(S)-thianeptin and its use in the treatment of disorders and conditions related to peroxisome proliferator-activated receptors.

Abstract

This disclosure provides the (S)-enantiomer ((S)-thianeptine) of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid and the (S)-enantiomer (11-D-(S)-thianeptine) of deuterated thianeptine, both characterized by containing 2% or less, or about 0.1% or less, of the corresponding (R)-enantiomer. This disclosure further provides salts, amides, esters, cocrystals, crystals, analogs and pharmaceutical compositions thereof, as well as methods for using the (S)-enantiomers and their compounds and compositions in the treatment of diseases, disorders or conditions of the CNS, and diseases, conditions and disorders associated with, or exacerbated by or modulated by, the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, while minimizing or eliminating the potential for opioid abuse. This disclosure also provides the (S)-enantiomers and 11-D-(S)-enantiomers of the disclosure, as well as methods for producing related compounds.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and benefits of U.S. Provisional Patent Application No. 63 / 454,958 filed on 27 March 2023, U.S. Provisional Patent Application No. 63 / 463,299 filed on 1 May 2023, U.S. Provisional Patent Application No. 63 / 466,999 filed on 16 May 2023, U.S. Provisional Patent Application No. 63 / 468,221 filed on 22 May 2023, and U.S. Provisional Patent Application No. 63 / 528,631 filed on 24 July 2023. The contents of each of the above applications are thus incorporated herein by reference in their entirety.

[0002] Technical field This disclosure relates to the (S)-enantiomer ((S)-thianeptine) of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid and the (S)-enantiomer (11-D-(S)-thianeptine) of deuterated thianeptine, both characterized by containing about 2% or less of the corresponding (R)-enantiomer, or about 0.1% or less. This disclosure further provides salts, amides, esters, cocrystals, crystals, analogs and pharmaceutical compositions thereof, as well as methods for using the (S)-enantiomers and their compounds and compositions in the treatment of diseases, disorders or conditions of the CNS, and diseases, conditions and disorders associated with, or exacerbated by or modulated by, the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, while minimizing or eliminating the potential for opioid abuse. These diseases, disorders, and conditions include CNS disorders (e.g., major depressive disorder, age-related cognitive impairment, and neurodegenerative conditions), asthma, and primary biliary cholangitis. The disclosure also provides the (S)-enantiomers and 11-D-(S)-enantiomers of the disclosure, as well as methods for producing related compounds. [Background technology]

[0003] background Tianeptine, a racemic mixture of 7-[(3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][2,1]1-enzothiazepine-11-yl)amino]heptanoic acid, is an antidepressant with neuroprotective and cognitive-restorative effects. Researchers have reported that tianeptine may 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 (Garcia-Alberca JM et al., J Alzheimers Dis. 2022), asthma (Lechin F et al., Methods Find Exp Clin Pharmacol. 2004), and fibromyalgia (ISRCTN16400909). Tianeptine shares structural similarities with classic tricyclic antidepressants, but its pharmacological behavior is unique. Tianeptine-containing drugs are not approved by the U.S. Food and Drug Administration (FDA) for any indication. However, tianeptine is currently available in Europe, Asia, and Central and South America as the active ingredient in products approved and marketed under brand names such as Stabolon®, Coaxil®, Tatinol, Tianeurax®, and Salymbra, among others, for the treatment of depression. For example, France first authorized the sale of tianeptine (e.g., Stabolon®) as an antidepressant in 1989 at a dose of 12.5 mg three times daily. Tianeptine-containing products are also available in certain areas of the United States as commercially available dietary supplements or research chemicals.

[0004] Racemic thianeptin has been reported to affect serotonin reuptake and modulate glutamate activity, and more recently, to slightly activate μ-opioid receptors. In animal studies involving severe stress exposure, thianeptin has been reported to restore neuroplasticity in the brain through synapse formation by exerting biological effects on neurons and glial cells that increase dendritic branching in important hippocampal circuits, thereby restoring hippocampal neurogenesis and reversing stress-induced dysfunction in synaptic glutamate neurotransmission (McEwen BS et al., Mol Psychiatry. 2010). Furthermore, thianeptin has been shown to increase brain-derived neurotrophic factor (BNDF) in the rat amygdala (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 are based on assays using a 50:50 mixture (racemate) of the (R)- and (S)-enantiomers of thianeptin.

[0005] Furthermore, in August 2018, the Centers for Disease Control and Prevention (CDC) published a Morbidity and Mortality Weekly Report (MMWR) describing an occurrence of thianeptine overdose from commercially available products linked to the potential abuse of thianeptine due to its opioid-like effects, and also issued a public health risk warning. In fact, its marketing authorization in Georgia was revoked in June 2010, and in Russia, Ukraine, and Armenia, thianeptine was added to the list of psychotropic drugs due to its misuse by “drug addicts” through intravenous injection. As a result of these measures and reports of abuse, in September 2012, thianeptine was added to the List I of Drugs in Special Circumstances Regarding Prescription and Dispensing Conditions in France. Other common adverse events associated with thianeptine include loss of appetite, nightmares, insomnia, somnolence, dizziness, headache, tachycardia, dyspnea, gastrointestinal disturbances, muscle pain, and asthenia.

[0006] Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-activated transcription factors belonging to the nuclear receptor superfamily, involved in regulating inflammatory responses and lipid metabolism in both the peripheral and central nervous system (CNS). The PPAR subfamily includes three isotypes: PPAR-α, PPAR-γ, and PPAR-β / δ. Studies suggest PPAR-α and PPAR-γ activation in the modulation of neuroinflammation, mitochondrial changes, and memory impairment. PPAR-γ has also been shown to play a role in depression, neurogenesis, and brain-derived neurotrophic factor (BDNF) expression (Nicolakakis N et al., J Neurosci. 2008, Heneka MT et al., Brain. 2005, Gold PW. Int J Mol Sci. 2021). PPAR-γ modulation is also used to treat diabetes with “thiazolidinedione” ("TZD") class agonists, often referred to as “glitazone,” including rosiglitazone (Avandia®) and pioglitazone (Actos®). Just as type 1 and type 2 diabetes are metabolic disorders of peripheral glucose metabolism, Alzheimer's disease is sometimes called “type 3 diabetes” to capture the concept that it may be a metabolic disorder of CNS glucose metabolism (de la Monte SM, Wands JR. J Diabetes Sci Technol. 2008). PPAR-β / δ downregulation is also associated with depressive behavior, while PPAR-β / δ activation has been shown to improve the clinical manifestations of CNS conditions by modulating oxidative stress and inflammatory responses (Chen F et al., Int J Neuropsychopharmacol. 2019, Strosznajder AK, Neuromolecular Med. 2021, Espinosa-Jimenez T et al. Front Pharmacol. 2022). PPAR-β / δ activation is also currently under investigation for the treatment of primary biliary cholangitis with MBX-8025 (Seladelpar®) from CymaBay Therapeutics, which is currently in a Phase 3 clinical trial.

[0007] Major depressive disorder (MDD) is a mood disorder lasting two weeks or longer and is the leading cause of disability worldwide. MDD affects how a person feels, thinks, and copes with daily activities, and can significantly impair all aspects of life as individuals report persistent sadness or anxiety, irritability, anhedonia, significant weight change, impaired appetite, impaired sleep, psychomotor agitation or stunting, fatigue or loss of energy, apathy, impaired ability to think or concentrate, indecisiveness, pain or aches without a clear physical cause, or recurrent thoughts of death or suicide. In 2020, an estimated 21 million adults in the United States (representing about 8.4% of all adults aged 18 or older) experienced at least one major depressive episode. The annual prevalence of major depressive episodes is higher among adult women (e.g., about 10.5%) compared to men (e.g., about 6.2%). Furthermore, the annual prevalence of major depressive episodes is highest among individuals aged 18–25 years (e.g., approximately 17.0%). Studies in humans and animals have shown that depression is associated with a reduction in the size of brain regions thought to regulate mood and cognition, including the prefrontal cortex and hippocampus. Moreover, these areas of the brain show a decrease in neuronal synapses in depression (MacQueen G, Frodl T. Mol Psychiatry. 2011, Price JL, Drevets WC. Neuropsychopharmacology. 2010).

[0008] Current mainstream pharmacological treatments 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. Furthermore, even with multiple sequential treatments, the proportion of patients who achieve asymptomatic status, i.e., remission, is small (Rush, Am J Psychiatry. 2007). Many patients who do not respond well to therapy with SSRIs, SNRIs, and TCAs receive augmentation therapy with mood stabilizers or antipsychotics (Strawbridge R et al., Br J Psychiatry. 2019), and other such patients may receive off-label opioids and narcotic analgesics (e.g., oxycodone, hydrocodone, fentanyl, and tramadol), although there is no solid basis of experimental evidence. The use of 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 intoxication.

[0009] Depression is also associated with dysfunctions in neural plasticity and cellular resilience. Conventional antidepressant medications act, in part, by normalizing this dysfunction and restoring neuronal connectivity. For example, ketamine, an N-methyl-D-aspartic acid (NMDA) receptor antagonist, produces rapid (within hours) antidepressant responses in patients with treatment-resistant depression and animal models, rapidly induces BDNF-dependent synaptogenesis, and reverses synapse deficits 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 US FDA for the emergency treatment of depression. Another NMDA receptor antagonist, dextromethorphan, in combination with bupropion as a fixed-dose oral product (Auvelity®), is also FDA-approved for the treatment of depression. However, ketamine, S-ketamine, dextromethorphan, and other ligands of the NDMA receptor have dissociative effects, which limit their use. Another proposed approach to inducing synaptogenesis is 5-HT 2A the receptor agonist psilocybin, but that approach is limited by hallucinatory symptoms, which are pseudo-psychotic side effects.

[0010] Thus, there is a long-unmet need to safely treat major depressive disorder (MDD) and various other CNS disorders and conditions, as well as various disorders and conditions associated with or modulated by altered activity of PPAR-β / δ and / or PPAR-γ. These disorders and conditions include stress (psychological, environmental, chemical, radiation, oxidative, hormonal, vascular and cardiac trauma), depression, aging, and chronic diseases, each of which is associated with a decrease in neuronal connectivity. (S)-enantiomers of tianeptine, its zwitterions, its co-crystals, its esters, amides and deuterated analogs of any of them, or pharmaceutically acceptable salts and crystal forms thereof of the (S)-enantiomer, and compositions thereof, and various analogs of the two tianeptine enantiomers and compositions thereof, and methods of using such compositions, satisfy this unmet need and minimize or eliminate the potential for opioid abuse while improving the treatment of various CNS disorders and conditions, including MDD, and disorders and conditions associated with or modulated by altered activity of PPAR-β / δ and / or PPAR-γ.

Prior Art Documents

Non-Patent Documents

[0011]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-licensed Document 17

Non-licensed Document 18

Non-licensed Document 19

Non-licensed Document 20

Non-licensed Document 21

[0012] Summary of Disclosure Some embodiments of this disclosure are as follows: 1. The (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid of general formula (Ia) (the (S)-enantiomer of thianeptine), its zwitterion of formula (Ib), or a pharmaceutically acceptable salt of the (S)-enantiomer, or a mixture of two or more of these species, wherein the (S)-enantiomer, zwitterion, or pharmaceutically acceptable salt is ≤ about 2% of thianeptine (R) - A mixture of two or more of these species, characterized by comprising the (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid of general formula (Ia) (S)-enantiomer of thianeptine), the zwitterion of formula (Ib), or a pharmaceutically acceptable salt of the (S)-enantiomer. [ka] . 2. The (S)-enantiomer according to Embodiment 1, characterized in that the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof contains ≤ about 0.1% of the (R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt thereof. 3. A pharmaceutically acceptable salt of the (S)-enantiomer described in Embodiment 1 or 2, wherein the pharmaceutically acceptable salt is (S)-thianeptine benzenesulfonate (1:1), (S)-thianeptine fumarate (1:1), (S)-thianeptine fumarate (2:1), (S)-thianeptine hippurate (1:1), (S)-thianeptine maleate (1:1), (S)-thianeptine maleate (2:1), or (S)-thianeptine p-toluenesulfone pharmaceutically acceptable salts are (1:1) (S)-thianeptine orotinate (1:1), (S)-thianeptine camphor sulfonate (1:1), (S)-thianeptine N-acetyl-L-tyrosineate (1:1), (S)-thianeptine polystyrene, (S)-thianeptine:L-DBTA (2:1), (S)-thianeptine sodium salt, (S)-thianeptine oxalate, or (S)-thianeptine hemishalate (2:1). 4. A pharmaceutically acceptable salt of the (S)-enantiomer described in Embodiment 3, wherein the pharmaceutically acceptable salt is (S)-thianeptine benzenesulfonate (1:1), (S)-thianeptine fumarate (1:1), (S)-thianeptine fumarate (2:1), (S)-thianeptine hippurate (1:1), (S)-thianeptine maleate (1:1), (S)-thianeptine maleate (2:1), (S)-thianeptine p-toluenesulfonate (1:1), or (S)-thianeptine orotinate (1:1). 5. A pharmaceutically acceptable salt of the (S)-enantiomer according to Embodiment 3, wherein the pharmaceutically acceptable salt is (S)-thianeptine camphor sulfonate (1:1), (S)-thianeptine N-acetyl-L-tyrosine (1:1), or (S)-thianeptine polysterix. 6. A pharmaceutically acceptable salt of the (S)-enantiomer according to Embodiment 3, wherein the pharmaceutically acceptable salt is (S)-thianeptine hemisulfate (2:1). 7. A zwitterion comprising the zwitterion of the (S)-enantiomer described in Embodiment 1 or 2. 8. A cocrystal of (S)-enantiomers 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. 9. The cocrystal according to Embodiment 8, wherein the complex comprises (S)-enantiomers or their zwitterions in a 1:1, 1:2, or 2:1 ratio and L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid. 10. The cocrystal according to Embodiment 8 or 9, wherein the cocrystal comprises an inorganic monoalte of the (S)-enantiomer and a zwitterion of the L-amino acid. 11. The cocrystal according to Embodiment 8 or 9, wherein the cocrystal comprises an inorganic monoate of an L-amino acid and a zwitterion of the (S)-enantiomer. 12. The cocrystal according to Embodiment 10 or 11, wherein the inorganic monoacid is hydrochloric acid (HCl). 13. An ester of an (S)-enantiomer according to Embodiment 1 or 2, characterized in that the (S)-enantiomer ester or a pharmaceutically acceptable salt thereof contains ≤ about 2% of an (R)-enantiomer ester or a pharmaceutically acceptable salt thereof. 14. An ester of an (S)-enantiomer according to Embodiment 13, characterized in that the (S)-enantiomer ester or a pharmaceutically acceptable salt thereof contains ≤ about 0.1% of the (R)-enantiomer ester or a pharmaceutically acceptable salt thereof. 15. The (S)-enantiomer ester according to Embodiment 13 or 14, wherein the (S)-enantiomer ester is a methyl ester of the (S)-enantiomer, an ethyl ester of the (S)-enantiomer, or another C1-C6 alkyl (alky) ester of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof. 16. An amide of an (S)-enantiomer according to Embodiment 1 or 2, characterized in that the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof contains ≤ about 2% of an (R)-enantiomer amide or a pharmaceutically acceptable salt thereof. 17. An amide of an (S)-enantiomer according to Embodiment 16, characterized in that the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof contains ≤ about 0.1% of an (R)-enantiomer amide or a pharmaceutically acceptable salt thereof. 18. The (S)-enantiomer amide according to Embodiment 13 or 14, wherein the (S)-enantiomer amide is a simple amide or a C1-C6 alkylamide optionally substituted with at least one hydroxyl group, or a pharmaceutically acceptable salt thereof. 19. The (S)-enantiomer (11-D-(S)-enantiomer of thianeptine) of deuterated 7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl-11-d)amino)heptanoic acid of general formula (IIa), in which deuterium is replaced by hydrogen at position 11, or its zwitterion of formula (IIb), or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a mixture of two or more of these species in which the 11-D-(S)-enantiomer or its zwitterion or pharmaceutically acceptable salt is ≤ about 2% A pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of thianeptine, or its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, characterized by comprising the (S)-enantiomer of deuterated 7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl-11-d)amino)heptanoic acid of general formula (IIa), or its zwitterion of formula (IIb), or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a mixture of two or more of these species. [ka] . 20. The (S)-enantiomer according to Embodiment 19, characterized in that the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof contains ≤ about 0.1% of the 11-D-(R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt thereof. 21. The (S)-enantiomer according to Embodiment 19 or 20, characterized in that the 11-D-(S)-enantiomer, or the zwitterion or pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, exhibits reduced racemization at the 11-position compared to the (S)-enantiomer of thianeptine, or the zwitterion or pharmaceutically acceptable salt of the enantiomer thereof. 22. The (S)-enantiomer according to any one of Embodiments 19 to 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. 23. The 11-D-(S)-enantiomer is the (S)-enantiomer of 3',3',4',4',11-pentaduteriothianeptine of formula (IIIa) or its zwitterion of formula (IIIb); the (S)-enantiomer of 2',2',3',3',4',4',5',5',6',6',7',7',11-tridecaduteriothianeptine of general formula (IVa) or its zwitterion of formula (IVb). The (S)-enantiomers described in Embodiment 22 are the (S)-enantiomers of 3',3',4',4',tetraduteriothianeptine of formula (Va) or its zwitterion of formula (Vb); or the (S)-enantiomers of 2',2',3',3',4',4',5',5',6',6',7',7',dodecaduteriothianeptine of general formula (VIa) or its zwitterion of formula (VIb). [ka] . 24. The pharmaceutically acceptable salts are 11-D-(S)-thianeptine benzenesulfonate (1:1), 11-D-(S)-thianeptine fumarate (1:1), 11-D-(S)-thianeptine fumarate (2:1), 11-D-(S)-thianeptine hippurate (1:1), 11-D-(S)-thianeptine maleate (1:1), 11-D-(S)-thianeptine maleate (2:1), 11-D-(S)-thianeptine p-toluenesulfonate (1:1), 11-D-(S)-thianeptine orotinate (1:1), and 11-D A pharmaceutically acceptable salt of the 11-D-(S) enantiomer described in any one of Embodiments 19 to 23, which is -(S)-thianeptine camphor sulfonate (1:1), 11-D-(S)-thianeptine N-acetyl-L-tyrosineate (1:1), 11-D-(S)-thianeptine polystyrene, 11-D-(S)-thianeptine:L-DBTA (2:1), 11-D-(S)-thianeptine sodium salt, 11-D-(S)-thianeptine oxalate, or 11-D-(S)-thianeptine hemioxalate (2:1). 25. A pharmaceutically acceptable salt of the 11-D-(S) enantiomer according to Embodiment 24, wherein the pharmaceutically acceptable salt is 11-D-(S)-thianeptine benzenesulfonate (1:1), 11-D-(S)-thianeptine fumarate (1:1), 11-D-(S)-thianeptine fumarate (2:1), 11-D-(S)-thianeptine hippurate (1:1), 11-D-(S)-thianeptine maleate (1:1), 11-D-(S)-thianeptine maleate (2:1), 11-D-(S)-thianeptine p-toluenesulfonate (1:1), or 11-D-(S)-thianeptine orotinate (1:1). 26. A pharmaceutically acceptable salt of the 11-D-(S) enantiomer according to Embodiment 24, wherein the pharmaceutically acceptable salt is 11-D-(S)-thianeptine camphor sulfonate (1:1), 11-D-(S)-thianeptine N-acetyl-L-tyrosineate (1:1), or 11-D-(S)-thianeptine polystyrene. 27. A pharmaceutically acceptable salt of the 11-D-(S)-enantiomer according to Embodiment 24, wherein the pharmaceutically acceptable salt is 11-D-(S)-thianeptine hemisulfate (2:1). 28. A zwitterion comprising the zwitterion of the 11-D-(S)-enantiomer described in any one of Embodiments 19 to 23. 29. A cocrystal of an 11-D-(S)-enantiomer according to any one of Embodiments 19 to 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. 30. The cocrystal according to Embodiment 29, wherein the complex comprises 11-D-(S)-enantiomers or their zwitterions in a 1:1, 1:2, or 2:1 ratio and L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid. 31. The cocrystal according to Embodiment 29 or 30, wherein the cocrystal comprises an inorganic monoate of the 11-D-(S)-enantiomer and a zwitterion of an L-amino acid. 32. The cocrystal according to Embodiment 29 or 30, wherein the cocrystal comprises an inorganic monoate of an L-amino acid and a zwitterion of an 11-D-(S)-enantiomer. 33. The cocrystal according to Embodiment 31 or 32, wherein the inorganic monoacid is hydrochloric acid (HCl). 34. An ester of an (S)-enantiomer according to any one of Embodiments 19 to 23, characterized in that the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof contains ≤ about 2% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof. 35. An ester of an (S)-enantiomer according to Embodiment 34, characterized in that the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof contains ≤ about 0.1% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof. 36. The (S)-enantiomer ester 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. 37. An amide of an (S) enantiomer according to any one of embodiments 19 to 23, characterized in that the 11-D-(S) enantiomer amide or a pharmaceutically acceptable salt thereof contains ≤ about 2% of the 11-D-(R) enantiomer amide or a pharmaceutically acceptable salt thereof. 38. An amide of an (S) enantiomer according to Embodiment 37, characterized in that the 11-D-(S) enantiomer amide or a pharmaceutically acceptable salt thereof contains ≤ about 0.1% of the 11-D-(R) enantiomer amide or a pharmaceutically acceptable salt thereof. 39. The (S)-enantiomer amide according to Embodiment 37 or 38, wherein the (S)-enantiomer amide is a simple amide or a C1-C6 alkylamide optionally substituted with at least one hydroxyl group, or a pharmaceutically acceptable salt thereof. 40. A pharmaceutically acceptable salt of the (S)-enantiomer or 11-D-(S)-enantiomer described in any one of Embodiments 1, 2, or 19-23, wherein the nitrogen atom in the carbon-11 (C-11) bonded side chain is 100% protonated, and the 100% protonated salt is less susceptible to air oxidation in solid or solution form compared to the (S)-enantiomer, the 11-D-(S)-enantiomer, either zwitterion, or either sodium salt. 41. A pharmaceutical composition comprising a (S)-enantiomer of thianeptine described in any one of Embodiments 1 to 12, 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 described in Embodiments 13 to 15 or a pharmaceutically acceptable salt of the (S)-enantiomer described in Embodiments 16 to 18, and a pharmaceutically acceptable carrier, diluent, or additive, wherein the composition comprises ≤ about 2% of the (R)-enantiomer of thianeptine, 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. 42. The pharmaceutical composition according to Embodiment 41, wherein the pharmaceutical composition comprises ≤ approximately 0.1% of (R)-enantiomers of thianeptine, their zwitterions or pharmaceutically acceptable salts of (R)-enantiomers, or cocrystals of (R)-enantiomers or their zwitterions, or esters of (R)-enantiomers or pharmaceutically acceptable salts of (R)-enantiomers, or amides of (R)-enantiomers or pharmaceutically acceptable salts of (R)-enantiomers. 43. The 11-D-(S)-enantiomer of thianeptin described in any one of Embodiments 19 to 33, 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 the ester of the 11-D-(S)-enantiomer described in any one of Embodiments 34 to 36 or a pharmaceutically acceptable salt thereof, or the amide of the 11-D-(S)-enantiomer described in any one of Embodiments 37 to 39 or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising a salt and a pharmaceutically acceptable carrier, diluent, or additive, wherein the composition comprises ≤ about 2% of 11-D-(R)-enantiomers of thianeptine, their zwitterions, or pharmaceutically acceptable salts of 11-D-(R)-enantiomers, or cocrystals of 11-D-(R)-enantiomers or their zwitterions, or esters of 11-D-(R)-enantiomers or their pharmaceutically acceptable salts, or amides of 11-D-(R)-enantiomers or their pharmaceutically acceptable salts. 44. The pharmaceutical composition according to Embodiment 43, wherein the pharmaceutical composition comprises ≤ approximately 0.1% of an 11-D-(R)-enantiomer of thianeptin, its zwitterion or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a cocrystal or its zwitterion of the 11-D-(R)-enantiomer, or an ester or a pharmaceutically acceptable salt of the (R)-enantiomer, or an amide or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer. 45. The pharmaceutical composition according to any one of Embodiments 41 to 44, wherein the composition is in the form of a tablet, a thin film, a powder, a caplet, a capsule, a soft gel, a suppository, a nasal spray, an oral spray, or a lung spray. 46. ​​The pharmaceutical composition according to any one of Embodiments 41 to 45, wherein the composition is formulated for immediate release, controlled release, sustained release, extended release, or sustained release of a (S)-enantiomer or 11-D-(S)-enantiomer, or any zwitterion, or ester or amide, or any pharmaceutically acceptable salt, or a cocrystal of a (S)-enantiomer or 11-D-(S)-enantiomer or any zwitterion. 47. The pharmaceutical composition according to Embodiment 46, wherein the composition is formulated for controlled release of a (S)-enantiomer or an 11-D-(S)-enantiomer, or either a zwitterion, ester, or amide, or either a pharmaceutically acceptable salt, or a cocrystal of a (S)-enantiomer or an 11-D-(S)-enantiomer, or either a zwitterion. 48. A pharmaceutical composition comprising a mixture of two or more pharmaceutically acceptable salts or cocrystals of the (S)-enantiomer or 11-D-(S)-enantiomer described in any one of Embodiments 41 to 47, wherein the mixture is characterized by an improved extended release when administered orally, compared to the administration of a composition comprising a single pharmaceutically acceptable salt or cocrystal of the (S)-enantiomer or 11-D-(S)-enantiomer described in any one of Embodiments 41 to 47. 49. A method for treating a disease, disorder or condition modulated, aggravated or associated with a modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, and one or more associated symptoms thereof, comprising the step of administering to a subject who needs or is at risk thereof a therapeutically effective amount of a (S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of a (S)-enantiomer, or a cocrystal or its zwitterion, or an ester or pharmaceutically acceptable salt of a (S)-enantiomer, or an amide or pharmaceutically acceptable salt of a (S)-enantiomer, or a pharmaceutically acceptable salt of a (S)-enantiomer, or one of the pharmaceutically acceptable salts 50. A method for treating a disease, disorder or condition modulated, aggravated or associated with a modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, and one or more associated symptoms thereof, comprising the step of administering to a subject who needs or is at risk thereof a therapeutically effective amount of an 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer described in any one of Embodiments 19 to 39, or a cocrystal of an 11-D-(S)-enantiomer or its zwitterion, or an ester of an 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in any one of Embodiments 43 to 48. 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, infections, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopause and chronic multiple pain conditions (COPC), and psychological, physical, metabolic or hormonal stress and COPC. 52. The method according to Embodiment 51, wherein the disease, disorder, or condition is a CNS disorder. 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 disorders, neurodegenerative or neuroinflammatory disorders, neurodevelopmental disorders, leukodystrophy, and CNS oxidative stress. 54. The method according to Embodiment 53, wherein the mood disorder is a depressive disorder, a bipolar disorder, or a substance-induced disorder. 55. The method according to Embodiment 54, wherein the depressive disorder is major depressive disorder (MDD). 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. 57. The method according to Embodiment 53, wherein the anxiety disorder is panic disorder, generalized anxiety disorder (GAD), specific phobia, agoraphobia, or social phobia. 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, prion disease, transverse myelitis, childhood autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), white matter disappearance disorder, childhood ataxia due to CNS hypomyelination, Creutzfeldt-Jakob disease, Gerstmann-Streussler-Scheinker disease, Kuru, or dementia. 59. The method according to Embodiment 53, wherein the neurodevelopmental disorder is attention-deficit / hyperactivity disorder (ADHD), schizophrenia, Prader-Willi syndrome (including bulimia and other symptoms (e.g., depression and anxiety)), or autism. 60. The method according to Embodiment 53, wherein leukodystrophy is leukoencephalopathy, hypomyelination or demyelinating disease, intellectual disability syndrome, cognitive impairment, glial cell dysfunction or brain injury. 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 symptoms or Alzheimer's disease, prodromal symptoms or FTD of frontotemporal dementia (FTD), prodromal symptoms or PCA of posterior cortical atrophy (PCA), cognitive impairment associated with schizophrenia, drug-induced cognitive impairment, radiation therapy-induced cognitive impairment, space travel-related cognitive decline, or cognitive deficits and neuropathic pain associated with diabetes. 62. The method according to 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. 63. The method according to Embodiment 60, wherein the brain injury is traumatic brain injury, hypoxia-induced brain injury, toxin-induced brain injury, stroke, or reperfusion injury after ischemic stroke. 64. The method according to Embodiment 51, wherein the inflammatory disease is asthma, postoperative cognitive impairment, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalopathy, 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. 65. Autoimmune diseases include ahepatitis, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid antibody 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, Behçet's disease, benign mucosal pemphigoid, bullous pemphigoid, and catfish disease. Sulman's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing polymyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), bullous pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), lupus discoid, Dressler syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes zoster of pregnancy or pemphigoid of pregnancy (PG), hidradenitis suppurativa (HS) (reverse acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mohren's ulcer, Mucher-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, sleep attacks, neonatal lupus, neuromyelitis optica, neutropenia,Ocular scarring pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Paley-Romberg syndrome, squamous cellulitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polysomnogenesis syndrome type I, polysomnogenesis syndrome type II, polysomnogenesis 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 gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy The method according to Embodiment 51, wherein the condition is Rophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Suzak syndrome, sympathetic ophthalmitis (SO), Takayasu arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, or Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)). 66. The method according to Embodiment 51, wherein the infectious disease is a viral infection or a post-viral infection state. 67. The method according to Embodiment 51, wherein the hearing loss condition is mitochondrial non-syndromic hearing loss and hearing loss, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or hereditary hearing loss, hearing loss experienced as a result of ototoxic exposure, hearing loss resulting from disease, or hearing loss resulting from trauma. 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. 69. The method according to Embodiment 51, wherein the musculoskeletal disorder is muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive bulbar spinal muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, fasciculations, Friedrich ataxia, muscle wasting disorder, inclusion body myopathy, motor neuron disease, or paralysis. 70. The method according to Embodiment 51, wherein the metabolic disease is non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes mellitus, phenylketonuria, proliferative retinopathy, and Keams-Thayer disease. 71. The method according to Embodiment 51, wherein the mitochondrial disease is Barth syndrome, chronic progressive extraophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome, mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial neuronal gastrointestinal encephalomyopathy (MNGIE), myoclonus epilepsy with red ragged fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome. 72. The method according to Embodiment 51, wherein the cancer is glioblastoma or glioma. 73. A method for treating a disease, disorder or condition, and one or more associated symptoms thereof, modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, in a subject that has experienced high stress, comprising the step of administering to the subject a therapeutically effective amount of the (S)-enantiomer, its zwitterion or a pharmaceutically acceptable salt of the (S)-enantiomer described in any one of Embodiments 1 to 18, or the cocrystal or its zwitterion or the (S)-enantiomer ester or a pharmaceutically acceptable salt of the (S)-enantiomer amide or a pharmaceutically acceptable salt of the (S)-enantiomer or a pharmaceutically acceptable salt of the same, or the pharmaceutical composition described in any one of Embodiments 41, 42 or 45 to 48. 74. A method for treating a disease, disorder or condition, and one or more associated symptoms thereof, modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, in a subject that has experienced high stress, comprising the step of administering to the subject a therapeutically effective amount of an 11-D-(S)-enantiomer, its zwitterion or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer described in any one of Embodiments 19 to 39, or a cocrystal or its zwitterion or an ester or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer, or an amide or a pharmaceutically acceptable salt of an (S)-enantiomer, 75. The method according to embodiment 73 or 74, wherein the stress is caused by an unfortunate event early in life or by a childhood trauma. 76. A method for treating a disease, disorder or condition modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, and one or more associated symptoms thereof, while reducing μ-opioid receptor agonism associated with treatment with racemic thianeptin, comprising the step of administering to a subject who needs or is at risk thereof a therapeutically effective amount of the (S)-enantiomer, its zwitterion or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal or its zwitterion or an ester or a pharmaceutically acceptable salt of the (S)-enantiomer, or an amide or a pharmaceutically acceptable salt of the (S)-enantiomer, or one of the pharmaceutically acceptable salts associated symptoms thereof. 77. A method for treating a disease, disorder or condition modulated, aggravated or associated with modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, and one or more associated symptoms thereof, while reducing μ-opioid receptor agonism associated with treatment with racemic thianeptin, comprising the step of administering to a subject who needs or is at risk thereof a therapeutically effective amount of an 11-D-(S)-enantiomer or cocrystal of an 11-D-(S)-enantiomer or its zwitterion, or an ester of an 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of Embodiments 43 to 48. 78. The method according to any one of Embodiments 49 to 77 or 104 to 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 an 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 a pharmaceutical composition is administered once or more times a day. 79. The method according to Embodiment 78, wherein (S)-enantiomers, their zwitterions or esters, pharmaceutically acceptable salts of (S)-enantiomers, cocrystals or their zwitterions, or esters or pharmaceutically acceptable salts of (S)-enantiomers, or amides or pharmaceutically acceptable salts of (S)-enantiomers, or 11-D-(S)-enantiomers, their zwitterions or esters, pharmaceutically acceptable salts of 11-D-(S)-enantiomers, cocrystals or their zwitterions, or esters or pharmaceutically acceptable salts of 11-D-(S)-enantiomers, or 11-D-(S)-enantiomers, or 11-D-(S)-enantiomers, or their zwitterions or esters, or pharmaceutically acceptable salts of 11-D-(S)-enantiomers, or 11-D-(S)-enantiomers, or pharmaceutically acceptable salts of 11-D-(S)-enantiomers, or a pharmaceutical composition, is administered once daily. 80. (S)-enantiomers, their zwitterions or esters, pharmaceutically acceptable salts of (S)-enantiomers, cocrystals or their zwitterions, or esters or pharmaceutically acceptable salts of (S)-enantiomers, or amides or pharmaceutically acceptable salts of (S)-enantiomers, or 11-D-(S)-enantiomers, their zwitterions or esters, or pharmaceutically acceptable salts of 11-D-(S)-enantiomers. The method according to any one of Embodiments 49 to 77 or 104 to 124, wherein a cocrystal of an 11-D-(S)-enantiomer or its zwitterion, or an ester of an 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered parenterally, orally, sublingually, intraorally, by inhalation, onto the palate, transdermally, transrectally, or transvaginally. 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 an 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 a pharmaceutical composition is administered orally. 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 an 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 a pharmaceutical composition is administered by inhalation. 83. (S)-enantiomers, their zwitterions or esters, pharmaceutically acceptable salts of (S)-enantiomers, cocrystals or zwitterions of (S)-enantiomers, or esters or pharmaceutically acceptable salts of (S)-enantiomers, or amides or pharmaceutically acceptable salts of (S)-enantiomers, or 11-D-(S)-enantiomers, their zwitterions or esters, pharmaceutically acceptable salts of 11-D-(S)-enantiomers, cocrystals or zwitterions of 11-D-(S)-enantiomers, or 11-D-(S)-enantiomers The method according to any one of embodiments 49-82 or 104-124, wherein tel or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered sequentially or concurrently 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, 5HT2 modulators, corticosteroids, anti-amyloid agents, anti-tau agents, and chemotherapeutic agents. 84. The method according to any one of Embodiments 49 to 82 or 104 to 124, wherein an (S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of an (S)-enantiomer, a cocrystal of an (S)-enantiomer or its zwitterion, or an ester of an (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of an (S)-enantiomer or its pharmaceutically acceptable salt, or an 11-D-(S)-enantiomer, its zwitterion or ester, a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer, a cocrystal of an 11-D-(S)-enantiomer or its zwitterion, or an ester of an 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or an amide of an 11-D-(S)-enantiomer or its pharmaceutically acceptable salt, or a pharmaceutical composition is administered as part of a treatment regimen that also includes psychotherapeutic intervention. 85. A method for reducing the potential racemization of an (S)-enantiomer, its zwitterion, a pharmaceutically acceptable salt of an (S)-enantiomer, a cocrystal or its zwitterion, an ester or its pharmaceutically acceptable salt, or an amide or its pharmaceutically acceptable salt, according to any one of Embodiments 1 to 19, comprising the step of deuterating the (S)-enantiomer, its zwitterion, a pharmaceutically acceptable salt of an (S)-enantiomer, a cocrystal or its zwitterion, an ester or its pharmaceutically acceptable salt, or an amide or its pharmaceutically acceptable salt at the C-11 position. 86. A method for producing the (S)-enantiomer of thianeptin according to Embodiment 1 or 2, (i) a racemic or other mixture of (S)- and (R)-enantiomers of a chiral amine thianeptine intermediate, comprising the steps of: (i) dividing a mixture characterized by ≥0.1% of the (R)-enantiomer of the chiral amine thianeptine intermediate in a solvent mixture by enantiomer-selective crystallization using the (S)-enantiomer-selective conformator to produce an (S)-amine thianeptine intermediate:(S)-enantiomer-selective conformator, which is crystallized from the solvent mixture and contains ≤2% of the (R)-amine thianeptine intermediate:(R)-enantiomer-selective conformator; (ii) The step of reacting an (S)-amine thianeptine intermediate: an (S)-enantiomer-selective conformational isomer with an alkyl 7-bromoheptanoate to produce an (S)-thianeptine alkyl ester intermediate: an (S)-enantiomer-selective conformational isomer; (iii) (S)-thianeptine alkyl ester intermediate: The step of reacting an (S)-enantiomer selective conformational isomer with a base to produce an (S)-thianeptine alkyl ester intermediate; (iv) A step of saponifying an (S)-thianeptine alkyl ester intermediate to produce a (S)-enantiomer of thianeptine, wherein the thianeptine comprises ≤2% of the (R) enantiomer of thianeptine. A method that includes this. 87. The method according to Embodiment 86, characterized in that the (S)-enantiomer of thianeptin is ≤0.1% of the (R)-enantiomer of thianeptin. 88. The chiral amine thianeptine intermediate is 3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][1,2]benzothiazepine-11-amine, and the (S)-amine thianeptine intermediate: (S)-enantiomer-selective conformational isomer is (11S)-3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][1,2]benzothiazepine-11-amine The method according to Embodiment 86, wherein the (S)-enantiomer-selective conformational isomer of the (S)-thianeptine ester intermediate is the (S)-enantiomer-selective conformational isomer of ethyl 7-[[(11S)-3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][1,2]benzothiazepine-11-yl]amino]heptanoate is the (S)-enantiomer-selective conformational isomer. 89. A method for producing 11-D-(S)-thianeptin according to Embodiment 19 or 20, (i) A racemic or other mixture of (S)- and (R)-enantiomers of a chiralamine 11-D-thianeptine intermediate, comprising the steps of: (i) dividing a mixture characterized by ≥0.1% of the (R)-enantiomer of the chiralamine 11-D-thianeptine intermediate in a solvent mixture by enantiomer-selective crystallization using the (S)-enantiomer-selective conformator to produce an (S)-amine 11-D-thianeptine intermediate:(S)-enantiomer-selective conformator, which is crystallized from the solvent mixture and contains ≤2% of the (R)-amine 11-D-thianeptine intermediate:(R)-enantiomer-selective conformator; (ii) The step of reacting an (S)-amine 11-D-thianeptine intermediate:(S)-enantiomer-selective conformational isomer with an alkyl 7-bromoheptanoate to produce an 11-D-(S)-thianeptine alkyl ester intermediate:(S)-enantiomer-selective conformational isomer; (iii) 11-D-(S)-thianeptin alkyl ester intermediate: The step of reacting an (S)-enantiomer-selective conformational isomer with a base to produce an 11-D-(S)-thianeptin alkyl ester intermediate; (iv) A step of saponifying an 11-D-(S)-thianeptine alkyl ester intermediate to produce an 11-D-(S)-enantiomer of thianeptine, wherein the 11-D-(S)-thianeptine contains ≤2% of the (R) enantiomer of 11-D-thianeptine. A method that includes this. 90. The method according to Embodiment 89, characterized in that the (S)-enantiomer of 11-D-thianeptine is ≤0.1% of the (R)-enantiomer of 11-D-thianeptine. 91. The chiralamine 11-D-thianeptine intermediate is 11-amino-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide-11-d, and the (S)-amine 11-D-thianeptine intermediate: (S)-enantiomer-selective conformational isomer is (S)-11-amino-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 5,5-dioxide-1 The method according to Embodiment 89, wherein 1-d:(S)-enantiomer selective conformational isomer, and the 11-D-(S)-thianeptin alkyl ester intermediate:(S)-enantiomer selective conformational isomer is ethyl(S)-7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl-11-d)amino)heptanoate:(S)-enantiomer selective conformational isomer. 92. A method for producing the (S)-enantiomer or zwitterion of thianeptin according to Embodiment 1 or 2, (i) A racemic or other mixture of (S)- and (R)-enantiomers of thianeptin alkyl esters, characterized by comprising ≥0.1% of the (R)-enantiomer of the thianeptin alkyl ester, divided in a solvent mixture by enantiomer-selective crystallization using an (R)-enantiomer-selective conformator to produce (R)-thianeptin alkyl ester:(R)-enantiomer-selective conformator and (S)-thianeptin alkyl ester:(R)-enantiomer-selective conformator, wherein the (R)-thianeptin alkyl ester remains in the solvent mixture and contains ≤2% of the (R)-thianeptin alkyl ester; (ii) A step of hydrolyzing an (S)-thianeptine alkyl ester:(R)-enantiomer selective conformation isomer with a strong acid to produce an (S)-thianeptine salt, wherein the thianeptine salt contains ≤2% of the (R)-thianeptine salt; (iii) The step of neutralizing the salt of (S)-thianeptine with a base to produce a zwitterion of the (S)-enantiomer of thianeptine, and A method that includes this. 93. A method for producing the 11-D-(S)-enantiomer or zwitterion described in Embodiment 19 or 20, (i) A racemic or other mixture of (S)- and (R)-enantiomers of 11-D-thianeptin alkyl ester, characterized by comprising ≥0.1% of the (R)-enantiomer of 11-D-thianeptin alkyl ester, divided in a solvent mixture by enantiomer-selective crystallization using an (R)-enantiomer-selective conformator to produce 11-D-(R)-thianeptin alkyl ester:(R)-enantiomer-selective conformator and 11-D-(S)-thianeptin alkyl ester:(R)-enantiomer-selective conformator, wherein the 11-D-(R)-thianeptin alkyl ester remains in the solvent mixture, comprising the steps of: (i) a racemic or other mixture of (S)- and (R)-enantiomers of 11-D-thianeptin alkyl ester, characterized by comprising ≤2% of 11-D-(R)-thianeptin alkyl ester; (ii) A step of hydrolyzing an 11-D-(S)-thianeptine alkyl ester:(R)-enantiomer-selective conformational isomer with a strong acid to produce an 11-D-(S)-thianeptine salt, wherein the 11-D-thianeptine salt contains ≤2% of an 11-D-(R)-thianeptine salt; (iii) The step of neutralizing the salt of 11-D-(S)-thianeptine with a base to produce a zwitterion of the 11-D-(S)-enantiomer of thianeptine, and A method that includes this. 94. The method according to any one of Embodiments 86, 89, 92, or 93, wherein the thianeptin alkyl ester is a methyl ester, an ethyl ester, or any other C1-C6 alkyl ester. 95. Enantiomer-selective crystallization is observed for L-dibenzoyl tartaric acid (DBTA), D-DBTA, di-o-toluyl-L-tartaric acid (LD(2-Me)BTA), DD(2-Me)BTA, other DBTA derivatives, hydrogen hydrogen phosphate (S)-1,1'-bi-2-naphthol-2,2'-diyl, hydrogen hydrogen phosphate (R)-1,1'-bi-2-naphthol-2,2'-diyl, (S)-(R)-mandelic acid, (R)-(S)-mandelic acid, ( The method according to any one of Embodiments 86, 89, 92, or 93, comprising using a conformational isomer selected from the group consisting of S)-(S)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid, (R)-(S)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid, (1S)-(R)-10-camphorsulfonic acid and (1R)-(R)-10-camphorsulfonic acid. 96. The method according to any one of Embodiments 86, 89, 92, or 93, wherein the solvent comprises a mixture of benzene, acetone, and trichloromethane. 97. The method according to Embodiment 96, wherein the solvent comprises benzene, acetone, and trichloromethane in a ratio of 2:1:1. 98. The method according to any one of Embodiments 86, 89, 92, or 93, wherein the enantiomer-selective crystallization of (S)-amine thianeptine intermediate: (S)-enantiomer-selective conformational isomer, (S)-amine 11-D-thianeptine intermediate: (S)-enantiomer-selective conformational isomer, (R)-thianeptine alkyl ester: (R)-enantiomer-selective conformational isomer, or 11-D-(R)-thianeptine alkyl ester: (R)-enantiomer-selective conformational isomer comprises a step of slow evaporation of a solvent mixture. 99. The method according to any one embodiment of 86, 89, 92, or 93, wherein enantiomer-selective crystallization is repeated to increase the enantiomer purity or chiral purity of the divided (S)-amine thianeptine intermediate, (S)-amine 11-D-thianeptine intermediate, (S)-thianeptine methyl ester, or 11-D-(S)-thianeptine methyl ester. 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. 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. 102. The method according to any one of Embodiments 86, 89, 92, or 93, wherein the step of dividing a racemic or other mixture is performed using high-performance liquid chromatography (HPLC). 103. The method according to any one embodiment of 86, 89, 92, or 93, wherein the step of separating a racemic or other mixture is performed using supercritical fluid chromatography with a chiral column. 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, infections, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopause and chronic multiple pain conditions (COPC), and psychological, physical, metabolic or hormonal stress and COPC, wherein a therapeutically effective amount of the (S)-enantiomer described in any one of Embodiments 1 to 18, or a cocrystal or zwitterion of the (S)-enantiomer, or an ester or pharmaceutically acceptable salt thereof, or an a(S)-enantiomer A method comprising the steps of administering a mid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of Embodiments 41, 42, or 45-48, or administering to a subject a therapeutically effective amount of an 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer according to any one of Embodiments 19-39, or a cocrystal or its zwitterion, or an ester or pharmaceutically acceptable salt of an 11-D-(S)-enantiomer, or an amide or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of Embodiments 43-48. 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 disorders, neurodegenerative or neuroinflammatory disorders, neurodevelopmental disorders, leukodystrophy, and CNS oxidative stress. 106. The method according to Embodiment 105, wherein the mood disorder is a depressive disorder, a bipolar disorder, or a substance-induced disorder. 107. The method according to Embodiment 106, wherein the depressive disorder is major depressive disorder (MDD). 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. 109. The method according to Embodiment 105, wherein the anxiety disorder is panic disorder, generalized anxiety disorder (GAD), specific phobia, agoraphobia, or social phobia. 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, prion disease, transverse myelitis, childhood autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), white matter disappearance disorder, childhood ataxia due to CNS hypomyelination, Creutzfeldt-Jakob disease, Gerstmann-Streussler-Scheinker disease, Kuru, or dementia. 111. The method according to Embodiment 105, wherein the neurodevelopmental disorder is attention-deficit / hyperactivity disorder (ADHD), schizophrenia, Prader-Willi syndrome (including bulimia and other symptoms (e.g., depression and anxiety)), or autism. 112. The method according to Embodiment 105, wherein leukodystrophy is leukoencephalopathy, hypomyelination or demyelinating disease, intellectual disability syndrome, cognitive impairment, glial cell dysfunction or brain injury. 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 symptoms or Alzheimer's disease, prodromal symptoms or FTD of frontotemporal dementia (FTD), prodromal symptoms or PCA of posterior cortical atrophy (PCA), cognitive impairment associated with schizophrenia, drug-induced cognitive impairment, radiation therapy-induced cognitive impairment, space travel-related cognitive decline, or cognitive deficits and neuropathic pain associated with diabetes. 114. The method according to 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. 115. The method according to Embodiment 112, wherein the brain injury is traumatic brain injury, hypoxia-induced brain injury, toxin-induced brain injury, stroke, or reperfusion injury after ischemic stroke. 116. The method according to Embodiment 104, wherein the inflammatory disease is asthma, postoperative cognitive impairment, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalopathy, 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. 117. Autoimmune diseases include: alamic laxity, Addison's disease, Adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid antibody 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, Behçet's disease, benign mucosal pemphigoid, bullous pemphigoid, and causative syndrome. Luman's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing polymyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), bullous pemphigoid scarring, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), lupus discoid, Dressler syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes zoster of pregnancy or bullous pemphigoid of pregnancy (PG), hidradenitis suppurativa (HS) (reverse acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing 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-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mohren's ulcer, Mucher-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, sleep attacks, neonatal lupus, neuromyelitis optica, neutropenia, ocular scarring pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR),PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Paley-Romberg syndrome, squamous cellulitis (peripheral uveitis), Personage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous 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, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restlessness The method according to Embodiment 104, which is Legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Suzak syndrome, sympathetic ophthalmitis (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, or Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)). 118. The method according to Embodiment 104, wherein the infectious disease is a viral infection or a post-viral infection state. 119. The method according to Embodiment 104, wherein the hearing loss condition is mitochondrial non-syndromic hearing loss and hearing loss, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or hereditary hearing loss, hearing loss experienced as a result of ototoxic exposure, hearing loss resulting from disease, or hearing loss resulting from trauma. 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. 121. The method according to Embodiment 104, wherein the musculoskeletal disorder is muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive bulbar spinal muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, fasciculations syndrome, Friedrich ataxia, muscle wasting disorder, inclusion body myopathy, motor neuron disease, or paralysis. 122. The method according to Embodiment 104, wherein the metabolic disease is non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes mellitus, phenylketonuria, proliferative retinopathy, and Kearns-Thayer disease. 123. The method according to Embodiment 104, wherein the mitochondrial disease is Barth syndrome, chronic progressive extraophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome, mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial neuronal gastrointestinal encephalomyopathy (MNGIE), myoclonus epilepsy with red ragged fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome. 124. The method according to Embodiment 104, wherein the cancer is glioblastoma or glioma. 125. A method for improving neurite outgrowth, comprising the steps of administering to a subject in need of such improvement the (S)-enantiomer described in any one of Embodiments 1 to 18, or a cocrystal or zwitterion of the (S)-enantiomer, or an ester or pharmaceutically acceptable salt thereof, or an amide or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in any one of Embodiments 41, 42, or 45 to 48, or administering to the subject a therapeutically effective dose. A method comprising the step of administering an 11-D-(S)-enantiomer described in any one of Embodiments 19 to 39, 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 described in any one of Embodiments 43 to 48. 126. The method according to embodiment 125, wherein neurite outgrowth is observed in glutamatergic neurons. 127. A method for treating a disease, disorder or condition modulated, aggravated, or associated with an excess level of metal ions in circulation, to a subject who needs or is at risk thereof, comprising a therapeutically effective amount of (S)-enantiomers described in any one of Embodiments 1 to 18, or cocrystals or zwitterions of (S)-enantiomers, or esters or pharmaceutically acceptable salts thereof of (S)-enantiomers, or amides or pharmaceutically acceptable salts thereof, or described in any one of Embodiments 41, 42, or 45 to 48. A method comprising the steps of administering the listed pharmaceutical composition, or administering to a subject a therapeutically effective amount of the 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer described in any one of Embodiments 19 to 39, 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 described in any one of Embodiments 43 to 48. 128. The method according to claim 127, wherein the metal ion is iron or copper. 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, infections, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopause and chronic multiple pain conditions (COPC), and psychological, physical, metabolic or hormonal stress and COPC. 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 disorders, neurodegenerative or neuroinflammatory disorders, neurodevelopmental disorders, leukodystrophy, and CNS oxidative stress. 131. A method for reducing violent or aggressive behavior associated with CNS disorders, comprising the steps of administering to a subject who needs or is at risk of such reduction a therapeutically effective amount of a (S)-enantiomer, or a cocrystal or zwitterion of a (S)-enantiomer, or an ester or pharmaceutically acceptable salt thereof, or an amide or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in any one of Embodiments 1 to 18, Alternatively, a method comprising the step of administering to a subject a therapeutically effective amount of an 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer described in any one of Embodiments 19 to 39, or a cocrystal of an 11-D-(S)-enantiomer or its zwitterion, or an ester of an 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in any one of Embodiments 43 to 48. 132. A method to reduce the likelihood of being admitted to or incarcerated in a psychiatric hospital for behaviors or actions related to CNS disorders, comprising, to a subject who needs or is at risk thereof, a therapeutically effective amount of (S)-enantiomer, or cocrystal or zwitterion of (S)-enantiomer, or ester or pharmaceutically acceptable salt thereof of (S)-enantiomer, or amide or pharmaceutically acceptable salt thereof of (S)-enantiomer, or a pharmaceutical composition of any one of Embodiments 41, 42, or 45-48. A method comprising the steps of administering a substance, or administering to a subject a therapeutically effective amount of an 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer described in any one of Embodiments 19 to 39, or a cocrystal of an 11-D-(S)-enantiomer or its zwitterion, or an ester of an 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in any one of Embodiments 43 to 48. 133. A method for treating a disease, disorder or condition modulated, aggravated or associated with high levels of S-nitrosylation of PPAR-β / δ and / or PPAR-γ, comprising, to a subject in need of or at risk thereof, a therapeutically effective amount of any one of Embodiments 1 to 18, or a cocrystal or zwitterion of an (S)-enantiomer, or an ester or pharmaceutically acceptable salt thereof, or an amide or pharmaceutically acceptable salt thereof, or Embodiments 41, 42 or 45 to 48. A method comprising the steps of administering a pharmaceutical composition described in any one of the above, or administering to a subject a therapeutically effective amount of an 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer described in any one of Embodiments 19 to 39, or a cocrystal of an 11-D-(S)-enantiomer or its zwitterion, or an ester of an 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in any one of Embodiments 43 to 48. 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, infections, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopause and chronic multiple pain conditions (COPC), and psychological, physical, metabolic or hormonal stress and COPC. 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 disorders, neurodegenerative or neuroinflammatory disorders, neurodevelopmental disorders, leukodystrophy, and CNS oxidative stress. 136. N-hydroxythianeptine of formula (XV) or its pharmaceutically acceptable salts [ka] . 137. The (S)-enantiomer of N-hydroxythianeptine of formula (XVI) (N-hydroxy-(S)-thianeptine) or a pharmaceutically acceptable salt thereof, characterized in that the (S)-enantiomer of N-hydroxythianeptine or the pharmaceutically acceptable salt thereof contains ≤ about 2% of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxythianeptine. [ka] . 138. The (S)-enantiomer of N-hydroxythianeptine according to Embodiment 137, characterized in that the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of N-hydroxythianeptine contains ≤ about 0.1% of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. 139. The (R)-enantiomer of N-hydroxythianeptine of formula (XVII) (N-hydroxy-(R)-thianeptine) or a pharmaceutically acceptable salt thereof, characterized in that the (R)-enantiomer of N-hydroxythianeptine or the pharmaceutically acceptable salt thereof contains ≤ about 2% of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxythianeptine. [ka] . 140. The (R)-enantiomer of N-hydroxythianeptine according to Embodiment 139, characterized in that the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of N-hydroxythianeptine contains ≤ about 0.1% of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. 141. N-nitroso-thianeptine of formula (XVIII) or its pharmaceutically acceptable salts. [ka] . 142. The (S)-enantiomer of N-nitroso-thianeptine of formula (XIX) (N-nitroso-(S)-thianeptine) or a pharmaceutically acceptable salt thereof, characterized in that the (S)-enantiomer of N-nitroso-thianeptine or the pharmaceutically acceptable salt thereof contains ≤ approximately 2% of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso-thianeptine. [ka] . 143. The (S)-enantiomer of N-nitroso-thianeptine according to Embodiment 142, characterized in that the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-thianeptine contains ≤ about 0.1% of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the enantiomer. 144. The (R)-enantiomer of N-nitroso-thianeptine of formula (XX) (N-nitroso-(R)-thianeptine) or a pharmaceutically acceptable salt thereof, characterized in that the (R)-enantiomer of N-nitroso-thianeptine or the pharmaceutically acceptable salt thereof contains ≤ approximately 2% of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-thianeptine. [ka] . 145. The (R)-enantiomer of N-nitroso-thianeptine according to Embodiment 144, characterized in that the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of N-nitroso-thianeptine contains ≤ about 0.1% of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. 146. Aryl-substituted thianeptine analogs or pharmaceutically acceptable salts thereof. 147. The aryl-substituted thianeptin derivatives are 7-((3-(furan-2-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-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]thiazepine-11-yl)amino)heptanoic acid of formula (XXII), and 7-((6- The aryl-substituted thianeptine analog according to Embodiment 146 is methyl-5,5-dioxide-3-(thiophen-3-yl)-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)heptanoic acid, or 2-(4-(((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)methyl)-2-methylphenoxy)acetic acid of formula (XXIV). [ka] . 148. A pharmaceutical composition comprising N-hydroxythianeptine or a pharmaceutically acceptable salt thereof as described in Embodiment 136, or N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof as described in Embodiment 141, or an aryl-substituted thianeptine analog or a pharmaceutically acceptable salt thereof as described in Embodiment 146 or 147, and a pharmaceutically acceptable carrier, diluent, or additive. 149. A pharmaceutical composition comprising a (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof as described in Embodiment 137 or 138, or a (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof as described in Embodiment 142 or 143, and a pharmaceutically acceptable carrier, diluent, or additive, wherein the composition contains ≤ about 2% or ≤ about 0.1% of a (R)-enantiomer of N-hydroxythianeptine or N-nitroso-thianeptine, or a pharmaceutically acceptable salt thereof of a pharmaceutically acceptable salt thereof. 150. A pharmaceutical composition comprising a (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof as described in Embodiment 139 or 140, or a (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof as described in Embodiment 144 or 145, and a pharmaceutically acceptable carrier, diluent, or additive, wherein the composition contains ≤ about 2% or ≤ about 0.1% of a (S)-enantiomer of N-hydroxythianeptine or N-nitroso-thianeptine, or a pharmaceutically acceptable salt thereof of a pharmaceutically acceptable salt of N-hydroxythianeptine or N-nitroso-thianeptine (S)-enantiomer. 151. A pharmaceutical composition according to any one of Embodiments 148 to 150, wherein the composition is in the form of a tablet, a thin film, a powder, a caplet, a capsule, a soft gel, a suppository, a nasal spray, an oral spray, or a lung spray. 152. A pharmaceutical composition according to any one of Embodiments 148 to 150, wherein the composition is formulated for immediate release, controlled release, sustained release, extended release or sustained release of N-hydroxythianeptine, an (S)-enantiomer of N-hydroxythianeptine, an (R)-enantiomer of N-hydroxythianeptine, N-nitroso-thianeptine, an (S)-enantiomer of N-nitroso-thianeptine, an (R)-enantiomer of N-nitroso-thianeptine, or an aryl-substituted thianeptine analog, or a pharmaceutically acceptable salt thereof. 153. A method for treating a disease, disorder or condition modulated, aggravated or associated with a disease, disorder or condition, and one or more associated symptoms thereof, modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, wherein a therapeutically effective amount of N-hydroxythianeptine, the (S)-enantiomer of N-hydroxythianeptine, or the (R)-enantiomer of N-hydroxythianeptine as described in any one of embodiments 136 to 140 is administered to a subject who needs or is at risk thereof. A method comprising the step of administering N-nitroso-thianeptine, or a pharmaceutically acceptable salt thereof, or N-nitroso-thianeptine, an (S)-enantiomer of N-nitroso-thianeptine, or an (R)-enantiomer of N-nitroso-thianeptine, or a pharmaceutically acceptable salt thereof, as described in any one of Embodiments 141 to 145, or an aryl-substituted thianeptine analog or a pharmaceutically acceptable salt thereof, as described in Embodiment 146 or 147, or a pharmaceutical composition as described in any one of Embodiments 148 to 152. 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, infections, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopause and chronic multiple pain conditions (COPC), and psychological, physical, metabolic or hormonal stress and COPC. 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 disorders, neurodegenerative or neuroinflammatory disorders, neurodevelopmental disorders, leukodystrophy, and CNS oxidative stress. 156. The method according to Embodiment 155, wherein the mood disorder is a depressive disorder, a bipolar disorder, or a substance-induced disorder. 157. The method according to Embodiment 156, wherein the depressive disorder is major depressive disorder (MDD). 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. 159. The method according to Embodiment 155, wherein the anxiety disorder is panic disorder, generalized anxiety disorder (GAD), specific phobia, agoraphobia, or social phobia. 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, prion disease, transverse myelitis, childhood autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), white matter disappearance disorder, childhood ataxia due to CNS hypomyelination, Creutzfeldt-Jakob disease, Gerstmann-Streussler-Scheinker disease, Kuru, or dementia. 161. The method according to Embodiment 155, wherein the neurodevelopmental disorder is attention-deficit / hyperactivity disorder (ADHD), schizophrenia, Prader-Willi syndrome (including bulimia and other symptoms (e.g., depression and anxiety)), or autism. 162. The method according to Embodiment 155, wherein leukodystrophy is leukoencephalopathy, hypomyelination or demyelinating disease, intellectual disability syndrome, cognitive impairment, glial cell dysfunction or brain injury. 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 symptoms or Alzheimer's disease, prodromal symptoms or FTD of frontotemporal dementia (FTD), prodromal symptoms or PCA of posterior cortical atrophy (PCA), cognitive impairment associated with schizophrenia, drug-induced cognitive impairment, radiation therapy-induced cognitive impairment, space travel-related cognitive decline, or cognitive deficits and neuropathic pain associated with diabetes. 164. The method according to 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. 165. The method according to Embodiment 162, wherein the brain injury is traumatic brain injury, hypoxia-induced brain injury, toxin-induced brain injury, stroke, or reperfusion injury after ischemic stroke. 166. The method according to Embodiment 154, wherein the inflammatory disease is asthma, postoperative cognitive impairment, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalopathy, 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. 167. Autoimmune diseases include: alamic laxity, Addison's disease, Adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid antibody 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, Behçet's disease, benign mucosal pemphigoid, bullous pemphigoid, and causative nephritis. Luman's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing polymyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), bullous pemphigoid scarring, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), lupus discoid, Dressler syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes zoster of pregnancy or bullous pemphigoid of pregnancy (PG), hidradenitis suppurativa (HS) (reverse acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing 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-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mohren's ulcer, Mucher-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, sleep attacks, neonatal lupus, neuromyelitis optica, neutropenia, ocular scarring pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR),PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Paley-Romberg syndrome, squamous cellulitis (peripheral uveitis), Personage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous 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, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restlessness The method according to Embodiment 154, which is Legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Suzak syndrome, sympathetic ophthalmitis (SO), Takayasu arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, or Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)). 168. The method according to Embodiment 154, wherein the infectious disease is a viral infection or a post-viral infection state. 169. The method according to Embodiment 154, wherein the hearing loss condition is mitochondrial non-syndromic hearing loss and hearing loss, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or hereditary hearing loss, hearing loss experienced as a result of ototoxic exposure, hearing loss resulting from disease, or hearing loss resulting from trauma. 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. 171. The method according to Embodiment 154, wherein the musculoskeletal disorder is muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive bulbar spinal muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, fasciculations syndrome, Friedrich ataxia, muscle wasting disorder, inclusion body myopathy, motor neuron disease, or paralysis. 172. The method according to Embodiment 154, wherein the metabolic disease is non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes mellitus, phenylketonuria, proliferative retinopathy, and Kearns-Thayer disease. 173. The method according to Embodiment 154, wherein the mitochondrial disease is Barth syndrome, chronic progressive extraophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome, mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy, mitochondrial neuronal gastrointestinal encephalomyopathy (MNGIE), myoclonus epilepsy with red ragged fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome. 174. The method according to Embodiment 154, wherein the cancer is glioblastoma or glioma. 175. A method for treating a disease, disorder or condition, and one or more associated symptoms thereof, modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, in a subject that has experienced high stress, comprising: a therapeutically effective amount of N-hydroxythianeptine, the (S)-enantiomer of N-hydroxythianeptine, the (R)-enantiomer of N-hydroxythianeptine, as described in any one of embodiments 136 to 140, A method comprising the step of administering any pharmaceutically acceptable salt thereof, or N-nitroso-thianeptine, an (S)-enantiomer of N-nitroso-thianeptine, or an (R)-enantiomer of N-nitroso-thianeptine as described in any one of Embodiments 141 to 145, or an pharmaceutically acceptable salt thereof, or an aryl-substituted thianeptine analog or a pharmaceutically acceptable salt thereof as described in Embodiment 146 or 147, or a pharmaceutical composition as described in any one of Embodiments 148 to 152. 176. The method according to Embodiment 175, wherein the stress is caused by an unfortunate event early in life or by a childhood trauma. 177. A method for treating a disease, disorder or condition, and one or more associated symptoms thereof, modulated, aggravated, or associated with a disease, disorder or condition, and one or more associated symptoms thereof, modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, while reducing μ-opioid receptor agonism associated with treatment with racemic thianeptin, comprising, to a subject in need of or at risk thereof, N-hydroxythianeptin, (S)-enantiomer of N-hydroxythianeptin, N-hydroxythianeptin, as described in any one of embodiments 136-140, in a therapeutically effective amount. A method comprising the step of administering a (R)-enantiomer of hydroxythianeptine, or a pharmaceutically acceptable salt thereof, or N-nitroso-thianeptine, an (S)-enantiomer of N-nitroso-thianeptine, or a (R)-enantiomer of N-nitroso-thianeptine, or a pharmaceutically acceptable salt thereof, as described in any one of Embodiments 141 to 145, or an aryl-substituted thianeptine analog or a pharmaceutically acceptable salt thereof, as described in Embodiment 146 or 147, or a pharmaceutical composition as described in any one of Embodiments 148 to 152. 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, cardiac hypertrophy, fibromyalgia, cancer, infection, COVID-19, long-term COVID, menopause and chronic multiple pain conditions (COPC), psychological, physical, metabolic or hormonal stress and COPC, and obesity, wherein the subject is N-hydroxythianeptine, (S)-enantiomer of N-hydroxythianeptine, or N-hydroxythianeptine as described in any one of embodiments 136 to 140 of an effective therapeutic dose. A method comprising the step of administering an (R)-enantiomer of or a pharmaceutically acceptable salt thereof, or N-nitroso-thianeptine, an (S)-enantiomer of N-nitroso-thianeptine, or an (R)-enantiomer of N-nitroso-thianeptine, or a pharmaceutically acceptable salt thereof, as described in any one of Embodiments 141 to 145, or an aryl-substituted thianeptine analog or a pharmaceutically acceptable salt thereof, as described in Embodiment 146 or 147, or a pharmaceutical composition as described in any one of Embodiments 148 to 152. 179. The method according to any one of Embodiments 153 to 178, wherein N-hydroxythianeptine, the (S)-enantiomer of N-hydroxythianeptine, the (R)-enantiomer of N-hydroxythianeptine, N-nitroso-thianeptine, the (S)-enantiomer of N-nitroso-thianeptine, the (R)-enantiomer of N-nitroso-thianeptine, or an aryl-substituted thianeptine analog, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered once or more times daily. 180. The method according to Embodiment 179, wherein N-hydroxythianeptine, the (S)-enantiomer of N-hydroxythianeptine, the (R)-enantiomer of N-hydroxythianeptine, N-nitroso-thianeptine, the (S)-enantiomer of N-nitroso-thianeptine, the (R)-enantiomer of N-nitroso-thianeptine, or an aryl-substituted thianeptine analog, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, is administered once daily. 181. The method according to any one of Embodiments 153 to 180, wherein N-hydroxythianeptine, the (S)-enantiomer of N-hydroxythianeptine, the (R)-enantiomer of N-hydroxythianeptine, N-nitroso-thianeptine, the (S)-enantiomer of N-nitroso-thianeptine, the (R)-enantiomer of N-nitroso-thianeptine, or an aryl-substituted thianeptine analog, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered parenterally, orally, sublingually, orally, by inhalation, palatially, transdermally, transrectally, or transvaginally. 182. The method according to Embodiments 153 to 181, wherein N-hydroxythianeptine, the (S)-enantiomer of N-hydroxythianeptine, the (R)-enantiomer of N-hydroxythianeptine, N-nitroso-thianeptine, the (S)-enantiomer of N-nitroso-thianeptine, the (R)-enantiomer of N-nitroso-thianeptine, or an aryl-substituted thianeptine analog, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered sequentially or concurrently 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, 5HT2 modulators, corticosteroids, anti-amyloid agents, anti-tau agents, and chemotherapeutic agents. 183. The method according to Embodiments 153-181, wherein N-hydroxythianeptine, the (S)-enantiomer of N-hydroxythianeptine, the (R)-enantiomer of N-hydroxythianeptine, N-nitroso-thianeptine, the (S)-enantiomer of N-nitroso-thianeptine, the (R)-enantiomer of N-nitroso-thianeptine, or an aryl-substituted thianeptine analog, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered as part of a treatment regimen that also includes a psychotherapeutic intervention. 184. A crystalline hemisodium salt of (S)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid 5,5-dioxide ((S)-thianeptin), wherein the salt exhibits an X-ray diffraction pattern (XRPD) containing at least one peak selected from 8.5, 20.6, 21.0 and 24.2 degrees 2θ ± 0.3 degrees 2θ. 185. The crystalline (S)-thianeptine hemisulfate according to Embodiment 184, wherein the salt exhibits an XRPD pattern further 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. 186. A crystalline free acid / free base of the (S)-enantiomer of thianeptine according to Embodiment 1, wherein the crystalline (S)-enantiomer of thianeptine exhibits an X-ray diffraction pattern (XRPD) including at least one peak selected from 10.6, 13.0, 21.1, and 23.7 degrees 2θ ± 0.3 degrees 2θ. 187. The crystalline free acid / free base of the (S)-enantiomer of thianeptin according to Embodiment 186, wherein the crystalline free acid / free base of the (S)-enantiomer of thianeptin exhibits an 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. [Brief explanation of the drawing]

[0013] [Figure 1] Figure 1 is a graph showing the separation of a mixture of thianeptine zwitterionic enantiomers obtained from a racemic mixture of thianeptine oxalate enantiomers by normal-phase preparative high-performance liquid chromatography (HPLC) at a wavelength of 220 nm. AU = absorbance units.

[0014] [Figure 2A]Figures 2A and 2B show the crystal structures of enantiomers of thianeptine having (-) optical rotation as a sodium salt complexed with L-dibenzoyl tartaric acid (DBTA). Figure 2A shows the crystal structure of the salt (S)-thianeptine:0.5L-DBTA. Figure 2B shows different crystal isoforms of the enantiomer of (S)-thianeptine ((S)-thianeptine:0.5L-DBTA) that have L-DBTA. [Figure 2B] Same as above.

[0015] [Figure 3A-B] Figures 3A and 3B show graphs of cyclic adenosine 3,5-monophosphate (cAMP) inhibition at μ-opioid receptors using various concentrations of [D-Ala2,NMe-Phe4,Gly-ol5]-enkephalin (DAMGO), racemic thianeptin, and (S)-thianeptin oxalate or (R)-thianeptin oxalate with 99.0%–99.35% purity. Figure 3A shows a graph of cAMP inhibition at steady state. Figure 3B shows a graph of the initial rate of cAMP inhibition. NFU stands for normalized fluorescence unit.

[0016] [Figure 4A-B] Figures 4A and 4B show graphs of concentration-response curves illustrating mean arrestin mobilization at μ-opioid receptors using various concentrations of DAMGO, racemic thianeptin, and (S)-thianeptin oxalate or (R)-thianeptin oxalate with 99.0%–99.35% purity. Figure 4A shows the steady-state arrestin mobilization response. Figure 4B shows the initial arrestin mobilization rate analysis.

[0017] [Figure 5A-B]Figures 5A and 5B show graphs of concentration-response curves for %cAMP inhibition at μ-opioid receptors using various logarithmic concentrations (M) of DAMGO, racemic thianeptin, and 99.35% purity (S)-thianeptin sodium salt or (R)-thianeptin sodium salt. The graphs show the initial %cAMP inhibition rate analysis (Figure 5A) and the %cAMP inhibition maximal effect analysis (Figure 5B).

[0018] [Figure 6A-B] Figures 6A–6B show concentration-response curves of %cAMP inhibition at μ-opioid receptors using various logarithmic concentrations (M) of DAMGO, racemic thianeptin, racemic thianeptin sodium salt, and 99.0%–99.35% purity (S)-thianeptin sodium salt or 98.5%–99.35% purity (R)-thianeptin sodium salt. The graphs show the initial rate analysis of %cAMP inhibition (Figure 6A) and the maximal effect analysis of %cAMP inhibition (Figure 6B).

[0019] [Figure 7A-B] Figures 7A–7B show graphs of the concentration-response curves of mean arrestin recruitment at μ-opioid receptors using various logarithmic concentrations (M) of DAMGO, thianeptin, racemic thianeptin sodium, and 99.9% purity (S)-thianeptin sodium or (R)-thianeptin sodium. The graphs show the initial rate analysis of arrestin recruitment (Figure 7A) and arrestin recruitment normalized to baseline (Figure 7B).

[0020] [Figure 8A-B] Figures 8A and 8B show graphs illustrating thianeptin agonism at μ-opioid receptors using various logarithmic concentrations (M) of DAMGO and 99.9% purity (S)-thianeptin sodium salt or (R)-thianeptin sodium salt. The graphs show peak cAMP inhibition (Figure 8A) and peak arrestin recruitment (Figure 8B).

[0021] [Figure 9A-B]Figures 9A-9D show graphs illustrating the activity of racemic thianeptin, racemic thianeptin oxalate, (S)-thianeptin and (R)-thianeptin (99.9% chiral purity), PPAR-β / δ agonist positive control GW0742, PPAR-β / δ agonist Ceradelper, and dimethyl sulfoxide (DMSO, negative control) at peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ). Figures 9B and 9D show magnified views of PPAR-β / δ activation by (S)-thianeptin at approximately 3 μM. [Figure 9C-D] Same as above.

[0022] [Figure 10A] Figures 10A and 10B show graphs illustrating the activity of racemic thianeptine, racemic thianeptine oxalate, (S)-thianeptine and (R)-thianeptine (99.9% chiral purity), PPAR-γ agonist-positive control rosiglitazone, PPAR-β / δ agonist seradelper, and DMSO (negative control) at peroxisome proliferator-activated receptor-γ (PPAR-γ). [Figure 10B] Same as above.

[0023] [Figure 11A] Figures 11A and 11B show graphs illustrating the activity of racemic thianeptine, racemic thianeptine oxalate, (S)-thianeptine and (R)-thianeptine (99.9% chiral purity), PPAR-α agonist-positive control GW7647, PPAR-β / δ agonist Ceradelpar, and DMSO (negative control) at peroxisome proliferator-activated receptor-α (PPAR-α). [Figure 11B] Same as above.

[0024] [Figure 12] Figure 12 shows the superposition of the crystal structures of PPAR-δ / β complexed with ligand GW2331, using computer models of PPAR-δ / β complexed with (S)-thianeptin and PPAR-δ / β complexed with (R)-thianeptin.

[0025] [Figure 13A-B] Figures 13A and 13B show computer models of (S)-thianeptin docked within PPAR-δ / β (Figure 13A) and (R)-thianeptin docked within PPAR-δ / β (Figure 13B), depicting the formation of a carbon-sulfur (CS) covalent bond between (S)-thianeptin and cysteine ​​285 of PPAR-δ / β. The bond length between (S)-thianeptin and Cys285 of PPAR-δ / β is 5.00 Å (Figure 13A), and the bond length between (R)-thianeptin and Cys285 of PPAR-δ / β is 7.92 Å (Figure 13B).

[0026] [Figure 14A-B] Figures 14A-14F show graphs illustrating the effects of (S)-thianeptin and (R)-thianeptin zwitterions (99.9% chiral purity) on neurite outgrowth in cultured glutamatergic neurons. Figures 14A and 14B show the mean neurite length (μm) at 24 hours (Figure 14A) and 72 hours (Figure 14B) post-treatment. Figures 14C and 14D show the total neurite length (μm) (Figure 14C) and mean neurite width (nm) (Figure 14D) at 5 days after treatment with (S)-thianeptin zwitterions (99.9% chiral purity). Figures 14E and 14F show the total neurite length (μm) (Figure 14E) and mean neurite width (nm) (Figure 14F) at 5 days after treatment with (R)-thianeptin zwitterions (99.9% chiral purity). Data are normalized against a 1% PBS control and compared using strictly standardized mean differences (SSMD). P-value: *p<0.05 [Figure 14C] Same as above. [Figure 14D] Same as above. [Figure 14E] Same as above. [Figure 14F] Same as above.

[0027] [Figure 15A]Figures 15A–15D show graphs illustrating the effects of (S)-thianeptin and (R)-thianeptin zwitterions (99.9% chiral purity) on mitochondrial staining (MitoTracker) in cultured glutamatergic neurons 5 days post-treatment. Figures 15A and 15B show mitochondrial staining in cell bodies (Figure 15A) and neurites (Figure 15B) after treatment with (S)-thianeptin zwitterions (99.9% chiral purity). Figures 15C and 15D show mitochondrial staining in cell bodies (Figure 15C) and neurites (Figure 15D) after treatment with (R)-thianeptin zwitterions (99.9% chiral purity). Data are normalized to a 1% PBS control and compared using strictly standardized mean differences (SSMD). p-value: *p<0.05. RFU = Relative Fluorescence Units [Figure 15B] Same as above. [Figure 15C] Same as above. [Figure 15D] Same as above.

[0028] [Figure 16A] Figures 16A-16C show graphs illustrating the effects of racemic sodium thianeptine (Figure 16A), (S)-thianeptine sodium (99.9% chiral purity, Figure 16B), and (R)-thianeptine sodium (99.9% chiral purity, Figure 16C) in novel object recognition (NOR) tests. ANOVA p-values: ***p<0.001, **p<0.1, *p<0.05. [Figure 16B] Same as above. [Figure 16C] Same as above.

[0029] [Figure 17A-B]Figures 17A–17F show graphs illustrating the effects of racemic thianeptine sodium salt (Figures 17A–17B), (R)-thianeptine sodium salt (99.9% chiral purity, Figures 17C–17D), and (S)-thianeptine sodium salt (99.9% chiral purity, Figures 17E–17F) in a forced swimming test (FST). Figures 17A, 17C, and 17E show timelines of the time spent immobile over a 6-minute period. Figures 17B, 17D, and 17F show the total time spent immobile during the 6-minute test. ANOVA p-values: ***p<0.001, *p<0.05. [Figure 17C-D] Same as above. [Figure 17E-F] Same as above.

[0030] [Figure 18A] Figures 18A to 18D show the XRPD patterns of crystalline (S)-thianeptine (Figure 18A), crystalline (S)-thianeptine hemishate (Figure 18B), and amorphous (S)-thianeptine sodium salt (Figure 18C), as well as graphs comparing the XRPDs of the three with those of racemic thianeptine hemishate (Figure 18D). [Figure 18B] Same as above. [Figure 18C] Same as above. [Figure 18D] Same as above. [Modes for carrying out the invention]

[0031] Detailed explanation In some embodiments, this disclosure provides the (S)-enantiomer ((S)-thianeptine) of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid, its zwitterion, ester or amide, or a pharmaceutically acceptable salt or crystalline form thereof of the (S)-enantiomer, or a pharmaceutically acceptable salt or crystalline form thereof of the ester or amide thereof, or a cocrystal or zwitterion of the (S)-enantiomer. In other embodiments, the disclosure provides (S)-enantiomers of deuterated thianeptine (11-D-(S)-thianeptine), their zwitterions, esters or amides, or pharmaceutically acceptable salts or crystalline forms thereof of the 11-D-(S)-enantiomer, or pharmaceutically acceptable salts thereof of the ester or amide, or cocrystals or zwitterions of the 11-D-(S)-enantiomer. In both embodiments, the (S)-enantiomer, zwitterion, cocrystal, ester, amide, and salt are characterized by containing ≤2% of the corresponding (R)-enantiomer, its zwitterion, ester, amide, or salt. In both embodiments, the (S)-enantiomer, zwitterion, ester, amide, and salt are characterized by containing ≤0.1% of the corresponding (R)-enantiomer, its zwitterion, ester, amide, or salt.

[0032] In other embodiments, the disclosure provides thianeptin analogs comprising N-hydroxythianeptin, the (S)- and (R)-enantiomers of N-hydroxythianeptin (i.e., N-hydroxy-(S)-thianeptin or N-hydroxy-(R)-thianeptin), N-nitroso-thianeptin, the (S)- and (R)-enantiomers of N-nitroso-thianeptin (i.e., N-nitroso-(S)-thianeptin or N-nitroso-(R)-thianeptin), aryl-substituted thianeptin analogs, and pharmaceutically acceptable salts thereof. In some embodiments, the (S)-enantiomer of N-hydroxythianeptin or N-nitroso-thianeptin is characterized by containing ≤2% of the corresponding (R)-enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or N-nitroso-thianeptine is characterized by containing ≤0.1% of the corresponding (R)-enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or N-nitroso-thianeptine is characterized by containing ≤2% of the corresponding (S)-enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or N-nitroso-thianeptine is characterized by containing ≤0.1% of the corresponding (S)-enantiomer.

[0033] In some embodiments, the Disclosure provides a pharmaceutical composition comprising one or more of the (S)-enantiomers or crystalline forms thereof, zwitterions, cocrystals, esters, amides, analogs, or salts of the Disclosure, the composition comprising ≤2% of the corresponding (R)-enantiomer. In some embodiments, the pharmaceutical composition comprising ≤0.1% of the corresponding (R)-enantiomer.

[0034] In some embodiments, the Disclosure provides methods for treating central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infections, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopause and chronic multiple pain conditions (COPC), as well as diseases, disorders or conditions and associated symptoms selected from the group consisting of psychological, physical, metabolic or hormonal stress and COPC, by administering the (S)-enantiomers of the Disclosure (i.e., the (S)-enantiomers and / or 11-D-(S)-enantiomers of thianeptin) or their crystalline forms, zwitterions, esters, amides, salts, analogs, and compositions in subjects requiring such treatment. In some embodiments, the disease, disorder, or condition is modulated, aggravated, or associated with the modified activity of PPAR-β / δ and / or PPAR-γ. In some embodiments, the disease, disorder, or condition is modulated, aggravated, 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 modulated, aggravated, or associated with excessive levels of metal ions in circulation. In some embodiments, the disease, disorder, or condition is modulated, aggravated, or associated with stress.

[0035] In some embodiments, the method minimizes the potential for opioid abuse as a result of administration of the (S)-enantiomers of the Disclosure (i.e., the (S)-enantiomers and / or 11-D-(S)-enantiomers of thianeptine) or their crystalline forms, their zwitterions, esters, amides, analogs or pharmaceutically acceptable salts, or compositions containing them.

[0036] In other embodiments, the Disclosure provides a method for producing the (S)-enantiomer and / or the 11-D-(S)-enantiomer of thianeptin of the Disclosure.

[0037] The practices of the various embodiments disclosed herein, unless otherwise specified, utilize prior art in the fields of molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA, and related fields within the scope of the art. These techniques are well described in the literature. definition

[0038] The term "as used herein" refers to the entire application.

[0039] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. In the event of any disagreement, this specification, including its definitions, shall prevail.

[0040] Any embodiment described herein may be combined with one or more embodiments of the Disclosure, including those described in different aspects and different parts of the Specification (including embodiments described only in the Examples section), unless expressly denied or otherwise inappropriate, and should be understood as being disclosed as embodiments in the Disclosure. The combinations of embodiments are not limited to the specific combinations described in the various dependent embodiments of the Disclosure.

[0041] All publications, patents, and patent application publications referenced in this application are incorporated herein by reference. In the event of any inconsistency, this specification shall prevail, including their specific definitions.

[0042] Throughout this application, the word “comprise” or variations such as “comprises” or “comprising” are synonymous with “including,” “containing,” or “characterizing,” and are inclusive or non-restrictive, and do not exclude additional unlisted elements or method steps.

[0043] Any examples following the phrase "e.g." or "for example" are not intended to be exhaustive or restrictive.

[0044] The terms "including" or "includes" are used to mean "includes but not limited to." "Including" and "includes but not limited to" are used interchangeably.

[0045] Unless the context requires a different meaning, singular terms shall include the plural form, and plural terms shall include the singular form.

[0046] In this specification, the articles "a," "an," and "the" are used to refer to one or more (i.e., at least one) grammatical object cases of the article.

[0047] Where used herein, the meaning of the term “about” depends on the context in which it is used. When used in relation to modifications of the quantities of components, parameters, calculations, or measurements of compositions used in the methods of the Disclosure, for example, through typical measurement and liquid handling procedures used in the real world to prepare the compounds or pharmaceutical compositions of the Disclosure; through unforeseen errors in these procedures; through differences in the manufacture, source, or purity of components used to prepare the enantiomers or compositions of the Disclosure or to perform the methods; and refers to the typical + / - of any quantity or use that does not have a substantial effect on the chemical or physical attributes of the compounds, compositions, or methods of the Disclosure. Such variations may be typically within 10%, more typically within 5%, of a given value or range. In some embodiments, the variation may be within 1%. The term “about” also encompasses different quantities resulting from different equilibrium states of compositions arising from a particular initial mixture. Whether modified by the term “about,” the paragraph includes equivalents to quantities. References to “approximately” values ​​or parameters herein include (and are described) embodiments relating to the value or parameter itself. For example, a description referring to “approximately X” includes a description of “X.” Numerical ranges include the digits defining the range. When used in relation to the position of a peak on a powder X-ray diffraction (XRPD) pattern, the term “approximately” includes a peak within the relevant tolerance of ±0.3 degrees 2θ. For example, as used herein, an XRPD peak at “approximately 10.0 degrees 2θ” means that the stated peak occurs between 9.7 and 10.3 degrees 2θ. Solid 13 When used in reference to the position of a peak on a 1C NMR spectrum, the term "approximately" includes peaks within ±0.2 ppm of the stated position. For example, as used herein, "approximately 100.0 ppm" means at 13 The 13C NMR spectrum peak indicates that the peak described occurs at 99.8–100.2 ppm.

[0048] As used herein, the term "substantially" with respect to XRPD patterns refers to a spectrum having at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks (which may have different amplitudes) in common with the referenced pattern, or a pattern with a tolerance of ±0.3 degrees 2θ within the referenced peaks. For NMR patterns, "substantially" refers to a spectrum having at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks (which may have different amplitudes) in common with the referenced pattern, or a pattern with a tolerance of ±0.2 ppm within the referenced peaks. For FT-IR patterns, "substantially" refers to a spectrum having at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks (which may have different amplitudes) in common with the referenced pattern, or a pattern with a tolerance of ±0.5 cm within the referenced peaks. -1 This refers to a pattern with a tolerance of [specify tolerance].

[0049] When used herein, the term "or" should be understood to mean "and / or" unless otherwise explicitly stated in the context.

[0050] Although the disclosed numerical ranges and parameters are approximations, the numerical values ​​specified in the specific examples are reported as accurately as possible. However, any numerical value inherently contains a certain degree of error that inevitably arises from the standard deviation observed in its respective test measurement. Furthermore, it should be understood that all ranges disclosed herein encompass all subranges that are included therein. For example, a range stated as "1 to 10" should be considered to include all subranges between (and including) the minimum value of 1 and the maximum value of 10, i.e., all subranges starting with a minimum value of 1 or more, e.g., 1 to 6.1, and ending with a maximum value of 10 or less, e.g., 5.5 to 10.

[0051] Where any aspect or embodiment is described in relation to the Markouche group or other alternative groups, this application encompasses not only the entire enumerated group as a whole, but also each member of the group individually, and all possible subgroups of the principal group, as well as principal groups that do not include one or more members of the group, even if such individuals and subgroups are not specifically mentioned in this disclosure.

[0052] While exemplary methods and materials are described herein, similar or equivalent methods and materials may also be used in the practice or testing of various aspects and embodiments. Materials, methods, and examples are illustrative only and not intended to be limiting.

[0053] To make this disclosure more easily understandable, certain terms are defined first. These definitions should be read in light of the rest of this disclosure so that they may be understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Additional definitions are provided throughout the detailed description.

[0054] As used herein, the term “to treat” and its cognates mean, but are not limited to, the complete or partial improvement or modulation of the symptoms or pathology of a disease, disorder, or condition, which can be achieved in particular by utilizing the compounds and compositions of this disclosure. This may also include, but are not limited to, even minimal changes or improvements in one or more measurable markers of the disease, disorder, or condition being treated. “To treat” also means delaying the onset, inhibiting or reversing the progression, reducing the severity, or mitigating or preventing the onset of, or one or more symptoms of, a disease, disorder, or condition, or any of the symptoms of such a disease, disorder, or condition, to which the term applies, such as, but are not limited to, slowing or reducing the rate of cognitive decline in age-related cognitive decline.

[0055] "Treating cognitive impairment" means taking measures to improve the cognitive function of a subject with cognitive impairment so that the subject's ability on one or more cognitive tests is improved to any detectable degree, or further decline is prevented, or the rate of such decline is reduced. Preferably, the subject's cognitive function after treatment for cognitive impairment is more closely similar to that of a normal, non-impaired subject. Treatment for cognitive impairment in humans can improve cognitive function to any detectable degree, but preferably, it is sufficient to enable the impaired subject to perform the daily activities of normal life with the same level of proficiency as a normal, non-impaired subject. In some cases, "treating cognitive impairment" means taking measures to improve the cognitive function of a subject with cognitive impairment so that the subject's ability on one or more cognitive tests is improved to any detectable degree, or further decline is prevented, or the rate of such decline is reduced. Preferably, the subject's cognitive function after treatment for cognitive impairment is more closely similar to that of a normal, non-impaired subject. In some cases, "treating cognitive impairment" in subjects affected by age-related cognitive impairment means taking measures to improve the subject's cognitive function so that, after treatment, the subject's cognitive function more closely resembles that of a normal subject without age-matched impairment, or that of a young adult subject. In some cases, "treating cognitive impairment" in subjects means taking measures to slow or delay the progression of cognitive impairment in subjects with cognitive impairment. In some cases, "treating cognitive impairment" in subjects means taking measures to reduce the rate of cognitive decline in subjects with cognitive impairment.

[0056] As used herein, “subject,” “patient,” or “individual” are interchangeable and include humans 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 human.

[0057] As used herein, the term "(S)-enantiomer of thianeptine" means the (S)-enantiomer of thianeptine 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 the 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 the amide of the 11-D-(S)-enantiomer or its pharmaceutically acceptable salt.

[0058] As used herein, the (S)-enantiomer of thianeptin of the Disclosure, or the “therapeutic effective amount” of any composition of the Disclosure, refers to the amount used to treat, prevent, or alleviate one or more symptoms of any disease or disorder of the Disclosure. In some embodiments, any disease or disorder, or any or more symptoms of any disease or disorder, are modulated, aggravated, or associated with modified activity of PPAR-β / δ and / or PPAR-γ. In some embodiments, some symptoms of any disease or disorder are associated with stress or the presence of excess metal ions. Those skilled in the art can easily determine the therapeutic effective amount of the (S)-enantiomer of thianeptin of the Disclosure (i.e., the (S)-enantiomer or 11-D-(S)-enantiomer), the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt to be administered, by considering factors such as the size, weight, age, and sex of the subject, the degree of disease erosion or persistence, and the severity of the symptoms, as well as the route of administration. Generally, the therapeutically effective doses of the (S)-enantiomer (i.e., (S)-enantiomer or 11-D-(S)-enantiomer) of thianeptin of the Disclosure administered to a subject, the zwitterion of the (S)-enantiomer of the Disclosure, and the pharmaceutically acceptable salts are approximately 1 mg / day to approximately 5000 mg / day, approximately 1 mg / day to approximately 4000 mg / day, approximately 1 mg / day to approximately 3000 mg / day, approximately 1 mg / day to approximately 2000 mg / day, approximately 1 mg / day to approximately 1000 mg / day, approximately 2 mg / day to approximately 600 mg / day, approximately 10 mg / day to approximately 400 mg / day, or approximately 25 mg / day to approximately 300 mg / day. Higher or lower doses are also intended.

[0059] As used herein, “pharmaceutically acceptable carrier” refers to any diluent or additive that is compatible with the other components of the formulation and is not harmful to the recipient. A pharmaceutically acceptable carrier may be selected based on the desired route of administration in accordance with standard pharmaceutical practices.

[0060] As used herein, “enantiomer” refers to each of two non-superimal isomers of a compound having at least one chiral / asymmetric atom. Each enantiomer is optically active with respect to its ability to rotate light. Single enantiomers are designated according to the Kahn-Ingold-Prelogue scheme, which is a well-known set of priority rules for ranking the four groups bonded to the asymmetric carbon. See, for example, March, Advanced Organic Chemist. 4. The Ed., (1992), p. 109, whose full disclosure is incorporated herein by reference.

[0061] As used herein, “optically active” refers to the property of a material to rotate the plane of plane-polarized light. Optically active isomers or enantiomers cannot be superimposed on their mirror image. As used herein, the property of an object that cannot be superimposed on its mirror image is called “chirality.” The most common structural feature that gives rise to chirality is an asymmetric carbon atom, that is, a carbon atom bonded to four non-equivalent groups.

[0062] As used herein, “racemic mixture” or “racemic compound” refers to a 50-50 mixture of two enantiomers, and the mixture does not rotate plane-polarized light and can often be separated into two peaks of equal weight by various means, including chromatography.

[0063] As used herein, the terms “substantially pure” or “pure” refer to an enantiomer or composition containing one enantiomer in an amount of 2% or less of one enantiomer. In some embodiments, substantially pure (S)-enantiomers of thianeptine of the Disclosure (i.e., (S)-enantiomer or 11-D-(S)-enantiomer), their zwitterions, pharmaceutically acceptable salts of the (S)-enantiomer, or compositions of the Disclosure contain about 2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less of one (R)-enantiomer of thianeptine (i.e., (R)-enantiomer or 11-D-(R)-enantiomer), the zwitterion of the (R)-enantiomer, or a pharmaceutically acceptable salt.

[0064] As used herein, the term "chiral purity" refers to the degree to which a mixture of enantiomers contains more of one enantiomer than the other.

[0065] As used herein, the term “cocrystal” refers to a solid crystalline supramolecular complex consisting of two or more components within the same crystal lattice, unlike a salt, where the components are in a neutral state and interact via nonionic interactions. The ability of an active pharmaceutical ingredient (API) and a cocrystal-forming material to form a cocrystal can be predicted by determining its ΔpKa value. If the ΔpKa of the API and cocrystal-forming material is negative (<0), there is no proton transfer, indicating that the system forms a cocrystal; on the other hand, if the ΔpKa is greater than 3, there is complete proton transfer, indicating that the system forms a salt. Often, the ΔpKa is between 0 and 3, resulting in only partial proton transfer, and therefore the system is generally called a salt cocrystal (Nugrahani & Jessica. Molecules. 2021).

[0066] As used herein, the terms “μ-opioid receptor assay” or “MOR assay” refer to methodologies for analyzing the activity of G protein-bound receptor signaling pathways in response to ligand binding at μ-opioid receptors.

[0067] As used herein, the term "Gi" refers to the Gi subunit in the G protein-binding receptor signaling pathway.

[0068] As used herein, the term "Gs" refers to the Gs subunit in the G protein-bound receptor signaling pathway.

[0069] As used herein, the terms "β-arrestin" and "arrestin" are interchangeable.

[0070] As used herein, the term "m / z" refers to the mass-to-charge ratio.

[0071] When used herein, "t R The term "retention time" refers to the interval between the injection of a sample and the detection of a substance in that sample.

[0072] As used herein, the term “neurite outgrowth” refers to the process by which a developing neuron generates new projections called neurites in response to guidance cues.

[0073] As used herein, the term “aryl” refers to any functional group or substituent obtained from an aromatic ring having 5 to 7 ring atoms containing 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 on (S)- or (R)-thianeptine as disclosed herein.

[0074] As used herein, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group (radical) of any length consisting of 1 to 6 carbon atoms (C1 to C6), which may be independently substituted with one or more substituents as necessary.

[0075] As used herein, the term “analog” refers to a compound relating to thianeptine but having a modified chemical structure. For example, thianeptine analogs may include additional functional groups, including hydroxyl, nitroso, or aryl groups. The thianeptine analogs of this disclosure include N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof. (S)-thianeptine enantiomer

[0076] In some embodiments, the Disclosure provides (S)-enantiomers of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid ((S)-enantiomers of thianeptine), or their zwitterions, or pharmaceutically acceptable salts of (S)-enantiomers, or mixtures of two or more of these species, characterized in that the (S)-enantiomer, zwitterion, or pharmaceutically acceptable salt contains about 2% or less (i.e., ≤ about 2%) of (R)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of (R)-enantiomer. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt is characterized by containing about 1% or less (i.e., ≤ about 1%) of the (R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt is characterized by containing about 0.9% or less (i.e., ≤ about 0.9%) of the (R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt is characterized by containing about 0.8% or less (i.e., ≤ about 0.8%) of the (R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt is characterized by containing about 0.7% or less (i.e., ≤ about 0.7%) of the (R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by containing about 0.6% or less (i.e., ≤ about 0.6%) of the (R)-enantiomer of thianeptine, 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 is characterized by containing about 0.5% or less (i.e., ≤ about 0.5%) of the (R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt is characterized by containing about 0.4% or less (i.e., ≤ about 0.4%) of the (R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt is characterized by containing about 0.3% or less (i.e., ≤ about 0.3%) of the (R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt is characterized by containing about 0.2% or less (i.e., ≤ about 0.2%) of the (R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof is characterized by containing about 0.1% or less (i.e., ≤ about 0.1%) of the (R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the (S)-enantiomers of the disclosure are in the form of their pharmaceutically acceptable salts or crystals. In some embodiments, the (S)-thianeptine of the disclosure is in the form of a zwitterionic ion.

[0078] In some embodiments, the Disclosure provides (S)-enantiomers of 7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl-11-d)amino)heptanoic acid (11-D-(S)-enantiomers of thianeptine), their zwitterions, or pharmaceutically acceptable salts of the 11-D-(S)-enantiomer, characterized in that the 11-D-(S)-enantiomer, zwitterion, or pharmaceutically acceptable salt contains about 2% or less (i.e., ≤ about 2%) of the 11-D-(R)-enantiomer, 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 containing about 1% or less (i.e., ≤ about 1%) of the 11-D-(R)-enantiomer of thianeptin, 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 containing about 0.9% or less (i.e., ≤ about 0.9%) of the 11-D-(R)-enantiomer of thianeptin, 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 containing about 0.8% or less (i.e., ≤ about 0.8%) of the 11-D-(R)-enantiomer of thianeptin, 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 containing about 0.7% or less (i.e., ≤ about 0.7%) of the 11-D-(R)-enantiomer of thianeptin, 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 containing about 0.6% or less (i.e., ≤ about 0.6%) of the 11-D-(R)-enantiomer of thianeptin, 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 containing about 0.5% or less (i.e., ≤ about 0.5%) of the 11-D-(R)-enantiomer of thianeptin, 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 containing about 0.4% or less (i.e., ≤ about 0.4%) of the 11-D-(R)-enantiomer of thianeptin, 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 containing about 0.3% or less (i.e., ≤ about 0.3%) of the 11-D-(R)-enantiomer of thianeptin, 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 containing about 0.2% or less (i.e., ≤ about 0.2%) of the 11-D-(R)-enantiomer of thianeptine, 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 containing about 0.1% or less (i.e., ≤ about 0.1%) of the 11-D-(R)-enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt thereof.In some embodiments, 11-D-(S)-thianeptine, its zwitterion, or any pharmaceutically acceptable salt thereof is characterized by reduced racemization at the 11-position compared to 11-D-(S)-thianeptine, its zwitterion, or any pharmaceutically acceptable salt thereof.

[0079] In some embodiments, 11-D-(S)-thianeptine of the Disclosure is in the form of its pharmaceutically acceptable salt or crystalline form. In some embodiments, 11-D-(S)-thianeptine of the Disclosure is in the form of a zwitterionic ion.

[0080] In some embodiments, the 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is deuterated at two 3' positions and, if necessary, at other positions on the aminoheptanoic acid side chain. In some embodiments, the 11-D-(S)-enantiomer is 3',3',4',4',11-pentatylated thianeptine of general formula (IIIa) or its zwitterion in formula (IIIb); 2',2',3',3',4',4',5',5',6',6',7',7',11-thirteenatylated thianeptine (of general formula (IVa)) or its zwitterion in formula (IVb); 3',3',4',4' tetratightened thianeptine of general formula (Va) or its zwitterion in formula (Vb); or 2',2',3',3',4',4',5',5',6',6',7',7'decatuutelylated thianeptine of general formula (VIa) or its zwitterion in formula (VIb). In some embodiments, the 11-D-(S)-enantiomer is 3',3',4',4',11-pentatulate thianeptine of general formula (IIIa) or its zwitterion of formula (IIIb). In some embodiments, the 11-D-(S)-enantiomer is 2',2',3',3',4',4',5',5',6',6',7',7',11-thirtabulate thianeptine of general formula (IVa) or its zwitterion of formula (IVb). In some embodiments, the 11-D-(S)-enantiomer is 3',3',4',4'tetrataturate thianeptine of general formula (Va) or its zwitterion of formula (Vb). In some embodiments, the 11-D-(S)-enantiomer is 2',2',3',3',4',4',5',5',6',6',7',7' deduodehydride thianeptine of general formula (VIa) or its zwitterion of general formula (VIb). [ka]

[0081] Methods for producing the compounds described herein as pharmaceutically acceptable salts of the (S)-enantiomers of the present disclosure are well known to those skilled in the art. For example, salts can be prepared from free bases using conventional methods typically involving a reaction with a suitable acid. Suitable acids for preparing acid addition salts are not limited to, but include, organic acids such as acetic acid, propionic acid, glycolic acid, gluconic acid, glucuronic acid, glutamic acid, pyruvate, 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, and benzenesulfonic acid. This includes both saccharic acid, salicylic acid, orotic acid, hippuric acid, anthranilic acid, mesylic acid, 4-hydroxybenzoic acid, 2-hydroxyethanesulfonic acid, phenylacetic acid, mandelic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, beta-hydroxybutyric acid, camphorsulfonic acid, galactaric acid, and galacturonic acid, as well as inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Conversely, the preparation of basic salts of S-enantiomers described herein can be similarly prepared 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-methylglucamine), procaine and trimethylamine.

[0082] In some embodiments, pharmaceutically acceptable salts of the (S)-enantiomers of the present disclosure and their crystalline forms include (S)-thianeptine benzenesulfonate (1:1), (S)-thianeptine fumarate (1:1), (S)-thianeptine fumarate (2:1), (S)-thianeptine hippurate (1:1), (S)-thianeptine maleate (1:1), (S)-thianeptine maleate (2:1), and (S)-thianeptine p-toluene. These include sulfonates (1:1), (S)-thianeptine orotinate (1:1), (S)-thianeptine camphor sulfonate (1:1), (S)-thianeptine N-acetyl-L-tyrosineate (1:1), (S)-thianeptine polystyrene, (S)-thianeptine:L-DBTA (2:1), (S)-thianeptine sodium salt, (S)-thianeptine oxalate, or (S)-thianeptine oxalate (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine benzenesulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine fumarate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine fumarate (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine hippurate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine maleate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine maleate (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine p-toluenesulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine orotinate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine camphor sulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine N-acetyl-L-tyrosine (1:1).In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine polystyrene. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine:L-DBTA (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine sodium salt. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine oxalate. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-thianeptine oxalate (2:1) (i.e., (S)-thianeptine hemioxate). In some embodiments, the hemioxate is in crystalline form.

[0083] In some embodiments, pharmaceutically acceptable salts of the 11-D-(S)-enantiomers of the present disclosure and their crystalline forms include 11-D-(S)-thianeptine benzenesulfonate (1:1), 11-D-(S)-thianeptine fumarate (1:1), 11-D-(S)-thianeptine fumarate (2:1), 11-D-(S)-thianeptine hippurate (1:1), 11-D-(S)-thianeptine maleate (1:1), 11-D-(S)-thianeptine maleate (2:1), and 11-D-(S)-thianeptine p-toluene. These include sulfonates (1:1), 11-D-(S)-thianeptine orotinate (1:1), 11-D-(S)-thianeptine camphor sulfonate (1:1), 11-D-(S)-thianeptine N-acetyl-L-tyrosineate (1:1), 11-D-(S)-thianeptine polystyrene, 11-D-(S)-thianeptine:L-DBTA (2:1), 11-D-(S)-thianeptine sodium salt, 11-D-(S)-thianeptine oxalate, or 11-D-(S)-thianeptine oxalate (2:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine benzenesulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine fumarate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine fumarate (2:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine hippurate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine maleate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine maleate (2:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine p-toluenesulfonate (1:1).In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine orotinate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine camphor sulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine N-acetyl-L-tyrosineate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine polystyrene. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is 11-D-(S)-thianeptine:L-DBTA (2:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine sodium salt. In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine oxalate. In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-thianeptine oxalate (2:1) (i.e., 11-D-(S)-thianeptine hemioxalate). In some embodiments, the hemioxalate is in crystalline form.

[0084] In some embodiments, for example, fumaric acid and maleic acid act as monoanions or dianions, resulting in different salt stoichiometry (i.e., thianeptine versus fumaric acid / maleic acid in a 1:1 or 2:1 ratio). These salts may also contain additional deutherium substituents at one or more positions on the aminoheptanoic acid side chain.

[0085] In some embodiments, a pharmaceutically acceptable salt or crystalline form thereof of the (S)-enantiomer of the disclosure, or a pharmaceutically acceptable salt or crystalline form thereof of the 11-D-(S)-enantiomer of the 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 thereof of the (S)-enantiomer of the disclosure, or a pharmaceutically acceptable salt or crystalline form thereof of the 11-D-(S)-enantiomer of the disclosure, is formed from orotic acid in 58% water / 42% tetrahydrofuran (THF).

[0086] In some embodiments, the Disclosure provides a cocrystal of the (S)-enantiomer of the 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 cocrystal contains the inorganic monoacid of the (S)-enantiomer and the zwitterion of the L-amino acid. In some embodiments, the cocrystal contains the inorganic monoacid of the L-amino acid and the zwitterion of the (S)-enantiomer. In some embodiments, the inorganic monoacid is hydrochloric acid (HCl).

[0087] In some embodiments, the Disclosure provides cocrystals of the 11-D-(S)-enantiomers of the 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 cocrystal contains the inorganic monoacid of the 11-D-(S)-enantiomer and the zwitterion of the L-amino acid. In some embodiments, the cocrystal contains the inorganic monoacid of the L-amino acid and the zwitterion of the 11-D-(S)-enantiomer. In some embodiments, the inorganic monoacid is hydrochloric acid (HCl).

[0088] In some embodiments, the Disclosure provides an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, characterized in that the (S)-enantiomer ester or a pharmaceutically acceptable salt thereof contains ≤ about 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 contains ≤ about 1% of the (R)-enantiomer ester or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer ester or a pharmaceutically acceptable salt thereof contains ≤ about 0.9% of the (R)-enantiomer ester or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer ester or a pharmaceutically acceptable salt thereof contains ≤ about 0.8% 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 containing ≤ about 0.7% 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 containing ≤ about 0.6% 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 containing ≤ about 0.5% 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 containing ≤ about 0.4% 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 containing ≤ about 0.3% 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 containing ≤ 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 containing ≤ about 0.1% of the (R)-enantiomer ester or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the Disclosure provides esters or pharmaceutically acceptable salts of the 11-D-(S)-enantiomers (and 11-D-(S)-enantiomers having at least one deutherium substitution on the aminoheptanoic acid side chain) of the Disclosure, wherein the esters or pharmaceutically acceptable salts of the 11-D-(S)-enantiomers contain ≤ about 2% of the esters or pharmaceutically acceptable salts of the 11-D-(R)-enantiomers. In some embodiments, the esters or pharmaceutically acceptable salts of the 11-D-(S)-enantiomers contain ≤ about 1% of the esters or pharmaceutically acceptable salts of the 11-D-(R)-enantiomers. In some embodiments, the esters or pharmaceutically acceptable salts of the 11-D-(S)-enantiomers contain ≤ about 0.9% of the esters or pharmaceutically acceptable salts of the 11-D-(R)-enantiomers. In some embodiments, the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.8% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.7% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.6% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.5% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.4% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.3% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof.In some embodiments, the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.2% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.1% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the esters include C1-C6 alkyl, C3-C6 branched alkyl, C3-C6 cyclic alkyl, and pivaloyloxyethyl esters. The esters are designed so that, although not wishing to be bound by theory, the ester dissolves slowly enough to provide sustained release of the ester, and so that the ester is enzymatically cleaved in the small intestine, serum, and / or brain to form active (S)-enantiomers or 11-D-(S)-enantiomers at a rate that allows for once-daily dosing of the ester salt, thereby providing sustained release of the (S)-enantiomer or 11-D-(S)-enantiomer.

[0091] Exemplary esters include 3',3',4',4'-tetrahydrogenated-(S)-thianeptine methyl oxalate 1:1 of formula (VII), 2',2',3',3',4',4',5',5',6',6',7',7'-decadyhydrogenated(S)-thianeptine isopropyl p-toluenesulfonate of formula (VIII), 3',3',4',4',11-pentatyhydrogenated-(S)-thianeptine pivaloyloxyethyl benzoate of formula (IX), and (S)-thianeptine ethyl orotate of formula (X). [ka] [ka]

[0092] In some embodiments, the Disclosure provides (S)-enantiomer amides or pharmaceutically acceptable salts thereof, characterized in that the (S)-enantiomer amides or pharmaceutically acceptable salts thereof contain ≤ about 2% of (R)-enantiomer amides or pharmaceutically acceptable salts thereof. In some embodiments, the (S)-enantiomer amides or pharmaceutically acceptable salts thereof contain ≤ about 1% of (R)-enantiomer amides or pharmaceutically acceptable salts thereof. In some embodiments, the (S)-enantiomer amides or pharmaceutically acceptable salts thereof contain ≤ about 0.9% of (R)-enantiomer amides or pharmaceutically acceptable salts thereof. In some embodiments, the (S)-enantiomer amides or pharmaceutically acceptable salts thereof contain ≤ about 0.8% of (R)-enantiomer amides or pharmaceutically acceptable salts 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 amide or a pharmaceutically acceptable salt thereof is characterized by containing ≤ about 0.2% 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 0.1% of the (R)-enantiomer amide or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the Disclosure provides amides or pharmaceutically acceptable salts of the 11-D-(S)-enantiomers (and 11-D-(S)-enantiomers having at least one deuterium substitution on the aminoheptanoic acid side chain) of the Disclosure, characterized in that the amides or pharmaceutically acceptable salts of the 11-D-(S)-enantiomers contain ≤ about 2% of the amides or pharmaceutically acceptable salts of the 11-D-(R)-enantiomers. In some embodiments, the amides or pharmaceutically acceptable salts of the 11-D-(S)-enantiomers contain ≤ about 1% of the amides or pharmaceutically acceptable salts of the 11-D-(R)-enantiomers. In some embodiments, the amides or pharmaceutically acceptable salts of the 11-D-(S)-enantiomers contain ≤ about 0.9% of the amides or pharmaceutically acceptable salts of the 11-D-(R)-enantiomers. 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.

[0094] In some embodiments, the amides include simple amides, C1-C6 alkyls optionally substituted with at least one hydroxyl, C3-C6 branched alkyls, and C3-C6 cyclic alkylamides. While we do not wish to be bound by theory, the amide salts are designed to provide cannabinoid activity through the binding of fatty acid amides to cannabinoid receptors, which may contribute to improved crystallization advantages compared to the (S)-enantiomer or 11-D-(S)-enantiomer of thianeptine, selective delivery to the CNS due to metabolism by brain-specific fatty acid amide hydrolase (FAAH), and pain reduction and antidepressant activity.

[0095] Exemplary amides are (S)-N-(7-amino-7-oxoheptyl-4,4,5,5-d4)-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-aminium 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]76hyazepine-11-aminium 5,5-dioxide p-thiaze This includes ensulfonates, (11S)-3-chloro-6-methyl-N-(7-oxo-7-((1-pivalamidoethyl)amino)heptyl-4,4,5,5-d4)-6,11-dihydrodibenzo[c,f][1,2]76hyazepine-11-d-11-aminium 5,5-dioxidebenzoate of formula (XIII), and (S)-3-chloro-N-(7-(ethylamino)-7-oxoheptyl)-6-methyl-6,11-dihydrodibenzo[c,f][1,2]76hyazepine-11-aminium 5,5-dioxideorote of formula (XIV). [ka] [ka]

[0096] In some embodiments, the Disclosure provides pharmaceutically acceptable salts of the (S)-enantiomer of the Disclosure (e.g., the (S)-enantiomer or the 11-D-(S)-enantiomer) in which the nitrogen atom in the carbon-11 (C-11) bonded side chain is 100% protonated, and the 100% protonated salt is less susceptible to air oxidation in solid or solution form compared to the (S)-enantiomer, the 11-D-(S)-enantiomer, either zwitterion, or either sodium salt.

[0097] In some embodiments, the Disclosure provides a crystalline hemixate of (S)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid 5,5-dioxide ((S)-thianeptine). In some embodiments, the crystalline (S)-thianeptine hemixate of the Disclosure exhibits an X-ray diffraction pattern (XRPD) including 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)-thianeptine hemixate further exhibits an XRPD pattern including 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.

[0098] In some embodiments, the disclosure provides crystalline free acid / free base of (S)-enantiomers of thianeptine. In some embodiments, the crystalline (S)-enantiomer of thianeptine exhibits an X-ray diffraction pattern (XRPD) including 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 thianeptine exhibits an X-ray diffraction pattern (XRPD) further including 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. (S)-thianeptine analog

[0099] In some embodiments, the disclosure provides the compound N-hydroxythianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides the (S)-enantiomer of N-hydroxythianeptine (i.e., N-hydroxy-(S)-thianeptine) or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides the (R)-enantiomer of N-hydroxythianeptine (i.e., N-hydroxy-(R)-thianeptine) or a pharmaceutically acceptable salt thereof. While we do not wish to be bound by theory, N-hydroxythianeptine does not exhibit μ-opioid receptor (MOR) agonism and acts as a potent PPAR-β / δ and / or PPAR-γ agonist.

[0100] In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 2% or less (i.e., ≤ about 2%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxythianeptine. In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 1% or less (i.e., ≤ about 1%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.9% or less (i.e., ≤ about 0.9%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.8% or less (i.e., ≤ about 0.8%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.7% or less (i.e., ≤ about 0.7%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.6% or less (i.e., ≤ about 0.6%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.5% or less (i.e., ≤ about 0.5%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof.In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.4% or less (i.e., ≤ about 0.4%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.3% or less (i.e., ≤ about 0.3%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.2% or less (i.e., ≤ about 0.2%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.1% or less (i.e., ≤ about 0.1%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 2% or less (i.e., ≤ about 2%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 1% or less (i.e., ≤ about 1%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.9% or less (i.e., ≤ about 0.9%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.8% or less (i.e., ≤ about 0.8%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.7% or less (i.e., ≤ about 0.7%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.6% or less (i.e., ≤ about 0.6%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.5% or less (i.e., ≤ about 0.5%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof.In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.4% or less (i.e., ≤ about 0.4%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.3% or less (i.e., ≤ about 0.3%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.2% or less (i.e., ≤ about 0.2%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.1% or less (i.e., ≤ about 0.1%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 2% or less (i.e., ≤ about 2%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso-thianeptine. In some embodiments, the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 1% or less (i.e., ≤ about 1%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.9% or less (i.e., ≤ about 0.9%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.8% or less (i.e., ≤ about 0.8%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.7% or less (i.e., ≤ about 0.7%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.6% or less (i.e., ≤ about 0.6%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.5% or less (i.e., ≤ about 0.5%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof.In some embodiments, the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.4% or less (i.e., ≤ about 0.4%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.3% or less (i.e., ≤ about 0.3%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.2% or less (i.e., ≤ about 0.2%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.1% or less (i.e., ≤ about 0.1%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 2% or less (i.e., ≤ about 2%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 1% or less (i.e., ≤ about 1%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.9% or less (i.e., ≤ about 0.9%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.8% or less (i.e., ≤ about 0.8%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.7% or less (i.e., ≤ about 0.7%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.6% or less (i.e., ≤ about 0.6%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.5% or less (i.e., ≤ about 0.5%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.4% or less (i.e., ≤ about 0.4%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer.In some embodiments, the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.3% or less (i.e., ≤ about 0.3%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.2% or less (i.e., ≤ about 0.2%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof is characterized by containing about 0.1% or less (i.e., ≤ about 0.1%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer.

[0104] In some embodiments, the disclosure provides the compound N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides the (S)-enantiomer of N-nitroso-thianeptine (i.e., N-nitroso-(S)-thianeptine) or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides the (R)-enantiomer of N-nitroso-thianeptine (i.e., N-nitroso-(R)-thianeptine) or a pharmaceutically acceptable salt thereof. While we do not wish to be bound by theory, N-hydroxythianeptine does not exhibit μ-opioid receptor (MOR) agonism and acts as a potent PPAR-β / δ and / or PPAR-γ agonist.

[0105] In some embodiments, the present disclosure provides aryl-substituted thianeptine derivatives. Exemplary derivatives include 7-((3-(furan-2-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-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]thiazepine-11-yl)amino)heptanoic acid of formula (XXI This includes formula (II) 7-((6-methyl-5,5-dioxide-3-(thiophen-3-yl)-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)heptanoic acid and formula (XXIV) 2-(4-(((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)methyl)-2-methylphenoxy)acetic acid. Although not bound by theory, aryl-substituted thianeptine derivatives show increased transmembrane activity compared to thianeptine, due to the aromatic ring, and (R)-enantiomers and racemic mixtures of aryl-substituted thianeptine derivatives show decreased MOR agonism compared to (R)-thianeptine and racemic thianeptine, due to the molecular shape. [ka] Pharmaceutical composition

[0106] The compounds described herein may be administered as the (S)-enantiomers or 11-D-(S)-enantiomers of the disclosure, or optionally, in the form of the zwitterions, salts (including crystalline salts), esters, ester salts, amides, amide salts, or cocrystals of the disclosure, provided that the zwitterions, salts, esters, ester salts, amides, amide salts, or cocrystals are pharmacologically preferable and effective, for example, in this method. The zwitterions, salts, esters, ester salts, or cocrystals of the (S)-enantiomers or 11-D-(S)-enantiomers of the disclosure may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry.

[0107] In some embodiments, the Disclosure provides a pharmaceutical composition comprising one or more of the (S)-enantiomers of the Disclosure, i.e., their zwitterions or pharmaceutically acceptable salts of the (S)-enantiomers of the Disclosure, or cocrystals (including crystalline salts thereof) or zwitterions of the (S)-enantiomers of the Disclosure, or esters or pharmaceutically acceptable salts thereof of the (S)-enantiomers of the Disclosure, or amides or pharmaceutically acceptable salts thereof of the (S)-enantiomers of the Disclosure, along with a pharmaceutically acceptable carrier, diluent or additive, the composition comprising about 2% or less (i.e., ≤ about 2%) of the (R)-enantiomer, its zwitterion, or pharmaceutically acceptable salts of the (R)-enantiomer, or cocrystals or zwitterions of the (R)-enantiomer, or esters or pharmaceutically acceptable salts thereof of the (R)-enantiomer, or amides or pharmaceutically acceptable salts thereof.

[0108] In some embodiments, the Disclosure relates to the (S)-enantiomers of thianeptine of the Disclosure, their zwitterions, or pharmaceutically acceptable salts of the (S)-enantiomers of the Disclosure (including their crystalline salts), or cocrystals or their zwitterions of the (S)-enantiomers of the Disclosure, or esters or their pharmaceutically acceptable salts, or amides or their pharmaceutically acceptable salts of the (S)-enantiomers of the Disclosure, and pharmaceutically acceptable The present invention provides a pharmaceutical composition comprising a carrier, diluent, or additive, wherein the composition comprises about 2% or less (i.e., ≤ about 2%) of the (R)-enantiomer of thianeptin of the present 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 about 1% or less (i.e., ≤ about 1%) of the (R)-enantiomer of thianeptin of the present 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 contains about 0.9% or less (i.e., ≤ about 0.9%) of the (R)-enantiomer of thianeptine of the Disclosure, its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal or its zwitterion of the (R)-enantiomer, or an ester or its pharmaceutically acceptable salt of the (R)-enantiomer, or an amide or its pharmaceutically acceptable salt of the (R)-enantiomer. In some embodiments, the composition contains about 0.8% or less (i.e., ≤ about 0.8%) of the (R)-enantiomer of thianeptine of the Disclosure, its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal or its zwitterion of the (R)-enantiomer, or an ester or its pharmaceutically acceptable salt of the (R)-enantiomer, or an amide or its pharmaceutically acceptable salt of the (R)-enantiomer.In some embodiments, the composition contains about 0.7% or less (i.e., ≤ about 0.7%) of the (R)-enantiomer of thianeptine of the Disclosure, its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal or its zwitterion of the (R)-enantiomer, or an ester or its pharmaceutically acceptable salt of the (R)-enantiomer, or an amide or its pharmaceutically acceptable salt of the (R)-enantiomer. In some embodiments, the composition contains about 0.6% or less (i.e., ≤ about 0.6%) of the (R)-enantiomer of thianeptine of the Disclosure, its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal or its zwitterion of the (R)-enantiomer, or an ester or its pharmaceutically acceptable salt of the (R)-enantiomer, or an amide or its pharmaceutically acceptable salt of the (R)-enantiomer. In some embodiments, the composition contains about 0.5% or less (i.e., ≤ about 0.5%) of the (R)-enantiomer of thianeptine of the Disclosure, its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal or its zwitterion of the (R)-enantiomer, or an ester or its pharmaceutically acceptable salt of the (R)-enantiomer, or an amide or its pharmaceutically acceptable salt of the (R)-enantiomer. In some embodiments, the composition contains about 0.4% or less (i.e., ≤ about 0.4%) of the (R)-enantiomer of thianeptine of the Disclosure, its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal or its zwitterion of the (R)-enantiomer, or an ester or its pharmaceutically acceptable salt of the (R)-enantiomer, or an amide or its pharmaceutically acceptable salt of the (R)-enantiomer. In some embodiments, the composition contains about 0.3% or less (i.e., ≤ about 0.3%) of the (R)-enantiomer of thianeptine of the Disclosure, its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal or its zwitterion of the (R)-enantiomer, or an ester or a pharmaceutically acceptable salt of the (R)-enantiomer, or an amide or a pharmaceutically acceptable salt of the (R)-enantiomer.In some embodiments, the composition contains about 0.2% or less (i.e., ≤ about 0.2%) of the (R)-enantiomer of thianeptine of the Disclosure, its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal or its zwitterion of the (R)-enantiomer, or an ester or its pharmaceutically acceptable salt of the (R)-enantiomer, or an amide or its pharmaceutically acceptable salt of the (R)-enantiomer. In some embodiments of the Disclosure, the composition contains about 0.1% or less (i.e., ≤ about 0.1%) of the (R)-enantiomer of thianeptine of the Disclosure, its zwitterion or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal or its zwitterion of the (R)-enantiomer, or an ester or its pharmaceutically acceptable salt of the (R)-enantiomer, or an amide or its pharmaceutically acceptable salt of the (R)-enantiomer.

[0109] In some embodiments, the pharmaceutical composition of the Disclosure comprises the (S)-enantiomer of thianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt (including its crystalline salt) of the (S)-enantiomer of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable cocrystal of the (S)-enantiomer of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises a zwitterion of the (S)-enantiomer of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises an ester of the (S)-enantiomer of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of an (S)-enantiomer ester of the disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises an (S)-enantiomer amide of the disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of an (S)-enantiomer amide of the disclosure and a pharmaceutically acceptable carrier, diluent, or additive.

[0110] In some embodiments, the Disclosure relates to the 11-D-(S)-enantiomer of thianeptine of the 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 of the 11-D-(S)-enantiomer of the Disclosure (including its crystalline salt), or a cocrystal or zwitterion of the 11-D-(S)-enantiomer of the Disclosure, or an ester or pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the Disclosure, or an a A pharmaceutical composition is provided comprising a mid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or additive, the composition comprising about 2% or less (i.e., ≤ about 2%) of an 11-D-(R) enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of an 11-D-(R) enantiomer, or a cocrystal or zwitterion of an 11-D-(R) enantiomer, or an ester or a pharmaceutically acceptable salt thereof of an 11-D-(R) enantiomer, or an amide or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 1% or less (i.e., ≤ about 1%) of an 11-D-(R) enantiomer of thianeptin, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or a cocrystal 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 contains about 0.9% or less (i.e., ≤ about 0.9%) of an 11-D-(R) enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or a cocrystal 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 contains about 0.8% or less (i.e., ≤ about 0.8%) of an 11-D-(R) enantiomer of thianeptine, its zwitterion or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or a cocrystal or zwitterion of the 11-D-(R) enantiomer, or an ester or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or an amide or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer. In some embodiments, the composition contains about 0.7% or less (i.e., ≤ about 0.7%) of an 11-D-(R) enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or a cocrystal 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 contains about 0.6% or less (i.e., ≤ about 0.6%) of an 11-D-(R) enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or a cocrystal 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 contains about 0.5% or less (i.e., ≤ about 0.5%) of an 11-D-(R) enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or a cocrystal 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 contains about 0.4% or less (i.e., ≤ about 0.4%) of an 11-D-(R) enantiomer of thianeptine, its zwitterion or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or a cocrystal or zwitterion of the 11-D-(R) enantiomer, or an ester or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or an amide or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer. In some embodiments, the composition contains about 0.3% or less (i.e., ≤ about 0.3%) of an 11-D-(R) enantiomer of thianeptine, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or a cocrystal 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 contains about 0.2% or less (i.e., ≤ about 0.2%) of the 11-D-(R) enantiomer of thianeptine, its zwitterion or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or a cocrystal or zwitterion of the 11-D-(R) enantiomer, or an ester or a pharmaceutically acceptable salt of the (R) enantiomer, or an amide or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer. In some embodiments of the present disclosure, the composition comprises about 0.1% or less (i.e., ≤ about 0.1%) of an 11-D-(R) enantiomer of thianeptine, its zwitterion or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or a cocrystal or its zwitterion of the 11-D-(R) enantiomer, or an ester or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer, or an amide or a pharmaceutically acceptable salt of the 11-D-(R) enantiomer.

[0111] In some embodiments, the pharmaceutical composition of the Disclosure comprises an 11-D-(S)-enantiomer of thianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt (including its crystalline salt) of the 11-D-(S)-enantiomer of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable cocrystal of the 11-D-(S)-enantiomer of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises a zwitterion of the 11-D-(S)-enantiomer of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises an ester of the 11-D-(S)-enantiomer of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer ester of the disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises an 11-D-(S)-enantiomer amide of the disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer amide of the disclosure and a pharmaceutically acceptable carrier, diluent, or additive.

[0112] In some embodiments, the composition comprises a mixture of two or more pharmaceutically acceptable salts (including crystalline salts thereof) or cocrystals of the (S)-enantiomer or 11-D-(S)-enantiomer (and the 11-D-(S)-enantiomer having at least one deutherium substitution on the aminoheptanoic acid side chain), the mixture of pharmaceutically acceptable salts or cocrystals characterized by an improved extended release when administered orally, compared to the 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, the improved extended release of the mixture of pharmaceutically acceptable salts or cocrystals is, however not theoretically, attributable to the different dissolution rates of each salt or cocrystal form in the intestinal tract.

[0113] In some embodiments, the pharmaceutical composition of the Disclosure comprises one or more of the thianeptine analogs of the Disclosure, namely N-hydroxythianeptine, the (S)-enantiomer of N-hydroxythianeptine, the (R)-enantiomer of N-hydroxythianeptine, N-nitroso-thianeptine, the (S)-enantiomer of N-nitroso-thianeptine, the (R)-enantiomer of N-nitroso-thianeptine, or the aryl-substituted analogs of thianeptine of the Disclosure, or any pharmaceutically acceptable salt thereof, along with a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises N-hydroxythianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises a pharmaceutically acceptable salt of N-hydroxythianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises the (S)-enantiomer of the N-hydroxythianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises a pharmaceutically acceptable salt of the (S)-enantiomer of the N-hydroxythianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises the (R)-enantiomer of the N-hydroxythianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises a pharmaceutically acceptable salt of the (R)-enantiomer of the N-hydroxythianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises the N-nitroso-thianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises a pharmaceutically acceptable salt of the N-nitroso-thianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises a (S)-enantiomer of the N-nitroso-thianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive.In some embodiments, the pharmaceutical composition of the Disclosure comprises a pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-thianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises the (R)-enantiomer of N-nitroso-thianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso-thianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises an aryl-substituted analog of thianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive. In some embodiments, the pharmaceutical composition of the Disclosure comprises a pharmaceutically acceptable salt of the aryl-substituted analog of thianeptine of the Disclosure and a pharmaceutically acceptable carrier, diluent, or additive.

[0114] In some embodiments, the Disclosure provides a pharmaceutical composition comprising the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or additive, the composition comprising about 2% or less (i.e., ≤ about 2%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxythianeptine. In some embodiments, the composition comprises about 1% or less (i.e., ≤ about 1%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises about 0.9% or less (i.e., ≤ about 0.9%) of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition contains about 0.8% or less (i.e., ≤ about 0.8%) of the (R) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.7% or less (i.e., ≤ about 0.7%) of the (R) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.6% or less (i.e., ≤ about 0.6%) of the (R) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.5% or less (i.e., ≤ about 0.5%) of the (R) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.4% or less (i.e., ≤ about 0.4%) of the (R) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.3% or less (i.e., ≤ about 0.3%) of the (R) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.2% or less (i.e., ≤ about 0.2%) of the (R) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer.In some embodiments, the composition contains about 0.1% or less (i.e., ≤ about 0.1%) of the (R) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of the enantiomer.

[0115] In some embodiments, the Disclosure provides a pharmaceutical composition comprising the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or additive, wherein the composition contains about 2% or less (i.e., ≤about 2%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 1% or less (i.e., ≤about 1%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 0.9% or less (i.e., ≤about 0.9%) of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 0.8% or less (i.e., ≤ about 0.8%) of the (S) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.7% or less (i.e., ≤ about 0.7%) of the (S) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.6% or less (i.e., ≤ about 0.6%) of the (S) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.5% or less (i.e., ≤ about 0.5%) of the (S) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.4% or less (i.e., ≤ about 0.4%) of the (S) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.3% or less (i.e., ≤ about 0.3%) of the (S) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.2% or less (i.e., ≤ about 0.2%) of the (S) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.1% or less (i.e., ≤ about 0.1%) of the (S) enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of its enantiomer.

[0116] In some embodiments, the Disclosure provides a pharmaceutical composition comprising the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or additive, the composition comprising about 2% or less (i.e., ≤ about 2%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso-thianeptine. In some embodiments, the composition comprises about 1% or less (i.e., ≤ about 1%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition comprises about 0.9% or less (i.e., ≤ about 0.9%) of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the enantiomer. In some embodiments, the composition contains about 0.8% or less (i.e., ≤ about 0.8%) of the (R) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.7% or less (i.e., ≤ about 0.7%) of the (R) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.6% or less (i.e., ≤ about 0.6%) of the (R) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.5% or less (i.e., ≤ about 0.5%) of the (R) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.4% or less (i.e., ≤ about 0.4%) of the (R) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition contains about 0.3% or less (i.e., ≤ about 0.3%) of the (R) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition contains about 0.2% or less (i.e., ≤ about 0.2%) of the (R) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the composition contains about 0.1% or less (i.e., ≤ about 0.1%) of the (R) enantiomer of N-nitrosothianeptine or a pharmaceutically acceptable salt of the enantiomer.

[0117] In some embodiments, the Disclosure provides a pharmaceutical composition comprising the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or additive, the composition comprising about 2% or less (i.e., ≤ about 2%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprising about 1% or less (i.e., ≤ about 1%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprising about 0.9% or less (i.e., ≤ about 0.9%) of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 0.8% or less (i.e., ≤ about 0.8%) of the (S) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.7% or less (i.e., ≤ about 0.7%) of the (S) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.6% or less (i.e., ≤ about 0.6%) of the (S) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.5% or less (i.e., ≤ about 0.5%) of the (S) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.4% or less (i.e., ≤ about 0.4%) of the (S) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.3% or less (i.e., ≤ about 0.3%) of the (S) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.2% or less (i.e., ≤ about 0.2%) of the (S) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. In some embodiments, the composition contains about 0.1% or less (i.e., ≤ about 0.1%) of the (S) enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of its enantiomer. Dosage form and administration method

[0118] Any suitable route of administration may be used to administer the (S)-enantiomers of thianeptine of the present disclosure (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), the zwitterions of the present disclosure, pharmaceutically acceptable salts, cocrystals, esters and pharmaceutically acceptable salts of these esters, amides and pharmaceutically acceptable salts of these amides, as well as analogs of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof), and pharmaceutically acceptable compositions thereof. The (S)-enantiomer of thianeptine disclosed herein, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer of the disclosed herein and its crystalline form, or a cocrystal of the (S)-enantiomer of the disclosed herein or its zwitterion, or an ester of the (S)-enantiomer of the disclosed herein or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer of the disclosed herein or its pharmaceutically acceptable salt, or an 11-D-(S)-enantiomer of thianeptine disclosed herein, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the disclosed herein and its crystalline form, or a cocrystal of the 11-D-(S)-enantiomer of the disclosed herein or its zwitterion Sex ions, or esters of the 11-D-(S)-enantiomers of the Disclosure or pharmaceutically acceptable salts thereof, or amides of the 11-D-(S)-enantiomers, or analogs of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs) or pharmaceutically acceptable salts thereof, as well as the pharmaceutical compositions of the Disclosure or exemplary routes of administration of the pharmaceutical compositions of the Disclosure, which are not limited to these, include parenteral, oral, sublingual, intraoral, aspiration, intrapalatal, transdermal, transrectal, and transvaginal administration.

[0119] In some embodiments, the (S)-enantiomers of thianeptine (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), zwitterions, pharmaceutically acceptable salts, cocrystals, esters and pharmaceutically acceptable salts of these esters, amides, or analogs of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitrosothianeptine, its (S)- and (R)-enantiomers, and also (or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof), and dosage forms useful for administering the pharmaceutical compositions of the present disclosure may include, but are not limited to, tablets, e.g., split tablets, coated tablets, small tablets, chewable tablets, orally dispersible tablets or soluble tablets; thin films; powders (e.g., pulmonary powder or dry powder inhalers); caplets; 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 thin film. In some embodiments, the dosage form is a powder. In some embodiments, the dosage form is a caplet. 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.

[0120] In some embodiments, the dosage forms of the present disclosure for parenteral administration may be in the form of aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions. For example, in the preparation of the dosage forms of the present disclosure for parenteral administration, at least one of the (S)-enantiomers of thianeptine of the present disclosure (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), zwitterions, cocrystals, esters or pharmaceutically acceptable salts, amides, or analogs of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs) or pharmaceutically acceptable salts thereof is mixed with a suitable pharmaceutically acceptable carrier, such as water, oil (especially vegetable oil), ethanol, saline (e.g., physiological saline), aqueous dextrose (glucose) and related sugar solutions, glycerol, or glycol, such as propylene glycol or polyethylene glycol. For parenteral administration, these dosage forms preferably contain at least one water-soluble salt of the (S)-enantiomer of thianeptine (i.e., (S)-enantiomer or 11-D-(S)-enantiomer), zwitterion, cocrystal, ester, amide, N-hydroxythianeptine, its (S)- or (R)-enantiomer, or thianeptine analog (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analog) or a pharmaceutically acceptable salt thereof. Stabilizers, antioxidants, and preservatives may also be added to the parenteral dosage forms. Suitable stabilizers include sulfites, ascorbic acid, citric acid and its salts, and sodium EDTA salt. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol.

[0121] For oral administration, in some embodiments, the dosage forms of the present disclosure comprise at least one of the following: (S)-enantiomers of thianeptine (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), zwitterions, cocrystals, esters, amides, or analogs of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs), and salts, in combination with one or more solid or liquid inert components to form tablets, capsules, pills, powders, or other suitable oral dosage forms. For example, at least one of the (S)-enantiomers of thianeptin according to the Disclosure (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), zwitterions, esters, amides, salts or cocrystals, or analogs of thianeptin (i.e., N-hydroxythianeptin, its (S)- and (R)-enantiomers, N-nitroso-thianeptin, its (S)- and (R)-enantiomers, or aryl-substituted thianeptin analogs), and salts may be combined with at least one pharmaceutically acceptable carrier, such as a solvent, filler, binder, humectant, disintegrant, dissolution retarder, absorption enhancer, wetting agent, absorbent or lubricant. In one embodiment, at least one of the (S)-enantiomers of thianeptine (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), zwitterions, esters, amides, salts or cocrystals of thianeptine, or analogs of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs), and salts of the disclosed thianeptine is combined with carboxymethylcellulose calcium, magnesium stearate, mannitol, and starch, and formed into tablets by a conventional tableting method.In one embodiment, the (S)-enantiomers of thianeptine (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), zwitterions, esters, amides, salts or cocrystals of thianeptine, or analogs of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs), and salts of the present disclosure are formulated into tablets containing cellulose and calcium salts, as described in U.S. Patent No. 5,888,542, the full disclosure of which is incorporated herein by reference.

[0122] In some embodiments, the dosage forms of the (S)-enantiomers or 11-D-(S)-enantiomers of the Disclosure, their zwitterions, salts, cocrystals, esters or amides, or thianeptine analogs (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitrosothianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs), and salts of the Disclosure are formulated for immediate release, controlled release, sustained release, extended release, or sustained release. In some embodiments, the dosage forms of the Disclosure are formulated for the immediate release of the (S)-enantiomers of the Disclosure, their zwitterions, salts, esters, amides or cocrystals, or analogs of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitrosothianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs), and their salts. In some embodiments, the dosage forms of the Disclosure are formulated for the immediate release of the 11-D-(S)-enantiomers, zwitterions, salts, esters, amides or cocrystals of the Disclosure. In some embodiments, the dosage forms of the Disclosure are formulated for the immediate release of analogs of thianeptine of the Disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitrosothianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs or pharmaceutically acceptable salts thereof). In some embodiments, the dosage forms of the Disclosure are formulated for the controlled release of the (S)-enantiomer, zwitterion, salt, ester, amide or cocrystal of the Disclosure. In some embodiments, the dosage forms of the Disclosure are formulated for the controlled release of the 11-D-(S)-enantiomer, zwitterion, salt, ester, amide or cocrystal of the Disclosure. In some embodiments, the dosage forms of the Disclosure are formulated for controlled release of analogs of thianeptine of the Disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitrosothianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof).In some embodiments, the compositions of the Disclosure are formulated for sustained release of the (S)-enantiomers, zwitterions, salts, esters, amides or cocrystals of the Disclosure. In some embodiments, the dosage forms of the Disclosure are formulated for sustained release of the 11-D-(S)-enantiomers, zwitterions, salts, esters, amides or cocrystals of the Disclosure. In some embodiments, the dosage forms of the Disclosure are formulated for sustained release of analogs of thianeptine of the Disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof). In some embodiments, the dosage forms of the Disclosure are formulated for extended release of the (S)-enantiomers, zwitterions, salts, esters, amides or cocrystals of the Disclosure. In some embodiments, the dosage forms of the Disclosure are formulated for extended release of the 11-D-(S)-enantiomers, zwitterions, salts, esters, amides or their cocrystals. In some embodiments, the dosage forms of the Disclosure are formulated for extended release of analogs of thianeptine of the Disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitrosothianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts). In some embodiments, the dosage forms of the Disclosure are formulated for sustained release of the (S)-enantiomers, zwitterions, salts, esters, amides or their cocrystals. In some embodiments, the dosage forms of the Disclosure are formulated for sustained release of the 11-D-(S)-enantiomers, zwitterions, salts, esters, amides or their cocrystals. In some embodiments, the dosage forms of the Disclosure are formulated for sustained release of analogs of thianeptine of the Disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitrosothianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs or pharmaceutically acceptable salts thereof).

[0123] Preferably, the controlled-release dosage forms of the present disclosure can release at least one of the (S)-enantiomers of thianeptine of the present disclosure (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), its zwitterions, esters, amides, salts, or cocrystals, or analogs of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof) into a target at a desired rate so as to maintain substantially constant pharmacological activity over a given period of time. Formulation of the controlled-release pharmaceutical compositions of the present invention is within the scope of the art of those skilled in the art. Suitable controlled-release formulations for use in the present invention are described, for example, in U.S. Patent No. 5,674,533 (Liquid Dosage Form), U.S. Patent No. 5,591,767 (Liquid Storage Transdermal Patch), U.S. Patent No. 5,120,548 (Device Equipped with Swellable Polymer), U.S. Patent No. 5,073,543 (Ganglioside-Liposome Vehicle), and U.S. Patent No. 5,639,476 (Stable Solid Formulation Coated with Hydrophobic Acrylic Polymer), the full disclosure thereof, which is incorporated herein by reference.

[0124] To formulate the controlled-release dosage forms of the present disclosure, biodegradable microparticles may also be used, for example, as described in U.S. Patent Nos. 5,354,556 and 5,733,566, whose full disclosures are incorporated herein by reference.

[0125] In one embodiment, a controlled-release dosage form of the present disclosure comprises at least one of the following: (S)-enantiomers of thianeptine (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), its zwitterion, a pharmaceutically acceptable salt of the (S)-enantiomer, a cocrystal 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 or a pharmaceutically acceptable salt thereof, or an analog of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs or pharmaceutically acceptable salts thereof), and a controlled-release component. As used herein, “controlled-release component” is a compound such as a polymer, polymer matrix, gel, permeable membrane, liposome and / or microsphere that induces controlled release into at least one of the (S)-enantiomers, zwitterions, cocrystals, esters, amides and salts of this disclosure upon exposure to a particular physiological compound or condition. For example, a controlled-release component may be biodegradable and may be activated by exposure to a particular pH or temperature, an aqueous environment or an enzyme. An example of a controlled-release component activated by exposure to a particular temperature is a sol-gel. In this embodiment, at least one of the (S)-enantiomers of thianeptine according to the Disclosure (i.e., (S)-enantiomers or 11-D-(S)-enantiomers), its zwitterion, a pharmaceutically acceptable salt of the (S)-enantiomer, a cocrystal or zwitterion of the (S)-enantiomer, an ester or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer, N-hydroxythianeptine, its (S)- or (R)-enantiomer, or an analog of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or an aryl-substituted thianeptine analog, or a pharmaceutically acceptable salt thereof) is incorporated into a sol-gel matrix that is solid at room temperature.When a sol-gel matrix is ​​implanted into a subject with a body temperature high enough to induce gel formation, thianeptin is released into the subject. Exemplary obstacles in this disclosure

[0126] The diseases, disorders, or conditions described herein include, but are not limited to, central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infections, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia (e.g., statin-resistant hypertriglyceridemia, combined hypertriglyceridemia, and familial hypertriglyceridemia), cancer (e.g., glioblastoma or glioma), menopause and chronic multiple pain conditions (COPC), as well as psychological, physical, metabolic or hormonal stress and COPC.

[0127] The CNS disorders described herein are not limited to, but include, mood disorders (e.g., major depressive disorder (MDD), bipolar disorder, or substance-induced disorders), trauma and stressor-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). Diseases such as Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, neuromyelitis optica, myasthenia gravis, autoimmune encephalitis, prion diseases, transverse myelitis, or childhood autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), neurodevelopmental disorders (e.g., attention deficit / hyperactivity disorder (ADHD), schizophrenia, Prader-Willi syndrome (including hyperegoating and other symptoms (e.g., depression and anxiety) or autism), leukoatrophy (e.g., leukoencephalopathy, hypomyelination or demyelinating disorders), intellectual disability syndromes (e.g., fragile X staining) Cognitive impairment (e.g., somatic syndromes), cognitive impairment (e.g., cognitive impairment associated with a disease, disorder or condition (e.g., mild cognitive impairment, prodromal symptoms or Alzheimer's disease, prodromal symptoms or FTD, prodromal symptoms or PCA, posterior cortical atrophy (PCA), cognitive impairment associated with schizophrenia, drug-induced cognitive impairment, e.g., corticosteroid-induced cognitive impairment, doxorubicin-induced cognitive impairment, chemotherapy-induced cognitive impairment, alcohol-induced cognitive impairment or substance-induced cognitive impairment, radiation therapy) This includes induced cognitive impairment, space travel-related cognitive decline (e.g., space flight-related optic syndrome (SANS) or cognitive decline associated with high cosmic ray 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, stroke, or reperfusion injury after ischemic stroke), as well as CNS oxidative stress.

[0128] The inflammatory diseases described herein 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 mellitus (e.g., juvenile-onset diabetes or type 1 diabetes), Guillain-Barré syndrome, Hashimoto's encephalopathy, 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.

[0129] The autoimmune diseases described herein are not limited to, but include: alamiculosis, Addison's disease, adult 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, Behçet's disease, and benign mucosal disorders. Pemphigus, bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing polymyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), scarring pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, herpetiform dermatitis, dermatomyositis, Devic's disease (neuromyelitis optica), lupus discoid, Dressler syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential condition Mixed-type cryoglobulinemia, Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes zoster of pregnancy or bullous pemphigoid of pregnancy (PG), hidradenitis suppurativa (HS) (reverse acne), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis ( IC), juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mohren's ulcer, Mucher-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, sleep attacks, neonatal lupus, neuromyelitis optica, neutropenia, ocular scarring pemphigoid, optic neuritis,Recurrent rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Paley-Romberg syndrome, squamous cellulitis (peripheral uveitis), Personage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polysomnogenesis syndrome type I, polysomnogenesis syndrome type II, polysomnogenesis 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 gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapse This includes polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Suzak syndrome, sympathetic ophthalmitis (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)).

[0130] The infectious diseases described herein include, but are not limited to, viral infections (e.g., COVID-19, influenza, human immunodeficiency virus (VIMS) (HIV), and herpes) or postviral conditions (e.g., long-term COVID).

[0131] The hearing loss conditions of this disclosure include, but are not limited to, mitochondrial non-syndromic hearing loss and hearing loss, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or hereditary hearing loss, hearing loss experienced as a result of ototoxic exposure, hearing loss resulting from disease, and hearing loss resulting from trauma.

[0132] The ocular diseases described herein include, but are not limited to, cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), and diabetic retinopathy.

[0133] The musculoskeletal disorders of this disclosure include, but are not limited to, muscular dystrophy (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-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 bulbar spinal muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, fasciculations, Friedrich ataxia, muscle wasting disorders (e.g., muscular atrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease, and paralysis.

[0134] Metabolic diseases as disclosed herein include, but are not limited to, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, obesity (e.g., diet-induced obesity), heart disease (e.g., cardiac hypertrophy), atherosclerosis, arthritis, cystinosis, diabetes (e.g., type 1 diabetes, type 2 diabetes, or gestational diabetes), phenylketonuria, proliferative retinopathy, and Kearns-Thayer disease.

[0135] The mitochondrial disorders of this disclosure include, but are not limited to, Barth syndrome, chronic progressive extraophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS or maternal Leigh syndrome), mitochondrial DNA depletion syndrome (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis and stroke-like episode (MELAS)), mitochondrial neurological gastrointestinal encephalomyopathy (MNGIE), myoclonus epilepsy with red ragged fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome.

[0136] In some embodiments, the diseases, disorders, or conditions exemplified in this disclosure are modulated, aggravated, or associated with modified activity of PPAR-β / δ and / or PPAR-γ. In some embodiments, the diseases, disorders, or conditions exemplified in this disclosure are modulated, 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 exemplified in this disclosure are modulated, aggravated, or associated with excess levels of metal ions (e.g., iron or copper) in circulation. CNS failure

[0137] Exemplary clinical symptoms of CNS disorders, diseases, and conditions include, but are not limited to, changes in cognitive function, including age-related cognitive decline that is similar to or less stable than that of age-matched controls; changes in attention and memory; difficulties in speaking, understanding, reading, or writing; inability to process thoughts; anxiety; irritability or aggression; muscle fatigue; muscle wasting; difficulty walking; headaches; hearing loss; seizures; spasticity; speech and swallowing difficulties; tremors; paralysis; blindness; and loss of sensation. Major Depressive Disorder

[0138] Major depressive disorder (MDD), also known as "clinical depression," is a mood disorder in which symptoms that affect how one feels, thinks, and handles daily activities are present nearly every day for at least two weeks. Symptoms associated with MDD include: (1) persistent sad, anxious, or "empty" mood; (2) feelings of hopelessness or pessimism; (3) irritability; (4) feelings of guilt, worthlessness, or helplessness; (5) loss of interest and pleasure in hobbies and activities (e.g., anhedonia); (6) decreased 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) sleep problems, early morning awakening, or oversleeping (e.g., insomnia or hypersomnia); (12) changes in appetite and / or weight (e.g., a change in weight of more than 5% in one month); (13) recurrent thoughts of death or suicide; (14) suicide attempts; (15) pain or aches, headaches, cramps, or indigestion without a clear physical cause and / or that do not improve with treatment.

[0139] MDD can be diagnosed based on: (1) a physical examination; (2) laboratory tests (e.g., blood tests for complete blood count and / or evaluation of thyroid function); (3) a psychiatric evaluation (e.g., a healthcare provider asks questions about symptoms, thoughts, feelings, and behavior patterns, and / or the patient fills out a questionnaire, such as the Hospital Anxiety and Depression Scale (HADS), Hamilton Depression Rating Scale (HDRS, HAM-D), and Montgomery-Åsberg Depression Rating Scale (MADRS)); (4) the Diagnostic and Statistical Manual of Mental Disorders (e.g., DSM-5 lists the criteria for depression published by the American Psychiatric Association).

[0140] The DSM-5 criteria for diagnosing MDD include at least five symptoms that are present during the same two-week period, with at least one of the symptoms being loss of interest and pleasure or a depressed mood. The symptoms related to the DSM-5 criteria for MDD are: (1) Depressed mood (for children and adolescents, this may be an irritable mood); (2) Loss of interest or pleasure in almost all activities (e.g., anhedonia); (3) Significant weight change or appetite disturbance (for children, this may be the inability to achieve expected weight gain); (4) Sleep disturbance (e.g., insomnia or hypersomnia); (5) Psychomotor agitation or retardation; (6) Fatigue or loss of energy; (7) Apathy; (8) Decreased ability to think or concentrate; Lack of decision-making ability; (9) Repeated thoughts about death, repeated suicidal thoughts without a specific plan, or a suicide attempt, or a specific plan to commit suicide. Age-related cognitive impairment

[0141] "Age-related cognitive impairment" refers to cognitive impairment in an aging subject, and the cognitive function of the subject is not as stable as expected in a normal subject of the same age or as expected in a young adult subject. In some cases, the cognitive function is reduced by about 5%, about 10%, about 30%, or more compared to the cognitive function expected in a normal subject of the same age. In some cases, the cognitive function is at the level expected in a normal subject of the same age but is reduced by about 5%, about 10%, about 30%, about 50%, or more compared to the cognitive function expected in a young adult subject. The cognitive function with age-related dysfunction may be related to mild cognitive impairment (MCI) (including amnestic MCI and non-amnestic MCI), age-related memory impairment (AAMI), and age-related cognitive decline (ARCD).

[0142] Age-related memory impairment (AAMI) refers to age-related memory decline. A patient may be considered to have AAMI if they are at least 50 years old and meet all of the following criteria: a) the patient is aware of a decline in memory; b) the patient performs worse on standard memory tests compared to a young adult; and c) all other obvious causes of memory decline other than normal aging have been ruled out (in other words, the memory decline cannot be due to other causes, such as a recent heart attack or head injury, depression, adverse drug reaction, or Alzheimer's disease).

[0143] Age-related cognitive decline (ARCD) refers to the decline in memory and cognitive abilities that is a normal consequence of aging in humans (e.g., Craik & Salthouse, 1992). This also holds true in virtually all mammalian species. Age-related memory impairment refers to older adults who have objective memory decline compared to their younger years but have normal cognitive function compared to their peers (Crook et al., 1986). Age-appropriate memory decline is a less derogatory term, emphasizing that these are normal developmental changes (Crook, 1993, Larrabee, 1996), not pathophysiological (Smith et al., 1991), and rarely progress to outright dementia (Youngjohn & Crook, 1993). DSM-IV (1994) systematized the diagnostic classification of ARCD, which continues in DSM-5 (2013) as code 780.9 for ARCD. Drug-induced cognitive dysfunction Corticosteroid-induced cognitive dysfunction

[0144] Due to their anti-inflammatory properties, corticosteroids are used in the treatment of many diseases and conditions, including asthma, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, nephritis syndromes, cancer, organ transplantation, autoimmune hepatitis, hypersensitivity reactions, cardiogenic and septic shock, glucocorticoid deficiency diseases (Addison's disease and panhypopituitarism), and multiple sclerosis. When the body experiences stress, the adrenal glands release corticosteroids such as cortisol. Synthetic corticosteroids function 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. The supplementation of the body's normal hormone levels by synthetic corticosteroids triggers a genomic cascade that reduces inflammation and suppresses the immune response. This genomic cascade is initiated by the binding of steroids to intracellular glucocorticoid receptors (GR) (Datson, NA et al. European Journal of Neuroscience. 2001).

[0145] Despite their broad use and therapeutic benefits, synthetic corticosteroids often cause numerous 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, alopecia, hirsutism, pulse, skin atrophy, purpura, obesity, diabetes, adrenal-pituitary axis depression, dyslipidemia, fluid and sodium retention, potassium, calcium and nitrogen loss, growth retardation, pseudotumor, peptic ulcer disease, pancreatitis, fatty liver, leukocytosis, neutropenia, lymphopenia (lymphophenia), oral candidiasis, increased risk of systemic infection, myopathy, osteoporosis, ischemic necrosis, cataracts, and glaucoma. Psychological side effects include mood and anxiety disorders, behavioral impairment, cognitive impairment, and psychosis.

[0146] Cognitive impairment, anxiety, and mood disorders are some of the most common psychological side effects of corticosteroid use. These effects, in particular, lead to a decline in quality of life in patients requiring long-term steroid treatment. For example, 33% (approximately 13 million) of individuals taking corticosteroids have been reported to exhibit deficits in work or short-term memory, declarative memory, attention span and concentration (academic and occupational abilities), and executive function (Stoudemire A et al. Gen Hosp Psychiatry. 1984). In extreme cases, steroids can further induce delirium, dementia (persistent memory impairment), and mania (Varney NR et al., Am J Psychiatry. 1984). Currently, there are no FDA-approved drugs designated for the treatment of cognitive impairment and similar psychiatric disorders associated with corticosteroid use, such as anxiety and mood disorders. Furthermore, there are no alternatives to corticosteroids for the treatment of inflammatory disorders, and corticosteroids must be used. Chemotherapy-induced cognitive dysfunction

[0147] Chemotherapy-related cognitive impairment, also known as chemofog or chemobrain, is described as a decline in various neuropsychological tasks after chemotherapy or other anti-cancer treatments, such as radiotherapy or surgery, in patients with non-central nervous system cancers. The domains most affected after chemotherapy are memory, processing speed, attention, and executive function (Lange M, et al. Ann Oncol. 2019). asthma

[0148] Asthma is a chronic inflammatory disease of the lung airways caused by a combination of genetic and environmental factors, including air pollution and exposure to allergens. Other potential triggers include medications such as aspirin and beta-blockers. Among other events, eosinophilic inflammation has been reported in the airways of asthma patients. The pathophysiology of the disease is characterized by variable airway obstruction, airway inflammation, excessive mucus secretion, and subepithelial fibrosis. Clinically, patients may present with cough, wheezing, and shortness of breath. Primary biliary cholangitis

[0149] Primary biliary cholangitis (PBC) is an organ-specific autoimmune disease characterized by chronic, progressive destruction of the bile ducts of the liver, accompanied by portal vein inflammation. The destruction of the bile ducts leads to the accumulation of bile and other toxins in the liver, causing scarring, fibrosis, and ultimately cirrhosis. PBC is a relatively rare disease, affecting up to 1 in 3,000 to 4,000 people, and primarily middle-aged women. Early symptoms of PBC include fatigue and itchy skin, while symptoms of advanced disease include dry eyes and mouth, pain in the right upper abdomen, splenomegaly, musculoskeletal pain, edema, ascites, lipoplasm (xanthoma) on the skin, jaundice, hyperpigmentation, osteoporosis, high cholesterol, diarrhea, and hypothyroidism (Boonstra K et al., J Hepatol. 2012). Hypertriglyceridemia

[0150] Hypertriglyceridemia (HTG) is a common metabolic disorder characterized by high concentrations of triglycerides in the plasma (i.e., levels greater than 150 mg / dl), which increases the risk of developing cardiovascular disease. Most people with hypertriglyceridemia are asymptomatic, while those with severe HTG may develop xanthomas. Severe HTG (i.e., levels greater than 500 mg / dl) is also associated with an increased risk of pancreatitis. Both genetic and lifestyle factors play a significant role in the pathophysiology of HTG. Medications, including corticosteroids, thiazides, non-selective beta-blockers, estrogens, tamoxifen, bile acid chelators, cyclophosphamide, antiretrovirals, and second-generation antipsychotics, can also elevate TG levels. The first and most beneficial approach to managing HTG is adjusting lifestyle contributors to HTG, including diet, weight, and management of non-TG components of metabolic syndromes; however, these approaches are often unreliable due to poor patient adherence. Fibrates (e.g., fenofibrate (PPAR-α agonist)), prescription omega-3 fatty acids (e.g., Vascepa® (icosapentaenoic acid, IPE)), and statins are also used to treat triglycerides (TG), but they are associated with side effects such as musculoskeletal pain, general weakness, edema, headache, drowsiness, rash, constipation, and changes in libido (Santos-Baez LS & Ginsberg HN. Front Endocrinol. 2020). Fibromyalgia, long-term COVID-19, menopause, and chronic multiple pain conditions (COPC)

[0151] Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances, and cognitive impairment or "brain fog." Originally a member of a group of conditions called "occurring chronic pain conditions" (OCPC), it is now more commonly referred to as "chronic co-occurring pain conditions" (COPC), further encompassing temporomandibular disorders (TMD), irritable bowel syndrome (IBS), vulvar lesions, myalgic encephalomyelitis / chronic fatigue syndrome, interstitial cystitis / bladder pain syndrome, endometriosis, chronic tension headaches, migraines, and chronic low back pain. Epidemiological studies estimate the prevalence of individual COPC to be between approximately 4 million (myalgic encephalomyelitis / chronic fatigue syndrome) and 44 million (IBS). Many COPC cases are defined as idiopathic, occurring spontaneously without a specific cause. However, central sensitization is now thought to contribute to these conditions (Maixner W, et al., J Pain. 2016). Exemplary clinical symptoms of fibromyalgia and other COPCs include, but are not limited to, widespread pain, fatigue, sleep disturbances, and cognitive impairment.

[0152] Post-acute sequelae of (SARS)-CoV-2 infection (PASC), commonly known colloquially as "long-term COVID," is a term used to describe a set of symptoms experienced by individuals with a history of latent or confirmed SARS-CoV-2 infection, typically occurring three months after the onset of COVID-19 infection, lasting at least two months, and unexplained by alternative diagnoses. PASC symptoms can be multi-organ, occur within syndrome clusters (i.e., neurological, non-neurological, and systemic), and may fluctuate or recur over time (Davis et al. EclinicalMedicine. 2021, Crook et al. BMJ. 2021, Bierle et al. J Prim Care Community Health. 2021, WHO 2021). The lack of a standardized definition of PASC makes it difficult to determine the strict epidemiology, incidence, and impact of the condition on long-term disability. A conservative estimate based on data collected from many countries suggests that an average of 30% of people with COVID-19 experience PASC (Nalbandian et al. Nat Med. 2021).

[0153] PASC is a multifaceted condition affecting multiple bodily systems. PASC symptoms may be a new onset after initial recovery from an acute or even mild COVID-19 episode (e.g., a new onset of pain), or they may persist from the initial illness. While PASC symptoms fluctuate, pain, fatigue, and sleep disturbances have been identified as the primary 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).

[0154] Exemplary clinical symptoms of long-term COVID include, but are not limited to, fatigue, muscle weakness, sweating, muscle pain, joint pain, chills, limb edema, dizziness, post-exertional discomfort, cognitive impairment, respiratory symptoms (tachypnea, chest pain, cough, sputum, sore throat), cardiovascular abnormalities, alopecia, olfactory dysfunction, neurocognitive difficulties including memory and concentration problems, psychological symptoms such as insomnia, depression, anxiety, inferiority complex, and a general decline in quality of life.

[0155] Menopause is the period following the cessation of the normal ovulation cycle, during which normal menstruation ceases. This period is characterized by a decrease in hormone production in the ovaries (e.g., estradiol (E2)), leading to a shift in the body's hormonal balance, which often results in a variety of symptoms associated with menopause. Perimenopausal, also known as premenopausal or perimenopause, is the period before menopause when the normal ovulation cycle gradually transitions to the cessation of menstruation. Symptoms of perimenopausal, perimenopause, and postmenopausal include physical symptoms such as transient hot flashes, chills, and sweating followed by vasomotor instability. In addition, psychological and emotional symptoms such as fatigue, irritability, insomnia, lack of concentration, depression, memory loss, headaches, anxiety, and nervousness may occur with the onset of perimenopause. Additional 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. Furthermore, genital changes, urinary incontinence, vaginal dryness, loss of pelvic muscle tone, increased risk of cardiovascular disease, and osteoporosis all increase with the onset of menopause. obesity

[0156] Obesity, defined by the U.S. Centers for Disease Control and Prevention (CDC) as an excessive amount of body fat or adipose tissue relative to lean body mass, is currently an epidemic worldwide and one of the most serious contributing factors to increased morbidity and mortality. Obesity is associated with leading causes of death, including diabetes, heart disease, stroke, and certain types of cancer.

[0157] In some embodiments, the (S)-enantiomers of the Disclosure (i.e., (S)-thianeptin or 11-D-(S)-thianeptin) are used to treat obesity and weight gain, particularly in individuals who tend to gain body weight and fat despite not having bulimia and despite a moderate or low-fat diet. In some embodiments, the (S)-enantiomers of the Disclosure (i.e., (S)-thianeptin or 11-D-(S)-thianeptin) or analogs of thianeptin (i.e., N-hydroxythianeptin, its (S)- and (R)-enantiomers, N-nitroso-thianeptin, its (S)- and (R)-enantiomers, or aryl-substituted thianeptin analogs, or pharmaceutically acceptable salts thereof) are used to treat obesity and weight gain in individuals with low levels of PPAR-β / δ and / or PPAR-γ expression and / or activity in neurons. Treatment method

[0158] In certain embodiments, the Disclosure relates to a method for treating a disease, disorder or condition modulated by the modified activity of peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ) and / or PPAR-γ, or one or more associated symptoms thereof, to a subject who needs or is at risk thereof, a therapeutically effective amount of the (S)-enantiomer of the Disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal or zwitterion of the (S)-enantiomer of the Disclosure, or an ester or pharmaceutically acceptable salt of the (S)-enantiomer of the Disclosure, or an amide or pharmaceutically acceptable salt of the (S)-enantiomer of the Disclosure, or the 11-D-(S)-enantiomer of the Disclosure. The present invention provides a method comprising the step of administering a pharmaceutical composition of the present disclosure comprising an 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the present disclosure, or a cocrystal 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 a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(S)-enantiomer of the present disclosure or a pharmaceutically acceptable salt thereof, or an analog of thianeptine of the present disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof), or one or more thereof.

[0159] In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes administering to a subject who needs or is at risk of having such a treatment, a therapeutically effective amount of the (S)-enantiomer of the Disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer (including its crystalline form), or a cocrystal or zwitterion of the (S)-enantiomer of the Disclosure, or an ester of the (S)-enantiomer of the Disclosure, or an amide or a pharmaceutically acceptable salt of the (S)-enantiomer of the Disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes administering to a subject who needs or is at risk of having such a treatment, a therapeutically effective amount of the (S)-enantiomer of the Disclosure. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of 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 having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of 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 having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of 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 having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a pharmaceutically acceptable cocrystal of the (S)-enantiomer zwitterions of the present disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition.In some embodiments, a method of treating a disease, disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to a subject that needs it or is at risk thereof a therapeutically effective amount of an ester of the (S)-enantiomer of the present disclosure. In some embodiments, a method of treating a disease, disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to a subject that needs it or is at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of an ester of the (S)-enantiomer of the present disclosure. In some embodiments, a method of treating a disease, disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to a subject that needs it or is at risk thereof a therapeutically effective amount of an amide of the (S)-enantiomer of the present disclosure. In some embodiments, a method of treating a disease, disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to a subject that needs it or is at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of an amide of the (S)-enantiomer of the present disclosure.

[0160] In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering to a subject who needs or is at risk of having such a therapeutically effective amount of the 11-D-(S)-enantiomer of the Disclosure, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a cocrystal or zwitterion of the 11-D-(S)-enantiomer of the Disclosure, or an ester of the 11-D-(S)-enantiomer of the Disclosure, or an amide or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the Disclosure. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering to a subject who needs or is at risk of having such a therapeutically effective amount of the 11-D-(S)-enantiomer of the Disclosure. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of the zwitterion of the 11-D-(S)-enantiomer of this disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of 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 having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a pharmaceutically acceptable cocrystal of the 11-D-(S)-enantiomer of this disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a pharmaceutically acceptable cocrystal of the 11-D-(S)-enantiomer zwitterions of the present disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition.In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of the 11-D-(S)-enantiomer ester of the present disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer ester of the present disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of the 11-D-(S)-enantiomer amide of the present disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer amide of the present disclosure to a subject who needs or is at risk thereof.

[0161] In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of N-hydroxythianeptine, the (S)-enantiomer of N-hydroxythianeptine, the (R)-enantiomer of N-hydroxythianeptine, or N-nitroso-thianeptine, the (S)-enantiomer of N-nitroso-thianeptine, or the (R)-enantiomer of N-nitroso-thianeptine, or a pharmaceutically acceptable salt thereof to a subject who needs or is at risk of having such disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of the N-hydroxythianeptine of this disclosure to a subject who needs or is at risk of having such disease, disorder, or condition. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a pharmaceutically acceptable salt of N-hydroxythianeptine of the present disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a (S)-enantiomer of N-hydroxythianeptine of the present disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a pharmaceutically acceptable salt of a (S)-enantiomer of N-hydroxythianeptine of the present disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of the N-hydroxythianeptine (R)-enantiomer of the present disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition.In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a pharmaceutically acceptable salt of the (R) enantiomer of N-hydroxythianeptine of this disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of the N-nitroso-thianeptine of this disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of the (S)-enantiomer of N-nitroso-thianeptine of this disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-thianeptine of this disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of the (R)-enantiomer of N-nitroso-thianeptine of this disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition. In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a pharmaceutically acceptable salt of the (R) enantiomer of N-nitrosothianeptine of the present disclosure to a subject who needs or is at risk thereof.In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of an aryl-substituted thianeptin analog of the present disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of a pharmaceutically acceptable salt of an aryl-substituted thianeptin analog of the present disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ.

[0162] In some embodiments, a method for treating a disease, disorder, or condition modulated with PPAR-β / δ and / or PPAR-γ includes the step of administering a therapeutically effective amount of the pharmaceutical composition of this disclosure to a subject who needs or is at risk of having such a disease, disorder, or condition.

[0163] In some embodiments, this disclosure provides methods for treating diseases, disorders, or conditions, and one or more symptoms associated therewith, in subjects who have experienced high stress. In some embodiments, the disease, disorder, or condition is caused by an unfortunate event prenatally or early in life, or by childhood trauma, and this disease, disorder, or condition manifests, in some embodiments, as subsequent violent behavior. In some embodiments, the disease, disorder, or condition in subjects who have experienced high stress is modulated, exacerbated, or associated with modified activity of peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ) and / or PPAR-γ. While we do not wish to be bound by theory, prolonged stress (prenatal, postnatal, or both) results in increased free radical production, particularly in the brain. The (S)-enantiomers of this disclosure (i.e., (S)-thianeptin or 11-D-(S)-thianeptin) are activated in the presence of free radicals to form thianeptin C11-free radical intermediates (which can be delocalized across 13 carbon atoms, 2 nitrogen atoms, 2 oxygen atoms, and 1 sulfur atom) capable of covalent interaction with PPAR-δ / β and / or PPAR-γ and their irreversible activation. These free radicals may be formed while the (S)-thianeptin enantiomers are bound to a PPAR ligand-binding site (LBS), resulting in preferential covalent binding of (S)-thianeptin to the PPAR LBS due to the chiral geometry of the site.

[0164] In some embodiments, the Disclosure provides a method for treating a disease, disorder, or condition modulated by high levels of receptor S-nitrosylation, aggravated, or associated with such disease, disorder, or condition. In some embodiments, the Disclosure provides a method for treating a disease, disorder, or condition modulated by high levels of S-nitrosylation of PPAR-β / δ and / or PPAR-γ, comprising, to a subject who needs or is at risk thereof, a therapeutically effective amount of the (S)-enantiomer of the Disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer of the Disclosure or its zwitterion, or an ester of the (S)-enantiomer of the Disclosure or a pharmaceutically acceptable salt of the (S)- The present invention provides a method comprising the step of administering a pharmaceutical composition of the present disclosure comprising an amide of an enantiomer or a pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer of the present disclosure, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the present disclosure, or a cocrystal 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 a pharmaceutically acceptable salt thereof, or one or more thereof. While we do not wish to be bound by theory, the (S)-enantiomers of this disclosure (i.e., (S)-thianeptine or 11-D-(S)-thianeptine) react with S-nitroso-PPAR-β / δ and / or S-nitroso-PPAR-γ to form S-nitroso-(S)-enantiomers and non-nitrosylated PPAR-β / δ and / or PPAR-γ.

[0165] In some embodiments, the methods of the present disclosure for treating diseases, disorders, or conditions modulated, aggravated, or associated with modified activity of peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ) and / or PPAR-γ are superior to methods using racemic mixtures of enantiomers of thianeptine, its zwitterions, salts, cocrystals, and esters, in that the methods of the present disclosure result in a reduction of μ-opioid receptor agonism. Compared to racemic mixtures of enantiomers of thianeptine, the reduction of μ-opioid receptor agonism of the (S)-enantiomer of the present disclosure (i.e., (S)-thianeptine or 11-D-(S)-thianeptine) minimizes the potential for opioid abuse, opioid toxicity, and opioid overdose (e.g., due to opioate-induced respiratory depression (OIRD)).

[0166] In certain embodiments, the Disclosure relates to a method for treating a disease, disorder or condition selected from the group consisting of central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infections, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopause and chronic multiple pain conditions (COPC), and psychological, physical, metabolic or hormonal stress and COPC, to a subject who needs or is at risk thereof, a therapeutically effective amount of the (S)-enantiomer of the Disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer of the Disclosure or its zwitterion, or an ester of the (S)-enantiomer of the Disclosure or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer of the Disclosure or its The present invention provides a method comprising the step of administering a pharmaceutical composition of the present disclosure comprising a pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer of the present disclosure, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the present disclosure, or a cocrystal or zwitterion of the 11-D-(S)-enantiomer of the present disclosure, or an ester or pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the present disclosure, or an amide of the 11-D-(S)-enantiomer, or an analog of thianeptine of the present disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof), or one or more thereof.

[0167] In certain embodiments, the Disclosure provides a method for treating a disease, disorder, or condition modulated, aggravated, or associated with an excess level of metal ions in circulation, to a subject who needs or is at risk of such treatment, comprising: a therapeutically effective amount of the (S)-enantiomer of the Disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer of the Disclosure or its zwitterion, or an ester of the (S)-enantiomer of the Disclosure or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer of the Disclosure or its pharmaceutically acceptable salt, or the 11-D-(S)-enantiomer of the Disclosure, its zwitterion, or the 11- The present invention provides a method comprising the step of administering a pharmaceutical composition of the present disclosure comprising a pharmaceutically acceptable salt of a D-(S)-enantiomer, or a cocrystal or zwitterion of the 11-D-(S)-enantiomer of the present disclosure, or an ester or pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the present disclosure, or an amide of the 11-D-(S)-enantiomer of the present disclosure, or an analog of thianeptine of the present disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof), or one or more thereof. In some embodiments, the metal ion is iron or copper. In some embodiments, the (S)-enantiomers of the Disclosure (i.e., (S)-thianeptine or 11-D-(S)-thianeptine) or analogs of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts) are administered to subjects having elevated levels of iron or copper ions as determined by blood tests or cerebrospinal fluid (CSF) tests.While we do not wish to be bound by theory, the (S)-enantiomers of the present disclosure (i.e., (S)-thianeptine or 11-D-(S)-thianeptine) or analogs of thianeptine (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine 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, forming thianeptine C11-free radical intermediates (which can be delocalized across 13 carbon atoms, 2 nitrogen atoms, 2 oxygen atoms, and 1 sulfur atom) that are capable of covalent interaction with PPAR-δ / β and / or PPAR-γ and their irreversible activation. These free radicals may be formed while the (S)-thianeptin enantiomer is bound to the PPAR ligand binding site (LBS), resulting in preferential covalent binding of (S)-thianeptin to the PPAR LBS due to the chiral geometry of the site. In some embodiments, aggravated or associated diseases, disorders, or conditions modulated by excess levels of metal ions in circulation are aggravated or associated diseases, disorders, or conditions modulated by modified activity of peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ) and / or PPAR-γ.

[0168] In certain embodiments, the Disclosure relates to methods for reducing violent or aggressive behavior associated with CNS disorders, to subjects who require or are at risk of such reduction, by providing a therapeutically effective amount of the (S)-enantiomer of the Disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal or zwitterion of the (S)-enantiomer of the Disclosure, or an ester or a pharmaceutically acceptable salt of the (S)-enantiomer of the Disclosure, or an amide or a pharmaceutically acceptable salt of the (S)-enantiomer of the Disclosure, or an 11-D-(S)-enantiomer of the Disclosure, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the Disclosure, or The present invention provides a method comprising the step of administering a pharmaceutical composition of the present disclosure comprising a cocrystal or zwitterion of the 11-D-(S)-enantiomer of the present disclosure, or an ester or pharmaceutically acceptable salt thereof of the 11-D-(S)-enantiomer of the present disclosure, or an amide or pharmaceutically acceptable salt thereof of the 11-D-(S)-enantiomer of the present disclosure, or an analog of thianeptine of the present disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof), or one or more thereof.

[0169] In certain aspects, the Disclosure relates to a method for reducing the likelihood of being admitted to or incarcerated in a psychiatric hospital for behaviors or actions related to CNS disorders, to a person who needs or is at risk of such admission, comprising a therapeutically effective amount of the (S)-enantiomer of the Disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal or zwitterion of the (S)-enantiomer of the Disclosure, or an ester or pharmaceutically acceptable salt of the (S)-enantiomer of the Disclosure, or an amide or pharmaceutically acceptable salt of the (S)-enantiomer of the Disclosure, or an 11-D-(S)-enantiomer, its zwitterion, or a drug of the 11-D-(S)-enantiomer of the Disclosure The present invention provides a method comprising the step of administering a pharmaceutical composition of the present disclosure comprising a pharmaceutically acceptable salt, or a cocrystal or zwitterion of the 11-D-(S)-enantiomer of the present disclosure, or an ester or pharmaceutically acceptable salt thereof of the 11-D-(S)-enantiomer of the present disclosure, or an amide or pharmaceutically acceptable salt thereof of the 11-D-(S)-enantiomer of the present disclosure, or an analog of thianeptine of the present disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof), or one or more thereof.

[0170] In some embodiments, the treatment method of the present disclosure involves the (S)-enantiomer of thianeptine of the present disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer of the present disclosure, or a cocrystal or zwitterion of the (S)-enantiomer of the present disclosure, or an ester or a pharmaceutically acceptable salt of the (S)-enantiomer of the present disclosure, or an amide or a pharmaceutically acceptable salt of the (S)-enantiomer of the present disclosure, or an 11-D-(S)-enantiomer of thianeptine of the present disclosure, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the present disclosure The step of administering a pharmaceutical composition of the Disclosure, comprising a cocrystal or zwitterion thereof, an ester of the 11-D-(S)-enantiomer of the Disclosure or a pharmaceutically acceptable salt thereof, an amide of the 11-D-(S)-enantiomer of the Disclosure or a pharmaceutically acceptable salt thereof, or an analog of thianeptine of the Disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof), or one or more thereof, once or more times daily.In some embodiments, the treatment method of the present disclosure involves the (S)-enantiomer of thianeptine of the present disclosure, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer of the present disclosure, or a cocrystal or zwitterion of the (S)-enantiomer of the present disclosure, or an ester or a pharmaceutically acceptable salt of the (S)-enantiomer of the present disclosure, or an amide or a pharmaceutically acceptable salt of the (S)-enantiomer of the present disclosure, or an 11-D-(S)-enantiomer of thianeptine of the present disclosure, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of the present disclosure The step of administering once daily a pharmaceutical composition of the present disclosure comprising a cocrystal of the body or its zwitterion, or an ester of the 11-D-(S)-enantiomer of the present disclosure or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(S)-enantiomer of the present disclosure or a pharmaceutically acceptable salt thereof, or an analog of thianeptine of the present disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof), or one or more thereof.

[0171] In some embodiments, the treatment method of the present disclosure involves the (S)-enantiomer of the present disclosure, its zwitterion, or a pharmaceutically acceptable salt, or a cocrystal of the (S)-enantiomer of the present disclosure, or an ester of the (S)-enantiomer of the present disclosure or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of the present disclosure or a pharmaceutically acceptable salt thereof, or an analog of thianeptine of the present disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitrosothianeptine, its (S)- and (R)- The present invention comprises administering a pharmaceutical composition of the present disclosure containing enantiomers or aryl-substituted thianeptine analogs (or pharmaceutically acceptable salts thereof), or a combination thereof, together 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, anti-amyloid agents, anti-tau agents, and chemotherapeutic agents. In some embodiments, the treatment method of the present disclosure includes the step of sequentially administering one or more additional therapeutic agents: the (S)-enantiomers of the present disclosure, their zwitterions, or pharmaceutically acceptable salts; or cocrystals of the (S)-enantiomers of the present disclosure; or esters of the (S)-enantiomers of the present disclosure; or amides or pharmaceutically acceptable salts of the (S)-enantiomers of the present disclosure; or analogs of thianeptine of the present disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs, or pharmaceutically acceptable salts thereof); or a pharmaceutical composition of the present disclosure containing the same.In some embodiments, the treatment method of the present disclosure includes administering, concurrently with one or more additional therapeutic agents, a (S)-enantiomer of the present disclosure, its zwitterion, or a pharmaceutically acceptable salt thereof, or a cocrystal of the (S)-enantiomer of the present disclosure, or an ester of the (S)-enantiomer of the present disclosure, or an amide of the (S)-enantiomer of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or an analog of thianeptine of the present disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitrosothianeptine, its (S)- and (R)-enantiomers, or an aryl-substituted thianeptine analog, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition of the present disclosure containing the same. Exemplary antidepressants include, but are not limited to, citalopram, fluoxetine, paroxetine, trazodone, or sertraline. Exemplary anticonvulsants include, but are not limited to, carbamazepine, divalproex, or dextromethorphan. Exemplary anxiolytics include, but are not limited to, lorazepam, oxazepam, or buspirone. Exemplary antipsychotics include, but are not limited to, quetiapine, promazine, 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, pimavanserin or cyclobenzaprine. Exemplary corticosteroids include, but are not limited to, prednisone, methylprednisolone, and dexamethasone. Examples of anti-amyloid agents include, but are not limited to, aducanumab (Aduhelm®), bapineozumab, solanezumab, or verbecestat.In some embodiments, the anti-amyloid agent and / or anti-tau agent is one or more of the agents described by Cummings et al. (Alzheimers Dement (NY), 2017), which are incorporated herein by reference. Exemplary chemotherapeutic agents include, but are not limited to, temozolomide, carmustine, bevacizumab, or lomustine.

[0172] In some embodiments of the combinations of the present disclosure, the (S)-enantiomers of the present disclosure, their zwitterions, or pharmaceutically acceptable salts of the (S)-enantiomers of the present disclosure, or cocrystals or their zwitterions of the (S)-enantiomers of the present disclosure, or esters or pharmaceutically acceptable salts of the (S)-enantiomers of the present disclosure, or amides or pharmaceutically acceptable salts of the (S)-enantiomers of the present disclosure, or analogs of thianeptine of the present disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present disclosure containing them, as well as one or more additional therapeutic agents, are formulated separately. In some embodiments of the combinations of the present disclosure, the (S)-enantiomers of the present disclosure, their zwitterions, or pharmaceutically acceptable salts of the (S)-enantiomers of the present disclosure, or cocrystals or their zwitterions, or esters or pharmaceutically acceptable salts of the (S)-enantiomers of the present disclosure, or amides or pharmaceutically acceptable salts of the (S)-enantiomers of the present disclosure, or analogs of thianeptine of the present disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present disclosure containing them, as well as one or more additional therapeutic agents, are formulated together.In certain such embodiments, the (S)-enantiomers of the Disclosure, their zwitterions, or pharmaceutically acceptable salts of the (S)-enantiomers of the Disclosure, or cocrystals or their zwitterions of the (S)-enantiomers of the Disclosure, or esters or pharmaceutically acceptable salts of the (S)-enantiomers of the Disclosure, or amides or pharmaceutically acceptable salts of the (S)-enantiomers of the Disclosure, or analogs of thianeptine of the Disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the Disclosure containing them, as well as one or more additional therapeutic agents, are packaged together. In some such embodiments, the (S)-enantiomers of the Disclosure, their zwitterions, or pharmaceutically acceptable salts of the (S)-enantiomers of the Disclosure, or cocrystals or their zwitterions of the (S)-enantiomers of the Disclosure, or esters or pharmaceutically acceptable salts of the (S)-enantiomers of the Disclosure, or amides or pharmaceutically acceptable salts of the (S)-enantiomers of the Disclosure, or analogs of thianeptine of the Disclosure (i.e., N-hydroxythianeptine, its (S)- and (R)-enantiomers, N-nitroso-thianeptine, its (S)- and (R)-enantiomers, or aryl-substituted thianeptine analogs) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions o...

Claims

1. (S)-enantiomers of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid of general formula (Ia) ((S)-enantiomers of thianeptine), its zwitterion of formula (Ib), or pharmaceutically acceptable salts of the said (S)-enantiomer, or mixtures of two or more of these species, wherein the said (S)-enantiomer, zwitterion, or pharmaceutically acceptable salt contains ≤ about 2% of thianeptine (R) A mixture of two or more of these species, characterized by comprising the enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the (R)-enantiomer, comprising the (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid of general formula (Ia) (the (S)-enantiomer of thianeptine), its zwitterion of formula (Ib), or a pharmaceutically acceptable salt of the (S)-enantiomer. 【Transformation 30】 。

2. The (S)-enantiomer according to claim 1, characterized in that the (S)-enantiomer, the zwitterion of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof contains ≤ about 0.1% of the (R)-enantiomer of thianeptin, or the zwitterion thereof, 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)-thianeptine benzenesulfonate (1:1), (S)-thianeptine fumarate (1:1), (S)-thianeptine fumarate (2:1), (S)-thianeptine hippurate (1:1), (S)-thianeptine maleate (1:1), (S)-thianeptine maleate (2:1), or (S)-thianeptine p-toluenesulfonate. pharmaceutically acceptable salts are (1:1) (S)-thianeptine orotinate (1:1), (S)-thianeptine camphor sulfonate (1:1), (S)-thianeptine N-acetyl-L-tyrosineate (1:1), (S)-thianeptine polystyrene, (S)-thianeptine:L-DBTA (2:1), (S)-thianeptine sodium salt, (S)-thianeptine oxalate, or (S)-thianeptine hemioxate (2:1).

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

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

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

7. An ester of an (S) enantiomer according to claim 1 or 2, characterized in that the (S) enantiomer ester or a pharmaceutically acceptable salt thereof contains ≤ about 2% of the (R) enantiomer ester or a pharmaceutically acceptable salt thereof.

8. An ester of the (S)-enantiomer according to claim 7, characterized in that the (S)-enantiomer ester or a pharmaceutically acceptable salt thereof contains ≤ about 0.1% of the (R)-enantiomer ester or a pharmaceutically acceptable salt thereof.

9. An amide of an (S) enantiomer according to claim 1 or 2, characterized in that the (S) enantiomer amide or a pharmaceutically acceptable salt thereof comprises ≤ about 2% of the (R) enantiomer amide or a pharmaceutically acceptable salt thereof.

10. An amide of an (S) enantiomer according to claim 9, characterized in that the (S) enantiomer amide or a pharmaceutically acceptable salt thereof contains ≤ about 0.1% of the (R) enantiomer amide or a pharmaceutically acceptable salt thereof.

11. The (S)-enantiomer of deuterated 7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl-11-d)amino)heptanoic acid of general formula (IIa), in which deuterium is replaced by hydrogen at the 11th position (11-D-(S)-enantiomer of thianeptine), or its zwitterion of formula (IIb), or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a mixture of two or more of these species, wherein the 11-D-(S)-enantiomer or its zwitterion or pharmaceutically acceptable salt is ≤ about 2% A pharmaceutically acceptable salt of the 11-D-(R)-enantiomer of thianeptine, or its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, characterized by comprising the (S)-enantiomer of deuterated 7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl-11-d)amino)heptanoic acid of general formula (IIa), or its zwitterion of formula (IIb), or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a mixture of two or more of these species. 【Chemistry 31】 。

12. The (S)-enantiomer according to claim 11, characterized in that the 11-D-(S)-enantiomer, the zwitterion of the 11-D-(S)-enantiomer, or a pharmaceutically acceptable salt thereof contains ≤ about 0.1% of the 11-D-(R)-enantiomer of thianeptin, or the zwitterion thereof, or a pharmaceutically acceptable salt thereof.

13. The (S)-enantiomer according to claim 11 or 12, characterized in that the 11-D-(S)-enantiomer, or the zwitterion or pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, exhibits reduced racemization at the 11-position compared to the (S)-enantiomer of thianeptin, or the zwitterion or pharmaceutically acceptable salt of the enantiomer.

14. The pharmaceutically acceptable salts are 11-D-(S)-thianeptine benzenesulfonate (1:1), 11-D-(S)-thianeptine fumarate (1:1), 11-D-(S)-thianeptine fumarate (2:1), 11-D-(S)-thianeptine hippurate (1:1), 11-D-(S)-thianeptine maleate (1:1), 11-D-(S)-thianeptine maleate (2:1), 11-D-(S)-thianeptine p-toluenesulfonate (1:1), 11-D-(S)-thianeptine orotinate (1:1), 11 A pharmaceutically acceptable salt of the 11-D-(S) enantiomer according to any one of claims 11 to 13, which is -D-(S)-thianeptine camphor sulfonate (1:1), 11-D-(S)-thianeptine N-acetyl-L-tyrosineate (1:1), 11-D-(S)-thianeptine polystyrene, 11-D-(S)-thianeptine:L-DBTA (2:1), 11-D-(S)-thianeptine sodium salt, 11-D-(S)-thianeptine oxalate, or 11-D-(S)-thianeptine 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)-thianeptine hemisulfate (2:1).

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

17. A cocrystal of an 11-D-(S)-enantiomer according to any one of claims 11 to 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 an (S)-enantiomer according to any one of claims 11 to 13, characterized in that the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof contains ≤ about 2% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof.

19. An ester of the (S)-enantiomer according to claim 18, characterized in that the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof contains ≤ about 0.1% of the 11-D-(R)-enantiomer ester or a pharmaceutically acceptable salt thereof.

20. An amide of an (S) enantiomer according to any one of claims 11 to 13, characterized in that the 11-D-(S) enantiomer amide or the pharmaceutically acceptable salt thereof contains ≤ about 2% of the 11-D-(R) enantiomer amide or the pharmaceutically acceptable salt thereof.

21. An amide of an (S) enantiomer according to claim 20, characterized in that the 11-D-(S) enantiomer amide or a pharmaceutically acceptable salt thereof comprises ≤ about 0.1% of the 11-D-(R) enantiomer amide or a pharmaceutically acceptable salt thereof.

22. A pharmaceutically acceptable salt of the (S)-enantiomer or 11-D-(S)-enantiomer according to any one of claims 1, 2, or 11 to 13, wherein the nitrogen atom in the side chain bonded to carbon-11 (C-11) is 100% protonated, and the 100% protonated salt is less susceptible to air oxidation in solid or solution form compared to the (S)-enantiomer, the 11-D-(S)-enantiomer, either of the zwitterions, or either of the sodium salts.

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

24. The pharmaceutical composition according to claim 23, wherein the pharmaceutical composition comprises ≤ about 0.1% of the (R)-enantiomer of thianeptin, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or the zwitterion thereof, or the ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or the amide of the (R)-enantiomer or a pharmaceutically acceptable salt thereof.

25. 11-D-(S)-enantiomer of thianeptin according to any one of claims 11 to 17, 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 according to claim 18 or 19 or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(S)-enantiomer according to claim 20 or 21, and a pharmaceutically acceptable A pharmaceutical composition comprising a carrier, diluent, or additive, wherein the composition comprises ≤ about 2% of 11-D-(R)-enantiomers of thianeptin, their zwitterions, or pharmaceutically acceptable salts of the 11-D-(R)-enantiomers, or cocrystals of the 11-D-(R)-enantiomers or their zwitterions, or esters of the 11-D-(R)-enantiomers or pharmaceutically acceptable salts thereof, or amides of the 11-D-(R)-enantiomers or pharmaceutically acceptable salts thereof.

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

27. The pharmaceutical composition according to any one of claims 23 to 26, wherein the composition is in the form of a tablet, a thin film, a powder, a caplet, a capsule, a soft gel, a suppository, a nasal spray, an oral spray, or a lung spray.

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

29. A pharmaceutical composition comprising a mixture of two or more pharmaceutically acceptable salts or cocrystals of the (S)-enantiomer or 11-D-(S)-enantiomer described in any one of claims 23 to 26, wherein the mixture is characterized by improved extended release when administered orally compared to administration of a composition comprising a single pharmaceutically acceptable salt or cocrystal of the (S)-enantiomer or 11-D-(S)-enantiomer described in any one of claims 23 to 26.

30. A method for treating a disease, disorder or condition modulated, aggravated or associated with a disease, disorder or condition modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, and one or more associated symptoms thereof, comprising the step of administering to a subject who needs or is at risk thereof a therapeutically effective amount of the (S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer according to any one of claims 1 to 10 and 22, or a cocrystal or its zwitterion, or an ester or pharmaceutically acceptable salt of the (S)-enantiomer, or an amide or pharmaceutically acceptable salt of the (S)-enantiomer, or one of claims 23, 24, and 27 to 29.

31. A method for treating a disease, disorder or condition modulated, aggravated or associated with a peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, and one or more associated symptoms thereof, comprising the step of administering to a subject who needs or is at risk thereof a therapeutically effective amount of an 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer according to any one of claims 11 to 22, or a cocrystal or its zwitterion, or an ester or pharmaceutically acceptable salt of an 11-D-(S)-enantiomer, or an amide or pharmaceutically acceptable salt of an (S)-enantiomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 25 to 29.

32. The method according to 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, infections, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopause and chronic multiple pain conditions (COPC), and psychological, physical, metabolic or hormonal stress and COPC.

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

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

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

36. A method for treating an aggravated or associated disease, disorder or condition, and one or more associated symptoms thereof, modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, in a subject that has experienced high stress, comprising the step of administering to the subject a therapeutically effective amount of a (S)-enantiomer, its zwitterion or a pharmaceutically acceptable salt of a (S)-enantiomer, or a cocrystal or its zwitterion or an ester or a pharmaceutically acceptable salt of a (S)-enantiomer, or an amide or a pharmaceutically acceptable salt of a (S)-enantiomer, or one of the pharmaceutical compositions of claims 23, 24 or 27-29.

37. A method for treating an aggravated or associated disease, disorder or condition, and one or more associated symptoms thereof, modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, in a subject that has experienced high stress, comprising the step of administering to the subject a therapeutically effective amount of the 11-D-(S)-enantiomer, its zwitterion or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer according to any one of claims 11 to 22, or the 11-D-(S)-enantiomer cocrystal or its zwitterion, or the 11-D-(S)-enantiomer ester or a pharmaceutically acceptable salt thereof, or the (S)-enantiomer amide or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 25 to 29.

38. The method according to claim 36 or 37, wherein the stress is caused by an unfortunate event early in life or by a childhood trauma.

39. A method for treating an aggravated or associated disease, disorder or condition, and one or more associated symptoms thereof, modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, while reducing μ-opioid receptor agonism associated with treatment with racemic thianeptin, comprising the step of administering to a subject who needs or is at risk thereof a therapeutically effective amount of the (S)-enantiomer, its zwitterion or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal or its zwitterion or an ester or a pharmaceutically acceptable salt of the (S)-enantiomer, or an amide or a pharmaceutically acceptable salt of the (S)-enantiomer, or one of the pharmaceutical compositions of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of the pharmaceutically acceptable salt of

40. A method for treating a disease, disorder or condition modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, and one or more associated symptoms thereof, while reducing μ-opioid receptor agonism associated with treatment with racemic thianeptin, comprising the step of administering to a subject who needs or is at risk thereof a therapeutically effective amount of the 11-D-(S)-enantiomer or cocrystal of the 11-D-(S)-enantiomer or 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 thereof, or any one of the pharmaceutical compositions thereof, according to any one of the claims 25 to 29.

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

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

43. The (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal or zwitterion of the (S)-enantiomer, or the ester or pharmaceutically acceptable salt thereof of the (S)-enantiomer, or the amide or pharmaceutically acceptable salt thereof of the (S)-enantiomer, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, the cocrystal or zwitterion of the 11-D-(S)-enantiomer, or the previous The method according to any one of claims 30 to 42 or 59, wherein the ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or the amide of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered sequentially or simultaneously 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, 5HT2 modulators, corticosteroids, anti-amyloid agents, anti-tau agents, and chemotherapeutic agents.

44. The (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal or zwitterion of the (S)-enantiomer, or the ester or pharmaceutically acceptable salt thereof of the (S)-enantiomer, or the amide or pharmaceutically acceptable salt thereof of the (S)-enantiomer, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, or the 11-D-(S The method according to any one of claims 30 to 42 or 59, wherein the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, the cocrystal or zwitterion of the 11-D-(S)-enantiomer, the ester or a pharmaceutically acceptable salt thereof of the 11-D-(S)-enantiomer, the amide or a pharmaceutically acceptable salt thereof of the 11-D-(S)-enantiomer, 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 an (S)-enantiomer, its zwitterion, a pharmaceutically acceptable salt of an (S)-enantiomer, a cocrystal or its zwitterion of an (S)-enantiomer, an ester or its pharmaceutically acceptable salt of an (S)-enantiomer, or an amide or its pharmaceutically acceptable salt of an (S)-enantiomer, comprising the step of deuterating the (S)-enantiomer, its zwitterion, the pharmaceutically acceptable salt of an (S)-enantiomer, the cocrystal or its zwitterion of an (S)-enantiomer, the ester or its pharmaceutically acceptable salt of an (S)-enantiomer, or the amide or its pharmaceutically acceptable salt of an (S)-enantiomer at the C-11 position.

46. A method for producing the (S)-enantiomer of thianeptin according to claim 1 or 2, (i) a racemic or other mixture of (S)- and (R)-enantiomers of a chiral aminethianeptine intermediate, characterized by ≥0.1% of the (R)-enantiomer of the chiral aminethianeptine intermediate, divided in a solvent mixture by enantiomer-selective crystallization using an (S)-enantiomer-selective conformator to produce an (S)-aminethianeptine intermediate:(S)-enantiomer-selective conformator, which is crystallized from the solvent mixture and contains ≤2% of the (R)-aminethianeptine intermediate:(R)-enantiomer-selective conformator; (ii) The step of reacting the (S)-amine thianeptine intermediate: (S)-enantiomer selective conformational isomer with an alkyl 7-bromoheptanoate to produce an (S)-thianeptine alkyl ester intermediate: (S)-enantiomer selective conformational isomer; (iii) The (S)-thianeptine alkyl ester intermediate: The step of reacting the (S)-enantiomer selective conformation isomer with a base to produce the (S)-thianeptine alkyl ester intermediate; (iv) A step of saponifying the (S)-thianeptine alkyl ester intermediate to produce the (S)-enantiomer of thianeptine, wherein the thianeptine comprises ≤2% of the (R) enantiomer of thianeptine. A method that includes this.

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

48. A method for producing 11-D-(S)-thianeptin according to claim 11 or 12, (i) a racemic or other mixture of (S)- and (R)-enantiomers of a chiralamine 11-D-thianeptine intermediate, comprising the steps of: (i) dividing a mixture characterized by ≥0.1% of the (R)-enantiomer of the chiralamine 11-D-thianeptine intermediate in a solvent mixture by enantiomer-selective crystallization using the (S)-enantiomer-selective conformator to produce an (S)-amine 11-D-thianeptine intermediate:(S)-enantiomer-selective conformator, which is crystallized from the solvent mixture and contains ≤2% of the (R)-amine 11-D-thianeptine intermediate:(R)-enantiomer-selective conformator; (ii) The step of reacting the (S)-amine 11-D-thianeptine intermediate: (S)-enantiomer selective conformational isomer with an alkyl 7-bromoheptanoate to produce an 11-D-(S)-thianeptine alkyl ester intermediate: (S)-enantiomer selective conformational isomer; (iii) The step of reacting the 11-D-(S)-thianeptine alkyl ester intermediate with a base to produce the 11-D-(S)-thianeptine alkyl ester intermediate: (S)-enantiomer selective conformation isomer; (iv) A step of saponifying the 11-D-(S)-thianeptine alkyl ester intermediate to produce an 11-D-(S)-enantiomer of thianeptine, wherein the 11-D-(S)-thianeptine contains ≤2% of the (R) enantiomer of 11-D-thianeptine. A method that includes this.

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

50. A method for producing the (S)-enantiomer or zwitterion of thianeptin according to claim 1 or 2, (i) A racemic or other mixture of (S)- and (R)-enantiomers of a thianeptin alkyl ester, comprising the steps of: (i) dividing a mixture characterized by ≥0.1% of the (R)-enantiomer of the thianeptin alkyl ester in a solvent mixture by enantiomer-selective crystallization using an (R)-enantiomer-selective conformator to produce (R)-thianeptin alkyl ester:(R)-enantiomer-selective conformator and (S)-thianeptin alkyl ester:(R)-enantiomer-selective conformator, and crystallizing and separating the (R)-thianeptin alkyl ester from the solvent mixture, wherein the (S)-thianeptin alkyl ester remains in the solvent mixture and contains ≤2% of the (R)-thianeptin alkyl ester; (ii) a step of hydrolyzing the (S)-thianeptine alkyl ester:(R)-enantiomer selective conformational isomer with a strong acid to produce an (S)-thianeptine salt, wherein the thianeptine salt comprises ≤2% of the (R)-thianeptine salt; (iii) The step of neutralizing the salt of (S)-thianeptine with a base to produce the zwitterion of the (S)-enantiomer of thianeptine, A method that includes this.

51. A method for producing the 11-D-(S)-enantiomer or its zwitterion according to claim 11 or 12, (i) A racemic or other mixture of (S)- and (R)-enantiomers of 11-D-thianeptine alkyl ester, wherein the mixture is characterized by ≥0.1% of the (R)-enantiomer of 11-D-thianeptine alkyl ester, and is divided in a solvent mixture by enantiomer-selective crystallization using an (R)-enantiomer-selective conformational isomer, thereby obtaining 11-D-(R)-thianeptine alkyl ester: (R)-enantiomer-selective conformational A step of generating an isomer and an 11-D-(S)-thianeptinalkyl ester:(R)-enantiomer-selective conformational isomer, and crystallizing and separating the 11-D-(R)-thianeptinalkyl ester from the solvent mixture, characterized in that the 11-D-(S)-thianeptinalkyl ester remains in the solvent mixture and contains ≤2% of the 11-D-(R)-thianeptinalkyl ester; (ii) a step of hydrolyzing the 11-D-(S)-thianeptine alkyl ester:(R)-enantiomer selective conformation isomer with a strong acid to produce an 11-D-(S)-thianeptine salt, wherein the 11-D-thianeptine salt comprises ≤2% of the 11-D-(R)-thianeptine salt; (iii) The step of neutralizing the salt of 11-D-(S)-thianeptine with a base to produce the zwitterion of the 11-D-(S)-enantiomer of thianeptine, A method that includes this.

52. The thianeptin alkyl ester is a methyl ester, ethyl ester, or any other C １ ~C ６ The method according to any one of claims 46 to 51, wherein the alkyl ester is used.

53. The enantiomer-selective crystallization described above applies to L-dibenzoyl tartaric acid (DBTA), D-DBTA, di-o-toluyl-L-tartaric acid (L-D(2-Me)BTA), D-D(2-Me)BTA, other DBTA derivatives, hydrogen hydrogen phosphate (S)-1,1'-bi-2-naphthol-2,2'-diyl, hydrogen hydrogen phosphate (R)-1,1'-bi-2-naphthol-2,2'-diyl, (S)-(R)-mandelic acid, (R)-(S)- The method according to any one of claims 46 to 51, comprising using a conformational isomer selected from the group consisting of mandelic acid, (S)-(S)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid, (R)-(S)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid, (1S)-(R)-10-camphorsulfonic acid and (1R)-(R)-10-camphorsulfonic acid.

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

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

56. The method according to any one of claims 46 to 55, wherein the enantiomer-selective crystallization is repeated to increase the enantiomer purity or chiral purity of the divided (S)-amine thianeptine intermediate, (S)-amine 11-D-thianeptine intermediate, (S)-thianeptine methyl ester, or 11-D-(S)-thianeptine methyl ester.

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

58. The method according to any one of claims 46 to 51, wherein the step of separating the racemic 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, infections, hearing loss conditions, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia, cancer, menopause and chronic multiple pain conditions (COPC), and psychological, physical, metabolic or hormonal stress and COPC, wherein a therapeutically effective amount of the (S)-enantiomer described in any one of claims 1 to 10 and 22, or a cocrystal or zwitterion of the (S)-enantiomer, or an ester or pharmaceutically acceptable salt thereof, or (S)-enantiomer A method comprising the steps of administering to a subject an amide of a body 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 an 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer according to any one of claims 11-22, or a cocrystal of an 11-D-(S)-enantiomer or its zwitterion, or an ester of an 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of a (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 25-29.

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

61. A method for treating a disease, disorder or condition modulated, aggravated or associated with an excess level of metal ions in circulation, comprising, to a subject in need of or at risk of such treatment, a therapeutically effective amount of (S)-enantiomers according to any one of claims 1 to 10 and 22, or cocrystals or zwitterions of (S)-enantiomers, or esters or pharmaceutically acceptable salts thereof of (S)-enantiomers, or amides or pharmaceutically acceptable salts thereof of (S)-enantiomers, or to any one of claims 23, 24 or 27 to 29. A method comprising the steps of administering the pharmaceutical composition described, or administering to the subject a therapeutically effective amount of the 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer described in any one of claims 11 to 22, 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 the pharmaceutical composition described in any one of claims 25 to 29.

62. A method for reducing violent or aggressive behavior associated with CNS disorder, comprising administering to a subject who needs or is at risk of such behavior a therapeutically effective amount of (S)-enantiomer, or (S)-enantiomer cocrystal or zwitterion thereof, or (S)-enantiomer ester or pharmaceutically acceptable salt thereof, or (S)-enantiomer amide or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 23, 24, or 27-29. A method comprising the step of administering to the subject a therapeutically effective amount of an 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer according to any one of claims 11 to 22, or a cocrystal of an 11-D-(S)-enantiomer or its zwitterion, or an ester of an 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 25 to 29.

63. A method to reduce the likelihood of being admitted to or incarcerated in a psychiatric hospital for behaviors or actions related to CNS disorder, comprising, to a subject who needs or is at risk thereof, a therapeutically effective amount of the (S)-enantiomer described in any one of claims 1 to 10 and 22, or a cocrystal or zwitterion of the (S)-enantiomer, or an ester or pharmaceutically acceptable salt thereof, or an amide or pharmaceutically acceptable salt thereof, or the pharmaceutical product described in any one of claims 23, 24, or 27 to 29. A method comprising the steps of administering a composition, or administering to a subject a therapeutically effective amount of an 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer according to any one of claims 11 to 22, or a cocrystal of an 11-D-(S)-enantiomer or its zwitterion, or an ester of an 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an (S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 25 to 29.

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

65. N-hydroxythianeptine of formula (XV) or its pharmaceutically acceptable salt 【Chemistry 32】 。

66. A (S)-enantiomer of N-hydroxythianeptine of formula (XVI) (N-hydroxy-(S)-thianeptine) or a pharmaceutically acceptable salt thereof, characterized in that the (S)-enantiomer of N-hydroxythianeptine or the pharmaceutically acceptable salt thereof contains ≤ about 2% of the (R)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxythianeptine. 【Transformation 33】 。

67. A (R)-enantiomer of N-hydroxythianeptine of formula (XVII) (N-hydroxy-(R)-thianeptine) or a pharmaceutically acceptable salt thereof, characterized in that the (R)-enantiomer of N-hydroxythianeptine or the pharmaceutically acceptable salt thereof contains ≤ about 2% of the (S)-enantiomer of N-hydroxythianeptine or a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxythianeptine. 【Transformation 34】 。

68. N-nitrosothianeptine of formula (XVIII) or its pharmaceutically acceptable salt 【Chemistry 35】 。

69. A (S)-enantiomer of N-nitroso-thianeptine of formula (XIX) (N-nitroso-(S)-thianeptine) or a pharmaceutically acceptable salt thereof, characterized in that the (S)-enantiomer of N-nitroso-thianeptine or the pharmaceutically acceptable salt thereof contains ≤ about 2% of the (R)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso-thianeptine. 【Transformation 36】 。

70. A (R)-enantiomer of N-nitroso-thianeptine of formula (XX) (N-nitroso-(R)-thianeptine) or a pharmaceutically acceptable salt thereof, characterized in that the (R)-enantiomer of N-nitroso-thianeptine or the pharmaceutically acceptable salt thereof contains ≤ about 2% of the (S)-enantiomer of N-nitroso-thianeptine or a pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-thianeptine. 【Chemistry 37】 。

71. An aryl-substituted thianeptine analog or a pharmaceutically acceptable salt thereof.

72. The aryl-substituted thianeptin derivatives are 7-((3-(furan-2-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-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]thiazepine-11-yl)amino)heptanoic acid of formula (XXII), and 7-(( The aryl-substituted thianeptin analog according to claim 71, which is 6-methyl-5,5-dioxide-3-(thiophen-3-yl)-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)heptanoic acid, or 2-(4-(((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-yl)amino)methyl)-2-methylphenoxy)acetic acid of formula (XXIV). 【Transformation 38】 。

73. A pharmaceutical composition comprising N-hydroxythianeptine or a pharmaceutically acceptable salt thereof as described in claim 65, or N-nitrosothianeptine or a pharmaceutically acceptable salt thereof as described in claim 68, or an aryl-substituted thianeptine analog or a pharmaceutically acceptable salt thereof as described in claim 71 or 72, and a pharmaceutically acceptable carrier, diluent, or additive.

74. A pharmaceutical composition comprising the (S)-enantiomer of N-hydroxythianeptine according to claim 66 or a pharmaceutically acceptable salt thereof, or the (S)-enantiomer of N-nitroso-thianeptine according to claim 69 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or additive, wherein the composition comprises ≤ about 2% or ≤ about 0.1% of the (R)-enantiomer of N-hydroxythianeptine or N-nitroso-thianeptine, or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxythianeptine or N-nitroso-thianeptine, or a pharmaceutically acceptable salt thereof.

75. A pharmaceutical composition comprising the (R)-enantiomer of N-hydroxythianeptine according to claim 67 or a pharmaceutically acceptable salt thereof, or the (R)-enantiomer of N-nitroso-thianeptine according to claim 70 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or additive, wherein the composition comprises ≤ about 2% or ≤ about 0.1% of the (S)-enantiomer of N-hydroxythianeptine or N-nitroso-thianeptine, or a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxythianeptine or N-nitroso-thianeptine, or a pharmaceutically acceptable salt thereof.

76. A method for treating a disease, disorder or condition modulated, aggravated or associated with a disease, disorder or condition, and one or more associated symptoms thereof, modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, comprising a therapeutically effective amount of N-hydroxythianeptine, N-hydroxythianeptine (S)-enantiomer, or N-hydroxythianeptine (R)-enantiomer according to any one of claims 65 to 67, to a subject who needs or is at risk thereof. A method comprising the step of administering an isomer, or a pharmaceutically acceptable salt thereof, or N-nitroso-thianeptine, the (S)-enantiomer of N-nitroso-thianeptine, or the (R)-enantiomer of N-nitroso-thianeptine, or a pharmaceutically acceptable salt thereof, as described in any one of claims 68 to 70, or an aryl-substituted thianeptine analog or a pharmaceutically acceptable salt thereof, as described in claim 71 or 72, or a pharmaceutical composition as described in any one of claims 73 to 75.

77. A method for treating a disease, disorder or condition, and one or more associated symptoms thereof, modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, in a subject that has experienced high stress, wherein the subject is given a therapeutically effective amount of N-hydroxythianeptine, the (S)-enantiomer of N-hydroxythianeptine, or the (R)-enantiomer of N-hydroxythianeptine according to any one of claims 65 to 67. A method comprising the step of administering an isomer, or a pharmaceutically acceptable salt thereof, or N-nitroso-thianeptine, the (S)-enantiomer of N-nitroso-thianeptine, or the (R)-enantiomer of N-nitroso-thianeptine, or a pharmaceutically acceptable salt thereof, as described in any one of claims 68 to 70, or an aryl-substituted thianeptine analog or a pharmaceutically acceptable salt thereof, as described in claim 71 or 72, or a pharmaceutical composition as described in any one of claims 73 to 75.

78. A method for treating a disease, disorder, or condition modulated by the modified activity of peroxisome proliferator-activated receptor (PPAR)-β / δ and / or PPAR-γ, and one or more associated symptoms thereof, while reducing μ-opioid receptor agonism associated with treatment with racemic thianeptin, comprising: a therapeutically effective amount of N-hydroxythianeptin, N-hydroxythianeptin (S)-enantiomer according to any one of claims 65 to 67, to a subject who needs or is at risk thereof. A method comprising the step of administering a pharmaceutical composition according to any one of the following: N-hydroxythianeptine (R)-enantiomer, or a pharmaceutically acceptable salt thereof; N-nitroso-thianeptine, N-nitroso-thianeptine (S)-enantiomer, or N-nitroso-thianeptine (R)-enantiomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 68 to 70; an aryl-substituted thianeptine analog or a pharmaceutically acceptable salt thereof, according to claim 71 or 72; or a pharmaceutical composition according to any one of claims 73 to 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, cardiac hypertrophy, fibromyalgia, cancer, infection, COVID-19, chronic COVID, menopause and chronic multiple pain conditions (COPC), psychological, physical, metabolic or hormonal stress and COPC, and obesity, wherein the subject is given a therapeutically effective amount of N-hydroxythianeptine, (S)-enantiomer of N-hydroxythianeptine, or N-hydroxythianeptine as described in any one of claims 65 to 67. A method comprising the step of administering a (R)-enantiomer of butin, or a pharmaceutically acceptable salt thereof, or N-nitroso-thianeptin according to any one of claims 68 to 70, a (S)-enantiomer of N-nitroso-thianeptin, or a (R)-enantiomer of N-nitroso-thianeptin, or a pharmaceutically acceptable salt thereof, or an aryl-substituted thianeptin analog according to claim 71 or 72, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 73 to 75.

80. A crystalline hemioxate of (S)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid 5,5-dioxide ((S)-thianeptin), wherein the salt exhibits an X-ray diffraction pattern (XRPD) including 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 thianeptin according to claim 1, wherein the crystalline (S)-enantiomer of thianeptin exhibits an X-ray diffraction pattern (XRPD) including at least one peak selected from 10.6, 13.0, 21.1, and 23.7 degrees 2θ ± 0.3 degrees 2θ.

Images