Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders

Patent metadata

Field	Value
Publication number	US-12016856-B2
Application number	US-202217711863-A
Country	US
Kind code	B2
Filing date	Apr 1, 2022
Priority date	Dec 31, 2008
Publication date	Jun 25, 2024
Grant date	Jun 25, 2024

Abstract

The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. The methods generally comprise administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto. The present disclosure is still further directed to a method wherein a mammal is administered such a compound with a fluid-absorbing polymer, such that the combination acts as described above and further provides the ability to sequester fluid and/or salt present in the GI tract.

First claim

What is claimed is:

1. A compound or a pharmaceutically acceptable salt thereof having the formula:

2. The compound of claim 1 , wherein said compound is the free base.

Assignees

• Ardelyx Inc

Inventors

• Charmot Dominique
• Navre Marc
• Carreras Christopher
• Bell Noah
• Leadbetter Michael
• Jacobs Jeffrey W

Classifications

• A61K31/662

  Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon · CPC title

• C07D217/16

  substituted by oxygen atoms · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D217/14

  other than aralkyl radicals · CPC title

• C07F9/4056

  Esters of arylalkanephosphonic acids (C07F9/4025 takes precedence) · CPC title