Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto

• US 10,351,531 B2
• Filed: 07/24/2017
• Issued: 07/16/2019
• Est. Priority Date: 10/03/2006
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Xiong, Yifeng, Cherrier, Martin C., Choi, Jin Sun Karoline, Dosa, Peter I., Smith, Brian M., Strah-Pleynet, Sonja, Ullman, Brett, Teegarden, Bradley
• Primary Examiner(s): Pagano, Alexander R
• Assistant Examiner(s): Sackey, Ebenezer O
• Application Number:
  US15/657,896
• Publication Number:
  US 20170320831A1
• Time in Patent Office: 722 Days
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 25/28 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 27/06 Antiglaucoma agents or miotics
• 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 31/12 Antivirals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• 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: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 231/14 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/16 : Halogen atoms or nitro radicals
• CPC Class Codes: C07D 231/54 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond

Abstract

Pyrazole derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the serotonin 5HT_2A receptor. Formula (Ia). Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of insomnia and related sleep disorders, platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, reducing the risk of blood clot formation, asthma or symptoms thereof, agitation or symptoms thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette'"'"'s syndrome, manic disorder, organic or NOS psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like. The present invention also relates to the methods for the treatment of 5-HT_2A serotonin receptor mediated disorders in combination with other pharmaceutical agents administered separately or together.

Claims

1. A method for treating a 5-HT_2A mediated disorder in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the 5-HT_2A mediated disorder is selected from the group consisting of agitation, dementia, Alzheimer'"'"'s disease, Lewy Body disease, Parkinson'"'"'s disease, Huntington'"'"'s disease, platelet aggregation, reducing the risk of blood clot formation, treating a diabetic-related disorder, treating progressive multifocal leukoencephalopathy, hypertension, pain, and sleep disorders.

2. A method for treating a sleep disorder in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

3. The method according to claim 2, wherein said sleep disorder is a dyssomnia.

4. The method according to claim 2, wherein said sleep disorder is insomnia.

5. The method according to claim 2, wherein said sleep disorder is a parasomnia.

6. A method for increasing slow wave sleep in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

7. A method for improving sleep consolidation in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

8. A method for improving sleep maintenance in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

9. A method for treating agitation an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

10. The method of claim 9, wherein the agitation is due to a psychiatric disorder other than dementia.

11. A method for the treatment of agitation or a symptom thereof in an individual in need thereof suffering from dementia comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

12. The method of claim 11, wherein the dementia is due to a degenerative disease of the nervous system.

13. The method of claim 11, wherein the dementia is selected from the group consisting of Alzheimer'"'"'s disease, Lewy Body, Parkinson'"'"'s disease, Huntington'"'"'s disease, dementia due to diseases that affect blood vessels, and any combination thereof.

14. A method of treating agitation or a symptom thereof in an individual in need thereof, where the individual is a cognitively intact elderly patient, comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

15. A method for treating a condition associated with platelet aggregation in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

16. A method for reducing the risk of blood clot formation in an angioplasty or coronary bypass surgery individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

17. A method for reducing the risk of blood clot formation in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

18. A method for reducing the risk of blood clot formation in an individual in need thereof suffering from atrial fibrillation, comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

19. A method for treating a diabetic-related disorder in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

20. A method for treating progressive multifocal leukoencephalopathy in an individual in need thereof comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

21. A method for treating hypertension in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

22. A method for treating pain in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound selected from the group consisting of 2-[4-(4-bromo-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, 2-[4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone, and 2-[(S)-4-(4-chloro-1-methyl-1-H-pyrazole-3-carbonyl)-3-methyl-piperazin-1-yl]-1-(4-fluoro-phenyl)-ethanone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.