Quinolinone-Carboxamide Compounds as 5-Ht4 Receptor Agonists

• US 20070281970A1
• Filed: 04/06/2005
• Published: 12/06/2007
• Est. Priority Date: 04/07/2004
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Adam Goldblum, Daniel Genov, Daniel Long, Daniel Marquess, Paul Fatheree, Seok-Ki Choi, Turner S. Derek
• Inventors: Choi, Seok-ki, Turner, S. Derek, Long, Daniel, Marquess, Daniel, Fatheree, Paul, Genov, Daniel, Goldblum, Adam
• Granted Patent: US 7,728,006 B2
• Time in Patent Office: Days
• US Class Current: 514/312
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/4858 Organic compounds
• 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: 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 of Formula (I). The invention also provides pharmaceutical compositions comprising such compounds, the use such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds. Wherein; R¹ is hydrogen, halo, hadroxy, C_1-4 alkyl, or C_1-4 alkoxy; R² is C_3-4 alkyl, or C_3-6cycloakyl; R³ is hydrogen or C_1-3 alkyl: R⁴ is —S(O)₂ R⁶ or —C(O)R⁷; R⁵ is hydrogen, C_1-3alkyl, C_2-3 alkyl subtituted with —OH or C_1-3 alkoxy, or —CH₂-pyrydyl; R⁶ is C_1-3 alkyl; or R⁵ and R⁶ taken together from C_3-4 alkylenyl; and R⁷ is hydrogen, C_1-3alkyl, or pyrydyl; or pharmaceutically-acceptable salt or solvate or stereoisomer thereof.

Claims

1-27. -27. (canceled)

28. A capsule comprising a therapeutically effective amount of a pharmaceutically acceptable carrier and a compound of the formula

29. The capsule of claim 28 wherein the pharmaceutically acceptable carrier comprises one or more ingredients selected from starches and lubricants.

30. The capsule of claim 28 wherein the pharmaceutically acceptable carrier comprises one or more ingredients selected from microcrystalline cellulose, lactose, sucrose, glucose, mannitol, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate.

31. The capsule of claim 28 wherein the pharmaceutically acceptable carrier comprises one or more ingredients selected from starches, microcrystalline cellulose and magnesium stearate.

36. A method of treating a disorder of reduced motility of the gastrointestinal tract in a mammal, the method comprising administering to the mammal, a capsule of claim 28.

37. The method of claim 36, wherein the disorder of reduced motility is chronic constipation, constipation-predominant irritable bowel syndrome, diabetic gastroparesis, drug-induced delayed transit, or functional dyspepsia.

38. A method of treating chronic constipation or constipation-predominant irritable bowel syndrome in a mammal, the method comprising administering to the mammal, a capsule of claim 28.

32. A capsule comprising a therapeutically effective amount of a hydrochloride salt of a compound of the formula

33. The capsule of claim 32 wherein the pharmaceutically acceptable carrier comprises one or more ingredients selected from starches and lubricants.

34. The capsule of claim 32 wherein the pharmaceutically acceptable carrier comprises one or more ingredients selected from microcrystalline cellulose, lactose, sucrose, glucose, mannitol, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate.

35. The capsule of claim 32 wherein the pharmaceutically acceptable carrier comprises one or more ingredients selected from starches, microcrystalline cellulose and magnesium stearate.

39. A method of treating a disorder of reduced motility of the gastrointestinal tract in a mammal, the method comprising administering to the mammal, a capsule of claim 32.

40. The method of claim 39, wherein the disorder of reduced motility is chronic constipation, constipation-predominant irritable bowel syndrome, diabetic gastroparesis, drug-induced delayed transit, or functional dyspepsia.

41. A method of treating chronic constipation or constipation-predominant irritable bowel syndrome in a mammal, the method comprising administering to the mammal, a capsule of claim 32.