(s)-tianeptine and use in the treatment of disorders and conditions associated with peroxisome proliferator receptor-activated receptor

Description

(S)-TIANEPTINE AND USE IN THE TREATMENT OF DISORDERS AND CONDITIONS ASSOCIATED WITH PEROXISOME PROLIFERATOR RECEPTOR-ACTIVATED RECEPTOR CROSS-REFERENCE TO RELATED REQUESTS

[0001] This application claims priority and benefit of U.S. Provisional Application No. 63 / 454,958, filed March 27, 2023, U.S. Provisional Application No. 63 / 463,299, filed May 1, 2023, U.S. Provisional Application No. 63 / 466,999, filed May 16, 2023, U.S. Provisional Application No. 63 / 468,221, filed May 22, 2023, and U.S. Provisional Application No. 63 / 528,631, filed July 24, 2023. The content of each of the foregoing applications is incorporated herein by reference in its entirety. FIELD OF TECHNIQUE

[0002] The present invention relates to the (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ylamino)heptanoic acid ((S)-tianeptine) and to the (S)-enantiomer of deuterated tianeptine (11-D-(S)-tianeptine), both being characterized as comprising not more than about 2%, or not more than about 0.1%, of the corresponding (R)-enantiomer. The present invention also provides salts, amides, esters, cocrystals, crystals, analogues and pharmaceutical compositions thereof, as well as methods of using the (S)-enantiomers and these compounds and compositions for the treatment of diseases, disorders or conditions of the CNS, as well as diseases, conditions and disorders associated with altered, exacerbated or modulated activity by peroxisome proliferator-activated receptors (PPAR)-p / õ and / or PPAR-γ, minimizing or eliminating the potential for opioid abuse.Among these diseases, disorders, and conditions are disorders of the Central Nervous System (CNS) (e.g., major depressive disorder, cognitive impairments). Petition 870250087689, dated 09 / 26 / 2025, page 12 / 421 2 / 233 related to age and neurodegenerative conditions), asthma and primary biliary cholangitis. The present invention also provides methods for the production of the (S)-enantiomer and the 11-D-(S)-enantiomer and related compounds of this invention. BACKGROUND

[0003] Tianeptine, a racemate of 7-[(3-chloro-6-methyl-5,5dioxo-11H-benzo[c][2,1]-enzothiazepine-11-yl)amino]heptanoic acid, is an antidepressant with neuroprotective and cognitive-restorative effects. Researchers have reported that tianeptine can be used to treat post-traumatic stress disorder (PTSD) (Onder E et al., Eur Psychiatry. 2005), attention deficit hyperactivity disorder (ADHD) (Niederhofer H., Neuropsychobiology. 2004), Alzheimer's disease (García-Alberca JM et al., J Alzheimers Dis. 2022), asthma (Lechin F et al., Methods Find Exp Clin Pharmacol. 2004), and fibromyalgia (ISRCTN16400909). Although tianeptine shares structural similarities with classic tricyclic antidepressants, its pharmacological behavior is unique. No drug containing tianeptine is approved by the US Food and Drug Administration (FDA) for any indication.Tianeptine, however, is currently available as an active ingredient in approved products sold under the trade names, among others, Stabion®, Coaxil®, Tatinol, Tianeurax®, and Salymbra, throughout Europe, Asia, and Latin America for the treatment of depression. For example, France first authorized the marketing of tianeptine (e.g., Stablon®) in 1989 as an antidepressant at a dose of 12.5 mg three times daily. Products containing tianeptine are also available in certain areas of the US as over-the-counter dietary supplements or research chemicals.

[0004] Racemic tianeptine has been reported to affect serotonin reuptake, modulate glutamatergic activity and, more recently, has been shown to weakly activate μ-opioid receptors. In studies with Petition 870250087689, dated 09 / 26 / 2025, page 13 / 421 In a study of 3 / 233 animals undergoing severe stress, tianeptine was reported to restore brain neuroplasticity through synaptogenesis, exerting biological effects on neurons and glial cells that increase dendritic arborization in critical hippocampal circuits, restoring hippocampal neurogenesis and reversing stress-induced deficiencies in synaptic glutamate neurotransmission (McEwen BS et al., Mol Psychiatry. 2010). Furthermore, tianeptine has been shown to increase brain-derived neurotrophic factor (BDNF) in the amygdala of rats (Reagan LP et al., Eur J Pharmacol. 2007; Della FP et al., Behav Brain Res. 2012). However, these mechanistic studies are difficult to interpret, as many are based on assays with a 50:50 mixture of the (R) and (S) enantiomers of tianeptine (the racemate).

[0005] In addition, the Centers for Disease Control and Prevention (CDC) published a Morbidity and Mortality Weekly Report (MMWR) in August 2018, which described incidences of tianeptine overdose from over-the-counter products, associated with the potential abuse of tianeptine due to its opioid-like effects, and issued a warning about the public health risk. In fact, marketing authorization in Georgia was revoked in June 2010, and tianeptine was included on the list of psychotropic agents in Russia, Ukraine, and Armenia due to its misappropriation by drug addicts via intravenous injection. As a result of these actions and reports of abuse, in September 2012, tianeptine was added to List I in France, for medicines that have a special status for prescription and dispensing conditions.Other common adverse events associated with tianeptine include anorexia, nightmares, insomnia, drowsiness, dizziness, headache, tachycardia, dyspnea, gastrointestinal discomfort, myalgia, and asthenia.

[0006] Peroxisome proliferator-activated receptors Petition 870250087689, dated 09 / 26 / 2025, page 14 / 421 4 / 233 (PPARs) are a group of ligand-activated transcription factors belonging to the nuclear receptor superfamily involved in the regulation of inflammatory reactions and lipid metabolism, both peripherally and in the central nervous system (CNS). The PPAR subfamily comprises three isotypes: PPAR-α, PPAR-γ, and PPAR-β / δ. Studies have implicated the activation of PPAR-α and PPAR-γ in the modulation of neuroinflammation, mitochondrial alterations, and memory impairment. PPAR-γ has also been shown to play roles in depression, neurogenesis, and the expression of brain-derived neurotrophic factor (BDNF) (Nicolakakis N et al., J Neurosci. 2008; Heneka M et al., Brain. 2005; Gold PW. Int J Mol Sci. 2021). PPAR-γ modulation is also used in the treatment of diabetes, for example, by agonists of the thiazolidinedione (TZD) class, often called glitazones, including rosiglitazone (Avandia®) and pioglitazone (Actos®).Alzheimer's disease has been termed type 3 diabetes to capture the concept that it may be a metabolic disorder of glucose metabolism in the CNS, similar to how type 1 and type 2 diabetes are metabolic disorders of peripheral glucose metabolism (de Ia Monte SM, Wands JR. J Diabetes Sci Technol. 2008). Downregulation of PPAR-β / δ has also been associated with depressive behaviors, while activation of PPAR-β / δ has been shown to improve clinical symptoms of CNS pathologies through modulation of oxidative stress and inflammatory responses (Chen F et al., Int J Neuropsychopharmacol, 2019; Strosznajder AK, Neuromolecular Med. 2021; Espinosa-Jiménez T et al. Front Pharmacol. 2022). PPAR-β / δ activation is also being investigated for the treatment of primary biliary cholangitis with MBX-8025 (Seladelpar®) from CymaBay Therapeutics, currently in Phase 3 trials.

[0007] Major depressive disorder (MDD) is a mood disorder that persists for 2 or more weeks and is a major cause Petition 870250087689, dated 09 / 26 / 2025, page 15 / 421 Major depressive disorder (MDD) accounts for 5 / 233 of disability worldwide. MDD affects how a person feels, thinks, and copes with daily activities and can significantly impair all aspects of life, as patients experience persistent sadness or anxiety, irritability, anhedonia, significant weight change, appetite disorders, sleep disorders, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness, decreased ability to think or concentrate, indecisiveness, pain without a clear physical cause, or recurrent thoughts of death or suicide. In 2020, an estimated 21 million adults in the U.S., a number representing about 8.4% of all adults (aged 18 and older), experienced at least one major depressive episode. The annual prevalence of a major depressive episode is higher among adult women (e.g., about 10.5%) compared to men (e.g., about 6.2%).Furthermore, the annual prevalence of a major depressive episode is higher among individuals aged 18 to 25 years (e.g., approximately 17.0%). Studies in humans and animals have demonstrated that depression is associated with a reduction in the size of brain regions believed to regulate mood and cognition, including the prefrontal cortex and hippocampus. Additionally, these brain areas exhibit decreased neuronal synapses in depression (MacQueen G, Frodl T. Mol Psychiatry. 2011; Price JL, Drevets WC. Neuropsychopharmacology. 2010).

[0008] Current mainstays of 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 frequently associated with undesirable side effects such as weight gain and sexual dysfunction. And, even with multiple consecutive treatments, Petition 870250087689, dated 09 / 26 / 2025, page 16 / 421 6 / 233 Only a small proportion of patients achieve an asymptomatic state, i.e., remission (Rush, Am J Psychiatry. 2007). Many patients who do not respond adequately to therapy with SSRIs, SNRIs, and TCAs receive replacement therapy with mood stabilizers or antipsychotics (Strawbridge Rt al., Br J Psychiatry. 2019), and other similar patients, without a solid basis of experimental evidence, sometimes receive opioids and narcotic analgesics not indicated (e.g., oxycodone, hydrocodone, fentanyl, and tramadol). The use of opioids to treat MDD is associated with an increased risk of prolonged use, abuse (e.g., abuse of parenteral, transmucosal, intranasal, or oral drugs), and addiction.

[0009] Depression is also associated with impaired neuroplasticity and cellular resilience. Traditional antidepressant medications work, in part, by normalizing this impairment and restoring neuronal connections. For example, ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been found to produce rapid antidepressant responses (within hours) in patients with treatment-resistant depression and, in animal models, rapidly induces BDNF-dependent synaptogenesis and reverses synaptic 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 acute treatment of depression. Dextromethorphan, another NMDA receptor antagonist, 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 NDMA receptor ligands exhibit dissociative effects that limit their use. Another proposed approach to induce synaptogenesis is the 5-HT2A receptor agonist, psilocybin, but this approach is... Petition 870250087689, dated 09 / 26 / 2025, page 17 / 421 7 / 233 limited by hallucinations, which represent a pseudopsychotic side effect.

[0010] There is, therefore, a long-felt and unmet need to safely treat MDD and several other CNS disorders and conditions, and several disorders and conditions associated with altered or modulated activity by PPAR-β / δ and / or PPAR-γ. These disorders and conditions include stress (psychological, environmental, chemical, radioactive, oxidative, hormonal, vascular, and traumatic), depression, aging, and chronic diseases, each of which is associated with decreased neuronal connections.

[0011] The (S)-enantiomer of tianeptine, zwitterion thereof, its cocrystals, its esters, amides and deuterated analogues of either thereof, or pharmaceutically acceptable salts and crystalline forms of the (S)-enantiomers and compositions thereof, as well as various analogues of the two enantiomers of tianeptine and compositions thereof, as described in various embodiments of this invention, and methods of use of these compositions meet this unmet need and improve the treatment of various CNS disorders and conditions, including MDD, and disorders and conditions associated with altered or modulated PPAR-β / δ and / or PPAR-γ activity, while minimizing or eliminating the potential for opioid abuse. SUMMARY OF THE INVENTION

[0012] Some embodiments of this invention are: 1. The (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ylamino)heptanoic acid ((S)enantiomer of tianeptine) of general formula (Ia), the zwitterion thereof 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, the zwitterion or the pharmaceutically acceptable salt are characterized by comprising < about 2% of the (R)-enantiomer of Petition 870250087689, dated 09 / 26 / 2025, page 18 / 421 8 / 233 tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer: Formula (Ia) Formula (Ib). 2. The (S)-enantiomer according to embodiment 1, wherein the (S)-enantiomer, the zwitterion or the pharmaceutically acceptable salt of the (S)-enantiomer are characterized by comprising < about 0.1% of the (R)-enantiomer of tianeptine or its zwitterion or a pharmaceutically acceptable salt of that enantiomer. 3. A pharmaceutically acceptable salt of the (S)-enantiomer according to embodiment 1 or 2, wherein the pharmaceutically acceptable salt is (S)-tianeptine benzenesulfonate (1:1), (S)-tianeptine fumarate (1:1), (S)-tianeptine fumarate (2:1), (S)-tianeptine hippurate (1:1), (S)-tianeptine maleate (1:1), (S)-tianeptine maleate (2:1), (S)-tianeptine p-toluenesulfonate (1:1), (S)-tianeptine orotate (1:1), (S)-tianeptine camphorsulfonate (1:1), (S)-tianeptine N-acetyl-L-tyrosinate (1:1), (S)-tianeptine polyesterix, (S)-tianeptine:L-DBTA (2:1), (S)-tianeptine sodium, (S)-tianeptine oxalate or (S)-tianeptine hemioxalate (2:1). 4. The pharmaceutically acceptable salt of the (S)-enantiomer according to embodiment 3, wherein the pharmaceutically acceptable salt is (S)-tianeptine benzenesulfonate (1:1), (S)-tianeptine fumarate (1:1), (S)-tianeptine fumarate (2:1), (S)-tianeptine hippurate (1:1), (S)-tianeptine maleate (1:1), (S)-tianeptine maleate (2:1), p Petition 870250087689, dated 09 / 26 / 2025, page 19 / 421 9 / 233 (S)-tianeptine toluenesulfonate (1:1) or (S)-tianeptine orotate (1:1). 5. The pharmaceutically acceptable salt of the (S)-enantiomer according to embodiment 3, wherein the pharmaceutically acceptable salt is (S)-tianeptine camphorsulfonate (1:1), (S)-tianeptine N-acetyl-L-tyrosinate (1:1) or (S)-tianeptine polysorbate. 6. The pharmaceutically acceptable salt of the (S)-enantiomer according to embodiment 3, wherein the pharmaceutically acceptable salt is (S)-tianeptine hemioxalate (2:1). 7. A zwitterion comprising the zwitterion of the (S)-enantiomer according to embodiment 1 or 2. 8. A cocrystal of the (S)-enantiomer according to embodiment 1 or 2, wherein the (S)-enantiomer or its zwitterion forms a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid. 9. The cocrystal according to embodiment 8, wherein the complex comprises a 1:1, 1:2 or 2:1 ratio of the (S)-enantiomer or its zwitterion 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 monoacid salt of the (S)-enantiomer and a zwitterion of the L-amino acid. 11. 0 cocrystal according to embodiment 8 or 9, wherein the cocrystal comprises an inorganic monoacid salt of the L-amino acid and the zwitterion of the (S)-enantiomer. 12. The cocrystal according to embodiment 10 or 11, in which the inorganic monoacid is hydrochloric acid (HCl). 13. An ester of the (S)-enantiomer according to embodiment 1 or 2, wherein the ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising <approximately Petition 870250087689, dated 09 / 26 / 2025, p. 20 / 421 10 / 233 of 2% of the ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof. 14. The (S)-enantiomer ester according to embodiment 13, wherein the (S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.1% of the (R)-enantiomer ester or pharmaceutically acceptable salt thereof. 15. The ester of the (S)-enantiomer according to embodiment 13 or 14, wherein the ester of the (S)-enantiomer is the methyl ester of the (S)-enantiomer, the ethyl ester of the (S)-enantiomer or another C1-C6 alkyl ester of the (S)-enantiomer or a pharmaceutically acceptable salt of any of them. 16. An amide of the (S)-enantiomer according to embodiment 1 or 2, wherein the amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof. 17. The (S)-enantiomer amide according to embodiment 16, wherein the (S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.1% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof. 18. The amide of the (S)-enantiomer according to embodiment 13 or 14, wherein the amide of the (S)-enantiomer is a simple amide or a C1-C6 alkylamide optionally substituted with at least one hydroxyl group or a pharmaceutically acceptable salt of either. 19. 0 (S)-enantiomer of 7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl-11-d)amino)heptanoic acid deuterated (11-D-(S)-enantiomer of tianeptine) of general formula (lia) Petition 870250087689, dated 09 / 26 / 2025, page 21 / 421 11 / 233 or its zwitterion of Formula (llb) or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a mixture of two or more of these species, wherein deuterium replaces hydrogen at position 11, and wherein the 11-D-(S)-enantiomer or zwitterion or pharmaceutically acceptable salt thereof, are characterized by comprising < about 2% of the 11-D-(R)-enantiomer of tianeptine or its zwitterion or pharmaceutically acceptable salt thereof, of the 11-D-(R)-enantiomer: Formula (IIa) Formula (llb). 20. The (S)-enantiomer according to embodiment 19, wherein the 11-D-(S)-enantiomer, the zwitterion or the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer are characterized by comprising < about 0.1% of the 11-D-(R)-enantiomer of tianeptine or its zwitterion or a pharmaceutically acceptable salt of that enantiomer. 21. The (S)-enantiomer according to embodiment 19 or 20, wherein the 11-D-(S)-enantiomer or the zwitterion or the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is characterized by reduced racemization at position 11 compared with the tianeptine (S)-enantiomer or the zwitterion or a pharmaceutically acceptable salt of that enantiomer. 22. The (S)-enantiomer according to any of the embodiments 19 to 21, wherein the 11-D-(S)-enantiomer, zwitterion thereof or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is further deuterated at least at one of the 3' positions, and optionally deuterated at other positions in the amino-heptanoic side chain. 23. The (S)-enantiomer according to embodiment 22, in Petition 870250087689, dated 09 / 26 / 2025, p. 22 / 421 12 / 233 that the 11-D-(S)-enantiomer is the (S)-enantiomer of 3', 3', 4', 4', 11-pentadeuterotianeptine of Formula (IIIa) or its zwitterion of Formula (lllb); the (S)-enantiomer of 2', 2', 3', 3', 4', 4', 5', 5', 6', 6', 7', 7', 11-tridecadeuterotianeptine of the general Formula (IVa) or its zwitterion of Formula (IVb); the (S)-enantiomer of 3', 3', 4', 4', tetradeuterotianeptine of Formula (Va) or its zwitterion of Formula (Vb); or the 2',2',3',3',4',4',5',5',6',6',7',7' dodecadeuterotianeptine (S)-enantiomer of the general formula (Via) or its zwitterion of the formula (Vlb). Formula (Va) Formula (Vb) Formula (Via) Formula (Vlb) 24. A pharmaceutically acceptable salt of the 11-D-(S) enantiomer according to any of the embodiments 19 to 23, wherein the pharmaceutically acceptable salt is benzenesulfonate of 11D-(S)-tianeptine (1:1), fumarate of 11-D-(S)-tianeptine (1:1), fumarate of 11-D-(S)-tianeptine (2:1), hippurate of 11-D-(S)-tianeptine (1:1), maleate of 11-D-(S)-tianeptine (1:1), maleate of 11-D-(S)-tianeptine (2:1), p-toluenesulfonate of 11-D-(S)-tianeptine (1:1), orotate of 11-D-(S)-tianeptine (1:1), camphorsulfonate of 11-D-(S)-tianeptine (1:1), 11-D-(S)-tianeptine N-acetyl-Ltyrosinate (1:1), 11-D-(S)-tiane polyesterix Petition 870250087689, dated 09 / 26 / 2025, p. 23 / 421 13 / 233 ptine, 11-D-(S)-tianeptine: L-DBTA (2:1), 11-D-(S)-tianeptine sodium, 11-D-(S)-tianeptine oxalate or 11-D-(S)-tianeptine hemi-oxalate (2:1). 25. The pharmaceutically acceptable salt of the 11-D-(S)-enantiomer according to embodiment 24, wherein the pharmaceutically acceptable salt is 11-D-(S)-tianeptine benzenesulfonate (1:1), 11-D-(S)-tianeptine fumarate (1:1), 11-D-(S)-tianeptine fumarate (2:1), 11-D-(S)-tianeptine hippurate (1:1), 11-D-(S)-tianeptine maleate (1:1), 11-D-(S)-tianeptine maleate (2:1), 11-D-(S)-tianeptine p-toluenesulfonate (1:1) or 11-D-(S)-tianeptine orotate (1:1). 26. The pharmaceutically acceptable salt of the 11-D-(S)-enantiomer according to embodiment 24, wherein the pharmaceutically acceptable salt is 11-D-(S)-tianeptine camphorsulfonate (1:1), 11-D-(S)-tianeptine N-acetyl-L-tyrosinate (1:1) or 11-D-(S)-tianeptine polyesterix. 27. The pharmaceutically acceptable salt of the 11-D-(S)-enantiomer according to embodiment 24, wherein the pharmaceutically acceptable salt is 11-D-(S)-tianeptine hemioxalate (2:1). 28. A zwitterion comprising the zwitterion of the 11-D-(S)enantiomer according to any of the embodiments 19 to 23. 29. A cocrystal of the 11-D-(S)-enantiomer according to any of the 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 a 1:1, 1:2 or 2:1 ratio of the 11-D-(S)enantiomer or its zwitterion 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 monoacid salt of 11-D-(S) Petition 870250087689, dated 09 / 26 / 2025, p. 24 / 421 14 / 233 enantiomer and a zwitterion of L-amino acid. 32. The cocrystal according to embodiment 29 or 30, wherein the cocrystal comprises an inorganic monoacid salt of the L-amino acid and the zwitterion of the 11-D-(S)-enantiomer. 33. The cocrystal according to embodiment 31 or 32, in which the inorganic monoacid is hydrochloric acid (HCl). 34. An ester of the (S)-enantiomer according to any of embodiments 19 to 23, wherein the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof. 35. The (S)-enantiomer ester according to embodiment 34, wherein the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.1% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof. 36. The ester of the (S)-enantiomer according to embodiment 34 or 35, wherein the ester of the 11-D-(S)-enantiomer is the methyl ester of the 11-D-(S)-enantiomer, the 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 of any of them. 37. An amide of the (S)-enantiomer according to any of embodiments 19 to 23, wherein the 11-D-(S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the 11-D-(R)-enantiomer amide or pharmaceutically acceptable salt thereof. 38. The (S)-enantiomer amide according to embodiment 37, wherein the 11-D-(S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.1% of the 11-D-(R)-enantiomer amide or pharmaceutically acceptable salt Petition 870250087689, dated 09 / 26 / 2025, p. 25 / 421 15 / 233 acceptable of the same. 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 of either. 40. A pharmaceutically acceptable acid salt of the (S)-enantiomer or 11-D-(S)-enantiomer according to any of embodiments 1, 2 or 19 to 23, wherein the nitrogen atom in the side chain attached to Carbon-11 (C-11) is 100% protonated, the 100% protonated salt being less susceptible to oxidation by air in solid forms or in solution when compared to the (S)-enantiomer, 11-D-(S)-enantiomer, the zwitterion of either or the sodium salts of either. 41. A pharmaceutical composition comprising the (S)-enantiomer of tianeptine, a zwitterion thereof or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or its zwitterion according to any of embodiments 1 to 12, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof according to any of embodiments 13 to 15, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof according to any of embodiments 16 to 18 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises < about 2% of the (R)-enantiomer of tianeptine, a zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or its zwitterion. 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. 42. Pharmaceutical composition of claim 41, wherein the pharmaceutical composition comprises < about 0.1% of (R) Petition 870250087689, dated 09 / 26 / 2025, p. 26 / 421 16 / 233 tianeptine enantiomer, zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or zwitterion, 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. 43. A pharmaceutical composition comprising the 11-D(S)-enantiomer of tianeptine, a zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a cocrystal of the 11-D-(S)-enantiomer or its zwitterion according to any of embodiments 19 to 33, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof according to any of embodiments 34 to 36, or an amide of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof according to any of embodiments 37 to 39 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises < about 2% of the 11-D-(R)-enantiomer of tianeptine, zwitterion of even or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a cocrystal of the 11-D-(R)-enantiomer or a zwitterion thereof, 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. 44. The pharmaceutical composition according to embodiment 43, wherein the pharmaceutical composition comprises < about 0.1% of the 11-D-(R)-enantiomer of tianeptine, a zwitterion thereof or a pharmaceutically acceptable salt of the 11-D-(R)-enantiomer, or a cocrystal of the 11-D-(R)-enantiomer or a zwitterion thereof, or the ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. 45. The pharmaceutical composition according to any Petition 870250087689, dated 09 / 26 / 2025, p. 27 / 421 17 / 233 one of the embodiments 41 to 44, in which the composition is in the form of a tablet, a thin film, a powder, a coated tablet, a capsule, a soft gel, a suppository, a nasal spray, an oral spray or a pulmonary spray. 46. ​​A pharmaceutical composition according to any of the embodiments 41 to 45, wherein the composition is formulated for immediate release, controlled release, sustained release, prolonged release or slow release of the (S)-enantiomer or the 11-D-(S)-enantiomer, or the zwitterion or an ester or an amide of both, or a pharmaceutically acceptable salt of both, or a cocrystal of the (S)-enantiomer or the 11-D-(S)-enantiomer or the zwitterion of both. 47. A pharmaceutical composition according to embodiment 46, wherein the composition is formulated for controlled release of the (S)-enantiomer or the 11-D-(S)-enantiomer, or the zwitterion or an ester or amide of either thereof, or a pharmaceutically acceptable salt of either thereof, or a cocrystal of the (S)-enantiomer or the 11-D-(S)-enantiomer or the zwitterion of either thereof. 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, according to any of embodiments 41 to 47, wherein the mixture is characterized by enhanced prolonged release when administered orally, compared with administration of a composition comprising a single pharmaceutically acceptable salt or cocrystal of the (S)-enantiomer or 11-D-(S)-enantiomer, according to any of embodiments 41 to 47. 49. A method for treating a disease, disorder, or condition modulated by, exacerbated by, or associated with activity. Petition 870250087689, dated 09 / 26 / 2025, p. 28 / 421 18 / 233 altered peroxisome proliferator-activated receptor (PPAR)β / δ and / or PPAR-γ and one or more symptoms associated therewith, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer, zwitterion thereof or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or zwitterion thereof, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, according to any of embodiments 1 to 18, or a pharmaceutical composition according to any of embodiments 41, 42 or 45 to 48. 50. A method for treating a disease, disorder, or condition modulated, exacerbated, or associated with altered activity of the peroxisome proliferator-activated receptor (PPAR)-β and / or PPAR-γ and one or more associated symptoms, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a cocrystal of the 11-D-(S)-enantiomer or 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, according to any of embodiments 19 to 39, or a pharmaceutical composition, according to any of embodiments 43 48. 51. The method according to modality 49 or 50, in which the disease, disorder, or condition is selected from the group consisting of a central nervous system (CNS) disorder, inflammatory disease, autoimmune disease, infectious disease, a hearing loss condition, eye disease, musculoskeletal disease, metabolic disease, mitochondrial disease, hypertriglyceridemia, cancer, menopause, and Petition 870250087689, dated 09 / 26 / 2025, page 29 / 421 19 / 233 overlapping chronic pain conditions (COPCs), and psychological, physical, metabolic, or hormonal stress and COPCs. 52. The method according to modality 51, in which the disease, disorder or condition is a CNS disorder. 53. The method according to modality 52, in which the CNS disorder is selected from the group consisting of a mood disorder, a trauma- and stress-related disorder, an anxiety disorder, obsessive-compulsive disorder, a neurodegenerative or neuroinflammatory disorder, a neurodevelopmental disorder, a leukodystrophy, and CNS oxidative stress. 54. The method according to modality 53, in which the mood disorder is a depressive disorder, a bipolar disorder, or a substance-induced disorder. 55. The method according to modality 54, in which the depressive disorder is a major depressive disorder (MDD). 56. The method according to modality 53, in which 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 modality 53, in which the anxiety disorder is panic disorder, generalized anxiety disorder (GAD), a specific phobia, agoraphobia, or social phobia. 58. The method according to modality 53, in which 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, pediatric autoimmune neuropsychiatric disorders associated with Petition 870250087689, dated 09 / 26 / 2025, page 30 / 421 20 / 233 streptococcal infections (PANDAS), vanishing white matter disease, infantile ataxia with CNS hypomyelination, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, kuru or dementia. 59. The method according to modality 53, in which the neurodevelopmental disorder is attention deficit / hyperactivity disorder (ADHD), schizophrenia, Prader-Willi syndrome (including hyperphagia and other symptoms (e.g., depression and anxiety)) or autism. 60. The method according to modality 53, in which leukodystrophy is leukoencephalopathy, a hypomyelinating or demyelinating disease, an intellectual disability syndrome, a cognitive impairment, a glial cell dysfunction, or a brain lesion. 61. The method according to modality 60, wherein cognitive impairment is age-related cognitive impairment, age-related cognitive decline (ARCD), age-associated memory impairment (AAMI), cognitive impairment associated with mild cognitive impairment, prodromal Alzheimer's disease or Alzheimer's disease, prodromal frontotemporal dementia (FTD) or FTD, prodromal posterior cortical atrophy (PCA) or PCA, cognitive impairment associated with schizophrenia, a drug-induced cognitive disorder, cognitive dysfunction caused by radiotherapy, cognitive decline related to space travel or cognitive deficit, and neuropathic pain associated with diabetes mellitus. 62. The method of modality 60, in which drug-induced cognitive impairment is corticosteroid-induced cognitive dysfunction, doxorubicin-induced cognitive dysfunction, chemotherapy-induced cognitive dysfunction, cognitive dysfunction induced by Petition 870250087689, dated 09 / 26 / 2025, p. 31 / 421 21 / 233 alcohol or substance-induced cognitive dysfunction. 63. The method according to modality 60, in which the brain injury is a traumatic brain injury, hypoxia-induced brain injury, toxin-induced brain injury, stroke, or reperfusion injury following ischemic stroke. 64. The method according to modality 51, in which the inflammatory disease is asthma, postoperative cognitive dysfunction, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis. 65. The method according to modality 51, in which the autoimmune disease is Achalasia, Addison's disease, Adult-onset Still's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM / anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, 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), Balo's disease, Behçet's disease, Benign mucous pemphigoid, Bullous pemphigoid, Castleman's disease (CD), Celiac disease, Chagas disease, Demyelinating polyneuropathy Chronic inflammatory bowel disease (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, syndrome of Petition 870250087689, dated 09 / 26 / 2025, page 32 / 421 22 / 233Cogan syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing 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), Gestational herpes or gestational pemphigoid (PG), hidradenitis suppurativa (HS) (inverse 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 sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Ménière's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry's syndrome Romberg syndrome, Pars planitis (peripheral uveitis), Parsonage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndrome type I, Polyglandular syndrome type IIPolyglandular syndrome type III, Polymyalgia rheumatica, Polymyositis, Post-myocardial infarction syndrome, Syndrome, Petition 870250087689, dated 09 / 26 / 2025, page 33 / 421 23 / 233 post-pericardiotomy, 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, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, testicular and spermatic autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, diabetes Type 1 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 modality 51, in which the infectious disease is a viral infection or post-viral condition. 67. The method according to modality 51, in which the hearing loss condition is non-syndromic mitochondrial hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or hereditary hearing loss, hearing loss resulting from exposure to ototoxic substances, hearing loss resulting from disease, or hearing loss resulting from trauma. 68. The method according to modality 51, in which 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 modality 51, in which the musculoskeletal disease is muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, atrophy Petition 870250087689, dated 09 / 26 / 2025, page 34 / 421 24 / 233 progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal cord spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, cramping fasciculation syndrome, Freidrich's ataxia, a muscular atrophy disorder, an inclusion body myopathy, motor neuron disease or paralysis. 70. The method according to modality 51, in which the metabolic disease is non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes, phenylketonuria, proliferative retinopathy, and Keams-Sayre disease. 71. The method according to modality 51, in which the mitochondrial disease is Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Keams-Sayre syndrome (KSS), Leigh syndrome, mitochondrial DNA depletion syndromes (MDDS), mitochondrial encephalomyopathy, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with irregular red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber hereditary optic neuropathy (LHON), and Pearson syndrome. 72. The method according to modality 51, in which the cancer is glioblastoma or glioma. 73. A method for treating a disease, disorder, or condition modulated, exacerbated, or associated with altered activity of peroxisome proliferator-activated receptor (PPAR)-β and / or PPAR-γ and one or more associated symptoms in an individual who has experienced high stress, comprising administering to the individual a therapeutically effective amount of the (S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or zwitterion thereof, or an ester Petition 870250087689, dated 09 / 26 / 2025, p. 35 / 421 25 / 233 of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, according to any of embodiments 1 to 18, or a pharmaceutical composition according to any of embodiments 41, 42 or 45 to 48. 74. A method for treating a disease, disorder, or condition modulated, exacerbated, or associated with altered activity of the peroxisome proliferator-activated receptor (PPAR)-pZo and / or PPAR-γ and one or more associated symptoms in an individual who has experienced high stress, comprising administering to the individual a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11-D-(S)-enantiomer or 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, according to any of embodiments 19 to 39, or a pharmaceutical composition, according to any of embodiments 43 to 44. 48. 75. The method according to modality 73 or 74, in which stress is caused by adversity early in life or by childhood trauma. 76. A method for treating a disease, disorder, or condition modulated by, exacerbated by, or associated with altered activity of peroxisome proliferator-activated receptor (PPAR)-pZo or PPAR-γ and one or more symptoms associated therewith, while reducing μ-opioid receptor agonism associated with racemic tianeptine treatment, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer, a zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or Petition 870250087689, dated 09 / 26 / 2025, p. 36 / 421 26 / 233 zwitterion thereof, or an ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof, according to any of embodiments 1 to 18, or a pharmaceutical composition according to any of embodiments 41, 42 or 45 to 48. 77. A method for treating a disease, disorder, or condition modulated, exacerbated, or associated with altered activity of the peroxisome proliferator-activated receptor (PPAR)-pZõ or PPAR-γ and one or more associated symptoms, while reducing μ-opioid receptor agonism associated with racemic tianeptine treatment, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of the 11-D(S)-enantiomer or a 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, according to any of embodiments 19 to 39, or a pharmaceutical composition according to any of embodiments 43 to 48. 78. The method according to any of the modalities 49-77 or 104-124, wherein the (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or the zwitterion thereof, or the ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, 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 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof or the pharmaceutical composition is administered one or Petition 870250087689, dated 09 / 26 / 2025, p. 37 / 421 27 / 233 more times a day. 79. The method according to embodiment 78, wherein the (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or the zwitterion thereof, or the ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or the amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, the cocrystal of the 11-D-(S)-enantiomer or the zwitterion thereof, or the ester of the 11-D-(S)-enantiomer or the pharmaceutically acceptable salt thereof, or the amide of 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof or the pharmaceutical composition is administered once daily. 80. The method according to any of embodiments 49 to 77 or 104 to 124, wherein the (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or the zwitterion thereof, or the ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, 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. either the 11-D-(S)-enantiomer amide or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered parenterally, orally, sublingually, buccally, by inhalation, palatial route, transdermally, rectally or vaginally. 81. The method according to embodiment 80, wherein the (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or Petition 870250087689, dated 09 / 26 / 2025, p. 38 / 421 28 / 233 of the zwitterion thereof, or the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or the amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, the cocrystal of the 11-D-(S)-enantiomer or zwitterion thereof, or the ester of the 11-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, or the amide of the 11-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered orally. 82. The method according to embodiment 80, wherein the (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or the zwitterion thereof, or the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or the amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, the cocrystal of the 11-D-(S)-enantiomer or the zwitterion thereof, or the ester of the 11-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, or the amide of 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered by inhalation. 83. The method according to any of embodiments 49 to 82 or 104 to 124, wherein the (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or the zwitterion thereof, or the ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or the amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, the cocrystal of the 11-D-(S)-enantiomer or the zwitterion thereof, or the ester of the 11-D Petition 870250087689, dated 09 / 26 / 2025, p. 39 / 421 29 / 233 (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the amide of 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered sequentially or concomitantly with one or more additional therapeutic agents selected from the group consisting of an antidepressant, an anticonvulsant, an anxiolytic, an antipsychotic, a cholinesterase inhibitor, an N-methyl-D-aspartate (NMDA) receptor antagonist, a 5HT2 modulator, a corticosteroid, an anti-amyloid agent, an anti-tau agent, and a chemotherapeutic agent. 84. The method according to any of embodiments 49 to 82 or 104 to 124, wherein the (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or the zwitterion thereof, or the ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, 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. either the 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered as part of a treatment regimen that also includes psychotherapeutic intervention. 85. A method for reducing the potential racemization of the (S)-enantiomer, zwitterion thereof, pharmaceutically acceptable salt thereof, cocrystal thereof, ester thereof or pharmaceutically acceptable salt thereof, or amide thereof or pharmaceutically acceptable salt thereof, according to any of embodiments 1 to 19, comprising the step of deuterating the (S)-enantiomer, zwitterion thereof, pharmaceutically acceptable salt thereof, cocrystal thereof, ester thereof or Petition 870250087689, dated 09 / 26 / 2025, page 40 / 421 30 / 233 pharmaceutically acceptable salt thereof, or amide thereof, or pharmaceutically acceptable salt thereof, in heading C-11. 86. A method for producing the (S)-enantiomer of tianeptine according to embodiment 1 or 2, said method comprising the steps of: (i) resolving a racemic or other mixture of the (S)- and (R)-enantiomers of a chiral amine tianeptine intermediate, wherein the mixtures are characterized by > 0.1% of the (R)-enantiomer of the chiral amine tianeptine intermediate, by enantioselective crystallization using a (S)-enantiomer selective conformer in a solvent mixture to produce a (S)amine tianeptine intermediate: (S)-enantiomer selective conformer, wherein the (S)amine tianeptine intermediate: (S)-enantiomer selective conformer is crystallized from the solvent mixture and characterized by comprising < 2% of the (R)amine tianeptine intermediate: (R)-enantiomer selective conformer; (ii) react the tianeptine intermediate of (S)-amine: selective conformer of the (S)-enantiomer with an alkyl ester of 7-bromo-heptanoate to produce an alkyl ester intermediate of 11-D-(S)-tianeptine: selective conformer of the (S)-enantiomer; (iii) react the 11-D-(S)-tianeptine alkyl ester intermediate: selective conformer of the (S)-enantiomer with a base to produce the 11-D-(S)-tianeptine alkyl ester intermediate and (iv) saponify the 11-D(S)-tianeptine alkyl ester intermediate to produce the tianeptine (S)-enantiomer, comprising < 2% of the tianeptine (R)-enantiomer. 87. The method according to embodiment 86, in which the (S)-enantiomer of tianeptine is characterized by < 0.1% of the (R)-enantiomer of tianeptine. 88. The method according to modality 86, in which the Petition 870250087689, dated 09 / 26 / 2025, p. 41 / 421 31 / 233 chiral amine intermediate of tianeptine is 3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][1,2]benzothiazepine-11-amine, the (S)-amine intermediate of tianeptine: selective (S)-enantiomer conformer is (11S)-3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][1,2]benzothiazepine-11-amine: selective (S)-enantiomer conformer and the (S)-ester intermediate of tianeptine: selective (S)-enantiomer conformer is ethyl 7-[[(11S)-3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][1,2]benzothiazepine-11-yl]amino]heptanoate: selective (S)-enantiomer conformer. 89. A method for producing 11-D-(S)-tianeptine according to embodiment 19 or 20, said method comprising the steps of: (i) resolving a racemic or other mixture of the (S)- and (R)-enantiomers of a chiral amine 11-D-tianeptine intermediate, wherein the mixtures are characterized by > 0.1% of the (R)-enantiomer of the chiral amine 11-D-tianeptine intermediate, by enantioselective crystallization using a (S)-enantiomer selective conformer in a solvent mixture to produce an (S)-amine 11-D-tianeptine intermediate: (S)-enantiomer selective conformer, the (S)-amine 11-D-tianeptine intermediate: (S)-enantiomer selective conformer being crystallized from the solvent mixture and being characterized in that it comprises < 2% of the (R)-amine 11-D-tianeptine intermediate: (R)-enantiomer selective conformer - conformer; (ii) react the 11-D-tianeptine intermediate of (S)-amine: selective conformer of the (S)-enantiomer with an alkyl ester of 7-bromo-heptanoate to produce an 11-D-(S)-tianeptine intermediate alkyl ester: selective conformer of the (S)-enantiomer; (iii) react the 11-D-(S)-tianeptine alkyl ester intermediate: selective conformer of the (S)-enantiomer with a base to produce the 11-D-(S)-tianeptine alkyl ester intermediate and Petition 870250087689, dated 09 / 26 / 2025, pp. 42 / 421 32 / 233 (iv) saponify the alkyl ester intermediate of 11-D(S)-tianeptine to produce 11-D-(S)-enantiomer of tianeptine, wherein 11-D-(S)-tianeptine comprises < 2% of the (R)-enantiomer of 11-D-tianeptine. 90. The method according to embodiment 89, in which the (S)-enantiomer of 11-D-tianeptine is characterized by < 0.1% of the (R)-enantiomer of 11-D-tianeptine. 91. The method according to embodiment 89, wherein the chiral amine 11-D-tianeptine intermediate is 11-amino-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 11-D-tianeptine intermediate: selective (S)-enantiomer conformer is 11-amino-3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepine 11-D-tianeptine intermediate: selective (S)-enantiomer conformer and the alkyl ester intermediate 11-D-(S)-tianeptine: selective (S)-enantiomer conformer 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: selective conformer of the (S)-enantiomer. 92. The method for producing the (S)-enantiomer of tianeptine or zwitterion thereof, according to embodiment 1 or 2, said method comprising the steps of: (i) resolving a racemic or other mixture of the (S)- and (R)-enantiomers of a tianeptine alkyl ester, such mixtures being characterized by > 0.1% of the (R)-enantiomer of a tianeptine alkyl ester, by enantioselective crystallization using an R-enantiomer-selective conformer in a solvent mixture to produce an (R)-tianeptine alkyl ester: R-enantiomer-selective conformer and an 11-D-(S)-tianeptine alkyl ester: R-enantiomer-selective conformer, crystallizing and separating the (R)-tianeptine alkyl ester from the solvent mixture, the 11-D-(S)-tianeptine alkyl ester remaining in the solvent mixture and being characterized in that Petition 870250087689, dated 09 / 26 / 2025, page 43 / 421 33 / 233 comprise < 2% of the alkyl ester of (R)-tianeptine; (ii) hydrolyze the alkyl ester of 11-D-(S)-tianeptine: selective conformer of (R)-enantiomer with a strong acid to produce the acid salt of 11-D-(S)-tianeptine, wherein the acid salt of tianeptine comprises < 2% of the acid salt of (R)-tianeptine; and (iii) neutralize the acid salt of 11-D-(S)-tianeptine with a base to produce the zwitterion of the (S)-enantiomer of tianeptine. 93. A method for producing the 11-D-(S)-enantiomer or zwitterion thereof according to embodiment 19 or 20, said method comprising the steps of: (i) resolving a racemic or other mixture of the (S)- and (R)-enantiomers of an 11-D-tianeptine alkyl ester, wherein the mixtures are characterized by > 0.1% of the (R)-enantiomer of an 11-D-tianeptine alkyl ester, by enantioselective crystallization using an R-enantiomer-selective conformer in a solvent mixture to produce an 11-D-(R)-tianeptine alkyl ester: R-enantiomer-selective conformer and an 11-D-(S)-tianeptine alkyl ester: R-enantiomer-selective conformer, crystallizing and separating the 11-D-(R)-tianeptine alkyl ester from the solvent mixture, the 11-D-(S)-tianeptine alkyl ester remaining in the solvent mixture and being characterized by comprising < 2% of the alkyl ester of 11-D-(R)tianeptine; (ii) hydrolyze the selective conformer of the alkyl ester (R) of 11-D-(S)-tianeptine with a strong acid to produce the acid salt of 11-D-(S)-tianeptine, wherein the acid salt of 11-D-tianeptine comprises < 2% of the acid salt of 11-D-(R)-tianeptine; and (iii) neutralize the acid salt of 11-D-(S)-tianeptine with a base to produce the zwitterion of the 11-D-(S)-enantiomer of tianeptine. 94. The method according to any of the embodiments 86, 89, 92 or 93, wherein the alkyl ester of tianeptine is an ester. Petition 870250087689, dated 09 / 26 / 2025, pp. 44 / 421 34 / 233 methyl, an ethyl ester or any other C1-C6 alkyl ester. 95. The method according to any of the embodiments 86, 89, 92 or 93, wherein the enantioselective crystallization comprises the use of a conformer selected from the group consisting of L-dibenzoyl tartaric acid (DBTA), D-DBTA, di-o-toluoyl-L-tartaric acid (LD(2-Me)BTA), DD(2-Me)BTA, other DBTA derivatives, (S)-1,T-Bi-2-naphthol-2,2'-diyl hydrogen phosphate, (R)-1,T-Bi2-naphthol-2,2'-diyl hydrogen phosphate, (S)-(R)-mandelic acid, (R)-(S)-mandelic acid, (S)-(S)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid, 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 of the embodiments 86, 89, 92 or 93, in which 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 the ratio of 2:1:1. 98. The method according to any of the embodiments 86, 89, 92 or 93, in which the enantioselective crystallization of the (S)-amine tianeptine intermediate: selective (S)-enantiomer conformer, the (S)-amine 11-D-tianeptine intermediate: selective (S)-enantiomer conformer, the (R)-tianeptine alkyl ester: selective (R)-enantiomer conformer or the 11-D-(R)-tianeptine alkyl ester: selective (R)-enantiomer conformer comprises the step of slow evaporation of the solvent mixture. 99. The method according to any of the embodiments 86, 89, 92 or 93, in which enantioselective crystallization is repeated to enhance the enantiomeric purity or the chiral purity of the resolved (S)-amine tianeptine intermediate, the (S)-amine 11-D-tianeptine intermediate, the 11-D-(S)-tianeptine methyl ester or the ester Petition 870250087689, dated 09 / 26 / 2025, pp. 45 / 421 35 / 233 11-D-(S)-tianeptine methyl. 100. The method according to embodiment 92 or 93, in which the strong acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid. 101. The method according to any of the modalities 86, 89, 92 or 93, in which the base is sodium bicarbonate, sodium carbonate, potassium bicarbonate or sodium hydroxide. 102. The method according to any of the embodiments 86, 89, 92 or 93, in which the resolution of the racemic mixture or other mixture is carried out by means of high-performance liquid chromatography (HPLC). 103. The method according to any of the embodiments 86, 89, 92 or 93, in which the resolution of the racemic mixture or other mixture is carried out by means of supercritical fluid chromatography with a chiral column. 104. A method for treating a disease, disorder or condition selected from the group consisting of a central nervous system (CNS) disorder, inflammatory disease, autoimmune disease, infectious disease, a hearing loss condition, eye disease, musculoskeletal disease, metabolic disease, mitochondrial disease, hypertriglyceridemia, cancer, menopause and overlapping chronic pain conditions (COPCs) and psychological, physical, metabolic or hormonal stress and COPCs, comprising administering to an individual in need, or at risk, a therapeutically effective amount of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or zwitterion thereof, or an ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, according to any of embodiments 1 to 18, or a pharmaceutical composition according to any of embodiments 41, 42 or 45 to 48, or administer by submitting a quantity Petition 870250087689, dated 09 / 26 / 2025, page 46 / 421 36 / 233 therapeutically effective 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of 11-D-(S)-enantiomer or a cocrystal of 11-D-(S)-enantiomer or zwitterion thereof, or an ester of 11-D-(S)-enantiomer or the pharmaceutically acceptable salt thereof, or an amide of (S)-enantiomer or pharmaceutically acceptable salt thereof, according to any of embodiments 19 to 39, or a pharmaceutical composition according to any of embodiments 43 to 48. 105. The method according to modality 104, in which the CNS disorder is selected from the group consisting of a mood disorder, a trauma- and stress-related disorder, an anxiety disorder, obsessive-compulsive disorder, a neurodegenerative or neuroinflammatory disorder, a neurodevelopmental disorder, a leukodystrophy, and CNS oxidative stress. 106. The method according to modality 105, in which the mood disorder is a depressive disorder, a bipolar disorder, or a substance-induced disorder. 107. The method according to modality 106, in which the depressive disorder is a major depressive disorder (MDD). 108. The method according to modality 105, in which 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 modality 105, in which the anxiety disorder is panic disorder, generalized anxiety disorder (GAD), specific phobia, agoraphobia, or social phobia. 110. The method according to modality 105, in which 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). Petition 870250087689, dated 09 / 26 / 2025, page 47 / 421 37 / 233 amyotrophic lateral sclerosis (ALS), traumatic brain injury, neuromyelitis optica, myasthenia gravis, autoimmune encephalitis, prion disease, transverse myelitis, pediatric streptococcal infection-associated autoimmune neuropsychiatric disorders (PANDAS), vanishing white matter disease, infantile ataxia with CNS hypomyelination, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, kuru or dementia. 111. The method according to modality 105, where the neurodevelopmental disorder is attention deficit / hyperactivity disorder (ADHD), schizophrenia, Prader-Willi syndrome (including hyperphagia and other symptoms (e.g., depression and anxiety)) or autism. 112. The method according to modality 105, in which leukodystrophy is leukoencephalopathy, a hypomyelinating or demyelinating disease, an intellectual disability syndrome, a cognitive impairment, a glial cell dysfunction, or a brain lesion. 113. The method according to modality 112, wherein cognitive impairment is age-related cognitive impairment, age-related cognitive decline (ARCD), age-associated memory impairment (AAMI), cognitive impairment associated with Mild Cognitive Impairment, prodromal Alzheimer's disease or Alzheimer's disease, prodromal frontotemporal dementia (FTD) or FTD, prodromal posterior cortical atrophy (PCA) or PCA, cognitive impairment associated with schizophrenia, a drug-induced cognitive disorder, radiotherapy-induced cognitive dysfunction, space travel-related cognitive decline or cognitive deficit, and neuropathic pain associated with diabetes mellitus. 114.0 method of modality 113, in which the disorder Petition 870250087689, dated 09 / 26 / 2025, pp. 48 / 421 38 / 233 Drug-induced cognitive dysfunction is corticosteroid-induced cognitive dysfunction, doxorubicin-induced cognitive dysfunction, chemotherapy-induced cognitive dysfunction, alcohol-induced cognitive dysfunction, or substance-induced cognitive dysfunction. 115. The method according to modality 112, wherein the brain injury is a traumatic brain injury, hypoxia-induced brain injury, toxin-induced brain injury, stroke, or reperfusion injury following ischemic stroke. 116. The method according to modality 104, in which the inflammatory disease is asthma, postoperative cognitive dysfunction, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis. 117. The method according to modality 104, in which the autoimmune disease is Achalasia, Addison's disease, Adult-onset Still's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM / anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, 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), Balo's disease, Behçet's disease, Benign mucous pemphigoid, Bullous pemphigoid, Castleman's disease (CD), Celiac disease, Chagas disease, Polyneuropathy Petition 870250087689, dated 09 / 26 / 2025, pp. 49 / 421 39 / 233 Chronic inflammatory demyelinating disease (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), Cicatricial pemphigoid, Cogan syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture syndrome, Granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), gestational herpes or gestational pemphigoid (PG),Hidradenitis suppurativa (HS) (inverse 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 sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Ménière's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, Neonatal Lupus, Neuromyelitis Optica, Neutropenia, Ocular Cicatricial Pemphigoid, Optic Neuritis, Palindromic Rheumatism (PR), PANDAS, Paraneoplastic Cerebellar Degeneration (PCD), Paroxysmal Nocturnal Hemoglobinuria (PNH), Parry-Romberg SyndromePars planitis (peripheral uveitis), Parsonage-Turner syndrome, Pemphigus, Peripheral neuropathy, Encephalomyelitis Petition 870250087689, dated 09 / 26 / 2025, page 50 / 421 40 / 233 perivenous, 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, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt's syndrome, Scleritis, Scleroderma, Sjögren's syndrome, Autoimmunity Testicular and spermatic hemorrhage, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis I, giant cell arteritis, thrombocytopenic purpura (TTP).Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, 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 modality 104, in which the infectious disease is a viral infection or a post-viral condition. 119. The method according to modality 104, where the hearing loss condition is non-syndromic mitochondrial hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or hereditary hearing loss, hearing loss resulting from exposure to ototoxic substances, hearing loss resulting from disease, or hearing loss resulting from trauma. 120. The method according to modality 104, in which the eye disease is cataract, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy. Petition 870250087689, dated 09 / 26 / 2025, page 51 / 421 41 / 233 121. The method according to modality 104, wherein the musculoskeletal disease is muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal cord spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, cramp fasciculation syndrome, Freidrich's ataxia, a muscular atrophy disorder, an inclusion body myopathy, motor neuron disease or paralysis. 122. The method according to modality 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, phenylketonuria, proliferative retinopathy, and Keams-Sayre disease. 123. The method according to modality 104, in which the mitochondrial disease is Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Keams-Sayre syndrome (KSS), Leigh syndrome, mitochondrial DNA depletion syndromes (MDDS), mitochondrial encephalomyopathy, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with irregular red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber hereditary optic neuropathy (LHON), and Pearson syndrome. 124. The method according to modality 104, in which the cancer is glioblastoma or glioma. 125. A method for enhancing neurite growth, comprising administering to an individual in need of, the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or a zwitterion thereof, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or the salt Petition 870250087689, dated 09 / 26 / 2025, p. 52 / 421 42 / 233 pharmaceutically acceptable thereof, according to any of embodiments 1 to 18, or a pharmaceutical composition according to any of embodiments 41, 42 or 45 to 48, or administering to the individual, a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11-D-(S)-enantiomer or zwitterion thereof, or an ester of the 11-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof, according to any of embodiments 19 to 39, or a pharmaceutical composition according to any of embodiments 43 to 48. 126. The method according to modality 125, in which neurite growth is observed in a glutamatergic neuron. 127. A method for treating a disease, disorder, or condition modulated by, exacerbated by, or associated with excessive levels of circulating metal ions, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or zwitterion thereof, or an ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof, according to any of embodiments 1 to 18, or a pharmaceutical composition according to any of embodiments 41, 42, or 45 to 48, or administering to the individual a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11-D-(S)-enantiomer or 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 the pharmaceutically acceptable salt thereof, according to any of embodiments 19 to 39, or a composition Petition 870250087689, dated 09 / 26 / 2025, page 53 / 421 43 / 233 pharmaceutical action, according to any of the modalities 43 to 48. 128. Method according to claim 127, wherein the metal ion is iron or copper. 129. The method according to modality 127 or 128, in which the disease, disorder or condition is selected from the group consisting of a central nervous system (CNS) disorder, inflammatory disease, autoimmune disease, infectious disease, a hearing loss condition, eye disease, musculoskeletal disease, metabolic disease, mitochondrial disease, hypertriglyceridemia, cancer, menopause and overlapping chronic pain conditions (COPCs), and psychological, physical, metabolic or hormonal stress and COPCs. 130. The method according to modality 129, in which the CNS disorder is selected from the group consisting of a mood disorder, a trauma- and stress-related disorder, an anxiety disorder, obsessive-compulsive disorder, a neurodegenerative or neuroinflammatory disorder, a neurodevelopmental disorder, a leukodystrophy, and CNS oxidative stress. 131. A method for reducing violent or aggressive behavior associated with a CNS disorder, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or zwitterion thereof, or an ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, according to any of embodiments 1 to 18, or a pharmaceutical composition, according to any of embodiments 41, 42 or 45 to 48, or administering to the individual a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11 Petition 870250087689, dated 09 / 26 / 2025, p. 54 / 421 44 / 233 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, according to any of embodiments 19 to 39, or a pharmaceutical composition according to any of embodiments 43 to 48. 132. A method for reducing the potential for hospitalization in a psychiatric hospital or incarceration due to behavior or actions associated with a CNS disorder, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or zwitterion thereof, or an ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof, according to any of embodiments 1 to 18, or a pharmaceutical composition according to any of embodiments 41, 42 or 45 to 48, or administering to the individual a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11D-(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 the pharmaceutically acceptable salt thereof, according to any one of embodiments 19 to 39, or a pharmaceutical composition according to any one of embodiments 43 to 48. 133. A method for treating a disease, disorder, or condition modulated by, exacerbated by, or associated with elevated levels of S-nitrosylation of PPAR-β / δ and / or PPAR-γ, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer, or a cocrystal of the (S) Petition 870250087689, dated 09 / 26 / 2025, p. 55 / 421 45 / 233 enantiomer or zwitterion thereof, or an ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, according to any of embodiments 1 to 18, or a pharmaceutical composition according to any of embodiments 41, 42 or 45 to 48, or administering to the individual a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11-D(S)-enantiomer or zwitterion thereof, or an ester of the 11-D-(S)-enantiomer or the pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, according to any of the embodiments 19 to 39, or a pharmaceutical composition, according to any of the embodiments 43 to 48. 134. The method according to modality 133, in which the disease, disorder or condition is selected from the group consisting of central nervous system (CNS) disorder, inflammatory disease, autoimmune disease, infectious disease, hearing loss, eye disease, musculoskeletal disease, metabolic disease, mitochondrial disease, hypertriglyceridemia, cancer, menopause and overlapping chronic pain conditions (COPCs), and psychological, physical, metabolic or hormonal stress and COPCs. 135. The method according to modality 134, in which the CNS disorder is selected from a group consisting of a mood disorder, a trauma- and stress-related disorder, an anxiety disorder, an obsessive-compulsive disorder, a neurodegenerative or neuroinflammatory disorder, a neurodevelopmental disorder, a leukodystrophy, and CNS oxidative stress. 136. N-hydroxy-tianeptine of Formula (XV) or a pharmaceutically acceptable salt thereof: Petition 870250087689, dated 09 / 26 / 2025, page 56 / 421 46 / 233 Formula (XV). 137. The (S)-enantiomer of N-hydroxy-tianeptine (N-hydroxy(S)-tianeptine) of Formula (XVI) or a pharmaceutically acceptable salt thereof, wherein the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy-tianeptine: Formula (XVI). 138. The (S)-enantiomer of N-hydroxy-tianeptine, according to embodiment 137, wherein the (S)-enantiomer or the pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxy-tianeptine is characterized by comprising < about 0.1% of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. 139. The (R)-enantiomer of N-hydroxy-tianeptine (N-hydroxy(R)-tianeptine) of Formula (XVII) or a pharmaceutically acceptable salt thereof, wherein the (R)-enantiomer of N-hydroxy-tianeptine or the pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the (S)-enantiomer of N-hydroxy-tianeptine or a Petition 870250087689, dated 09 / 26 / 2025, page 57 / 421 47 / 233 pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxy-tianeptine: Formula (XVII). 140. 0 (R)-enantiomer of N-hydroxy-tianeptine according to embodiment 139, wherein the (R)-enantiomer or the pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy-tianeptine is characterized by comprising < about 0.1% of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. 141. N-nitroso-tianeptine of Formula (XVIII) or a pharmaceutically acceptable salt thereof: Formula (XVIII). 142. 0 (S)-enantiomer of N-nitroso-tianeptine (N-nitroso(S)-tianeptine) of Formula (XIX) or a pharmaceutically acceptable salt thereof, wherein the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso- Petition 870250087689, dated 09 / 26 / 2025, page 58 / 421 48 / 233 tianeptine: Formula (XIX). 143. The (S)-enantiomer of N-nitroso-tianeptine according to embodiment 142, wherein the (S)-enantiomer or the pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-tianeptine is characterized by comprising < about 0.1% of the (R)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. 144. 0 (R)-enantiomer of N-nitroso-tianeptine (N-nitroso(R)-tianeptine) of Formula (XX) or a pharmaceutically acceptable salt thereof, wherein the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-tianeptine: Formula (XX). 145. The (R)-enantiomer of N-nitroso-tianeptine, according to embodiment 144, wherein the (R)-enantiomer or the pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso-tianeptine is characterized by comprising < about 0.1% of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof. Petition 870250087689, dated 09 / 26 / 2025, page 59 / 421 49 / 233 enantiomer. 146. An aryl substituted tianeptine analogue or a pharmaceutically acceptable salt thereof. 147. The aryl-substituted tianeptine analogue according to embodiment 146, wherein the aryl-substituted tianeptine derivative is 7-((3-(furan-2-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]tiazepin-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]tiazepin-11-yl)amino)heptanoic acid of Formula (XXII), 7-((6-methyl-5,5-dioxide-3-(thiophen-3-yl)-6,11-dihydrodibenzo[c,f][1,2]tiazepin-11-yl)amino)heptanoic acid of Formula (XXIII) or 2-(4-(((3-chloro-6-methyl5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino)methyl)-2methylphenoxy)acetic acid of Formula (XXIV). Formula (XXI) Formula (XXII) Formula (XXIII) Formula (XXIV) 148. A pharmaceutical composition comprising N-hydroxy-tianeptine, or a pharmaceutically acceptable salt thereof, according to embodiment 136, or N-nitroso-tianeptine, or a pharmaceutically acceptable salt thereof, according to embodiment 141, or an aryl-substituted tianeptine analogue, or a pharmaceutically acceptable salt thereof, according to embodiment 146 or 147, and a pharmaceutically acceptable carrier, diluent or excipient. 149. A pharmaceutical composition comprising (S) Petition 870250087689, dated 09 / 26 / 2025, p. 60 / 421 50 / 233 enantiomer of N-hydroxy-tianeptine, or a pharmaceutically acceptable salt thereof, according to embodiment 137 or 138, or the (S)enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt thereof, according to embodiment 142 or 143, and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises < about 2%, or < about 0.1%, of the (R)enantiomer of N-hydroxy-tianeptine or N-nitroso-tianeptine, or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy-tianeptine or N-nitroso-tianeptine, or a pharmaceutically acceptable salt thereof. 150. A pharmaceutical composition comprising the (R)enantiomer of N-hydroxy-tianeptine, or a pharmaceutically acceptable salt thereof, according to embodiment 139 or 140, or the (R)enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt thereof, according to embodiment 144 or 145, and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises < about 2%, or < about 0.1%, of the (S)enantiomer of N-hydroxy-tianeptine or N-nitroso-tianeptine, or a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxy-tianeptine or N-nitroso-tianeptine, or a pharmaceutically acceptable salt thereof. 151. A pharmaceutical composition according to any of the embodiments 148 to 150, wherein the composition is in the form of a tablet, a thin film, a powder, a coated tablet, a capsule, a soft gel, a suppository, a nasal spray, an oral spray or a pulmonary spray. 152. The pharmaceutical composition according to any of the embodiments 148 to 150, in which the composition is formulated for immediate release, controlled release, sustained release, prolonged release or slow release of N-hydroxy-tianeptine, of (S) Petition 870250087689, dated 09 / 26 / 2025, page 61 / 421 51 / 233 enantiomer of N-hydroxy-tianeptine, of the (R)-enantiomer of N-hydroxy-tianeptine, of N-nitroso-tianeptine, of the (S)-enantiomer of N-nitroso-tianeptine, of the (R)-enantiomer of N-nitroso-tianeptine, or of an aryl-substituted tianeptine analogue or of a pharmaceutically acceptable salt of any of the same. 153. A method for treating a disease, disorder, or condition modulated by, exacerbated by, or associated with altered activity of peroxisome proliferator-activated receptor (PPAR)-β and / or PPAR-γ and one or more associated symptoms, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of N-hydroxytianeptine, the (S)enantiomer of N-hydroxytianeptine, the (R)-enantiomer of N-hydroxytianeptine, or a pharmaceutically acceptable salt of any of them, according to any of embodiments 136 to 140, or N-nitrosotianeptine, the (S)-enantiomer of N-nitrosotianeptine, or the (R)-enantiomer of N-nitrosotianeptine, or a pharmaceutically acceptable salt of any of them, according to any of embodiments 141 to 142. 145,or an aryl substituted tianeptine analogue or a pharmaceutically acceptable salt thereof according to embodiment 146 or 147 or the pharmaceutical composition according to any of embodiments 148 to 152. 154. The method according to modality 153, in which the disease, disorder or condition is selected from the group consisting of a central nervous system disorder, inflammatory disease, autoimmune disease, infectious disease, a hearing loss condition, eye disease, musculoskeletal disease, metabolic disease, mitochondrial disease, hypertriglyceridemia, cancer, menopause and chronic overlapping pain conditions (COPCs), and psychological, physical, metabolic or hormonal stress and COPCs. 155. The method according to modality 154, in which the Petition 870250087689, dated 09 / 26 / 2025, page 62 / 421 52 / 233 CNS disorder is selected from the group consisting of a mood disorder, a trauma- and stress-related disorder, an anxiety disorder, obsessive-compulsive disorder, a neurodegenerative or neuroinflammatory disorder, a neurodevelopmental disorder, a leukodystrophy, and CNS oxidative stress. 156. The method according to modality 155, in which the mood disorder is a depressive disorder, a bipolar disorder, or a substance-induced disorder. 157. The method according to modality 156, in which the depressive disorder is a major depressive disorder (MDD). 158. The method according to modality 155, in which 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 modality 155, in which the anxiety disorder is panic disorder, generalized anxiety disorder (GAD), specific phobia, agoraphobia, or social phobia. 160. The method according to modality 155, in which 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, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), vanishing white matter disease, infantile ataxia with CNS hypomyelination, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, kuru, or dementia. 161. The method according to modality 155, in which the neurodevelopmental disorder is a deficit disorder of Petition 870250087689, dated 09 / 26 / 2025, page 63 / 421 53 / 233 Attention / Hyperactivity Disorder (ADHD), schizophrenia, Prader-Willi Syndrome (including hyperphagia and other symptoms (e.g., depression and anxiety)) or autism. 162. The method according to modality 155, in which leukodystrophy is leukoencephalopathy, a hypomyelinating or demyelinating disease, an intellectual disability syndrome, a cognitive impairment, a glial cell dysfunction, or a brain lesion. 163. The method according to modality 162, wherein cognitive impairment is age-related cognitive impairment, age-related cognitive decline (ARCD), age-associated memory impairment (AAMI), cognitive impairment associated with mild cognitive impairment, prodromal Alzheimer's disease or Alzheimer's disease, prodromal frontotemporal dementia (FTD) or FTD, prodromal posterior cortical atrophy (PCA) or PCA, cognitive impairment associated with schizophrenia, a drug-induced cognitive disorder, radiotherapy-induced cognitive dysfunction, space travel-related cognitive decline or cognitive deficit, and neuropathic pain associated with diabetes mellitus. 164. The method of modality 163, in which drug-induced cognitive impairment is corticosteroid-induced cognitive dysfunction, doxorubicin-induced cognitive dysfunction, chemotherapy-induced cognitive dysfunction, alcohol-induced cognitive dysfunction, or substance-induced cognitive dysfunction. 165. The method according to modality 162, wherein the brain injury is a traumatic brain injury, hypoxia-induced brain injury, toxin-induced brain injury, stroke, or reperfusion injury following ischemic stroke. 166. The method according to modality 154, in which the Petition 870250087689, dated 09 / 26 / 2025, p. 64 / 421 54 / 233 Inflammatory disease includes asthma, postoperative cognitive dysfunction, arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis. 167. The method according to modality 154, in which the autoimmune disease is Achalasia, Addison's disease, Adult-onset Still's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM / anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, 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), Balo's disease, Behçet's disease, Benign mucous pemphigoid, Bullous pemphigoid, Castleman's disease (CD), Celiac disease, Chagas disease, Polyneuropathy Chronic inflammatory demyelinating disease (ClDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), Cicatricial pemphigoid, Cogan syndrome, Cold agglutinin disease, Congenital heart block,Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis Petition 870250087689, dated 09 / 26 / 2025, page 65 / 421 55 / 233 Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's syndrome, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schönlein purpura (HSP), Gestational herpes or gestational pemphigoid (PG), Hidradenitis suppurativa (HS) (acne inversa), 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 Sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Ménière's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease.Multifocal Motor Neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neonatal lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Pars planitis (peripheral uveitis), Parsonage-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, Syndrome post-pericardiotomy, 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, restless legs syndrome (RLS), retroperitoneal fibrosis, Petition 870250087689, dated 09 / 26 / 2025, page 66 / 421 56 / 233 rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, testicular and spermatic autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (HHS), transverse myelitis, type 1 diabetes, 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 modality 154, in which the infectious disease is a viral infection or post-viral condition. 169. The method according to modality 154, where the hearing loss condition is non-syndromic mitochondrial hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or hereditary hearing loss, hearing loss resulting from exposure to ototoxic substances, hearing loss resulting from disease, or hearing loss resulting from trauma. 170. The method according to modality 154, in which 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 modality 154, in which the musculoskeletal disease is muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal cord spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, cramping fasciculation syndrome, Freidrich's ataxia, atrophy disorder Petition 870250087689, dated 09 / 26 / 2025, page 67 / 421 57 / 233 muscular, inclusion body myopathy, motor neuron disease or paralysis. 172. The method according to modality 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, phenylketonuria, proliferative retinopathy, and Keams-Sayre disease. 173. The method according to modality 154, in which the mitochondrial disease is Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Keams-Sayre syndrome (KSS), Leigh syndrome, mitochondrial DNA depletion syndromes (MDDS), mitochondrial encephalomyopathy, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with irregular red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber hereditary optic neuropathy (LHON), and Pearson syndrome. 174. The method according to modality 154, in which the cancer is glioblastoma or glioma. 175. A method for treating a disease, disorder, or condition modulated by, exacerbated by, or associated with altered activity of peroxisome proliferator-activated receptor (PPAR)-β and / or PPAR-γ and one or more symptoms associated therewith, in an individual who has experienced high stress, comprising administering to the individual a therapeutically effective amount of N-hydroxy-tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, or a pharmaceutically acceptable salt of any of them, according to any of embodiments 136 to 140, or N-nitroso-tianeptine, the (S)-enantiomer of N-nitrosotianeptine, or the (R)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt of any of them, according to any of embodiments 141 to 142. 145, or an analogue of tianeptine Petition 870250087689, dated 09 / 26 / 2025, p. 68 / 421 58 / 233 replaced by aryl or a pharmaceutically acceptable salt thereof, according to embodiment 146 or 147, or the pharmaceutical composition, according to any of embodiments 148 to 152. 176. The method according to modality 175, in which stress is caused by adversity early in life or by childhood trauma. 177. A method for treating a disease, disorder, or condition modulated by, exacerbated by, or associated with altered activity of peroxisome proliferator-activated receptor (PPAR)-β and / or PPAR-γ and one or more symptoms associated therewith, while reducing μ-opioid receptor agonism associated with racemic tianeptine treatment, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of N-hydroxy-tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, or a pharmaceutically acceptable salt thereof, according to any of embodiments 136 to 140, or N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or the (R)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt of either of them, according to any of the embodiments 141 to 145,or an aryl substituted tianeptine analogue or a pharmaceutically acceptable salt thereof according to embodiment 146 or 147 or the pharmaceutical composition according to any of embodiments 148 to 152. 178. A method for treating a disease, disorder, or condition selected from the group consisting of a central nervous system (CNS) disorder, asthma, primary biliary cholangitis, hypertriglyceridemia, cardiac hypertrophy, fibromyalgia, cancer, infectious disease, COVID-19, long COVID, menopause and overlapping chronic pain conditions (COPCs), psychological, physical, metabolic, or hormonal stress and Petition 870250087689, dated 09 / 26 / 2025, page 69 / 421 59 / 233 COPDs, and obesity, comprising administering to the individual a therapeutically effective amount of N-hydroxy-tianeptine, the (S)enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, or a pharmaceutically acceptable salt of any of the same, according to any of embodiments 136 to 140, or of N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or the (R)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt of any of the same, according to any of embodiments 141 to 145, or an aryl-substituted tianeptine analogue or a pharmaceutically acceptable salt thereof, according to embodiment 146 or 147, or the pharmaceutical composition according to any of embodiments 148 to 152. 179. The method according to any of the embodiments 153 to 178, wherein N-hydroxy-tianeptine, (S)-enantiomer of N-hydroxy-tianeptine, (R)-enantiomer of N-hydroxy-tianeptine, N-nitroso-tianeptine, (S)-enantiomer of N-nitroso-tianeptine, (R)-enantiomer of N-nitroso-tianeptine, or an aryl-substituted tianeptine analogue, or a pharmaceutically acceptable salt of any of them, or the pharmaceutical composition is administered once or more times daily. 180. The method according to embodiment 179, wherein N-hydroxy-tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or an aryl-substituted tianeptine analogue, or a pharmaceutically acceptable salt of any of the same, or the pharmaceutical composition is administered once daily. 181. The method according to any of the embodiments 153 to 180, wherein N-hydroxy-tianeptine, (S)-enantiomer of N-hydroxy-tianeptine, (R)-enantiomer of N-hydroxy-tianeptine, N Petition 870250087689, dated 09 / 26 / 2025, p. 70 / 421 60 / 233 nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or an aryl-substituted tianeptine analogue, or a pharmaceutically acceptable salt of any of them, or the pharmaceutical composition is administered parenterally, orally, sublingually, buccally, by inhalation, palatial route, transdermally, rectally or vaginally. 182. The method according to embodiments 153 to 181, wherein N-hydroxy-tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or an aryl-substituted tianeptine analogue, or a pharmaceutically acceptable salt of any of the same, or the pharmaceutical composition is administered sequentially or concomitantly with one or more additional therapeutic agents selected from the group consisting of an antidepressant, an anticonvulsant, an anxiolytic agent, an antipsychotic agent, a cholinesterase inhibitor, an N-methyl-D-aspartate (NMDA) receptor antagonist, a 5HT2 modulator, a corticosteroid, an anti-amyloid agent, an anti-tau agent, and a chemotherapeutic agent. 183. The method according to embodiments 153 to 181, wherein N-hydroxy-tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or an aryl-substituted tianeptine analogue, or a pharmaceutically acceptable salt of any of the same, or the pharmaceutical composition is administered as part of a treatment regimen that also includes psychotherapeutic intervention. 184. A crystalline hemioxalate salt of (S)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ylamino)heptanoic acid dioxide ((S)-tianeptine), wherein the salt exhibits a pattern of Petition 870250087689, dated 09 / 26 / 2025, page 71 / 421 61 / 233 X-ray diffraction (XRPD) comprising at least one peak selected between 8.5, 20.6, 21.0 and 24.2 degrees 20 ± 0.3 degrees 20. 185. The crystalline 11-D-(S)-tianeptine hemioxalate salt, according to embodiment 184, wherein the salt exhibits an XRPD pattern also comprising at least one selected peak from the group consisting of 12.1,13.3,16.1,18.9,19.1,22,0 and 22.4 degrees 20 ±0.3 degrees 20. 186. A crystalline free base / free acid of the (S)-enantiomer of tianeptine, according to embodiment 1, wherein the crystalline (S)-enantiomer of tianeptine exhibits an X-ray diffraction pattern (XRPD) comprising at least one peak selected from 10.6, 13.0, 21.1 and 23.7 degrees 20 ± 0.3 degrees 20. 187. The crystalline free base / free acid of the (S)-enantiomer of tianeptine according to embodiment 186, wherein the crystalline free base / free acid of the (S)-enantiomer of tianeptine exhibits an XRPD pattern also comprising at least one selected peak from the group consisting of 8.7, 9.1, 12.6, 18.1, 20.4, 23.0 and 26.1 degrees 20 ± 0.3 degrees 20. BRIEF DESCRIPTION OF THE FIGURES

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

[0014] Figures 2A and 2B show the crystal structures of the tianeptine enantiomer, which has an optical rotation (-) like the sodium salt, complexed with L-dibenzoyltartaric acid (DBTA). Figure 2A shows the crystal structure of the (S)-tianeptine salt: 0.5 L-DBTA. Figure 2B shows a different crystal isoform of the 11-D-(S)-tianeptine enantiomer with L-DBTA ((S)-tianeptine: 0.5 L-DBTA). Petition 870250087689, dated 09 / 26 / 2025, p. 72 / 421 62 / 233

[0015] Figures 3A and 3B show graphs of the inhibition of cyclic adenosine 3,5-monophosphate (cAMP) using varying concentrations of [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO), racemic tianeptine, and 99.0% to 99.35% pure 11-D-(S)-tianeptine oxalate or 98.5% to 99.35% pure (R)-tianeptine oxalate at the μ-opioid receptor. Figure 3A shows a graph of cAMP inhibition at steady state. Figure 3B shows a graph of the initial rate of cAMP inhibition. NFU is a normalized fluorescence unit.

[0016] Figures 4A and 4B show concentration-response curve graphs illustrating the mean arrestin recruitment using varying concentrations of DAMGO, racemic tianeptine, and 99.0% to 99.35% pure 11-D-(S)-tianeptine oxalate or 98.5% to 99.35% pure (R)-tianeptine oxalate at the μ-opioid receptor. Figure 4A shows the steady-state arrestin recruitment response. Figure 4B shows the initial arrestin recruitment rate analysis.

[0017] Figures 5A and 5B show concentration-response curve graphs of the percentage of cAMP inhibition using varying logarithmic (M) concentrations of DAMGO, racemic tianeptine, and (S) 99.35% pure tianeptine sodium or (R)-tianeptine sodium at the μopioid receptor. The graphs show the analysis of the initial rate of cAMP inhibition (Figure 5A) and the analysis of the maximum cAMP inhibition effect (Figure 5B).

[0018] Figures 6A and 6B show concentration-response curve graphs of the percentage of cAMP inhibition using varying logarithmic (M) concentrations of DAMGO, racemic tianeptine, racemic sodium tianeptine, and 99.0% to 99.35% pure 11-D-(S)-tianeptine sodium or 98.5% to 99.35% pure (R)-tianeptine sodium at the μopioid receptor. The graphs show the analysis of the initial rate of cAMP inhibition (Figure 6A) and the analysis of the maximum cAMP inhibition effect (Figure 6B). Petition 870250087689, dated 09 / 26 / 2025, page 73 / 421 63 / 233

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

[0020] Figures 8A and 8B show graphs describing tianeptine agonism at the μ-opioid receptor using varying logarithmic concentrations (M) of DAMGO and (S)-99.9% pure tianeptine sodium or (R)-tianeptine sodium. The graphs show the peak of cAMP inhibition (Figure 8A) and the peak of recruitment disruption (Figure 8B).

[0021] Figures 9A to 9D show graphs depicting the activity of racemic tianeptine, racemic tianeptine oxalate, (S)-tianeptine and (R)-tianeptine (99.9% chiral purity), the positive control PPAR-β / δ agonist GW0742, the PPAR-β / δ agonist Seladelpar and dimethyl sulfoxide (DMSO, negative control) and at the peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ). Figures 9B and 9D show an enlarged view of PPAR-β / δ activation by (S)-tianeptine at ~3 μM.

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

[0023] Figures 11A and 11B show graphs describing the activity of racemic tianeptine, racemic tianeptine oxalate, (S)tianeptine and (R)-tianeptine (99.9% chiral purity), the positive control PPAR-α agonist GW7647, and the PPAR-β / δ agonist Seladelpar. Petition 870250087689, dated 09 / 26 / 2025, page 74 / 421 64 / 233 and DMSO (negative control) and peroxisome proliferator-activated receptor α (PPAR-α).

[0024] Figure 12 depicts the superposition of the crystal structure of PPAR-δ / β in complex with the ligand GW2331 with a computational model of PPAR-δ / β in complex with (S)-tianeptine and a computational model of PPAR-δ / β in complex with (R)-tianeptine.

[0025] Figures 13A and 13B show the computational modeling of (S)-tianeptine coupled to PPAR-δ / β (Figure 13A) and (R)-tianeptine coupled to PPAR-δ / β (Figure 13B), representing the formation of a carbon-sulfur (CS) covalent bond between (S)-tianeptine and cysteine ​​285 of PPAR-δ / β. The bond length between (S)-tianeptine and Cys285 of PPAR-δ / β is 5.00 Å (Figure 13A) and the bond length between (R)-tianeptine and Cys285 of PPAR-δ / β is 7.92 Å (Figure 13B).

[0026] Figures 14A to 14F show graphs describing the effects of (S)-tianeptine zwitterion and (R)-tianeptine zwitterion (99.9% chiral purity) on the growth of neurites from cultured glutamatergic neurons. Figures 14A and 14B represent the mean neurite length (pm) at 24 hours (Figure 14A) and 72 hours (Figure 14B) after treatment. Figures 14C and 14D represent the total neurite length (pm) (Figure 14C) and the mean neurite width (nm) (Figure 14D) at 5 days after treatment with (S)tianeptine zwitterion (99.9% chiral purity). Figures 14E and 14F represent the total neurite length (pm) (Figure 14E) and the mean neurite width (nm) (Figure 14F) 5 days after treatment with zwitterion of (R)-tianeptine (99.9% chiral purity). Data were normalized to the 1% PBS control and compared using strictly standardized mean difference (SSMD). p-value: *p<0.05.

[0027] Figures 15A to 15D show graphs describing the effects of the (S)-tianeptine zwitterion and the (R)-tianeptine zwitterion. Petition 870250087689, dated 09 / 26 / 2025, page 75 / 421 65 / 233 (99.9% chiral purity) mitochondrial staining (MitoTracker) was performed on cultured glutamatergic neurons 5 days after treatment. Figures 15A and 15B depict mitochondrial staining in cell bodies (Figure 15A) and neurites (Figure 15B) after treatment with the (S)-tianeptine zwitterion (99.9% chiral purity). Figures 15C and 15D depict mitochondrial staining in cell bodies (Figure 15C) and neurites (Figure 15D) after treatment with the (R)-tianeptine zwitterion (99.9% chiral purity). Data were normalized to a 1% PBS control and compared using strictly standardized mean difference (SSMD). p-value: *p<0.05. RFU = Relative Fluorescence Units

[0028] Figures 16A to 16C show graphs describing the effects of racemic tianeptine sodium (Figure 16A), (S)-tianeptine sodium (99.9% chiral purity, Figure 16B) and (R)-tianeptine sodium (99.9% chiral purity, Figure 16C) on a novel object recognition test (NOR). ANOVA test p-values: ***p<0.001, **p<0.1, *p<0.05.

[0029] Figures 17A-17F show graphs describing the effects of racemic tianeptine sodium (Figure 17A-17B), (R)-tianeptine sodium (99.9% chiral purity, Figure 17C-17D) and (S)-tianeptine sodium (99.9% chiral purity, Figure 17E-17F) in a forced swim test (FST). Figures 17A, 17C and 17E show the timeline of time spent motionless over 6 minutes. Figures 17B, 17D and 17F show the total time spent motionless during the 6-minute test. ANOVA p-values: ***p<0.001, *p<0.05.

[0030] Figures 18A to 18D show graphs describing the XRPD patterns of crystalline 11-D-(S)-tianeptine (Figure 18A), crystalline 11-D-(S)-tianeptine hemioxalate (Figure 18B), amorphous sodium (S)-tianeptine (Figure 18C), and a comparison of the three XRPDs with the racemic tianeptine hemioxalate XRPD (Figure 18D). Petition 870250087689, dated 09 / 26 / 2025, page 76 / 421 66 / 233 DETAILED DESCRIPTION

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

[0032] In other embodiments, this invention provides tianeptine analogs, including N-hydroxy-tianeptine, the (S)- and (R)-enantiomers of N-hydroxy-tianeptine (i.e., N-hydroxy-(S)-tianeptine or N-hydroxy-(R)-tianeptine), N-nitroso-tianeptine, the (S)- and (R)-enantiomers of N-nitrosotianeptine (i.e., N-nitroso-(S)-tianeptine or N-nitroso-(R)-tianeptine), an aryl-substituted tianeptine analog, and its pharmaceutically acceptable salts. In some embodiments, the (S)-enantiomers of N-hydroxy-tianeptine or N-nitroso-tianeptine are characterized by comprising < 2% of the corresponding (R)-enantiomer. In some embodiments, (S)-enantiomers of N-hydroxy-tianeptine or N-nitroso Petition 870250087689, dated 09 / 26 / 2025, p. 77 / 421 67 / 233 tianeptine are characterized by comprising < 0.1% of the corresponding (R)-enantiomer. In some embodiments, the (R)-enantiomers of N-hydroxy-tianeptine or N-nitroso-tianeptine are characterized by comprising < 2% of the corresponding (S)-enantiomer. In some embodiments, the (R)-enantiomers of N-hydroxy-tianeptine or N-nitroso-tianeptine are characterized by comprising < 0.1% of the corresponding (S)-enantiomer.

[0033] In some embodiments, this invention provides a pharmaceutical composition comprising one or more of the (S)-enantiomers or their crystalline form, zwitterions, cocrystals, esters, amides, analogs or salts of this invention, the compositions comprising < 2% of the corresponding (R)-enantiomer. In some embodiments, the pharmaceutical composition comprises < 0.1% of the corresponding (R)-enantiomer.

[0034] In some embodiments, this invention provides methods for treating selected diseases, disorders or conditions from the group consisting of a central nervous system (CNS) disorder, inflammatory disease, autoimmune disease, infectious disease, a hearing loss condition, eye disease, musculoskeletal disease, metabolic disease, mitochondrial disease, hypertriglyceridemia, cancer, menopause and overlapping chronic pain conditions (COPCs), and psychological, physical, metabolic or hormonal stress and COPCs and associated symptoms in an individual in need thereof, by administering the (S)-enantiomers (i.e., the (S)-enantiomer of tianeptine and / or the 11-D-(S)-enantiomer of tianeptine) or crystalline forms thereof, zwitterions, esters, amides, salts, analogues and compositions of this invention. In some modalities, diseases, disorders, or conditions are modulated, exacerbated, or associated with altered PPAR-β / δ and / or PPAR-γ activity.In some modalities, diseases, disorders, or conditions are modulated, exacerbated, or associated with high levels of S-nitrosylation of PPAR-β / δ and / or PPAR-γ. In some modalities, diseases... Petition 870250087689, dated 09 / 26 / 2025, p. 78 / 421 68 / 233 Diseases, disorders, or conditions are modulated, exacerbated, or associated with excessive levels of circulating metal ions. In some modalities, diseases, disorders, or conditions are modulated, exacerbated, or associated with stress.

[0035] In some embodiments, the methods minimize the potential for opioid abuse as a result of administering the (S)-enantiomers (i.e., the (S)-enantiomer of tianeptine and / or the 11-D-(S)-enantiomer of tianeptine) or crystalline forms thereof, zwitterions, esters, amides, pharmaceutically acceptable analogs or salts thereof, or compositions comprising them, of this invention.

[0036] In other embodiments, the invention provides methods for producing the tianeptine (S)-enantiomer and / or the 11-D-(S)-tianeptine enantiomer of this invention.

[0037] The practice of the various modalities described here employs, unless otherwise indicated, conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA, and related fields, according to the experience of the technique. These techniques are fully explained in the literature. Definitions

[0038] The term “here” means the entirety of the request.

[0039] Unless otherwise indicated, the scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. In case of conflict, this descriptive report, including the definitions, shall prevail.

[0040] It should be understood that any of the embodiments described herein, including those described in different aspects of the invention and in different parts of the descriptive report (including the embodiments described only in the Examples), may be combined with a Petition 870250087689, dated 09 / 26 / 2025, p. 79 / 421 69 / 233 or other embodiments of this invention, unless explicitly disclaimed or improper, are thus described as embodiments of the invention. The combination of embodiments is not limited to the specific combinations described in the multiple dependent embodiments of this invention.

[0041] All published publications, patents and patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, this descriptive report, including its specific definitions, shall prevail.

[0042] Throughout this descriptive report, the word “comprise” or variations such as “comprises” or “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional elements or steps of the method not mentioned.

[0043] Any examples following the term “for example.” or “for instance” should not be exhaustive or limiting.

[0044] The term “including” or “includes” is used to mean “including, but not limited to”. “Including” and “including, but not limited to” are used interchangeably.

[0045] Unless the context requires otherwise, singular terms should include plurals and plural terms should include the singular.

[0046] The articles “a”, “an” and “the” are used here to refer to one or more of a (i.e., at least one) grammatical object of the article.

[0047] As used herein, the meaning of the term “about” depends on the context in which it is used. When used in relation to the modification of the quantity of an ingredient, parameter, calculation or measurement in the compositions employed in the methods of the invention, it refers to the variation in numerical quantity that may occur, for example, by means of Petition 870250087689, dated 09 / 26 / 2025, page 80 / 421 70 / 233 of typical liquid measurement and handling procedures used for the manufacture of the compounds of this invention or pharmaceutical compositions in the real world; due to inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to produce the enantiomer or compositions of this invention or to perform the methods; and the typical + / - variation of any amount or use without having a substantial effect on the chemical or physical attributes of the compounds, compositions, or methods of the invention. Such variation may typically be 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 amounts that differ due to different equilibrium conditions for a composition resulting from a specific initial mixture. Modified or not by the term about, the paragraphs include equivalents to the amounts.The reference to about a value or parameter here includes (and describes) modalities that are directed to that value or parameter itself. For example, the description referring to about X includes the description of X. Numerical ranges include the numbers that define the range. When used in relation to the position of a peak in a powder X-ray diffraction (XRPD) pattern, the term about includes peaks within an associated tolerance of ± 0.3 degrees 20. For example, as used here, an XRPD peak at about 10.0 degrees 20 means that the stated peak occurs from 9.7 to 10.3 degrees 20. When used in relation to the position of a peak in a solid-state 13C NMR spectrum, the term about includes peaks within ± 0.2 ppm of the stated position. For example, as used here, a 13C NMR spectrum peak at approximately 100.0 ppm means that the stated peak occurs from 99.8 to 100.2 ppm.

[0048] As used herein, the term “substantially” in reference to an XRPD standard refers to a spectrum having at least 4, 5, 6, Petition 870250087689, dated 09 / 26 / 2025, page 81 / 421 71 / 233 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks (perhaps differing in amplitude) in common with the referenced standard; or a standard having a tolerance of ± 0.3 degrees within the referenced peaks. In reference to an NMR standard, “substantially” refers to a spectrum having at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks (perhaps differing in amplitude) in common with the referenced standard; or a standard having a tolerance of ± 0.2 ppm within the referenced peaks. In reference to an FT-IR standard, "substantially" refers to a spectrum with at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks (perhaps differing in amplitude) in common with the referenced standard; or a standard with a tolerance of ± 0.5 cm-1 within the referenced peaks.

[0049] The term “or”, as used here, should be understood as “and / or”, unless the context clearly indicates otherwise.

[0050] Although the ranges and numerical parameters described are approximations, the numerical values ​​presented in the specific examples are reported to the greatest extent possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in its respective test measurements. Furthermore, all ranges described herein should be understood as encompassing any and all sub-ranges included therein. For example, a stated range of “1 to 10” should be considered as including any and all sub-ranges between (and including) the minimum value of 1 and the maximum value of 10; that is, all sub-ranges that begin with a minimum value of 1 or more, for example, 1 to 6.1, and end with a maximum value of 10 or less, for example, 5.5 to 10.

[0051] When aspects or embodiments are described in terms of a Markush group or other grouping of alternatives, the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups. Petition 870250087689, dated 09 / 26 / 2025, page 82 / 421 72 / 233 of the main group, and also the main group in the absence of one or more members of the group, although such individuals and subgroups are not specifically mentioned in this description.

[0052] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the various aspects and modalities. The materials, methods and examples are for illustrative purposes only and should not be considered limiting.

[0053] In order to make the description easier to understand, certain terms are defined first. These definitions should be read in the light of the rest of the description, as understood by a person skilled in the art. Unless otherwise indicated, all technical and scientific terms used herein have the same meaning commonly understood by a person skilled in the art. Additional definitions are provided throughout the detailed description.

[0054] As used herein, the term “treat” and its cognates refer to a total or partial improvement or modulation of the symptoms or pathology of a disease, disorder, or condition, particularly those that can be effected using the compounds and compositions of this invention, and may include, but are not limited to, even minimal changes or improvements in one or more measurable markers of the disease, disorder, or condition to be treated. “Treat” also refers to delaying the onset, slowing or reversing the progression, reducing the severity, alleviating, or preventing the disease, disorder, or condition to which the term applies, or one or more symptoms of such disease, disorder, or condition, for example, and without limitation, slowing or reducing the rate of decline in cognitive function in age-related cognitive decline.

[0055] “Treating cognitive impairment” refers to taking steps to improve cognitive function in an individual with impaired cognitive function. Petition 870250087689, dated 09 / 26 / 2025, p. 83 / 421 73 / 233 Cognitive impairment, so that the individual's performance on one or more cognitive tests is enhanced to any detectable degree, or is prevented from further decline, or the rate of such decline is reduced. Preferably, the cognitive function of this individual, after treatment of cognitive impairment, more closely resembles the function of a normal, unimpaired individual. Treatment of cognitive impairment in humans can improve cognitive function to any detectable degree, but is preferably enhanced enough to enable the impaired individual to perform normal daily life activities at a level of proficiency similar to that of a normal, unimpaired individual.In some cases, treating cognitive impairment refers to taking steps to improve cognitive function in an individual with cognitive impairment, so that the individual's performance on one or more cognitive tests is improved to any detectable degree, further decline is prevented, or the rate of such decline is reduced. Preferably, the cognitive function of this individual, after treatment of cognitive impairment, more closely resembles the function of a normal, unimpaired individual. In some cases, treating cognitive impairment in an individual affected by age-related cognitive impairment refers to taking steps to improve the individual's cognitive function, so that the individual's cognitive function, after treatment of cognitive impairment, more closely resembles the function of a normal, unimpaired individual of the same age, or the function of a young adult individual.In some cases, treating cognitive impairment in an individual refers to taking steps to slow or reduce the progression of cognitive impairment in an individual with cognitive impairment. In some cases, treating cognitive impairment in an individual refers to taking steps to reduce it. Petition 870250087689, dated 09 / 26 / 2025, page 84 / 421 74 / 233 is the rate of decline in cognitive function in an individual with cognitive impairment.

[0056] As used herein, the terms “subject,” “patient,” or “individual” are used interchangeably and include both human beings and non-human mammals. Non-human mammals include cattle, sheep, pigs, horses, dogs, cats, and rodents (e.g., rat, mouse, guinea pig, and rabbit). Preferably, the individual is a human being.

[0057] As used herein, the term “(S)-enantiomers of tianeptine” refers to the (S)-enantiomer of tianeptine or crystalline forms thereof, zwitterion thereof, a pharmaceutically acceptable salt of the (S)-enantiomer or crystalline forms thereof, a cocrystal of the (S)-enantiomer or zwitterion thereof, an ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or an amide of the (S)-enantiomer or its pharmaceutically acceptable salt, or 11-D(S)-enantiomer, crystalline forms thereof, zwitterion thereof, a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, a cocrystal of the 11-D-(S)-enantiomer or zwitterion thereof, an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof.

[0058] As used herein, “therapeutically effective amount” of the tianeptine (S)-enantiomers of this invention, or compositions of this invention, refers to the amount used to treat, prevent, or alleviate one or more symptoms of a disease or disorder of this invention. In some embodiments, the disease or disorder, or one or more symptoms of a disease or disorder, are modulated, exacerbated, or associated with altered PPAR-β / δ and / or PPAR-γ activity. In some embodiments, some of the diseases or disorders are associated with stress or the presence of excess metal ions. Someone skilled in the art can easily determine a therapeutic amount. Petition 870250087689, dated 09 / 26 / 2025, p. 85 / 421 75 / 233 effective of the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 1 1D-(S)-enantiomer) of this invention, zwitterions, pharmaceutically acceptable salts of the (S)-enantiomers of this invention to be administered, taking into account factors such as size, weight, age and sex of the individual, the extent of penetration or persistence of the disease and the severity of the symptoms, and the route of administration.Generally, a therapeutically effective amount of the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 11-D-(S)-enantiomer) of this invention, zwitterions, pharmaceutically acceptable salts of the (S)-enantiomers of this invention, administered to an individual, is between about 1 mg / day and about 5,000 mg / day, between about 1 mg / day and about 4,000 mg / day, between about 1 mg / day and about 3,000 mg / day, between about 1 mg / day and about 2,000 mg / day, between about 1 mg / day and about 1,000 mg / day, between about 2 mg / day and about 600 mg / day, between about 10 mg / day and about 400 mg / day, or between about 25 mg / day and 300 mg / day. mg / day. Higher or lower doses are also considered.

[0059] As used herein, “pharmaceutically acceptable vehicle” refers to any diluent or excipient that is compatible with the other ingredients in the formulation and is not harmful to the recipient. The pharmaceutically acceptable vehicle 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-superimposable isomers of a compound with at least one chiral / asymmetric atom. Each enantiomer is optically active in the context of its ability to rotate light. Individual enantiomers are designated according to the Cahn-Ingold-Prelog system, which is a well-known set of priority rules for classifying the four groups attached to an asymmetric carbon. See, for example, Petition 870250087689, dated 09 / 26 / 2025, page 86 / 421 76 / 233 March, Advanced Organic Chemistry. 4th Ed., (1992), p. 109, the full description of which is incorporated here by reference.

[0061] As used herein, “optically active” refers to a property whereby a material rotates the plane of plane-polarized light. An isomer or enantiomer that is optically active does not superimposable on its mirror image. As used herein, the property of non-superimposability of an object on its mirror image is called “chirality.” The most common structural feature that produces chirality is an asymmetric carbon atom, that is, a carbon atom with four non-equivalent groups attached to it.

[0062] As used herein, “racemate” or “racemic compound” refers to a 50-50 mixture of two enantiomers, such that the mixture does not rotate plane-polarized light and can, in many cases, be separated into 2 peaks of equal weight by various means, including chromatography.

[0063] As used herein, the term “substantially pure” or “pure” refers to an enantiomer or composition comprising it, comprising no more than 2% of the homologous enantiomer. In some embodiments, the substantially pure (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or the 1 1D-(S)-enantiomer) of this invention, their zwitterions, pharmaceutically acceptable salts of the (S)enantiomers, or compositions of this invention comprise no more than about 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the equivalent (R)-enantiomers of tianeptine (i.e., the (R)-enantiomer or the 1 1D-(R)-enantiomer), zwitterions, or pharmaceutically acceptable salts of the (R)-enantiomers.

[0064] As used herein, the term “chiral purity” refers to the extent to which a mixture of enantiomers comprises one enantiomer over the other.

[0065] As used herein, the term “cocrystal” is distinct from a salt and Petition 870250087689, dated 09 / 26 / 2025, page 87 / 421 77 / 233 refers to a solid crystalline supramolecular complex composed of two or more components within the same crystal lattice, where the components are in a neutral state and interact through non-ionic interactions. The ability of an active pharmaceutical ingredient (API) and coformer to form a cocrystal can be predicted by determining the ApKa value. When the ApKa of the API and coformer is negative (<0), there is no proton transfer, indicating that the system will form a cocrystal; conversely, when the ApKa is above 3, there is total proton transfer, indicating that the system forms a salt. Frequently, the ApKa is between 0 and 3, in which only partial proton transfer occurs, so the system is commonly called a salt cocrystal (Nugrahani & Jessica. Molecules. 2021).

[0066] As used herein, the term “μ-opioid receptor assay” or “MOR assay” refers to a methodology for analyzing the activity of the G protein-coupled receptor signaling pathway in response to ligand binding at the μ-opioid receptor.

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

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

[0069] As used herein, the terms “β-arrestina” and “arrestina” are used interchangeably.

[0070] As used herein, the term “m / z” refers to the mass-to-load ratio.

[0071] As used herein, the term “retention time” refers to the interval between sample injection and detection of substances in that sample.

[0072] As used herein, the term “neurite growth” refers to the process by which developing neurons produce new Petition 870250087689, dated 09 / 26 / 2025, p. 88 / 421 78 / 233 projections, called neurites, in response to orientation signals.

[0073]

[0073] as used herein, the term “aryl” refers to any functional group or substituent derived from an aromatic ring, with 5 to 7 atoms in the ring, including 1 to 4 heteroatoms selected from the group consisting of carbon, nitrogen, sulfur, or oxygen. The aryl group may be added at any possible position in the tianeptines (S) or (R) of this description.

[0074]

[0074] as used herein, the term “alkyl” refers to a saturated, linear or branched monovalent hydrocarbon radical of any length from one to six carbon atoms (C1-C6), wherein the alkyl radical may be optionally substituted independently by one or more substituents.

[0075] As used herein, the term “analog” refers to a compound related to tianeptine but with an altered chemical structure. For example, the tianeptine analog may comprise additional functional groups, including hydroxyl, nitroso, or aryl groups. The tianeptine analogs of this invention include N-hydroxy-tianeptine, its (S)- and (R)-enantiomers, N-nitroso-tianeptine, its (S)- and (R)-enantiomers, aryl-substituted tianeptine analogs, or pharmaceutically acceptable salts. Enantiomers of (S)-tianeptine

[0076] In some aspects, this invention provides the (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepine-11-ylamino)heptanoic acid ((S)-enantiomer of tianeptine) or a zwitterion thereof, 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 characterized by comprising no more than about 2% (i.e., < about 2%) of the (R)-enantiomer or zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer. In some ways Petition 870250087689, dated 09 / 26 / 2025, page 89 / 421 79 / 233 embodiments, the (S)-enantiomer, zwitterion or a pharmaceutically acceptable salt of the (S)-enantiomer are characterized by comprising no more than about 1% (i.e., < about 1%) of the (R)-enantiomer of tianeptine or of the zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer, zwitterion or a pharmaceutically acceptable salt of the (S)-enantiomer are characterized by comprising no more than about 0.9% (i.e., < about 0.9%) of the (R)-enantiomer of tianeptine or of the zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer is characterized by comprising no more than about 0.8% (i.e., < about 0.8%) of the (R)-enantiomer of tianeptine or the zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the (S)-enantiomer, the zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer are characterized by comprising no more than about 0.7% (i.e., < about 0.7%) of the (R)-enantiomer of tianeptine or the zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer, the zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer are characterized by comprising no more than about 0.6% (i.e., < about 0.6%) of the (R)-enantiomer of tianeptine or the zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer is characterized by comprising no more than about 0.5% (i.e., < about 0.5%) of the tianeptine (R)-enantiomer or zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the (S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer are characterized by... Petition 870250087689, dated 09 / 26 / 2025, p. 90 / 421 80 / 233 comprising no more than about 0.4% (i.e., < about 0.4%) of the (R)-enantiomer of tianeptine or of the zwitterion thereof, or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer, zwitterion or a pharmaceutically acceptable salt of the (S)-enantiomer are characterized by comprising no more than about 0.3% (i.e., < about 0.3%) of the (R)-enantiomer of tianeptine or of the zwitterion thereof, or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer is characterized by comprising no more than about 0.2% (i.e., < about 0.2%) of the tianeptine (R)-enantiomer or zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the (S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the (S)-enantiomer is characterized by comprising no more than about 0.1% (i.e., < about 0.1%) of the tianeptine (R)-enantiomer or zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer.

[0077] In some embodiments, the (S)-enantiomer of this invention is in the form of a pharmaceutically acceptable salt or a crystalline form thereof. In some embodiments, the (S)-tianeptine of this invention is in the form of a zwitterion.

[0078] In some respects, this invention provides an (S)-enantiomer 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)-enantiomer of tianeptine), the zwitterion thereof 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, the zwitterion or the pharmaceutically acceptable salt are characterized by comprising no more than about 2% (i.e., < about 2%) of the 11-D-(R)-enantiomer or zwitterion thereof or a pharmaceutically acceptable salt of the Petition 870250087689, dated 09 / 26 / 2025, p. 91 / 421 81 / 233 11-D-(R)-enantiomer. In some embodiments, the 11-D-(S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is characterized by comprising no more than about 1% (i.e., < about 1%) of the 11-D-(R)-enantiomer of tianeptine or the zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the 11-D-(S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is characterized by comprising no more than about 0.9% (i.e., < about 0.9%) of the 11-D-(R)-enantiomer of tianeptine or its zwitterion, or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the 11-D-(S)-enantiomer, the zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer are characterized by comprising no more than about 0.8% (i.e., < about 0.8%) of the 11-D-(R)-enantiomer of tianeptine or the zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the 11-D-(S)-enantiomer, the zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer are characterized by comprising no more than about 0.7% (i.e., < about 0.7%) of the 11-D-(R)-enantiomer of tianeptine or the zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the 11-D-(S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is characterized by comprising no more than about 0.6% (i.e., < about 0.6%) of the 11-D-(R)-enantiomer of tianeptine or its zwitterion, or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the 11-D-(S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is characterized by comprising no more than about 0.5% (i.e., < about 0.5%) of the 11-D-(R)-enantiomer of tianeptine or its zwitterion, or a pharmaceutically acceptable salt. Petition 870250087689, dated 09 / 26 / 2025, p. 92 / 421 82 / 233 acceptable of this enantiomer. In some embodiments, the 11-D-(S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the 11D-(S)-enantiomer are characterized by comprising no more than about 0.4% (i.e., < about 0.4%) of the 11-D-(R)-enantiomer of tianeptine or the zwitterion thereof, or a pharmaceutically acceptable salt of this enantiomer. In some embodiments, the 11-D(S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is characterized by comprising no more than about 0.3% (i.e., < about 0.3%) of the 11-D-(R)-enantiomer of tianeptine or its zwitterion, or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the 11-D(S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is characterized by comprising no more than about 0.2% (i.e., < about 0.2%) of the 11-D-(R)-enantiomer of tianeptine or its zwitterion, or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the 11-D-(S)-enantiomer, zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is characterized by comprising no more than about 0.1% (i.e., < about 0.1%) of the 11-D-(R)-enantiomer of tianeptine or its zwitterion, or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, 11-D-(S)-tianeptine, its zwitterion, or a pharmaceutically acceptable salt of either, is characterized by reduced racemization at position 11 compared with 11-D-(S)-tianeptine, its zwitterion, or a pharmaceutically acceptable salt of either.

[0079] In some embodiments, the 11-D-(S)-tianeptine of this invention is in the form of a pharmaceutically acceptable salt or a crystalline form thereof. In some embodiments, the 11-D-(S)-tianeptine of this invention is in the form of a zwitterion.

[0080] In some embodiments, 11-D-(S)-enantiomer, zwitter Petition 870250087689, dated 09 / 26 / 2025, p. 93 / 421 83 / 233 A ion of the same or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is deuterated at the two 3' positions and optionally deuterated at other positions in the amino-heptanoic side chain. In some embodiments, the 11-D-(S)-enantiomer is 3', 3', 4', 4', 11-pentadeuterotianeptine of General Formula (Illa) or a zwitterion thereof, of Formula (lllb); 2', 2', 3', 3', 4', 4', 5', 5', 6', 6', 7', 7', 11-tridecadeuterotianeptine (of General Formula (IVa)) or a zwitterion thereof, of Formula (IVb); 3', 3', 4', 4', tetradeuterotianeptine of the general formula (Va) or the zwitterion thereof, of formula (Vb) or 2', 2', 3', 3', 4', 4', 5', 5', 6', 6', 7', 7', dodecadeuterotianeptine of the general formula (Via) or the zwitterion thereof, of formula (Vlb). In some embodiments, the 11-D-(S)-enantiomer is 3', 3', 4', 4', 11-pentadeuterotianeptine of the general formula (llla) or the zwitterion thereof, of formula (lllb).In some embodiments, the 11-D-(S)-enantiomer is 2', 2', 3', 3', 4', 4', 5', 5', 6', 6', 7', 7', 11-tridecadeuterotianeptine of General Formula (IVa) or a zwitterion thereof, of Formula (IVb). In some embodiments, the 11-D-(S)-enantiomer is 3', 3', 4', 4', tetradeuterotianeptine of General Formula (Va) or a zwitterion thereof, of Formula (Vb). In some embodiments, the 11-D-(S)-enantiomer is 2',2',3',3',4',4',5',5',6',6',7',7',dodecadeuterotianeptine of the general formula (Via) or the zwitterion of the general formula (Vlb). Formula (Va) Formula (Vb) Formula (Via) Formula (Vlb) Petition 870250087689, dated 09 / 26 / 2025, p. 94 / 421 84 / 233

[0081] Methods for producing the compounds described herein as pharmaceutically acceptable salts of the (S)-enantiomers of this invention, and the like, are well known to those skilled in the art. For example, salts can be prepared from the free base using conventional methodology that typically involves reaction with a suitable acid.Suitable acids for preparing acid addition salts include, but are not limited to, both organic acids, for example, acetic, propionic, glycolic, gluconic, glucuronic, glutamic, pyruvic, oxalic, lactic, malic, malonic, succinic, maleic, fumaric, formic, tartaric, citric, aspartic, ascorbic, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic, salicylic, orotic, hippuric, anthranilic, mesylic, 4-hydroxybenzoic, 2-hydroxyethanesulfonic, phenylacetic, mandelic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, beta-hydroxybutyric, camphorsulfonic, galactaric and galacturonic and the like, as well as inorganic acids, for example, Hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric and similar compounds. On the other hand, the preparation of basic salts of the S-enantiomers described here can be carried out in a similar manner, using a pharmaceutically acceptable base.Suitable pharmaceutically acceptable base addition salts of the (S)-enantiomers of this invention include metallic salts made of calcium, magnesium, potassium, sodium, ammonium and zinc or the like, or organic salts made of N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine and trimethylamine or the like.

[0082] In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomers and crystalline forms thereof of this invention is (S)-tianeptine benzenesulfonate (1:1), (S)-tianeptine fumarate (1:1), (S)-tianeptine fumarate (2:1), (S)-tianeptine hippurate (1:1), (S)-tianeptine maleate (1:1), (S)-tianeptine maleate (2:1), p Petition 870250087689, dated 09 / 26 / 2025, page 95 / 421 85 / 233 (S)-tianeptine toluenesulfonate (1:1), (S)-tianeptine orotate (1:1), (S)-tianeptine camphorsulfonate (1:1), (S)-tianeptine N-acetyl-L-tyrosinate (1:1), (S)-tianeptine polyesterix, (S)-tianeptine:L-DBTA (2:1), (S)-tianeptine sodium, (S)-tianeptine oxalate, or (S)-tianeptine oxalate (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine benzenesulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine fumarate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine fumarate (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine hippurate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine maleate (1:1).In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine maleate (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine p-toluenesulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine orotate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine camphorsulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine N-acetylL-tyrosinate (1:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is the polyesterix of (S)-tianeptine. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine: L-DBTA (2:1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine sodium.In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine oxalate. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine oxalate (2:1) (i.e., (S)-tianeptine hemioxalate). Petition 870250087689, dated 09 / 26 / 2025, p. 96 / 421 86 / 233 In some forms, the hemioxalate salt is in a crystalline form.

[0083] In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer and crystalline forms thereof of this invention is 11-D-(S)-tianeptine benzenesulfonate (1:1), 11-D-(S)-tianeptine fumarate (1:1), 11-D-(S)-tianeptine fumarate (2:1), 11-D-(S)-tianeptine hippurate (1:1), 11-D-(S)-tianeptine maleate (1:1), 11-D-(S)-tianeptine maleate (2:1), 11-D-(S)-tianeptine p-toluenesulfonate (1:1), 11-D-(S)-tianeptine orotate (1:1), 11-D-(S)-tianeptine camphorsulfonate (1:1), 11-D-(S)-tianeptine N-acetyl-L-tyrosinate (1:1), 11-D-(S)-tianeptine polyesterix, 11-D-(S)-tianeptine: L-DBTA (2:1), 11-D-(S)-tianeptine sodium, 11-D-(S)-tianeptine oxalate or 11-D-(S)-tianeptine oxalate (2:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tianeptine benzenesulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tianeptine fumarate (1:1).In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tianeptine fumarate (2:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tianeptine hippurate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tianeptine maleate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tianeptine maleate (2:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tianeptine p-toluenesulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tianeptine orotate (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tianeptine camphorsulfonate (1:1). In some embodiments, the pharmaceutically acceptable salt... Petition 870250087689, dated 09 / 26 / 2025, p. 97 / 421 87 / 233 The pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is N-acetyl-L-tyrosinate of 11D-(S)-tianeptine (1:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is polyesterix of 11-D-(S)-tianeptine. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is 11-D-(S)-tianeptine: L-DBTA (2:1). In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tianeptine sodium. In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is oxalate of 11-D(S)-tianeptine. In some embodiments, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer is 11-D-(S)-tianeptine oxalate (2:1) (i.e., 11-D-(S)-tianeptine hemioxalate). In some embodiments, the hemioxalate salt is in crystalline form.

[0084] In some embodiments, for example, fumaric acid and maleic acid act as monoanions or dianions, leading to different salt stoichiometries (i.e., a 1:1 or 2:1 ratio of tianeptine to fumaric acid / maleic acid). These salts may also comprise additional deuterium substitutions at one or more positions in the amino-heptanoic side chain.

[0085] In some embodiments, the pharmaceutically acceptable salt or crystalline forms thereof of the (S)-enantiomer of this invention or the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of this invention are formed from benzenesulfonic, fumaric, hippuric, maleic or p-toluenesulfonic acid in acetone and 2-propanol. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer or crystalline forms thereof of this invention, or the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or crystalline forms thereof of this invention, is formed from orotic acid in 58% water / 42% tetrahydrofuran (THF).

[0086] In some respects, this description provides a cocrystal of the (S)-enantiomer of this invention, wherein the (S)-enantiomer or zwitte Petition 870250087689, dated 09 / 26 / 2025, page 98 / 421 88 / 233 The (S)-enantiomer or zwitterion of the same forms a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid. In some embodiments, the (S)-enantiomer or zwitterion of the same forms a complex with L-tyrosine. In some embodiments, the (S)-enantiomer or zwitterion of the same forms a complex with L-tryptophan. In some embodiments, the (S)-enantiomer or zwitterion of the same forms a complex with L-phenylalanine. In some embodiments, the (S)-enantiomer or zwitterion of the same forms a complex with another L-amino acid. In some embodiments, the ratio of the (S)-enantiomer or zwitterion of the same to the L-amino acid is 1:1, 1:2, or 2:1. In some embodiments, the ratio of the (S)-enantiomer or zwitterion thereof to the L-amino acid is 1:1. In some embodiments, the ratio of the (S)-enantiomer or zwitterion thereof to the L-amino acid is 1:2. In some embodiments, the ratio of the (S)-enantiomer or zwitterion thereof to the L-amino acid is 2:1.In some embodiments, the cocrystal comprises an inorganic monoacid salt of the (S)-enantiomer and a zwitterion of the L-amino acid. In some embodiments, the cocrystal comprises an inorganic monoacid salt of the L-amino acid and the zwitterion of the (S)-enantiomer. In some embodiments, the inorganic monoacid is hydrochloric acid (HCl).

[0087]

[0087] In some aspects, this invention provides a cocrystal of the 11-D-(S)-enantiomer of this invention (and of an 11-D-(S)-enantiomer having at least one deuterium substitution in the amino-heptanoic chain), wherein the (S)-enantiomer or zwitterion thereof forms a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid. In some embodiments, the 11-D-(S)-enantiomer or zwitterion thereof forms a complex with L-tyrosine. In some embodiments, the 11-D-(S)-enantiomer or zwitterion thereof forms a complex with L-tryptophan. In some embodiments, the 11-D-(S)-enantiomer or zwitterion thereof forms a complex with L-tryptophan. Petition 870250087689, dated 09 / 26 / 2025, p. 99 / 421 89 / 233 phenylalanine. In some embodiments, the 11-D-(S)-enantiomer or zwitterion thereof forms a complex with another L-amino acid. In some embodiments, the ratio of the 11-D-(S)-enantiomer or zwitterion thereof 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 zwitterion thereof to the L-amino acid is 1:1. In some embodiments, the ratio of the 11-D-(S)-enantiomer or zwitterion thereof to the L-amino acid is 1:2. In some embodiments, the ratio of the 11-D(S)-enantiomer or zwitterion thereof to the L-amino acid is 2:1. In some embodiments, the cocrystal comprises an inorganic monoacid salt of the 11-D-(S)-enantiomer and a zwitterion of the L-amino acid. In some embodiments, the cocrystal comprises an inorganic monoacid salt 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 aspects, this invention provides an ester of the (S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, wherein the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 1% of the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.9% of the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising < about 0.8% of the ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof. Petition 870250087689, dated 09 / 26 / 2025, p. 100 / 421 90 / 233 In some embodiments, the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.7% of the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.6% of the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.5% of the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.4% of the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof.In some embodiments, the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.3% of the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.2% of the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.1% of the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof.

[0089] In some embodiments, this invention provides an ester of the 11-D-(S)-enantiomer of this invention (and of an 11-D-(S)-enantiomer with at least one deuterium substitution in the aminoheptanoic chain) or a pharmaceutically acceptable salt thereof, wherein the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof. In Petition 870250087689, dated 09 / 26 / 2025, p. 101 / 421 91 / 233 In some embodiments, the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 1% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.9% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.8% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.7% of the 11D-(R) enantiomer ester or pharmaceutically acceptable salt thereof.In some embodiments, the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.6% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.5% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.4% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.3% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof.In some embodiments, the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.2% of the 11-D-(R)-enantiomer ester or salt. Petition 870250087689, dated 09 / 26 / 2025, p. 102 / 421 92 / 233 pharmaceutically acceptable thereof. In some embodiments, the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.1% of the 11-D-(R)-enantiomer ester or 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. Esters are designed so that the ester salts, without wishing to be limited to theory, dissolve slowly enough to provide slow release of the esters, and so that the esters can undergo enzymatic cleavage to form the active (S)-enantiomer or 11-D-(S)-enantiomer in the intestine, serum and / or brain at a rate that provides slow release of the (S)-enantiomer or 11-D-(S)-enantiomer, allowing once-daily dosing of the ester salt.

[0091] Exemplary esters include 3', 3', 4', 4', tetradeutero-(S)-tianeptine methyl ester oxalate of Formula (VII), 2', 2', 3', 3', 4', 4', 5', 5', 6', 6', 7', 7'-dodecadeutero(S)-tianeptine isopropyl ester p-toluenesulfonate of Formula (VIII), 3', 3', 4', 4', 11-pentadeutero-(S)-tianeptine pivaloyloxyethyl ester benzoate of Formula (IX) and 11-D-(S)-tianeptine ethyl ester orotate of Formula (X). Formula (VIII) Formula (VII) Formula (IX) Petition 870250087689, dated 09 / 26 / 2025, p. 103 / 421 93 / 233

[0092] In some aspects, this description provides an amide of the (S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, wherein the (S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 1% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.9% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.8% of the amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof.In some embodiments, the (S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.7% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.6% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.5% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.4% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof is characterized by comprising... Petition 870250087689, dated 09 / 26 / 2025, page 104 / 421 94 / 233 der < about 0.3% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.2% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.1% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof.

[0093] In some embodiments, this invention provides an 11-D-(S)-enantiomer amide of this invention (and of an 11-D-(S)-enantiomer with at least one deuterium substitution in the aminoheptanoic chain) or a pharmaceutically acceptable salt thereof, wherein the 11-D-(S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the 11-D-(R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 1% of the 11-D-(R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.9% of the 11-D-(R)-enantiomer amide or pharmaceutically acceptable salt thereof.In some embodiments, the 11-D-(S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.8% of the 11-D-(R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.7% of the 11-D-(R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or pharmaceutically acceptable salt... Petition 870250087689, dated 09 / 26 / 2025, p. 105 / 421 95 / 233 pharmaceutically acceptable thereof, is characterized by comprising < about 0.6% of the 11-D-(R) enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S) enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.5% of the 11-D-(R) enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S) enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.4% of the 11-D-(R) enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.3% of the 11-D-(R)-enantiomer amide or pharmaceutically acceptable salt thereof.In some embodiments, the 11-D-(S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.2% of the 11-D-(R)-enantiomer amide or pharmaceutically acceptable salt thereof. In some embodiments, the 11-D-(S)-enantiomer amide or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.1% of the 11-D-(R)-enantiomer amide or pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the amides include simple amides, C1-C6 alkyl optionally substituted with at least one hydroxyl group, C3-C6 branched alkyl, and C3-C6 cyclic alkylamides. The amides are designed such that the amide salts, without wishing to be limited to theory, provide advantages of enhanced crystallization compared to the (S)-enantiomer or 11-D-(S)-enantiomer of tianeptine, targeted administration to the CNS due to metabolism by brain-specific fatty acid amide hydrolases (FAAHs), and cannabinoid activity through the binding of fatty acid amides to cannabinoid receptors, which may contribute to the Petition 870250087689, dated 09 / 26 / 2025, p. 106 / 421 96 / 233 pain reduction and antidepressant activity.

[0095] Exemplary amides include 5,5-dioxide-oxalate of (S)-N-(7amino-7-oxo-heptyl-4,4,5,5-d4)-3-chloro-6-methyl-6,11 -di-hydrodibenzo[c,f] [1,2amine-1]thia (XI), p -toluenesulfonate of 5,5-dioxide of (S)-3-chloro-N-(7-(isopropylamine)-7-oxo-heptyl-1,1,2,2,3, 3,4,4,5,5,6,6-d 12)-6-methyl-[di-6,hydrof]- 1,2]thiazepine-11 amine of Formula (XII), 5,5-dioxydobenzoate of (11S)-3-chloro-6-methylN-(7-oxo-7-((1 -pivalamidoethyl)amino)heptyl-4,4,5,5-d1 rod4)-6 ibenzo[c,f][1,2] hyazepine-11-d-11-amine of Formula (XIII) and 5,5-dioxide orotate of (S)-3-chloro-N-(7-(ethylamine)-7-oxo-heptyl)-6-methyl-hydrof[1,6,11-dibenzo hyazepine-11-amine Formula (XIV). Formula (XI) Formula (XII) Formula (XIII) Formula (XIV)

[0096] In some embodiments, this invention provides a pharmaceutically acceptable acid salt of the (S)-enantiomers (e.g., (S)-enantiomer or 11-D-(S)-enantiomer) of this invention, wherein the nitrogen atom in the side chain attached to Carbon-11 (C-11) is 100% protonated, the 100% protonated salt being less sensitive to air oxidation in solid forms or in solution when compared to the (S)-enantiomer, 11-D-(S)-enantiomer, the zwitterion of either, or the Petition 870250087689, dated 09 / 26 / 2025, p. 107 / 421 97 / 233 sodium salts of any kind.

[0097] In some respects, this invention provides a crystalline hemioxalate salt of 5,5-dioxide of (S)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ylamino)heptanoic acid ((S)-tianeptine). In some embodiments, the crystalline 11-D-(S)-tianeptine hemioxalate salt of this invention exhibits an X-ray diffraction pattern (XRPD) comprising at least one peak selected from 8.5, 20.6, 21.0 and 24.2 degrees 20 ± 0.3 degrees 20. In some embodiments, the crystalline 11-D-(S)-tianeptine hemioxalate salt further exhibits an XRPD pattern also 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 20 ± 0.3 degrees 20.

[0098] In some aspects, this invention provides a crystalline base / acid-free (S)-enantiomer of tianeptine. In some embodiments, the crystalline (S)-enantiomer of tianeptine exhibits an X-ray diffraction pattern (XRPD) comprising at least one peak selected from 10.6, 13.0, 21.1 and 23.7 degrees 20 ± 0.3 degrees 20. In some embodiments, the crystalline (S)-enantiomer of tianeptine exhibits an X-ray diffraction pattern (XRPD) also 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 20 ± 0.3 degrees 20. (S)-Tianeptine Analogs

[0096] In some respects, this invention provides the compound N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof. In some respects, this invention provides the (S)-enantiomer of N-hydroxy-tianeptine (i.e., N-hydroxy-(S)-tianeptine) or a pharmaceutically acceptable salt thereof. In some respects, this invention provides the (R)-enantiomer of N-hydroxy-tianeptine (i.e., N-hydroxy-(R)tianeptine) or a pharmaceutically acceptable salt thereof. Without intending to be limited to theory, N-hydroxy-tianeptine does not exhibit agonism. Petition 870250087689, dated 09 / 26 / 2025, p. 108 / 421 98 / 233 of the μ-opioid receptor (MOR) and acts as a potent agonist of PPAR-β / δ and / or PPAR-γ.

[0097] In some embodiments, the (S)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 2% (i.e., < about 2%) of the (R)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxytianeptine. In some embodiments, the (S)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 1% (i.e., < about 1%) of the (R)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.9% (i.e., < about 0.9%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.8% (i.e., < about 0.8%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.7% (i.e., < about 0.7%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof; is characterized by comprising no more than about 0.6% (i.e., < about 0.6%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof; is characterized by comprising no more than about 0.5% (i.e., < about 0.5%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments... Petition 870250087689, dated 09 / 26 / 2025, p. 109 / 421 99 / 233 embodiments, the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.4% (i.e., < about 0.4%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.3% (i.e., < about 0.3%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.2% (i.e., < about 0.2%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.1% (i.e., < about 0.1%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.

[0098] In some embodiments, the (R)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 2% (i.e., < about 2%) of the (S)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 1% (i.e., < about 1%) of the (S)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.9% (i.e., < about 0.9%) of the (S)-enan Petition 870250087689, dated 09 / 26 / 2025, p. 110 / 421 100 / 233 N-hydroxy-tianeptine thiomer or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.8% (i.e., < about 0.8%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.7% (i.e., < about 0.7%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.6% (i.e., < about 0.6%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.5% (i.e., < about 0.5%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.4% (i.e., < about 0.4%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.3% (i.e., < about 0.3%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is used. Petition 870250087689, dated 09 / 26 / 2025, page 111 / 421 101 / 233 characterized by comprising no more than about 0.2% (i.e., < about 0.2%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.1% (i.e., < about 0.1%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.

[0099] In some embodiments, the (S)-enantiomer of N-nitrosotianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 2% (i.e., < about 2%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso-tianeptine. In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 1% (i.e., < about 1%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.9% (i.e., < about 0.9%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.8% (i.e., < about 0.8%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.7% (i.e., < about 0.7%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. Petition 870250087689, dated 09 / 26 / 2025, p. 112 / 421 102 / 233 pharmaceutically acceptable thereof. In some embodiments, the (S)enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.6% (i.e., < about 0.6%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.5% (i.e., < about 0.5%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.4% (i.e., < about 0.4%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.3% (i.e., < about 0.3%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.2% (i.e., < about 0.2%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.1% (i.e., < about 0.1%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer.

[00100] In some embodiments, the (R)-enantiomer of N-nitrosotianeptine or a pharmaceutically acceptable salt thereof is characterized Petition 870250087689, dated 09 / 26 / 2025, p. 113 / 421 103 / 233 characterized by comprising no more than about 2% (i.e., < about 2%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 1% (i.e., < about 1%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.9% (i.e., < about 0.9%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.8% (i.e., < about 0.8%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.7% (i.e., < about 0.7%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.6% (i.e., < about 0.6%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.5% (i.e., < about 0.5%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer is characterized by comprising no more than about 0.4% (i.e., < about 0.4%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. Petition 870250087689, dated 09 / 26 / 2025, page 114 / 421 104 / 233 thiomer. In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.3% (i.e., < about 0.3%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.2% (i.e., < about 0.2%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is characterized by comprising no more than about 0.1% (i.e., < about 0.1%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer.

[00101] In some respects, this invention provides the compound N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof. In some respects, this invention provides the (S)-enantiomer of N-nitroso-tianeptine (i.e., N-nitroso-(S)-tianeptine) or a pharmaceutically acceptable salt thereof. In some respects, this invention provides the (R)-enantiomer of N-nitroso-tianeptine (i.e., N-nitroso(R)-tianeptine) or a pharmaceutically acceptable salt thereof. Without wishing to be limited to theory, N-hydroxy-tianeptine does not exhibit μ-opioid receptor (MOR) agonism and acts as a potent PPAR-β / δ and / or PPAR-γ agonist.

[00102] In some respects, this invention provides aryl-substituted tianeptine derivatives. Exemplary derivatives include: 7-((3-(furan-2-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino)heptanoic acid of Formula (XXI), acid 7-((3-(furan-3yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino) heptanoic acid of Formula (XXII), 7-((6-methyl-5,5-dioxide-3-(thiophen-3 Petition 870250087689, dated 09 / 26 / 2025, p. 115 / 421 105 / 233 il)-6,11-dihydrodibenzo[c,f][1,2]tiazepin-11-yl)amino)heptanoic acid of Formula (XXIII) and 2-(4-(((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]tiazepin-11-yl)amino)methyl)-2-methylphenoxy)acetic acid of Formula (XXIV). Without limiting ourselves to theory, aryl-substituted tianeptine derivatives exhibit greater membrane penetration compared to tianeptine due to the aromatic ring, and the (R)-enantiomer of aryl-substituted tianeptine derivatives and the racemic mixture exhibit lower MOR agonism compared to (R)-tianeptine and racemic tianeptine due to the shape of the molecule. Formula (XXIII) Formula (XXIV) Pharmaceutical Composition

[00103] The compounds described herein may be administered as the (S)-enantiomer or the 11-D-(S)-enantiomer of this invention or, if desired, in the form of a zwitterion, salt (including crystalline salts), ester, ester salt, amide, amide salt or cocrystal of this invention, provided that the zwitterion, salt, ester, ester salt, amide, amide salt or cocrystal is pharmacologically suitable, for example, effective in the present methods. Zwitterions, salts, esters, ester salts or cocrystals of the (S)-enantiomer or the 11-D-(S)-enantiomer of this invention may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry.

[00104] In some embodiments, this invention provides a composition Petition 870250087689, dated 09 / 26 / 2025, p. 116 / 421 106 / 233 pharmaceutical composition comprising one or more of the (S)-enantiomers of this invention, i.e., zwitterions thereof or pharmaceutically acceptable salts of the (S)-enantiomers of this invention, or cocrystals of the (S)-enantiomers (including crystalline salts thereof) of this invention or zwitterions thereof, or esters of the (S)-enantiomers or pharmaceutically acceptable salts thereof of this invention, or amides of the (S)-enantiomers thereof or pharmaceutically acceptable salts thereof of this invention and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises not more than about 2% (i.e., < about 2%) of the (R)-enantiomers, zwitterions thereof or pharmaceutically acceptable salts of the (R)-enantiomers, or cocrystals of the (R)-enantiomers or zwitterions thereof, or esters of the (R)-enantiomers or pharmaceutically acceptable salts thereof, or amides of the (R)-enantiomers or pharmaceutically acceptable salts thereof.

[00105] In some embodiments, this invention provides a pharmaceutical composition comprising the (S)-enantiomer of tianeptine of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt (including crystalline salts thereof) of the (S)-enantiomer of this invention, or a cocrystal of the (S)-enantiomer of this invention or the zwitterion thereof, or an ester of the (S)-enantiomer thereof or a pharmaceutically acceptable salt of this invention, or an amide of the (S)-enantiomer thereof or a pharmaceutically acceptable salt of this invention and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises no more than about 2% (i.e., < about 2%) of the (R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer thereof or a pharmaceutically acceptable salt thereof. Petition 870250087689, dated 09 / 26 / 2025, p. 117 / 421 107 / 233 acceptable of this invention. In some embodiments, the composition comprises no more than about 1% (i.e., < about 1%) of the (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt thereof of this invention. In some embodiments, the composition comprises no more than about 0.9% (i.e., < about 0.9%) of the (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt thereof of this invention.In some embodiments, the composition comprises no more than about 0.8% (i.e., < about 0.8%) of the (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt thereof of this invention. In some embodiments, the composition comprises no more than about 0.7% (i.e., < about 0.7%) of the (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt thereof of this invention.In some embodiments, the composition comprises no more than about 0.6% (i.e., < about 0.6%) of the (R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt thereof. Petition 870250087689, dated 09 / 26 / 2025, p. 118 / 421 108 / 233 (R)-enantiomer, or cocrystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt thereof of this invention. In some embodiments, the composition comprises no more than about 0.5% (i.e., < about 0.5%) of the (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or cocrystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt thereof of this invention.In some embodiments, the composition comprises no more than about 0.4% (i.e., < about 0.4%) of the (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt thereof of this invention. In some embodiments, the composition comprises no more than about 0.3% (i.e., < about 0.3%) of the (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt thereof of this invention.In some embodiments, the composition comprises no more than about 0.2% (i.e., < about 0.2%) of the (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt thereof. Petition 870250087689, dated 09 / 26 / 2025, p. 119 / 421 109 / 233 same as this invention. In some embodiments of this invention, the composition comprises no more than about 0.1% (i.e., < about 0.1%) of the (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or a pharmaceutically acceptable salt thereof of this invention.

[00106] In some embodiments, the pharmaceutical composition of this invention comprises the (S)-enantiomer of tianeptine of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt (including crystalline salts thereof) of the (S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable cocrystal of the (S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises the zwitterion of the (S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises an ester of the (S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient.In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the (S)-enantiomer ester of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises an amide of the (S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of... Petition 870250087689, dated 09 / 26 / 2025, pp. 120 / 421 110 / 233 amide of the (S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent or excipient.

[00107] In some embodiments, this invention provides a pharmaceutical composition comprising the 11-D-(S)-enantiomer of tianeptine of this invention (and of an 11-D-(S)-enantiomer having at least one deuterium substitution in the amino-heptanoic side chain), the zwitterion thereof, or a pharmaceutically acceptable salt (including crystalline salts thereof) of an 11-D-(S)-enantiomer of this invention, or a cocrystal of an 11-D-(S)-enantiomer of this invention or the zwitterion thereof, or an ester of an 11-D-(S)-enantiomer or pharmaceutically acceptable salt thereof of this invention, or an amide of an 11-D-(S)-enantiomer or pharmaceutically acceptable salt thereof of this invention and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises no more than about 2% (i.e., < about 2%) of an 11-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an 11-D-(R)-enantiomer,or a cocrystal of an 11-D-(R)-enantiomer or zwitterion thereof, or an ester of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 1% (i.e., < about 1%) of an 11-D-(R)-enantiomer of tianeptine, a zwitterion thereof, or a pharmaceutically acceptable salt of an 11-D-(R)-enantiomer, or a cocrystal of an 11-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.9% (i.e., < about 0.9%) of an 11-D-(R)-enantiomer of tianeptine, a zwitterion thereof, or a salt, Petition 870250087689, dated 09 / 26 / 2025, pp. 121 / 421 111 / 233 pharmaceutically acceptable of an 11-D-(R)-enantiomer, or cocrystal of an 11-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.8% (i.e., < about 0.8%) of an 11-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an 11-D-(R)-enantiomer, or a cocrystal of an 11-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.In some embodiments, the composition comprises no more than about 0.7% (i.e., < about 0.7%) of an 11-D-(R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of an 11-D-(R)-enantiomer, or a cocrystal of an 11-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.6% (i.e., < about 0.6%) of an 11-D-(R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of an 11-D-(R)-enantiomer, or a cocrystal of an 11-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.In some embodiments, the composition comprises no more than about 0.5% (i.e., < about 0.5%) of an 11-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an 11-D-(R)-enantiomer, or a cocrystal of the 11-D-(R)-enantiomer, or a zwitterion. Petition 870250087689, dated 09 / 26 / 2025, pp. 122 / 421 112 / 233 river of the same, or an ester of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.4% (i.e., < about 0.4%) of an 11-D-(R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of an 11-D-(R)-enantiomer, or a cocrystal of an 11-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.In some embodiments, the composition comprises no more than about 0.3% (i.e., < about 0.3%) of an 11-D-(R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of an 11-D-(R)-enantiomer, or a cocrystal of an 11-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.2% (i.e., < about 0.2%) of an 11-D-(R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of an 11-D-(R)-enantiomer, or a cocrystal of an 11-D-(R)-enantiomer or a zwitterion thereof, or an ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.In some embodiments of this invention, the composition comprises no more than about 0.1% (i.e., < about 0.1%) of an 11-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an 11-D-(R)-enantiomer, or a cocrystal of an 11-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt. Petition 870250087689, dated 09 / 26 / 2025, pp. 123 / 421 113 / 233 vel of the same, or an amide of an 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

[00108] In some embodiments, the pharmaceutical composition of this invention comprises an 11-D-(S)-enantiomer of tianeptine of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt (including crystalline salts thereof) of an 11-D-(S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable cocrystal of an 11-D-(S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a zwitterion of an 11-D-(S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient.In some embodiments, the pharmaceutical composition comprises an ester of an 11-D(S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the ester of an 11-D-(S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises an amide of the 11-D-(S)-enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the amide of the 11-D-(S) enantiomer of this invention and a pharmaceutically acceptable carrier, diluent, or excipient.

[00109] 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 of the 11 Petition 870250087689, dated 09 / 26 / 2025, pp. 124 / 421 114 / 233 D-(S)-enantiomer (and of an 11-D-(S)-enantiomer having at least one deuterium substitution in the amino-heptanoic side chain), wherein the mixture of pharmaceutically acceptable salts or cocrystals is characterized by enhanced prolonged 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 of this invention. In some embodiments, the enhanced prolonged release of the mixture of pharmaceutically acceptable salts or cocrystals is due, without being linked to the theory, to the different dissolution rates of each of the salt or cocrystal forms in the intestinal tract.

[00110] In some embodiments, the pharmaceutical composition of this invention comprises one or more tianeptine analogs of this invention, namely, N-hydroxy-tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or an aryl substitution analog of tianeptine of this invention or a pharmaceutically acceptable salt of any of the same and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this invention comprises the N-hydroxy-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this invention comprises a pharmaceutically acceptable salt of the N-hydroxy-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent or excipient.In some embodiments, the pharmaceutical composition of this invention comprises the (S)-enantiomer of N-hydroxy-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition of this invention comprises a pharmaceutically acceptable salt of (S)-enan. Petition 870250087689, dated 09 / 26 / 2025, p. 125 / 421 115 / 233 thiomer of N-hydroxy-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this invention comprises the (R)-enantiomer of N-hydroxy-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this invention comprises a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this invention comprises N-nitroso-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this invention comprises a pharmaceutically acceptable salt of N-nitroso-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent or excipient.In some embodiments, the pharmaceutical composition of this invention comprises the (S)-enantiomer of N-nitroso-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition of this invention comprises a pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition of this invention comprises the (R)-enantiomer of N-nitroso-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition of this invention comprises a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso-tianeptine of this invention and a pharmaceutically acceptable carrier, diluent, or excipient.In some embodiments, the pharmaceutical composition of this invention comprises an aryl substitute analogue of tianeptine of this invention and a pharmaceutical carrier, diluent or excipient. Petition 870250087689, dated 09 / 26 / 2025, pp. 126 / 421 116 / 233 pharmaceutically acceptable. In some embodiments, the pharmaceutical composition of this invention comprises a pharmaceutically acceptable salt of an aryl substitute analogue of tianeptine of this invention and a pharmaceutically acceptable carrier, diluent or excipient.

[00111] In some embodiments, this invention provides a pharmaceutical composition comprising the (S)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises no more than about 2% (i.e., < about 2%) of the (R)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxytianeptine. In some embodiments, the composition comprises no more than about 1% (i.e., < about 1%) of the (R)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.9% (i.e., < about 0.9%) of the (R)-enantiomer of N-hydroxytianeptine or of a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the composition comprises no more than about 0.8% (i.e., < about 0.8%) of the (R)-enantiomer of N-hydroxy-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.7% (i.e., < about 0.7%) of the (R)-enantiomer of N-hydroxy-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.6% (i.e., < about 0.6%) of the (R)-enantiomer of N-hydroxy-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.5% (i.e., < about 0.5%) of the (R)-enantiomer of N-hydroxy-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some... Petition 870250087689, dated 09 / 26 / 2025, p. 127 / 421 In some embodiments, the composition comprises no more than about 0.4% (i.e., < about 0.4%) of the (R)-enantiomer of N-hydroxy-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.3% (i.e., < about 0.3%) of the (R)-enantiomer of N-hydroxy-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.2% (i.e., < about 0.2%) of the (R)-enantiomer of N-hydroxy-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.1% (i.e., < about 0.1%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.

[00112] In some embodiments, this invention provides a pharmaceutical composition comprising the (R)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises no more than about 2% (i.e., < about 2%) of the (S)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 1% (i.e., < about 1%) of the (S)-enantiomer of N-hydroxytianeptine or a pharmaceutically acceptable salt of the same enantiomer. In some embodiments, the composition comprises no more than about 0.9% (i.e., < about 0.9%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the composition comprises no more than about 0.8% (i.e., < about 0.8%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about... Petition 870250087689, dated 09 / 26 / 2025, pp. 128 / 421 118 / 233 0.7% (i.e., < about 0.7%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.6% (i.e., < about 0.6%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.5% (i.e., < about 0.5%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.4% (i.e., < about 0.4%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.3% (i.e., < about 0.3%) of the (S)enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the composition comprises no more than about 0.2% (i.e., < about 0.2%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.1% (i.e., < about 0.1%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.

[00113] In some embodiments, this invention provides a pharmaceutical composition comprising the (S)-enantiomer of N-nitrosotianeptine or a pharmaceutically acceptable salt thereof of this invention, and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises no more than about 2% (i.e., < about 2%) of the (R)-enantiomer of N-nitrosotianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitrosotianeptine. In some embodiments, the composition comprises at most about 1% (i.e., < about 1%) of the (R)-enantiomer of Petition 870250087689, dated 09 / 26 / 2025, p. 129 / 421 119 / 233 N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises at most about 0.9% (i.e., < about 0.9%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises at most about 0.8% (i.e., < about 0.8%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises at most about 0.7% (i.e., < about 0.7%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises at most about 0.6% (i.e., < about 0.6%) of the (R)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the composition comprises no more than about 0.5% (i.e., < about 0.5%) of the (R)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.4% (i.e., < about 0.4%) of the (R)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises at most about 0.3% (i.e., < about 0.3%) of the (R)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises at most about 0.2% (i.e., < about 0.2%) of the (R)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the composition comprises no more than about 0.1% (i.e., < about 0.1%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer.

[00114] In some embodiments, this invention provides a with Petition 870250087689, dated 09 / 26 / 2025, p. 130 / 421 120 / 233 pharmaceutical position comprising the (R)-enantiomer of N-nitrosotianeptine or a pharmaceutically acceptable salt thereof of this invention, and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises no more than about 2% (i.e., < about 2%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at most about 1% (i.e., < about 1%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at most about 0.9% (i.e., < about 0.9%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at most about 0.8% (i.e., < about 0.8%) of the (S)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the composition comprises at most about 0.7% (i.e., < about 0.7%) of the (S)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises at most about 0.6% (i.e., < about 0.6%) of the (S)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises at most about 0.5% (i.e., < about 0.5%) of the (S)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises at most about 0.4% (i.e., < about 0.4%) of the (S)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer.In some embodiments, the composition comprises at most about 0.3% (i.e., < about 0.3%) of the (S)-enantiomer of N-nitroso-tianeptine or of a pharmaceutically acceptable salt of that enantiomer. In some... Petition 870250087689, dated 09 / 26 / 2025, page 131 / 421 In some embodiments, the composition comprises no more than about 0.2% (i.e., < about 0.2%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.1% (i.e., < about 0.1%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. Dosages, Forms and Methods of Administration

[00115] Any suitable route of administration may be employed to administer the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 1 1D-(S)-enantiomer) of this invention, zwitterions, pharmaceutically acceptable salts, cocrystals, esters and pharmaceutically acceptable salts thereof, amides and pharmaceutically acceptable salts thereof, and tianeptine analogues (i.e., N-hydroxy-tianeptine, the (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)-enantiomers thereof or aryl-substituted tianeptine analogues, or pharmaceutically acceptable salts thereof) and pharmaceutical compositions thereof of this invention.Exemplary routes of administration of the (S)-enantiomer of tianeptine of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer and crystalline forms thereof of this invention, or a cocrystal of the (S)-enantiomer of this invention or the zwitterion thereof, or an ester of the (S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, or an 11-D-(S)-enantiomer of tianeptine of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer and crystalline forms thereof of this invention, or a cocrystal of an 11-D-(S)-enantiomer of this invention or the zwitterion thereof, or an ester of a 11-D-(S)-enantiomer of this invention or pharmaceutical salt. Petition 870250087689, dated 09 / 26 / 2025, p. 132 / 421 122 / 233 pharmaceutically acceptable thereof, or an amide of the 11-D-(S)-enantiomer, or an analogue of tianeptine (i.e., N-hydroxy-tianeptine, the (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)-enantiomers thereof, or aryl-substituted tianeptine analogues) or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof of this invention or a pharmaceutical composition of this invention include, but are not limited to, parenteral, oral, sublingual, buccal, inhalation, palatal, transdermal, rectal, and vaginal administration.

[00116] In some embodiments, useful dosage forms for administering the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 1 1D-(S)-enantiomer) of this invention, zwitterions, pharmaceutically acceptable salts, cocrystals, esters and pharmaceutically acceptable salts of these esters, amides or an analogue of tianeptine (i.e., N-hydroxy-tianeptine, the (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)-enantiomers thereof or aryl-substituted tianeptine analogues or pharmaceutically acceptable salts thereof) and pharmaceutical compositions of this invention may include, but are not limited to, tablets, such as scored tablets, coated tablets, minitablets, chewable tablets, orodispersible tablets or dissolvable tablets; thin films; powders (e.g., lung powder or dry powder inhaler); coated tablets; capsules (e.g., hard gelatin capsules); soft gels; suppositories;Nasal sprays and other forms of inhaled sprays. In some embodiments, the pharmaceutical form is a tablet. In some embodiments, the pharmaceutical form is a thin film. In some embodiments, the pharmaceutical form is a powder. In some embodiments, the pharmaceutical form is a coated tablet. In some embodiments, the pharmaceutical form is a capsule. In some embodiments, the pharmaceutical form is a suppository. Petition 870250087689, dated 09 / 26 / 2025, p. 133 / 421 123 / 233 In some embodiments, the pharmaceutical form is an inhalation spray. In some embodiments, the spray is a nasal spray. In some embodiments, the spray is an oral spray.

[00117] The dosage form of this invention for parenteral administration in some modalities may take the form of an aqueous or non-aqueous solution, dispersion, suspension or emulsion.For example, in the preparation of the dosage forms of this invention for parenteral administration, at least one of the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 11D-(S)-enantiomer) of this invention, zwitterions, cocrystals, esters or pharmaceutically acceptable salts, amides or an analogue of tianeptine (i.e., N-hydroxy-tianeptine, the (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)-enantiomers thereof or an aryl-substituted analogue of tianeptine) or pharmaceutically acceptable salts thereof are mixed with a suitable pharmaceutically acceptable vehicle, such as water, oil (particularly a vegetable oil), ethanol, saline solutions (e.g., normal saline solution), aqueous dextrose (glucose) and related sugar solutions, glycerol or Glycols, such as propylene glycol or polyethylene glycol.For parenteral administration, these dosage forms preferably contain a water-soluble salt of at least one of the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 11D-(S)-enantiomer), zwitterions, cocrystals, esters, amides, N-hydroxy-tianeptine, the (S)- or (R)-enantiomer thereof, or an analog of tianeptine (i.e., N-hydroxy-tianeptine, the (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)-enantiomers thereof, or an aryl-substituted tianeptine analog) or pharmaceutically acceptable salts thereof of this invention. Stabilizing agents, antioxidants, and preservatives may also be added to the parenteral pharmaceutical forms. Suitable antioxidants include sulfite, ascorbic acid, citric acid and its salts, and EDTA. Petition 870250087689, dated 09 / 26 / 2025, p. 134 / 421 124 / 233 sodium. Suitable preservatives include benzalkonium chloride, methyl or propylparaben, and chlorbutanol.

[00118] For oral administration, in some embodiments, the dosage forms of this invention comprise at least one of the (S)enantiomers of tianeptine (i.e., the (S)-enantiomer or 11-D-(S)enantiomer), zwitterions, cocrystals, esters, amides or analogues of tianeptine (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof or aryl-substituted tianeptine analogue) and salts of this invention combined with one or more solid or liquid inactive ingredients to form tablets, capsules, pills, powders or other suitable oral dosage forms.For example, at least one of the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 1 1D-(S)-enantiomer), zwitterions, esters, amides, salts or cocrystals, or tianeptine analogue (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof or tianeptine analogue substituted with an aryl group) and salts of this invention is combined with at least one pharmaceutically acceptable vehicle, such as a solvent, filler, binder, humectant, disintegrating agent, solution retardant, absorption accelerator, wetting agent, absorbent or lubricant.In one embodiment, at least one of the (S)enantiomers of tianeptine (i.e., the (S)-enantiomer or 11-D-(S)enantiomer), zwitterions, esters, amides, salts, or cocrystals or an analogue of tianeptine (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof, or an aryl-substituted tianeptine analogue) and salts of this invention are combined with calcium carboxymethylcellulose, magnesium stearate, mannitol, and starch, and are formed into tablets by conventional tablet production methods. In another embodiment, the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 11-D-(S)-enantiomer) are formed into tablets using conventional tablet production methods. Petition 870250087689, dated 09 / 26 / 2025, p. 135 / 421 125 / 233 mero), zwitterions, esters, amides, salts or cocrystals, or an analogue of tianeptine (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof or an aryl-substituted tianeptine analogue) and salts of this invention are formulated in a tablet comprising cellulose and a calcium salt, as described in U.S. Patent No. 5,888,542, the full description of which is incorporated herein by reference.

[00119] In some embodiments, the dosage form of the (S)-enantiomer or an 11-D-(S)-enantiomer, zwitterions, salts, cocrystals, esters or amides thereof, or tianeptine analog (i.e., N-hydroxy-tianeptine, the (S)- and (R)-enantiomers thereof, N-nitrosotianeptine, the (S)- and (R)-enantiomers thereof or aryl-substituted tianeptine analog) and salts of this invention are formulated for immediate release, controlled release, sustained release, prolonged release or slow release. In some embodiments, the dosage form of this invention is formulated for immediate release of the (S)enantiomer, zwitterion, salt, ester, amide or cocrystal thereof, or tianeptine analogue (i.e., N-hydroxy-tianeptine, the (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)-enantiomers thereof or aryl-substituted tianeptine analogue) and salts thereof of this invention.In some embodiments, the pharmaceutical form of this invention is formulated for immediate release of an 11D-(S)-enantiomer, zwitterion, salt, ester, amide, or cocrystal thereof. In some embodiments, the pharmaceutical form of this invention is formulated for immediate release of a tianeptine analogue (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof, or an aryl-substituted tianeptine analogue or a pharmaceutically acceptable salt thereof) of this invention. In some embodiments, the pharmaceutical form of this invention is formulated for controlled release of (S). Petition 870250087689, dated 09 / 26 / 2025, p. 136 / 421 126 / 233 enantiomer, zwitterion, salt, ester, amide or cocrystal thereof of this invention. In some embodiments, the pharmaceutical form of this invention is formulated for controlled release of an 11-D-(S)-enantiomer, zwitterion, salt, ester, amide or cocrystal thereof of this invention. In some embodiments, the pharmaceutical form of this invention is formulated for controlled release of a tianeptine analogue (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof, or aryl-substituted tianeptine analogue or pharmaceutically acceptable salts thereof) of this invention. In some embodiments, the composition of this invention is formulated for sustained release of the (S)-enantiomer, zwitterion, salt, ester, amide, or cocrystal thereof of this invention.In some embodiments, the dosage form of this invention is formulated for sustained release of an 11-D-(S)-enantiomer, zwitterion, salt, ester, amide, or cocrystal thereof of this invention. In some embodiments, the dosage form of this invention is formulated for sustained release of a tianeptine analog (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof, or an aryl-substituted tianeptine analog or pharmaceutically acceptable salts) of this invention. In some embodiments, the pharmaceutical form of this invention is formulated for prolonged release of the (S)-enantiomer, zwitterion, salt, ester, amide, or cocrystal thereof. In some embodiments, the pharmaceutical form of this invention is formulated for prolonged release of an 11-D-(S)-enantiomer, zwitterion, salt, ester, amide, or cocrystal thereof.In some embodiments, the pharmaceutical form of this invention is formulated for prolonged release of a tianeptine analogue (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof, or aryl-substituted tianeptine analogue or pharmaceutically acceptable salts) thereof. Petition 870250087689, dated 09 / 26 / 2025, p. 137 / 421 127 / 233 invention. In some embodiments, the pharmaceutical form of this invention is formulated for slow release of the (S)-enantiomer, zwitterion, salt, ester, amide or cocrystal thereof of this invention. In some embodiments, the pharmaceutical form of this invention is formulated for slow release of an 11-D-(S)-enantiomer, zwitterion, salt, ester, amide or cocrystal thereof of this invention. In some embodiments, the pharmaceutical form of this invention is formulated for slow release of a tianeptine analogue (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof, or aryl-substituted tianeptine analogue or pharmaceutically acceptable salts) of this invention.

[00120] Preferably, a controlled-release dosage form of this invention is capable of releasing at least one of the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 11-D-(S)-enantiomer), zwitterions, esters, amides, salts or cocrystals thereof, or a tianeptine analogue (i.e., N-hydroxy-tianeptine, the (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)-enantiomers thereof, or an aryl-substituted tianeptine analogue or pharmaceutically acceptable salts thereof) of this invention into an individual at a desired rate so as to maintain a substantially constant pharmacological activity over a given period of time. The formulation of controlled-release pharmaceutical compositions of the invention is within 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 pharmaceutical forms), U.S. Patent No. 5,591.767 (transdermal patch with liquid reservoir), US Patent No. 5,120,548 (device comprising swelling polymers), US Patent No. 5,073,543 (ganglioside-liposome vehicle), US Patent No. 5,639,476 (stable solid formulation coated with a hydrophobic acrylic polymer), whose... Petition 870250087689, dated 09 / 26 / 2025, page 138 / 421 128 / 233 full descriptions are incorporated here by reference.

[00121] Biodegradable microparticles can also be used to formulate controlled-release dosage forms of this invention, for example, as described in U.S. Patents Nos. 5,354,556 and 5,733,566, the full descriptions of which are incorporated herein by reference.

[00122] In one embodiment, the controlled-release dosage form of this invention comprises at least one of the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 1 1D-(S)-enantiomer), zwitterions thereof, pharmaceutically acceptable salts of the (S)-enantiomers, cocrystals of the (S)-enantiomers or zwitterions thereof, esters of the (S)-enantiomers or pharmaceutically acceptable salts thereof, or amides of the (S)-enantiomers or pharmaceutically acceptable salts thereof, or an analog of tianeptine (i.e., N-hydroxytianeptine, the (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)-enantiomers thereof, or an analog of tianeptine). replaced by aryl or pharmaceutically acceptable salts thereof) and a controlled-release component.As used herein, a “controlled-release component” is a compound, such as a polymer, polymeric matrix, gel, permeable membrane, liposome, and / or microsphere, that induces the controlled release of at least one of the (S)-enantiomers, zwitterions, cocrystals, esters, amides, and salts of this invention in the individual upon exposure to a particular compound or physiological condition. For example, the controlled-release component may be biodegradable, activated by exposure to a particular pH or temperature, by exposure to an aqueous environment, or by exposure to enzymes. An example of a controlled-release component that is activated by exposure to a particular temperature is a gel solution. In this embodiment, at least one of the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 1 1D-(S)-enantiomer) of this invention. Petition 870250087689, dated 09 / 26 / 2025, p. 139 / 421 129 / 233 tion, zwitterions thereof, pharmaceutically acceptable salts of the (S)-enantiomers, cocrystals of the (S)-enantiomers or zwitterions thereof, esters of the (S)-enantiomers or pharmaceutically acceptable salts thereof, or amides of the (S)-enantiomers, N-hydroxytianeptine, (S)- or (R)-enantiomers thereof, or an analogue of tianeptine (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof or an aryl-substituted analogue of tianeptine or pharmaceutically acceptable salts thereof) is incorporated into a solution-gel matrix that is solid at room temperature. When the solution-gel matrix is ​​implanted in an individual with a body temperature high enough to induce gel formation of the solution-gel matrix, tianeptine is released into the individual. Exemplary disorders of this invention

[00123] Diseases, disorders or conditions of this invention include, but are not limited to, central nervous system (CNS) disorders, inflammatory diseases, autoimmune diseases, infectious diseases, hearing loss, eye diseases, musculoskeletal diseases, metabolic diseases, mitochondrial diseases, hypertriglyceridemia (e.g., statin-resistant hypertriglyceridemia, mixed hypertriglyceridemia and familial hypertriglyceridemia), cancer (e.g., glioblastoma or glioma), menopause and overlapping chronic pain conditions (COPCs) and psychological, physical, metabolic or hormonal stress and COPCs.

[00124] The CNS disorders of this invention include, but are not limited to, mood disorders (e.g., major depressive disorder (MDD), bipolar disorder, or substance-induced disorder), 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, Petition 870250087689, dated 09 / 26 / 2025, pp. 140 / 421 130 / 233 generalized anxiety disorder (GAD), a specific phobia, agoraphobia, or social phobia), obsessive-compulsive disorder, neurodegenerative or neuroinflammatory disorders (e.g., mild cognitive impairment, Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury, neuromyelitis optica, myasthenia gravis, autoimmune encephalitis, prion disease, transverse myelitis, or pediatric streptococcal infection-associated autoimmune neuropsychiatric disorders (PANDAS)), neurodevelopmental disorders (e.g., attention deficit / hyperactivity disorder (ADHD), schizophrenia, Prader-Willi syndrome (including hyperphagia and other symptoms (e.g., depression and anxiety) or autism), leukodystrophy (e.g., leukoencephalopathy, a hypomyelinating disease, or demyelinating, an intellectual disability syndrome (e.g.,Fragile X syndrome), a cognitive impairment (e.g., cognitive impairment associated with a disease, disorder, or condition (e.g., mild cognitive impairment, prodromal Alzheimer's disease or Alzheimer's disease, prodromal frontotemporal dementia (FTD) or FTD, prodromal posterior cortical atrophy (PCA) or PCA, cognitive impairment associated with schizophrenia, a drug-induced cognitive disorder - such as corticosteroid-induced cognitive dysfunction, doxorubicin-induced cognitive dysfunction, chemotherapy-induced cognitive dysfunction, alcohol-induced cognitive dysfunction or substance-induced cognitive dysfunction, radiation therapy-induced cognitive dysfunction, space travel-related cognitive decline (e.g., space travel-associated neuro-ocular syndrome (SANS) or cognitive decline associated with high exposure to space radiation),or cognitive impairment and neuropathic pain associated with diabetes mellitus), cognitive impairment associated with aging (e.g., Petition 870250087689, dated 09 / 26 / 2025, pp. 141 / 421 131 / 233 age-related cognitive impairment, age-related cognitive decline (ARCD), age-associated 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 following ischemic stroke) and CNS oxidative stress.

[00125] Inflammatory diseases of this invention include, but are not limited to, postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile-onset diabetes or type 1 diabetes mellitus), Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, injury to Reperfusion syndrome, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[00126] The autoimmune diseases of this invention include, but are not limited to, achalasia, Addison's disease, adult-onset Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, 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 (AMN), Balo's disease, Behçet's disease, Petition 870250087689, dated 09 / 26 / 2025, pp. 142 / 421 132 / 233 benign mucous pemphigoid, bullous pemphigoid, Castleman's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (ClDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia,Henoch-Schönlein purpura (HSP), gestational herpes or gestational pemphigoid (PG), hidradenitis suppurativa (HS) (acne inversa), 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 sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Ménière's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, motor neuropathy multifocal (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD),Paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Parsplanitis (uveitis, Petition 870250087689, dated 09 / 26 / 2025, page 143 / 421 133 / 233 peripheral), Parsonage-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, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Fever Rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, testicular and spermatic autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis,Temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)).

[00127] The infectious diseases of this invention include, but are not limited to, viral infection (e.g., COVID-19, influenza, human immunodeficiency virus (HIV), and herpes) or post-viral condition (e.g., long COVID).

[00128] The hearing loss conditions of this invention include, but are not limited to, non-syndromic mitochondrial hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or hereditary hearing loss, hearing loss resulting from exposure to ototoxic substances, hearing loss resulting from disease, and hearing loss resulting from trauma. Petition 870250087689, dated 09 / 26 / 2025, page 144 / 421 134 / 233

[00129] The eye diseases of this invention include, but are not limited to, cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), and diabetic retinopathy.

[00130] The musculoskeletal diseases of this invention include, but are not limited to, muscular dystrophy (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy type 1 or myotonic muscular dystrophy type 2), multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal cord spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, cramp fasciculation syndrome, Freidrich ataxia, a muscular atrophy disorder (e.g., muscular atrophy, sarcopenia, cachexia), a Inclusion body myopathy, motor neuron disease, and paralysis.

[00131] The metabolic diseases of this invention 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 I diabetes, type II diabetes, or gestational diabetes), phenylketonuria, proliferative retinopathy, and Keams-Sayre disease.

[00132] The mitochondrial diseases of this invention include, but are not limited to: Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Keams-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS or maternally inherited Leigh syndrome), syndromes Petition 870250087689, dated 09 / 26 / 2025, p. 145 / 421 135 / 233 mitochondrial DNA depletion syndrome (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with red irregular fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber hereditary optic neuropathy (LHON), and Pearson syndrome.

[00133] In some embodiments, the diseases, disorders, or conditions exemplified in this invention are modulated, exacerbated, or associated with altered PPAR-β / δ and / or PPAR-γ activity. In some embodiments, the diseases, disorders, or conditions exemplified in this invention are modulated, exacerbated, 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 invention are modulated, exacerbated, or associated with excessive levels of circulating metal ions (e.g., iron or copper). CNS Disorders

[00134] Exemplary clinical symptoms of CNS disorders, diseases, and conditions include, but are not limited to, changes in cognitive function, including age-related decline in cognitive function that is similar to or not as robust as age-matched controls; changes in attention and memory; difficulty speaking, understanding, reading, or writing; inability to process thoughts; anxiety; irritability or aggressiveness; muscle fatigue; muscle atrophy; difficulty walking; headache; hearing loss; seizures; spasticity; speech and swallowing disorders; tremors; paralysis; blindness; and loss of sensation. Major Depressive Disorder

[00135] Major depressive disorder (MDD), also known as "clinical depression," is a mood disorder in which the symptoms Petition 870250087689, dated 09 / 26 / 2025, page 146 / 421 136 / 233 but which affect how a person feels, thinks and deals with daily activities are present almost every day for at least two weeks.Symptoms associated with MDD include (1) persistently sad, anxious, or “empty” mood; (2) feelings of hopelessness or pessimism; (3) irritability; (4) feelings of guilt, worthlessness, or helplessness; (5) loss of interest or pleasure in hobbies and activities (e.g., anhedonia); (6) decreased energy or fatigue; (7) moving or speaking more slowly; (8) psychomotor agitation or retardation; (9) feeling restless or having difficulty sitting still; (10) difficulty concentrating, remembering, or making decisions; (11) difficulty sleeping, waking up early in the morning, or sleeping too much (e.g., insomnia or hypersomnia); (12) changes in appetite and / or weight (e.g., a change of more than 5% of body weight in one month); (13) recurrent thoughts of death or suicide; (14) suicide attempts; (15) pains or discomfort, headaches, cramps or digestive problems without a clear physical cause and / or that do not improve even with treatment.

[00136] MDD can be diagnosed based on (1) a physical examination; (2) laboratory tests (e.g., complete blood count and / or thyroid function assessment); (3) psychiatric evaluation (e.g., the healthcare professional asks about symptoms, thoughts, feelings, and behavioral patterns and / or the patient completes a questionnaire, such as the Hospital Anxiety and Depression Scale (HADS), the Hamilton Depression Rating Scale (HDRS, HAM-D), and the Montgomery-Asberg Depression Rating Scale (MADRS)); (4) Diagnostic and Statistical Manual of Mental Disorders (e.g., the DSM-5 lists the criteria for depression published by the American Psychiatric Association).

[00137] The DSM-5 criteria for the diagnosis of MDD include at least 5 symptoms present during the same 2-week period. Petition 870250087689, dated 09 / 26 / 2025, page 147 / 421 137 / 233, with at least one of them being decreased interest and pleasure or depressed mood. Symptoms associated with the DSM-5 criteria for MDD include (1) depressed mood (for children and adolescents, this may also be irritable mood); (2) decreased interest or loss of pleasure in nearly 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) feelings of worthlessness; (8) decreased ability to think or concentrate; indecisiveness; (9) recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide. Age-related cognitive impairment

[00138] Age-related cognitive impairment refers to cognitive impairment in older individuals where their cognitive function is not as robust as expected in a normal individual of the same age or in young adult individuals. In some cases, cognitive function is reduced by about 5%, 10%, 30% or more compared to the cognitive function expected in a normal individual of the same age. In some cases, cognitive function is as expected in a normal individual of the same age, but reduced by about 5%, 10%, 30% or more compared to the cognitive function expected in a young adult individual. Age-related cognitive impairment may be associated with mild cognitive impairment (MCI) (including amnestic MCI and non-amnestic MCI), age-related memory impairment (AAMI), and age-related cognitive decline (ARCD).

[00139] Age-related memory impairment (AAMI) refers to a decline in memory due to aging. A patient Petition 870250087689, dated 09 / 26 / 2025, page 148 / 421 138 / 233 may be considered to have AAMI if they are at least 50 years old and meet all of the following criteria: a) The patient has noticed a decline in memory performance; b) The patient performs worse on a standard memory test compared to younger adults; c) All other obvious causes of memory decline, except normal aging, have been ruled out (in other words, the memory decline cannot be attributed to other causes such as a recent heart attack or head injury, depression, adverse drug reactions, Alzheimer's disease, etc.).

[00140] “Age-related Cognitive Decline (ARCD)” refers to declines in memory and cognitive abilities that are a normal consequence of aging in humans (e.g., Craik & Salthouse, 1992). This also applies to virtually all mammalian species. Age-associated memory impairment refers to older adults with objective memory declines relative to their youth, but with normal cognitive functioning relative to their age-matched peers (Crook et al., 1986). Age-consistent memory decline is a less pejorative term, emphasizing that these are normal developmental changes (Crook, 1993; Larrabee, 1996), are not pathophysiological (Smith et al., 1991), and rarely progress to overt dementia (Youngjohn & Crook, 1993). The DSM-IV (1994) codified the diagnostic classification of ARCD, which continued in the DSM-5 (2013) under code 780.9 for ARCD. Drug-induced cognitive dysfunction Corticosteroid-induced cognitive dysfunction

[00141] 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, nephritic syndrome, cancer, organ transplantation, Petition 870250087689, dated 09 / 26 / 2025, page 149 / 421 139 / 233 autoimmune hepatitis, hypersensitivity reactions, cardiogenic and septic shock, glucocorticoid deficiency diseases (Addison's disease and panhypopituitarism), and multiple sclerosis. When the body is under stress, the adrenal glands release corticosteroids, such as cortisol. Synthetic corticosteroids work by mimicking the steroid hormones naturally produced by the adrenal glands. When released into the body's circulatory system, these hormones help regulate inflammation and the immune response. Common synthetic corticosteroids include prednisone, cortisone, hydrocortisone, and methylprednisone. Supplementation of the body's normal hormone levels with synthetic corticosteroids induces a genomic cascade that reduces inflammation and suppresses the immune response. This genomic cascade is initiated by the binding of steroids to intracellular glucocorticoid receptors (GRs) (Datson, NA et al. European Journal of Neuroscience. 2001).

[00142] Despite their widespread use and therapeutic benefits, synthetic corticosteroids frequently cause numerous adverse psychological, metabolic, and somatic side effects (Warrington TP et al. Mayo Clinic Proceedings. 2006). Examples of such somatic side effects include hypertension, accelerated atherosclerosis, acne, alopecia, hirsutism, striae, skin atrophy, purpura, obesity, diabetes mellitus, suppression of the adrenal-pituitary axis, hyperlipidemia, fluid and sodium retention, potassium, calcium, and nitrogen loss, growth retardation, pseudotumor cerebri, peptic ulcer, pancreatitis, hepatic steatosis, leukocytosis, neutrophilia, lymphophageal anemia, oral candidiasis, increased risk of systemic infection, myopathy, osteoporosis, avascular necrosis, cataracts, and glaucoma. Psychological side effects include mood and anxiety disorders, behavioral disturbances, cognitive impairment, and psychosis.

[00143] Cognitive impairment, anxiety and disorders Petition 870250087689, dated 09 / 26 / 2025, page 150 / 421 140 / 233 Mood disorders are among the most common psychological side effects of corticosteroid use. Especially for patients requiring prolonged steroid treatment, these effects result in decreased quality of life. For example, 33% of individuals taking corticosteroids (approximately 13 million) experience deficits in working or short-term memory, declarative memory, attention span and concentration (academic and occupational performance), and executive function (Stoudemire Aefa / .Gen / - / ospPsyc / ? / afry. 1984). In extreme cases, steroids can even induce delirium, dementia (persistent memory impairment), and mania (Varney NRef al., Am J Psychiatry. 1984). Currently, there is no FDA-approved drug for the treatment of cognitive impairment and similar psychiatric disorders, such as anxiety and mood disorders, associated with corticosteroid use.Furthermore, there are no alternatives to corticosteroids for the treatment of inflammatory disorders – corticosteroids must be used. Chemotherapy-induced cognitive dysfunction

[00144] Chemotherapy-related cognitive dysfunction, also known as chemotherapy-related cognitive impairment or chemotherapy fog or chemotherapy brain, is defined as a decline in various neuropsychological tasks following chemotherapy or other anticancer treatments, such as radiation therapy or surgery, in patients with cancers unrelated to the central nervous system. After chemotherapy, the domains most affected are memory, processing speed, attention, and executive functions (Lange M, et al. Ann Oncol. 2019). Asthma

[00145] Asthma is a chronic inflammatory disease of the airways in the lungs caused by a combination of genetic and environmental factors, including exposure to air pollution and allergens. Other Petition 870250087689, dated 09 / 26 / 2025, page 151 / 421 141 / 233 Potential triggers include medications such as aspirin and beta-blockers. Among other events, eosinophilic inflammation has been reported in the airways of patients with asthma. The pathophysiology of the disease is characterized by variable airflow obstruction, airway inflammation, mucus hypersecretion, and subepithelial fibrosis. Clinically, patients may present with cough, wheezing, and shortness of breath. Primary Biliary Cholangitis

[00146] Primary biliary cholangitis (PBC) is an organ-specific autoimmune disease characterized by the progressive and chronic destruction of the small bile ducts of the liver, associated with portal inflammation. The destruction of the bile ducts leads to the accumulation of bile and other toxins in the liver, resulting in scarring, fibrosis, and eventually cirrhosis. PBC is a relatively rare disease, affecting up to one in every 3,000 to 4,000 people, but it predominantly affects 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 upper right abdomen, splenomegaly, musculoskeletal pain, edema, ascites, fatty deposits (xanthomas) on the skin, jaundice, hyperpigmentation, osteoporosis, high cholesterol, diarrhea, and hypothyroidism (Boonstra Kef et al., J Hepatol. 2012). Hypertriglyceridemia

[00147] Hypertriglyceridemia (HTG) is a common metabolic disorder characterized by elevated plasma triglyceride concentrations (i.e., levels above 150 mg / dL), which increases the risk of developing cardiovascular disease. Although most people with hypertriglyceridemia are asymptomatic, those with severe HTG may develop xanthomas. Severe HTG (i.e., levels above 500 mg / dL) has also been associated with an increased risk of pancreatitis. Genetic and lifestyle factors play significant roles in the pathophysiology of HTG. Medications including Petition 870250087689, dated 09 / 26 / 2025, page 152 / 421 142 / 233 Corticosteroids, thiazides, non-selective beta-blockers, estrogen, tamoxifen, bile acid sequestrants, cyclophosphamide, antiretrovirals, and second-generation antipsychotics can also elevate TG levels. The initial and most valuable approach to treating HTG is adapting lifestyle factors that contribute to HTG, including controlling diet, weight, and the non-triglyceride components of metabolic syndrome. However, these approaches are often unreliable due to low patient adherence. Medications such as fibrates (e.g., fenofibrate (PPAR-α agonist)), prescribed omega-3 fatty acids (e.g., Vascepa® (icosapent ethyl, IPE)), and statins are also used to treat TG, but are associated with side effects such as musculoskeletal pain, general weakness, edema, headaches, drowsiness, rash, constipation, and changes in libido (Santos-Baez LS & Ginsberg HN. Front Endocrinol. 2020). Fibromyalgia, long COVID, menopause, and overlapping chronic pain conditions (COPCs)

[00148] Fibromyalgia is a condition characterized by widespread pain, fatigue, sleep disturbances, and cognitive dysfunction or brain fog. It is part of the group of conditions originally called Overlapping Chronic Pain Conditions (OCPCs), but now more commonly called Overlapping Chronic Pain Conditions (OCPCs), which also includes temporomandibular dysfunction (TMD), irritable bowel syndrome (IBS), vulvodynia, myalgic encephalomyelitis / chronic fatigue syndrome, interstitial cystitis / painful bladder syndrome, endometriosis, chronic tension headache, migraine, and chronic low back pain. Epidemiological studies estimate that the prevalence of individual COPCs ranges from approximately 4 million (myalgic encephalomyelitis / chronic fatigue syndrome) to 44 million (IBS). Many COPCs are defined as idiopathic, arising spontaneously without a specific cause. Petition 870250087689, dated 09 / 26 / 2025, page 153 / 421 143 / 233 remains. However, it is currently believed that central sensitization contributes 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 dysfunction.

[00149] Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) (colloquially known as long COVID) is a term used to describe a set of symptoms experienced by people with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months after the onset of COVID-19 infection, with symptoms lasting at least 2 months and not explainable by an alternative diagnosis. PASC symptoms span multiple organ systems, may occur in symptom clusters (i.e., neurological, non-neurological, and systemic), and may also fluctuate or recur over time (Davis et al. EclinicalMedicine. 2021, Crookef al. BMJ. 2021, Bierleef al. J PrimCare Community Health. 2021, WHO 2021). The lack of a standardized definition of PASC makes it difficult to accurately determine the epidemiology, incidence rates, and long-term disability impact of the disease.A conservative estimate, based on data collected in several countries, indicates that, on average, 30% of people with COVID-19 will present with acute respiratory infections (ARI). (Nalbandian et al. Nat Med. 2021).

[00150] PASC is a multifaceted condition affecting multiple body systems. PASC symptoms may appear recently (e.g., recurrent pain), following initial recovery from an acute or even mild episode of COVID-19, or persist from the onset of the illness. Although PASC symptoms vary, pain, fatigue, and sleep disturbances have been considered the main 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). Petition 870250087689, dated 09 / 26 / 2025, page 154 / 421 144 / 233 2021, Sahin et al. EurNeurol. 2021).

[00151] Exemplary clinical symptoms of long COVID include, but are not limited to, fatigue, muscle weakness, diaphoresis, myalgia, arthralgia, chills, limb edema, dizziness, post-exertion malaise, cognitive dysfunction, respiratory symptoms (taprouts, chest pain, cough, expectoration, sore throat), cardiovascular abnormalities, alopecia, olfactory abnormalities, neurocognitive difficulties, including memory and concentration problems, psychological symptoms such as sleep difficulties, depression, anxiety, feelings of inferiority and, generally, poorer quality of life.

[00152] Menopause is the period following the cessation of normal ovulation cycles, during which menstruation ceases. This period is marked by a decrease in hormone production (e.g., estradiol (E2)) in the ovaries, resulting in a change in the body's hormonal balance, which often gives rise to a variety of symptoms associated with menopause. Perimenopause, also known as pre-menopause or climacteric, is the period before menopause, during which normal ovulation cycles gradually give way to the cessation of menstruation. Symptoms of perimenopause, menopause, and post-menopause include physical symptoms such as hot flashes, chills, and sweating, secondary to vasomotor instability. In addition, psychological and emotional symptoms may accompany the onset of the climacteric, such as fatigue, irritability, insomnia, inability to concentrate, depression, memory loss, headache, anxiety, and nervousness.Additional symptoms may include intermittent dizziness, paresthesia, palpitations, and tachycardia, as well as nausea, constipation, diarrhea, arthralgia, myalgia, cold hands and feet, and weight gain. Furthermore, changes in the genitals, urinary incontinence, vaginal dryness, loss of pelvic muscle tone, and an increased risk of cardiovascular disease and osteoporosis increase with the onset of the condition. Petition 870250087689, dated 09 / 26 / 2025, page 155 / 421 145 / 233 menopause. Obesity

[00153] Obesity, defined by the U.S. Centers for Disease Control and Prevention (CDC) as an excessively high amount of body fat or adipose tissue relative to lean body mass, is currently a worldwide epidemic and a major contributor to increased morbidity and mortality. Obesity is associated with leading causes of death, including deaths from diabetes, heart disease, stroke, and some types of cancer.

[00154] In some embodiments, the (S)-enantiomers of this invention (i.e., (S)-tianeptine or 1 lD-(S)-tianeptine) are used to treat obesity and weight gain, particularly in individuals who tend to gain body weight and fat content despite the absence of hyperphagia and a medium- or low-fat diet.In some embodiments, the (S)-enantiomers of this invention (i.e., (S)tianeptine or 11D-(S)-tianeptine) or a tianeptine analogue (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof, or a tianeptine analogue substituted with pharmaceutically acceptable aryl or salts) 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 methods.

[00155] In some respects, the present invention provides a method of treating a disease, disorder or condition modulated by, exacerbated by, or associated with altered activity of peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ) and / or PPAR-γ and one or more symptoms associated therewith, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or Petition 870250087689, dated 09 / 26 / 2025, p. 156 / 421 146 / 233 cocrystal of the (S)-enantiomer of this invention or the zwitterion thereof, or an ester of the (S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, or an 11D-(S)-enantiomer of this invention, the zwitterion thereof or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer of this invention, or a cocrystal of an 11-D-(S)-enantiomer of this invention, or the zwitterion thereof, or an ester of an 11-D-(S)-enantiomer of this invention, or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(S)-enantiomer of this invention, or a pharmaceutically acceptable salt thereof, or a tianeptine analogue (i.e., N-hydroxy-tianeptine, the (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)-enantiomers thereof, or an aryl-substituted tianeptine analogue, or pharmaceutically acceptable salts thereof) of this invention,or a pharmaceutical composition of this invention comprising one or more of the same.

[00156] In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt (including crystalline forms thereof) of the (S)-enantiomer, or cocrystal of the (S)-enantiomer of this invention, or the zwitterion thereof, or an ester of the (S)-enantiomer of this invention, or an amide of the (S)-enantiomer of this invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer of this invention. In some modalities, the method of treating the disease, Petition 870250087689, dated 09 / 26 / 2025, p. 157 / 421 147 / 233 A disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the zwitterion of the (S)-enantiomer of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable salt of the (S)-enantiomer of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable cocrystal of the (S)-enantiomer of this invention.In some embodiments, the method of treating the disease, disorder, or condition modulated by PPARβ / δ and / or PPAR-γ comprises administering to an individual in need of or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable cocrystal of the zwitterion of the (S)-enantiomer of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of or at risk thereof a therapeutically effective amount of an ester of the (S)-enantiomer of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the ester of the (S)-enantiomer of this invention.In some modalities, the treatment method for a disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ involves administering a therapeutically effective amount of a substance to an individual in need of, or at risk of, such a disease. Petition 870250087689, dated 09 / 26 / 2025, page 158 / 421 148 / 233 amide of the (S)-enantiomer of this invention. In some embodiments, the method of treating the disease, disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable salt of an amide of the (S)-enantiomer of this invention.

[00157] In some embodiments, the method of treating the disease, disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of an 11-D-(S)-enantiomer, the zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer of this invention, or a cocrystal of an 11-D-(S)-enantiomer of this invention or the zwitterion thereof, or an ester of an 11-D-(S)-enantiomer of this invention, or an amide of an 11-D-(S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPARY comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of an 11-D-(S)enantiomer of this invention.In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the zwitterion of an 11-D-(S)-enantiomer of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ. Petition 870250087689, dated 09 / 26 / 2025, page 159 / 421 149 / 233 and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable cocrystal of an 11-D-(S)-enantiomer of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable cocrystal of a zwitterion of an 11-D-(S)-enantiomer of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of an ester of an 11-D-(S)-enantiomer of this invention.In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable salt of the ester of an 11D-(S)-enantiomer of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPARβ / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of an amide of an 11-D-(S)-enantiomer of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable amide salt of an 11-D-(S)-enantiomer of this invention.

[00158] In some modalities, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ involves administering to an individual in need of, or at risk of Petition 870250087689, dated 09 / 26 / 2025, page 160 / 421 150 / 233 of, a therapeutically effective amount of N-hydroxy-tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, or N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or the (R)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating the disease, disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the N-hydroxy-tianeptine of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable salt of the N-hydroxy-tianeptine of this invention.In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer of N-hydroxy-tianeptine of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxy-tianeptine of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the (R)-enantiomer of N-hydroxy-tianeptine of this invention.In some modalities, the treatment method for the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ involves administering a therapeutic amount to an individual in need of, or at risk of, such a condition. Petition 870250087689, dated 09 / 26 / 2025, page 161 / 421 151 / 233 therapeutically effective of a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy-tianeptine of this invention. In some embodiments, the method of treating the disease, disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the N-nitroso-tianeptine of this invention. In some embodiments, the method of treating the disease, disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable salt of the N-nitroso-tianeptine of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer of N-nitroso-tianeptine of this invention.In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-tianeptine of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the (R)-enantiomer of N-nitroso-tianeptine of this invention. In some embodiments, the method of treating the disease, disorder, or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable salt of the (R)enantiomer of N-nitroso-tianeptine of this invention.In some modalities, the method of treating the disease, disorder, or condition. Petition 870250087689, dated 09 / 26 / 2025, page 162 / 421 152 / 233 modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the aryl-substituted tianeptine analogue of this invention. In some embodiments, the method of treating the disease, disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutically acceptable salt of the aryl-substituted tianeptine analogue of this invention.

[00159] In some embodiments, the method of treating the disease, disorder or condition modulated by PPAR-β / δ and / or PPAR-γ comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of a pharmaceutical composition of this invention.

[00160] In some aspects, the present invention provides a method for treating a disease, disorder, or condition, and one or more associated symptoms thereof, in an individual who has experienced high stress. In some embodiments, the disease, disorder, or condition is caused by prenatal or early life adversity, or by childhood trauma, and such disease, disorder, or condition, in some embodiments, manifests itself by subsequent violent behavior. In some embodiments, the disease, disorder, or condition in an individual who has experienced high stress is modulated, exacerbated, or associated with altered activity of peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ) and / or PPAR-γ. Without wishing to be bound by theory, prolonged stress (prenatal, postnatal, or both) leads to an increase in the production of free radicals, primarily in the brain.The (S)-enantiomers of this invention (i.e., (S)-tianeptine or 11-D-(S)tianeptine) are activated in the presence of free radicals, forming a C11 tianeptine free radical intermediate (a radical that can be displaced). Petition 870250087689, dated 09 / 26 / 2025, p. 163 / 421 153 / 233 (composed of 13 carbon atoms, 2 nitrogen atoms, 2 oxygen atoms, and 1 sulfur atom), capable of covalent interaction and irreversible activation of PPAR-δ / β and / or PPAR-γ. These free radicals can form while the (S)-tianeptine enantiomer is bound to the PPAR ligand binding site (LBS), leading to preferential covalent binding of (S)-tianeptine to a PPAR LBS due to the chiral geometry of the site.

[00161] In some respects, the present invention provides a method of treating a disease, disorder or condition modulated by, exacerbated by, or associated with high levels of S-nitrosylation of the receptor. In some respects, the present invention provides a method of treating a disease, disorder, or condition modulated by, exacerbated by, or associated with elevated levels of S-nitrosylation of PPAR-β / δ and / or PPAR-γ, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer of this invention or the zwitterion thereof, or an ester of the (S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, or an 11-D-(S)-enantiomer of this invention, the zwitterion thereof.or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer of this invention, or a cocrystal of an 11-D-(S)-enantiomer of this invention or the zwitterion thereof, or an ester of an 11-D-(S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, or an amide of the 11D-(S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this invention comprising one or more of the same. Without wishing to be bound by theory, the (S)-enantiomer of this invention (i.e., (S)-tianeptine or 11-D-(S)tianeptine) reacts with S-nitroso-PPAR-β / δ and / or S-nitroso-PPAR-γ to, Petition 870250087689, dated 09 / 26 / 2025, p. 164 / 421 154 / 233 form S-nitroso-(S)-enantiomer and non-nitrosylated PPAR-β / δ and / or PPAR-γ.

[00162] In some respects, the methods of treating a disease, disorder, or condition modulated by, exacerbated by, or associated with altered activity of the peroxisome proliferator-activated receptor-β / δ (PPAR-β / δ) and / or PPAR-γ of this invention are improved over methods using racemic mixtures of tianeptine enantiomers, their zwitterions, salts, cocrystals, and esters, since the methods of this invention result in reduced μ-opioid receptor agonism. The reduced μ-opioid receptor agonism of the (S)-enantiomers of this invention (i.e., (S)-tianeptine or 11D-(S)-tianeptine) compared with racemic mixtures of tianeptine enantiomers minimizes the potential for opioid abuse, opioid toxicity, and opioid overdose (e.g., opioid-induced respiratory depression). (OIRD).

[00163] In some respects, the present invention provides a method of treating a disease, disorder or condition selected from the group consisting of a central nervous system (CNS) disorder, inflammatory disease, autoimmune disease, infectious disease, a hearing loss condition, eye disease, musculoskeletal disease, metabolic disease, mitochondrial disease, hypertriglyceridemia, cancer, menopause and overlapping chronic pain conditions (COPCs) and psychological, physical, metabolic or hormonal stress and COPCs, comprising administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or cocrystal of the (S)-enantiomer of this invention or the zwitterion thereof, or an ester of the (S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof,or an amide of the (S)enantiomer of this invention or a pharmaceutically acceptable salt of, Petition 870250087689, dated 09 / 26 / 2025, p. 165 / 421 155 / 233 itself or an 11-D-(S)-enantiomer of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer of this invention, or a cocrystal of an 11-D-(S)-enantiomer of this invention or the zwitterion thereof, or an ester of an 11-D-(S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(S)-enantiomer, or a tianeptine analogue (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof or an aryl-substituted tianeptine analogue or pharmaceutically acceptable salts thereof) of this invention or a pharmaceutical composition of this invention comprising one or more of them.

[00164] In some respects, the present invention provides a method of treating a disease, disorder, or condition modulated by, exacerbated by, or associated with excessive levels of circulating metal ions, comprising administering to an individual in need of or at risk thereof a therapeutically effective amount of the (S)-enantiomer of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer of this invention, or the zwitterion thereof, or an ester of the (S)-enantiomer of this invention, or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this invention, or a pharmaceutically acceptable salt thereof, or an 11-D-(S)-enantiomer of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer of this invention, or a cocrystal of an 11-D-(S)-enantiomer of this invention, or the zwitterion thereof, or an ester of an 11-D-(S)-enantiomer of this invention,or a pharmaceutically acceptable salt thereof, or an amide of the 11-D(S)-enantiomer of this invention, or a tianeptine analogue (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof, or a tianeptine analogue, Petition 870250087689, dated 09 / 26 / 2025, p. 166 / 421 156 / 233 aryl-substituted tianeptine or pharmaceutically acceptable salts thereof) of this invention, or a pharmaceutical composition of this invention comprising one or more thereof. In some embodiments, the metal ion is iron or copper. In some embodiments, the (S)-enantiomer of this invention (i.e., (S)-tianeptine or 1 1D-(S)-tianeptine) or tianeptine analogue (i.e., N-hydroxy-tianeptine, (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, (S)- and (R)-enantiomers thereof, or an aryl-substituted tianeptine analogue or pharmaceutically acceptable salt) is administered to an individual with elevated levels of iron or copper ions as determined by a blood test or a cerebrospinal fluid (CSF) test.Without wishing to be bound by theory, the (S)-enantiomers of this invention (i.e., (S)-tianeptine or 1 1D-(S)-tianeptine) or tianeptine analogue (i.e., N-hydroxytianeptine, the (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)-enantiomers thereof or an aryl-substituted tianeptine analogue or pharmaceutically acceptable salts thereof) are activated in the presence of free radicals (e.g., hydroxyl radicals) produced by the reaction of free iron or copper with oxygen and hydrogen peroxide, forming a C11 free radical intermediate of tianeptine (which radical can be delocalized into 13 carbon atoms, 2 nitrogen atoms, 2 oxygen atoms and 1 sulfur atom) capable of covalent interaction with and irreversible activation of PPARδ / β and / or PPAR-γ.These free radicals can form while the (S)-tianeptine enantiomer is bound to the PPAR ligand binding site (LBS), leading to preferential covalent binding of (S)-tianeptine to a PPAR LBS due to the chiral geometry of the site. In some modalities, the disease, disorder, or condition modulated, exacerbated, or associated with excessive levels of circulating metal ions is a disease, disorder, or condition modulated, exacerbated, or associated with altered peroxisome proliferator-activated receptor activity. Petition 870250087689, dated 09 / 26 / 2025, p. 167 / 421 157 / 233 ma-β / δ (PPAR-β / δ) and / or PPAR-γ.

[00165] In some respects, the present invention provides a method for reducing violent or aggressive behavior associated with a CNS disorder, comprising administering to an individual in need of or at risk thereof a therapeutically effective amount of the (S)-enantiomer of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer of this invention, or the zwitterion thereof, or an ester of the (S)-enantiomer of this invention, or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this invention, or a pharmaceutically acceptable salt thereof, or an 11-D-(S)-enantiomer of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer of this invention, or a cocrystal of an 11-D-(S)-enantiomer of this invention. invention, or a zwitterion thereof, or an ester of an 11-D-(S)-enantiomer of this invention, or a pharmaceutically acceptable salt thereof,or an amide of the 11-D(S)-enantiomer of this invention, or a pharmaceutically acceptable salt thereof, or a tianeptine analogue (i.e., N-hydroxy-tianeptine, the (S)- and (R)-enantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)-enantiomers thereof, or an aryl-substituted tianeptine analogue or pharmaceutically acceptable salts thereof) of this invention, or a pharmaceutical composition of this invention comprising one or more thereof.

[00166] In some respects, the present invention provides a method for reducing the potential for hospitalization in a psychiatric hospital or incarceration due to behavior or actions associated with a CNS disorder, comprising administering to an individual in need or at risk thereof a therapeutically effective amount of the (S)-enantiomer of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or cocrystal of Petition 870250087689, dated 09 / 26 / 2025, p. 168 / 421158 / 233 (S)-enantiomer of this invention or the zwitterion thereof, or an ester of the (S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof or an 11-D-(S)-enantiomer of this invention, the zwitterion thereof, or a pharmaceutically acceptable salt of an 11-D-(S)-enantiomer of this invention, or a cocrystal of an 11-D-(S)-enantiomer of this invention or the zwitterion thereof, or an ester of an 11-D-(S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof, or an amide of the 11-D(S)-enantiomer of this invention or a pharmaceutically acceptable salt thereof or a tianeptine an...

Claims

1. (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ylamino)heptanoic acid ((S)-enantiomer of tianeptine) of general formula (Ia), the zwitterion thereof of formula (Ib) or a pharmaceutically acceptable salt of the (S)-enantiomer, or a mixture of two or more of these species, characterized in that the (S)-enantiomer, zwitterion or pharmaceutically acceptable salt is particularized by comprising < about 2% of the (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer:

2. (S)-enantiomer, according to claim 1, characterized in that the (S)-enantiomer, the zwitterion or the pharmaceutically acceptable salt of the (S)-enantiomer are particularized by comprising < about 0.1% of the (R)-enantiomer of tianeptine or the zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer.

3. Pharmaceutically acceptable salt of the (S)-enantiomer, according to claim 1 or 2, characterized in that the pharmaceutically acceptable salt is (S)-tianeptine benzenesulfonate (1:1), (S)-tianeptine fumarate (1:1), (S)-tianeptine fumarate (2:1), (S)-tianeptine hippurate (1:1), (S)-tianeptine maleate (1:1), (S)-tianeptine maleate (2:1), (S)-tianeptine p-toluenesulfonate (1:1), (S)-tianeptine orotate (1:1), (S)-tianeptine camphorsulfonate (1:1), (S)-tianeptine N-acetyl-L-tyrosinate (1:1), (S)-tianeptine polyesterix, Petition 870250087689, dated 09 / 26 / 2025, page 245 / 421 2 / 28 (S)-tianeptine: L-DBTA (2:1), (S)-tianeptine sodium, (S)-tianeptine oxalate or (S)-tianeptine hemioxalate (2:1).

4. Pharmaceutically acceptable salt of the (S)-enantiomer according to claim 3, characterized in that the pharmaceutically acceptable salt is (S)-tianeptine hemioxalate (2:1).

5. Zwitterion, characterized in that it comprises the zwitterion of the (S)-enantiomer, as defined in claim 1 or 2.

6. Cocrystal of the (S)-enantiomer, as defined in claim 1 or 2, characterized in that the (S)-enantiomer or zwitterion thereof forms a complex with L-tyrosine, L-tryptophan, L-phenylalanine or another L-amino acid.

7. Ester of the (S)-enantiomer, as defined in claim 1 or 2, characterized in that the ester of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof, is particularized by comprising < about 2% of the ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof.

8. Ester of the (S)-enantiomer, according to claim 7, characterized in that the ester of the (S)-enantiomer, or a pharmaceutically acceptable salt thereof, is particularized by comprising < about 0.1% of the ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof.

9. (S)-enantiomer amide, as defined in claim 1 or 2, characterized in that the (S)-enantiomer amide, or a pharmaceutically acceptable salt thereof, is particularized by comprising < about 2% of the (R)-enantiomer amide or a pharmaceutically acceptable salt thereof.

10. (S)-enantiomer amide, according to claim 9, characterized in that the (S)-enantiomer amide, or pharmaceutically acceptable salt thereof, is particularized by comprising < about 0.1% of the (R)-enantiomer amide or pharmaceutically acceptable salt thereof.

11. (S)-enantiomer of deuterated 7-((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl-11-d)amino)heptanoic acid (11-D-(S)-enantiomer of tianeptine) of general formula (IIa) or the zwitterion thereof of formula (IIb) or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a mixture of two or more of these species, characterized in that deuterium replaces the hydrogen at position 11, and wherein the 11-D-(S)-enantiomer or zwitterion, or pharmaceutically acceptable salt thereof, is particularized by comprising < about 2% of the 11-D-(R)-enantiomer of tianeptine or the zwitterion thereof, or pharmaceutically acceptable salt thereof, of the 11-D-(R) enantiomer: Formula (IIa) Formula (llb).

12. (S)-enantiomer, according to claim 11, characterized in that the 11-D-(S)-enantiomer, the zwitterion or the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer are particularized by comprising < about 0.1% of the 11-D-(R)-enantiomer of tianeptine or the zwitterion thereof, or a pharmaceutically acceptable salt of that enantiomer.

13. (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 is particularized by reduced racemization at position 11 compared with the (S)-enantiomer of tianeptine or the zwitterion or a pharmaceutically acceptable salt of that enantiomer.

14. Pharmaceutically acceptable salt of 11-D-(S) Petition 870250087689, dated 09 / 26 / 2025, p. 247 / 421 4 / 28 enantiomer, according to any one of claims 11 to 13, characterized in that the pharmaceutically acceptable salt is benzenesulfonate of 11-D-(S)-tianeptine (1:1), fumarate of 11-D-(S)-tianeptine (1:1), fumarate of 11-D-(S)-tianeptine (2:1), hippurate of 11-D-(S)-tianeptine (1:1), maleate of 11-D-(S)-tianeptine (1:1), maleate of 11-D-(S)-tianeptine (2:1), p-toluenesulfonate of 11-D-(S)-tianeptine (1:1), orotate of 11-D-(S)-tianeptine (1:1), camphorsulfonate of 11-D-(S)-tianeptine (1:1), 11-D-(S)-tianeptine N-acetyl-L-tyrosinate (1:1), 11-D-(S)-tianeptine polyesterixde, 11-D-(S)-tianeptine: L-DBTA(2:1), 11-D(S)-tianeptine sodium, 11-D-(S)-tianeptine oxalate or sodium hemi-oxalate 11-D-(S)-tianeptine (2:1).

15. Pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, according to claim 14, characterized in that the pharmaceutically acceptable salt is the 11-D-(S)-tianeptine hemioxalate (2:1).

16. Zwitterion, characterized in that it comprises the zwitterion of the 11-D-(S)-enantiomer, as defined in any one of claims 11 to 13.

17. Cocrystal of the 11-D-(S)-enantiomer, as defined in any one of claims 11 to 13, characterized in that the 11-D-(S)-enantiomer or its zwitterion forms a complex with L-tyrosine, L-tryptophan, L-phenylalanine or another L-amino acid.

18. Ester of the (S)-enantiomer, as defined in any one of claims 11 to 13, characterized in that the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof is particularized by comprising < about 2% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof.

19. Ester of the (S)-enantiomer, according to claim 18, characterized in that the 11-D-(S)-enantiomer ester or pharmaceutically acceptable salt thereof, is particularized by Petition 870250087689, dated 09 / 26 / 2025, p. 248 / 421 5 / 28 comprising < about 0.1% of the 11-D-(R)-enantiomer ester or pharmaceutically acceptable salt thereof.

20. Amide of the (S)-enantiomer, as defined in any one of claims 11 to 13, characterized in that the amide of the 11-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, is particularized by comprising < about 2% of the amide of the 11-D-(R)-enantiomer or pharmaceutically acceptable salt thereof.

21. Amide of the (S)-enantiomer, according to claim 20, characterized in that the amide of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, is particularized by comprising < about 0.1% of the amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

22. Pharmaceutically acceptable acid salt of the (S)-enantiomer or 11-D-(S)-enantiomer, according to any one of claims 1, 2 or 11 to 13, characterized in that the nitrogen atom in the side chain attached to Carbon-11 (C-11) is 100% protonated, the 100% protonated salt being less susceptible to oxidation by air, in solid forms or in solution, when compared to the (S)-enantiomer, the 11-D-(S)-enantiomer, the zwitterion of either, or the sodium salts of either.

23. Pharmaceutical composition, characterized in that it comprises the (S)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or zwitterion thereof, as defined in any of claims 1 to 6, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, as defined in claim 7 or 8, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, as defined in claim 9 or 10 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises < about 2% of Petition 870250087689, dated 09 / 26 / 2025, p.249 / 421 6 / 28 (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or 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.

24. Pharmaceutical composition, according to claim 23, characterized in that the pharmaceutical composition comprises < about 0.1% of the (R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the (R)-enantiomer, or a cocrystal of the (R)-enantiomer or 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. Pharmaceutical composition, characterized in that it comprises the 11-D-(S)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a cocrystal of the 11-D-(S)-enantiomer or zwitterion thereof, as defined in any one of claims 11 to 17, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, as defined in claim 18 or 19, or an amide of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, as defined in claim 20 or 21, and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition comprises < about 2% of the 11-D-(R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the 11-D(R)-enantiomer, or a cocrystal of the 11-D-(R)-enantiomer or zwitterion thereof, or an ester of the 11-D-(R)-enantiomer, or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(R)-enantiomer,or a pharmaceutically acceptable salt thereof.

26. Pharmaceutical composition, according to claim 25, characterized in that the pharmaceutical composition Petition 870250087689, dated 09 / 26 / 2025, page 250 / 421 7 / 28 comprises < about 0.1% of the 11-D-(R)-enantiomer of tianeptine, the zwitterion thereof or a pharmaceutically acceptable salt of the 11-D(R)-enantiomer, or cocrystal of the 11-D-(R)-enantiomer or zwitterion thereof, or the ester of the (R)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the 11-D-(R)-enantiomer or a pharmaceutically acceptable salt thereof.

27. Pharmaceutical composition, according to any one of claims 23 to 26, characterized in that the composition is in the form of a tablet, a thin film, a powder, a coated tablet, a capsule, a soft gel, a suppository, a nasal spray, an oral spray or a lung spray.

28. Pharmaceutical composition, according to any one of claims 23 to 26, characterized in that the composition is formulated for immediate release, controlled release, sustained release, prolonged release or slow release of the (S)-enantiomer or the 11-D-(S)-enantiomer, or the zwitterion, or an ester or an amide of either, or a pharmaceutically acceptable salt of either, or a cocrystal of the (S)-enantiomer or the 11-D-(S)-enantiomer or the zwitterion of either.

29. Pharmaceutical composition, characterized in that it comprises a mixture of two or more pharmaceutically acceptable salts or cocrystals of the (S)-enantiomer or 11-D-(S)-enantiomer, as defined in any one of claims 23 to 26, wherein the mixture is particularized by enhanced prolonged release when administered orally compared with the administration of a composition comprising a single pharmaceutically acceptable salt or cocrystal of the (S)-enantiomer or 11-D-(S)-enantiomer, as defined in any one of claims 23 to 26.

30. Method for treating a disease, disorder or condition modulated, exacerbated or associated with altered activity of Petition 870250087689, dated 09 / 26 / 2025, p. 251 / 421 8 / 28 peroxisome proliferator-activated receptor (PPAR)-pZõ and / or PPAR-γ and one or more associated symptoms thereof, characterized in that it comprises administering to an individual in need of or at risk thereof, a therapeutically effective amount of the (S)-enantiomer, the zwitterion thereof or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or the zwitterion thereof, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 10 and 22, or a pharmaceutical composition, as defined in any one of claims 23, 24 and 27 to 29.

31. A method for treating a disease, disorder, or condition modulated, exacerbated, or associated with altered activity of the peroxisome proliferator-activated receptor (PPAR)-pZõ or PPAR-γ and one or more associated symptoms thereof, characterized in that it comprises administering to an individual in need of or at risk thereof, a therapeutically effective amount of the 11-D(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, or a 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 (S)-enantiomer or its pharmaceutically acceptable salt, as defined in any one of claims 11 to 22, or a pharmaceutical composition, as defined in any one of claims 11 to 22. 25 to 29.

32. Method, according to claim 30 or 31, characterized in that the disease, disorder or condition is selected from the group consisting of a central nervous system (CNS) disorder, inflammatory disease, autoimmune disease, infectious disease, Petition 870250087689, dated 09 / 26 / 2025, page 252 / 421 9 / 28 hearing loss, eye disease, musculoskeletal disease, metabolic disease, mitochondrial disease, hypertriglyceridemia, cancer, menopause and overlapping chronic pain conditions (COPCs), and psychological, physical, metabolic or hormonal stress and COPCs.

33. Method, according to claim 32, characterized in that the CNS disorder is selected from the group consisting of a mood disorder, a trauma- and stress-related disorder, an anxiety disorder, obsessive-compulsive disorder, a neurodegenerative or neuroinflammatory disorder, a neurodevelopmental disorder, a leukodystrophy, and CNS oxidative stress.

34. Method according to claim 33, characterized in that the mood disorder is a depressive disorder, a bipolar disorder, or a substance-induced disorder.

35. Method, according to claim 34, characterized in that the depressive disorder is major depressive disorder (MDD).

36. A method for treating a disease, disorder, or condition modulated, exacerbated, or associated with altered activity of peroxisome proliferator-activated receptor (PPAR)-pZo or PPAR-γ and one or more associated symptoms thereof, in an individual who has suffered high stress, characterized in that it comprises administering to the individual a therapeutically effective amount of the (S)-enantiomer, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or the zwitterion thereof, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 10 and 22, or a pharmaceutical composition, as defined in any one of claims 23, 24. 870250087689, of 09 / 26 / 2025, p. 253 / 421 10 / 28 or 27 to 29.

37. A method for treating a disease, disorder, or condition modulated, exacerbated, or associated with altered activity of the peroxisome proliferator-activated receptor (PPAR)-pZo and / or PPAR-γ and one or more associated symptoms thereof, in an individual who has suffered high stress, characterized in that it comprises administering to the individual a therapeutically effective amount of the 11-D-(S)-enantiomer, the zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11-D-(S)-enantiomer or the 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, as defined in any one of claims 11 to 22, or a pharmaceutical composition, as defined in any one of claims 11 to 22. 25 to 29.

38. A method according to claim 36 or 37, characterized in that the stress is caused by childhood adversity or childhood trauma.

39. A method for treating a disease, disorder, or condition modulated by, exacerbated by, or associated with altered activity of the peroxisome proliferator-activated receptor (PPAR)-pZõ or PPAR-γ and one or more associated symptoms thereof, while reducing the μ-opioid receptor agonism associated with racemic tianeptine treatment, characterized in that it comprises administering to an individual in need of, or at risk of, a therapeutically effective amount of the (S)-enantiomer, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or the zwitterion thereof, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof. Petition 870250087689, of 26 / 09 / 2025, p.254 / 421 11 / 28 acceptable of the same, as defined in any one of claims 1 to 10 and 22, or a pharmaceutical composition as defined in any one of claims 23, 24 and 27 to 29.

40. A method for treating a disease, disorder, or condition modulated, exacerbated, or associated with altered activity of the peroxisome proliferator-activated receptor (PPAR)-β and / or PPAR-γ and one or more symptoms thereof, while reducing μ-opioid receptor agonism associated with racemic tianeptine treatment, characterized in that it comprises administering to an individual in need of, or at risk of, the same, a therapeutically effective amount 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, as defined in any one of claims 11 to 22, or a pharmaceutical composition, as defined in any one of claims 25 to 26.

29.

41. A method according to any one of claims 30 to 40 or 59, characterized in that the (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or the zwitterion thereof, or the ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or the amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, the cocrystal of the 11-D-(S)-enantiomer or the zwitterion thereof, or the ester of the 11-D-(S)-enantiomer or the pharmaceutically acceptable salt thereof, or 11-D-(S)-enantiomer amide or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered once or more times daily. Petition 870250087689, dated 09 / 26 / 2025, p. 255 / 421 12 / 28 42. A method according to any one of claims 30 to 40 or 59, characterized in that the (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or the zwitterion thereof, or the ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or the amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, the cocrystal of the 11-D-(S)-enantiomer or the zwitterion thereof, or the ester of the 11-D-(S)-enantiomer or the pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer amide or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered parenterally, orally, sublingually, buccally, by inhalation, palatial route, transdermally, rectally or vaginally.

43. A method according to any one of claims 30 to 42 or 59, characterized in that the (S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or the zwitterion thereof, or the ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or the amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer, the zwitterion or ester thereof, the pharmaceutically acceptable salt of the 11-D-(S)-enantiomer, the cocrystal of the 11-D-(S)-enantiomer or the zwitterion thereof, or the ester of the 11-D-(S)-enantiomer or the pharmaceutically acceptable salt thereof, or the 11-D-(S)-enantiomer amide or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered sequentially or concomitantly with one or more additional therapeutic agents selected from the group consisting of an antidepressant, an anticonvulsant, an anxiolytic, an antipsychotic,a cholinesterase inhibitor, an N-methyl-D-aspartate (NMDA) receptor antagonist, a 5HT2 modulator, a corticosteroid, an anti-amyloid agent, an anti-tau agent, and a chemotherapeutic agent.

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

45. Method for reducing the potential racemization of the (S)-enantiomer, its zwitterion, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or its zwitterion, or the ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or the amide of the (S)-enantiomer or its pharmaceutically acceptable salt, as defined in any one of claims 1 to 10 and 22, characterized in that it comprises the step of deuterating the (S)-enantiomer, its zwitterion, the pharmaceutically acceptable salt of the (S)-enantiomer, the cocrystal of the (S)-enantiomer or its zwitterion, or the ester of the (S)-enantiomer or its pharmaceutically acceptable salt, or the amide of the (S)-enantiomer or its salt. pharmaceutically acceptable of the same in position C-11.

46. ​​Method for producing the (S)-enantiomer of tianeptine, Petition 870250087689, dated 09 / 26 / 2025, p. 257 / 421 14 / 28 as defined in claim 1 or 2, characterized in that said method comprises the steps of: (i) resolving a racemic mixture or other mixture of the (S)- and (R)-enantiomers of a chiral amine tianeptine intermediate, wherein the mixtures are particularized by > 0.1% of the (R)-enantiomer of the chiral amine tianeptine intermediate, by enantioselective crystallization using a (S)-enantiomer selective conformer in a solvent mixture to produce a (S)amine tianeptine intermediate: (S)-enantiomer selective conformer, wherein the (S)amine tianeptine intermediate: (S)-enantiomer selective conformer crystallized from the solvent mixture is particularized by comprising < 2% of the (R)amine tianeptine intermediate: (R)-enantiomer selective conformer;(ii) reacting the tianeptine intermediate of (S)-amine: selective conformer of (S)-enantiomer with an alkyl ester of 7-bromoheptanoate to produce an alkyl ester intermediate of 11-D-(S)-tianeptine: selective conformer of (S)-enantiomer; (iii) reacting the alkyl ester intermediate of 11-D-(S)-tianeptine: selective conformer of (S)-enantiomer with a base to produce the alkyl ester intermediate of 11-D-(S)-tianeptine; and (iv) saponifying the alkyl ester intermediate of 11-D(S)-tianeptine to produce the (S)-enantiomer of tianeptine, comprising < 2% of the (R)-enantiomer of tianeptine.

47. Method according to claim 46, characterized in that the (S)-enantiomer of tianeptine is particularized by < 0.1% of the (R)-enantiomer of tianeptine.

48. Method for producing 11-D-(S)-tianeptine, as defined in claim 11 or 12, characterized in that it comprises the steps of: (i) resolving a racemic mixture or other mixture of (S) Petition 870250087689, dated 09 / 26 / 2025, p. 258 / 421 15 / 28 and (R)-enantiomers of a chiral amine 11-D-tianeptine intermediate, mixtures which are particularized by > 0.1% of the (R)-enantiomer of the chiral amine 11-D-tianeptine intermediate by enantioselective crystallization using a (S)-enantiomer selective conformer in a solvent mixture to produce an (S)-amine 11-D-tianeptine intermediate: (S)-enantiomer selective conformer, the (S)-amine 11-D-tianeptine intermediate: (S)-enantiomer selective conformer being crystallized from the solvent mixture and being particularized by comprising < 2% of the (R)-amine 11-D-tianeptine intermediate: (R)-enantiomer selective conformer;(ii) reacting the 11-D-tianeptine intermediate of (S)-amine: selective conformer of the (S)-enantiomer with an alkyl ester of 7-bromoheptanoate to produce an alkyl ester intermediate of 11D-(S)-tianeptine: selective conformer of the (S)-enantiomer; (iii) reacting the alkyl ester intermediate of 11-D-(S)-tianeptine: selective conformer of the (S)-enantiomer with a base to produce the alkyl ester intermediate of 11-D-(S)-tianeptine; and (iv) saponifying the alkyl ester intermediate of 11-D-(S)tianeptine to produce the 11-D-(S)-enantiomer of tianeptine, wherein the 11D-(S)-tianeptine comprises < 2% of the (R)-enantiomer of 11-D-tianeptine.

49. Method according to claim 48, characterized in that the (S)-enantiomer of 11-D-tianeptine is particularized by < 0.1% of the (R)-enantiomer of 11-D-tianeptine.

50. Method for producing the (S)-enantiomer of tianeptine or zwitterion thereof, as defined in claim 1 or 2, characterized in that said method comprises the steps of: (i) resolving a racemic mixture or other mixture of the (S)- and (R)-enantiomers of an alkyl ester of tianeptine, such mixtures Petition 870250087689, dated 09 / 26 / 2025, p. 259 / 421 16 / 28 particularized by > 0.1% of the (R)-enantiomer of a tianeptine alkyl ester by enantioselective crystallization using a (R)-enantiomer selective conformer in a solvent mixture to produce a (R)-tianeptine alkyl ester: (R)-enantiomer selective conformer and an 11-D-(S)-tianeptine alkyl ester: (R)-enantiomer selective conformer, crystallizing and separating the (R)-tianeptine alkyl ester from the solvent mixture, the 11-D-(S)-tianeptine alkyl ester remaining in the solvent mixture and being particularized by comprising < 2% of the (R)-tianeptine alkyl ester;(ii) hydrolyze the alkyl ester of 11-D-(S)-tianeptine: selective conformer of (R)-enantiomer with a strong acid to produce the acid salt of 11-D-(S)-tianeptine, wherein the acid salt of tianeptine comprises < 2% of the acid salt of (R)-tianeptine; and (iii) neutralize the acid salt of 11-D-(S)-tianeptine with a base to produce the zwitterion of the (S)-enantiomer of tianeptine.

51. Method for producing the 11-D-(S)-enantiomer or zwitterion thereof, as defined in claim 11 or 12, characterized in that said method comprises the steps of: (i) resolving a racemic or other mixture of the (S)- and (R)-enantiomers of an 11-D-tianeptine alkyl ester, said mixtures being particularized by >0.1% of the (R)-enantiomer of an 11-D-tianeptine alkyl ester, by enantioselective crystallization using an R-enantiomer-selective conformer in a solvent mixture to produce an 11-D-(R)-tianeptine alkyl ester: R-enantiomer-selective conformer and an 11-D-(S)-tianeptine alkyl ester: R-enantiomer-selective conformer, crystallizing and separating the alkyl ester of 11-D-(R)-tianeptine from the solvent mixture, the alkyl ester of 11-D-(S)-tianeptine remaining in the solvent mixture and being particularized by comprising < 2% of the alkyl ester of 11-D-(R)-tianeptine; Petition 870250087689, dated 09 / 26 / 2025, p.260 / 421 17 / 28 (ii) hydrolyze the selective conformer of the alkyl ester (R) of 11-D-(S)-tianeptine with a strong acid to produce the acid salt of 11-D-(S)-tianeptine, wherein the acid salt of 11-D-tianeptine comprises < 2% of the acid salt of 11-D-(R)-tianeptine; and (iii) neutralize the acid salt of 11-D-(S)-tianeptine with a base to produce the zwitterion of the 11-D-(S)-enantiomer of tianeptine.

52. Method according to any one of claims 46 to 51, characterized in that the alkyl ester of tianeptine is a methyl ester, an ethyl ester or any other C1C6 alkyl ester.

53. Method, according to any one of claims 46 to 51, characterized in that the enantioselective crystallization comprises the use of a conformer selected from the group consisting of L-dibenzoyl tartaric acid (DBTA), D-DBTA, di-o-toluoyl-L-tartaric acid (LD(2-Me)BTA), DD(2-Me)BTA, other DBTA derivatives, (S)-1,1'-Bi-2-naphthol-2,2'-di-yl hydrogen phosphate, (R)-1,1'-Bi-2-naphthol-2,2'-di-yl hydrogen phosphate, (S)-(R)-mandelic acid, (R)-(S)-mandelic acid, (S)-(S)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid, acid (R)(S)-alpha-methoxy-alpha-trifluoromethylphenylacetic (1S)-(R)-10-camphorsulfonic acid and (1R)-(R)-10-camphorsulfonic acid.

54. Method according to any one of claims 46 to 51, characterized in that the solvent comprises a mixture of benzene, acetone and trichloromethane.

55. Method, according to any one of claims 46 to 51, characterized in that the enantioselective crystallization of the (S)-amine tianeptine intermediate: selective conformer (S)-enantiomer, of the (S)-amine 11-D-tianeptine intermediate: selective conformer (S)-enantiomer, of the (R)-tianeptine alkyl ester: selective conformer (R)-enantiomer or of the 11-D-(R)tianeptine alkyl ester: selective conformer (R)-enantiomer comprises the step of slow evaporation of the solvent mixture.

56. Method, according to any one of claims 46 to 55, characterized in that enantioselective crystallization is repeated to enhance the enantiomeric purity or chiral purity of the resolved (S)-amine tianeptine intermediate, the (S)-amine 11-D-tianeptine intermediate, the 11-D-(S)-tianeptine methyl ester, or the 11-D-(S)-tianeptine methyl ester.

57. Method, according to any one of claims 46 to 51, characterized in that the resolution of the racemic mixture or other mixture is carried out by means of high-performance liquid chromatography (HPLC).

58. Method, according to any one of claims 46 to 51, characterized in that the resolution of the racemic mixture or other mixture is carried out by means of supercritical fluid chromatography with a chiral column.

59. A method for treating a selected disease, disorder or condition from the group consisting of a central nervous system (CNS) disorder, inflammatory disease, autoimmune disease, infectious disease, a hearing loss condition, eye disease, musculoskeletal disease, metabolic disease, mitochondrial disease, hypertriglyceridemia, cancer, menopause and overlapping chronic pain conditions (COPCs) and psychological, physical, metabolic or hormonal stress and COPCs, characterized in that it comprises administering to an individual in need of, or at risk of, the same, a therapeutically effective amount of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or zwitterion thereof, or an ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 10 and 22, or a pharmaceutical composition, as defined in any one of claims 23,Petition 870250087689, dated 09 / 26 / 2025, p. 262 / 421 19 / 28 24 or 27 to 29 or administer to the individual a therapeutically effective amount of the 11-D-(S)-enantiomer, its zwitterion, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a 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 (S)-enantiomer or its pharmaceutically acceptable salt, as defined in any one of claims 11 to 22, or a pharmaceutical composition, as defined in any one of claims 25 to 29.

60. Method for enhancing neurite growth, characterized in that it comprises administering to an individual in need, the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or zwitterion thereof, or an ester of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 10 and 22, or a pharmaceutical composition, as defined in any one of claims 23, 24 or 27 to 29; or administering to the individual, a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11-D-(S)-enantiomer or 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, as defined in any one of claims 11 to 22,or a pharmaceutical composition, as defined in any one of claims 25 to 29.

61. Method for treating a disease, disorder or condition modulated by, exacerbated by, or associated with excessive levels of circulating metal ions, characterized in that it comprises administering to an individual in need of, or at risk of, the same, Petition 870250087689, dated 09 / 26 / 2025, p.263 / 421 20 / 28 a therapeutically effective amount of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or a zwitterion thereof, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 10 and 22, or a pharmaceutical composition, as defined in any one of claims 23, 24 or 27 to 29, or administering to the individual, a therapeutically effective amount of the 11-D-(S)-enantiomer, a zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11-D-(S)-enantiomer or a zwitterion thereof, or an ester of the 11-D-(S)-enantiomer or the pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, as defined in any one of claims 11 to 22, or a pharmaceutical composition, as defined in any one of claims 25 to 29.

62. A method for reducing violent or aggressive behavior associated with a CNS disorder, characterized in that it comprises administering to an individual in need of, or at risk of, such behavior, a therapeutically effective amount of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or a zwitterion thereof, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 10 and 22, or a pharmaceutical composition, as defined in any one of claims 23, 24 or 27 to 29, or administering to the individual a therapeutically effective amount of the 11-D-(S)-enantiomer, a zwitterion thereof, or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11-D-(S)-enantiomer or zwitterion thereof, or an ester of the 11-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof,or an amide of the (S)-enantiomer Petition 870250087689, dated 09 / 26 / 2025, p. 264 / 421 21 / 28 or a pharmaceutically acceptable salt thereof, as defined in any one of claims 11 to 22, or a pharmaceutical composition, as defined in any one of claims 25 to 29.

63. A method for reducing the potential for hospitalization in a psychiatric hospital or incarceration due to behavior or actions associated with a CNS disorder, characterized in that it comprises administering to an individual in need of, or at risk of, such a disorder, a therapeutically effective amount of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or a zwitterion thereof, or an ester of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 10 and 22, or a pharmaceutical composition, as defined in any one of claims 23, 24 or 27 to 29, or administering to the individual a therapeutically effective amount of the 11D-(S)-enantiomer, a zwitterion thereof, or a pharmaceutically acceptable salt thereof. 11-D-(S)-enantiomer or a 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, as defined in any one of claims 11 to 22, or a pharmaceutical composition, as defined in any one of claims 25 to 29.

64. Method for treating a disease, disorder or condition modulated by, exacerbated by, or associated with elevated levels of PPAR-β / δ and / or PPAR-γ S-nitrosylation, characterized in that it comprises administering to an individual in need of, or at risk of, the same, a therapeutically effective amount of the (S)-enantiomer, or a cocrystal of the (S)-enantiomer or zwitterion thereof, or an ester of the (S)-enantiomer or the pharmaceutically acceptable salt of Petition 870250087689, dated 09 / 26 / 2025, p.265 / 421 22 / 28 itself, or an amide of the (S)-enantiomer or the pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 10 and 22, or a pharmaceutical composition, as defined in any one of claims 23, 24 or 27 to 29, or administering to the individual, a therapeutically effective amount of the 11-D-(S)-enantiomer, zwitterion thereof or a pharmaceutically acceptable salt of the 11-D-(S)-enantiomer or a cocrystal of the 11-D-(S)-enantiomer or 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, as defined in any one of claims 11 to 22, or a composition pharmaceutical, according to any one of claims 25 to 29.

65. N-hydroxy-tianeptine, characterized in that it has Formula (XV) or a pharmaceutically acceptable salt thereof: Formula (XV).

66. (S)-enantiomer of N-hydroxy-tianeptine (N-hydroxy-(S)-thi-aneptine) of Formula (XVI) or a pharmaceutically acceptable salt thereof, characterized in that the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof is particularized by comprising < about 2% of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy-tianeptine: Formula (XVI). Petition 870250087689, dated 09 / 26 / 2025, p. 266 / 421 23 / 28 67. (R)-enantiomer of N-hydroxy-tianeptine, (N-hydroxy-(R)tianeptine) of Formula (XVII) or a pharmaceutically acceptable salt thereof, characterized in that the (R)-enantiomer of N-hydroxy-tianeptine, or a pharmaceutically acceptable salt thereof, is particularly noted in that it comprises < about 2% of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxy-tianeptine: Formula (XVII).

68. N-nitroso-tianeptine, characterized in that Formula (XVIII) or a pharmaceutically acceptable salt of Formula (XVIII).

69. (S)-enantiomer of N-nitroso-tianeptine (N-nitroso-(S)-tianeptine) of Formula (XIX) or a pharmaceutically acceptable salt thereof, characterized in that the (S)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt thereof, is particularly noted in comprising < about 2% of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of the (R)-enantiomer of N-nitroso-tianeptine: Formula (XIX). Petition 870250087689, dated 26 / 09 / 2025, p. 267 / 421 24 / 28 70. (R)-enantiomer of N-nitroso-tianeptine (N-nitroso-(R)-tianeptine) of Formula (XX) or a pharmaceutically acceptable salt thereof, characterized in that the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof is particularly characterized by comprising < about 2% of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of the (S)-enantiomer of N-nitroso-tianeptine: Formula (XX).

71. A tianeptine analogue, characterized in that it is replaced by an aryl or a pharmaceutically acceptable salt thereof.

72. Aryl-substituted tianeptine analogue according to claim 71, characterized in that the aryl-substituted tianeptine derivative is 7-((3-(furan-2-yl)-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepin-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]thiazepin-11-yl)amino)heptanoic acid of Formula (XXII), 7-((6-methyl-5,5-dioxide-3-(thiophen-3-yl)-6,11-dihydrodi- benzo[c,f][1,2]thiazepin-11-yl)amino)heptanoic acid of Formula (XXIII) or 2-(4-(((3-chloro-6-methyl-5,5-dioxide-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino)methyl)-2-methylphenoxy)acetic acid of Formula (XXIV). Petition 870250087689, dated 09 / 26 / 2025, p. 268 / 421 25 / 28 Formula (XXIII) Formula (XXIV) 73. Pharmaceutical composition, characterized in that it comprises N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof, as defined in claim 65, or N-nitrosotianeptine, or a pharmaceutically acceptable salt thereof, as defined in claim 68, or an aryl-substituted tianeptine analogue, or a pharmaceutically acceptable salt thereof, as defined in claim 71 or 72, and a pharmaceutically acceptable carrier, diluent, or excipient.

74. Pharmaceutical composition, characterized in that it comprises the (S)-enantiomer of N-hydroxy-tianeptine, or a pharmaceutically acceptable salt thereof, as defined in claim 66, or the (S)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt thereof, as defined in claim 69, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises < about 2%, or < about 0.1%, of the (R)-enantiomer of N-hydroxy-tianeptine, or N-nitroso-tianeptine, or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy-tianeptine or N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof.

75. Pharmaceutical composition, characterized in that it comprises (R)-enantiomer of N-hydroxy-tianeptine, or a pharmaceutically acceptable salt thereof, as defined in claim 67, or (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof, as defined in claim 70, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein Petition 870250087689, dated 09 / 26 / 2025, p. 269 / 421 26 / 28 the composition comprises < about 2%, or < about 0.1%, of the (S)enantiomer of N-hydroxy-tianeptine, or N-nitroso-tianeptine or a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxy-tianeptine or N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof.

76. A method for treating a disease, disorder, or condition modulated by, exacerbated by, or associated with altered activity of peroxisome proliferator-activated receptor (PPAR)-pZo or PPAR-γ and one or more associated symptoms thereof, characterized in that it comprises administering to an individual in need of, or at risk of, the same, a therapeutically effective amount of N-hydroxy-tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, (R)-enantiomer of N-hydroxy-tianeptine, or a pharmaceutically acceptable salt of any of them, as defined in any of claims 65 to 67, or N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or (R)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt of any of them, as defined in any of claims 68 to 69. 70, or an aryl-substituted tianeptine analogue, or a pharmaceutically acceptable salt thereof,as defined in claim 71 or 72 or the pharmaceutical composition as defined in any of claims 73 to 75.

77. A method for treating a disease, disorder, or condition modulated by, exacerbated by, or associated with altered activity of peroxisome proliferator-activated receptor (PPAR)-pZõ and Z or PPAR-γ and one or more associated symptoms thereof, in an individual who has experienced elevated stress, characterized in that it comprises administering to the individual a therapeutically effective amount of N-hydroxy-tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, (R)-enantiomer of N-hydroxy-tianeptine, or a pharmaceutically acceptable salt of any of them, as defined in any of claims 65 to 67, or N-nitroso-tianeptine, the (S) Petition 870250087689, dated 09 / 26 / 2025, p.270 / 421 27 / 28 enantiomer of N-nitroso-tianeptine, or (R)-enantiomer of N-nitrosotianeptine, or a pharmaceutically acceptable salt of either, as defined in any one of claims 68 to 70, or an aryl-substituted tianeptine analogue, or a pharmaceutically acceptable salt thereof, as defined in claim 71 or 72, or the pharmaceutical composition, as defined in any one of claims 73 to 75.

78. A method for treating a disease, disorder, or condition modulated by, exacerbated by, or associated with altered activity of peroxisome proliferator-activated receptor (PPAR)-β and / or PPAR-γ and one or more associated symptoms thereof, while reducing μ-opioid receptor agonism associated with racemic tianeptine treatment, characterized in that it comprises administering to an individual in need of, or at risk of, the same, a therapeutically effective amount of N-hydroxy-tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, (R)-enantiomer of N-hydroxy-tianeptine, or a pharmaceutically acceptable salt of any of them, as defined in any of claims 65 to 67, or an N-nitrosotianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or (R)-enantiomer of N-nitroso-tianeptine, or a a pharmaceutically acceptable salt of either, as defined in any of claims 68 to 70, or an aryl substituted tianeptine analogue,or a pharmaceutically acceptable salt thereof, as defined in claim 71 or 72, or a pharmaceutical composition, as defined in any of claims 73 to 75.

79. Method for treating a disease, disorder or condition selected from the group consisting of a central nervous system disorder, asthma, primary biliary cholangitis, hypertriglyceridemia, cardiac hypertrophy, fibromyalgia, cancer, infectious disease, COVID-19, long COVID, menopause and chronic overlapping pain conditions. Petition 870250087689, dated 09 / 26 / 2025, p.271 / 421 28 / 28 (COPCs), psychological, physical, metabolic or hormonal stress and COPCs, and obesity, characterized in that it comprises administering to the individual a therapeutically effective amount of N-hydroxytianeptine, the (S)-enantiomer of N-hydroxytianeptine, (R)-enantiomer of N-hydroxytianeptine, or a pharmaceutically acceptable salt of either, as defined in any of claims 65 to 67, or N-nitrosotianeptine, the (S)-enantiomer of N-nitrosotianeptine, or (R)-enantiomer of N-nitrosotianeptine, or a pharmaceutically acceptable salt of either, as defined in any of claims 68 to 70, or an aryl-substituted tianeptine analogue, or a pharmaceutically acceptable salt thereof, as defined in claim 71 or 72, or the pharmaceutical composition, as defined in any of claims 73 to 75.

80. Crystalline hemioxalate salt of 5,5-dioxide of (S)7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ylamino)heptanoic acid ((S)-tianeptine), characterized in that the salt exhibits an X-ray diffraction pattern (XRPD) comprising at least one peak selected from 8.5, 20.6, 21.0 and 24.2 degrees 20 ± 0.3 degrees 20.

81. Crystalline free acid / free base of the (S)-enantiomer of tianeptine, as defined in claim 1, characterized in that the crystalline (S)-enantiomer of tianeptine exhibits an X-ray diffraction pattern (XRPD) comprising at least one peak selected from 10.6, 13.0, 21.1 and 23.7 degrees 20 ± 0.3 degrees 20.

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