Quinolinone compounds as 5-HT4 receptor agonists

• US 7,875,629 B2
• Filed: 09/22/2008
• Issued: 01/25/2011
• Est. Priority Date: 03/02/2005
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Choi, Seok-ki, Jiang, Lan, Long, Daniel D., Turner, S. Derek, Marquess, Daniel, Goldblum, Adam A., Gendron, Roland, Fatheree, Paul R.
• Primary Examiner(s): Seaman; D. Margaret
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US12/234,906
• Publication Number:
  US 20090036483A1
• Time in Patent Office: 855 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 1/10 Laxatives
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems

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 a disorder of reduced motility of the gastrointestinal tract in a mammal, the method comprising administering to the mammal a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I):

2. The method of claim 1, wherein Z is a moiety of formula (c), wherein X is nitrogen and Q is selected from —

OC(O)—

, —

S(O)₂—

, —

S(O)₂(CH₂)₂—

, —

S(O)₂N(R^7a)(CH₂)₂—

, —

N{C(O)C_1-3alkoxy}(CH₂)₂—

, and —

N{S(O)₂C_1-3alkyl}(CH₂)₂—

.

3. The method of claim 1, wherein Z is a moiety of formula (c), wherein X is carbon and Q is selected from —

N{C(O)C_1-3alkoxy}-, —

N{C(O)NR^6aR^6b}—

, —

N{S(O)₂C_1-3alkyl}, and —

S(O)₂N(R^7a)—

.

4. The method of claim 1, wherein Z is a moiety of formula (d), wherein Q is selected from —

OC(O)— and

—

S(O)₂—

.

5. The method of claim 1, wherein the compound of formula (I) is selected from:

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(4-methanesulfonylpiperazine-1-sulfonyl)propyl]-8-azabicyclo[3.2.1]-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(3-dimethylaminopyrrolidine-1-sulfonyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-{3-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]propyl}-8-azabicyclo[3.2.1]-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(4-methylpiperazine-1-sulfonyl)propyl]-8-azabicyclo[3.2.1]-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[methanesulfonyl-(1-propylpiperidin-4-yl)amino]ethyl}-8-azabicyclo[3.2.1]-3-yl)-amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [(1S,3R,5R)-8-(3-{[1-(2-methoxyethyl)piperidin-4-yl]methylsulfamoyl]propyl)-8-azabicyclo[3.2.1]-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{3-[(1-methanesulfonylpiperidin-4-yl)methylsulfamoyl]propyl}-8-azabicyclo[3.2.1]-3-yl]amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [(1S,3R,5R)-8-(3-{[1-(2-cyanoethyl)piperidin-4-yl]methylsulfamoyl}propyl)-8-azabicyclo[3.2.1]-3-yl]amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[(1,1-dioxotetrahydro-1λ

⁶-thiophen-3-yl)methanesulfonylamino]ethyl}-8-azabicyclo[3.2.1]-3-yl)amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[1-(1,1-dioxotetrahydro-1λ

⁶-thiophen-3-yl)-3,3-dimethylureido]ethyl}-8-azabicyclo[3.2.1]-oct-3-yl)amide;

(1,1-dioxo-tetrahydro-1λ

⁶-thiophen-3-yl)-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]-8-yl}ethyl)-carbamic acid methyl ester;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [(1S,3R,5R)-8-(2-{[2-(4-dimethylcarbamoylpiperazin-1-yl)ethyl]methanesulfonylamino}ethyl)-8-azabicyclo-[3.2.1]-3-yl]amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[2-(4-methanesulfonylpiperazin-1-yl)ethanesulfonyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [(1S,3R,5R)-8-(2-{2-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]ethanesulfonyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[2-(4-ethanesulfonylpiperazin-1-yl)ethanesulfonyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

(1,1-dioxo-hexahydro-1λ

⁶-thiopyran-4-yl)-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]-8-yl}ethyl)-carbamic acid methyl ester;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-[1-(1,1-dioxotetrahydro-1λ

⁶-thiophen-3-yl)-3-methylureido]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)-amino]-8-azabicyclo[3.2.1]-8-yl}ethyl)-[2-(4-methanesulfonylpiperazin-1-ylethyl]-carbamic acid methyl ester;

[2-(4-dimethylcarbamoylpiperazin-1-yl)ethyl]-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]-8-yl}-ethyl)-carbamic acid methyl ester;

[2-(4-acetyl-piperazin-1-yl)ethyl]-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]-8-yl}ethyl)-carbamic acid methyl ester;

[2-(1,1-dioxo-1λ

⁶-thiomorpholin-4-yl)ethyl]-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]-8-yl}ethyl)-carbamic acid methyl ester;

(1,1-dioxo-tetrahydro-1λ

⁶-thiophen-3-yl)-(3-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]-8-yl}propyl)-carbamic acid methyl ester;

((S)-1,1-dioxo-tetrahydro-1λ

⁶-thiophen-3-yl)-(2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]-8-yl}ethyl)-carbamic acid methyl ester;

1-isopropyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(methyl-{2-[4-(tetrahydro furan-2-carbonyl)piperazin-1-yl]ethyl}sulfamoyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{3-[4-(tetrahydrofuran-2-carbonyl)piperazine-1-sulfonyl]propyl}-8-azabicyclo-[3.2.1]oct-3-yl)amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(4-acetylpiperazine-1-sulfonyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

4-methanesulfonyl-piperazine-1-carboxylic acid 3-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]-8-yl}propyl ester;

4-(tetrahydrofuran-2-carbonyl)piperazine-1-carboxylic acid 3-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]-8-yl}propyl ester;

4-acetyl-piperazine-1-carboxylic acid 3-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]-8-yl}propyl ester; and

4-hydroxypiperidine-1-carboxylic acid 3-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]-8-yl}-propyl ester;

and pharmaceutically-acceptable salts thereof.

6. The method of claim 1, wherein the disorder of reduced motility is chronic constipation, irritable bowel syndrome, gastroparesis, post-operative ileus, intestinal pseudo-obstruction, drug-induced delayed transit, or functional dyspepsia.

7. The method of claim 6, wherein the disorder of reduced motility is chronic constipation, constipation-predominant irritable bowel syndrome, gastroparesis, or functional dyspepsia.

8. The method of claim 5, wherein the disorder of reduced motility is chronic constipation, irritable bowel syndrome, gastroparesis, post-operative ileus, intestinal pseudo-obstruction, drug-induced delayed transit, or functional dyspepsia.

9. The method of claim 8, wherein the disorder of reduced motility is chronic constipation, constipation-predominant irritable bowel syndrome, gastroparesis, or functional dyspepsia.

10. A method of treating a mammal having a medical condition ameliorated by treatment with a 5-hydroxytryptamine 4 (5-HT₄) receptor agonist, the method comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I) as defined in claim 1 or a pharmaceutically-acceptable salt or stereoisomer thereof.

11. The method of claim 10 wherein the medical condition is irritable bowel syndrome, chronic constipation, functional dyspepsia, delayed gastric emptying, gastroesophageal reflux disease, gastroparesis, post-operative ileus, intestinal pseudo-obstruction, or drug-induced delayed transit.