Quinolinone-carboxamide compounds as 5-HT4, receptor agonists

• US 7,763,637 B2
• Filed: 03/13/2008
• Issued: 07/27/2010
• Est. Priority Date: 04/07/2004
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Long, Daniel D., Turner, S. Derek, Fatheree, Paul R., Marquess, Daniel, Goldblum, Adam A., Choi, Seok-Ki, Genov, Daniel
• Primary Examiner(s): Seaman; D. Margaret
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US12/075,669
• Publication Number:
  US 20080176895A1
• Time in Patent Office: 866 Days
• Field of Search: 514/304
• US Class Current: 514/304
• 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 1/10 Laxatives
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 451/02 containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 451/04 with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Abstract

The invention provides novel quinolinone-carboxamide 5-HT₄ receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT₄ receptor activity, and processes and intermediates useful for preparing such compounds.

Claims

1. A method of treating chronic constipation in a mammal, the method comprising administering to the mammal a compound of formula (I):

2. The method of claim 1 wherein

R¹ is hydrogen;

R² is C_3-4alkyl or C_4-5cycloalkyl;

R³ is hydrogen;

R⁴ is —

S(O)₂R⁶ or —

C(O)R⁷;

R⁵ is hydrogen or C_1-3alkyl;

R⁶ is C_1-3alkyl; and

R⁷ is hydrogen or C_1-3alkyl.

3. The method of claim 2 wherein R⁴ is —

S(O)₂R⁶.

4. The method of claim 1 wherein the compound of formula (I) is 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

or a pharmaceutically-acceptable salt thereof.

5. A method of treating constipation-predominant irritable bowel syndrome in a mammal, the method comprising administering to the mammal a compound of formula (I):

6. The method of claim 5 wherein

R¹ is hydrogen;

R² is C_3-4alkyl or C_4-5cycloalkyl;

R³ is hydrogen;

R⁴ is —

S(O)₂R⁶ or —

C(O)R⁷;

R⁵ is hydrogen or C_1-3alkyl;

R⁶ is C_1-3alkyl; and

R⁷ is hydrogen or C_1-3alkyl.

7. The method of claim 6 wherein R⁴ is —

S(O)₂R⁶.

8. The method of claim 5 wherein the compound of formula (I) is 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

or a pharmaceutically-acceptable salt thereof.

9. A method of treating functional dyspepsia in a mammal, the method comprising administering to the mammal a compound of formula (I):

10. The method of claim 9 wherein

R¹ is hydrogen;

R² is C_3-4alkyl or C_4-5cycloalkyl;

R³ is hydrogen;

R⁴ is —

S(O)₂R⁶ or —

C(O)R⁷;

R⁵ is hydrogen or C_1-3alkyl;

R⁶ is C_1-3alkyl; and

R⁷ is hydrogen or C_1-3alkyl.

11. The method of claim 10 wherein R⁴ is —

S(O)₂R⁶.

12. The method of claim 9 wherein the compound of formula (I) is 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

or a pharmaceutically-acceptable salt thereof.

13. A method of treating gastroparesis in a mammal, the method comprising administering to the mammal a compound of formula (I):

14. The method of claim 13 wherein

R¹ is hydrogen;

R² is C_3-4alkyl or C_4-5cycloalkyl;

R³ is hydrogen;

R⁴ is —

S(O)₂R⁶ or —

C(O)R⁷;

R⁵ is hydrogen or C_1-3alkyl;

R⁶ is C_1-3alkyl; and

R⁷ is hydrogen or C_1-3alkyl.

15. The method of claim 14 wherein R⁴ is —

S(O)₂R⁶.

16. The method of claim 13 wherein the compound of formula (I) is 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

or a pharmaceutically-acceptable salt thereof.

17. A method of treating a mammal having a disease or medical condition mediated by treatment with a 5-HT₄ receptor agonist, wherein the disease or medical condition is chronic constipation, constipation-predominant irritable bowel syndrome, functional dyspepsia, gastroparesis, gastroesophageal reflux disease, or drug-induced delayed transit, the method comprising administering to the mammal, a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I):

18. The method of claim 17 wherein

R¹ is hydrogen;

R² is C_3-4alkyl or C_4-5cycloalkyl;

R³ is hydrogen;

R⁴ is —

S(O)₂R⁶ or —

C(O)R⁷;

R⁵ is hydrogen or C_1-3alkyl;

R⁶ is C_1-3alkyl; and

R⁷ is hydrogen or C_1-3alkyl.

19. The method of claim 18 wherein R⁴ is —

S(O)₂R⁶.