Indazole-carboxamide compounds as 5-HT4 receptor agonists

• US 8,044,045 B2
• Filed: 01/19/2010
• Issued: 10/25/2011
• Est. Priority Date: 02/18/2004
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Liu, Jyanwei, Gendron, Roland, Long, Daniel D., Turner, S. Derek, Fatheree, Paul R., Marquess, Daniel, Goldblum, Adam A., Choi, Seok-Ki
• Primary Examiner(s): Seaman; D M
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US12/689,763
• Publication Number:
  US 20100261716A1
• Time in Patent Office: 644 Days
• Field of Search: 514/228.2, 514/253.04, 514/304
• 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 1/10 Laxatives
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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
• CPC Class Codes: G01N 2333/70571 for neuromediators, e.g. serotonin receptor, dopamine receptor
• CPC Class Codes: G01N 33/5008 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/5044 involving specific cell types

Abstract

The invention provides novel indazole-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 method of treating a disorder of reduced motility of the gastrointestinal tract in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I):

2. The method of claim 1 wherein R¹ is hydrogen or halo and R² is isopropyl or C_4-5cycloalkyl.

3. The method of claim 1 wherein W is a group of formula (II) wherein R^a is C_1-3alkyl and R^b is methyl.

4. The method of claim 1 wherein W is a group of formula (III) wherein p is 0 and n is 1.

5. The method of claim 1 wherein W is a group of formula (IV) wherein m is 1 and q is 1.

6. The method of claim 1:

wherein;

R¹ is hydrogen or halo;

R² is C_3-4alkyl or C_4-5cycloalkyl; and

W is selected from the group consisting of;

(i) a group of formula (II) wherein X is NC(O)CH₃, S(O)₂, or NS(O)₂CH₃;

(ii) a group of formula (III) wherein p is 0, n is 1, and Y is NCH₃C(O)CH₃; and

(iii) a group of formula (IV) wherein R^z is methyl, m is 1, q is 1, and Z is NC(O)CH₃, S(O)₂, or NS(O)₂CH₃.

7. The method of claim 1 wherein the disorder of reduced motility is chronic constipation, constipation-predominant irritable bowel syndrome, diabetic and idiopathic gastroparesis, or functional dyspepsia.

8. The method of claim 6 wherein the disorder of reduced motility is chronic constipation, constipation-predominant irritable bowel syndrome, diabetic and idiopathic gastroparesis, or functional dyspepsia.

9. A method of treating a mammal having a medical condition ameliorated by treatment with a 5-HT₄ receptor agonist, wherein the medical condition is irritable bowel syndrome, chronic constipation, functional dyspepsia, delayed gastric emptying, gastroesophageal reflux disease, gastroparesis, post-operative ileus, intestinal pseudo-obstruction, or drug-induced delayed transit, the method comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I):

10. The method of claim 9

wherein:

R¹ is hydrogen or halo;

R² is C_3-4alkyl or C_4-5cycloalkyl; and

W is selected from the group consisting of;

(i) a group of formula (II) wherein X is NC(O)CH₃, S(O)₂, or NS(O)₂CH₃;

(ii) a group of formula (III) wherein p is 0, n is 1, and Y is NCH₃C(O)CH₃; and

(iii) a group of formula (IV) wherein R^z is methyl, m is 1, q is 1, and Z is NC(O)CH₃, S(O)₂, or NS(O)₂CH₃.