5-HT4 receptor agonist compounds

• US 7,399,862 B2
• Filed: 11/04/2005
• Issued: 07/15/2008
• 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:
  US11/266,881
• Publication Number:
  US 20060100236A1
• Time in Patent Office: 984 Days
• Field of Search: 546/156, 546/123
• 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 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; and

(c) —

S—

C_1-4alkyl.

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-{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-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 process for preparing a compound of formula (I):

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

12. A compound of formula (III):