1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment

• US 9,861,630 B1
• Filed: 08/10/2017
• Issued: 01/09/2018
• Est. Priority Date: 06/16/2006
• Status: Active Grant

• Current Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Original Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Inventors: Faldt, Andr, Lopez de Diego, Heidi, Holm, Rene
• Primary Examiner(s): Rao, Savitha M
• Assistant Examiner(s): Polansky, Gregg
• Application Number:
  US15/674,043
• Publication Number:
  US 20170360777A1
• Time in Patent Office: 152 Days
• Field of Search: None
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: 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
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 25/34 : Tobacco-abuse
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 295/096 : with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
• CPC Class Codes: Y10T 428/2982 : Particulate matter [e.g., sphere, flake, etc.]

Abstract

1-[2-(2,4-dimethylphenylsulphanyl)phenyl)]piperazine exhibits potent activity on SERT, 5-HT₃ and 5-HT_1A and may as such be useful for the treatment of cognitive impairment, especially in depressed patients.

Claims

1. A method of alleviating a symptom or complication of depression or major depressive disorder, or delaying progression of depression or major depressive disorder, comprising:

administering to a patient in need thereof a pharmaceutical composition comprising a hydrobromide salt of a 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine selected from the group consisting of

1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form,

1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form,

1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form,

1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate,

1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt ethyl acetate solvate, and mixtures thereof,

wherein said method alleviates a symptom or complication of depression or major depressive disorder, or delays the progression of depression or major depressive disorder, in said patient.

2. The method of claim 1, wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form.

3. The method of claim 2, wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form characterized by an XRPD pattern as shown in FIG. 2.

4. The method of claim 2, wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form is characterized by XRPD peaks at 5.85, 9.30, 17.49, and 18.58+/−

0.10°

2θ

.

5. The method of claim 1, wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form.

6. The method of claim 5, wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form characterized by an XRPD pattern as shown in FIG. 3.

7. The method of claim 5, wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form is characterized by XRPD peaks at 6.89, 9.73, 13.78, and 14.62+/−

0.10°

2θ

.

8. The method of claim 1, wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form.

9. The method of claim 8, wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form characterized by an XRPD pattern as shown in FIG. 4.

10. The method of claim 8, wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form is characterized by XRPD peaks at 11.82, 16.01, 17.22, and 18.84+/−

0.10°

2θ

.

11. The method of claim 1, wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate.

12. The method of claim 11, wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate characterized by an XRPD pattern as shown in FIG. 5.

13. The method of claim 11, wherein the 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate is characterized by XRPD peaks at 10.69, 11.66, 15.40, and 17.86+/−

0.10°

2θ

.

14. The method of claim 1, wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt ethyl acetate solvate.

15. The method of claim 14, wherein the 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine hydrobromide ethyl acetate solvate is characterized by XRPD peaks at 8.29, 13.01, 13.39, and 16.62+/−

0.10°

2θ

.

16. The method of claim 1, wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is a mixture of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt ethyl acetate solvate and 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form characterized by an XRPD pattern as shown in FIG. 6.