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-11318129-B2
Application number	US-202016773723-A
Country	US
Kind code	B2
Filing date	Jan 27, 2020
Priority date	Dec 31, 2008
Publication date	May 3, 2022
Grant date	May 3, 2022

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 pharmaceutical composition comprising:
a) a compound having the structure of Formula (X):

wherein:
n is 2;
NHE has the structure

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 H;
R 7 is H;
R 8 is a bond linking to L;
L is a polyalkylene glycol linker;
Core has the following structure:

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 1-8 alkylene, optionally substituted benzene, pyridinyl, a polyethylene glycol linker, and —(CH 2 ) 1-6 O(CH 2 ) 1-6 —
b) a pharmaceutically acceptable carrier, diluent or excipient, and
c) a fluid-absorbing polymer.

2. The pharmaceutical composition of claim 1 , wherein the fluid-absorbing polymer has a fluid absorbency of at least about 15 g of isotonic fluid per g of polymer under a static pressure of about 5 kPa.

3. The pharmaceutical composition of claim 1 , wherein the fluid-absorbing polymer has a fluid absorbency of at least about 15 g of isotonic fluid per g of polymer under a static pressure of about 10 kPa.

4. The pharmaceutical composition of claim 1 , wherein the fluid-absorbing polymer is characterized by a fluid absorbency of at least about 10 g/g.

5. The pharmaceutical composition of claim 1 , wherein the fluid-absorbing polymer is characterized by a fluid absorbency of at least about 15 g/g.

6. The pharmaceutical composition of claim 1 , wherein the fluid-absorbing polymer is a crosslinked polyacrylate.

7. The pharmaceutical composition of claim 1 , wherein the fluid-absorbing polymer is calcium Carbophil.

8. The pharmaceutical composition of claim 1 , wherein the fluid-absorbing polymer is a hydrogel.

9. The pharmaceutical composition of claim 1 , wherein the fluid-absorbing polymer is an N-alkyl acrylamide.

10. The pharmaceutical composition of claim 1 , wherein the fluid-absorbing polymer is a superporous gel.

11. The pharmaceutical composition of claim 1 , wherein the fluid-absorbing polymer is selected from the group consisting of xanthan, guar, wellan, hemicelluloses, alkyl-cellulose hydro-alkyl-cellulose, carboxy-alkyl-cellulose, carrageenan, dextran, hyaluronic acid and agarose.

12. The pharmaceutical composition of claim 1 , the fluid-absorbing polymer is psyllium.

13. The pharmaceutical composition of claim 1 , wherein the fluid-absorbing polymer is a polysaccharide that includes xylose and arabinose.

14. The pharmaceutical composition of claim 1 , further comprising another pharmaceutically active agent or compound.

15. The pharmaceutical composition of claim 14 wherein the composition further comprises another pharmaceutically active agent or compound selected from the group consisting of a diuretic, cardiac glycoside, ACE inhibitor, angiotensin-2 receptor antagonist, calcium channel blocker, beta blocker, alpha blocker, central alpha agonist, vasodilator, blood thinner, anti-platelet agent, lipid-lowering agent, and peroxisome proliferator-activated receptor (PPAR) gamma agonist agent.

16. The pharmaceutical composition of claim 14 wherein the composition further comprises another pharmaceutically active agent or compound selected from the group consisting of an analgesic peptide or agent.

17. The composition of claim 1 , wherein NHE has one of the following structures:

18. The composition of claim 1 , wherein L is a polyethylene glycol linker.

19. The composition of claim 1 , wherein Core is selected from the group consisting of:

Assignees

• Ardelyx Inc

Inventors

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

Classifications

• C07D217/16

  substituted by oxygen atoms · CPC title

• C07D217/04

  with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom · CPC title

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• C07F9/3882

  Arylalkanephosphonic acids (C07F9/3839 takes precedence) · CPC title

• A61K31/4725 Primary

  containing further heterocyclic rings · CPC title