Quinolinone-carboxamide compounds

• US 20080167295A1
• Filed: 03/13/2008
• Published: 07/10/2008
• Est. Priority Date: 11/05/2004
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Adam A. Goldblum, Daniel D Long, Daniel Marquess, Jiang Lan, Paul Fatheree, Roland Gendron, Seok-Ki Choi
• Inventors: Jiang, Lan, Gendron, Roland, Long, Daniel D., Marquess, Daniel, Goldblum, Adam A., Choi, Seok-Ki, Fatheree, Paul
• Granted Patent: US 7,498,442 B2
• Time in Patent Office: Days
• US Class Current: 514/228.2
• 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

1-21. -21. (canceled)

22. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I):

23. The pharmaceutical composition of claim 22 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.

24. The pharmaceutical composition of claim 22 wherein R² is C_3-4alkyl.

25. The pharmaceutical composition of claim 24 wherein n is 2 or 3.

26. The pharmaceutical composition of claim 22 wherein the compound of formula (I) is a compound of formula (II):

27. The pharmaceutical composition of claim 26 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.

28. The pharmaceutical composition of claim 22 wherein the compound of formula (I) is a compound of formula (III):

29. The pharmaceutical composition of claim 22 wherein the compound of formula (I) is a compound of formula (IV):

30. The pharmaceutical composition of claim 22 wherein the compound of formula (I) is a compound of formula (V):

31. The pharmaceutical composition of claim 22 wherein the compound of formula (I) is a compound 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-ylmethyl)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; and

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.

32. 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 22.

33. The method of claim 32 wherein the disease or medical condition is chronic constipation or constipation-predominant irritable bowel syndrome.

34. The method of claim 32 wherein the disease or medical condition is functional dyspepsia, gastroparesis, gastroesophageal reflux disease, or drug-induced delayed transit.

35. 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 26.

36. The method of claim 35 wherein the disease or medical condition is chronic constipation or constipation-predominant irritable bowel syndrome.

37. The method of claim 35 wherein the disease or medical condition is functional dyspepsia, gastroparesis, gastroesophageal reflux disease, or drug-induced delayed transit.