1-Isopropyl-2-Oxo-1,2-Dihydropyridine-3-Carboxamide Derivatives Having 5-Ht4 Receptor Agonistic Activity

• US 20080293767A1
• Filed: 01/18/2005
• Published: 11/27/2008
• Est. Priority Date: 01/29/2004
• Status: Active Grant

• Current Assignee: Chikara Uchida, Kiyoshi Kawamura, Tomoki Kato
• Original Assignee: Chikara Uchida, Kiyoshi Kawamura, Tomoki Kato
• Inventors: Kawamura, Kiyoshi, Kato, Tomoki, Uchida, Chikara
• Granted Patent: US 7,691,881 B2
• Time in Patent Office: Days
• US Class Current: 514/318
• 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 1/14 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• 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 405/14 containing three or more hetero rings

Abstract

This invention provides a compound of formula (I): wherein R¹ represents an alkyl group having from 1 to 4 carbon atoms or a halogen atom, R² represents an alkyl group having from 1 to 4 carbon atoms, R³ represents a hydrogen atom or a hydroxy group, and A represents an oxygen atom or a group of the formula —C(R⁴)(R⁵)— (in which R⁴ represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms and R⁵ represents a hydroxy group or an alkoxy group having from 1 to 4 carbon atoms) or a pharmaceutically acceptable salts thereof. These compounds have 5-HT₄ receptor agonistic activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans.

Claims

1-11. -11. (canceled)

12. A compound of the formula (I):

wherein

R¹ is alkyl having 1 to 4 carbons or halogen;

R² is alkyl having 1 to 4 carbons;

R³ is hydrogen or hydroxy;

A is oxygen or —

C(R⁴)(R⁵)—

;

R⁴ is alkyl having 1 to 4 carbons or hydrogen; and

R⁵ is alkyl having 1 to 4 carbons or hydroxy;

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12, wherein R¹ is halogen.

14. The compound of claim 12, wherein R² is alkyl having 1 to 2 carbons.

15. The compound of claim 13, wherein R² is alkyl having 1 to 2 carbons.

16. The compound of claim 12, wherein R³ is hydroxy.

17. The compound of claim 13, wherein R³ is hydroxy.

18. The compound of claim 15, wherein R³ is hydroxy.

19. The compound of claim 12, wherein A is oxygen.

20. The compound of claim 13, wherein A is oxygen.

21. The compound of claim 18, wherein A is oxygen.

23. A pharmaceutical composition comprising a compound of claim 12 or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier.

24. A method for treating a condition mediated by 5-HT₄ receptor agonist activity, in a mammalian subject comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 12 or a pharmaceutically acceptable salt thereof.

25. A method for treating 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, diabetes, apnea syndrome, cardiac failure, or heart arrhythmia comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 12 or a pharmaceutically acceptable salt thereof.

26. A method for treating gastroesophageal reflux disease comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 12 or a pharmaceutically acceptable salt thereof.

22. A compound selected from:

5-chloro-N-({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide;

5-chloro-6-ethyl-N-({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide;

N-({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-1-isopropyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide;

5-bromo-N-({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide;

5-fluoro-H-({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide;

5-chloro-N-({1-(cyclohexylmethyl)piperidin-4-yl]methyl}-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide;

or

5-chloro-N-({1-[(1-hydroxycyclohexyl)methyl]piperidin-4-yl}methyl)-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide;

or a pharmaceutically acceptable salt thereof.