Quinolinone-carboxamide compounds

• US 7,396,933 B2
• Filed: 11/04/2005
• Issued: 07/08/2008
• 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, Gendron, Roland, 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:
  US11/267,720
• Publication Number:
  US 20060100426A1
• Time in Patent Office: 977 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• 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

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:

R⁵ is hydrogen or C_1-4alkyl, wherein C_1-4alkyl is optionally substituted with hydroxy, C_1-3alkoxy, or cyano;

R⁶ and R⁷ are independently selected from hydrogen, hydroxy, halo, and C_1-4alkyl, wherein C_1-4alkyl is optionally substituted with hydroxy or C_1-3alkoxy;

R⁸ is hydrogen or C_1-4alkyl;

R¹⁰ is hydrogen or C_1-4alkyl, wherein C_1-4alkyl is optionally substituted with —

SO₂R^c, C_3-6cycloalkyl or with from 1 to 3 halo;

R¹¹ is hydrogen, C_1-4alkyl, or —

NR^bR^c; and

R¹⁵ is hydrogen or C_1-4alkyl, wherein C_1-4alkyl is optionally substituted with hydroxy.

3. The compound of claim 1 wherein R² is C_3-4alkyl.

4. The compound of claim 3 wherein n is 2 or 3.

5. The compound of claim 3 wherein n is 2.

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

7. The compound of claim 6 wherein:

R¹ is hydrogen;

R² is C_3-4alkyl;

R³ is hydroxy, methoxy, hydroxymethyl, —

OC(O)N(H)CH₃, or —

OC(O)N(CH₃)₂;

R⁶ is hydrogen;

X is selected from —

N(R⁸)C(O)R⁹;

—

N(R⁸)S(O)₂R¹⁰, —

S(R¹¹)O₂, and —

N(R⁸)C(O)NR¹³R¹⁴;

R⁵ and R⁸ taken together form C₂alkylenyl;

R⁹ is hydrogen or C_1-3alkyl;

R¹⁰ is hydrogen, C_1-3alkyl, or methanesulfonylmethyl;

R⁵ and R¹¹ taken together form C₂alkylenyl; and

R¹³ and R¹⁴ are independently hydrogen or C_1-3alkyl.

8. The compound of claim 1 wherein the compound is of formula (III):

9. The compound of claim 1 wherein the compound is of formula (IV):

10. The compound of claim 1 wherein the compound is of formula (V):

11. 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-(4-methanesulfonylpiperazin-1-yl)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-hydroxy-3-[4-(propane-2-sulfonyl)piperazin-1-yl]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-(1,1-dioxo-1λ

⁶-thiomorpholin-4-yl)-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-[(S)-2-hydroxy-3-(4-methanesulfonylpiperazin-1-yl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

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

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

⁶-thiomorpholin-4-yl)-2-methoxypropyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

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

methylcarbamic acid 1-(4-dimethylcarbamoylpiperazin-1-ylmethyl)-2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-aza-bicyclo[3.2.1]oct-8-yl}ethyl ester;

methylcarbamic acid 1-[3-(acetylmethylamino)pyrrolidin-1-ylmethyl]-2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-8-aza-bicyclo[3.2.1]oct-8-yl}ethyl ester;

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

methylcarbamic acid (R)-2-{(1S,3R,5R)-3-[(1-isopropyl-2-oxo-1,2-dihydro-quinoline-3-carbonyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}-1-(4-methanesulfonyl-piperazin-1-ylmethyl)ethyl ester;

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

pharmaceutically-acceptable salts thereof.

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

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