(s)-tianeptine and use in treating post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions

Abstract

The present disclosure provides the (S)-enantiomer of 7-(3-chloro-6-methyl-5,5- dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-ylamino)heptanoic acid ((S)-tianeptine) and the (S)-enantiomer of deuterated tianeptine (11-D-(S)-tianeptine), both being characterized as comprising no more than 2%, or no more than about 0.1%, of the corresponding (R)- enantiomer. The present disclosure further provides salts, amides, esters, co-crystals, crystals, analogs and pharmaceutical compositions thereof and methods of using the (S)-enantiomers and those compounds and compositions for treating post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions, while minimizing or eliminating the potential for opioid abuse. The present disclosure also provides methods of producing the (S)- enantiomer and 11-D-(S)-enantiomer and related compounds of this disclosure.

Description

Attorney Docket No.: 104545-0096-W02(S)-TIANEPTINE AND USE IN TREATING POST-CONCUSSIVE SYNDROME, NOCIPLASTIC PAIN SYNDROME AND CHRONIC OVERLAPPING PAIN CONDITIONS5 CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit from United States Provisional Application No. 63 / 700,316, filed September 27, 2024, the disclosure of which is hereby incorporated by reference in its entirety.10 TECHNICAL FIELD

[0002] The present disclosure relates to the (S)-enantiomer of 7-(3-chloro-6-methyl- 5,5-dioxido-6,l l-dihydrodibenzo[c,f][l,2]thiazepin-l l-ylamino)heptanoic acid ((S)- tianeptine) and the (S)-enantiomer of deuterated tianeptine (l l-D-(S)-tianeptine), both being characterized as comprising no more than about 2%, or no more than about 0.1%, of the corresponding (R)-enantiomer. The present disclosure further provides salts, amides, esters, co-crystals, crystals, analogs and pharmaceutical compositions thereof and methods of using the (S)-enantiomers and those compounds and compositions for treating post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions, while minimizing or eliminating the potential for opioid abuse. The present disclosure also provides20 methods of producing the (S)-enantiomer and 1 l-D-(S)-enantiomer and related compounds of this disclosure.BACKGROUND

[0003] Tianeptine, a racemate of 7-[(3-chloro-6-methyl-5,5-dioxo-l 1H- benzo[c][2,l]lenzothiazepine-l l-yl)amino]heptanoic acid, is an antidepressant with neuroprotective and cognitive restorative effects. Investigators 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 (Garcia-Alberca JM et al., J Alzheimer s Dis. 2022), asthma (Lechin30 F et al., Methods Find Exp Clin Pharmacol. 2004), and fibromyalgia (ISRCTN16400909). Although tianeptine shares structural similarities to classic tricyclic antidepressants, its pharmacological behavior is unique. No tianeptine-containing drug is approved by the U.S. Food and Drug Administration (FDA) for any indication. Tianeptine is, however, currently available, as the active ingredient of products approved and sold under the commercial names,Attorney Docket No.: 104545-0096-W02 inter alia, 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., Stabion®) in 1989 as an antidepressant at a dose of 12.5 mg, three times daily. Tianeptine-containing products are also available in certain areas of the U.S. as5 over-the-counter food supplements or research chemicals.

[0004] Racemic tianeptine has been reported to affect serotonin reuptake, modulate glutamatergic activity, and has more recently been reported to weakly activate p-opioid receptors. In animal studies involving severe stress exposure, tianeptine was reported to restore brain neuroplasticity through synaptogenesis by exerting biological effects on neurons and glial10 cells that increase arborization of dendrites in critical hippocampal circuits, to restore hippocampal neurogenesis, and to reverse stress-induced impairments in synaptic glutamate neurotransmission (McEwen BS et al., Mol Psychiatry. 2010). Further, tianeptine was shown to increase brain-derived neurotrophic factor (BNDF) in the rat amygdala (Reagan LP et al., Eur J Pharmacol. 2007; Della FP, et al., Behav Brain Res . 2012). However, these mechanistic studies are difficult to interpret as many are based on assays with a 50:50 mixture of the (R)- and (S)-enantiomers of tianeptine (the racemate).

[0005] Moreover, the Center for Disease Control and Prevention (CDC) published a Morbidity and Mortality Weekly Report (MMWR) in August 2018 that described incidences of tianeptine overdose from over-the-counter products, associated with the abuse potential of20 tianeptine due to its opioid-like effects, and issued a warning of public health risk. Indeed, marketing authorization in the country of Georgia was withdrawn in June 2010, and tianeptine was included on the list of psychotropic agents in Russia, Ukraine and Armenia because of its misappropriation by “drug addicts” by 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 in which there is special status for prescribing and dispensing conditions. Other common adverse events associated with tianeptine include anorexia, nightmares, insomnia, somnolence, dizziness, headache, tachycardia, dyspnea, gastrointestinal distress, myalgia, and asthenia.

[0006] Post-concussive syndrome (PCS) describes a collection of physical, emotional, cognitive and behavioral symptoms that persist for several weeks to months after sustaining a30 mild traumatic brain injury (concussion). Symptoms associated with a concussion usually develop immediately or within hours to days after a brain injury. In most cases, these symptoms ease within a couple of weeks, however the concussion-related symptoms may persist for months, or even years, and have significant negative effects on daily life.Attorney Docket No.: 104545-0096-W02

[0007] Chronic pam can be defined as pain that persists for longer than three months. Neuropathic and nociceptive pain are categorized by pain or chronic pain with a suspected or confirmed underlying mechanism. Nociplastic pain, on the other hand, arises from altered nociception in the absence of clear lesion or disease of the somatosensory nervous system and / or the absence of actual or threatened tissue damage. Chronic overlapping pain conditions represent a subset of chronic pain conditions which commonly occur simultaneously in a patient (Fitzcharles, MA et al. Lancet. 2021 and Johnston KJ A, et al. medRxiv. 2024).

[0008] Due to a lack of understanding of the pathophysiologic mechanisms associated with post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions, there are no specific treatments available for these disorders. Instead, the symptoms of these disorders are often managed through the use of pain medication (e.g., corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids), which are associated with adverse side effects with long-term use. There is therefore an unmet need to safely treat post- concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions.

[0009] The (S)-enantiomer of tianeptine, its zwitterion, its co-crystals, its esters, amides and deuterated analogs of any of them or pharmaceutically acceptable salts and crystalline forms thereof of the (S)-enantiomers and compositions thereof, as well as various analogs of the two tianeptine enantiomers and compositions of them, as described in various embodiments of this disclosure, and methods of using those compositions meet this unmet need and improve the treatment of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions, while at the same time minimizing or eliminating the potential for opioid abuse.SUMMARY OF THE DISCLOSURE

[0010] Some embodiments of this disclosure are:1. A method of treating a disease, disorder or condition selected from the group consisting of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprising administering to a subject in need or at risk thereof a therapeutically effective amount of an (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxido-6,l l-dihydrodibenzo[c,f][l,2]thi azepin- 11- ylamino)heptanoic acid ((S)-enantiomer of tianeptine) of the general Formula (la), the zwitterion thereof of Formula (lb), a co-crystal of the (S)-enantiomer, or a pharmaceutically acceptable salt of the (S)-enantiomer, or an ester of the (S)-Attorney Docket No.: 104545-0096-W02 enantiomer or pharmaceutically acceptable salt thereof, or an amide of the (S)- enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of them, wherein the (S)-enantiomer, the zwitterion of the (S)-enantiomer, co-crystal of the (S)-enantiomer or pharmaceutically acceptable salt of5 the (S)-enantiomer, ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof, amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition of any of them is characterized by comprising < about 2% of the (R)-enantiomer of tianeptine, the zwitterion of the (R)-enantiomer, co-crystal of the (R)-enantiomer or pharmaceutically acceptable salt of the (R)-enantiomer, ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, amide of the (R)- enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition of any of them:Formula (la) Formula (lb).152. The method according to embodiment 1, wherein the (S)-enantiomer, the zwitterion of the (S)-enantiomer, co-crystal of the (S)-enantiomer or pharmaceutically acceptable salt of the (S)-enantiomer, ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof, amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising any of them is characterized by comprising < about 0.1% of the (R)-enantiomer of tianeptine, the zwitterion thereof, co-crystal of the (R)-enantiomer or pharmaceutically acceptable salt of the (R)-enantiomer, ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, amide of the (R)- enantiomer or pharmaceutically acceptable salt thereof, or the pharmaceutical25 composition of any of them.3. The method according to embodiment 1 or 2, wherein the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine benzenesulfonate (1 : 1), (S)-tianeptineAttorney Docket No.: 104545-0096-W02 fumarate (1 : 1), (S)-tianeptme fumarate (2: 1), (S)-tianeptme 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 polisterix, (S)-tianeptine: L-DBTA (2: 1),5 (S)-tianeptine sodium, (S)-tianeptine oxalate or (S)-tianeptine hemi-oxalate (2:1).4. The method according to embodiment 3, wherein the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine benzenesulfonate (1 : 1), (S)-tianeptine fumarate (1 : 1), (S)-tianeptine fumarate (2: 1), (S)-tianeptine hippurate (1 : 1), (S)-tianeptine10 maleate (1 : 1), (S)-tianeptine maleate (2: 1), (S)-tianeptine p-toluenesulfonate (1: 1) or (S)-tianeptine orotate (1 : 1).5. The method according to embodiment 3, wherein the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine camphorsulfonate (1 : 1), (S)-tianeptine N-acetyl- L-tyrosinate (1 : 1) or (S)-tianeptine polisterix.6. The method according to embodiment 3, wherein the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine hemi-oxalate (2: 1).20 7. The method according to embodiment 1 or 2, wherein the co-crystal of the (S)- enantiomer comprises the (S)-enantiomer or the zwitterion thereof in a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid.8. The method according to embodiment 7, wherein the complex comprises a 1 : 1, 1 :2, or 2: 1 ratio of the (S)-enantiomer or the zwitterion thereof and L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid.9. The method according to embodiment 7 or 8, wherein the co-crystal comprises an inorganic monoacid salt of the (S)-enantiomer and a zwitterion of the L-amino acid.3010. The method according to embodiment 7 or 8, wherein the co-crystal comprises an inorganic monoacid salt of the L-amino acid and the zwitterion of the (S)-enantiomer.Attorney Docket No.: 104545-0096-W0211. The method according to embodiment 9 or 10, wherein the inorganic monoacid is hydrochloric acid (HC1).12. The method according to embodiment 1 or 2, wherein the ester of the (S)-enantiomer is the methyl ester of the (S)-enantiomer, the ethyl ester of the (S)-enantiomer, or another Ci-Ce alkyl ester of the (S)-enantiomer or a pharmaceutically acceptable salt of any of them.13. The method according to embodiment 1 or 2, wherein the amide of the (S)-enantiomer is a simple amide or a Ci-Ce alkyl amide optionally substituted with at least one hydroxyl or a pharmaceutically acceptable salt of either.14. A method of treating a disease, disorder or condition selected from the group consisting of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprising administering to a subject in need or at risk thereof a therapeutically effective amount of an (S)-enantiomer of deuterated 7-((3-chloro-6-methyl-5,5-dioxido-6,l l- dihydrodibenzo[c,f][l,2]thiazepin-l l-yl-l l-d)amino) heptanoic acid (l l-D-(S)- enantiomer of tianeptine) of the general Formula (Ila), the zwitterion thereof of Formula (lib), a co-crystal of the l l-D-(S)-enantiomer, or pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer, or an ester of the 1 l-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the 1 l-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of them, wherein the 1 l-D-(S)-enantiomer, the zwitterion of the 1 l-D-(S)-enantiomer, co-crystal of the l l-D-(S)-enantiomer or pharmaceutically acceptable salt of the l l-D-(S)- enantiomer, ester of the l l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, amide of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition of any of them is characterized by comprising < about 2% of the 1 l-D-(R)-enantiomer of tianeptine, the zwitterion of the 11-D-(R)- enantiomer, co-crystal of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt of the l l-D-(R)-enantiomer, ester of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof, amide of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition of any of them:Attorney Docket No.: 104545-0096-W02Formula (Ila) Formula (lib).15. The method according to embodiment 14, wherein the 1 l-D-(S)-enantiomer, the5 zwitterion of the 1 l-D-(S)-enantiomer, co-crystal of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt of the l l-D-(S)-enantiomer, ester of the l l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof, amide of the l l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising any of them is characterized by comprising < about 0.1% of the 1 l-D-(R)- enantiomer of tianeptine, the zwitterion thereof, co-crystal of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt of the 1 l-D-(R)-enantiomer, ester of the 11-D-(R)- enantiomer or pharmaceutically acceptable salt thereof, amide of the 11-D-(R)- enantiomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any of them.16. The method according to embodiment 14 or 15, wherein the 1 l-D-(S)-enantiomer or the zwitterion thereof or the pharmaceutically acceptable salt of the l l-D-(S)- enantiomer is characterized by reduced racemization at position 11 as compared to the (S)-enantiomer of tianeptine or the zwitterion or a pharmaceutically acceptable salt of that enantiomer.17. The method according to any one of embodiments 14-16, wherein the l l-D-(S)- enantiomer, the zwitterion thereof or a pharmaceutically acceptable salt of the 11-D- (S)-enantiomer is further deuterated at at least one of the 3 ’positions, and optionally25 deuterated at other positions on the aminoheptanoic side chain.18. The method according to embodiment 17, wherein the 1 l-D-(S)-enantiomer is the (S)- enantiomer of 3', 3', 4', 4', 11- pentadeuterotianeptine of Formula (Illa) or the zwitterionAttorney Docket No.: 104545-0096-W02 thereof of Formula (Illb); the (S)-enantiomer of 2', 2', 3', 3', 4', 4', 5', 5', 6', 6', 7', 7', 11- tridecadeuterotianeptine of the general Formula (IVa) or the zwitterion thereof of Formula (IVb); the (S)-enantiomer of 3', 3', 4', 4', tetradeuterotianeptine of Formula (Va) or the zwitterion thereof of Formula (Vb); or the (S)-enantiomer of 2', 2', 3', 3', 4',5 4', 5', 5', 6', 6', 7', 7', dodecadeuterotianeptine of the general formula (Via) or the zwitterion thereof of Formula (VIb):19. The method according to any one of embodiments 14-16, wherein the pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer is l l-D-(S)-tianeptine benzenesulfonate15 (1 : 1), l l-D-(S)-tianeptine fumarate (1 : 1), l l-D-(S)-tianeptine fumarate (2: 1), 11-D- (S)-tianeptine hippurate (1: 1), l l-D-(S)-tianeptine maleate (1 : 1), l l-D-(S)-tianeptine maleate (2: 1), l l-D-(S)-tianeptine p-toluenesulfonate (1: 1), l l-D-(S)-tianeptine orotate (1 : 1), l l-D-(S)-tianeptine camphorsulfonate (1 : 1), l l-D-(S)-tianeptine N- acetyl-L-tyrosinate (1 : 1), 1 l-D-(S)-tianeptine polisterix, 1 l-D-(S)-tianeptine: L-DBTAAttorney Docket No.: 104545-0096-W02(2: 1), l l-D-(S)-tianeptine sodium, l l-D-(S)-tianeptine oxalate or l l-D-(S)-tianeptine hemi-oxalate (2: 1).20. The method according to embodiment 19, wherein the pharmaceutically acceptable salt of the l l-D-(S)-enantiomer is 1 l-D-(S)-tianeptine benzenesulfonate (1 : 1), l l-D-(S)- tianeptine fumarate (1: 1), l l-D-(S)-tianeptine fumarate (2: 1), l l-D-(S)-tianeptine hippurate (1 : 1), l l-D-(S)-tianeptine maleate (1 : 1), l l-D-(S)-tianeptine maleate (2:1), l l-D-(S)-tianeptine p-toluenesulfonate (1 : 1) or l l-D-(S)-tianeptine orotate (1 : 1).21. The method according to embodiment 19, wherein the pharmaceutically acceptable salt of the l l-D-(S)-enantiomer is 1 l-D-(S)-tianeptine camphorsulfonate (1 : 1), l l-D-(S)- tianeptine N-acetyl-L-tyrosinate (1: 1) or 1 l-D-(S)-tianeptine polisterix.22. The method according to embodiment 19, wherein the pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer is 1 l-D-(S)-tianeptine hemi-oxalate (2:1).23. The method according to embodiment 14 or 15, wherein the co-crystal of the 1 l-D-(S)- enantiomer comprises the 1 l-D-(S)-enantiomer or the zwitterion thereof in a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid.24. The method according to embodiment 23, wherein the complex comprises a 1 : 1, 1 :2, or 2: 1 ratio of the l l-D-(S)-enantiomer or the zwitterion thereof and L-tyrosine, L- tryptophan, L-phenylalanine, or another L-amino acid.25. The method according to embodiment 23 or 24, wherein the co-crystal comprises an inorganic monoacid salt of the 1 l-D-(S)-enantiomer and a zwitterion of the L-amino acid.26. The method according to embodiment 23 or 24, wherein the co-crystal comprises an inorganic monoacid salt of the L-amino acid and the zwitterion of the l l-D-(S)- enantiomer.27. The method according to embodiment 25 or 26, wherein the inorganic monoacid is hydrochloric acid (HC1).Attorney Docket No.: 104545-0096-W0228. The method according to embodiment 14 or 15, wherein the ester of the l l-D-(S)- enantiomer is the methyl ester of the 1 l-D-(S)-enantiomer, the ethyl ester of the 11-D- (S)-enantiomer, or another Ci-Ce alkyl ester of the 1 l-D-(S)-enantiomer or a5 pharmaceutically acceptable salt of any of them.29. The method according to embodiment 14 or 15, wherein the amide of the (S)- enantiomer is a simple amide or a Ci-Ce alkyl amide optionally substituted with at least one hydroxyl or a pharmaceutically acceptable salt of either.1030. A method of treating a disease, disorder or condition selected from the group consisting of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprising administering to a subject in need or at risk thereof a therapeutically effective amount of N-hydroxy- tianeptine of the Formula (XV), the (S)-enantiomer of N-hydroxy-tianeptine of the Formula (XVI), the (R)-enantiomer of N-hydroxy-tianeptine of the Formula (XVII), N- nitroso-tianeptine of the Formula (XVIII), the (S)-enantiomer of N-nitroso-tianeptine of the Formula (XIX), the (R)-enantiomer of N-nitroso-tianeptine of the Formula (XX), an aryl substituted tianeptine analog, a pharmaceutically acceptable salt of any of them20 or a pharmaceutical composition comprising any of them:Attorney Docket No.: 104545-0096-W0231. The method according to embodiment 30, wherein the (S)-enantiomer of N-hydroxy -5 tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or the pharmaceutically acceptable salts thereof are characterized by comprising < about 2% of the (R)- enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy -tianeptine or (R)- enantiomer of N-nitroso-tianeptine.32. The method according to embodiment 31, wherein the (S)-enantiomer of N-hydroxy- tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or the pharmaceutically acceptable salts thereof are characterized by comprising < about 0.1% of the (R)- enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or a15 pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy -tianeptine or (R)- enantiomer of N-nitroso-tianeptine.33. The method according to embodiment 30, wherein the (R)-enantiomer of N-hydroxy - tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or the pharmaceutically acceptable salts thereof are characterized by comprising < about 2% of the (S)- enantiomer of N-hydroxy -tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxy -tianeptine or (S)- enantiomer of N-nitroso-tianeptine.25 34. The method according to embodiment 33, wherein the (R)-enantiomer of N-hydroxy - tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or the pharmaceutically acceptable salts thereof are characterized by comprising < about 0.1% of the (S)-Attorney Docket No.: 104545-0096-W02 enantiomer of N-hydroxy -tianeptine, the (S)-enantiomer of N-mtroso-tianeptine, or a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxy -tianeptine or (S)- enantiomer of N-nitroso-tianeptine.5 35. The method according to embodiment 30, wherein the aryl substituted tianeptine derivative is 7-((3-(furan-2-yl)-6-methyl-5,5-dioxido-6,l l- dihydrodibenzo[c,f][l,2]thiazepin-l l-yl)amino)heptanoic acid of Formula (XXI), 7-((3-(furan-3-yl)-6-methyl-5,5-dioxido-6,l l-dihydrodibenzo[c,f][l,2]thiazepin-l l- yl)amino)heptanoic acid of Formula (XXII), 7-((6-methyl-5,5-dioxido-3-(thiophen-3- yl)-6,l l-dihydrodibenzo[c,f][l,2]thiazepin-l l-yl)amino)heptanoic acid of Formula (XXIII) or 2-(4-(((3-chloro-6-methyl-5,5-dioxido-6,l l- dihydrodibenzo[c,f][l,2]thiazepin-l l-yl)amino)methyl)-2-methylphenoxy)acetic acidFormula (XXIII) Formula (XXIV).36. The method according to any one of embodiments 1, 2, 14, 15 and 30, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent, or excipient.37. The method according to embodiment 36, wherein the pharmaceutical composition is25 in the form of a tablet, a thin film, a powder, a caplet, a capsule, a soft gel, a suppository, a nasal spray, an oral spray or a lung spray.Attorney Docket No.: 104545-0096-W0238. The method according to embodiment 36 or 37, wherein the pharmaceutical composition is formulated for immediate release, controlled release, sustained release, extended release, or slow release of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal5 of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the zwitterion of the (S)-enantiomer or the l l-D-(S)-enantiomer, or the N-hydroxy-tianeptine, the (S)-enantiomer of N- hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, the N-nitroso- tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso- tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt10 of any of them.39. The method according to embodiment 38, wherein the pharmaceutical composition is formulated for controlled release of the (S)-enantiomer or the l l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a cocrystal of the (S)-enantiomer or the l l-D-(S)-enantiomer, or the zwitterion of the (S)- enantiomer or the l l-D-(S)-enantiomer, or the N-hydroxy-tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, the N-nitroso- tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso- tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt20 of any of them.40. The method according to any one of embodiments 1-39, wherein the (S)-enantiomer or the l l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer or the l l-D-(S)-enantiomer, or the zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy- tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N- hydroxy-tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso- tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical30 composition is administered one or more times daily.41. The method according to embodiment 40, wherein the (S)-enantiomer or the 1 l-D-(S)- enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer, or the 1 l-D-(S)-enantiomer or the zwitterionAttorney Docket No.: 104545-0096-W02 of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy -tianeptine, the (S)- enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N-hydroxy -tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically5 acceptable salt of any of them or the pharmaceutical composition is administered once daily.42. The method according to any one of embodiments 1-42, wherein the (S)-enantiomer or the l l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable10 salt of any of them, or a co-crystal of the (S)-enantiomer or the l l-D-(S)-enantiomer, or the zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy - tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N- hydroxy-tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso- tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical composition is administered parenterally, orally, sublingually, buccally, inhalationally, palatially, transdermally, rectally, or vaginally.43. The method according to embodiment 42, wherein the (S)-enantiomer or the 1 l-D-(S)-20 enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy-tianeptine, the (S)- enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical composition is administered orally.44. The method according to embodiment 42, wherein the (S)-enantiomer or the 1 l-D-(S)- enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of30 them, or a co-crystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy-tianeptine, the (S)- enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceuticallyAttorney Docket No.: 104545-0096-W02 acceptable salt of any of them or the pharmaceutical composition is administered inhalationally.45. The method according to any one of embodiments 1-44, wherein the (S)-enantiomer or5 the l l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer or the zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy- tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N- hydroxy-tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-10 tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical composition is administered sequentially or concurrently with one or more additional therapeutic agents selected from the group consisting of an antidepressant, an anticonvulsant, an anti-anxiety agent, an antipsychotic agent, a cholinesterase inhibitor, an N-m ethyl -D -aspartate (NMDA) receptor antagonist, a 5HT2 modulator, a corticosteroid, an anti-amyloid agent, an anti-tau agent and a chemotherapeutic agent.46. The method according to any one of embodiments 1-45, wherein the (S)-enantiomer or the l l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable20 salt of any of them, or a co-crystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer or the zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy- tianeptine, the (S)-enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N- hydroxy-tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso- tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical composition is administered as part of a treatment regime also including psychotherapeutic intervention.47. The method according to any one of embodiments 1-46, wherein the disease, disorder30 or condition is post-concussive syndrome.48. The method according to any one of embodiments 1-46, wherein the disease, disorder or condition is nociplastic syndrome.Attorney Docket No.: 104545-0096-W0249. The method according to any one of embodiments 1-46, wherein the disease, disorder or condition is a chronic overlapping pain condition.50. The method according to embodiment 1 or 2, wherein the pharmaceutically acceptable salt of the (S)-enantiomer of tianeptine is a crystalline hemi-oxalate salt of (S)- tianeptine which exhibits an X-ray diffraction pattern (XRPD) comprising at least one peak selected from the group consisting of 8.5, 20.6, 21.0 and 24.2 degrees 20 ±0.3 degrees 20.51. The method according to embodiment 50, wherein the crystalline (S)-tianeptine hemi- oxalate salt exhibits an XRPD pattern further comprising at least one peak selected from the group consisting of 12.1, 13.3, 16.1, 18.9, 19.1, 22.0 and 22.4 degrees 20 ±0.3 degrees 20.52. The method according to embodiment 1 or 2, wherein the (S)-enantiomer of tianeptine is a crystalline free acid / free base of (S)-tianeptine which exhibits an X-ray diffraction pattern (XRPD) comprising at least one peak selected from the group consisting of 10.6, 13.0, 21.1 and 23.7 degrees 20 ±0.3 degrees 20.53. The method according to embodiment 52, wherein the crystalline free acid / free base of (S)-tianeptine exhibits an XRPD pattern further comprising at least one peak selected from the group consisting of 8.7, 9.1, 12.6, 18.1, 20.4, 23.0 and 26.1 degrees 20 ±0.3 degrees 20.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] 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.

[0012] Figures 2A and 2B show the crystal structures of the enantiomer of tianeptine which has a (-) optical rotation as the sodium salt, complexed with L-dibenzoyl tartaric acid (DBTA). Figure 2A shows the crystal structure of the salt (S)-tianeptine: 0.5 L-DBTA. Figure 2B shows a different crystalline isoform of (S)-tianeptine enantiomer with L-DBTA ((S)- Tianeptine: 0.5 L-DBTA).Attorney Docket No.: 104545-0096-W02

[0013] Figures 3A-3B show graphs of cyclic adenosine 3, 5 -monophosphate (cAMP) inhibition using varying concentrations of [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO), racemic tianeptine, and 99.0%-99.35% pure (S)-tianeptine oxalate or 98.5%- 99.35% pure (R)- tianeptine oxalate at the p-opioid receptor. Figure 3A shows a graph of5 cAMP inhibition at steady state. Figure 3B shows a graph of the initial rate of cAMP inhibition. NFU is a normalized fluorescence unit.

[0014] Figures 4A-4B show graphs of concentration-response curves showing average arrestin recruitment using varying concentrations of DAMGO, racemic tianeptine, and 99.0%- 99.35% pure (S)-tianeptine oxalate or 98.5%-99.35% pure (R)-tianeptine oxalate at the p-10 opioid receptor. Figure 4A shows arrestin recruitment response at steady state. Figure 4B shows arrestin recruitment initial rate analysis.

[0015] Figures 5A-5B show graphs of concentration-response curves of % cAMP inhibition using varying log concentrations (M) of DAMGO, racemic tianeptine, and 99.35% pure (S)-tianeptine sodium or (R)-tianeptine sodium at the p-opioid receptor. The graphs show % cAMP inhibition initial rate analysis (Figure 5A) and % cAMP inhibition maximum effect analysis (Figure 5B).

[0016] Figures 6A-6B show graphs of concentration-response curves % cAMP inhibition using varying log concentrations (M) of DAMGO, racemic tianeptine, racemic tianeptine sodium, and 99.0%-99.35% pure (S)-tianeptine sodium or 98.5%-99.35% pure (R)-20 tianeptine sodium at the p-opioid receptor. The graphs show % cAMP inhibition initial rate analysis (Figure 6A) and % cAMP inhibition maximum effect analysis (Figure 6B).

[0017] Figures 7A-7B show graphs of concentration-response curves of average arrestin recruitment at the p-opioid receptor using varying log concentrations (M) of DAMGO, tianeptine, racemic tianeptine sodium, and 99.9% pure (S)-tianeptine sodium or (R)-tianeptine sodium. The graphs show arrestin recruitment initial rate analysis (Figure 7A) and arrestin recruitment normalized to baseline (Figure 7B).

[0018] Figures 8A-8B show graphs depicting tianeptine agonism at the p-opioid receptor using varying log concentrations (M) of DAMGO and 99.9% pure (S)-tianeptine sodium or (R)- tianeptine sodium. The graphs show peak cAMP inhibition (Figure 8A) and30 peak arrestin recruitment (Figure 8B).

[0019] Figures 9A-9F show graphs depicting the effects of (S)-tianeptine and (R)- tianeptine zwitterion (99.9% chiral purity) on neurite outgrowth of cultured glutamatergic neurons. Figures 9A and 9B depict the average neurite length (pm) at 24 hours (Figure 9A) and 72 hours (Figure 9B) post treatment. Figures 9C and 9D depict the total neurite lengthAttorney Docket No.: 104545-0096-W02(pm) (Figure 9C) and average neunte width (nm) (Figure 9D) at 5 days post treatment with (S)-tianeptine zwitterion (99.9% chiral purity). Figures 9E and 9F depict the total neurite length (pm) (Figure 9E) and average neurite width (nm) (Figure 9F) at 5 days post treatment with (R)-tianeptine zwitterion (99.9% chiral purity). Data normalized to 1% PBS control and5 compared using strictly standardized mean difference (SSMD). P-value: *p<0.05

[0020] Figures 10A-10D show graphs depicting the effects of (S)-tianeptine and (R)- tianeptine zwitterion (99.9% chiral purity) on mitochondrial staining (MitoTracker) in cultured glutamatergic neurons at 5 days post treatment. Figures 10A and 10B depict the mitochondrial staining in cell bodies (Figure 10 A) and neurites (Figure 10B) post treatment with (S)-10 tianeptine zwitterion (99.9% chiral purity). Figures 10C and 10D depict the mitochondrial staining in cell bodies (Figure 10C) and neurites (Figure 10D) post treatment with (R)- tianeptine zwitterion (99.9% chiral purity). Data normalized to 1% PBS control and compared using strictly standardized mean difference (SSMD). p-value: *p<0.05. RFU = Relative Fluorescence Units

[0021] Figures 11A-11C show graphs depicting the effects of racemic tianeptine sodium (Figure 11 A), (S)-tianeptine sodium (99.9% chiral purity, Figure 1 IB) and (R)- tianeptine sodium (99.9% chiral purity, Figure 11C) in a novel object recognition (NOR) test. ANOVA p-values: ***p<0.001, **p<0.1, *p<0.05.

[0022] Figures 12A-12F show graphs depicting the effects of racemic tianeptine20 sodium (Figure 12A-12B), (R)-tianeptine sodium (99.9% chiral purity, Figure 12C-12D) and (S)-tianeptine sodium (99.9% chiral purity, Figure 12E-12F) in a forced swim test (FST). Figures 12A, 12C and 12E show the timeline of the time spent immobile over 6 minutes. Figures 12B, 12D and 12F show the total time spent immobile during the 6-minute test. ANOVA p-values: ***p<0.001, *p<0.05.

[0023] Figures 13A-13D show graphs depicting the XRPD patterns of crystalline (S)- tianeptine (Figure 13 A), crystalline (S)-tianeptine hemi-oxalate (Figure 13B), amorphous (S)- tianeptine sodium (Figure 13C) and a comparison of the three XRPDs with the XRPD of racemic tianeptine hemi-oxalate (Figure 13D).30 DETAILED DESCRIPTION

[0024] This disclosure provides in some embodiments, a method of treating a disease, disorder or condition selected from the group consisting of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associatedAttorney Docket No.: 104545-0096-W02 symptoms thereof comprising administering to a subject in need or at risk thereof a therapeutically effective amount of an (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxido- 6,l l-dihydrodibenzo[c,f][l,2]thiazepin-l l-ylamino)heptanoic acid ((S)-enantiomer of tianeptine), the zwitterion, a co-crystal or pharmaceutically acceptable salt thereof, or an ester5 of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the (S)- enantiomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of them, wherein the (S)-enantiomer, zwitterion, co-crystal or pharmaceutically acceptable salt 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, or10 pharmaceutical composition is characterized by comprising < about 2% of the (R)-enantiomer of tianeptine, the zwitterion, co-crystal or pharmaceutically acceptable salt thereof, or the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, or the amide of the (R)- enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the (S)- enantiomer, the zwitterion, co-crystal or pharmaceutically acceptable salt 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 pharmaceutical composition comprising them is characterized by comprising < about 0.1% of the (R)-enantiomer of tianeptine, the zwitterion, co-crystal or pharmaceutically acceptable salt thereof, or the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, or the amide of the (R)-20 enantiomer or pharmaceutically acceptable salt thereof.

[0025] In other embodiments, this disclosure provides a method of treating a disease, disorder or condition selected from the group consisting of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprising administering to a subject in need or at risk thereof a therapeutically effective amount of an (S)-enantiomer of deuterated 7-((3-chloro-6-methyl-5,5- dioxido-6,l l-dihydrodibenzo[c,f][l,2]thiazepin-l l-yl-l l-d)amino) heptanoic acid (l l-D-(S)- enantiomer of tianeptine), the zwitterion thereof, a co-crystal or pharmaceutically acceptable salt thereof, or an ester of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the l l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, or a30 pharmaceutical composition comprising any of them, wherein the 1 l-D-(S)-enantiomer, zwitterion, co-crystal or pharmaceutically acceptable salt thereof, or the ester of the l l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof, or the amide of the 11 -D-(S)-enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition is characterized by comprising < about 2% of the 1 l-D-(R)-enantiomer of tianeptine, the zwitterion, co-crystal orAttorney Docket No.: 104545-0096-W02 pharmaceutically acceptable salt thereof, or the ester of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof, or the amide of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the l l-D-(S)-enantiomer, the zwitterion, co-crystal or pharmaceutically acceptable salt thereof, or the ester of the l l-D-(S)-5 enantiomer or pharmaceutically acceptable salt thereof, or the amide of the 11 -D-(S)-enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising them is characterized by comprising < about 0.1% of the 1 l-D-(R)-enantiomer of tianeptine, the zwitterion, co-crystal or pharmaceutically acceptable salt thereof, or the ester of the 11-D-(R)- enantiomer or pharmaceutically acceptable salt thereof, or the amide of the l l-D-(R)-10 enantiomer or pharmaceutically acceptable salt thereof.

[0026] In other embodiments, this disclosure provides a method of treating a disease, disorder or condition selected from the group consisting of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprising administering to a subject in need or at risk thereof a therapeutically effective amount of 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, an aryl substituted tianeptine analog, a pharmaceutically acceptable salt of any of them or a pharmaceutical composition comprising any of them. In some embodiments, the (S)-20 enantiomers of N-hydroxy-tianeptine or N-nitroso-tianeptine are characterized by comprising <2% of the corresponding (R)-enantiomer. In some embodiments, the (S)-enanti omers of N- hydroxy-tianeptine or N-nitroso-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.

[0027] In some embodiments, this disclosure provides the (S)-enantiomer of 7-(3-chloro- 6-methyl-5, 5-dioxido-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 of30 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 the zwitterion thereof. In other embodiments, this disclosure provides the (S)-enantiomer of deuterated tianeptine (l l-D-(S)- tianeptine), the zwitterion, ester or amide thereof, or a pharmaceutically acceptable salt of the l l-D-(S)-enantiomer, or a crystalline form thereof, or a pharmaceutically acceptable salt of anAttorney Docket No.: 104545-0096-W02 ester or amide thereof, or a cocrystal of the 1 l-D-(S)-enantiomer or the 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)-enanti omers, zwitterions, esters, amides and salts5 are characterized by comprising <0.1% of the corresponding (R)-enantiomer, its zwitterions, esters, amides or salts.

[0028] In other embodiments, this disclosure provides tianeptine analogs including N- hydroxy -tianeptine, the (S)- and (R)-enanti omers of N-hydroxy -tianeptine (z.e., N-hydroxy-(S)- tianeptine or N-hydroxy-(R)-tianeptine), N-nitroso-tianeptine, the (S)- and (R)-enantiomers of10 N-nitroso-tianeptine (z.e., N-nitroso-(S)-tianeptine or N-nitroso-(R)-tianeptine), an aryl substituted tianeptine analog and pharmaceutically acceptable salts thereof. 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, the (S)-enantiomers of N-hydroxy-tianeptine or N-nitroso-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.20

[0029] In some embodiments, this disclosure provides a pharmaceutical composition comprising one or more of the (S)-enantiomers or crystalline form thereof, zwitterions, cocrystals, esters, amides, analogs or salts of this disclosure, the compositions comprising <2% of the corresponding (R)-enantiomer. In some embodiments, the pharmaceutical composition comprises <0.1% of the corresponding (R)-enantiomer.

[0030] In some embodiments, this disclosure provides methods for treating diseases, disorders or conditions selected from the group consisting of a central nervous system (CNS) disorder, post-concussive syndrome, nociplastic pain syndrome or chronic overlapping pain conditions (COPCS), including menopause and COPCs, and psychological, physical, metabolic or hormonal stress and COPCs, and associated symptoms thereof in a subject in need thereof by30 administering the (S)-enantiomers (z.e., the (S)-enantiomer of tianeptine and / or the l l-D-(S)- enantiomer of tianeptine) or crystalline forms thereof, zwitterions, esters, amides, salts, analogs and compositions of this disclosure.

[0031] In some embodiments, the methods minimize the potential for opioid abuse as the result of administration of the (S)-enanti omers (z.e., the (S)-enantiomer of tianeptine and / or theAttorney Docket No.: 104545-0096-W021 l-D-(S)-enantiomer of tianeptine) or crystalline forms thereof, their zwitterions, esters, amides, analogs or pharmaceutically acceptable salts, or compositions comprising them of this disclosure.

[0032] In other embodiments, the disclosure provides methods of producing the (S)-5 enantiomer of tianeptine and / or the 1 l-D-(S)-enantiomer of tianeptine of this disclosure.

[0033] Practice of the methods of various embodiments disclosed herein employ, unless otherwise indicated, conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA and related fields as are within the skill of the art. These techniques are fully explained in the literature.10Definitions

[0034] The term “herein” means the entire application.

[0035] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control.

[0036] It should be understood that any of the embodiments described herein, including those described under different aspects of the disclosure and different parts of the specification (including embodiments described only in the Examples) can be combined with one or more other embodiments of this disclosure, unless explicitly disclaimed or improper,20 and are so disclosed as embodiments to the disclosure. Combination of embodiments are not limited to those specific combinations described in the multiple dependent embodiments of this disclosure.

[0037] All of the publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0038] Throughout this specification, 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, unrecited elements or method steps.30

[0039] Any example(s) following the term “e.g.” or “for example” is not meant to be exhaustive or limiting.

[0040] The term “including” or “includes” is used to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably.Attorney Docket No.: 104545-0096-W02

[0041] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0042] The articles “a”, “an” and “the” are used herein to refer to one or to more than one ( / .e., to at least one) of the grammatical object of the article.5

[0043] As used herein, the meaning of the term “about” depends upon the context in which it is used. When used with respect to modifying the quantity of an ingredient, parameter, calculation, or measurement in the compositions employed in the methods of the disclosure refers to the variation in the numerical quantity that can occur, for example, through typical measuring and liquid handling procedures used for making the compounds of this disclosure10 or pharmaceutical compositions in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make the enantiomer or compositions of this disclosure or to carry out the methods; and the typical + / - of any amount or use without having a substantial effect on the chemical or physical attributes of the compounds, compositions or methods of the disclosure. Such variation can be typically within 10%, more typically within 5%, of a given value or range. In some embodiments the variation can be within 1%. The term “about” also encompasses amounts that differ due to different equilibrium conditions for a composition resulting from a particular initial mixture. Whether or not modified by the term “about,” the paragraphs include equivalents to the quantities. Reference to “about” a value or parameter20 herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.” Numeric ranges are inclusive of the numbers defining the range. When used with respect to the position of a peak on an X-ray powder diffraction (XRPD) pattern, the term “about” includes peaks within an associated tolerance of ±0.3 degrees 29. For example, as used herein, an XRPD peak at “about 10.0 degrees 29” means that the stated peak occurs from 9.7 to 10.3 degrees 29. When used with respect to the position of a peak on a solid state13C NMR spectrum, the term “about” includes peaks within ±0.2 ppm of the stated position. For example, as used herein, a13C NMR spectrum peak at “about 100.0 ppm” means that the stated peak occurs from 99.8 to 100.2 ppm.

[0044] As used herein, the term “substantially” in reference to an XRPD pattern refers30 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 pattern; or a pattern having a tolerance of ±0.3 degrees 29 within the referenced peaks. In reference to an NMR pattern, “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 pattern; or a pattern having a tolerance of ±0.2Attorney Docket No.: 104545-0096-W02 ppm within the referenced peaks. In reference to an FT-IR pattern, “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 pattern; or a pattern having a tolerance of ± 0.5 cm’ 1 within the referenced peaks.5

[0045] The term “or” as used herein should be understood to mean “and / or,” unless the context clearly indicates otherwise.

[0046] Notwithstanding that the disclosed numerical ranges and parameters are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors10 necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range of “1 to 10” should be considered to include any and all subranges between (and inclusive of) the minimum value of 1 and the maximum value of 10; that is, all subranges beginning with a minimum value of 1 or more, e.g., 1 to 6.1, and ending with a maximum value of 10 or less, e.g., 5.5 to 10.

[0047] Where aspects or embodiments are described in terms of a Markush group or other grouping of alternatives, the present application encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, and also the main group absent one or more of the group members, notwithstanding20 such individuals and subgroups are not specifically referred to in this disclosure.

[0048] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the various aspects and embodiments. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0049] In order that the disclosure may be more readily understood, certain terms are first defined. These definitions should be read in light of the remainder of the disclosure as understood by a person of ordinary skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. Additional definitions are set forth throughout the detailed description.30

[0050] As used herein, the term “treat” and its cognates refer to a full or partial amelioration or modulation of the symptoms or pathology of a disease, disorder or condition, particularly those that can be effected utilizing the compounds and compositions of this disclosure, 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 being treated. “Treat”Attorney Docket No.: 104545-0096-W02 also refers to delaying the onset of, retarding or reversing the progress of, reducing the seventy of, or alleviating or preventing either 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, delaying or reducing the rate of a decline in cognitive function in post-5 concussive syndrome, nociplastic pain syndrome or chronic overlapping pain conditions.

[0051] “Treating cognitive impairment” refers to taking steps to improve cognitive function in a subject with cognitive impairment so that the subject’s performance in one or more cognitive tests is improved to any detectable degree or is prevented from further decline or the rate of such decline is reduced. Preferably, that subject’s cognitive function, after10 treatment of cognitive impairment, more closely resembles the function of a normal, unimpaired subject. Treatment of cognitive impairment in humans may improve cognitive function to any detectable degree, but is preferably improved sufficiently to allow the impaired subject to carry out daily activities of normal life at a similar level of proficiency as a normal, unimpaired subject. In some cases, “treating cognitive impairment” refers to taking steps to improve cognitive function in a subject with cognitive impairment so that the subject’s performance in one or more cognitive tests is improved to any detectable degree, is prevented from further decline, or the rate of such decline is reduced. Preferably, that subject’s cognitive function, after treatment of cognitive impairment, more closely resembles the function of a normal, unimpaired subject. In some cases, “treating cognitive impairment” in a subject refers20 to taking steps to delay or slow the progression of cognitive impairment in a subject with cognitive impairment. In some cases, “treating cognitive impairment” in a subject refers to taking steps to reduce the rate of decline of cognitive function in a subject with cognitive impairment.

[0052] As used herein, the term “subject”, “patient”, or “individual” are used interchangeably and includes humans and non-human mammals. Non-human mammals include bovines, ovines, porcines, equines, canines, felines, and rodents (e.g., rat, mouse, guinea pig and rabbit). Preferably, the subject is a human.

[0053] As used herein the term “(S)-enantiomers of tianeptine” refers to the (S)- enantiomer of tianeptine or crystalline forms thereof, the zwitterion thereof, a pharmaceutically30 acceptable salt of the (S)-enantiomer or crystalline forms thereof, a co-crystal of the (S)- enantiomer or the zwitterion thereof, an ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or 1 l-D-(S)-enantiomer, crystalline forms thereof, the zwitterion thereof, a pharmaceutically acceptable salt of the l l-D-(S)-enantiomer, a co-crystal of the l l-D-(S)-Attorney Docket No.: 104545-0096-W02 enantiomer or the zwitterion thereof, an ester of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof.

[0054] As used herein, “therapeutically effective amount” of the (S)-enantiomers of5 tianeptine of this disclosure, or compositions of this disclosure refers to the amount used to treat, prevent, or alleviate one or more symptoms of a disease or disorder of this disclosure. In some embodiments the disease or disorder or one or more symptoms of a disease or disorder is modulated by, exacerbated by, or associated with altered activity of PPAR-p / 5 and / or PPAR- y. In some embodiments, some of the diseases or disorders are associated with stress or the10 presence of excess metal ions. One skilled in the art can readily determine a therapeutically effective amount of the (S)-enanti omers of tianeptine (ie., the (S)-enantiomer or l l-D-(S)- enantiomer) of this disclosure, zwitterions, pharmaceutically acceptable salts of the (S)- enantiomers of this disclosure to be administered, by taking into account factors such as the size, weight, age and sex of the subject, the extent of disease penetration or persistence and severity of symptoms, and the route of administration. Generally, a therapeutically effective amount of the (S)-enanti omers of tianeptine (ie., the (S)-enantiomer or 1 l-D-(S)-enantiomer) of this disclosure, zwitterions, pharmaceutically acceptable salts of the (S)-enantiomers of this disclosure administered to a subject is between about 1 mg / day to about 5000 mg / day, between about 1 mg / day to about 4000 mg / day between, between about 1 mg / day to about 3000 mg / day,20 between about 1 mg / day to about 2000 mg / day, between about 1 mg / day to about 1000 mg / day, between about 2 mg / day to about 600 mg / day, between about 10 mg / day to about 400 mg / day, or between about 25 mg / day to 300 mg / day. Higher or lower doses are also contemplated.

[0055] As used herein, “pharmaceutically acceptable carrier” refers to any diluent or excipient that is compatible with the other ingredients of the formulation, and which is not deleterious to the recipient. The pharmaceutically acceptable carrier can be selected on the basis of the desired route of administration, in accordance with standard pharmaceutical practices.

[0056] As used herein, “enantiomer” refers to each of the two nonsuperimposable isomers of a compound having at least one chiral / asymmetric atom. Each enantiomer is30 optically active in the context of its ability to rotate light. Single enantiomers are designated according to the Cahn-Ingold-Prelog system, which is a well-known set of priority rules for ranking the four groups attached to an asymmetric carbon. See, e.g., March, Advanced Organic Chemist. 4. Th Ed., (1992), p. 109, the entire disclosure of which is herein incorporated by reference.Attorney Docket No.: 104545-0096-W02

[0057] 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 is nonsuperimposable on its mirror image. As used herein, the property of nonsuperimposability of an object on its mirror image is called “chirality.” The most common structural feature5 producing chirality is an asymmetric carbon atom, z.e., a carbon atom having four nonequivalent groups attached thereto.

[0058] 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 weights by various means, including chromatography.10

[0059] As used herein, the term “substantially pure” or “pure” refers to an enantiomer or composition comprising it comprising no more than 2% of the counterpart enantiomer. In some embodiments, the substantially pure (S)-enanti omers of tianeptine (z.e., the (S)-enantiomer or the l l-D-(S)-enantiomer) of this disclosure, the zwitterions thereof, pharmaceutically acceptable salts of the (S)-enantiomers or compositions of this disclosure 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 counterpart (R)-enanti omers of tianeptine (z.e., the (R)-enantiomer or 1 l-D-(R)-enantiomer), zwitterions or pharmaceutically acceptable salts of the (R)-enantiomers.

[0060] As used herein, the term “chiral purity” refers to the extent to which a mixture of enantiomers comprises one enantiomer over the other.20

[0061] As used herein, the term “co-crystal” is distinct from a salt and refers to a solid crystalline supramolecular complex composed of two or more components within the same crystal lattice, wherein the components are in a neutral state and interact via non-ionic interactions. The ability of an active pharmaceutical ingredient (API) and co-former to form a co-crystal can be predicted by determining the ApKa value. When the ApKa of the API and coformer is negative (<0), there is no proton transfer, which indicates that the system will form a co-crystal; in contrast, when the ApKa is above 3, there is full proton transfer, indicating that the system forms a salt. Often, the ApKa is between 0 and 3, in which only a partial proton transfer occurs, so the system is commonly referred to as a salt co-crystal (Nugrahani & Jessica. Molecules. 2021).30

[0062] As used herein, the term “p-opioid receptor assay” or “MOR assay” refers to a methodology of analyzing the activity of the G-protein coupled receptor signaling pathway in response to a ligand binding at the p-opioid receptor.

[0063] As used herein, the terms “Gi” refers to the Gi subunit in the G-protein coupled receptor signaling pathway.Attorney Docket No.: 104545-0096-W02

[0064] As used herein, the terms “Gs” refers to the Gs subunit in the G-protein coupled receptor signaling pathway.

[0065] As used herein, the terms “P-arrestin” and “arrestin” are used interchangeably.

[0066] As used herein, the term “m / z” refers to the mass-to-charge ratio.5

[0067] As used herein, the term “IR” or “retention time” refers to the interval between the injection of the sample and the detection of the substances in that sample.

[0068] As used herein, the term “neurite outgrowth” refers to the process in which developing neurons produce new projections, called neurites, in response to guidance cues.

[0069] As used herein, the term “aryl” refers to any functional group or substituent derived10 from an aromatic ring, having from 5 to 7 ring atoms, including 1 to 4 heteroatoms selected from the group consisting of carbon, nitrogen, sulfur, or oxygen. The aryl group may be added at any possible position on the (S)- or (R)- tianeptines of this disclosure.

[0070] As used herein, the term “alkyl” refers to a saturated linear or branched-chain monovalent hydrocarbon radical of any length from one to six carbon atoms (Ci-Ce), wherein the alkyl radical may be optionally substituted independently with one or more substituents.

[0071] As used herein, the term “analog” refers to a compound related to tianeptine, but having an altered chemical structure. For example, the tianeptine analog may comprise additional functional groups including hydroxyl, nitroso or aryl groups. The analogs of tianeptine of this disclosure include N-hydroxy-tianeptine, the (S)- and (R)- enantiomers thereof, N-nitroso-20 tianeptine, the (S)- and (R)- enantiomers thereof, aryl-substituted tianeptine analogs or pharmaceutically acceptable salts thereof.(S)-Tianeptine Enantiomers

[0072] In some aspects, this disclosure provides the (S)-enantiomer of 7-(3-chloro-6- methyl-5,5-dioxido-6,l l-dihydrodibenzo[c,f][l,2]thiazepine-l l-ylamino)heptanoic acid ((S)- enantiomer of tianeptine) or the 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, or the zwitterion or pharmaceutically acceptable salt thereof are characterized by comprising no more than about 2% (z.e., < about 2%) of the (R)-enantiomer or the zwitterion thereof or a30 pharmaceutically acceptable salt of the (R)-enantiomer. In some embodiments, the (S)- enantiomer, the zwitterion thereof or a pharmaceutically acceptable salt of the (S)-enantiomer are characterized by comprising no more than about 1% (z.e., < about 1%) of the (R)- enantiomer of tianeptine or the zwitterion thereof or a pharmaceutically acceptable salt of thatAttorney Docket No.: 104545-0096-W02 enantiomer. In some embodiments, the (S)-enantiomer, zwitterion thereof or a pharmaceutically acceptable salt of the (S)-enantiomer are characterized by comprising no more than about 0.9% (z.e., < about 0.9%) of the (R)-enantiomer of tianeptine or the zwitterion thereof or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the5 (S)-enantiomer, zwitterion thereof or a pharmaceutically acceptable salt of the (S)-enantiomer are 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, zwitterion thereof or a pharmaceutically acceptable salt of the (S)-enantiomer are characterized by comprising no10 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, 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 are characterized by comprising no more than about 0.5% i.e., < about 0.5%) 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 are characterized by20 comprising no more than about 0.4% (i.e., < about 0.4%) 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 are characterized by comprising no more than about 0.3% (i.e., < about 0.3%) 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 are characterized by comprising no more than about 0.2% (i.e., < about 0.2%) 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 are characterized by30 comprising no more than about 0.1% (i.e., < about 0.1%) of the (R)-enantiomer of tianeptine or the zwitterion thereof or a pharmaceutically acceptable salt of that enantiomer.

[0073] In some embodiments, the (S)-enantiomer of this disclosure is in the form of a pharmaceutically acceptable salt or a crystalline form thereof. In some embodiments, the (S)- tianeptine of this disclosure is in the form of a zwitterion.Attorney Docket No.: 104545-0096-W02

[0074] In some aspects, this disclosure provides an (S)-enantiomer of 7-((3-chloro-6- methyl-5,5-dioxido-6,l l-dihydrodibenzo[c,f][l,2]thi azepine- 11-yl-l l-d)amino)heptanoic acid (l l-D-(S)-enantiomer of tianeptine), the zwitterion thereof or a pharmaceutically acceptable salt of the l l-D-(S)-enantiomer, or a mixture of two or more of these species,5 wherein the 1 l-D-(S)-enantiomer, zwitterion or pharmaceutically acceptable salt are characterized by comprising no more than about 2% (j.e., < about 2%) of the 11 -□-(Rmenantiomer or the zwitterion thereof or a pharmaceutically acceptable salt of the 11-D-(R)- enantiomer. In some embodiments, the 1 l-D-(S)-enantiomer, zwitterion or a pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer are characterized by comprising no more than about10 1% i.e., < about 1%) of the l l-D-(R)-enantiomer of tianeptine or the zwitterion thereof or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the l l-D-(S)- enantiomer, zwitterion or a pharmaceutically acceptable salt of the l l-D-(S)-enantiomer are characterized by comprising no more than about 0.9% i.e., < about 0.9%) of the 11-D-(R)- enantiomer of tianeptine or the zwitterion thereof or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the 1 l-D-(S)-enantiomer, zwitterion or a pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer are characterized by comprising no more than about 0.8% i.e., < about 0.8%) of the 1 l-D-(R)-enantiomer of tianeptine or the zwitterion thereof or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the l l-D-(S)- enantiomer, zwitterion or a pharmaceutically acceptable salt of the l l-D-(S)-enantiomer are20 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 1 l-D-(S)-enantiomer, zwitterion or a pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer are characterized by comprising no more than about 0.6% {i.e., < about 0.6%) of the 1 l-D-(R)-enantiomer of tianeptine or the zwitterion thereof or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the l l-D-(S)- enantiomer, zwitterion or a pharmaceutically acceptable salt of the l l-D-(S)-enantiomer are characterized by comprising no more than about 0.5% {i.e., < about 0.5%) of the 11-D-(R)- enantiomer of tianeptine or the zwitterion thereof or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the 1 l-D-(S)-enantiomer, zwitterion or a pharmaceutically30 acceptable salt of the 1 l-D-(S)-enantiomer are characterized by comprising no more than about 0.4% i.e., < about 0.4%) of the 1 l-D-(R)-enantiomer of tianeptine or the zwitterion thereof or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the l l-D-(S)- enantiomer, zwitterion or a pharmaceutically acceptable salt of the l l-D-(S)-enantiomer are characterized by comprising no more than about 0.3% {i.e., < about 0.3%) of the 11-D-(R)-Attorney Docket No.: 104545-0096-W02 enantiomer of tianeptine or the zwitterion thereof or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the 1 l-D-(S)-enantiomer, zwitterion or a pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer are characterized by comprising no more than about 0.2% ( / %., < about 0.2%) of the 1 l-D-(R)-enantiomer of tianeptine or the zwitterion thereof or5 a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the l l-D-(S)- enantiomer, zwitterion or a pharmaceutically acceptable salt of the l l-D-(S)-enantiomer are characterized by comprising no more than about 0.1% (i.e., < about 0.1%) of the 11-D-(R)- enantiomer of tianeptine or the zwitterion thereof or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the 1 l-D-(S)-tianeptine, zwitterion thereof, or10 pharmaceutically acceptable salt of either is characterized by reduced racemization at position 11 as compared to the 1 l-D-(S)-tianeptine, zwitterion thereof or a pharmaceutically acceptable salt of either.

[0075] In some embodiments, the 1 l-D-(S)-tianeptine of this disclosure is in the form of a pharmaceutically acceptable salt or a crystalline form thereof. In some embodiments, the 1 l-D-(S)-tianeptine of this disclosure is in the form of a zwitterion.

[0076] In some embodiments, the 1 l-D-(S)-enantiomer, the zwitterion thereof or a pharmaceutically acceptable salt of the l l-D-(S)-enantiomer is deuterated at the two 3’ positions, and optionally deuterated at other positions on the aminoheptanoic side chain. In some embodiments, the 1 l-D-(S)-enantiomer is 3’, 3’, 4’, 4’, 11- pentadeuterotianeptine of the20 general Formula (Illa) or the zwitterion thereof of Formula (Illb); 2’, 2’, 3’, 3’, 4’, 4’, 5’, 5’, 6’, 6’, 7’, 7’, 11 -tridecadeuterotianeptine (of the general Formula (IVa)) or the 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 (VIb). In some embodiments, the l l-D-(S)-enantiomer is 3’, 3’, 4’, 4’, 11- pentadeuterotianeptine of the general Formula (Illa) or the zwitterion thereof of Formula (Illb). In some embodiments, the 1 l-D-(S)-enantiomer is 2’, 2’, 3’, 3’, 4’, 4’, 5’, 5’, 6’, 6’, 7’, 7’, 11- tridecadeuterotianeptine of the general Formula (IVa) or the zwitterion thereof of Formula (IVb). In some embodiments, the l l-D-(S)-enantiomer is 3’, 3’, 4’, 4’, tetradeuterotianeptine30 of the general formula (Va) or the zwitterion thereof of Formula (Vb). In some embodiments, the l l-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 thereof of the general formula (VIb).Attorney Docket No.: 104545-0096-W025

[0077] Methods of producing the compounds described herein as pharmaceutically acceptable salts of the (S)-enantiomers of this disclosure, and the like are well known to those of skill 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, e.g., 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 acid and the like, as well as inorganic acids, e.g., hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, and the like. Conversely, preparation of basic salts of the S-enantiomers described herein can be prepared in a similar manner using a pharmaceutically acceptable base. Suitable pharmaceutically acceptable base20 addition salts of the (S)-enantiomers of this disclosure, include metallic salts made fromAttorney Docket No.: 104545-0096-W02 calcium, magnesium, potassium, sodium, ammonium and zinc or the like, or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-m ethylglucamine), procaine and trimethylamine or the like.

[0078] In some embodiments, the pharmaceutically acceptable salt of the (S)-5 enantiomers and crystalline forms thereof of this disclosure 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 polisterix, (S)-tianeptine: L-DBTA (2: 1),10 (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 some20 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-acetyl-L-tyrosinate (1 : 1). In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer is (S)- tianeptine polisterix. 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)-tianeptine30 oxalate (2:1) (z.e., (S)-tianeptine hemi-oxalate). In some embodiments, the hemi-oxalate salt is in a crystalline form.

[0079] In some embodiments, the pharmaceutically acceptable salt of the l l-D-(S)- enantiomer and crystalline forms thereof of this disclosure is l l-D-(S)-tianeptine benzenesulfonate (1 :1), l l-D-(S)-tianeptine fumarate (1 : 1), l l-D-(S)-tianeptine fumarateAttorney Docket No.: 104545-0096-W02(2: 1), l l-D-(S)-tianeptine hippurate (1 : 1), l l-D-(S)-tianeptine maleate (1 : 1), l l-D-(S)- tianeptine maleate (2: 1), H-D-(S)-tianeptine p-toluenesulfonate (1 : 1), 1 l-D-(S)-tianeptine orotate (1 : 1), l l-D-(S)-tianeptine camphorsulfonate (1 : 1), l l-D-(S)-tianeptine N-acetyl-L- tyrosinate (1 : 1), 1 l-D-(S)-tianeptine polisterix, 1 l-D-(S)-tianeptine: L-DBTA (2: 1), l l-D-(S)- tianeptine sodium, 1 l-D-(S)-tianeptine oxalate, or 1 l-D-(S)-tianeptine oxalate (2:1). In some embodiments, the pharmaceutically acceptable salt of the l l-D-(S)-enantiomer is l l-D-(S)- tianeptine benzenesulfonate (1: 1). In some embodiments, the pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer is 11-D- (S)-tianeptine fumarate (1 : 1). In some embodiments, the pharmaceutically acceptable salt of the l l-D-(S)-enantiomer is l l-D-(S)-tianeptine fumarate (2: 1). In some embodiments, the pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer is 1 l-D-(S)-tianeptine hippurate (1 : 1). In some embodiments, the pharmaceutically acceptable salt of the l l-D-(S)-enantiomer is l l-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 1 l-D-(S)-enantiomer is l l-D-(S)-tianeptine p-toluenesulfonate (1 : 1). In some embodiments, the pharmaceutically acceptable salt of the l l-D-(S)-enantiomer is 1 l-D-(S)-tianeptine orotate (1 : 1). In some embodiments, the pharmaceutically acceptable salt of the l l-D-(S)-enantiomer is l l-D-(S)- tianeptine camphorsulfonate (1: 1). In some embodiments, the pharmaceutically acceptable salt of the l l-D-(S)-enantiomer is 1 l-D-(S)-tianeptine N-acetyl-L-tyrosinate (1 : 1). In some embodiments, the pharmaceutically acceptable salt of the l l-D-(S)-enantiomer is l l-D-(S)- tianeptine polisterix. In some embodiments, the pharmaceutically acceptable salt of the (S)- enantiomer is 1 l-D-(S)-tianeptine: L-DBTA (2: 1). In some embodiments, the pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer is 1 l-D-(S)-tianeptine sodium. In some embodiments, the pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer is 11-D- (S)-tianeptine oxalate. In some embodiments, the pharmaceutically acceptable salt of the 11- D-(S)-enantiomer is 1 l-D-(S)-tianeptine oxalate (2: 1) (z.e., 1 l-D-(S)-tianeptine hemi-oxalate). In some embodiments the hemi-oxalate salt is in crystalline form.

[0080] In some embodiments, e.g., fumaric acid and maleic acid act as a monoanions or a dianion, 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 on the aminoheptanoic side chain.

[0081] In some embodiments, the pharmaceutically acceptable salt or crystalline forms thereof of the (S)-enantiomer of this disclosure or the pharmaceutically acceptable salt of the l l-D-(S)-enantiomer or crystalline forms thereof of this disclosure is formed from theAttorney Docket No.: 104545-0096-W02 benzenesulfonic, fumaric, hippunc, maleic, or p-toluenesulfomc acid m acetone and 2- propanol. In some embodiments, the pharmaceutically acceptable salt of the (S)-enantiomer or crystalline forms thereof of this disclosure or the pharmaceutically acceptable salt of the 11-D- (S)-enantiomer or crystalline forms thereof of this disclosure is formed from orotic acid in 58%5 water / 42% tetrahydrofuran (THF).

[0082] In some aspects, this disclosure provides a co-crystal of the (S)-enantiomer of this disclosure, wherein the (S)-enantiomer or the zwitterion thereof forms a complex with L- tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid. In some embodiments, the (S)-enantiomer or the zwitterion thereof forms a complex with L- tyrosine. In some10 embodiments, the (S)-enantiomer or the zwitterion thereof forms a complex with L-tryptophan. In some embodiments, the (S)-enantiomer or the zwitterion thereof forms a complex with L- phenylalanine. In some embodiments, the (S)-enantiomer or the zwitterion thereof forms a complex with another L-amino acid. In some embodiments, the ratio of the (S)-enantiomer or the zwitterion thereof to the L-amino acid is 1 : 1, 1 :2, or 2: 1. In some embodiments, the ratio of the (S)-enantiomer or the zwitterion thereof to the L-amino acid is 1 :1. In some embodiments, the ratio of the (S)-enantiomer or the zwitterion thereof to the L-amino acid is 1 :2. In some embodiments, the ratio of the (S)-enantiomer or the zwitterion thereof to the L- amino acid is or 2: 1. In some embodiments, the co-crystal comprises an inorganic monoacid salt of the (S)-enantiomer and a zwitterion of the L-amino acid. In some embodiments, the co¬20 crystal 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 (HC1).

[0083] In some aspects, this disclosure provides a co-crystal of the l l-D-(S)- enantiomer of this disclosure (and of an 1 l-D-(S)-enantiomer having at least one deuterium substitution on the aminoheptanoic side chain), wherein the (S)-enantiomer or the zwitterion thereof forms a complex with L- tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid. In some embodiments, the l l-D-(S)-enantiomer or the zwitterion thereof forms a complex with L- tyrosine. In some embodiments, the 1 l-D-(S)-enantiomer or the zwitterion thereof forms a complex with L-tryptophan. In some embodiments, the 1 l-D-(S)-enantiomer or the zwitterion thereof forms a complex with L-phenylalanine. In some embodiments, the30 1 l-D-(S)-enantiomer or the zwitterion thereof forms a complex with another L-amino acid. In some embodiments, the ratio of the l l-D-(S)-enantiomer or the zwitterion thereof to the L- amino acid is 1 : 1, 1 :2, or 2: 1. In some embodiments, the ratio of the l l-D-(S)-enantiomer or the zwitterion thereof to the L-amino acid is 1 : 1. In some embodiments, the ratio of the 11-D- (S)-enantiomer or the zwitterion thereof to the L-amino acid is 1 :2. In some embodiments, theAttorney Docket No.: 104545-0096-W02 ratio of the l l-D-(S)-enantiomer or the zwitterion thereof to the L-amino acid is or 2: 1. In some embodiments, the co-crystal comprises an inorganic monoacid salt of the l l-D-(S)- enantiomer and a zwitterion of the L-amino acid. In some embodiments, the co-crystal comprises an inorganic monoacid salt of the L-amino acid and the zwitterion of the 1 l-D-(S)-5 enantiomer. In some embodiments, the inorganic monoacid is hydrochloric acid (HC1).

[0084] In some aspects, this disclosure provides an ester of the (S)-enantiomer of this disclosure 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,10 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 pharmaceutically acceptable salt thereof is characterized by comprising < about 0.8% 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 0.7% of the ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the (S)-enantiomer or pharmaceutically acceptable20 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 the30 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.Attorney Docket No.: 104545-0096-W02

[0085] In some embodiments, this disclosure provides an ester of the l l-D-(S)- enantiomer of this disclosure (and of an 1 l-D-(S)-enantiomer having at least one deuterium substitution on the aminoheptanoic side chain) or a pharmaceutically acceptable salt thereof, wherein the ester of the l l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof is5 characterized by comprising < about 2% of the ester of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the l l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 1% of the ester of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the l l-D-(S)-enantiomer or pharmaceutically acceptable salt10 thereof is characterized by comprising < about 0.9% of the ester of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the l l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.8% of the ester of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the l l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.7% of the ester of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the l l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.6% of the ester of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the l l-D-(S)-enantiomer or pharmaceutically acceptable salt20 thereof is characterized by comprising < about 0.5% of the ester of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the l l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.4% of the ester of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the l l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.3% of the ester of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the l l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.2% of the ester of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the ester of the l l-D-(S)-enantiomer or pharmaceutically acceptable salt30 thereof is characterized by comprising < about 0.1% of the ester of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the esters include Ci-Ce alkyl, C3-C6 branched alkyl, C3- Ce cyclic alkyl, and pivaloyloxyethyl esters. The esters are designed such that the salts of the esters, without wishing to be bound by theory, dissolve slowly enough to provide slow releaseAttorney Docket No.: 104545-0096-W02 of the esters, and such that the esters can undergo enzymatic cleavage to form the active (S)- enantiomer or 1 l-D-(S)-enantiomer in the intestine, serum and / or brain at such a rate as to provide slow release of the (S)-enantiomer or 1 l-D-(S)-enantiomer allowing once-a-day dosing of the ester salt.5

[0087] Exemplary esters include 3’, 3’, 4’, 4’, tetradeutero-(S)-tianeptine methyl ester oxalate 1 : 1 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 (S)-tianeptine ethyl ester orotate of Formula (X):F ormul a (IX) F ormul a (X) .15

[0088] In some aspects, this disclosure provides an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, wherein the amide of the (S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < aboutAttorney Docket No.: 104545-0096-W022% of the amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 1% of the amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the (S)-5 enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.9% of the amide of the (R)-enantiomer 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 amide of the (S)-10 enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.7% of the amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.6% of the amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the (S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.5% of the amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.4% of the amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the (S)-20 enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.3% of the amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.2% of the amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the (S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.1% of the amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof.

[0089] In some embodiments, this disclosure provides an amide of the l l-D-(S)- enantiomer of this disclosure (and of an l l-D-(S)-enantiomer having at least one deuterium substitution on the aminoheptanoic side chain) or a pharmaceutically acceptable salt thereof,30 wherein the amide of the l l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 2% of the amide of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the l l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 1% of the amide of the l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. InAttorney Docket No.: 104545-0096-W02 some embodiments, the amide of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.9% of the amide of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the 1 l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about5 0.8% of the amide of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.7% of the amide of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the 1 l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about10 0.6% of the amide of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.5% of the amide of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the 1 l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.4% of the amide of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.3% of the amide of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the 1 l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about20 0.2% of the amide of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the amide of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof is characterized by comprising < about 0.1% of the amide of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the amides include simple amides, Ci-Ce alkyl optionally substituted with at least one hydroxyl, C3-C6 branched alkyl, and C3-C6 cyclic alkyl amides. The amides are designed such that the salts of the amides, without wishing to be bound by theory, provide advantages of improved crystallization in comparison to the (S)-enantiomer or the 1 l-D-(S)-enantiomer of tianeptine, selected delivery to the CNS due to metabolism by the brain specific fatty acid amide hydrolases (FAAH), and cannabinoid activity through binding30 of fatty acid amides to cannabinoid receptors which may contribute to pain reduction and antidepressive activity.

[0091] Exemplary amides include (S)-N-(7-amino-7-oxoheptyl-4,4,5,5-d4)-3-chloro- 6-methyl-6,l l-dihydrodibenzo[c,f][l,2]thiazepine-l 1-aminium 5,5-dioxide oxalate 1 : 1 of Formula (XI), (S)-3-chloro-N-(7-(isopropylamino)-7-oxoheptyl-l,l,2,2,3,3,4,4,5,5,6,6-dl2)-Attorney Docket No.: 104545-0096-W026-methyl-6,l l-dihydrodibenzo[c,f][l,2]41hiazepine-l 1-aminium 5,5-dioxide p- toluenesulfonate of Formula (XII), (HS)-3-chloro-6-methyl-N-(7-oxo-7-((l- pivalamidoethyl)amino)heptyl-4,4,5, 5-d4)-6, 11 -dihydrodibenzo[c,f] [ 1 ,2] 41 hi azepine- 11 -d-11-aminium 5,5-dioxide benzoate of Formula (XIII) and (S)-3-chloro-N-(7-(ethylamino)-7-5 oxoheptyl)-6-methyl-6,l l-dihydrodibenzo[c,f][l,2]41hiazepine-l 1-aminium 5,5-dioxide orotate of Formula (XIV):F ormul a (XIII) F ormul a (XI V) .

[0092] In some embodiments, this disclosure provides a pharmaceutically acceptable acid salt of the (S)-enantiomers (e.g., (S)-enantiomer or 1 l-D-(S)-enantiomer) of this disclosure, wherein the nitrogen atom in the sidechain attached to Carbon-11 (C-l l) is 100% 15 protonated, the 100% protonated salt being less sensitive to air oxidation in solid or solutionAttorney Docket No.: 104545-0096-W02 forms when compared to the (S)-enantiomer, the 1 l-D-(S)-enantiomer, the zwitterion of either or the sodium salts of either.

[0093] In some aspects, this disclosure provides a crystalline hemi-oxalate salt of (S)- 7-(3-chloro-6-methyl-6,l l-dihydrodibenzo[c,f] [l,2]thiazepin-l l-ylamino)heptanoic acid 5,5-5 dioxide ((S)-tianeptine). In some embodiments, the crystalline (S)-tianeptine hemi-oxalate salt of this disclosure exhibits an X-ray diffraction pattern (XRPD) comprising at least one peak selected from the group consisting of 8.5, 20.6, 21.0 and 24.2 degrees 20 ±0.3 degrees 20. In some embodiments, the crystalline (S)-tianeptine hemi-oxalate salt further exhibits an XRPD pattern further comprising at least one peak selected from the group consisting of 12.1, 13.3,10 16.1, 18.9, 19.1, 22.0 and 22.4 degrees 20 ±0.3 degrees 20.

[0094] In some aspects, this disclosure provides a crystalline free acid / free base of the (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 the group consisting of 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) further comprising at least one peak selected from the group consisting of 8.7, 9.1, 12.6, 18.1, 20.4, 23.0 and 26.1 degrees 20 ±0.3 degrees 20.(S)-Tianeptine Analogs20

[0095] In some aspects, this disclosure provides the compound N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure provides the (S)- enantiomer of N-hydroxy-tianeptine (z.e., N-hydroxy-(S)-tianeptine) or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure provides the (R)-enantiomer of N- hydroxy -tianeptine (z.e., N-hydroxy-(R)-tianeptine) or a pharmaceutically acceptable salt thereof. Without wishing to be bound by theory, N-hydroxy-tianeptine shows no p-opioid receptor (MOR) agonism and / or acts as a potent PPAR-p / 5 and / or PPAR-y agonist.

[0096] In some embodiments, the (S)-enantiomer of N-hydroxy-tianeptine or pharmaceutically acceptable salt thereof, are characterized by comprising no more than about 2% (z.e., < about 2%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically30 acceptable salt of the (R)-enantiomer of N-hydroxy-tianeptine. In some embodiments, the (S)- enantiomer of N-hydroxy-tianeptine or pharmaceutically acceptable salt thereof are characterized by comprising no more than about 1% (z.e., < about 1%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In someAttorney Docket No.: 104545-0096-W02 embodiments, the (S)-enantiomer of N-hydroxy -tianeptine or pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.9 % (z.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 or5 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.8% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.7% (z.e., < about 0.7%) of the (R)-enantiomer of N-hydroxy-tianeptine or a10 pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxy-tianeptine or pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.6% (z.e., < about 0.6%) 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 pharmaceutically acceptable salt thereof are 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, the (S)-enantiomer of N-hydroxy-tianeptine or pharmaceutically acceptable salt thereof are 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 of20 that enantiomer. In some embodiments, the (S)-enantiomer of N-hydroxy-tianeptine or pharmaceutically acceptable salt thereof are 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 pharmaceutically acceptable salt thereof are 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 pharmaceutically acceptable salt thereof are 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.30

[0097] In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or pharmaceutically acceptable salt thereof, are characterized by comprising no more than about 2% (i.e., < about 2%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or pharmaceutically acceptable salt thereof are characterized by comprising no more than aboutAttorney Docket No.: 104545-0096-W021% (z.e., < about 1%) 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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.9 % (z.e., < about 0.9%) of the (S)-enantiomer of N-hydroxy-tianeptine or a5 pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (R)-enantiomer of N-hydroxy-tianeptine or pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.8% (z.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 pharmaceutically acceptable salt thereof are10 characterized by comprising no more than about 0.7% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.6% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.5% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more20 than about 0.4% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.3% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.2% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.1% (z.e., < about30 0.1%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.

[0098] In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof, are characterized by comprising no more than about 2% (z.<?., < about 2%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceuticallyAttorney Docket No.: 104545-0096-W02 acceptable salt of the (R)-enantiomer of N-mtroso-tianeptine. In some embodiments, the (S)- enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof are characterized by comprising no more than about 1% (z.e., < about 1%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some5 embodiments, the (S)-enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.9% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about10 0.8% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.7% (z.e., < about 0.7%) 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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.6% (z.e., < about 0.6%) 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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.5% (z.e., < about 0.5%) of the (R)-20 enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.4% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.3% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.2% (z.e., < about 0.2%) of the (R)-enantiomer of N-nitroso-tianeptine or a30 pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (S)-enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.1% (z.e., < about 0.1%) of the (R)-enantiomer of N-nitroso- tianeptine or a pharmaceutically acceptable salt of that enantiomer.Attorney Docket No.: 104545-0096-W02

[0099] In some embodiments, the (R)-enantiomer of N-mtroso-tianeptine or pharmaceutically acceptable salt thereof, are 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 or5 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 1% < 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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.9% (z.e., < about 0.9%) of the (S)-enantiomer of N-nitroso-tianeptine or a10 pharmaceutically acceptable salt of that enantiomer. In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.8% (z.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 pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.7% (z.e., < about 0.7%) 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 pharmaceutically acceptable salt thereof are 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 of that20 enantiomer. In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof are 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 pharmaceutically acceptable salt thereof are 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. In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof are 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 of that enantiomer. In some embodiments, the30 (R)-enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof are 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 of that enantiomer. In some embodiments, the (R)-enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof are characterized by comprising no more than about 0.1% (i.e., < about 0.1%) ofAttorney Docket No.: 104545-0096-W02 the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer.

[0100] In some aspects, this disclosure provides the compound N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure provides the (S)-5 enantiomer of N-nitroso-tianeptine (z.e., N-nitroso-(S)-tianeptine) or a pharmaceutically acceptable salt thereof. In some aspects, this disclosure provides the (R)-enantiomer of N- nitroso-tianeptine (z.e., N-nitroso-(R)-tianeptine) or a pharmaceutically acceptable salt thereof. Without wishing to be bound by theory, N-hydroxy-tianeptine shows no p-opioid receptor (MOR) agonism and acts as a potent PPAR-p / 5 and / or PPAR-y agonist.

[0101] In some aspects, this disclosure provides aryl-substituted tianeptine derivatives. Exemplary derivatives include 7-((3-(furan-2-yl)-6-methyl-5,5-dioxido-6,l l- dihydrodibenzo[c,f][l,2]thiazepin-l l-yl)amino)heptanoic acid of Formula (XXI), 7-((3- (furan-3-yl)-6-methyl-5, 5-dioxido-6, 11 -dihydrodibenzo[c,f| [ 1 ,2 ]thi azepin- 11- yl)amino)heptanoic acid of Formula (XXII), 7-((6-methyl-5,5-dioxido-3-(thiophen-3-yl)-6,l l-15 dihydrodibenzo[c,f][l,2]thiazepin-l l-yl)amino)heptanoic acid of Formul (XXIII) and 2-(4- (((3-chloro-6-methyl-5,5-dioxido-6,l l-dihydrodibenzo[c,f][l,2]thiazepin-l 1- yl)amino)methyl)-2-methylphenoxy)acetic acid of Formula (XXIV). Without being bound to theory, the aryl-substituted tianeptine derivatives exhibit increased membrane penetration compared to tianeptine due to the aromatic ring, and the (R)-enantiomer of the aryl-substituted tianeptine derivatives and the racemic mixture show decreased MOR agonism compared to (R)-tianeptine and racemic tianeptine due to the shape of the molecule.25Formula (XXIV)Attorney Docket No.: 104545-0096-W02Pharmaceutical composition

[0102] The compounds described herein can be administered as the (S)-enantiomer or the l l-D-(S)-enantiomer of this disclosure or, if desired, in the form of a zwitterion, salt5 (including crystalline salts), ester, ester salt, amide, amide salt or co-crystal of this disclosure, provided the zwitterion, salt, ester, ester salt, amide, amide salt or co-crystal is suitable pharmacologically, e.g., effective in the present method(s). Zwitterions, salts, esters, ester salts or co-crystals of the (S)-enantiomer or the 1 l-D-(S)-enantiomer of this disclosure can be prepared using standard procedures known to those skilled in the art of synthetic organic10 chemistry.

[0103] In some embodiments, this disclosure provides a pharmaceutical composition comprising one or more of the (S)-enanti omers of this disclosure, i.e., the zwitterions thereof or pharmaceutically acceptable salts of the (S)-enantiomers of this disclosure, or co-crystals of the (S)-enantiomers (including crystalline salts thereof) of this disclosure or zwitterions thereof, or esters of the (S)-enantiomers or pharmaceutically acceptable salts thereof of this disclosure, or amides of the (S)-enantiomers or pharmaceutically acceptable salts thereof of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises no more than about 2% (z.e., < about 2%) of the (R)-enanti omers, the zwitterions thereof, or pharmaceutically acceptable salts of the (R)-enantiomers, or co-crystals20 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.

[0104] In some embodiments, this disclosure provides a pharmaceutical composition comprising the (S)-enantiomer of tianeptine of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt (including crystalline salts thereof) of the (S)-enantiomer of this disclosure, or a co-crystal of the (S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure, or an amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition30 comprises no more than about 2% (z.e., < about 2%) of the (R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer, or co-crystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer orAttorney Docket No.: 104545-0096-W02 pharmaceutically acceptable salt thereof of this disclosure. In some embodiments, the composition comprises no more than about 1% (z'.e., < about 1%) of the (R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer, or co-crystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer5 or pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure. In some embodiments, the composition comprises no more than about 0.9% (z.e., < about 0.9%) of the (R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer, or co-crystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer10 or pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure. In some embodiments, the composition comprises no more than about 0.8% (z.e., < about 0.8%) of the (R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer, or co-crystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure. In some embodiments, the composition comprises no more than about 0.7% (z.e., < about 0.7%) of the (R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer, or co-crystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer20 or pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure. In some embodiments, the composition comprises no more than about 0.6% (z.e., < about 0.6%) of the (R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer, or co-crystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure. In some embodiments, the composition comprises no more than about 0.5% (z.e., < about 0.5%) of the (R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer, or co-crystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer30 or pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure. In some embodiments, the composition comprises no more than about 0.4% (z.e., < about 0.4%) of the (R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer, or co-crystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomerAttorney Docket No.: 104545-0096-W02 or pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure. In some embodiments, the composition comprises no more than about 0.3% (z.e., < about 0.3%) of the (R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer,5 or co-crystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure. 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,10 or co-crystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure. In some embodiments of this disclosure, the composition comprises no more than about 0.1% (z.e., < about 0.1%) of the (R)- enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of the (R)-enantiomer, or co-crystal of the (R)-enantiomer or the zwitterion thereof, or an ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure.

[0105] In some embodiments, the pharmaceutical composition of this disclosure comprises the (S)-enantiomer of tianeptine of this disclosure and a pharmaceutically acceptable20 carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt (including crystalline salts thereof) of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable cocrystal of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments the pharmaceutical composition comprises the zwitterion of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises an ester of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises a30 pharmaceutically acceptable salt of the ester of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises an amide of the (S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the amide of theAttorney Docket No.: 104545-0096-W02(S)-enantiomer of this disclosure and a pharmaceutically acceptable earner, diluent or excipient.

[0106] In some embodiments, this disclosure provides a pharmaceutical composition comprising the 1 l-D-(S)-enantiomer of tianeptine of this disclosure (and of an l l-D-(S)-5 enantiomer having at least one deuterium substitution on the aminoheptanoic side chain), the zwitterion thereof, or a pharmaceutically acceptable salt (including crystalline salts thereof) of an l l-D-(S)-enantiomer of this disclosure, or a co-crystal of an 1 l-D-(S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of an 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof of this disclosure, or an amide of an l l-D-(S)-enantiomer or10 pharmaceutically acceptable salt thereof of this disclosure and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises no more than about 2% (z.e., < about 2%) of an l l-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(R)-enantiomer, or co-crystal of an l l-D-(R)- enantiomer or the zwitterion thereof, or an ester of an 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of an l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 1% (z.e., < about 1%) of an 1 l-D-(R)-enantiomer of tianeptine, a zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(R)-enantiomer, or co-crystal of an l l-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 1 l-D-(R)-enantiomer or20 pharmaceutically acceptable salt thereof, or an amide of an l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.9% (i.e., < about 0.9%) of an 1 l-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(R)-enantiomer, or cocrystal of an l l-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)- enantiomer or pharmaceutically acceptable salt thereof, or an amide of an 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.8% (i.e., < about 0.8%) of an 1 l-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(R)-enantiomer, or cocrystal of an l l-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)-30 enantiomer or pharmaceutically acceptable salt thereof, or an amide of an 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.7% (i.e., < about 0.7%) of an 1 l-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(R)-enantiomer, or cocrystal of an l l-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)-Attorney Docket No.: 104545-0096-W02 enantiomer or pharmaceutically acceptable salt thereof, or an amide of an 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.6% (z.e., < about 0.6%) of an 1 l-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(R)-enantiomer, or co¬5 crystal of an l l-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)- enantiomer or pharmaceutically acceptable salt thereof, or an amide of an 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.5% (i.e., < about 0.5%) of an 1 l-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(R)-enantiomer, or co¬10 crystal of the l l-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)- enantiomer or pharmaceutically acceptable salt thereof, or an amide of an 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.4% (i.e., < about 0.4%) of an 1 l-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(R)-enantiomer, or cocrystal of an l l-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)- enantiomer or pharmaceutically acceptable salt thereof, or an amide of an 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.3% i.e., < about 0.3%) of an 1 l-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(R)-enantiomer, or co¬20 crystal of an l l-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 11-D-(R)- enantiomer or pharmaceutically acceptable salt thereof, or an amide of an 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 0.2% (i.e., < about 0.2%) of an 1 l-D-(R)-enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(R)-enantiomer, or cocrystal of an 1 l-D-(R)-enantiomer or a zwitterion thereof, or an ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of an l l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof. In some embodiments of this disclosure, the composition comprises no more than about 0.1% (i.e., < about 0.1 %) of an l l-D-(R)- enantiomer of tianeptine, the zwitterion thereof, or a pharmaceutically acceptable salt of an 11-30 D-(R)-enantiomer, or co-crystal of an 1 l-D-(R)-enantiomer or a zwitterion thereof, or an ester of an 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of an 11- D-(R)-enantiomer or pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the pharmaceutical composition of this disclosure comprises an 1 l-D-(S)-enantiomer of tianeptine of this disclosure and a pharmaceuticallyAttorney Docket No.: 104545-0096-W02 acceptable earner, 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 disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises a5 pharmaceutically acceptable co-crystal of an l l-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments the pharmaceutical composition comprises a zwitterion of an 1 l-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises an ester of an l l-D-(S)-enantiomer10 of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the ester of an l l-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises an amide of the l l-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the amide of the l l-D-(S)-enantiomer of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient.

[0108] In some embodiments, the composition comprises a mixture of two or more pharmaceutically acceptable salts (including crystalline salts thereof) or co-crystals of the (S)-20 enantiomer or the 1 l-D-(S)-enantiomer (and of an 1 l-D-(S)-enantiomer having at least one deuterium substitution on the aminoheptanoic side chain), wherein the mixture of the pharmaceutically acceptable salts or co-crystals is characterized by an enhanced extended release when administered orally as compared to administering a composition comprising a single pharmaceutically acceptable salt or co-crystal of the (S)-enantiomer or the l l-D-(S)- enantiomer of this disclosure. In some embodiments, the enhanced extended release of the mixture of the pharmaceutically acceptable salts or co-crystals is due, without being bound by theory, to the different dissolution rates of each of the salt or co-crystal forms in the intestinal track.

[0109] In some embodiments, the pharmaceutical composition of this disclosure30 comprises one or more of the tianeptine analogs of this disclosure, i.e., 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 -substitute analog of tianeptine of this disclosure or a pharmaceutically acceptable salt of any of them and a pharmaceutically acceptable carrier,Attorney Docket No.: 104545-0096-W02 diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises the N-hydroxy-tianeptine of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises a pharmaceutically acceptable salt of the N-hydroxy-tianeptine of this5 disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises the (S)-enantiomer of N-hydroxy-tianeptine of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises a pharmaceutically acceptable salt of the (S)-enantiomer of the N-hydroxy-10 tianeptine of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises the (R)- enantiomer of N-hydroxy-tianeptine of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises a pharmaceutically acceptable salt of the (R)-enantiomer of the N- hydroxy-tianeptine of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises the N-nitroso-tianeptine of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises a pharmaceutically acceptable salt of the N-nitroso-tianeptine of this disclosure and a20 pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises the (S)-enantiomer of N-nitroso- tianeptine of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises a pharmaceutically acceptable salt of the (S)-enantiomer of the N-nitroso-tianeptine of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises the (R)-enantiomer of N-nitroso-tianeptine of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises a pharmaceutically acceptable salt of the (R)-enantiomer of the N-nitroso-tianeptine of this30 disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprises an aryl-substitute analog of tianeptine of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition of this disclosure comprisesAttorney Docket No.: 104545-0096-W02 a pharmaceutically acceptable salt of aryl -substitute analog of tianeptine of this disclosure and a pharmaceutically acceptable carrier, diluent or excipient.

[0110] In some embodiments, this disclosure provides a pharmaceutical composition comprising the (S)-enantiomer of N-hydroxy-tianeptine or pharmaceutically acceptable salt5 thereof of this disclosure, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises no more than about 2% (z.e., < about 2%) of the (R)- enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of the (R)- enantiomer of N-hydroxy-tianeptine. In some embodiments, the composition comprises no more than about 1% (z.e., < about 1%) of the (R)-enantiomer of N-hydroxy-tianeptine or a10 pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.9% (z.e., < about 0.9%) of the (R)-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% (z.e., < about 0.8%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.7% (z.e., < about 0.7%) of the (R)-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% (z.e., < about 0.6%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about20 0.5% (z.e., < about 0.5%) of the (R)-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% (z.e., < about 0.4%) of the (R)-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% (z.e., < about 0.3%) of the (R)-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% (z.e., < about 0.2%) of the (R)-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% (z.e., < about 0.1%) of the (R)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that30 enantiomer.

[0111] In some embodiments, this disclosure provides a pharmaceutical composition comprising the (R)-enantiomer of N-hydroxy-tianeptine or pharmaceutically acceptable salt thereof of this disclosure, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises no more than about 2% (z.e., < about 2%) of the (S)-Attorney Docket No.: 104545-0096-W02 enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 1% (z.e., < about 1%) 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 0.9% (z.e., < about 0.9%)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 0.8% (z.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 0.7% (z.e., < about 0.7%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically10 acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.6% (z.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% (z.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% (z.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% (z.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% (z.e.,20 < 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% (z.e., < about 0.1%) of the (S)-enantiomer of N-hydroxy-tianeptine or a pharmaceutically acceptable salt of that enantiomer.

[0112] In some embodiments, this disclosure provides a pharmaceutical composition comprising the (S)-enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof of this disclosure, and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the composition comprises no more than about 2% (z.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 composition comprises no more than about30 1% (z.e., < about 1%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.9% (z.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 no more than about 0.8% (z.e., < about 0.8%) of the (R)-enantiomer of N-nitroso-Attorney Docket No.: 104545-0096-W02 tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.7% (z.<?., < 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 no more than about 0.6% (z.e., < about 0.6%) of the5 (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.5% (z.e.,< about 0.5%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.4% (z.e., < about 0.4%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically10 acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.3% (z.e., < about 0.3%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.2% (z.e., < about 0.2%) of the (R)-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% (z.e., < about 0.1%) of the (R)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that enantiomer.

[0113] In some embodiments, this disclosure provides a pharmaceutical composition comprising the (R)-enantiomer of N-nitroso-tianeptine or pharmaceutically acceptable salt thereof of this disclosure, and a pharmaceutically acceptable carrier, diluent, or excipient,20 wherein the composition comprises no more than about 2% (z.e., < about 2%) of the (S)- enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises no more than about 1% (z.e., < about 1%) 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 0.9% (z.e., < about 0.9%) 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 0.8% (z.e.,< about 0.8%) 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 0.7% (z.e., < about 0.7%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically30 acceptable salt of that enantiomer. In some embodiments, the composition comprises no more than about 0.6% (z.e., < about 0.6%) 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 0.5% (z.e., < about 0.5%) of the (S)-enantiomer of N-nitroso- tianeptine or a pharmaceutically acceptable salt of that enantiomer. In some embodiments, theAttorney Docket No.: 104545-0096-W02 composition comprises no more than about 0.4% (z.e., < about 0.4%) 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 0.3% (z.e., < about 0.3%) of the (S)-enantiomer of N-nitroso-tianeptine or a pharmaceutically acceptable salt of that5 enantiomer. In some embodiments, the composition comprises no more than about 0.2% (i.e., < about 0.2%) of the (S)-enantiomer of N-nitroso-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.10Dosages Forms and Modes of Administration

[0114] Any suitable route of administration may be employed for administering the (S)-enantiomers of tianeptine (i.e., the (S)-enantiomer or 1 l-D-(S)-enantiomer) of this disclosure, zwitterions, pharmaceutically acceptable salts, co-crystals, esters and pharmaceutically acceptable salts of these esters, amides and pharmaceutically acceptable salts of these amides, and the analogs of tianeptine (i.e., N-hydroxy -tianeptine, the (S)- and (R)- enanti omers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or the arylsubstituted tianeptine analogs, or pharmaceutically acceptable salts thereof) and pharmaceutical compositions thereof of this disclosure. Exemplary routes of administration of20 the (S)-enantiomer of tianeptine of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer and crystalline forms thereof of this disclosure, or a cocrystal of the (S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of the (S)- enantiomer of this disclosure or pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this disclosure or pharmaceutically acceptable salt thereof, or an 1 l-D-(S)- enantiomer of tianeptine of this disclosure, a zwitterion thereof, or a pharmaceutically acceptable salt of an 1 l-D-(S)-enantiomer and crystalline forms thereof of this disclosure, or a co-crystal of an 1 l-D-(S)-enantiomer of this disclosure or a zwitterion thereof, or an ester of an l l-D-(S)-enantiomer of this disclosure or pharmaceutically acceptable salt thereof, or an amide of the l l-D-(S)-enantiomer, or an analog of tianeptine (i.e., N-hydroxy -tianeptine, the30 (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or the aryl -substituted tianeptine analogs) or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof of this disclosure or a pharmaceutical composition ofAttorney Docket No.: 104545-0096-W02 this disclosure include, but are not limited to parenteral, oral, sublingual, buccal, inhalational, palatial, transdermal, rectal, and vaginal administration.

[0115] In some embodiments, dosage forms useful for administering the (S)- enantiomers of tianeptine (z.e., the (S)-enantiomer or 1 l-D-(S)-enantiomer) of this disclosure,5 zwitterions, pharmaceutically acceptable salts, co-crystals, esters and pharmaceutically acceptable salts of these esters, amides, or an analog of tianeptine (z.e., N-hydroxy -tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or the aryl -substituted tianeptine analogs or pharmaceutically acceptable salts thereof), and pharmaceutical compositions of this disclosure may include, but are not limited to tablets,10 such as scored tablets, coated tablets, mini-tablets, chewable tablets, orodispersible tablets or dissolving tablets; thin films; powders (<?.g., a lung powder or dry powder inhaler); caplets; capsules (e.g., hard gelatin capsules); soft gels; suppositories; nasal and other forms of inhalational sprays. In some embodiments, the dosage form is a tablet. In some embodiments, the dosage form is a thin film. In some embodiments, the dosage form is a powder. In some embodiments, the dosage form is a caplet. In some embodiments, the dosage form is a capsule. In some embodiments, the dosage form is a suppository. In some embodiments, the dosage form is an inhalational spray. In some embodiments, the spray is a nasal spray. In some embodiments, the spray is an oral spray.

[0116] The dosage form of this disclosure for parenteral administration in some20 embodiments can take the form of an aqueous or nonaqueous solution, dispersion, suspension or emulsion. For example, in preparing the dosage forms of this disclosure for parenteral administration, at least one of the (S)-enantiomers of tianeptine (z.e., the (S)-enantiomer or 11- D-(S)-enantiomer) of this disclosure, zwitterions, co-crystals, esters or pharmaceutically acceptable salts, amides, or an analog of tianeptine (z.e., N-hydroxy -tianeptine, the (S)- and(R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl -substituted tianeptine analog) or pharmaceutically acceptable salts thereof are mixed with a suitable pharmaceutically acceptable carrier such as water, oil (particularly a vegetable oil), ethanol, saline solutions e.g., normal saline), aqueous dextrose (glucose) and related sugar solutions, glycerol, or glycols such as propylene glycol or polyethylene glycol. For parenteral30 administration, these dosage forms preferably contain a water-soluble salt of at least one of the(S)-enantiomers of tianeptine (z.e., the (S)-enantiomer or 1 l-D-(S)-enantiomer), zwitterions, co-crystals, esters, amides, the 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, the N- nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl -substituted tianeptineAttorney Docket No.: 104545-0096-W02 analogs) or pharmaceutically acceptable salts thereof of this disclosure. Stabilizing agents, antioxidizing agents and preservatives can also be added to the for parenteral dosage forms. Suitable antioxidizing agents include sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and5 chlorbutanol.

[0117] For oral administration, in some embodiments the dosage forms of this disclosure comprise at least one of the (S)-enanti omers of tianeptine (ie., the (S)-enantiomer or l l-D-(S)-enantiomer), zwitterions, co-crystals, esters, amides, or analog of tianeptine {i.e., N-hydroxy -tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)-10 and (R)- enantiomers thereof or an aryl-substituted tianeptine analog) and salts of this disclosure 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 l-D-(S)-enantiomer), zwitterions, esters, amides, salts or co-crystals, or analog of tianeptine i.e., N-hydroxy-tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl-substituted tianeptine analog) and salts of this disclosure is combined with at least one pharmaceutically acceptable carrier such as a solvent, filler, binder, humectant, disintegrating agent, solution retarder, absorption accelerator, wetting agent absorbent or lubricating agent. In one embodiment, at least one of the (S)-enanti omers of tianeptine {i.e., the20 (S)-enantiomer or 1 l-D-(S)-enantiomer), zwitterions, esters, amides, salts or co-crystals or analog of tianeptine {i.e., N-hydroxy-tianeptine, the (S)- and (R)- enantiomers thereof, the N- nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl-substituted tianeptine analog) and salts of this disclosure is combined with carboxymethylcellulose calcium, magnesium stearate, mannitol and starch, and is formed into tablets by conventional tableting methods. In one embodiment, the (S)-enanti omers of tianeptine {i.e., the (S)-enantiomer or l l-D-(S)-enantiomer), zwitterions, esters, amides, salts or co-crystals, or analog of tianeptine {i.e., N-hydroxy-tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl-substituted tianeptine analog) and salts of this disclosure is formulated into a tablet comprising cellulose and a calcium salt, as described in30 U.S. Pat. No. 5,888,542, the entire disclosure of which is herein incorporated by reference.

[0118] In some embodiments, the dosage form of the (S)-enantiomer or an l l-D-(S)- enantiomer, zwitterions, salts, co-crystals, esters or amides thereof, or analog of tianeptine {i.e., N-hydroxy-tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl-substituted tianeptine analog) and salts of thisAttorney Docket No.: 104545-0096-W02 disclosure are formulated for immediate release, controlled release, sustained release, extended release, or slow release. In some embodiments, the dosage form of this disclosure is formulated for immediate release of the (S)-enantiomer, zwitterion, salt, ester, amide or co-crystal thereof, or analog of tianeptine (z.e., N-hydroxy -tianeptine, the (S)- and (R)- enantiomers thereof, the5 N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl -substituted tianeptine analog) and salts thereof of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for immediate release of an 1 l-D-(S)-enantiomer, zwitterion, salt, ester, amide or co-crystal thereof of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for immediate release of an analog of tianeptine (z.e., N-hydroxy-10 tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl -substituted tianeptine analog or a pharmaceutically acceptable salt thereof) of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for controlled release of the (S)-enantiomer, zwitterion, salt, ester, amide or cocrystal thereof of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for controlled release of an l l-D-(S)-enantiomer, zwitterion, salt, ester, amide or cocrystal thereof of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for controlled release of an analog of tianeptine (z.e., N-hydroxy -tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl-substituted tianeptine analog or pharmaceutically acceptable salts thereof) of this20 disclosure. In some embodiments, the composition of this disclosure is formulated for sustained release of the (S)-enantiomer, zwitterion, salt, ester, amide or co-crystal thereof of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for sustained release of an l l-D-(S)-enantiomer, zwitterion, salt, ester, amide or co-crystal thereof of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for sustained release of an analog of tianeptine (z.e., N-hydroxy -tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl-substituted tianeptine analog or pharmaceutically acceptable salts thereof) of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for extended release of the (S)- enantiomer, zwitterion, salt, ester, amide or co-crystal thereof of this disclosure. In some30 embodiments, the dosage form of this disclosure is formulated for extended release of an 11-D- (S)-enantiomer, zwitterion, salt, ester, amide or co-crystal thereof of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for extended release of an analog of tianeptine (z.e., N-hydroxy-tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso- tianeptine, the (S)- and (R)- enantiomers thereof or an aryl-substituted tianeptine analog orAttorney Docket No.: 104545-0096-W02 pharmaceutically acceptable salts) of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for slow release of the (S)-enantiomer, zwitterion, salt, ester, amide or co-crystal thereof of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for slow release of an 1 l-D-(S)-enantiomer, zwitterion, salt, ester, amide5 or co-crystal thereof of this disclosure. In some embodiments, the dosage form of this disclosure is formulated for slow release of an analog of tianeptine (z.e., N-hydroxy -tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl-substituted tianeptine analog or pharmaceutically acceptable salts thereof) of this disclosure.10

[0119] Preferably, a controlled-release dosage form of this disclosure is capable of releasing at least one of the (S)-enanti omers of tianeptine (z.e., the (S)-enantiomer or 1 l-D-(S)- enantiomer), zwitterions, esters, amides, salts, or co-crystals thereof, or analog of tianeptine (z.e., N-hydroxy -tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl -substituted tianeptine analog or pharmaceutically acceptable salts thereof) of this disclosure into a subject at a desired rate, so as to maintain a substantially constant pharmacological activity over a given period of time. Formulation of controlled-release pharmaceutical compositions of the invention is within the skill in the art. Controlled release formulations suitable for use in the present invention are described in, for example, U.S. Pat. No. 5,674,533 (liquid dosage forms), U.S. Pat. No. 5,591,767 (liquid20 reservoir transdermal patch), U.S. Pat. No. 5,120,548 (device comprising swellable polymers), U.S. Pat. No. 5,073,543 (ganglioside-liposome vehicle), U.S. Pat. No. 5,639,476 (stable solid formulation coated with a hydrophobic acrylic polymer), the entire disclosures of which are herein incorporated by reference.

[0120] Biodegradable microparticles can also be used to formulate controlled-release dosage forms of this disclosure, for example, as described in U.S. Pat. Nos. 5,354,556 and 5,733,566, the entire disclosures of which are herein incorporated by reference.

[0121] In one embodiment, controlled-release dosage form of this disclosure comprises at least one the (S)-enanti omers of tianeptine (z.e., the (S)-enantiomer or 1 l-D-(S)-enantiomer), zwitterions thereof, pharmaceutically acceptable salts of the (S)-enantiomers, cocrystals of the30 (S)-enantiomers or their zwitterions, 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 (z.e., N-hydroxy -tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an aryl -substituted tianeptine analog or pharmaceutically acceptable salts thereof) and a controlled-releaseAttorney Docket No.: 104545-0096-W02 component. As used herein, a “controlled-release component” is a compound, such as a polymer, polymer matrix, gel, permeable membrane, liposome and / or microsphere, that induces the controlled-release of the at least one of the (S)-enantiomers, zwitterions, cocrystals, esters, amides and salts of this disclosure into the subject upon exposure to a certain5 physiological compound or condition. For example, the controlled-release component can be biodegradable, activated by exposure to a certain pH or temperature, by exposure to an aqueous environment, or by exposure to enzymes. An example of a controlled-release component which is activated by exposure to a certain temperature is a sol-gel. In this embodiment, at least one of the (S)-enanti omers of tianeptine (ie., the (S)-enantiomer or 1 l-D-(S)-enantiomer)10 of this disclosure, zwitterions thereof, pharmaceutically acceptable salts of the (S)- enantiomers, cocrystals of the (S)-enanti omers or their zwitterions, esters of the (S)- enanti omers or pharmaceutically acceptable salts thereof, or amides of the (S)-enanti omers, the N-hydroxy -tianeptine, the (S)- or (R)- enantiomer thereof, or an analog of tianeptine (z.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) is incorporated into a sol-gel matrix that is a solid at room temperature. When the sol-gel matrix is implanted into a subject having a body temperature high enough to induce gel formation of the sol -gel matrix, the tianeptine is released into the subject.20 Exemplary Disorders of this Disclosure

[0122] Diseases, disorders or conditions of this disclosure include but are not limited to a central nervous system (CNS) disorder, post-concussive syndrome, nociplastic pain syndrome, or chronic overlapping pain conditions (COPCS), including menopause and COPCs, and psychological, physical, metabolic or hormonal stress and COPCs.

[0123] CNS disorders of this disclosure include but are not limited to a cognitive impairment (e.g., cognitive impairment associated with a disease, disorder or condition (e.g., cognitive impairment associated with post-concussive syndrome, nociplastic pain syndrome or chronic overlapping pain conditions) or a brain injury (e.g., a traumatic brain injury (such as a mild traumatic brain injury (mTBI)), and CNS oxidative stress.30CNS Disorders

[0124] Exemplary clinical symptoms of CNS disorders, diseases and conditions include, but are not limited to, changes in cognitive function, changes in attention and memory;Attorney Docket No.: 104545-0096-W02 difficulty with speaking, understanding, reading or writing; inability to process thoughts; anxiety; irritability or aggressiveness; muscle fatigue; muscle wasting; difficulty with walking; headache; hearing loss; seizures; spasticity; speech and swallowing disorders; tremors; paralysis; blindness; and loss of sensation.5Fibromyalgia, Long CO VID, Menopause and Chronic Overlapping Pain Conditions (COPCs)

[0125] Fibromyalgia is a condition characterized by widespread pain, fatigue, sleep disorders and cognitive dysfunction or “brain fog”. It is a member of the group of conditions originally called “Overlapping Chronic Pain Conditions” (OCPCs), but now more commonly10 called “Chronic Overlapping Pain Conditions” (COPCs), further including the temporomandibular disorder (TMD), irritable bowel syndrome (IBS), vulvodynia, myalgic encephalomyelitis / chronic fatigue syndrome, interstitial cystitis / painful bladder syndrome, endometriosis, chronic tension-type headache, migraine headache, and chronic lower back pain. Epidemiological studies, estimates that the prevalence of the individual COPCs ranges from approximately 4 million (myalgic encephalomyelitis / chronic fatigue syndrome) to 44 million (IBS). Many COPCs are defined as being idiopathic, arising spontaneously with no specific cause. However, central sensitization is currently thought to contribute to these conditions (Maixner W, et al., J Pain. 2016). Exemplary clinical symptoms of fibromyalgia and other COPCs include, but are not limited to, widespread pain, fatigue, sleep disorders and20 cognitive dysfunction.

[0126] 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 from the onset of COVID-19 infection with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. PASC symptoms span multiple organ systems, can occur within symptom clusters (i.e., neurologic, non-neurologic, and systemic) and may also fluctuate or relapse over time (Davis et al. EclinicalMedicine . 2021, Crook et al. BMJ. 2021, Bierle et al. J Prim Care Community Health. 2021, WHO 2021). The lack of a standardized definition of PASC makes it difficult to determine the exact epidemiology, incidence rates, and the impact30 of the condition on long-term disability. A conservative estimate based on data collected from numerous countries is that on average 30% of people with COVID-19 will experience PASC (Nalbandian et al. Nat Med. 2021).

[0127] PASC is a multi-faceted condition affecting multiple body systems. Symptoms of PASC may be new onset (e.g., new onset of pain), following initial recovery from an acute,Attorney Docket No.: 104545-0096-W02 or even mild, COVID-19 episode, or persist from the initial illness. While the symptoms of PASC vary, pain, fatigue and sleep disturbances were found to be 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. EclmicalMedicine . 2021, Sahin et al. Eur Neurol. 2021).5

[0128] Exemplary clinical symptoms of long COVID include, but are not limited to, fatigue, muscle weakness, diaphoresis, myalgia, arthralgia, chills, limb edema, dizziness, post- exertional malaise, cognitive dysfunction, respiratory symptoms (polypnea, chest pain, cough, sputum, sore throat), cardiovascular abnormalities, alopecia, olfactory abnormalities, neurocognitive difficulties including memory and concentration problems, psychological10 symptoms such as sleep difficulties, depression, anxiety, feelings of inferiority, and generally a worse quality of life.

[0129] Menopause is that period after the cessation of normal ovulation cycles, during which normal menstruation ceases. This period is marked by a decrease in hormone production (e.g., estradiol (E2)) in the ovaries resulting in a shift in hormone balance in the body, which often gives rise to a variety of symptoms associated with menopause. Peri-menopause, which is also known as pre-menopause or the climacteric, is that period prior to menopause during which normal ovulation cycles gradually give way to cessation of menses. The symptoms of peri-menopause, menopause and post-menopause include physical symptoms such as hot flashes, chills and sweating secondary to vasomotor instability. Additionally, psychological20 and emotional symptoms may accompany onset of climacteric, such as fatigue, irritability, insomnia, inability to concentrate, depression, memory loss, headache, anxiety and nervousness. Additional symptoms can include intermittent dizziness, paresthesias, palpitations and tachycardia as well as nausea, constipation, diarrhea, arthralgia, myalgia, cold hands and feet and weight gain. In addition, changes to the genitals, urinary incontinence, vaginal dryness, loss of pelvic muscle tone, increased risk of cardiovascular disease and osteoporosis increase with onset of menopause.Post-concussive Syndrome

[0130] Post-concussive syndrome (PCS) describes the collection of symptoms that30 commonly occur after head trauma. Most cases of PCS occur with a mild traumatic brain injury (mTBI) (z.e., a concussion), but can occur with TBI of any severity, and patients who suffer more than one brain injury are at increased risk. Symptoms may be physical, cognitive, behavioral, and / or emotional in nature. Common symptoms seen in patients with PCS include headache, fatigue, vision changes, disturbances in balance, confusion, dizziness, insomnia,Attorney Docket No.: 104545-0096-W02 difficulty concentrating, irritability, changes in mood, and changes in personality. Approximately 90% of concussion symptoms are transient and typically resolve within 10 to 14 days, however symptoms may linger for weeks. Persistent PCS occurs when symptoms persist beyond 3 months. Mild TBI resulting in persistent post-concussive syndrome may have5 lasting effects on cognition, memory, learning, and executive function.Nociplastic Pain Syndrome

[0131] Nociplastic pain syndrome is a new category of chronic pain and includes conditions that arise from altered nociception despite no clear evidence of actual or threatened10 tissue damage. The symptoms observed in nociplastic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems. This type of pain can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back pain (Fitzcharles, MA et al. Lancet. 2021). Nociplastic pain is also associated with greater risk of CNS-related symptoms such as fatigue, changes in cognition and memory, depression, anxiety, and sleep issues, as also commonly seen in COPCs, compared to nociceptive or neuropathic pain (Johnston KJ A, et al. medRxiv. 2024).20Methods of Treating

[0132] In some aspects, the present disclosure provides a method of treating a disease, disorder or condition selected from the group consisting of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof, comprising administering to a subject in need or at risk thereof a therapeutically effective amount of the (S)-enantiomer of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or co-crystal of the (S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this30 disclosure or a pharmaceutically acceptable salt thereof, or an l l-D-(S)-enantiomer of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(S)- enantiomer of this disclosure, or a co-crystal of an 1 l-D-(S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of an 1 l-D-(S)-enantiomer of this disclosure or aAttorney Docket No.: 104545-0096-W02 pharmaceutically acceptable salt thereof, or an amide of the l l-D-(S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an analog of tianeptine (z'.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 pharmaceutically5 acceptable salts thereof) of this disclosure, or a pharmaceutical composition of this disclosure comprising one or more of them.

[0133] In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a10 therapeutically effective amount of the (S)-enantiomer of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt (including crystalline forms thereof) of the (S)- enantiomer, or co-crystal of the (S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of the (S)-enantiomer of this disclosure, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of the (S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome20 and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of the zwitterion of the (S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure. In some embodiments, the method of treating post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective30 amount of a pharmaceutically acceptable co-crystal of the (S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable co-crystal of the zwitterion of the (S)-enantiomer ofAttorney Docket No.: 104545-0096-W02 this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of an ester of the (S)-enantiomer of this disclosure. In some5 embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the ester of the (S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-concussive syndrome,10 nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of an amide of the (S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of an amide of the (S)-enantiomer of this disclosure.

[0134] In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated20 symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of an l l-D-(S)-enantiomer, the zwitterion thereof, or a pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer of this disclosure, or a co-crystal of an 1 l-D-(S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of an 11-D- (S)-enantiomer of this disclosure, or an amide of an 1 l-D-(S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of an 1 l-D-(S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain30 syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of the zwitterion of an 1 l-D-(S)-enantiomer of this disclosure. In some embodiments, the method of treating post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprisesAttorney Docket No.: 104545-0096-W02 administering to a subject m need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of an l l-D-(S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof5 comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable co-crystal of an l l-D-(S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a10 therapeutically effective amount of a pharmaceutically acceptable co-crystal of a zwitterion of an l l-D-(S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of an ester of an l l-D-(S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the ester of an 11-D- (S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-20 concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of an amide of an 1 l-D-(S)-enantiomer of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the amide of an 11- D-(S)-enantiomer of this disclosure.

[0135] In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated30 symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of the N-hydroxy-tianeptine, the (S)-enantiomer of N- hydroxy -tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, or the 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 theAttorney Docket No.: 104545-0096-W02 post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of the N-hydroxy -tianeptine of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain5 syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the N-hydroxy-tianeptine of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof10 comprises administering to a subject in need or at risk thereof a therapeutically effective amount of the (S)-enantiomer of the N-hydroxy-tianeptine of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the (S)-enantiomer of the N-hydroxy- tianeptine of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of the (R)-enantiomer of the N-hydroxy-tianeptine of this20 disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the (R)-enantiomer of the N-hydroxy-tianeptine of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of the N-nitroso-tianeptine of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated30 symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the N-nitroso- tianeptine of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof aAttorney Docket No.: 104545-0096-W02 therapeutically effective amount of the (S)-enantiomer of the N-mtroso-tianeptine of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a5 therapeutically effective amount of a pharmaceutically acceptable salt of the (S)-enantiomer of the N-nitroso-tianeptine of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of the (R)-enantiomer of the N-nitroso-10 tianeptine of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the (R)-enantiomer of the N-nitroso-tianeptine of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of an aryl -substituted tianeptine analog of this disclosure. In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more20 associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutically acceptable salt of an aryl -substituted tianeptine analog of this disclosure.

[0136] In some embodiments, the method of treating the post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprises administering to a subject in need or at risk thereof a therapeutically effective amount of a pharmaceutical composition of this disclosure.

[0137] In some aspects, the present disclosure provides a method of treating a disease, disorder or condition and one or more associated symptoms thereof, in a subject who has experienced high stress. In some embodiments, the disease, disorder or condition is caused by30 adversity prenatally or early in life, or by childhood trauma, which disease, disorder or condition in some embodiments is manifested by subsequent violent behavior. Without wishing to be bound by theory, prolonged stress (prenatal, postnatal, or both) leads to an increase in the production of free radicals, particularly in the brain. The (S)-enantiomers of this disclosure (ie., (S)-tianeptine or 1 l-D-(S)-tianeptine) may act as free radical scavengersAttorney Docket No.: 104545-0096-W02 to interact with and neutralize the free radicals.

[0138] In some aspects, the methods of treating a disease disorder or condition selected from the group consisting of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof of this disclosure are5 improved over methods using racemic mixtures of the enantiomers of tianeptine, their zwitterions, salts, co-crystals and esters in that the methods of this disclosure result in reduced agonism of the p-opioid receptors. The reduced p-opioid receptor agonism of the (S)- enanti omers of this disclosure (z.e., (S)-tianeptine or 1 l-D-(S)-tianeptine) compared to racemic mixtures of the enantiomers of tianeptine minimizes the potential for opioid abuse, opioid10 toxicity and opioid overdose (e.g., by opiate-induced respiratory depression (OIRD).

[0139] In some aspects, the present disclosure provides a method of treating a disease, disorder or condition selected from the group consisting of a central nervous system (CNS) disorder, menopause and chronic overlapping pain conditions (COPCs), and psychological, physical, metabolic or hormonal stress and COPCs, comprising administering to a subject in need or at risk thereof a therapeutically effective amount of the (S)-enantiomer of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or co-crystal of the (S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof or an 11-20 D-(S)-enantiomer of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt of an 1 l-D-(S)-enantiomer of this disclosure, or a co-crystal of an 11 -D-(S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of an 11 -D-(S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an amide of the l l-D-(S)-enantiomer, 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 disclosure or a pharmaceutical composition of this disclosure comprising one or more of them.

[0140] In some aspects, the present disclosure provides a method of reducing violent or aggressive behavior associated with a CNS disorder, comprising administering to a subject30 in need or at risk thereof a therapeutically effective amount of the (S)-enantiomer of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer, or co-crystal of the (S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof or an 11-Attorney Docket No.: 104545-0096-W02D-(S)-enantiomer of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt of an 1 l-D-(S)-enantiomer of this disclosure, or a co-crystal of an 1 l-D-(S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of an 11 -D-(S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an amide of the l l-D-(S)-enantiomer of this5 disclosure or a pharmaceutically acceptable salt 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 disclosure, or a pharmaceutical composition of this disclosure comprising one or more of them.10

[0141] In some embodiments, the methods of treating of this disclosure comprise administering the (S)-enantiomer of tianeptine of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or a co-crystal of the(S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of the (S)-enantiomer of this disclosure or pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this disclosure or pharmaceutically acceptable salt thereof, or an l l-D-(S)-enantiomer of tianeptine of this disclosure, a zwitterion thereof, or a pharmaceutically acceptable salt of an l l-D-(S)-enantiomer of this disclosure, or a co-crystal of an 1 l-D-(S)-enantiomer of this disclosure or a zwitterion thereof, or an ester of an 1 l-D-(S)-enantiomer of this disclosure or pharmaceutically acceptable salt thereof, or an amide of the 1 l-D-(S)-enantiomer of this20 disclosure or pharmaceutically acceptable salt 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 disclosure, or a pharmaceutical composition of this disclosure comprising one or more of them one or more times daily. In some embodiments, the method of treating of this disclosure comprises administering the (S)-enantiomer of tianeptine of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or a co-crystal of the (S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of the (S)-enantiomer of this disclosure or pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this disclosure or pharmaceutically acceptable30 salt thereof or an 1 l-D-(S)-enantiomer of tianeptine of this disclosure, a zwitterion thereof, or a pharmaceutically acceptable salt of an 1 l-D-(S)-enantiomer of this disclosure, or a co-crystal of an 1 l-D-(S)-enantiomer of this disclosure or a zwitterion thereof, or an ester of an 1 l-D-(S)- enantiomer of this disclosure or pharmaceutically acceptable salt thereof, or an amide of the l l-D-(S)-enantiomer of this disclosure or pharmaceutically acceptable salt thereof, or anAttorney Docket No.: 104545-0096-W02 analog of tianeptine (z.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 disclosure, or a pharmaceutical composition of this disclosure comprising one or more of them once daily.5

[0142] In some embodiments, the methods of treating of this disclosure comprise administering the (S)-enantiomers of this disclosure, their zwitterions, or a pharmaceutically acceptable salts or co-crystals of the (S)-enantiomers of this disclosure or esters of the (S)- enantiomers of this disclosure or pharmaceutically acceptable salts thereof, or amides of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salt thereof, or an analog of10 tianeptine (z.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 disclosure or pharmaceutical compositions of this disclosure comprising them in compositions or combinations comprising them with one or more of an additional therapeutic agent selected from the group consisting of an antidepressant, an anticonvulsant, an anti-anxiety agent, an antipsychotic agent, a cholinesterase inhibitor, an N-methyl-D-aspartate (NMDA) receptor antagonist, a 5-HT2 modulator, a corticosteroid, an anti-amyloid agent, an anti-tau agent and a chemotherapeutic agent. In some embodiments, the methods of treating of this disclosure comprise administering the (S)-enantiomers of this disclosure, their zwitterions, or a pharmaceutically acceptable salts or co-crystals of the (S)-20 enantiomers of this disclosure, or esters of the (S)-enantiomers of this disclosure, or amides of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, or an analog of tianeptine (z.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 disclosure, or pharmaceutical compositions of this disclosure comprising them sequentially with one or more of an additional therapeutic agent. In some embodiments, the methods of treating of this disclosure comprise administering the (S)-enantiomers of this disclosure, their zwitterions, or a pharmaceutically acceptable salts, or co-crystals of the (S)-enanti omers of this disclosure, or esters of the (S)-enantiomers of this disclosure, or amides of the (S)-enantiomers of this disclosure, or pharmaceutically acceptable30 salts thereof or pharmaceutically acceptable salts thereof, or an analog of tianeptine (z.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 disclosure, or pharmaceutical compositions of this disclosure comprising them concurrently with one or more of an additional therapeutic agent. ExemplaryAttorney Docket No.: 104545-0096-W02 antidepressants include, but are not limited to, citalopram, fluoxetine, paroxetine, trazodone or sertraline. Exemplary anticonvulsants include, but are not limited to, carbamazepine, divalproex, or dextromethorphan. Exemplary anti-anxiety agents include, but are not limited to, lorazepam, oxazepam, or buspirone. Exemplary antipsychotic agents include, but are not limited to,5 quetiapine, promazine, aripiprazole, ziprasidone, olanzapine, or risperidone. Exemplary cholinesterase inhibitors include, but are not limited to, donepezil, rivastigmine, galantamine, or tacrine. Exemplary NMDA receptor antagonists include, but are not limited to, amantadine or memantine. Exemplary 5-HT2 modulators include, but are not limited to, pimavanserin or cyclobenzaprine. Exemplary corticosteroids include, but are not limited to prednisone,10 methylprednisolone and dexamethasone. Exemplary anti-amyloid agents include, but are not limited to, aducanumab (Aduhelm®), bapineuzumab, solanezumab, or verubecestat. In some embodiments, the anti-amyloid agent and / or anti-tau agent is one or more of the agents as described by Cummings et al. incorporated herein by reference (Cummings et al. Alzheimers Dement (NY), 2017). Exemplary chemotherapeutic agents include, but are not limited to, temozolomide, carmustine, bevacizumab, or lomustine.

[0143] In some embodiments of the combinations of this disclosure, the (S)-enantiomers of this disclosure, their zwitterions, or a pharmaceutically acceptable salts of the (S)- enantiomers of this disclosure, or co-crystals of the (S)-enantiomers of this disclosure or zwitterions thereof, or esters of the (S)-enantiomers of this disclosure or pharmaceutically20 acceptable salts thereof, or amides of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, or an analog of tianeptine (i.e., N-hydroxy -tianeptine, the (S)- and (Rmenantiomers thereof, N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof, or an arylsubstituted tianeptine analog) or pharmaceutically acceptable salts thereof of this disclosure, or pharmaceutical compositions of this disclosure comprising them and the one or more additional therapeutic agents are formulated separately. In some embodiments of the combinations of this disclosure, the (S)-enantiomers of this disclosure, their zwitterions, or a pharmaceutically acceptable salts of the (S)-enantiomers of this disclosure, or co-crystals of the (S)-enantiomers of this disclosure or zwitterions thereof, or esters of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, or amides of the (S)-enantiomers of this disclosure30 or pharmaceutically acceptable salts 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 disclosure, or pharmaceutical compositions of this disclosure comprising them and the one or more additional therapeutic agents are formulated together. In certain suchAttorney Docket No.: 104545-0096-W02 embodiments, the (S)-enantiomers of this disclosure, their zwitterions, or a pharmaceutically acceptable salts of the (S)-enantiomers of this disclosure, or co-crystals of the (S)-enantiomers of this disclosure or zwitterions thereof, or esters of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, or amides of the (S)-enantiomers of this disclosure5 or pharmaceutically acceptable salts thereof, or an analog of tianeptine (z.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 disclosure, or pharmaceutical compositions of this disclosure comprising them and the one or more additional therapeutic agents are packaged together. In some of such10 embodiments, the (S)-enantiomers of this disclosure, their zwitterions, or a pharmaceutically acceptable salts of the (S)-enantiomers of this disclosure, or co-crystals of the (S)-enantiomers of this disclosure or zwitterions thereof, or esters of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, or amides of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, or an analog of tianeptine (z.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 disclosure, or pharmaceutical compositions of this disclosure comprising them and the one or more additional therapeutic agents are packaged separately.

[0144] In some embodiments of this disclosure, the (S)-enantiomers of this disclosure,20 their zwitterions, or a pharmaceutically acceptable salts of the (S)-enantiomers of this disclosure, or co-crystals of the (S)-enantiomers of this disclosure or zwitterions thereof, or esters of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, or amides of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, or an analog of tianeptine (z.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 disclosure or pharmaceutical compositions of this disclosure comprising them and the one or more additional therapeutic agents in a combination (where they are not formulated together) of this disclosure are administered simultaneously or concurrently (z.e., with a time separation of no more than about 15 minutes and30 in some embodiments no more than 10 minutes) or sequentially (z.e., with a time separation of more than about 15 minutes and in some embodiments more than one hour or up to 12-24 hours).

[0145] In some embodiments, the method of treating of this disclosure comprises administering the (S)-enantiomers of this disclosure, their zwitterions, or a pharmaceutically acceptable salts of the (S)-enantiomers of this disclosure, or co-crystals of the (S)-enantiomersAttorney Docket No.: 104545-0096-W02 of this disclosure or zwitterions thereof, or esters of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, or amides of the (S)-enantiomers of this disclosure or pharmaceutically acceptable salts thereof, 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 disclosure, or pharmaceutical compositions of this disclosure comprising them as part of a treatment regime also including psychotherapeutic intervention. In some embodiments, the psychotherapeutic intervention includes psychotherapeutic therapies including, but not limited to, exposure therapies, eye movement desensitization and reprocessing therapy, somatic therapies, cognitive behavioral therapy, and ecotherapy.Methods of Reducing Racemization of the (S)-enantiomer

[0146] In some aspects, the present disclosure provides a method of reducing the racemization of the (S)-enantiomer of this disclosure, the zwitterion thereof, a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, a co-crystal of the (S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of the (S)-enantiomer of this disclosure or pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer of this disclosure or pharmaceutically acceptable salt thereof comprising the step of deuterating the (S)- enantiomer, the zwitterion thereof, a pharmaceutically acceptable salt of the (S)-enantiomer, a co-crystal of the (S)-enantiomer or the zwitterion thereof, or an ester of the (S)-enantiomer pharmaceutically acceptable salt thereof, at position C-l 1.Methods of Producing

[0147] In some aspects, the present disclosure provides a method of producing the (S)- enantiomer of this disclosure, said method comprising the steps of resolving a racemic or other mixture of the (S)- and (R)-enanti omers of a chiral amine tianeptine intermediate (see, e.g., Compound 3 of Table 2), which mixtures are characterized by more than 0.1% (z.e., >0.1%) of the (R)-enantiomer of the chiral amine tianeptine intermediate (see, e.g., Compound 5 of Table 2) by enantioselective crystallization using L- or D- enantiomeric selective conformers in a solvent to produce an (S)-amine tianeptine intermediate: (S)-enanti omer-selective- conf ormer, the (S)-amine tianeptine intermediate :(S)-enantiomer-selective-conf ormer being crystallized from the solvent mixture and being characterized in that it comprises <2% (in some embodiments <0.1%) of the (R)-amine tianeptine intermediate :D- conformer (see, e.g., nAttorney Docket No.: 104545-0096-W02Compounds 4 or 5 of Table 2), reacting the (S)-amme tianeptine intermediate:(S)-enantiomer- selective-conformer with a 7-bromoheptanoate alkyl ester to produce an (S)-tianeptine alkyl ester intermediate:(S)-enantiomer-selective-conformer and reacting that intermediate with a base to remove the conformer to produce an (S)-tianeptine alkyl ester intermediate (see, e.g.,5 Compound 6 of Table 2), and saponifying the (S)-tianeptine alkyl ester intermediate to produce the (S)-enantiomer of tianeptine (see, e.g, Compound 8 of Table 2).

[0148] In some embodiments, the chiral amine tianeptine intermediate is 3-chloro-6- methyl-5,5-dioxo-l lH-benzo[c][l,2]benzothiazepin-l 1 -amine, (S)-amine tianeptine intermediate:(S)-enantiomer-selective-conformer is (1 lS)-3-chloro-6-methyl-5,5-dioxo-l 1H-10 benzo[c][l,2]benzo 78hiazepine-l l-amine: (S)-enantiomer-selective-conformer and the (S)- tianeptine ester intermediate:(S)-enantiomer-selective-conformer is ethyl 7-[[(l lS)-3-chloro- 6-methyl-5,5-dioxo-l lH-benzo[c][l,2]benzothiazepin-l l-yl]amino]heptanoate:(S)- enantiomer-selective-conformer.

[0149] In some aspects, the present disclosure provides a method of producing the 11- D-(S)-enantiomer of this disclosure, said method comprising the steps of resolving a racemic or other mixture of the (S)- and (R)-enantiomers of a chiral amine 11-D-tianeptine intermediate (see, e.g., Compound 11 of Table 3), which mixtures are characterized by more than 0.1% (i.e., >0.1%) of the (R)-enantiomer of the chiral amine 11-D-tianeptine intermediate (see, e.g., Compound 12 of Table 3) by enantioselective crystallization using L- or D-20 enantiomeric selective conformers in a solvent 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% (in some embodiments <0.1%) of the (R)- amine 11-D-tianeptine intermediated- conformer (see, e.g., Compounds 12 or 13 of Table 3), reacting the (S)-amine 11-D-tianeptine intermediate :(S)-enantiomer-selective-conf ormer with a 7-bromoheptanoate alkyl ester to produce an l l-D-(S)-tianeptine alkyl ester intermediate:(S)-enantiomer-selective-conformer and reacting that intermediate with a base to remove the conformer to produce an 1 l-D-(S)-tianeptine alkyl ester intermediate (see, e.g., Compound 15 of Table 3), and saponifying the 1 l-D-(S)-tianeptine alkyl ester intermediate to30 produce the 1 l-D-(S)-enantiomer of tianeptine (see, e.g, Compound 17 of Table 3).

[0150] In some embodiments, the chiral amine 11-D-tianeptine intermediate is 11- amino-3-chloro-6-methyl-6,l l-dihydrodibenzo[c,f][l,2]thiazepine 5,5-dioxide-l 1-d, the (S)- amine 11-D-tianeptine intermediate:(S)-enantiomer-selective-conformer is (S)-l l-amino-3- chloro-6-methyl-6, 1 l-dihydrodibenzo[c, / |[l,2]thiazepine 5,5-dioxide-l 1-d: (S)-enantiomer-Attorney Docket No.: 104545-0096-W02 selective-conformer, and the l l-D-(S)-tianeptine ester intermediate:(S)-enantiomer-selective- conformer is ethyl (S)-7-((3-chloro-6-methyl-5,5-dioxido-6,l l- dihydrodibenzo[c, ][l,2]thiazepine-l l-yl-l l-tZ)amino)heptanoate:(S)-enantiomer-selective- conformer.5

[0151] In some aspects, the present disclosure provides a method of producing the (S)- enantiomer of this disclosure or zwitterion thereof, said method comprising the steps of: (i) resolving a racemic or other mixture of the (S)- and (R)-enantiomers of a tianeptine alkyl ester (see, e.g., Compound 18 of Table 4) using an L- or D- enantiomeric selective conformer in a solvent, which mixtures are characterized by more than 0.1% i.e., >0.1%) of the (R)-10 enantiomer of the tianeptine alkyl ester (see, e.g., Compound 19 of Table 4) by enantioselective crystallization to produce crystalline (R)-tianeptine alkyl ester: (R)- enantiomer-selective-conformer salt, the (S)-tianeptine alkyl ester: (R)-enantiom er-selective- conformer (see, e.g., Compound 20 of Table 4) remaining in solution, the (S)-tianeptine alkyl ester (R)-enantiomer-selective-conformer being characterized in that it comprises <2% (in some embodiments <0.1%) of the (R)-tianeptine alkyl ester: (R)-enantiom er-selective- conformer, (ii) hydrolyzing the (S)-tianeptine alkyl ester: (R)-enantiomer-selective-conformer with a strong acid to produce the (S)-tianeptine acid salt, which tianeptine acid salt comprises <2% of the (R)-tianeptine acid salt; and (iii) neutralizing the (S)-tianeptine acid salt with a base to produce the zwitterion of the (S)-enantiomer of tianeptine (see, e.g., Compound 22 of20 Table 4).

[0152] In some aspects, the present disclosure provides a method of producing the 11- D-(S)-enantiomer of this disclosure or zwitterion thereof, 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 (see, e.g., Compound 23 of Table 5) using an L- or D- enantiomeric selective conformer in a solvent, which mixtures are characterized by more than 0.1% i.e., >0.1%) of the (R)-enantiomer of the l l-D-tianeptine alkyl ester (see, e.g., Compound 24 of Table 5) by enantioselective crystallization to produce crystalline 1 l-D-(R)-tianeptine alkyl ester: (R)-enantiomer-selective-conformer salt, the l l-D-(S)-tianeptine alkyl ester:(R)- enantiomer-selective-conformer (see, e.g., Compound 25 of Table 5) remaining in solution,30 the 1 l-D-(S)-tianeptine alkyl ester (R)-enantiomer-selective-conform er being characterized in that it comprises <2% (in some embodiments <0.1%) of the 1 l-D-(R)-tianeptine alkyl ester:(R)-enantiomer-selective-conformer, (ii) hydrolyzing the 1 l-D-(S)-tianeptine alkyl ester: (R)-enantiomer-selective-conformer with a strong acid to produce the l l-D-(S)- tianeptine acid salt, which 11-D-tianeptine acid salt comprises <2% of the 1 l-D-(R)-tianeptineAttorney Docket No.: 104545-0096-W02 acid salt; and (in) neutralizing the l l-D-(S)-tianeptine acid salt with a base to produce the zwitterion of the 1 l-D-(S)-enantiomer of tianeptine (see, e.g., Compound 27 of Table 5).

[0153] In some embodiments of any of the above embodiments the tianeptine alkyl ester is a methyl ester, an ethyl ester or another straight or branched chain Ci-Ce alkyl ester.5

[0154] In some embodiments, the enantioselective crystallization, including those of the above embodiments, may be repeated to increase the enantiomeric purity or chiral purity of a resolved tianeptine or ester thereof. Optionally, supercritical fluid chromatography (or in some embodiments high performance liquid chromatography (HPLC)) can be used to initially resolve the enantiomeric mixtures or can be used to increase the enantiomeric purity or chiral10 purity of a resolved (S)-tianeptine of this disclosure.

[0155] In some embodiments, the enantioselective crystallization used in the methods of producing of this disclosure comprises using a conformer. Non-limiting examples of conformers include L-dibenzoyl tartaric acid (DBTA), D-DBTA, Di-o-toluoyl-L-tartaric acid (L-D(2-Me)BTA), D-D(2-Me)BTA, other DBTA derivatives, (S)-l,l'-Bi-2-naphthol-2,2'-diyl hydrogen phosphate, (R)-l,l'-Bi-2-naphthol-2,2'-diyl hydrogen phosphate, (S)-(R)-mandelic acid, (R)-(S)-mandelic acid, (S)-(S)-alpha-methoxy-alpha-trifluoromethylphenylacetic acid, (R)-(S)-alpha-methoxy-alpha-trifluorom ethylphenylacetic acid, (1 S)-(R)-10-camphorsulfonic acid and (lR)-(R)-10-camphorsulfonic acid.

[0156] In some embodiments, the solvent comprises a mixture of benzene, acetone and20 trichloromethane. In some embodiments, the solvent comprises benzene, acetone and trichloromethane in a ratio of 2: 1 : 1. In some embodiments, enantiomeric crystallization further comprises slow evaporation of the solvent mixture.

[0157] In some embodiments, the hydrolysis is performed using a strong acid. Nonlimiting examples of strong acids include hydrochloric acid, sulfuric acid and phosphoric acid.

[0158] In some embodiments, other known methods of producing the (S)-enanti omers of this disclosure may be used, for example, chirality pools and asymmetric synthesis.Methods of Inducing Neurite Outgrowth

[0159] In some aspects, the present disclosure provides a method of enhancing neurite30 outgrowth comprising administering to a subject in need thereof the (S)-enantiomer of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt of the (S)-enantiomer of this disclosure, or a co-crystal of the (S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of the (S)-enantiomer of this disclosure or a pharmaceutically acceptableAttorney Docket No.: 104545-0096-W02 salt thereof, or an amide of the (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an 1 l-D-(S)-enantiomer of this disclosure, the zwitterion thereof, or a pharmaceutically acceptable salt of an 1 l-D-(S)-enantiomer of this disclosure, or a co-crystal of an 1 l-D-(S)-enantiomer of this disclosure or the zwitterion thereof, or an ester of an 11-D- (S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an amide of the 1 l-D-(S)-enantiomer of this disclosure or a pharmaceutically acceptable salt thereof, or an analog of tianeptine of this disclosure (z.e., N-hydroxy-tianeptine, the (S)- and (R)- enantiomers thereof, the N-nitroso-tianeptine, the (S)- and (R)- enantiomers thereof or an arylsubstituted tianeptine analog) or pharmaceutically acceptable salts of any of them, or a pharmaceutical composition of this disclosure comprising one or more of them. In some embodiments, the neurite outgrowth is observed in a glutamatergic neuron.EXAMPLES

[0160] Some of the embodiments of this disclosure will further be described in more detail by the following examples which describe the methods whereby the (S)-enantiomers of tianeptine of this disclosure may be prepared, purified, analyzed and tested. These examples are not to be construed as limiting the disclosure. The skilled worker will readily appreciate that the following examples are merely illustrative and can be modified according to methods and techniques commonly known in the art.Example 1: Preparation and Analysis of Chiral Tianeptine

[0161] A racemic mixture of tianeptine oxalate (9.6 g, 18.3 mmol) was converted into a racemic mixture of tianeptine zwitterion and separated by direct phase preparative high- performance liquid chromatography (HPLC) using a ChiralPak IG 4.6 x 250 mm column and a solvent gradient of 5-60% [ACN / EtOH in 10 mM aq. AmForm] in supercritical CO2 with a run time of 10 min, and flow rate of 3 mL / min to yield (S)-tianeptine zwitterion (Figure 1, Peak 1) and (R)-tianeptine zwitterion (Figure 1, Peak 2). Analytical HPLC was performed using ChiralPak IG 4.6 x 250 mm, 5-60% [ACN / EtOH in 10 mM aq. AmForm], Run time = 10 min, Flow = 3 mL / min. The chiral purity of the two enantiomers was assessed by analytical SFC using a ChiralPak IG 4.6 x 250 mm column and a solvent gradient of 5-60% [MeCN / EtOH in 10 mM AmForm] with a run time of 10 min, and flow rate of 3 mL / min. (S)-tianeptine: tR = 4.19 min, 99.8% chiral purity; (R)-tianeptine: tR = 4.53 min, 97.6% chiral purity. Residual ammonium formate was removed via lyophilization.Attorney Docket No.: 104545-0096-W02

[0162] In another method, a racemic mixture of tianeptine sodium (20 g, 42.3 mmol) was converted to a racemic mixture of tianeptine zwitterion and separated by preparative SFC using a ChiralPak AD 21 x 250 mm column and a solvent mixture of 35% [MeCN / EtOH in 10 mM AmForm] in supercritical CO2 with a flow rate of 50 mL / min to yield (S)-tianeptine5 zwitterion and (R)-tianeptine zwitterion. The separation was discontinued when 3 g of each enantiomer were isolated. Both enantiomers of zwitterionic tianeptine (> 98% chiral purity, each) were separately submitted to a second purification under the conditions identical to the first purification. Fractions were separately concentrated, and the residues were diluted with DCM (300 mL). The organic phases were washed with water (3 x 300 mL) and brine (30010 mL), dried over Na2SC>4, filtered and concentrated. The residues were dried under vacuum at 50 °C to yield 1.9 g of (S)-tianeptine zwitterion and 2.2 g of (R)-tianeptine zwitterion. The chiral purity of the two enantiomers was assessed by analytical SFC using a ChiralPak AD 4.6 x 150 mm column and a solvent mixture of 5-60% [MeCN / EtOH in 10 mM AmForm] with a run time of 10 min and a flow rate of 3 mL / min. (S)-tianeptine: tR = 3.38 min, >99.9% chiral purity; (R)-tianeptine: tR = 3.76 min, > 99.9% chiral purity.

[0163] For ammonium-formate-free separation, a racemic mixture of tianeptine sodium(6.00 g, 12.7 mmol) was converted into a racemic mixture of tianeptine zwitterion and separated by preparative supercritical fluid chromatography (SFC) using a Phenomenex Lux Amylose-1 21.2x250 mm column and a solvent mixture of 35% [MeCN / EtOH] in supercritical20 CO2 with a run time of 10 min and a flow rate of 17.5 mL / min to yield 2.2 g of (S)-tianeptine zwitterion and 2.0 g of (R)-tianeptine zwitterion. The chiral purity of the two enantiomers was assessed by analytical SFC using a ChiralPak IG 4.6 x 250 mm column with a solvent mixture of 5-60% [MeCN / EtOH in 10 mM AmForm] with a run time of 10 min and a flow rate of 3 mL / min. (S)-tianeptine: tR = 4.18 min, >99.9% chiral purity; (R)-tianeptine: tR = 4.51 min, 99.1% chiral purity.

[0164] The absolute stereochemistry of the tianeptine sodium enantiomers was determined based on X-ray crystallography. In one experiment, dibenzoyl-L-tartaric acid (L- DBTA) (12.3 mg, 0.0343 mmol) was added to a mixture of (S)-tianeptine sodium (>99.9% chiral purity, 15.0 mg, 0.0343 mmol) in EtOH (0.500 mL). The clear solution was allowed to30 slowly evaporate to dryness. EtOH (0.500 mL) was added, and the process was repeated to provide crystalline material, which was suitable for X-ray crystallography. Crystallization studies using 2: 1 tianeptine sodium: L-DBTA determined with 93% certainty (Flack X parameter = 0.07) that the absolute stereochemistry of (-)-tianeptine sodium salt is the (S)- enantiomer (Figure 2A).Attorney Docket No.: 104545-0096-W02

[0165] In a separate experiment, L-DBTA (12.3 mg, 0.0343 mmol) was added to a mixture of (S)-tianeptine sodium (>99.9% chiral purity, 15.0 mg, 0.0343 mmol) in EtOH (0.250 mL). The clear solution was slowly diluted with methyl tert-butyl ether (MTBE) by vapor diffusion to provide crystalline material, which was suitable for X-ray crystallography.5 Crystallization studies performed using 2: 1 tianeptine sodium: L-DBTA also confirmed with 96.5% certainty (Flack X parameter = 0.035) that the absolute stereochemistry of (-)-tianeptine sodium salt is the (S)-enantiomer (Figure 2B).

[0166] The optical rotations of various tianeptine enantiomers of this disclosure and various of their salts are listed in Table 1. In methanol, the optical rotation for (S)-tianeptine10 depends on the type and concentration of the counterion (z.e., the pH). For example, at pH ~ 7 the optical rotation of the for (S)-tianeptine zwitterion is [a]o26= +18.00°, while at pH < 7, the optical rotation of the 1 : 1 (S)-tianeptine oxalate salt is [a]o23 2= +77.0°. In contrast, at pH > 12 (S)-tianeptine sodium with 3 equivalents (eq.) of sodium hydroxide (NaOH) in methanol has an optical rotation of [O,]D26'9= -4.40°. As shown in Table 1, similar pH dependency is had for the (R) enantiomers of tianeptine.20Table 1. Optical Rotation of Various Tianeptine EnantiomersAttorney Docket No.: 104545-0096-W02Attorney Docket No.: 104545-0096-W02Example 2. Stereospecific Synthesis of Tianeptine (S) and (R) EnantiomersGeneral Methods

[0167] Silica gel chromatography was performed on Teledyne Isco instruments using5 pre-packaged disposable SiCh stationary phase columns with eluent flow rate range of 15 mL / min to 200 mL / min, UV detection (200-300, 254 and 280 nm).

[0168] Reverse phase preparative HPLC was carried out using C18 columns, UV detection (214 nm and 254 nm) eluting with gradients of MeCN in H2O (0.03% (NHfhCCh / 0.375% NH4OH) (high pH), MeCN in H2O (0.1% HCOOH) (low pH) or MeCN in H2O (neutral10 pH).

[0169] The analytical HPLC chromatograms were performed using an Agilent 1100 series instrument with DAD detector (190 nm to 300 nm). The mass spectra were recorded with a Waters Micromass ZQ detector at 130 °C. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive ion mode and was set to scan between m / z 150-750 with a scan time of 0.3 s.

[0170] Products and intermediates were analyzed by HPLC / MS on a Gemini -NX (5 pM, 2.0 x 30 mm) using a high pH buffer gradient of 5% to 100% of MeCN in H2O (0.03% (NEL^CCh / 0.375% NH4OH) over 10 minutes at 1.8 mL / min for a 10 minute run (B05), EVO C18 (5 pM, 3.0 x 50 mm) using a low pH buffer gradient of 5% to 100% of MeCN in H2O20 (0.1% HCOOH) over 2.5 min at 2.2 mL / min for a 3.5 min run (A05). The 'H NMR spectra were recorded on a Bruker UltraShield 500 MHz / 54 mm instrument (BZH 43 / 500 / 70B, D221 / 54-3209) or on a 300 MHz instrument. The chemical shifts are referenced to solvent peaks, which in 'H NMR appears at 7.26 ppm for CDCI3, 2.50 for DMSO-t / g, and 3.31 ppm for CD3OD.Attorney Docket No.: 104545-0096-W02Scheme 1: Exemplary Synthetic Scheme for Tianeptine EnantiomersCompound 8 or 95

[0171] The compounds of Scheme 1 are shown in Table 2.Attorney Docket No.: 104545-0096-W02Table 2. Compounds of Scheme 1Attorney Docket No.: 104545-0096-W02Attorney Docket No.: 104545-0096-W02

[0172] In Step 1 (Scheme 1), 3-chloro-6-methyl-5,5-dioxo-l lH- benzo[c][l,2]benzothiazepin-l l-ol (compound 2) was prepared according to International Patent Application Publication No. W02003 / 051276 A2, incorporated herein by reference.5 NaBH4 (4.61 g, 122 mmol) was added to a mixture of a chiral 3-chloro-6-methyl-5,5-dioxo- benzo[c][l,2]benzothiazepin-l l-one (compound 1) (15.0 g, 48.7 mmol) in methanol (MeOH) (133 mL) and dichloromethane (DCM) (444 mL) at 22 °C under nitrogen. The mixture was stirred at 22 °C for 2 hours and concentrated. The residue was diluted with DCM (400.0 mL). The organic phase was washed with saturated aqueous (sat. aq.) NaHCCh (300 mL), water (300 mL) and brine (300 mL), dried over Na2SO4, filtered and concentrated to provide the title compound as a solid (11.0 g, 73%). m / z (ES+) [M+Na]+= 332.02; LCMS (A05); tR= 0.57 min.

[0173] In step 2 (Scheme 1), 3-chloro-6-methyl-5,5-dioxo-l lH- benzo[c][l,2]benzothiazepin- 11 -amine (compound 3) (a chiral amine tianeptine intermediate)15 was prepared according to W02003 / 051276 A2 with modifications. Dimethylformamide (DMF) (0.356 mL, 4.84 mmol) was added to compound 2 (3.00 g, 9.68 mmol) and cobalt chloride (CoCl)2 (4.15 mL, 48.4 mmol) in DCM (100 mL) and the mixture was stirred at 22 °C for 1 hour and concentrated. The residue was diluted with toluene (20.0 mL) and concentrated. The residue was diluted with DCM (176 mL) and placed under an atmosphere of NH3. The mixture was stirred at 22°C for 18 hours and diluted with DCM (50.0 mL). The organic phase was washed with sat. aq. NaHCCL (2 x 200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) with DCM and MeOH (0-10%) to provide compound 3 as a solid (1.88 g, 63%).1H NMR (300 MHz, DMSO-d6) 57.84 (d, J = 8.3 Hz, 1H), 7.79 - 7.65 (m, 2H), 7.62 - 7.56 (m,25 1H), 7.52 - 7.47 (m, 1H), 7.37 (td, J= 6.2, 3.2 Hz, 2H), 5.60 (s, 1H), 3.36 (s, 3H), 2.63 (s, 2H); m / z: [M-NH2]+= 292.0; LCMS (A05); tR= 1.85 min.Attorney Docket No.: 104545-0096-W02

[0174] In step 3 (Scheme 1), (HS)-3-chloro-6-methyl-5,5-dioxo-l lH- benzo[c][l,2]benzo thiazepin-l l-amine: L-2, 3 -dibenzoyloxybutanedioic acid (compound 4:L- DBTA) was prepared according to European Patent Application Publication No. EP0671173 Al, incorporated herein by reference. Compound 3 (6.09 mmol, 1.88 g) was added5 to L-2,3-dibenzoyloxybutanedioic acid (L-DBTA) (6.08 mmol, 2.18 g) in ethanol (EtOH) (35.0 mL) at 22 °C. The mixture was stirred at 70 °C for 2 hours and the precipitated solid was filtered and washed with EtOH (5.00 ml). The solid was dried and re-crystallized 3 times from EtOH (35.0 ml, 25.0 mL, and 15.0 mL, respectively). The final solid of compound 4 was dried to provide enantiomerically pure material (chiral purity > 99 %, 362 mg, 12 %). m / z: [M-10 NH2]+= 292.0; LCMS (A05); tR = 1.74 min; enantiopurity determined using ChiralPak IG 4.6 x 250 mm, 5-60% MeOH in 10 mM aq. AmForm, 10 min, tR = 4.53 min.

[0175] (1 lR)-3-chloro-6-methyl-5,5-dioxo-l lH-benzo[c][l,2]benzothiazepin-l l- amine: dibenzoyl- D-tartaric acid (compound 5:D-DBTA) is prepared by washing the combined filtrates with sat. aq. NaHCOs, dried over Na2SO4, filtered and concentrated. Then the residue is dissolved in EtOH and D-DBTA (1.0 eq) is added, followed by fractional crystallization as described above (chiral purity >99%).

[0176] In step 4 (Scheme 1), Ethyl 7-[[(l lS)-3-chloro-6-methyl-5,5-dioxo-l lH- benzo[c][l,2]benzothiazepin-l l-yl]amino]heptanoate (compound 6) was prepared according to EP0671173A1 with modifications. Compound 4:L-DBTA (294 mg, 0.952 mmol) was20 diluted with DCM (10.0 mL) and aq. Sodium carbonate (5M, 10.0 mL). The organic phase was separated and dried over Na2SO4, filtered, and concentrated. The residue was dissolved in MeCN (5.88 mL), and ethyl 7-bromoheptanoate (339 mg, 1.43 mmol), Nal (143 mg, 0.952 mmol), and dipotassium carbonate (263 mg, 1.90 mmol) were added at 22 °C under nitrogen. The mixture was stirred at 75 °C for 3 days and cooled to room temperature. The mixture was filtered through Celite, washing with MeCN (3.00 mL), and the filtrate was concentrated. The residue was diluted with ethyl acetate (EtOAc) (10.0 mL) and sat. aq. NaHCCL (10.0 mL) to remove the L-DBTA conformer. The organic phase was washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated to provide compound 6 as an oil (95% pure, 245 mg, 55.3%). m / z: [M+H]+= 465.7; LCMS (A05); tR= 2.85 min.30

[0177] Alternatively, the reaction can be run using KI as a promoter, and Na2COs or KHCO3 can be used as alternative bases to remove the L-DBTA conformer.

[0178] Ethyl 7-[[(l lR)-3-chloro-6-methyl-5,5-dioxo-l lH- benzo[c][l,2]benzothiazepin-l l-yl]amino]heptanoate (compound 7) is prepared using compound 5:D-DBTA and the same steps as described above.Attorney Docket No.: 104545-0096-W02

[0179] In step 5 (Scheme 1), sodium 7-[[(l lS)-3-chloro-6-methyl-5,5-dioxo-l lH- benzo[c][l,2]benzothiazepin-l l-yl]amino]heptanoate (compound 8) was prepared according to EP0671173A1 by mixing NaOH (0.3M, 9.95 mL) with compound 6 (869 mg, 1.86 mmol) in EtOH (9.95 mL) at 22 °C. After stirring the mixture at 22 °C for 5 hours, the mixture was5 worked up by diluting the aqueous phase with HC1 (IN) to reach pH 7, extracting with DCM, drying the organic phase over Na2SO4, filtering, and concentrating. The residue was purified further by silica gel chromatography (24 g cartridge) with DCM and MeOH (0%-5%). The sodium salt can be obtained by diluting with aq. NaOH (IN, 1.00 eq) and stirring the mixture until it is homogeneous. Water (20.0 mL) was added, and the mixture was lyophilized to10 provide compound 8 as a solid.

[0180] Alternatively, the compound is prepared by cleaving the ester with acetic acid / hydrochloride (AcOH / HCl), diluting with water, adding Na2COs to reach pH 7, and extracting with DCM. The purification is done as described above.

[0181] Sodium 7-[[(l lR)-3-chloro-6-methyl-5,5-dioxo-l lH-benzo[c][l,2] benzothiazepin-l l-yl]amino]heptanoate (compound 9) is prepared using compound 7 and following the steps as described above.Scheme 2: Exemplary Synthetic Scheme for Deuterated Tianeptine EnantiomersCompound 16 or 1720

[0182] In Scheme 2, the deuterated form of sodium 7-[[(l lS)-3-chloro-6-methyl-5,5-Attorney Docket No.: 104545-0096-W02 dioxo-HH-benzo[c][l,2]benzothiazepin-l l-yl-l l-d-]amino]heptanoate or sodium 7-[[(l lR)- 3-chloro-6-methyl-5,5-dioxo-l lH-benzo[c][l,2]benzothiazepin-l 1-yl-l 1-d-]amino]heptanoate is prepared according to Steps 1 to 5 as described above for Scheme 1, but in Step 1, the reductant NaBH4 is replaced with NaBD4. The compounds of Scheme 2 are5 shown in Table 3.Table 3. Compounds of Scheme 2Attorney Docket No.: 104545-0096-W02Attorney Docket No.: 104545-0096-W02Synthesis of Tianeptine (S) and (R) Enantiomers from Tianeptine Methyl EsterScheme 3: Exemplary Synthetic Scheme for Tianeptine Enantiomers from TianeptineMethyl EsterCompound 225Attorney Docket No.: 104545-0096-W02Table 4. Compounds of Scheme 3Attorney Docket No.: 104545-0096-W02

[0183] Racemic tianeptine methyl ester (compound 18) is commercially available. In step 1 (Scheme 3) D-D(2-Me)BTA (Di-o-toluoyl-D-tartaric acid = (2S,3S)-2,3-bis[(2- methylbenzoyl)oxy]butanedioic acid) (88.4 mg, 0.229 mmol) was added to a solution of5 racemic tianeptine methyl ester (compound 18) (103 mg, 0.229 mmol) in acetonitrile (MeCN, 1.2 mL, 0.2M). The reaction mixture was stirred at 22 °C for 15 min and filtered resulting in the preferential precipitation of crystalline (R)-tianeptine methyl ester (compound 19) as the D-D(2-Me)BTA salt (99.8% chiral purity) and leaving (S)-tianeptine methyl ester (compound 20): D-D(2-Me)BTA salt (99.2% chiral purity) in solution in the filtrate. The filtrate was concentrated, and the residue was diluted with sat. aq. NaHCO3 (15.0 mL) to remove the D- D(2-Me)BTA and extracted with DCM (3 X 15.0 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide (S)-tianeptine methyl ester (compound 20).

[0184] Optionally, subsequent rounds of enantioselective crystallization are applied to further purify the (S)-tianeptine methyl ester. In one embodiment, L-DBTA (44.2 mg, 0.114 mmol) was added to the residue obtained from Step 1 in MeCN (600 pL) at 22 °C. The mixture was cooled to -15 °C for 48 h and filtered. The solid was washed with cold MeCN (0 °C, 3 X 1.00 mL) and dried to provide (S)-tianeptine methyl ester. The chiral purity was assessed by analytical SFC using a Lux Cellulose-4, 4.6 x 250mm, 5pm column and a solvent gradient of 5-60% [MeOH / 0.1% NH40H as a modifier] with a run time of 7.00 min, and flow rate of 3.00 mL / min. (S)-tianeptine methyl ester: tR = 4.08 min, chiral purity > 99.8%.

[0185] Alternatively, MeCN (1.08 mL) and toluene (0.120 mL) were added to L-DBTA (81.8 mg, 0.228 mmol) and racemic tianeptine methyl ester (103 mg, 0.228 mmol) at 22 °C. The mixture was stirred at 22 °C until all solids were dissolved and cooled to -15 °C for 72 h25 and filtered. The solid was washed with cold MeCN (3 x 1.00 mL). The solid was dissolved in MeCN (0.600 mL) at 60 °C, cooled to -15 °C for 72 h, filtered, washing with cold MeCN (3 xAttorney Docket No.: 104545-0096-W021.00 mL). The recrystallization was repeated another two times with MeCN (1.20 mL and 1.00 mL) to provide the (S)-tianeptine methyl ester / L-DBTA salt. The chiral purity was assessed by analytical SFC using a Lux Cellulose-4, 4.6 x 250mm, 5pm column and a solvent gradient of 5-60% [MeOH / 0.1% NH40H as a modifier] with a run time of 7.00 min, and flow rate of 3.005 mL / min. (S)-tianeptine methyl ester: tR = 4.10 min, >99.9% chiral purity.

[0186] Optionally, racemic tianeptine methyl ester is separated by preparative supercritical fluid (SFC) using a chiral column to yield (S)-tianeptine methyl ester.

[0187] To prepare the zwitterion of the methyl ester (Compound 22), in step 2 (Scheme3), 2M HC1 (10 mL) is added to the (S)-tianeptine methyl ester: D-D(2-Me)BTA salt10 (Compound 20: D-D(2-Me)BTA) (1 mmol) at 22 °C. The mixture is stirred at 100 °C until all starting material is consumed, cooled to 22 °C, and neutralized with 2M NaOH. The mixture is filtered and the solid is washed with H2O and dried to yield (S)-tianeptine zwitterion (Compound 22) in very high optical purity.

[0188] Optionally, other aqueous acids, such as sulfuric or phosphoric acid, are used for hydrolysis. Basic hydrolysis with a strong base, such as NaOH in methanol can also be used, but may result in racemization under some conditions. Hydrolysis is also performed with lithium hydroxide (1 eq.) in methanol / THF.

[0189] In Scheme 4, the deuterated form of (S)-tianeptine-HCl or (S)-tianeptine-HCl is prepared according to Steps 1 to 2 as described above for Scheme 3, but in Step 1, the20 deuterated tianeptine methyl ester is used as the starting product, or in some embodiments, using the alternative methods described above.Attorney Docket No.: 104545-0096-W02Scheme 4: Exemplary Synthetic Scheme for 11-D-Tianeptine Enantiomers from 11-D-Tianeptine Methyl Ester5 Table 5. Compounds of Scheme 4Attorney Docket No.: 104545-0096-W02Attorney Docket No.: 104545-0096-W02Example 3: Tianeptine Oxalate Activity at the p-Opioid Receptor -Opioid Receptor (MOR) Assay

[0190] Fluorescent biosensors (e.g, cADDis or 0-arrestin) from Montana Molecular were used to measure p-opioid receptor (MOR) signaling in real-time in live cells (e.g,5 HEK293T cells) using the Hamamatsu Functional Drug Screening System (FDSS) / pCell reader. cAMP inhibition, following pre-incubation with forskolin, and P-arrestin2 (arrestin) recruitment were measured. The MOR response at steady state, 60 minutes after compound addition, and the initial rate of MOR signaling were quantified.

[0191] Baseline fluorescence was measured, and after a baseline recording of 4 minutes10 a compound (e.g, [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO), racemic tianeptine, (S)-tianeptine, or (R)-tianeptine) was added. Control experiments measuring cAMP inhibition and arrestin recruitment were performed using a 10 pM compound (e.g., DAMGO, racemic tianeptine, and 99.0%-99.35% pure (S)-tianeptine oxalate or 98.5%-99.35% pure (R)- tianeptine oxalate) with or without MOR receptor overexpression and vehicle with MOR receptor overexpression. DAMGO, racemic tianeptine, (S)-tianeptine oxalate, and (R)- tianeptine oxalate were added at various concentrations including 0 nM (vehicle), 0.001 nM, 0.00316 nM, 0.01 nM, 0.0316 nM, 0.1 nM, 0.316 nM, 1 nM, 3.16 nM, lOnM, 31.6 nM, 100 nM, 316 nM, 1000 nM, 3160 nM, 10000 nM and 31600 nM. Data were normalized to the baseline and transferred to GraphPad Prism and represented as a mean ± SEM from 3 replicates.20 Data were fit to a fall-to-plateau model with baseline drift and the activity at steady state and initial rate of signaling were quantified.

[0192] Racemic tianeptine was a moderate potency full agonist for inhibition of cAMP production (Table 6 and Figures 3A and 3B), and a low potency near-full agonist for arrestin recruitment (Table 7 and Figures 4A and 4B). Comparatively, 99.0%-99.35% pure (S)- tianeptine oxalate was an order of magnitude less potent (ECso of 560 nM and 40nM for (S)- tianeptine oxalate and tianeptine, respectively) and had a similar Emaxof cAMP inhibition to racemic tianeptine (82% vs. 90% for (S)-tianeptine oxalate and racemic tianeptine, respectively) (Table 6 and Figures 3A, 3B, 4A and 4B) while 98.5%-99.35% pure (R)- tianeptine oxalate had a similar ECso (z.e., potency) and Emaxto racemic tianeptine (Table 630 and Figures 3 A, 3B, 4A and 4B). The steady state concentration response and the initial rate analysis of cAMP inhibition (Table 6) and arrestin recruitment (Table 7) are shown below.Attorney Docket No.: 104545-0096-W02Table 6. cAMP Inhibition using (S)-tianeptine oxalate and (R)- tianeptine oxalateTable 7. Arrestin recruitment using (S)-tianeptine oxalate and (R)-tianeptine oxalateAttorney Docket No.: 104545-0096-W02Example 4: Tianeptine Sodium Activity at the g-Opioid ReceptorMOR Assay

[0193] Fluorescent biosensors (e.g., cADDis or P-arrestin) from Montana Molecular were used to measure p-opioid receptor (MOR) signaling in real-time in live cells (e.g,5 HEK293T cells) using the Hamamatsu Functional Drug Screening System (FDSS) / pCell reader. The signals measured were Gi signaling (z.e., cAMP production or cAMP inhibition in cells pre-incubated with forskolin) and P-arrestin2 (arrestin) recruitment (z.e., arrestin activation). The activity at steady state and initial rate of signaling were quantified. The compounds tested include DAMGO, racemic tianeptine, racemic mixture of tianeptine sodium,10 and (S)- or (R)-tianeptine sodium. Various concentrations of the compounds include 0 nM, 0.001 nM, 0.003 nM, 0.010 nM, 0.032 nM, 0.1 nM, 0.316 nM, 1 nM, 3.162 nM, lOnM, 31.62 nM, lOOnM, 316.2 nM, 1000 nM, 3162 nM, 10000 nM, and 31620 nM.Gi Signaling

[0194] Live HEK293T cells were transduced with cADDis biosensor, and p-opioid receptor (MOR) (Gene ID: OPRM1), Dopamine Receptor D2 (Gene ID: DRD2) as a positive control or no receptor as a negative control. Baseline fluorescence was measured for 20 minutes, followed by stimulation with 10 pM forskolin for 70 minutes. Compounds (e.g, DAMGO, racemic tianeptine, racemic mixture of tianeptine sodium, (S)-tianeptine sodium,20 and (R)-tianeptine sodium) were added at minute 90. The negative controls (cells with no MOR overexpression) were treated with vehicle-only or forskolin + vehicle treated samples. The positive controls (cells expressing DRD2) were treated with 3.2 pM quinpirole.

[0195] The time course data after compound addition was normalized to the baseline fluorescence and adjusted to the time course data from forskolin + vehicle treated samples. Data were transferred to GraphPad Prism and is shown as a mean ± SEM from 4 replicates. Data were best fit to either a fall-and-rise to steady state or a rise-and-fall to steady state model, depending on cAMP production or % cAMP inhibition. Percent inhibition of cAMP data was used to obtain dose-concentration curves.

[0196] (S)-Tianeptine sodium (99.0%-99.35%chiral purity) was a low potency partial30 MOR agonist as indicated by % cAMP inhibition in two separate experiments, while (R)- Tianeptine sodium (99.35% chiral purity) showed similar potency and efficacy as compared to racemic tianeptine (Table 8, Figures 5A, 5B, 6A and 6B). The potency of the racemic mixtureAttorney Docket No.: 104545-0096-W02 of tianeptine sodium was approximately 3.5-fold lower than (R)-tianeptine sodium when comparing the EC50 (Table 8).

[0197] The concentration-response and the initial rate analysis of cAMP inhibition is shown in Table 8.Table 8. cAMP Inhibition using (S)- and (R)- tianeptine sodiumAttorney Docket No.: 104545-0096-W02Arrestin Recruitment

[0198] Live HEK293T cells were transduced with 0-arrestin (arrestin) biosensor, and OPRM1, angiotensin II type 1 receptor (AT1R; Gene ID: AGTR1) as a positive control, or no receptor as a negative control. Baseline fluorescence was measured for 20 minutes, then5 compounds (<?.g., DAMGO, racemic tianeptine, racemic mixture of tianeptine, (S)-tianeptine sodium and (R)-tianeptine sodium) were added and fluorescence was measured for 90 minutes. The negative controls (cells with no MOR overexpression) were treated with vehicle-only treated samples. The positive controls (cells expressing AT1R) were treated with 3.2 pM angiotensin II.10

[0199] The time course data after compound addition was normalized to the baseline fluorescence. Data were transferred to GraphPad Prism and is shown as a mean ± SEM from 4 replicates. Data were best fit to an arrestin recruitment and degradation model. Initial rate and maximum effect at peak arrestin recruitment was used to obtain dose-concentration curves.

[0200] (S)-Tianeptine sodium (99.9% chiral purity) showed no agonist effect at the p- opioid receptor. However, (R)-Tianeptine sodium (99.9% chiral purity) was near full efficacy as an agonist at the p-opioid receptor (90% of DAMGO) and showed similar potency as compared to racemic tianeptine (Figures 7A and 7B). The potency of the racemic mixture of tianeptine sodium was approximately 1.8-fold lower than (R)-tianeptine sodium as determined by the EC50 of the arrestin recruitment (maximum effect), showing full efficacy but slightly20 slower kinetics (82.5% of the (R)-tianeptine sodium initial rate) (Table 9).

[0201] The concentration-response and the initial rate analysis of arrestin recruitment is shown in Table 9.Table 9. Arrestin Recruitment using 99.9% pure (S)- and (R)- tianeptine sodiumAttorney Docket No.: 104545-0096-W02

[0202] Overall, (S)-tianeptine and (R)-tianeptine exhibit distinct activities at the p- opioid receptor, further recapitulated by the analysis of substantially pure tianeptine enantiomers, isolated by chiral chromatography, on MOR agonism. For example, 99.9% pure5 (S)-tianeptine showed no MOR agonism assessed by cAMP inhibition (Figure 8A) and arrestin recruitment (Figures 7A, 7B and 8B). In contrast, 99.35% pure or lower (S)-tianeptine was a low potency partial MOR agonist assessed by cAMP inhibition (Tables 6, 7 and 8, and Figures 3 A, 3B, 4A, 4B, 5A, 5B, 6A and 6B). Therefore, MOR agonism was determined to be entirely due to (R)-tianeptine, where it was about 800-fold more active than (S)-tianeptine, suggesting that the use of pure or substantially pure (S)-tianeptine has the potential to reduce the potential for opioid abuse, or opioid toxicity, or opioid overdose. Table 10 shows the EC50 of the 99.9% pure tianeptine enantiomers. No activity was observed at any achievable concentration for 99.9% pure (S)-tianeptine (Figures 7A, 7B, 8A and 8B).Table 10. EC50 of 99.9% pure (S)-tianeptine sodium and (R)-tianeptine sodiumExample 7: Evaluation of Tianeptine (R)- and (S)- Enantiomers in Neurite Outgrowth

[0203] The effects of (S)- and (R)-tianeptine on neuronal dynamics were assessed using the Ready-2-Go Neurite Outgrowth Assay Service (PhenoVista). iCell Glutaneurons (Fujifilm Cellular Dynamics) were thawed and cultured according to manufacturer’s protocol and allowed to grow for 7 days to allow synapse network formation. Cells were incubated in the presence of either (S)- or (R)-tianeptine zwitterion (99.9% chiral purity) dissolved in PBS at various concentrations (e.g., 0.03 pM, 0.1 pM, 0.32 pM, 1.0 pM, 3.2 pM and 10 pM), staurosporine (positive control, 0.063 pM and 0.2 pM), vincristine (negative control, 2 pM and 20 pM), PBS and DMSO for 24 hours and 72 hours. The cells were then fixed at 24 or 7225 hours and stained for imaging and analysis. Nuclei were stained with Hoechst and cell bodies and neurites with CellMask.

[0204] At 24 and 72 hours, the positive and negative controls (staurosporine and vincristine, respectively) had the expected effects on average neurite length, with staurosporineAttorney Docket No.: 104545-0096-W02 treatment increasing average neunte length and vincristine treatment decreasing average neurite length (Figures 9A and 9B). At 24 hours, (R)-tianeptine and (S)-tianeptine did not differ with respect to neurite outgrowth (Figure 9A). However, by 72 hours, (S)-tianeptine significantly increased neurite outgrowth relative to the Phosphate Buffered Saline (PBS)5 control with a maximum effect at 0.1 pM (Figure 9B). In contrast, (R)-tianeptine (1.0 pM) did not significantly increase neurite outgrowth relative to the PBS control, and actually decreased neurite outgrowth at 1.0 pM (Figure 9B). These data indicate that (S)-tianeptine induces neurite outgrowth while (R)-tianeptine inhibits neurite outgrowth, suggesting that, without wishing to be bound by theory, (S)-tianeptine may induce anti-depressive effects by restoring10 neuroplasticity while minimizing or eliminating the potential for opioid abuse.

[0205] The experiment above was repeated by incubating cells in the presence of either (S)- or (R)-tianeptine zwitterion (99.9% chiral purity) dissolved in PBS at various concentrations (e.g., 0.1 pM, 1.0 pM, and 10 pM) - alone or in combination with dexamethasone, dexamethasone being at various concentrations (e.g., 0.001 pM, 0.01 pM, 0.1 pM, 1.0 pM, 10 pM and 100 pM) PBS or DMSO for 5 days. For the control compounds (i.e., staurosporine (0.063 pM and 0.2 pM), vincristine (2 pM and 20 pM) and carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone (FCCP, 6.2 pM and 62.0 pM)), the cells were incubated for 24 hours, 24 hours, and 2 hours, respectively due to known toxicity in response to prolonged treatment. The cells were then fixed and stained for imaging and analysis. Nuclei were stained20 with Hoechst, cell body morphology and neurite network were assessed using CellMask Green and mitochondrial function was assessed using MitoTracker CMXRos. Data was normalized to the 1% PBS control.

[0206] As described above, staurosporine and vincristine had the expected effects on average neurite outgrowth, with staurosporine treatment increasing total neurite length and average neurite width and vincristine treatment decreasing both metrics (Figures 9C-9F). Likewise, (S)- performed as previously described significantly increasing neurite outgrowth relative to the 1% PBS control particularly at 1.0 pM, and 10 pM (Figures 9C and 9D). However, treatment with (R)-tianeptine showed no significant effect on neurite outgrowth (Figures 9E and 9F). (S)-tianeptine also increased the mitochondrial staining in neurites,30 indicating an increase in the localization and activity of mitochondria in neurites (Figure 10B), although mitochondrial staining in the cell body remained unchanged (Figure 10A). On the other hand, (R)-tianeptine was found to decrease mitochondrial staining in cell bodies (Figure 10C), indicating a decrease in the localization and activity of mitochondria in cell bodies, while no change was observed in the mitochondrial staining in neurites (Figure 10D).Attorney Docket No.: 104545-0096-W02

[0207] Dexamethasone was used as an in vitro proxy for stress as it inhibits growth or causes cell shrinkage in many systems. However, in this cell line, dexamethasone was found to have pro-growth effects, increasing neurite outgrowth except at the highest doses (z.e., 10 pM and 100 pM, Figures 9C-9F), and increasing mitochondrial staining in neurites (Figures5 10B and 10C). Dexamethasone did not have a significant effect on the mitochondrial staining in cell bodies (Figures 10A and 10C). (S)-tianeptine acted synergistically with dexamethasone to enhance its trophic effects (Figures 9C, 9D, 10A and 10D), while (R)-tianeptine antagonized the trophic effects of dexamethasone (Figures 9E, 9F, 10B and 10C). The increase in mitochondrial staining in neurites observed with (S)-tianeptine may play a major role in the10 observed neuroplastic remodeling. Further, the synergy observed with (S)-tianeptine and dexamethasone suggests that (S)-tianeptine will have its maximal effects under stress conditions. The inhibitory effects of R-tianeptine on mitochondria may be mediated by its p- opioid agonism.Example 8: Evaluation of Tianeptine in Novel Object Recognition Test

[0208] The memory enhancing capabilities of racemic tianeptine sodium were assessed using the novel object recognition (NOR) test in rats. The study was conducted at PsychoGenics, Inc and performed using adult male Long-Evans rats (275-299 g) from Charles River Laboratory. Rats were housed 2 per cage and acclimated for at least 7 days prior to20 testing. During the course of the study, 12h / 12h light / dark cycles were maintained. The room temperature was maintained between 20 and 23 °C with a relative humidity maintained around 50%. Chow and water were provided ad libitum for the duration of the study. Each rat was randomly assigned across the treatment groups. Testing was performed during the animals’ light cycle phase. Rats were assessed for cognitive ability in a test apparatus comprising an open-field arena (40 x 40 cm) under dimmed lighting. All training and testing trials were videotaped and scored by an observer blind to treatments.

[0209] Rats were treated by intraperitoneal (i.p.) injection with galantamine dissolved in saline at a dose volume of 1 mg / kg 30 minutes prior to training and prior to testing, or with racemic tianeptine sodium dissolved in saline at a dose volume of 1 ml / kg prior to training or30 at a dose volume of 3, 10 or 30 mg / kg 60 minutes prior to testing. On Days 1 and 2, rats were allowed to freely explore the arena (no objects inside) for a 10-minute habituation period. On Day 3, rats were administered saline, galantamine or racemic tianeptine sodium, and following the appropriate pretreatment time (30 min for saline and galantamine; 60 min for racemic tianeptine sodium, rats were placed into the test arena in the presence of two identical objects.Attorney Docket No.: 104545-0096-W02Each rat was placed in the arena facing the same direction at the same position, and the time spent actively exploring the objects during a 3 -minute T1 was recorded. The rat was returned to its home cage following training. After 48 hours, the rats were administered saline, galantamine or racemic tianeptine sodium again, and following the appropriate pretreatment5 time, they were placed into the test arena in the presence of one familiar object and one novel object, and the time spent exploring each object were recorded for 5 minutes in the testing session (T2). The presentation order and position of the objects (left / right) in T2 is randomized between rats to prevent bias from order or place preference. Data were expressed as Recognition Index, which is defined as the ratio of the time spent exploring the novel object10 over the total time spent exploring both objects (Novel / (Familiar + Novel) * 100%) during the 5 min test session. A value of 50% in recognition index means entire forgetting. Data were analyzed by one-way ANOVA followed by Dunnett’ s post hoc analysis. Statistical outliers that exceeded two standard deviations from the mean were removed from the final analysis. Once one data point was identified as outlier, the whole animal was removed. Animals with recognition index above 90% or below 30% were also eliminated because they suggest strong (non-memory) bias between two objects.

[0210] Racemic tianeptine sodium (10 and 30 mg / kg) and galantamine significantly increased the Recognition Index during the 5 -minute test as well as during the first 3 minutes of the test. Racemic tianeptine sodium (3 mg / kg) showed a non-significant trend to increasing20 recognition index during these two timepoints. During the first minute of the test, racemic tianeptine sodium (3 and 10 mg / kg) significantly increased the Recognition Index (Figure 11 A). These results suggest that racemic tianeptine sodium is capable of memory enhancement.

[0211] The memory enhancing capabilities of (S)- and (R)-tianeptine sodium was also assessed in the NOR test using substantially pure enantiomers (z.e., 99.9% chiral purity). Rats were treated by i.p. injection with (S)- or (R)-tianeptine sodium dissolved in saline at a dose volume of 1 ml / kg prior to training or at a dose volume of 3, 10 or 30 mg / kg 60 minutes prior to testing or with galantamine or racemic tianeptine sodium, and the experiments and analysis were conducted as described above.30

[0212] As predicted, (S)-tianeptine sodium showed a significant increase in the Recognition Index during the NOR test with similar activity to racemic tianeptine sodium (Figure 1 IB), suggesting that (S)-tianeptine sodium is efficacious in improving recognition memory. (R)-tianeptine, on the other hand, showed no efficacy in the NOR test at 3 and 10Attorney Docket No.: 104545-0096-W02 mg / kg (Figure 11C). 30 mg / kg (R)-tianeptine was not evaluated in the NOR test due to overt sedation and catalepsy-like behavior in rats, perhaps due to MOR agonism.Example 9: Evaluation of Tianeptine (R)- and (S)- Enantiomers for Genotoxicity

[0213] Racemic tianeptine and (R)-tianeptine (99.9% chiral purity) and (S)-tianeptine (99.9% chiral purity) were evaluated for the potential to induce micronuclei in TK6 cells during short (4-hour) and long (72-hour) incubations with or without an exogenous metabolic activation system using an in vitro micronuclease assay. The micronuclease assay evaluates the ability of a test article to interfere with normal mitotic cell division.

[0214] The test compounds (racemic tianeptine, (R)- tianeptine and (S)-tianeptine) were prepared in DMSO using serial dilutions to achieve the test concentrations. Target concentrations of the test compounds were determined by range finding-assay. DMSO (1%) was used as a vehicle control and positive controls used included mitomycin C (MMC, Sigma- Aldrich Inc.) for the 4-hour treatments without metabolic activation, vinblastine sulfate (VIN, Sigma-Aldrich Inc.) for the 27-hour treatments without metabolic activation and cyclophosphamide monohydrate (CP, Sigma-Aldrich Inc.) for the 4-hour treatments with metabolic activation. TK6 cell cultures, a human lymphoblast cell line, were treated with the test compounds, positive control or vehicle control in the presence or absence of phenobarbital / 5,6-benzoflavone-induced rat liver S9 microsomal fraction, the metabolic activation system. Cytotoxicity was assessed using cell count data obtained from Coulter counts and micronucleus evaluation was performed by flow cytometry using a FACSCanto II (or equivalent) with FACSDiva Software.

[0215] Racemic tianeptine was positive for inducing micronuclei in TK6 cells in the 27-hour treatment without metabolic activation and negative for inducing micronuclei in TK6 cells in the 4-hour treatments with and without metabolic activation. (R)-tianeptine was positive for inducing micronuclei in TK6 cells in the 4-hour and the 27-hour treatments without metabolic activation and negative for inducing micronuclei in TK6 cells in the 4-hour treatments with metabolic activation. By comparison, (S)-tianeptine was found to be negative for inducing micronuclei in TK6 cells at all test conditions. See Tables 11-13. These data suggest that (S)-tianeptine is non-genotoxic as compared to racemic tianeptine and (R)- tianeptine.Attorney Docket No.: 104545-0096-W02Table 11. 4-hour Treatment without Metabolic ActivationDMSO = Dimethyl sulfoxide, MN = Micronucleated Cells, Cytotox. = Cytotoxicity, MMC =Mitomycin C, *= z’ > 0.65 Table 12. 27-hour Treatment without Metabolic ActivationAttorney Docket No.: 104545-0096-W02DMSO = Dimethyl sulfoxide, MN = Micronucleated Cells, Cytotox. = Cytotoxicity, VIN =Vinblastine Sulfate, *= z’ > 0.6Table 13. 4-hour Treatment with Metabolic Activation5 DMSO = Dimethyl sulfoxide, MN = Micronucleated Cells, Cytotox. = Cytotoxicity, CP =Cyclophosphamide Monohydrate, *= z’ > 0.6Example 10: Synthesis of Racemic N-nitroso-tianeptineGeneral Methods10

[0216] Reagent grade chemicals and anhydrous solvents were purchased from commercial sources and, unless otherwise mentioned, were used without further purification. Silica gel chromatography was performed on Teledyne Isco instruments using pre-packaged disposable SiO2 stationary phase columns with eluent flow-rate ranges of 15 to 200 mL / min,Attorney Docket No.: 104545-0096-W02UV detection (254 and 280 nm). Reverse phase purification was earned out using Cl 8 columns, UV detection (214 and 254 nm).

[0217] The analytical QA / QC chromatograms were performed using a Waters Acquity UPLC instrument with DAD detector (200 nm to 320 nm) and a thermostatted column5 compartment. The mass spectra were recorded with a Waters SQD detector with the desolvation temperature set to 450 °C, the source temperature set to 150 °C, and the desolvation gas flow set to 1000 L / h. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive, or negative, ion mode and was set to scan between m / z 100-2000 with a scan time of 0.2 s.10

[0218] Products were analyzed by ultra-performance liquid chromatography-mass spectrometry (UPLC / MS) using an Acquity UPLC Premier BEH C 18 VanGuard FIT (1.7 pM, 2.1 x 50 mm) column heated to 35 °C, a flow rate of 0.700 mL / min, consisting of MeCN, H2O, and 10 mM aq. NH4HCO2 adjusted to pH 7.4 (80: 18:2) for 10 min ((XCB / XCM / XCW)_ACN_AmForm_QC_10min V2). The percentage of MeCN increased from 5% to 100% from 0.00-9.00 min and was maintained at 100% from 9.00-10.00 min.

[0219] TheJH NMR spectra were recorded on a Varian Mercury 300 MHz / 54 mm instrument, a Varian AS 400 MHz / 54 mm instrument, and a Bruker UltraShield 500 MHz / 54 mm instrument (BZH 43 / 500 / 70B, D221 / 54-3209). The chemical shifts were reported in parts- per-million and were referenced to solvent peaks, which in!H NMR appeared at 7.26 ppm for20 CDCh, 2.50 for DMSO-t / e, and 3.31 ppm for CD3OD.Scheme 5: Exemplary Synthetic Scheme for Racemic N-nitroso-tianeptineAttorney Docket No.: 104545-0096-W02Table 14. Compounds of Scheme 5

[0220] S-Nitrosoglutathione (compound 29, 116 mg, 0.345 mmol) was added to a mixture of racemic sodium 7-[[(l lR)-3-chloro-6-methyl-5,5-dioxo-HH-5 benzo[c][l,2]benzothiazepine-l l-yl]amino]heptanoate (compound 28, 158 mg, 0.345 mmol) in water (15.8 mL) at 23 °C. The mixture was stirred at 80 °C for 23 hours and concentrated.The residue was purified by preparative HPLC (Phenomenex Gemini NX Prep Cl 8, 50x50mm AXIA) with water (0.1% HCOOH) and MeCN (5-100%) to provide racemic 7-((3-chloro-6- methyl-5,5-dioxido-6, 11-dihy drodibenzo[c,f][ l,2]thi azepin- 1 l-yl)(nitroso)amino)heptanoicAttorney Docket No.: 104545-0096-W02 acid (compound 30) as a solid (15.2 mg, 10%).XH NMR (400 MHz, DMSO- cfc) 5 11.82 (s, 1H), 7.95 - 7.85 (m, 1H), 7.80 (dd, J = 8.4, 2.0 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.67 (dd, J = 7.9, 1.3 Hz, 1H), 7.60 (td, J = 7.7, 1.6 Hz, 1H), 7.50 (td, J = 7.5, 1.4 Hz, 1H), 6.71 (s, 1H), 3.63 (ddd, J= 13.2, 9.9, 5.6 Hz, 1H), 3.05 (s, 4H), 2.13 (t, J = 7.3 Hz, 2H), 1.37 (g, J = 7.4 Hz, 3H),5 1.14 - 0.87 (m, 5H). m / z (ES+) [M+Na]+ = 488.1 and 490.1; UPLC (XCB_AcN_AmForm_QC lOmin V2) tR = 4.33 min.Example 11: Crystalline Forms of Pharmaceutically Acceptable Salts of (S)-Tianeptine. General Methods10

[0221] Crystalline forms of pharmaceutically acceptable salts of (S)-tianeptine of this disclosure can be made by methods known in the art. The crystalline forms may then be characterized by methods known in the art, including but not limited to X-Ray powder diffraction (XRPD), Fourier Transform Infrared (FT-IR) spectra, Differential Scanning calorimetry (DSC), Thermogravimetric Analysis (TGA), and Nuclear Magnetic Resonance (NMR). It should be understood that operator, instrument and other related changes may result in some margin of error with respect to analytical characterization of the salts or crystalline forms.X-Ray Powder Diffraction (XRPD)20

[0222] X-ray powder diffraction patterns were obtained using a Rigaku MiniFlex600 X-ray Diffractometer. Diffractogram was acquired using the Miniflex Guidance application software. The measurement and instrument details are listed in Tables 15 and 16 below.Table 15. X-Ray Powder Diffraction (XRPD): Measurement DetailsAttorney Docket No.: 104545-0096-W02Table 16. X-Ray Powder Diffraction (XRPD): Instrument DetailsAttorney Docket No.: 104545-0096-W02

[0223] The XRPD pattern of crystalline (S)-tianeptine are illustrated in Figure 13A and in Table 17.Table 17. XRPD peaks list of (S)-Tianeptine hemi-oxalateAttorney Docket No.: 104545-0096-W02

[0224] The XRPD pattern of crystalline (S)-tianeptine hemi-oxalate salt are illustrated in Figure 13B and in Table 18.Table 18. XRPD peaks list of (S)-Tianeptine sodiumAttorney Docket No.: 104545-0096-W02

[0225] (S)-tianeptine sodium salt also forms an amorphous salt (Form B) depicted in Figure 13C. A comparison of the XRPDs of crystalline (S)-tianeptine, crystalline (S)- tianeptine hemi-oxalate, (S)-tianeptine sodium and crystalline racemic tianeptine hemi-oxalate5 is depicted in Figure 13D.Attorney Docket No.: 104545-0096-W02Example 12: Synthesis of Aryl Substituted Tianeptine DerivativesGeneral Methods

[0226] Reagent grade chemicals and anhydrous solvents were purchased from5 commercial sources and, unless otherwise mentioned, were used without further purification. The names of the products were determined using the naming software included in Biovia Draw version 18.1 or ChemDraw Professional version 20.1.1.125. Silica gel chromatography was performed on Teledyne Isco instruments using pre-packaged disposable SiCh stationary phase columns with eluent flow-rate ranges of 15 to 200 mL / min, UV detection (254 and 28010 nm). Reverse phase purification was carried out using Cl 8 columns, UV detection (214 and 254 nm).

[0227] The analytical QA / QC chromatograms were performed using a Waters Acquity UPLC instrument with DAD detector (200 nm to 320 nm) and a thermostatted column compartment. The mass spectra were recorded with a Waters SQD detector with the desolvation temperature set to 450 °C, the source temperature set to 150 °C, and the desolvation gas flow set to 1000 L / h. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive, or negative, ion mode and was set to scan between m / z 100-2000 with a scan time of 0.2 s. Products were analyzed by UPLC / MS using one of the following methods:20 1. XCB_4min_iiormaI_AlBl_ELS_EVO: a 4.00 min method which used a Kinetex EVO C18 100 A (2.6 pM, 3.0 x 50mm) column heated to 40°C, a flow rate of 1.200 mL / min, a buffer consisting of 0.1% TFA in H2O, and 0.1% TFA in MeCN as the organic solvent. The percentage MeCN increases from 5% to 35% from 0.00-1.00 min and from 35% to 95% from 1.00-2.70 min and then kept stable at 95% from 2.70-3.55 min;2. XCB_4min_medium_A2B2_EVO: a 4.00 min method which used a Kinetex EVO Cl 8 100 A (2.6 pM, 3.0 x 50mm) column heated to 40°C, a flow rate of 1.200 mL / min, a buffer consisting of 10 mM NH4HCO2 in H2O adjusted to pH 7.4 with NH4OH, and 180 mL H2O 800 mL MeCN and 20 mL NH4HCO2 buffer pH 7.4 as the organic30 solvent. The percentage of organic solvent increases from 30% to 70% from 0.00-1.00 min and from 70% to 90% from 1.00-3.00 min and then kept stable at 90% from 3.00- 3.55 min; or3. (XCB / XCM / XCW)_ACN_TFA QC_10min VI: a 10.00 min method which used an Acquity UPLC BEH C18 (1.7 pM, 2.1 x 50 mm) column heated to 35 °C, a flowAttorney Docket No.: 104545-0096-W02 rate of 0.700 mL / min, a buffer consisting of 0.1% aq TFA and MeCN. The percentage of MeCN increases from 5% to 100% from 0.00-9.00 min and is maintained at 100% from 9.00-10.00 min.

[0228] The!H NMR spectra were recorded on a Varian Mercury 300 MHz / 54 mm5 instrument, a Varian AS 400 MHz / 54 mm instrument, and a Bruker UltraShield 500 MHz / 54 mm instrument (BZH 43 / 500 / 70B, D221 / 54-3209). The chemical shifts were reported in parts- per-million and were referenced to solvent peaks, which inJH NMR appeared at 7.26 ppm for CDC13, 2.50 for DMSO4 and 3.31 ppm for CD3OD.Scheme 6: Exemplary Synthetic Scheme for 7-((3-(furan-2-yI)-6-methyI-5,5-dioxido-6,ll- dihydrodibenzo[c,f] [l,2]thiazepin-ll-yl)amino)heptanoic acidCompound 28 Compound 31

[0229] Racemic sodium;7-[[(l lR)-3-chloro-6-methyl-5,5-dioxo-l lH-benzo[c][l,2]15 benzothiazepine-l l-yl]amino]heptanoate (compound 28, 500 mg, 1.09 mmol) was added to a mixture of 2-furanboronic acid (183 mg, 1.63 mmol), PEPPSI™-IPr (74.0 mg, 0.109 mmol) and CS2CO3 (710 mg, 2.18 mmol) in a 10: 1 mixture of 1,4-dioxane and water (20.0 mL) at rt under argon. The mixture was stirred at 90 °C for 16 h, and concentrated. The residue was diluted with THF (10.0 mL) and filtered through Celite, washing with THF (4.00 mL), and the filtrate was concentrated. The residue was purified by reverse phase chromatography (Cl 8, 50 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-100%) and by preparative HPLC (Phenom enex Gemini 5um NX-Prep C18 50x50mm AXIA) with water [10 mM (NH4XHCO3)] and MeCN (20-100%) to provide 7-((3-(furan-2-yl)-6-methyl-5,5-dioxido-6,l l- dihydrodibenzo[c,f][l,2] thiazepin-1 l-yl)amino)heptanoic acid (compound 31) as a solid (11625 mg, 23%).JH NMR (400 MHz, DMSO-fifc) 5 8.04 (d, J = 1.9 Hz, 1H), 7.93 (dd, J = 8.1, 1.9 Hz, 1H), 7.81 (d, J= 1.8 Hz, 1H), 7.71 (d, J= 8.2 Hz, 1H), 7.50 (dt, J= 7.5, 2.1 Hz, 2H), 7.37 (dtd, .7= 19.5, 7.4, 1.6 Hz, 2H), 7.14 (d, J = 3.4 Hz, 1H), 6.63 (dd, J= 3.4, 1.8 Hz, 1H), 5.18 (s, 1H), 3.37 (s, 3H), 2.41 (t, J= 7.1 Hz, 2H), 2.15 (t, J= 7.3 Hz, 2H), 1.45 (h, J= 7.1 Hz, 4H),Attorney Docket No.: 104545-0096-W021.23 (dd, J = 8.3, 4.5 Hz, 4H), two protons not observed; m / z (ES ) [M+H] = 469.2; UPLC(XCB_AcN_TFA_QC_10minJVl) tR= 3.71 min.)Scheme 7: Exemplary Synthetic Scheme for 7-((3-(furan-3-yI)-6-methyl-5,5-dioxido-6,ll-5 dihydrodibenzo[c,f] [l,2]thiazepin-ll-yl)amino)heptanoic acidCompound 28 Compound 32

[0230] Racemic sodium;7-[[(l lR)-3-chloro-6-methyl-5,5-dioxo-l lH-benzo[c][l,2] benzothiazepine-l l-yl]amino]heptanoate (compound 28, 500 mg, 1.09 mmol) was added to a mixture of 3-furanboronic acid (122 mg, 1.09 mmol), PEPPSI™-IPr (74.0 mg, 0.109 mmol) and CS2CO3 (710 mg, 2.18 mmol) in a 10: 1 mixture of 1,4-dioxane and water (20.0 mL) at rt under argon. The mixture was stirred at 90 °C for 16 h, and concentrated. The residue was diluted with THF (10.0 mL) and filtered through Celite, washing with THF (10.0 mL), and the filtrate was concentrated. The residue was purified by reverse phase chromatography (Cl 8, 50 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-100%), by preparative HPLC (Phenomenex Gemini 5um NX-Prep C 18 50x50mm AXIA) with water [0.1% TFA] and MeCN (0-95%), and by reverse phase chromatography (C18, 50 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-100%) to provide 7-((3-(furan-3-yl)-6-methyl-5,5-dioxido-6,l l- dihydrodibenzo[c,f][l,2]thiazepin-l l-yl)amino)heptanoic acid (compound 32) as a solid (61.0 mg, 12%). ’HNMR (400 MHz, DMSO-Je) 8 8.35 (t, J= 1.2 Hz, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.86 (dd, 7= 8.1, 1.9 Hz, 1H), 7.77 (t, J= 1.7 Hz, 1H), 7.67 (d, 7= 8.2 Hz, 1H), 7.49 (ddd, J = 7.5, 3.2, 1.6 Hz, 2H), 7.37 (dtd, J= 19.6, 7.4, 1.6 Hz, 2H), 7.04 (dd, J= 1.9, 0.9 Hz, 1H), 5.17 (s, 1H), 3.36 (s, 3H), 2.41 (t, J= 7.1 Hz, 2H), 2.16 (t, J= 7.4 Hz, 2H), 1.45 (h, J= 12 Hz, 4H), 1.23 (dd, J = 7.9, 4.3 Hz, 4H), two protons not observed; m / z (ES+) [M+H]+= 469.2; UPLC (XCB_AcN_TFA_QC_10minJVl) tR= 3.62 min.25Attorney Docket No.: 104545-0096-W02Scheme 8: Exemplary Synthetic Scheme for 7-((6-methyI-5,5-dioxido-3-(thiophen-3-yI)-6,ll-dihydrodibenzo[c,f|[l,2]thiazepm-ll-yl)ammo)heptanoic acid5

[0231] Racemic sodium;7-[[(l lR)-3-chloro-6-methyl-5,5-dioxo-l lH-benzo[c][l,2] benzothiazepine-l l-yl]amino]heptanoate (compound 28, 500 mg, 1.09 mmol) was added to a mixture of thiophene-3-boronic acid (139 mg, 1.09 mmol), PEPPSI™-IPr (74.0 mg, 0.109 mmol) and CS2CO3 (710 mg, 2.18 mmol) in a 10:1 mixture of 1,4-dioxane and water (20.0 mL) at rt under argon. The mixture was stirred at 90 °C for 16 h, and concentrated. The residue was diluted with THF (10.0 mL) and filtered through Celite, washing with THF (4.00 mL), and the filtrate was concentrated. The residue was purified by reverse phase chromatography (Cl 8, 50 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-100%) to provide 7-((6-methyl- 5, 5-dioxido-3 -(thi ophen-3 -y l)-6, 11 -dihydrodibenzo[c,f] [ 1 ,2] thi azepin- 11 -yl)amino)heptanoic acid (compound 33) as a solid (187 mg, 35%).!H NMR (400 MHz, DMSO-tfc) 8 8.04 (dd, J =15 2.9, 1.5 Hz, 2H), 7.96 (dd, J= 8.1, 2.0 Hz, 1H), 7.73 - 7.64 (m, 2H), 7.60 (dd, J= 5.1, 1.4 Hz, 1H), 7.50 (dd, J= 7.7, 1.6 Hz, 2H), 7.37 (dtd, J= 19.3, 7.4, 1.6 Hz, 2H), 5.19 (s, 1H), 3.36 (s, 3H), 2.54 (s, 1H), 2.42 (t, J= 7.1 Hz, 2H), 2.14 (t, J= 7.4 Hz, 2H), 1.51 - 1.38 (m, 4H), 1.23 (dq, J = 10.8, 5.7 Hz, 4H), one proton not observed; m / z (ES+) [M+H]+= 485.2; UPLC (XCB_AcN_TFA_QC_10minJVl) tR= 3.91 min.25Attorney Docket No.: 104545-0096-W02Scheme 9: Exemplary Synthetic Scheme for 2-(4-(((3-chIoro-6-methyI-5,5-dioxido-6,ll- dihydrodibenzo[c,f|[l,2]thiazepin-ll-yI)amino)methyI)-2-methyIphenoxy)acetic acid5

[0232] In step 1, 3-chloro-6-methyl-5,5-dioxo-l lH-benzo[c][l,2]benzothiazepin-l l-ol (compound 2) was added to a mixture of oxalyl chloride (1.40 mL, 16.1 mmol) and DMF (12.5 |1L, 0.161 mmol) in DCM (10.0 mL) at rt. The mixture was stirred at 23 °C for 1 h, and concentrated. The residue was diluted with toluene (20.0 mL) and concentrated twice. The residue was diluted with THF (20.0 mL) and stirred at 60 °C in an autoclave under ammonia10 (2 bars) for 16 h. The mixture was concentrated, and diluted with DCM (50.0 mL), water (50.0 mL) and sat. aq. NaHCCL (20.0 mL). The mixture was filtered through Celite, washing with DCM (20.0 mL). The aqueous phase of the filtrate was extracted with DCM (2 x 30.0 mL) and the combined organic extracts were concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of MeOH in DCM (0-20%) to provide 3- chloro-6-methyl-5,5-dioxo-HH-benzo[c][l,2]benzothiazepin-l 1 -amine (compound 3) as a solid (401 mg, 40%). m / z (ES+) [M-NH2]+= 292.0; UPLC (4min norma AlBl ELS EVO) tR = 1.41 min.

[0233] Synthesis of tert-butyl 2-(4-formyl-2-methylphenoxy)acetate: 4-Hydroxy-3- methylbenzaldehyde (300 mg, 2.20 mmol) was added to tert-butyl bromoacetate (390 pL, 2.6420 mmol) in MeCN (17.2 mL) at rt under argon. The mixture was stirred at 80 °C for 3 h. The mixture was filtered through Celite, washing with MeCN (50.0 mL), and the filtrate was concentrated to provide tert-butyl 2-(4-formyl-2-methylphenoxy)acetate as a solid (542 mg, 98%). m / z (ES+) [M]+= 250.0; GCMS (23min normal_HP5MS.amx) tR = 13.42 min.Attorney Docket No.: 104545-0096-W02

[0234] In step 2, 3-chloro-6-methyl-5,5-dioxo-l lH-benzo[c][l,2]benzothiazepin-l 1- amine (compound 3) was added to tert-butyl 2-(4-formyl-2-methylphenoxy)acetate (324 mg, 1.30 mmol), NaBH3CN (40.7 mg, 0.648 mmol) and AcOH (37.0 uL, 0.648 mmol) in MeOH (2.57 mL) at rt. The mixture was stirred at 65 °C for 16 h, and cooled to 23 °C. The pH of the5 mixture was adjusted to 2 with 12 M aq. HC1, then to 12 with 50% aq. NaOH. The mixture was concentrated, and the residue was diluted with water (10.0 mL) and DCM (10.0 mL). The aqueous phase was extracted with DCM (2 x 10.0 mL, and the combined organic extracts were washed with brine (20.0 mL) and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide racemic tert-butyl 2-[4-[[(3-chloro-6-methyl-5,5-dioxo-l lH-benzo[c][l,2]benzothiazepin-l 1- yl)amino]methyl]-2-methyl-phenoxy] acetate (compound 34) as a solid (326 mg, 93%). m / z (ES+) [M+H]+ = 543.2; UPLC (4min nedium__ A2B2_ EVO) tR = 3.04 min.

[0235] In step 3, TFA (2.20 mL, 29.1 mmol) was added to tert-butyl 2-[4-[[(3-chloro- 6-methyl-5, 5 -di oxo- HH-benzo[c][l,2]benzothi azepin- 1 l-yl)amino]methyl]-2-methyl-15 phenoxy] acetate (compound 34, 316 mg, 582 pmol) in DCM (5.57 mL) at rt. The mixture was stirred at rt for 16 h and concentrated. The residue was purified by reverse phase chromatography (Cl 8, 13 g cartridge) with water [10 mM (NH4)(HCO3)] and MeCN (0-50%), and by reverse phase chromatography (C18, 13 g cartridge) with water [10 mM (NH4)(HCO3)] and MeCN (0-20%) to provide 2-(4-(((3-chloro-6-methyl-5,5-dioxido-6,l l- dihydrodibenzo[c,f][l,2]thiazepin-l l-yl)amino)methyl)-2-methylphenoxy)acetic acid (compound 35) as a solid (70.0 mg, 25%). 1H NMR (400 MHz, DMSO-d6) 5 7.77 (d, J = 2.1 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.54 - 7.47 (m, 2H), 7.45 - 7.35 (m, 2H), 7.03 (s, 1H), 6.98 (d, J = 9.0 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.19 (s, 1H), 4.47 (s, 2H), 3.59 - 3.49 (m, 2H), 3.31 (s, 3H), 2.14 (s, 3H), two protons not observed; m / z (ES+) [M+H]+ = 487.1; HPLC25 (XCB AcN TFA QC Omin Vl) tR = 3.55 min.Attorney Docket No.: 104545-0096-W02Table 19. Compounds of Schemes 6-9Attorney Docket No.: 104545-0096-W02

Claims

1. Attorney Docket No.: 104545-0096-W02CLAIMSWhat is claimed is:5 1. A method of treating a disease, disorder or condition selected from the group consisting of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprising administering to a subject in need or at risk thereof a therapeutically effective amount of an (S)-enantiomer of 7-(3-chloro-6-methyl-5,5-dioxido-6,l l- dihydrodibenzo[c,f][l,2]thiazepin-l l-ylamino)heptanoic acid ((S)-enantiomer of tianeptine) of the general Formula (la), the zwitterion thereof of Formula (lb), a cocrystal of the (S)-enantiomer, or a pharmaceutically acceptable salt of the (S)- enantiomer, or an ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or an amide of the (S)-enantiomer or a pharmaceutically acceptable salt15 thereof, or a pharmaceutical composition comprising any of them, wherein the (S)- enantiomer, the zwitterion of the (S)-enantiomer, co-crystal of the (S)-enantiomer or pharmaceutically acceptable salt of the (S)-enantiomer, ester of the (S)-enantiomer or pharmaceutically acceptable salt thereof, amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition of any of them is characterized by comprising < about 2% of the (R)-enantiomer of tianeptine, the zwitterion of the (R)-enantiomer, co-crystal of the (R)-enantiomer or pharmaceutically acceptable salt of the (R)-enantiomer, ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, amide of the (R)-enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition of any of25 them:Formula (la) Formula (lb).Attorney Docket No.: 104545-0096-W022. The method according to claim 1, wherein the (S)-enantiomer, the zwitterion of the (S)-enantiomer, co-crystal of the (S)-enantiomer or pharmaceutically acceptable salt of the (S)-enantiomer, ester of the (S)-enantiomer or pharmaceutically acceptable salt5 thereof, amide of the (S)-enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising any of them is characterized by comprising < about 0.1% of the (R)-enantiomer of tianeptine, the zwitterion thereof, co-crystal of the (R)-enantiomer or pharmaceutically acceptable salt of the (R)-enantiomer, ester of the (R)-enantiomer or pharmaceutically acceptable salt thereof, amide of the (R)-10 enantiomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any of them.

3. The method according to claim 1 or 2, wherein the pharmaceutically acceptable salt of the (S)-enantiomer 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 polisterix, (S)-tianeptine: L-DBTA (2: 1), (S)- tianeptine sodium, (S)-tianeptine oxalate or (S)-tianeptine hemi-oxalate (2: 1).

204. The method according to claim 3, wherein the pharmaceutically acceptable salt of the (S)-enantiomer 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) or (S)- tianeptine orotate (1 : 1).

5. The method according to claim 3, wherein the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine camphorsulfonate (1 : 1), (S)-tianeptine N-acetyl-L- tyrosinate (1 : 1) or (S)-tianeptine polisterix.

306. The method according to claim 3, wherein the pharmaceutically acceptable salt of the (S)-enantiomer is (S)-tianeptine hemi-oxalate (2: 1).Attorney Docket No.: 104545-0096-W027. The method according to claim 1 or 2, wherein the co-crystal of the (S)-enantiomer comprises the (S)-enantiomer or the zwitterion thereof in a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid.5 8. The method according to claim 7, wherein the complex comprises a 1 : 1, 1 :2, or 2: 1 ratio of the (S)-enantiomer or the zwitterion thereof and L-tyrosine, L-tryptophan, L- phenylalanine, or another L-amino acid.

9. The method according to claim 7 or 8, wherein the co-crystal comprises an inorganic10 monoacid salt of the (S)-enantiomer and a zwitterion of the L-amino acid.

10. The method according to claim 7 or 8, wherein the co-crystal comprises an inorganic monoacid salt of the L-amino acid and the zwitterion of the (S)-enantiomer.

11. The method according to claim 9 or 10, wherein the inorganic monoacid is hydrochloric acid (HC1).

12. The method according to claim 1 or 2, wherein the ester of the (S)-enantiomer is the methyl ester of the (S)-enantiomer, the ethyl ester of the (S)-enantiomer, or another20 Ci-Ce alkyl ester of the (S)-enantiomer or a pharmaceutically acceptable salt of any of them.

13. The method according to claim 1 or 2, wherein the amide of the (S)-enantiomer is a simple amide or a Ci-Ce alkyl amide optionally substituted with at least one hydroxyl or a pharmaceutically acceptable salt of either.

14. A method of treating a disease, disorder or condition selected from the group consisting of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprising30 administering to a subject in need or at risk thereof a therapeutically effective amount of an (S)-enantiomer of deuterated 7-((3-chloro-6-methyl-5,5-dioxido-6,l l- dihydrodibenzo[c,f][l,2]thiazepin-l l-yl-l l-d)amino) heptanoic acid (l l-D-(S)- enantiomer of tianeptine) of the general Formula (Ila), the zwitterion thereof of Formula (lib), a co-crystal of the 1 l-D-(S)-enantiomer, or pharmaceuticallyAttorney Docket No.: 104545-0096-W02 acceptable salt of the 1 l-D-(S)-enantiomer, or an ester of the 1 l-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or an amide of the 1 l-D-(S)-enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of them, wherein the 1 l-D-(S)-enantiomer, the zwitterion of the 11-5 D-(S)-enantiomer, co-crystal of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer, ester of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, amide of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition of any of them is characterized by comprising < about 2% of the 1 l-D-(R)-enantiomer of tianeptine, the zwitterion of the 1 l-D-(R)-enantiomer, co-crystal of the 1 l-D-(R)- enantiomer or pharmaceutically acceptable salt of the 1 l-D-(R)-enantiomer, ester of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof, amide of the 11- D-(R)-enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition of any of them:15Formula (Ila)15. The method according to claim 14, wherein the 1 l-D-(S)-enantiomer, the zwitterion of the 1 l-D-(S)-enantiomer, co-crystal of the 1 l-D-(S)-enantiomer or pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer, ester of the 1 l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof, amide of the 1 l-D-(S)- enantiomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising any of them is characterized by comprising < about 0.1% of the 1 l-D-(R)-enantiomer of tianeptine, the zwitterion thereof, co-crystal of the 11-D- (R)-enantiomer or pharmaceutically acceptable salt of the 1 l-D-(R)-enantiomer, ester25 of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof, amide of the 1 l-D-(R)-enantiomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any of them.Attorney Docket No.: 104545-0096-W0216. The method according to claim 14 or 15, wherein the 1 l-D-(S)-enantiomer or the zwitterion thereof or the pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer is characterized by reduced racemization at position 11 as compared to the (S)- enantiomer of tianeptine or the zwitterion or a pharmaceutically acceptable salt of that5 enantiomer.

17. The method according to any one of claims 14-16, wherein the 1 l-D-(S)-enantiomer, the zwitterion thereof or a pharmaceutically acceptable salt of the 1 l-D-(S)- enantiomer is further deuterated at at least one of the 3 ’positions, and optionally10 deuterated at other positions on the aminoheptanoic side chain.

18. The method according to claim 17, wherein the 1 l-D-(S)-enantiomer is the (S)- enantiomer of 3’, 3', 4', 4’, 11- pentadeuterotianeptine of Formula (Illa) or the zwitterion thereof of Formula (Illb); the (S)-enantiomer of 2', 2', 3', 3', 4', 4', 5’, 5', 6', 6', 7', 7', 11 -tridecadeuterotianeptine of the general Formula (IVa) or the zwitterion thereof of Formula (IVb); the (S)-enantiomer of 3', 3', 4', 4', tetradeuterotianeptine of Formula (Va) or the zwitterion thereof of Formula (Vb); or the (S)-enantiomer of 2', 2', 3', 3', 4', 4', 5', 5', 6', 6', 7', 7', dodecadeuterotianeptine of the general formula (Via) or the zwitterion thereof of Formula (VIb):20Formula (Illa) Formula (IITb) Formula (IVa) Formula (IVb)Attorney Docket No.: 104545-0096-W025 19. The method according to any one of claims 14-16, wherein the pharmaceutically acceptable salt of the 1 l-D-(S)-enantiomer is 1 l-D-(S)-tianeptine benzenesulfonate (1:1), 1 l-D-(S)-tianeptine fumarate (1:1), 1 l-D-(S)-tianeptine fumarate (2:1), 11-D- (S)-tianeptine hippurate (1:1), 1 l-D-(S)-tianeptine maleate (1:1), 1 l-D-(S)-tianeptine maleate (2:1), 11 -D-(S)-tianeptine p-toluenesulfonate (1:1), ll-D-(S)-tianeptine orotate (1 : 1), 1 l-D-(S)-tianeptine camphorsulfonate (1 : 1), 1 l-D-(S)-tianeptine N- acetyl-L-tyrosinate (1:1), ll-D-(S)-tianeptine polisterix, 1 l-D-(S)-tianeptine: L- DBTA (2:1), H-D-(S)-tianeptine sodium, 1 l-D-(S)-tianeptine oxalate or ll-D-(S)- tianeptine hemi-oxalate (2:1).15 20. The method according to claim 19, wherein the pharmaceutically acceptable salt of the ll-D-(S)-enantiomer is 1 l-D-(S)-tianeptine benzenesulfonate (1:1), ll-D-(S)- tianeptine fumarate (1:1), ll-D-(S)-tianeptine fumarate (2:1), ll-D-(S)-tianeptine hippurate (1 : 1), 1 l-D-(S)-tianeptine maleate (1 : 1), 1 l-D-(S)-tianeptine maleate (2:1), ll-D-(S)-tianeptine p-toluenesulfonate (1:1) or ll-D-(S)-tianeptine orotate (1:1).

21. The method according to claim 19, wherein the pharmaceutically acceptable salt of the ll-D-(S)-enantiomer is 1 l-D-(S)-tianeptine camphorsulfonate (1:1), ll-D-(S)- tianeptine N-acetyl-L-tyrosinate (1:1) or 1 l-D-(S)-tianeptine polisterix.25 22. The method according to claim 19, wherein the pharmaceutically acceptable salt of the ll-D-(S)-enantiomer is 1 l-D-(S)-tianeptine hemi-oxalate (2:1).132Attorney Docket No.: 104545-0096-W0223. The method according to claim 14 or 15, wherein the co-crystal of the 1 l-D-(S)- enantiomer comprises the 1 l-D-(S)-enantiomer or the zwitterion thereof in a complex with L-tyrosine, L-tryptophan, L-phenylalanine, or another L-amino acid.5 24. The method according to claim 23, wherein the complex comprises a 1 : 1, 1 :2, or 2: 1 ratio of the 1 l-D-(S)-enantiomer or the zwitterion thereof and L-tyrosine, L- tryptophan, L-phenylalanine, or another L-amino acid.

25. The method according to claim 23 or 24, wherein the co-crystal comprises an10 inorganic monoacid salt of the 1 l-D-(S)-enantiomer and a zwitterion of the L-amino acid.

26. The method according to claim 23 or 24, wherein the co-crystal comprises an inorganic monoacid salt of the L-amino acid and the zwitterion of the 1 l-D-(S)- enantiomer.

27. The method according to claim 25 or 26, wherein the inorganic monoacid is hydrochloric acid (HC1).20 28. The method according to claim 14 or 15, wherein the ester of the 1 l-D-(S)- enantiomer is the methyl ester of the 1 l-D-(S)-enantiomer, the ethyl ester of the 11-D- (S)-enantiomer, or another Ci-Ce alkyl ester of the 1 l-D-(S)-enantiomer or a pharmaceutically acceptable salt of any of them.

29. The method according to claim 14 or 15, wherein the amide of the (S)-enantiomer is a simple amide or a Ci-Ce alkyl amide optionally substituted with at least one hydroxyl or a pharmaceutically acceptable salt of either.

30. A method of treating a disease, disorder or condition selected from the group30 consisting of post-concussive syndrome, nociplastic pain syndrome and chronic overlapping pain conditions or one or more associated symptoms thereof comprising administering to a subject in need or at risk thereof a therapeutically effective amount of N-hydroxy -tianeptine of the Formula (XV), the (S)-enantiomer of N-hydroxy- tianeptine of the Formula (XVI), the (R)-enantiomer of N-hydroxy-tianeptine of the133Attorney Docket No.: 104545-0096-W02Formula (XVII), N-nitroso-tianeptine of the Formula (XVIII), the (S)-enantiomer of N-nitroso-tianeptine of the Formula (XIX), the (R)-enantiomer of N-nitroso-tianeptine of the Formula (XX), an aryl substituted tianeptine analog, a pharmaceutically acceptable salt of any of them or a pharmaceutical composition comprising any of5 them:

31. The method according to claim 30, wherein the (S)-enantiomer of N-hydroxy - tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or the pharmaceutically acceptable salts thereof are characterized by comprising < about 2% of the (R)-15 enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy -tianeptine or (R)-enantiomer of N-nitroso-tianeptine.134Attorney Docket No.: 104545-0096-W0232. The method according to claim 31, wherein the (S)-enantiomer of N-hydroxy- tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or the pharmaceutically acceptable salts thereof are characterized by comprising < about 0.1% of the (R)- enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or a5 pharmaceutically acceptable salt of the (R)-enantiomer of N-hydroxy -tianeptine or(R)-enantiomer of N-nitroso-tianeptine.

33. The method according to claim 30, wherein the (R)-enantiomer of N-hydroxy - tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or the pharmaceutically10 acceptable salts thereof are characterized by comprising < about 2% of the (S)- enantiomer of N-hydroxy -tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxy -tianeptine or(S)-enantiomer of N-nitroso-tianeptine.

34. The method according to claim 33, wherein the (R)-enantiomer of N-hydroxy- tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, or the pharmaceutically acceptable salts thereof are characterized by comprising < about 0.1% of the (S)- enantiomer of N-hydroxy -tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, or a pharmaceutically acceptable salt of the (S)-enantiomer of N-hydroxy -tianeptine or20 (S)-enantiomer of N-nitroso-tianeptine.

35. The method according to claim 30, wherein the aryl substituted tianeptine derivative is 7-((3-(furan-2-yl)-6-methyl-5,5-dioxido-6,l l-dihydrodibenzo[c,f][l,2]thiazepin-l l- yl)amino)heptanoic acid of Formula (XXI), 7-((3-(furan-3-yl)-6-methyl-5,5-dioxido-6,1 l-dihydrodibenzo[c,f][l,2]thiazepin-l l-yl)amino)heptanoic acid of Formula(XXII), 7-((6-methyl-5,5-dioxido-3-(thiophen-3-yl)-6,l l- dihydrodibenzo[c,f|[l,2]thiazepin-l l-yl)amino)heptanoic acid of Formula (XXIII) or 2-(4-(((3-chloro-6-methyl-5,5-dioxido-6,l l-dihydrodibenzo[c,f][l,2]thiazepin-l l- yl)amino)methyl)-2-methylphenoxy)acetic acid of Formula (XXIV):30Attorney Docket No.: 104545-0096-W02Formula (XXI) Formula (XXII)Formula (XXIII) Formula (XXIV).

536. The method according to any one of claims 1, 2, 14, 15 and 30, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent, or excipient.10 37. The method according to claim 36, wherein the pharmaceutical composition is in the form of a tablet, a thin film, a powder, a caplet, a capsule, a soft gel, a suppository, a nasal spray, an oral spray or a lung spray.

38. The method according to claim 36 or 37, wherein the pharmaceutical composition is formulated for immediate release, controlled release, sustained release, extended release, or slow release of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the zwitterion of the (S)-enantiomer or the l l-D-(S)-enantiomer, or the N-hydroxy -tianeptine, the (S)-enantiomer ofN-20 hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, the N-nitroso- tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N- nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them.

39. The method according to claim 38, wherein the pharmaceutical composition is formulated for controlled release of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a cocrystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the zwitterion of the (S)- enantiomer or the l l-D-(S)-enantiomer, or the N-hydroxy-tianeptine, the (S)-30 enantiomer of N-hydroxy-tianeptine, the (R)-enantiomer of N-hydroxy-tianeptine, the136Attorney Docket No.: 104545-0096-W02N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them.5 40. The method according to any one of claims 1-39, wherein the (S)-enantiomer or the1 l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy - tianeptine, the (S)-enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N-10 hydroxy -tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso- tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical composition is administered one or more times daily.

41. The method according to claim 40, wherein the (S)-enantiomer or the 1 l-D-(S)- enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer, or the 1 l-D-(S)-enantiomer or the zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy -tianeptine, the (S)- enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N-hydroxy -tianeptine, the20 N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical composition is administered once daily.

42. The method according to any one of claims 1-42, wherein the (S)-enantiomer or the1 l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy - tianeptine, the (S)-enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N-30 hydroxy -tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso- tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical composition is administered parenterally, orally, sublingually, buccally, inhalationally, palatially, transdermally, rectally, or vaginally.137Attorney Docket No.: 104545-0096-W0243. The method according to claim 42, wherein the (S)-enantiomer or the 1 l-D-(S)- enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the zwitterion5 of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy -tianeptine, the (S)- enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N-hydroxy -tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical composition is administered10 orally.

44. The method according to claim 42, wherein the (S)-enantiomer or the 1 l-D-(S)- enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy -tianeptine, the (S)- enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N-hydroxy -tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso-tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical composition is administered20 inhalationally.

45. The method according to any one of claims 1-44, wherein the (S)-enantiomer or the1 l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer or the zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy - tianeptine, the (S)-enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N- hydroxy -tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso- tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical30 composition is administered sequentially or concurrently with one or more additional therapeutic agents selected from the group consisting of an antidepressant, an anticonvulsant, an anti-anxiety agent, an antipsychotic agent, a cholinesterase inhibitor, an N-methyl-D-aspartate (NMD A) receptor antagonist, a 5HT2 modulator, a corticosteroid, an anti-amyloid agent, an anti-tau agent and a chemotherapeutic agent.138Attorney Docket No.: 104545-0096-W0246. The method according to any one of claims 1-45, wherein the (S)-enantiomer or the1 l-D-(S)-enantiomer, an ester or an amide of either, or a pharmaceutically acceptable salt of any of them, or a co-crystal of the (S)-enantiomer or the 1 l-D-(S)-enantiomer or the5 zwitterion of the (S)-enantiomer or the 1 l-D-(S)-enantiomer, or the N-hydroxy- tianeptine, the (S)-enantiomer of N-hydroxy -tianeptine, the (R)-enantiomer of N- hydroxy -tianeptine, the N-nitroso-tianeptine, the (S)-enantiomer of N-nitroso- tianeptine, the (R)-enantiomer of N-nitroso-tianeptine, an aryl substituted tianeptine analog, or a pharmaceutically acceptable salt of any of them or the pharmaceutical10 composition is administered as part of a treatment regime also including psychotherapeutic intervention.

47. The method according to any one of claims 1-46, wherein the disease, disorder or condition is post-concussive syndrome.

48. The method according to any one of claims 1-46, wherein the disease, disorder or condition is nociplastic syndrome.

49. The method according to any one of claims 1-46, wherein the disease, disorder or20 condition is a chronic overlapping pain condition.

50. The method according to claim 1 or 2, wherein the pharmaceutically acceptable salt of the (S)-enantiomer of tianeptine is a crystalline hemi-oxalate salt of (S)-tianeptine which exhibits an X-ray diffraction pattern (XRPD) comprising at least one peak selected from the group consisting of 8.5, 20.6, 21.0 and 24.2 degrees 20 ±0.3 degrees 20.

51. The method according to claim 50, wherein the crystalline (S)-tianeptine hemi-oxalate salt exhibits an XRPD pattern further comprising at least one peak selected from the30 group consisting of 12.1, 13.3, 16.1, 18.9, 19.1, 22.0 and 22.4 degrees 20 ±0.3 degrees 20.

52. The method according to claim 1 or 2, wherein the (S)-enantiomer of tianeptine is a crystalline free acid / free base of (S)-tianeptine which exhibits an X-ray diffractionAttorney Docket No.: 104545-0096-W02 pattern (XRPD) comprising at least one peak selected from the group consisting of 10.6, 13.0, 21.1 and 23.7 degrees 20 ±0.3 degrees 20.

53. The method according to claim 52, wherein the crystalline free acid / free base of (S)-5 tianeptine exhibits an XRPD pattern further comprising at least one peak selected from the group consisting of 8.7, 9.1, 12.6, 18.1, 20.4, 23.0 and 26.1 degrees 20 ±0.3 degrees 20.

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