5-HT4 receptor agonist compounds

• US 7,534,889 B2
• Filed: 06/11/2008
• Issued: 05/19/2009
• 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, Turner, S. Derek, Marquess, Daniel, Choi, Seok-Ki, Fatheree, Paul, Long, Daniel D, Goldblum, Adam A
• Primary Examiner(s): Seaman; D. Margaret
• Assistant Examiner(s): Chandrakumar; Nizal S
• Application Number:
  US12/136,891
• Publication Number:
  US 20080255187A1
• Time in Patent Office: 342 Days
• Field of Search: 546/156
• US Class Current: 546/156
• 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 pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I):

2. The pharmaceutical composition 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; and

(c) —

S—

C_1-4alkyl.

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

4. The pharmaceutical composition of claim 1 wherein the compound of formula (I) is a compound of formula (II):

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

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

S(O)₂CH₃, —

C(O)OCH₃, and —

C(O)CH₃.

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

8. The pharmaceutical composition 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 pharmaceutical composition 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-[(2-ethylsulfanylethyl)methanesulfonylamino]-2-hydroxypropyl}-8-aza-bicyclo[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-1λ

⁶-isothiazolidin-2-yl)ethyl]methylamino}ethyl)amino]-2-hydroxypropyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

and pharmaceutically-acceptable salts and stereoisomers thereof.

10. 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, the pharmaceutical composition of claim 1.

11. The method of claim 10 wherein the disease or medical condition is chronic constipation or constipation-predominant irritable bowel syndrome.

12. The method of claim 10 wherein the disease or medical condition is functional dyspepsia, gastroparesis, gastroesophageal reflux disease, or 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, the pharmaceutical composition of claim 1.

14. 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, the pharmaceutical composition of claim 4.

15. The method of claim 14 wherein the disease or medical condition is chronic constipation or constipation-predominant irritable bowel syndrome.

16. The method of claim 14 wherein the disease or medical condition is functional dyspepsia, gastroparesis, gastroesophageal reflux disease, or drug-induced delayed transit.