# US 10,946,027 B2 · Tianeptine oxalate salts and polymorphs

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- Number: US 10,946,027 B2
- Document ID: US10946027B2
- Status: Granted
- Kind: B2
- Application number: 16/597,065
- Filed: 2019-10-09
- Published: 2020-09-03
- Granted: 2021-03-16
- Earliest claimed: 2016-12-28
- Assignees: Tonix Pharma Holdings Limited
- Applicants: Tonix Pharma Holdings Limited
- Inventors: Stefano Luca Giaffreda; Enrico Modena; Serena Fabbroni; Michel Chiarucci; Mark T. Edgar
- Web page: https://patentgrep.com/patent/US10946027B2

## CPC

- A61K 31/554: having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 281/02: Seven-membered rings
- A61P 25/24: Antidepressants
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed herein is an oxalate salt/co-crystal (tianeptine oxalate) of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide (tianeptine) as shown in Formula I:

## Claims

### Claim 1

A pharmaceutical composition comprising an anhydrous crystalline hemi-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide (anhydrous crystalline tianeptine hemi-oxalate salt) and a pharmaceutically acceptable carrier or excipient, wherein the anhydrous crystalline tianeptine hemi-oxalate salt is characterized by an X-ray diffraction pattern (XRPD) comprising at least one peak selected from the group consisting of 8.2, 8.6, 9.1, and 9.5 degrees 2θ±0.3 degrees 2θ.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the XRPD pattern further comprises at least one peak selected from the group consisting of 11.5, 14.2, 15.2, 15.8, 16.4, 19.2, 22.1, 23.9, 26.9, and 27.4 degrees 2θ±0.3 degrees 2θ.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in a solid form, a suspension form, or a liquid form.

### Claim 4

A pharmaceutical composition comprising an anhydrous crystalline mono-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide (anhydrous crystalline tianeptine mono-oxalate salt) and a pharmaceutically acceptable carrier or excipient, wherein the anhydrous crystalline tianeptine mono-oxalate salt is characterized by an X-ray diffraction pattern (XRPD) comprising at least one peak selected from the group consisting of 10.1 and 10.5 degrees 2θ±0.3 degrees 2θ.

### Claim 5 (depends on 4)

The pharmaceutical composition of claim 4, wherein the XRPD pattern further comprises at least one peak selected from the group consisting of 7.5, 8.3, 11.9, 14.7, 16.2, 17.9, 18.7, 21.0, 21.7, and 22.1 degrees 2θ±0.3 degrees 2θ.

### Claim 6 (depends on 4)

The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is in a solid form, a suspension form, or a liquid form.

### Claim 7

A pharmaceutical composition comprising a mixture of an anhydrous crystalline hemi-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide and an anhydrous crystalline mono-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide, and a pharmaceutically acceptable carrier or excipient, wherein the mixture is characterized by an XRPD pattern comprising at least one peak selected from the group consisting of 10.1, 10.5, 15.8, and 19.2 degrees 2θ±0.3 degrees 2θ.

### Claim 8 (depends on 7)

The pharmaceutical composition of claim 7, wherein the XRPD pattern further comprises at least one additional peak selected from the group consisting of 7.5, 8.3, 11.5, 11.9, 14.2, 14.7, 15.2, 16.2, 16.3, 16.4, 17.9, 18.7, 21.0, 21.7, 22.1, 23.9, 26.9, and 27.4 degrees 2θ±0.3 degrees 2θ.

### Claim 9 (depends on 7)

The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is in a solid form, a suspension form, or a liquid form.

### Claim 10 (depends on 1, 4)

The pharmaceutical composition of any one of claims 1, 4, and 7, wherein the pharmaceutical composition is in an extended release form.

### Claim 11 (depends on 10)

The pharmaceutical composition of claim 10, wherein the extended release form is a sustained release form, a controlled release form, or a delayed release form.

### Claim 12 (depends on 1, 4)

The pharmaceutical composition of any one of claims 1, 4, and 7, wherein the pharmaceutical composition is formulated for once daily administration.

### Claim 13 (depends on 1, 4)

The pharmaceutical composition of any one of claims 1, 4, and 7, wherein the pharmaceutical composition is suitable for oral administration.

### Claim 14 (depends on 1, 4)

The pharmaceutical composition of any one of claims 1, 4, and 7, wherein the pharmaceutical composition is osmotically active.

### Claim 15

A pharmaceutical composition comprising two or more layers, each layer comprising one or more of:
(a) an anhydrous crystalline hemi-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide (anhydrous crystalline tianeptine hemi-oxalate salt), wherein the anhydrous crystalline tianeptine hemi-oxalate salt is characterized by an X-ray diffraction pattern (XRPD) comprising at least one peak selected from the group consisting of 8.2, 8.6, 9.1, and 9.5 degrees 2θ±0.3 degrees 2θ;
(b) an anhydrous crystalline mono-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide (anhydrous crystalline tianeptine mono-oxalate salt), wherein the anhydrous crystalline tianeptine mono-oxalate salt is characterized by an X-ray diffraction pattern (XRPD) comprising at least one peak selected from the group consisting of 10.1 and 10.5 degrees 2θ±0.3 degrees 2θ; or
(c) a mixture of (a) and (b);
wherein one layer is substantially released prior to the substantial release of another layer in vivo.

### Claim 16 (depends on 1, 4, 7)

A method of treating: (a) a psychiatric disorder induced by corticosteroid treatment, (b) asthma, or (c) chronic obstructive pulmonary disorder, in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of any one of claims 1, 4, 7, and 15.

### Claim 17

A method of producing an anhydrous crystalline hemi-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide, said method comprising the following steps:
(a) preparing a mixture of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide free base and oxalic acid in acetone;
(b) heating the mixture of step (a) to about 40° C. 60° C. to afford a solution;
(c) cooling the solution of step (b) to about 25° C. to form a precipitate comprising the anhydrous crystalline hemi-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide; and
(d) recovering the precipitate of step (c) to afford the anhydrous crystalline hemi-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide.

### Claim 18

A method of producing a mixture of an anhydrous crystalline hemi-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide and an anhydrous crystalline mono-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide, said method comprising the following steps:
(a) dissolving (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide free base in acetone to afford solution A;
(b) heating solution A to reflux;
(c) adding oxalic acid to the refluxing solution A of step (b) to afford solution B;
(d) cooling solution B to about 40° C. 60° C. to form a precipitate comprising the mixture of the anhydrous crystalline hemi-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide and the anhydrous crystalline mono-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide; and
(e) recovering the precipitate of step (d) to afford the mixture of the anhydrous crystalline hemi-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide and the anhydrous crystalline mono-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide.

### Claim 19

A method of producing an anhydrous crystalline mono-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide, said method comprising the following steps:
(a) dissolving (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide free base in ethyl acetate to afford a mixture;
(b) heating the mixture of step (a) to about 40° C. −60° C. to afford a solution;
(c) cooling the solution of step (b) to about 25° C. to afford solution A;
(d) dissolving oxalic acid in ethyl acetate to afford solution B;
(e) adding solution B to solution A at about 25° C. to form a precipitate comprising the anhydrous crystalline mono-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide; and
(f) recovering the precipitate of step (e) to afford the anhydrous crystalline mono-oxalate salt of (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f] [1,2]thiazepin-11-ylamino)heptanoic acid S,S-dioxide.

### Claim 20 (depends on 16)

The method of claim 16, wherein the psychiatric disorder induced by corticosteroid treatment is a trauma- and stressor-related disorder, a depressive disorder, a neurodegenerative disorder, or a neurodevelopmental disorder.

### Claim 21 (depends on 20)

The method of claim 20, wherein the trauma- and stressor-related disorder is post-traumatic stress disorder (PTSD) or acute stress disorder (ASD); the depressive disorder is a major depressive disorder, a persistent depressive disorder, a bipolar depression, or a premenstrual dysphoric disorder; the neurodegenerative disorder is Alzheimer's disease or a multi-infarct dementia; or the neurodevelopmental disorder is an attention-deficit/hyperactivity disorder (ADHD).