Pyrazole derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto

Patent metadata

Field	Value
Publication number	US-2017320831-A1
Application number	US-201715657896-A
Country	US
Kind code	A1
Filing date	Jul 24, 2017
Priority date	Oct 3, 2006
Publication date	Nov 9, 2017
Grant date	—

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.

First claim

1 - 80 . (canceled)

81 . 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.

82 . The method according to claim 81 , wherein said 5-HT 2A mediated disorder is selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation.

83 . 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.

84 . The method according to claim 83 , wherein said sleep disorder is a dyssomnia.

85 . The method according to claim 83 , wherein said sleep disorder is insomnia.

86 . The method according to claim 83 , wherein said sleep disorder is a parasomnia.

87 . 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.

88 . 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.

89 . 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.

90 . 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.

91 . The method of claim 90 , wherein the agitation is due to a psychiatric disorder other than dementia.

92 . 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.

93 . The method of claim 92 , wherein the dementia is due to a degenerative disease of the nervous system.

94 . The method of claim 92 , 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.

95 . 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.

96 . 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.

97 . 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.

98 . 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.

99 . A method for reducing the risk o

Assignees

• Arena Pharm Inc

Inventors

• Xiong Yifeng
• Cherrier Martin C
• Choi Jin Sun Karoline
• Dosa Peter I
• Smith Brian M
• Strah-Pleynet Sonja
• Ullman Brett
• Teegarden Bradley

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/12

  Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10) · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/06

  Antiarrhythmics · CPC title