Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto

Patent metadata

Field	Value
Publication number	US-9273035-B2
Application number	US-201414332207-A
Country	US
Kind code	B2
Filing date	Jul 15, 2014
Priority date	Jul 22, 2003
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

The present invention relates to certain pyrazole derivatives of Formula (I) and pharmaceutical compositions thereof that modulate the activity of the 5-HT 2A serotonin receptor.

Compounds and pharmaceutical compositions thereof are directed to methods useful in the prophylaxis or treatment of 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 a symptom, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders and the like.
The present invention also relates to the method of prophylaxis or treatment of 5-HT 2A serotonin receptor mediated disorders in combination with a dopamine D2 receptor antagonist such as haloperidol, administered separately or together.

First claim

What is claimed is:

1. A process for preparing a composition comprising admixing a compound of Formula (IIa):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier; wherein:
R 1 is phenyl or naphthyl optionally substituted with R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 each selected independently from the group consisting of C 1-6 acyl, C 1-6 alkoxy, C 1-6 alkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkylimino, cyano, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 together with the atoms to which they are attached form a C 5-7 cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C 1-6 alkyl, C 1-6 alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C 1-6 alkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, and hydroxyl;
R 2 is C 1-6 alkyl;
R 3 is H or halogen;
R 4 is selected from the group consisting of H, C 1-6 alkyl and C 1-6 haloalkyl;
R 5 is selected from the group consisting of C 1-6 alkoxy, C 1-6 haloalkoxy, and hydroxyl, wherein said C 1-6 alkoxy group is optionally substituted with 1 to 5 further substituents selected independently from the group consisting of amino, C 2-8 dialkylamino, carboxy, and phenyl, and wherein said amino and phenyl are each optionally substituted with 1 to 5 further substituents selected from the group consisting of halogen and carbo-C 1-6 -alkoxy;
R 6a , R 6b , and R 6c are each independently selected from the group consisting of H, C 1-6 alkoxy, C 1-6 alkyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, cyano, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, hydroxyl, and nitro;
R 7 and R 8 are both H;
X is O; and
Q is a bond.

2. The process according to claim 1 , or pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 1 is phenyl or naphthyl each optionally substituted with R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 each selected independently from the group consisting of —OCH 3 , —CH 3 , cyano, —F, —Cl, —Br, —OCF 3 , and —CF 3 .

3. The process according to claim 1 , or pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 2 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 and —CH 2 CH 2 CH 2 CH 3 .

4. The process according to claim 1 , or pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 2 is —CH 3 or —CH(CH 3 ) 2 .

5. The process according to claim 1 , or pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 3 is H, F, Cl, or Br.

6. The process according to claim 1 , or pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 4 is H or —CF 3 .

7. A process according to claim 1 , or pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 5 is selected from the group consisting of —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , hydroxyl, benzyloxy, 4-chloro-benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy, 3-dimethylamino-propoxy, carboxymethoxy, and 2-tert-butoxycarbonylamino-ethoxy.

8. The process according to claim 1 , or pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 6a , R 6b , and R 6c are each independently selected from the group consisting of —H, —OCH 3 , —CH 3 , —N(CH 3 ) 2 , cyano, —F, —Cl, —Br, —OCF 3 , hydroxyl, and nitro.

9. The process according to claim 1 , or pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 6a , R 6b , and R 6c are all —H.

10. The process according to claim 1 , wherein said compound is a compound of Formula (IIa):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 1 is phenyl or naphthyl optionally substituted with R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 each selected independently from the group consisting of —C(O)CH 3 , —OCH 3 , —CH 3 , —CH(CH 3 ) 2 , —CH(OH)CH 3 , —N(CH 3 ) 2 , (2-dimethylamino-ethyl)-methyl-amino, (3-dimethylamino-propyl)-methyl-amino, —C(═NOH)CH 3 , cyano, —F, —Cl, —Br, —OCF 3 , —CF 3 , 4-methyl-piperazin-1-yl, morpholin-4-yl, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl;
R 2 is —CH 3 or —CH(CH 3 ) 2 ;
R 3 is —H, —F, —Cl, or —Br;
R 4 is —H, or —CF 3 ;
R 5 is selected from the group consisting of —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , hydroxyl, benzyloxy, 4-chloro-benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy, 3-dimethylamino-propoxy, carboxymethoxy, and 2-tert-butoxycarbonylamino-ethoxy;
R 6a , R 6b , and R 6c are each independently selected from the group consisting of —H, —OCH 3 , —CH 3 , —N(CH 3 ) 2 , cyano, —F, —Cl, —Br, —OCF 3 , hydroxyl, and nitro;
R 7 and R 8 are both —H;
X is O; and
Q is a bond.

11. The process according to claim 1 , wherein said compound is a compound of Formula (IIa):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 1 is phenyl optionally substituted with R 9 , R 10 , R 11 , R 12 , and R 13 each selected independently from the group consisting of —C(O)CH 3 , —OCH 3 , —CH 3 , —CH(CH 3 ) 2 , —CH(OH)CH 3 , —N(CH 3 ) 2 , (2-dimethylamino-ethyl)-methyl-amino, (3-dimethylamino-propyl)-methyl-amino, —C(═NOH)CH 3 , cyano, —F, —Cl, —Br, —OCF 3 , —CF 3 , 4-methyl-piperazin-1-yl, morpholin-4-yl, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl;
R 2 is —CH 3 or —CH(CH 3 ) 2 ;
R 3 is —H, —F, —Cl, or —Br;
R 4 is —H, or —CF 3 ;
R 5 is selected from the group consisting of —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , hydroxyl, benzyloxy, 4-chloro-benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy, 3-dimethylamino-propoxy, carboxymethoxy, and 2-tert-butoxycarbonylamino-ethoxy;
R 6a , R 6b , and R 6c are each independently selected from the group consisting of —H, —OCH 3 , —CH 3 , —N(CH 3 ) 2 , cyano, —F, —Cl, —Br, —OCF 3 , hydroxyl, and nitro;
R 7 and R 8 are both —H;
X is O; and
Q is a bond.

12. The process according to claim 1 , wherein said compound is a compound of Formula (IIa):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 1 is phenyl optionally substituted with R 9 , R 10 , R 11 , R 12 , and R 13 each selected independently from the group consisting of —C(O)CH 3 , —OCH 3 , —CH 3 , —CH(CH 3 ) 2 , —N(CH 3 ) 2 , cyano, —F, —Cl, —Br, —OCF 3 , —CF 3 , hydroxyl, and nitro;
R 2 is —CH 3 ;
R 3 is —H, —F, —Cl, or —Br;
R 4 is —H;
R 5 is selected from the group consisting of —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , hydroxyl, benzyloxy, 4-chloro-benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy, 3-dimethylamino-propoxy, carboxymethoxy, and 2-tert-butoxycarbonylamino-ethoxy;
R 6a , R 6b , and R 6c are each —H;
R 7 and R 8 are both —H;
X is O; and
Q is a bond.

13. The process according to claim 1 , wherein the compound is selected from the group consisting of:
1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-chloro-phenyl)-urea;
1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-fluoro-phenyl)-urea;
1-[3-(4-Bromo-2-methyl-2H-pyrazo

Assignees

• Arena Pharm Inc

Inventors

• Teegarden Bradley
• Jayakumar Honnappa
• Li Hongmei
• Strah-Pleynet Sonja
• Dosa Peter I

Classifications

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P43/00

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