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 8,722,684 B2
• Filed: 06/15/2007
• Issued: 05/13/2014
• 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: Bang-Andersen, Benny, Faldt, Andre, Mork, Arne, Lopez de Diego, Heidi, Holm, Rene, Stensbol, Tine Bryan, Moore, Nicholas
• Primary Examiner(s): Rao, Savitha
• Assistant Examiner(s): Polansky, Gregg
• Application Number:
  US12/301,061
• Publication Number:
  US 20100297240A1
• Time in Patent Office: 2,524 Days
• Field of Search: None
• US Class Current: 514/255.03
• 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. Compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof in a crystalline form characterized by an XRPD pattern as shown in any of FIGS. 1-17.

2. Compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt in a crystalline form which is characterized by XRPD reflections at 6.89, 9.73, 13.78 and 14.64 +/−

0.10°

2θ

.

3. The compound according to claim 2 wherein said crystalline form is characterized by an XRPD as shown in FIG. 3.

4. The compound according to claim 2, which compound has a particle size distribution corresponding to

D98%:

650-680 μ

m;

D50%;

230-250 μ

m; and

D5%;

40-60 μ

m;

D98%;

370-390 μ

m;

D50%;

100-120 μ

m; and

D5%;

5-15 μ

m;

D98%;

100-125 μ

m;

D50%;

15-25 μ

m; and

D5%;

1-3 μ

m;

or

D98%;

50-70 μ

m;

D50%;

3-7 μ

m; and

D5%;

0.5-2 μ

m.

5. A composition comprising a compound according to claim 2 and a pharmaceutically acceptable excipient.

6. The composition according to claim 5, said composition being a tablet prepared by wet granulation and comprising anhydrous calcium hydrogen phosphate, corn starch, PVP-VA copolymer, microcrystalline cellulose, sodium starch glycolate, talc and magnesium stearate.

7. The composition according to claim 6 comprising

8. The composition according to claim 6 comprising