amino)methyl)-2-methylphenoxy)acetic acid 。 73. A pharmaceutical composition comprising N-hydroxy-tiaponectin or a pharmaceutically acceptable salt thereof as claimed in claim 65, or N-nitroso-tiaponectin or a pharmaceutically acceptable salt thereof as claimed in claim 68, or an aryl-substituted tiaponectin analogue or a pharmaceutically acceptable salt thereof as claimed in claim 71 or 72, and a pharmaceutically acceptable carrier, diluent, or excipient.

74. A pharmaceutical composition comprising the (S)-enantiomer of N-hydroxy-tianaphthol as claimed in claim 66 or a pharmaceutically acceptable salt thereof, or the (S)-enantiomer of N-nitroso-tianaphthol as claimed in claim 69 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises ≤ about 2% or ≤ about 0.1% of the (R)-enantiomer of N-hydroxy-tianaphthol or N-nitroso-tianaphthol or a pharmaceutically acceptable salt thereof of the (R)-enantiomer of said N-hydroxy-tianaphthol or N-nitroso-tianaphthol.

75. A pharmaceutical composition comprising the (R)-enantiomer of N-hydroxy-tianaphthol as claimed in claim 67 or a pharmaceutically acceptable salt thereof, or the (R)-enantiomer of N-nitroso-tianaphthol as claimed in claim 70 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises ≤ about 2% or ≤ about 0.1% of the (S)-enantiomer of N-hydroxy-tianaphthol or N-nitroso-tianaphthol or a pharmaceutically acceptable salt thereof of the (S)-enantiomer of said N-hydroxy-tianaphthol or N-nitroso-tianaphthol.

76. A method for treating diseases, disorders, or conditions and one or more associated symptoms caused by, exacerbated by, or associated with altered activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, comprising administering to a subject in need or at risk a therapeutically effective amount of N-hydroxy-tiaponectin, an (S)-enantiomer of N-hydroxy-tiaponectin, an (R)-enantiomer of N-hydroxy-tiaponectin, or a pharmaceutically acceptable salt thereof, according to any one of claims 65-67; ​​or N-nitroso-tiaponectin, an (S)-enantiomer of N-nitroso-tiaponectin, or an (R)-enantiomer of N-nitroso-tiaponectin, or a pharmaceutically acceptable salt thereof, according to any one of claims 68-70; or an aryl-substituted tiaponectin analogue according to claim 71 or 72 or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition according to any one of claims 73-75.

77. A method for treating a subject experiencing high stress with a disease, disorder, or condition and one or more associated symptoms of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ whose activity is modulated, exacerbated, or associated therewith, is affected by or exacerbated by such alterations, comprising administering to the subject a therapeutically effective amount of N-hydroxy-tiaponectin, an (S)-enantiomer of N-hydroxy-tiaponectin, an (R)-enantiomer of N-hydroxy-tiaponectin, or a pharmaceutically acceptable salt thereof, according to any one of claims 65-67; ​​or N-nitroso-tiaponectin, an (S)-enantiomer of N-nitroso-tiaponectin, or an (R)-enantiomer of N-nitroso-tiaponectin, or a pharmaceutically acceptable salt thereof, according to any one of claims 68-70; or an aryl-substituted tiaponectin analogue according to claim 71 or 72 or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition according to any one of claims 73-75.

78. A method for treating diseases, disorders, or conditions and one or more associated symptoms caused by altered activity regulation of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, exacerbated by or associated with such diseases, disorders, or conditions, while reducing µ-opioid receptor agonism associated with treatment with racemic tiannaphthol, said method comprising administering to a subject in need or at risk a therapeutically effective amount of N-hydroxy-tiannaphthol, the (S)-enantiomer of N-hydroxy-tiannaphthol, or N... The pharmaceutical composition of any of the following: (R)-enantiomers of hydroxy-tiaponectin, or pharmaceutically acceptable salts thereof; or N-nitroso-tiaponectin, (S)-enantiomers of N-nitroso-tiaponectin, or (R)-enantiomers of N-nitroso-tiaponectin, or pharmaceutically acceptable salts thereof, or aryl-substituted tiaponectin analogues according to claims 71 or 72, or pharmaceutical compositions according to any of claims 73-75.

79. A method for treating a disease, disorder, or condition selected from the group consisting of central nervous system (CNS) disorders, asthma, primary biliary cholangitis, hypertriglyceridemia, cardiomegaly, fibromyalgia, cancer, infectious diseases, COVID-19, prolonged COVID, menopausal and chronic overlapping pain syndrome (COPC), psychological, physiological, metabolic or hormonal stress, and COPC, and obesity, comprising administering to the subject a therapeutically effective amount of N-hydroxy-tiaponectin, N-hydroxy-tiaponectin (S...) according to any one of claims 65-67. (R)-enantiomer of N-hydroxy-tiaponectin, or a pharmaceutically acceptable salt thereof, or N-nitroso-tiaponectin, (S)-enantiomer of N-nitroso-tiaponectin, or (R)-enantiomer of N-nitroso-tiaponectin, or a pharmaceutically acceptable salt thereof, or an aryl-substituted tiaponectin analogue or a pharmaceutically acceptable salt thereof, as described in any one of claims 71 or 72, or a pharmaceutical composition according to any one of claims 73-75.

80. A crystalline hemioxalate of (S)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiaza-11-ylamino)heptanoic acid 5,5-dioxide ((S)-tiaponectin), wherein the salt exhibits an X-ray diffraction (XRPD) pattern containing at least one peak selected from 8.5, 20.6, 21.0, and 24.2 degrees 2θ ± 0.3 degrees 2θ.

81. A crystalline free acid / free base of the (S)-enantiomer of tianapordine according to claim 1, wherein the (S)-enantiomer of crystalline tianapordine exhibits an X-ray diffraction (XRPD) pattern comprising at least one peak selected from 10.6, 13.0, 21.1 and 23.7 degrees 2θ ± 0.3 degrees 2θ.

Images