Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT 2A serotonin receptor

• US 8,481,535 B2
• Filed: 05/17/2007
• Issued: 07/09/2013
• Est. Priority Date: 05/18/2006
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated
• Original Assignee: Arena Pharmaceuticals Incorporated
• Inventors: Gharbaoui, Tawfik, Sengupta, Dipanjan, Krishnan, Ashwin M., Hart, Ryan M., Macias, Mark, Lally, Edward A., Duffield, Jonathan, Shah, Nainesh
• Primary Examiner(s): Anderson, Rebecca
• Assistant Examiner(s): Otton, Alicia L
• Application Number:
  US12/301,212
• Publication Number:
  US 20100234380A1
• Time in Patent Office: 2,245 Days
• Field of Search: None
• US Class Current: 514/236.5
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

The present invention relates to processes for preparing phenyl-pyrazoles of Formula (I) and salts and pharmaceutical compositions thereof, useful as modulators of 5-HT_2A serotonin receptor activity. The present invention also relates to intermediates used in the processes, and their preparation. The present invention also relates to crystalline forms of 5-HT_2A serotonin receptor modulators, compositions thereof and methods of using the same.

Claims

1. A process for preparing a compound of Formula (I):

2. The process of claim 1, wherein R¹ is methoxy and X is O.

3. The process according to claim 1, wherein said trisubstituted phosphine is triphenylphosphine.

4. The process according to claim 1, wherein R^a and R^b are each, independently, C₁-C₄ alkyl.

5. The process according to claim 4, wherein R^a and R^b are both prop-2-yl.

6. The process according to claim 1, wherein said reacting is carried out at a temperature of about −

50 °

C. to about 75 °

C.

7. The process according to claim 6, wherein said reacting is carried out at a temperature of about 0 °

C. to about 25 °

C.

8. The process according to claim 1, wherein said reacting is carried out in an ether-forming solvent.

9. The process according claim 8, wherein said ether-forming solvent comprises tetrahydrofuran.

10. The process according to claim 1, wherein the molar ratio of said compound of Formula (A) to said compound of Formula (II) is about 4:

1 to about 1;

1.

11. The process according to claim 10, wherein the molar ratio of said compound of Formula (A) to said compound of Formula (II) is about 1.6:

1 to about 1.4;

1.

12. The process according to claim 1, wherein the molar ratio of said trisubstituted phosphine to said compound of Formula (II) is about 4:

1 to about 1;

1.

13. The process according to claim 12, wherein the molar ratio of said trisubstituted phosphine to said compound of Formula (II) is about 1.6:

1 to about 1.4;

1.

14. The process according to claim 1, wherein the molar ratio of said compound of Formula (A) to said trisubstituted phosphine is about 1:

1.

15. The process according to claim 1, wherein the molar ratio of said compound of Formula (III) to said compound of Formula (II) is about 2.5:

1 to about 0.5;

1.

16. The process according to claim 15, wherein the molar ratio of said compound of Formula (III) to said compound of Formula (II) is about 2:

1 to about 1;

1.

17. The process according to claim 1, wherein said compound of Formula (II) is prepared by the method comprising reacting a compound of Formula (IV):

18. The process according to claim 17, wherein said compound of Formula (V) or a salt thereof is prepared by the method comprising reacting a compound of Formula (VI):

19. The process according to claim 18, wherein said compound of Formula (VI) is prepared by the method comprising reacting a compound of Formula (VII):

20. The process according to claim 18, wherein said compound of Formula (VI) is prepared by the method comprising reacting a compound of Formula (VIII):

21. The process according to claim 18, wherein said compound of Formula (VI) is prepared by the method comprising reacting a compound of Formula (XIV):

22. The process according to claim 21, wherein said compound of Formula (XIV) is prepared by the method comprising reacting a compound of Formula (XV):

23. A process for preparing a salt of a compound of Formula (I):

24. The process of claim 23, wherein R¹ is methoxy and X is O.

25. The process according to claim 24, wherein said reacting is carried out in a salt-forming solvent.

26. The process according to claim 25, wherein said salt-forming solvent comprises isopropanol.

27. The process according to claim 25, wherein said salt-forming solvent comprises ethanol.

28. The process according to claim 23, wherein said reacting is carried out at a temperature of about −

10 °

C. to about reflux temperature.

29. The process according to claim 28, wherein said reacting is carried out at a temperature of about 20 °

C. to about 80 °

C.

30. The process according to claim 23, wherein said salt-forming acid is hydrochloric acid.

31. The process according to claim 23, wherein said salt is a hydrochloride salt.

32. The process according to claim 23, wherein said salt-forming acid is oxalic acid.