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 20100297240A1
• Filed: 06/15/2007
• Published: 11/25/2010
• 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: Moore, Nicholas, Faldt, Andre, Brodersen, Jorgen, Mork, Arne, Mealy, Michael J., Ringgaard, Lone Munch, Stensbol, Tine Bryan, Bang-Andersen, Benny, Jorgensen, Morten, Rock, Michael Harold, Holm, Rene, Lopez De Diego, Heidi
• Granted Patent: US 8,722,684 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• 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. 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine and pharmaceutically acceptable salts thereof, provided said compound is not the free base in a non-crystalline form.

2. A compound according to claim 1, which compound is the hydrobromide, hydrochloride, mesylate, fumerate, maleate, meso-tatrate, L-(+)-tatrate, D-(−

)-tatrate, sulphate, phosphate or nitrate salt.

3. The compound according to claim 1, which compound is crystalline.

4. The compound according to claim 3, which compound has an XRDP as shown in any of FIGS. 1-17.

5. The compound according to claim 1 which is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt in a crystalline form.

6. The compound according to claim 5, which compound has XRPD reflections at approximately 6.89, 9.73, 13.78 and 14.64 (°

2θ

)

7. The compound according to claim 5, which compound has an XRDP as shown in FIG. 3.

8. The compound according to claim 6, 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;

d50%;

100-120 μ

m;

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.

10. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable excipient.

11. The composition according to claim 10 comprising a compound according to claim 5 or 6.

12. The composition according to claim 10, 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.

13. The composition according to claim 12 comprising

14. The composition according to claim 12 comprising

15. A method of treating a disease selected from affective disorders, depression, major depressive disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer'"'"'s disease, psychosis, cancer, age or Parkinson'"'"'s disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia, stress urinary incontinence, emesis, IBS, eating disorders, chronic pain, partial responders, treatment resistant depression, Alzheimer'"'"'s disease, cognitive impairment, ADHD, melancholia, PTSD, hot flushes, sleep apnoea, alcohol, nicotine or carbohydrate craving, substance abuse and alcohol or drug abuse, the method comprising administering a therapeutically effective amount of a compound according to any of claims 1-8 to patient in need thereof.

17. A compound according to claim 1 for use in the treatment of a disease selected from affective disorders, depression, major depressive disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer'"'"'s disease, psychosis, cancer, age or Parkinson'"'"'s disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia, stress urinary incontinence, emesis, IBS, eating disorders, chronic pain, partial responders, treatment resistant depression, Alzheimer'"'"'s disease, cognitive impairment, ADHD, melancholia, PTSD, hot flushes, sleep apnea, alcohol, nicotine or carbohydrate craving, substance abuse and alcohol or drug abuse.

9. (canceled)

16. (canceled)

18. A process for the preparation of

19. The process according to claim 18, wherein compound II and compound III are reacted in a first reaction, and wherein the reaction product

20. The process according to claim 18, wherein compound II, compound III and compound IV are mixed together at the start of the process.

21. The process according to claim 18 wherein X₁ and X₂ independently represent Br or I.

22. The process according to claim 21, wherein X₁ represents Br and X₂ represents I.

23. The process according to claim 18, wherein said solvent is an aprotic solvent.

24. The process according to claim 18, wherein the solvent in selected from toluene, xylene, triethyl amine, tributyl amine, dioxin or N-methylpyrrolidone.

25. The process according to claim 24, wherein the solvent is toluene.

26. The process according to claim 18, wherein the palladium source is selected from Pddba₂, Pd(OAc)₂ and Pd₂ dba₃.

27. The process according to claim 26, wherein said palladium source is Pddba₂ or Pd₂ dba₃.

28. The process according to claim 18, wherein said phosphine ligand is selected from

2,2′

-bis-diphenylphosphanyl-[1,1′

]binaphtalenyl(rac-BINAP),

1,1′

-bis(diphenylphosphino)ferrocene (DPPF),

bis-(2-diphenylphosphinophenyl)ether (DPEphos),

tri-t-butyl phsophine (Fu'"'"'s salt),

biphenyl-2-yl-di-t-butyl-phosphine,

biphenyl-2-yl-dicyclohexyl-phosphine,

(2′

-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine

[2′

-(di-t-butyl-phosphanyl)-biphenyl-2-yl]-dimethyl-amine, and

dicyclohexyl-(2′

,4′

,6′

-tri-propyl-biphenyl-2-yl)-phosphane.

29. The process according to claim 28, wherein said phosphine ligand is rac-BINAP.

30. The process according to claim 18, wherein said base is selected from NaO(t-Bu), KO(t-Bu), Cs₂CO₃, DBU and DABCO.

31. The process according to claim 30, wherein said base is NaO(t-Bu).

32. The process according to claim 18, wherein R represents hydrogen

33. The process according to claim 18, wherein R represents a protecting group selected from Boc, Bn, Cbz, C(═

O)Oet and Me.

34. The process according to claim 18, wherein R′

is hydrogen.

35. The process according to claim 18, wherein the temperature is between approximately 80°

C. and approximately 120°

C.

36. The process according to claim 20, comprising the steps of

a. Dissolving or dispersing 1-1.5 equivalents of compounds I, II and III in toluene to obtain mixture A;

b. Adding 1-2 mole-% of Pddba₂ and 1-2 mole-% of rac-BINAP together with 2-3 equivalents of NaO(t-Bu) to mixture A to obtain mixture B, which is heated to around 100°

C. until compound II and III are fully converted;

c. Increasing the temperature of the mixture obtained in step b to around 120°

C. until compound IV is fully converted; and

d. Optionally removing the protecting group by the addition of aqueous acid if compound IV is a protected piperazine.

37. The process according to claim 20, wherein 1-1.5 equivalents of 2,4-dimethyl-thiol, 1-bromo-1-iodo-benzene (or 1,2-dibromo-benzene), and piperazine are dispersed in toluene followed by the addition of 2-5 equivalents NaO(t-Bu) and 1-2 mole-% Pd₂ dba₃ and rac-BINAP dispersed in toluene to obtain a mixture which is heated to 100-130°

C. for 2-10 hours to obtain the product 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine.

38. The process according to claim 37, wherein said mixture is heated to reflux for 3-5 hours, and which process is followed by a subsequent step in which the obtained product is further reacted with aqueous HBr to obtain the corresponding hydrobromic acid addition salt.

39. The process according to claim 20, wherein 2-5 equivalents of NaO(t-Bu), 2-5 equivalents piperazine, 0.2-0.6 mole-% Pddba₂, and 0.6-1 mole-% rac-BINAP are dispersed in toluene to obtain mixture A′

, to which mixture approximately 1 equivalent 2-bromo-iodobenzene is added to obtain mixture B′

, to which mixture 1 equivalent 2,4-dimenthylthiophenol is added and the resulting mixture is heated to reflux for 3-7 hours to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine.

40. The process according to claim 39, wherein said resulting mixture is heated to reflux for 4-6 hours, and which process is followed by a subsequent step in which the obtained product is further reacted with aqueous HBr to obtain the corresponding hydrobromic acid addition salt.

41. The process according to claim 18 with the additional step of adding aqueous HBr to the product

42. A process for the manufacturing of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt in which process 1-1.5 equivalents of 2,4-dimethyl-thiol, 1-bromo-1-iodo-benzene (or 1,2-dibromo-benzene), and piperazine are dispersed in toluene followed by the addition of 2-5 equivalents NaO(t-Bu) and 1-2 mole-% Pd₂ dba₃ and rac-BINAP dispersed in toluene to obtain a mixture which is heated to reflux 3-5 hours to obtain the product 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, which is further reacted with aqueous hydrobromic acid.

43. A process for the manufacturing of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt in which process 2-5 equivalents of NaO(t-Bu), 2-5 equivalents piperazine, 0.2-0.6 mole-% Pddba₂, and 0.6-1 mole-% rac-BINAP are dispersed in toluene to obtain mixture A′

, to which mixture approximately 1 equivalent 2-bromo-iodobenzene is added to obtain mixture B′

, to which mixture 1 equivalent 2,4-dimenthylthiophenol is added and the resulting mixture is heated to reflux for 4-6 hours to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, which is further reacted with aqueous hydrobromic acid.