Quinolinone compounds as 5-HT4 receptor agonists

• US 20060199839A1
• Filed: 03/01/2006
• Published: 09/07/2006
• 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, Gendron, Roland, Long, Daniel D., Turner, S. Derek, Fatheree, Paul R., Marquess, Daniel, Goldblum, Adam A.
• Granted Patent: US 7,446,114 B2
• Time in Patent Office: Days
• 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 compound of formula (I):

2. The compound of claim 1 wherein R¹ is hydrogen or halo, R² is C_3-4alkyl, and d is 0.

3. The compound of claim 2, wherein:

X is carbon and Q is -A-;

or X is nitrogen and Q is selected from —

OC(O)—

, —

S(O)₂—

, —

S(O)₂(CH₂)₂—

, and -A(CH₂)₂—

.

4. The compound of claim 3, wherein:

X is carbon and Q is selected from —

N{C(O)R⁵}—

, —

N{C(O)NR^6aR^6b}—

, —

N{S(O)₂C_1-3alkyl}—

, and —

S(O)₂N(R^7a)—

;

or 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)R⁵}(CH₂)₂—

, and —

N{S(O)₂C_1-3alkyl}(CH₂)₂.

5. The compound of claim 3, wherein:

G is W and c is 0, wherein W is selected from —

N{C(O)R⁹}—

, —

N{S(O)₂R¹⁰}—

, —

N{C(O)NR¹³R¹⁴}—

, —

N{R¹⁶}—

, and —

S(O)₂—

;

or G is carbon, c is 1, and Y is a moiety of formula (b), wherein W′

is selected from —

N(R⁸)C(O)R⁹, —

N(R⁸)S(O)₂R¹⁰, —

S(R¹¹)(O)₂, —

N(R⁸)C(O)NR¹³R¹⁴, —

OR¹⁵, and —

N(R⁸)R¹⁶.

6. The compound of claim 5, wherein G is W and c is 0.

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically-acceptable carrier.

13. A method of treating a mammal having a medical condition associated with 5-HT₄ receptor activity, the method comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of claim 1.

14. The method of claim 13 wherein the medical condition is selected from the group consisting of irritable bowel syndrome (IBS), chronic constipation, functional dyspepsia, delayed gastric emptying, gastroesophageal reflux disease (GERD), gastroparesis, diabetic and idiopathic gastropathy, post-operative ileus, intestinal pseudo-obstruction, and drug-induced delayed transit.

15. A method of treating a disorder of reduced motility of the gastrointestinal tract in a mammal, the method comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of claim 1.

16. The method of claim 15, wherein the disorder of reduced motility is selected from the group consisting of chronic constipation, constipation-predominant irritable bowel syndrome, diabetic and idiopathic gastroparesis, and functional dyspepsia.

17. A process for preparing a compound of formula (I):

18. A process for preparing a compound of formula (I-a):

19. A process for preparing a compound of formula (I-b):

20. A method of studying a biological system or sample comprising a 5-HT₄ receptor, the method comprising:

(a) contacting the biological system or sample with a compound of claim 1;

and

(b) determining the effect caused by the compound on the biological system or sample.

7. A compound of formula (I):

8. The compound of claim 7, 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—

.

9. The compound of claim 7, 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)—

.

10. The compound of claim 7, wherein Z is a moiety of formula (d), wherein Q is selected from —

OC(O)— and

—

S(O)₂—

.

11. The compound of claim 7, wherein the compound 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]oct-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-hydroxyethyl)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-methylpiperazine-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-{2-[methanesulfonyl-(1-propylpiperidin-4-yl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [(1S,3R,5R)-8-(3-{[1-(2-methoxyethyl)piperidin-4-yl]methsulfamoyl}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-[(1-methanesulfonylpiperidin-4-yl)methylsulfamoyl]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-{[1-(2-cyanoethyl)piperidin-4-yl]methylsulfamoyl}propyl)-8-azabicyclo[3.2.1]oct-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]oct-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]oct-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]oct-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]oct-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]oct-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]oct-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]oct-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]oct-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]oct-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]oct-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-(tetrahydrofuran-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]oct-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-aza-bicyclo[3.2.1]oct-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]oct-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]oct-8-yl}-propyl ester;

and pharmaceutically-acceptable salts and solvates and stereoisomers thereof.