Oxyindole derivatives

• US 20060194842A1
• Filed: 02/22/2006
• Published: 08/31/2006
• Est. Priority Date: 02/22/2005
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Kawamura, Kiyoshi, Uchida, Chikara, Sone, Hiroki
• Granted Patent: US 7,589,109 B2
• Time in Patent Office: Days
• US Class Current: 514/323
• 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 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 25/06 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 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 405/14 containing three or more hetero rings

Abstract

This invention relates to compounds of the formula (I): or a pharmaceutically acceptable salt thereof, wherein:
A, R¹, R², R³, R⁴ and R⁵ are each as described herein or a pharmaceutically acceptable salt, and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HT₄ agonistic activity such as, but not limited to, as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal 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.

Claims

1. A compound of the formula (I):

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

A is a C₁-C₂ alkylene group, said alkylene group being unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of a C₁-C₄ alkyl group, a hydroxy-C₁-C₄ alkyl group and a C₁-C₂ alkoxy-C₁-C₄ alkyl group, wherein two of said substituents may optionally form a bridge to yield a 3 to 6 membered ring; and

R² and R³ are both methyl, or R² and R³ may together form a tetramethylene bridge to yield 5 membered ring.

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

A is a C₁-C₂ alkylene group, said alkylene group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a C₁-C₄ alkyl group, a hydroxy-C₁-C₄ alkyl group and a C₁-C₂ alkoxy-C₁-C₄ alkyl group, wherein two of said substituents may optionally form a bridge to yield a 3 to 6 membered ring;

R¹ is a hydrogen atom or a halogen atom;

R⁴ is a hydrogen atom; and

R⁵ is a carboxy group, a tetrazolyl group, a 5-oxo-1,2,4-oxadiazole-3-yl group, or a 5-oxo-1,2,4-thiadiazole-3-yl group.

4. The compound or the pharmaceutically acceptable salt as claimed in claim 3, wherein:

A is a C₁-C₂ alkylene group, said alkylene group being unsubstituted or substituted with 2 substituents independently selected from the group consisting of a C₁-C₄ alkyl group and a hydrox-C₁-C₄ alkyl group, wherein two of said substituents may optionally form a bridge to yield a 3 to 6 membered ring;

R¹ is a hydrogen atom or a fluorine atom; and

R⁵ is a carboxy group or a tetrazolyl group.

5. The compound or the pharmaceutically acceptable salt as claimed in claim 4, wherein A is

7. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient.

9. A method of treating a mammal, including a human, for a disease for which a 5-HT₄ agonist is indicated, comprising administering an effective amount of the compound of claim 1 or the pharmaceutically acceptable salt thereof.

11. A method of treating a mammal, including a human, for gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal 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, comprising administering an effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 1.

13. A method of treating a mammal, including a human, for gastroesophageal reflux disease, comprising administering an effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 1.

15. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 1 and another pharmacologically active agent.

6. A compound selected from:

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

1-{[4-({[(6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid;

or

3-[4-({[(6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]-2,2-dimethylpropanoic acid;

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of claim 6 or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient.

10. A method of treating a mammal, including a human, for a disease for which a 5-HT₄ agonist is indicated, comprising administering an effective amount of the compound of claim 6 or the pharmaceutically acceptable salt thereof.

12. A method of treating a mammal, including a human, for gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal 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, comprising administering an effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 6.

14. A method of treating a mammal, including a human, for gastroesophageal reflux disease, comprising administering an effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 6.