Benzimidazolone carboxylic acid derivatives

• US 20050277671A1
• Filed: 06/14/2005
• Published: 12/15/2005
• Est. Priority Date: 06/15/2004
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Ando, Koji, Numata, Toyoharu, Uchida, Chikara, Sone, Hiroki, Iguchi, Satoru, Murata, Yoshinori, Ueki, Tatsuo, Murase, Noriaki
• Granted Patent: US 7,595,329 B2
• Time in Patent Office: Days
• US Class Current: 514/322
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

This invention relates to compounds of the formula (I):
wherein R¹, R², R³, A and m are each as described herein or a pharmaceutically acceptable salt or solvate thereof, and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HT₄ receptor activity such as, but not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer'"'"'s disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.

Claims

1. A compound of the formula:

2. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein

R¹ is an isopropyl group;

R² is a hydrogen atom, a fluorine atom, or a hydroxy group;

R³ is a carboxy group or a tetrazolyl group;

A is an alkylene group having 1 to 2 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 2 substituents independently selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms, or an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; and

m is the integer 2.

3. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 2, wherein

R³ is a carboxy group;

A is an alkylene group having 1 to 2 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 2 substituents independently selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms, or an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any two non-halogen geminal substituents can be taken together with the carbon atom to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; and

m is the integer 2.

4. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein

R¹ is an isopropyl group;

R² is a hydrogen atom;

R³ is a carboxy group or a tetrazolyl group;

A is an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 geminal substituents independently selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms, or an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein two non-halogen geminal substituents can be taken together with the carbon atom to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; and

m is the integer 2.

5. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein

R¹ is an isopropyl group;

R² is a hydrogen atom;

R³ is a carboxy group or a tetrazolyl group;

A is

m is the integer 2.

6. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein

R¹ is an isopropyl group;

R² is a hydrogen atom, a fluorine atom or a hydroxy group;

R³ is a carboxy group;

A is

m is the integer 2.

8. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, with or without at least one pharmaceutically acceptable carrier.

10. A pharmaceutical composition as claimed in claim 1, further comprising at least one pharmacologically active agent in addition to the compound.

12. A method for the treatment of a condition mediated by 5-HT₄ receptor activity, in a mammalian subject, including a human, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1.

14. The method as claimed in claim 12, wherein said condition is gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer'"'"'s disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes, or apnea syndrome.

16. A method for treating gastroesophageal reflux disease comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1.

7. A compound selected from:

1-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylic acid; and

1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;

or a pharmaceutically acceptable salt or solvate thereof.

9. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 7, with or without at least one pharmaceutically acceptable carrier.

11. A pharmaceutical composition as claimed in claim 7, further comprising at least one pharmacologically active agent in addition to the compound.

13. A method for the treatment of a condition mediated by 5-HT₄ receptor activity, in a mammalian subject, including a human, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 7.

15. The method as claimed in claim 13, wherein said condition is gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer'"'"'s disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes, or apnea syndrome.

17. A method for treating gastroesophageal reflux disease comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 7.

18. A compound of formula