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

Patent metadata

Field	Value
Publication number	US-9408840-B2
Application number	US-201514592200-A
Country	US
Kind code	B2
Filing date	Jan 8, 2015
Priority date	Dec 31, 2008
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

The present disclosure is directed to compounds of the structure (X):

Core L-NHE) n   (X)

wherein:
n is 2 or 3; NHE has the structure

wherein:
R 1 is H or —SO 2 —NR 7 R 8 —; R 2 is selected from H, —NR 7 (CO)R 8 , —SO 2 —NR 7 R 8 — and —NR 7 R 8 ; R 3 is hydrogen; R 7 is hydrogen; R 8 is a bond linking to L; L is a polyalkylene glycol linker; and Core has the following structure:

wherein:
X is selected from the group consisting of a bond, —O—, —NH—, NHC(═O)—, —NHC(═O)NH— and —NHSO 2 —; and Y is selected from the group consisting of a bond, optionally substituted C 1-6 alkylene, optionally substituted benzene, pyridinyl, a polyethylene glycol linker and —(CH 2 ) 1-6 O(CH 2 ) 1-6 —, and methods of using such compounds for the treatment of irritable bowel syndrome, chronic kidney disease and end-stage renal disease.

First claim

The invention claimed is:

1. A method for treating irritable bowel syndrome in a subject in need thereof comprising administering a compound, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure (X):
Core L-NHE) n   (X)

wherein:
n is 2;
NHE has the structure

wherein:
R 1 is H or —SO2-NR 7 R 8 —;
R 2 is selected from H, —NR 7 (CO)R 8 , —SO 2 —NR 7 R 8 — and —NR 7 R 8 ;
R 3 is hydrogen;
R 7 is hydrogen;
R 8 is a bond linking to L;
L is a polyalkylene glycol linker; and
Core has the following structure:

wherein:
X is selected from the group consisting of a bond, —O—, —NH—, NHC(═O)—, —NHC(═O)NH—, and —NHSO 2 —;
Y is selected from the group consisting of a bond, optionally substituted C 1-6 alkylene, optionally substituted phenyl, pyridinyl, a polyethylene glycol linker and —(CH 2 ) 1-6 O(CH 2 ) 1-6 —.

2. A method of claim 1 , wherein the NHE has one of the following structures:

or pharmaceutically acceptable salt thereof.

3. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is a polyethylene glycol linker.

4. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the Core is selected from the group consisting of:

5. The method of claim 1 , wherein the compound is selected from:

6. The method of claim 1 , wherein the pharmaceutically acceptable salt is selected from:

Assignees

• Ardelyx Inc

Inventors

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

Classifications

• A61P9/12

  Antihypertensives · CPC title

• C07D215/14

  Radicals substituted by oxygen atoms · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/662

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

• A61K31/472

  Non-condensed isoquinolines, e.g. papaverine · CPC title