5-HT4 receptor agonist compounds

• US 20060100236A1
• Filed: 11/04/2005
• Published: 05/11/2006
• Est. Priority Date: 11/05/2004
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Jiang, Lan, Long, Daniel D., Turner, S. Derek, Marquess, Daniel, Goldblum, Adam A., Choi, Seok-Ki, Fatheree, Paul
• Granted Patent: US 7,399,862 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• 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: 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 compound of formula (I):

2. The compound of claim 1 wherein Y is selected from:

(a) a moiety of formula (a), wherein Z is selected from —

N(R⁸)SO₂R^a, —

N(R⁸)C(O)R^c, —

S(O₂)R⁸, —

N(R⁸)C(O)NR^eR^f, —

C(O)NRⁱR^j, —

OC(O)NR^kR^l, —

OR⁸, and cyano;

(b) —

O—

C_1-4alkyl, wherein C_1-4alkyl is optionally substituted with 1 to 2 substituents selected from hydroxy;

(c) —

S—

C_1-4alkyl; and

(d) pyridinyl, imidazolyl, indolyl, and tetrahydrofuranyl, wherein pyrrolidinyl is optionally substituted with oxo.

3. The compound of claim 1 wherein Y is a moiety of formula (a).

4. The compound of claim 1 which is a compound of formula (II):

5. The compound of claim 4 wherein wherein R¹ is hydrogen, R² is C_3-4alkyl, and R³ is hydrogen.

6. The compound of claim 5 wherein R⁴ is selected from —

S(O)₂CH₃, —

C(O)OCH₃, and —

C(O)CH₃.

7. The compound of claim 6 wherein n is 1, and m is 1, 2 or 3.

8. The compound of claim 7 wherein Z is selected from —

N(R⁸)SO₂R^a, —

N(R⁸)C(O)R^c, —

S(O₂)R⁸, and —

N(R⁸)C(O)NR^eR^f.

9. The compound of claim 1 wherein, the compound is selected from:

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{2-hydroxy-3-[(3-imidazol-1-yl-propyl)methanesulfonylamino]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-[(2-ethylsulfanylethyl)methanesulfonylamino]-2-hydroxypropyl}-8-aza-bicyclo[3.2.1]oct-3-yl)amide;

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

(2-hydroxy-3-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydro-quinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}propyl)-{2-[3-(methanesulfonylmethylamino)piperidin-1-yl]ethyl}-carbamic acid methyl ester;

[2-(3-acetylaminopiperidin-1-yl)ethyl]-(2-hydroxy-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;

[2-(3-acetylaminopyrrolidin-1-yl)ethyl]-(2-hydroxy-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;

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

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

{2-[3-(1,1-dioxo-1λ

⁶-isothiazolidin-2-yl)pyrrolidin-1-yl]ethyl}-(2-hydroxy-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)-carbamic acid methyl ester;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [(1S,3R,5R)-8-(3-{acetyl-[2-(3-carbamoylpiperidin-1-yl)ethyl]amino}-2-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl]-amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(acetyl-{2-[4-(methanesulfonylaminomethyl)piperidin-1-yl]ethyl}amino)-2-hydroxypropyl]-8-aza-bicyclo[3.2.1]oct-3-yl}amide;

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

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(acetyl-{2-[3-(dimethylaminosulfonylmethylamino)pyrrolidin-1-yl]ethyl}amino)-2-hydroxypropyl]-8-aza-bicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(acetyl-{2-[3-(trimethylureido)pyrrolidin-1-yl]ethyl}amino)-2-hydroxy-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-(acetyl-{2-[(1-dimethylsulfamoylpyrrolidin-3-yl)methylamino]ethyl}amino)-2-hydroxypropyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{3-[acetyl-(2-{[2-(methanesulfonylmethylamino)ethyl]methylamino}-ethyl)amino]-2-hydroxypropyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[3-(acetyl-{2-[(2-methanesulfonylaminoethyl)methylamino]ethyl}amino)-2-hydroxypropyl]-8-aza-bicyclo[3.2.1]oct-3-yl}amide; and

1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ((1S,3R,5R)-8-{3-[acetyl-(2-{[2-(1,1-dioxo-1 _⁶-isothiazolidin-2-yl)ethyl]methylamino}ethyl)amino]-2-hydroxypropyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

and pharmaceutically-acceptable salts and solvates and stereoisomers thereof.

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

11. 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.

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

13. 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.

14. The method of claim 13, wherein the disorder of reduced motility is selected from chronic constipation, constipation-predominant irritable bowel syndrome, diabetic and idiopathic gastroparesis, and functional dyspepsia.

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

16. A process for preparing a compound of formula (II):

17. The product prepared by the process of claim 15.

18. The product prepared by the process of claim 16.

19. A compound of formula (III):

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

(a) contacting a 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.