Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor

• US 9,556,149 B2
• Filed: 10/24/2014
• Issued: 01/31/2017
• Est. Priority Date: 04/02/2008
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated
• Original Assignee: Arena Pharmaceuticals Incorporated
• Inventors: Krishnan, Ashwin M., Gharbaoui, Tawfik
• Primary Examiner(s): Pagano, Alexander R
• Assistant Examiner(s): Sackey, Ebenezer O
• Application Number:
  US14/523,224
• Publication Number:
  US 20150045372A1
• Time in Patent Office: 830 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• 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: C07D 231/16 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention relates to processes for preparing pyrazole derivatives of Formula (I) and salts and pharmaceutical compositions of the salts 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 salts of compounds of Formula (I) and pharmaceutical compositions thereof.

Claims

1. A hydrochloride salt of a compound of Formula (I):

2. The hydrochloride salt according to claim 1, wherein said compound of Formula (I) is the S enantiomer.

3. The hydrochloride salt according to claim 1, wherein R¹ is chloro.

4. The hydrochloride salt according to claim 1, wherein said hydrochloride salt is (S)-2-(4-(4-chloro-1-methyl-1H-pyrazole-3-carbonyl)-3-methylpiperazin-1-yl)-1-(4-fluorophenyl)ethanone hydrochloride, represented by the following structure:

5. A pharmaceutical composition comprising the hydrochloride salt according to any one of claims 1 to 4 together with a pharmaceutically acceptable carrier.

6. A process for preparing a composition comprising admixing the hydrochloride salt according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

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

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

9. The process according to claim 8, wherein said compound of Formula (I) is the S enantiomer.

10. The process according to claim 8 or 9, wherein R¹ is chloro and R² is 1H-imidazol-1-yl.

11. The process according to claim 8 or 9, wherein said reacting a compound of Formula (II) or a salt thereof, with a compound of Formula (III) or a salt thereof is carried out in the presence of a base.

12. The process according to claim 8 or 9, wherein said reacting a compound of Formula (II) or a salt thereof, with a compound of Formula (III) or a salt thereof is carried out in the presence of a catalyst.

13. The process according to claim 8 or 9, wherein said reacting a compound of Formula (II) or a salt thereof, with a compound of Formula (III) or a salt thereof is carried out at a temperature of about 20°

C. to about reflux temperature.

14. The process according to claim 8 or 9, wherein said reacting a compound of Formula (II) or a salt thereof, with a compound of Formula (III) or a salt thereof is carried out in an amide-forming solvent.

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

16. The process according to claim 15, wherein said compound of Formula (I) is the S enantiomer.

17. The process according to claim 15 or 16, wherein said salt of a compound of Formula (I) is the hydrochloride salt.

18. The process according to claim 15 or 16, wherein R¹ is chloro.

19. The process according to claim 15 or 16, wherein said reacting said compound of Formula (I) with a salt-forming acid is carried out in a salt-forming solvent.

20. The process according to claim 15 or 16, wherein said reacting said compound of Formula (I) with a salt-forming acid is carried out at a temperature of about −

10°

C. to about reflux temperature.

21. The process according to claim 15 or 16, wherein said salt-forming acid is hydrochloric acid.