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-9732039-B2
Application number	US-201514692807-A
Country	US
Kind code	B2
Filing date	Apr 22, 2015
Priority date	Oct 3, 2006
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

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 Ia 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

What is claimed is:

1. A method for treating a sleep disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound a compound having Formula (Ie):

or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein:
R 1 is H, halogen or C 1 -C 6 alkylaryl;
R 2 is H, C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, heteroaryl, or nitro; or
R 1 and R 2 together with the carbon atoms to which they are bonded form a C 3 -C 7 carbocyclyl;
R 3 is H, C 1 -C 6 alkyl, aryl, or aryl substituted with C 1 -C 6 alkoxy;
A and X are each —CH 2 CH 2 —, each optionally substituted with C 1 -C 3 alkyl;
J is —CH 2 CH 2 — optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C 1 -C 3 alkyl, hydroxyl, oxo and ═NO—C 1 -C 3 alkyl; and
Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkoxy, halogen and C 3 -C 7 heterocyclyl; provided that said compound is other than 1-(4-(1H-pyrazole-3-carbonyl)piperazin-1-yl)-2-(4-fluoro-1H-indol-3-yl)ethane-1,2-dione.

2. The method according to claim 1 , wherein said sleep disorder is a dyssomnia.

3. The method according to claim 1 , wherein said sleep disorder is insomnia.

4. The method according to claim 1 , wherein said sleep disorder is a parasomnia.

5. A method for increasing slow wave sleep in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound a compound having Formula (Ie):

or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein:
R 1 is H, halogen or C 1 -C 6 alkylaryl;
R 2 is H, C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, heteroaryl, or nitro; or
R 1 and R 2 together with the carbon atoms to which they are bonded form a C 3 -C 7 carbocyclyl;
R 3 is H, C 1 -C 6 alkyl, aryl, or aryl substituted with C 1 -C 6 alkoxy;
A and X are each —CH 2 CH 2 —, each optionally substituted with C 1 -C 3 alkyl;
J is —CH 2 CH 2 — optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C 1 -C 3 alkyl, hydroxyl, oxo and ═NO—C 1 -C 3 alkyl; and
Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkoxy, halogen and C 3 -C 7 heterocyclyl; provided that said compound is other than 1-(4-(1H-pyrazole-3-carbonyl)piperazin-1-yl)-2-(4-fluoro-1H-indol-3-yl)ethane-1,2-dione.

6. A method for improving sleep consolidation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound a compound having Formula (Ie):

or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein:
R 1 is H, halogen or C 1 -C 6 alkylaryl;
R 2 is H, C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, heteroaryl, or nitro; or
R 1 and R 2 together with the carbon atoms to which they are bonded form a C 3 -C 7 carbocyclyl;
R 3 is H, C 1 -C 6 alkyl, aryl, or aryl substituted with C 1 -C 6 alkoxy;
A and X are each —CH 2 CH 2 —, each optionally substituted with C 1 -C 3 alkyl;
J is —CH 2 CH 2 — optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C 1 -C 3 alkyl, hydroxyl, oxo and ═NO—C 1 -C 3 alkyl; and
Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkoxy, halogen and C 3 -C 7 heterocyclyl; provided that said compound is other than 1-(4-(1H-pyrazole-3-carbonyl)piperazin-1-yl)-2-(4-fluoro-1H-indol-3-yl)ethane-1,2-dione.

7. A method for improving sleep maintenance in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound a compound having Formula (Ie):

or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein:
R 1 is H, halogen or C 1 -C 6 alkylaryl;
R 2 is H, C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, heteroaryl, or nitro; or
R 1 and R 2 together with the carbon atoms to which they are bonded form a C 3 -C 7 carbocyclyl;
R 3 is H, C 1 -C 6 alkyl, aryl, or aryl substituted with C 1 -C 6 alkoxy;
A and X are each —CH 2 CH 2 —, each optionally substituted with C 1 -C 3 alkyl;
J is —CH 2 CH 2 — optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C 1 -C 3 alkyl, hydroxyl, oxo and ═NO—C 1 -C 3 alkyl; and
Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkoxy, halogen and C 3 -C 7 heterocyclyl; provided that said compound is other than 1-(4-(1H-pyrazole-3-carbonyl)piperazin-1-yl)-2-(4-fluoro-1H-indol-3-yl)ethane-1,2-dione.

8. A method for treating agitation in a patient in need of such treatment comprising administering to said patient a composition comprising a compound having Formula (Ie):

or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein:
R 1 is H, halogen or C 1 -C 6 alkylaryl;
R 2 is H, C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, heteroaryl, or nitro; or
R 1 and R 2 together with the carbon atoms to which they are bonded form a C 3 -C 7 carbocyclyl;
R 3 is H, C 1 -C 6 alkyl, aryl, or aryl substituted with C 1 -C 6 alkoxy;
A and X are each —CH 2 CH 2 —, each optionally substituted with C 1 -C 3 alkyl;
J is —CH 2 CH 2 — optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C 1 -C 3 alkyl, hydroxyl, oxo and ═NO—C 1 -C 3 alkyl; and
Ar is aryl or heteroaryl each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkoxy, halogen and C 3 -C 7 heterocyclyl; provided that said compound is other than 1-(4-(1H-pyrazole-3-carbonyl)piperazin-1-yl)-2-(4-fluoro-1H-indol-3-yl)ethane-1,2-dione.

9. The method of claim 8 , wherein the agitation is due to a psychiatric disorder other than dementia.

10. A method for the treatment of agitation or a symptom thereof in a patient suffering from dementia comprising administering to said patient a composition comprising a compound having Formula (Ie):

or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein:

Assignees

• Arena Pharm Inc
• Arena Pharmeceuticals 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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P7/12

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

• A61P9/12

  Antihypertensives · CPC title