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-10543207-B2
Application number	US-201715402211-A
Country	US
Kind code	B2
Filing date	Jan 9, 2017
Priority date	Dec 31, 2008
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

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 method for treating a disorder selected from the group consisting of heart failure, chronic kidney disease, end-stage renal disease, liver disease, gastrointestinal tract disorder, hypertension, edema, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound having the formula (X):
Core L-NHE) n   (X)

wherein:
n is 2;
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 .

2. The method of claim 1 , wherein the heart failure is congestive heart failure.

3. The method of claim 1 , wherein the hypertension is associated with dietary salt intake.

4. The method of claim 1 , wherein the heart failure is associated with fluid overload.

5. The method of claim 4 , wherein the fluid overload is associated with peroxisome proliferator-activated receptor (PPAR) gamma agonist therapy.

6. The method of claim 1 , wherein the edema is caused by chemotherapy, pre-menstrual fluid overload or preeclampsia.

7. The method of claim 1 , wherein the compound is administered orally, by rectal suppository, or enema.

8. The method of claim 1 , wherein the method comprises administering a pharmaceutically effective amount of the compound in combination with one or more additional pharmaceutically active compounds or agents.

9. The method of claim 8 , wherein the one or more additional pharmaceutically active compounds or agents is selected from the group consisting of a diuretic, cardiac glycoside, ACE inhibitor, angiotensin-2 receptor antagonist, aldosterone 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.

10. The method of claim 9 , wherein the diuretic is selected from the group consisting of a high ceiling loop diuretic, a benzothiadiazide diuretic, a potassium sparing diuretic, and a osmotic diuretic.

11. The method of 10 , wherein the pharmaceutically effective amount of the compound or composition, and the one or more additional pharmaceutically active compounds or agents, are administered as part of a single pharmaceutical preparation.

12. The method of 10 , wherein the pharmaceutically effective amount of the compound , and the one or more additional pharmaceutically active compounds or agents, are administered as individual pharmaceutical preparations.

13. The method of claim 12 , wherein the individual pharmaceutical preparation are administered sequentially.

14. The method of claim 13 , wherein the individual pharmaceutical preparation are administered simultaneously.

15. A method for treating a gastrointestinal tract disorder selected from the group consisting of constipation, chronic intestinal pseudo obstruction, colonic pseudo obstruction, Crohn's disease, ulcerative colitis, and inflammatory bowel disease, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound having the formula (X):
Core L-NHE) n   (X)

wherein:
n is 2;
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 .

16. The method of claim 15 , wherein the gastrointestinal tract disorder is chronic constipation.

17. The method of claim 15 , wherein the gastrointestinal tract disorder is chronic idiopathic constipation.

18. The method of claim 15 , wherein the gastrointestinal tract disorder is chronic constipation occurring in cystic fibrosis patients.

19. The method of claim 15 , wherein the gastrointestinal tract disorder is opioid-induced constipation.

20. The method of claim 15 , wherein the gastrointestinal tract disorder is selected from the group consisting of chronic intestinal pseudo-obstruction and colonic pseudo-obstruction.

21. The method of claim 15 , wherein the gastrointestinal tract disorder is Crohn's disease.

22. The method of claim 15 , wherein the gastrointestinal tract disorder is ulcerative colitis.

23. The method of claim 15 , wherein the gastrointestinal tract disorder is a disease referred to as inflammatory bowel disease.

24. The method of claim 15 , wherein the gastrointestinal tract disorder is associated with chronic kidney disease (stage 4 or 5).

25. The method of claim 15 , wherein the gastrointestinal tract disorder is constipation induced by calcium supplement.

26. The method of claim 15 , wherein the constipation to be treated is associated with the use of a therapeutic agent.

27. The method of claim 15 , wherein the constipation to be treated is associated with a neuropathic disorder.

28. The method of claim 15 , wherein the constipation to be treated is post-surgical constipation .

29. The method of claim 15 , wherein the constipation to be treated is idiopathic.

30. The method of claim 15 , wherein the constipation to be treated is associated with neuropathic, metabolic or an endocrine disorder .

31. The method of claim 15 , wherein the constipation to be treated is due the use of drugs selected from analgesics , antihypertensives, anticonvulsants, antidepressants, antispasmodics or antipsychotics.

32. The method of claim 15 , wherein the compound is administered to treat or reduce pain associated with a gastrointestinal tract disorder.

33. The method of claim 15 , wherein the compound is administered to treat or reduce visceral hypersensitivity associated with a gastrointestinal tract disorder.

34. The method of claim 15 , wherein the compound is administered to treat or reduce

Assignees

• Ardelyx Inc

Inventors

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

Classifications

• C07D217/04

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

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07F9/4056

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