SLC26A3 inhibitors and use thereof

Patent metadata

Field	Value
Publication number	US-12187694-B2
Application number	US-202318156333-A
Country	US
Kind code	B2
Filing date	Jan 18, 2023
Priority date	Apr 25, 2018
Publication date	Jan 7, 2025
Grant date	Jan 7, 2025

Abstract

Provided herein are inhibitors of SLC26A3, which is an anion (Cl − , HCO 3 − , oxalate) exchanger expressed in intestinal epithelial cells. SLC26A3 inhibitors have potential utility for treatment of constipation including chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), constipation-predominant irritable bowel syndrome (IBS-C), cystic fibrosis-associated constipation, meconium ileus, distal intestinal obstruction syndrome, calcium oxalate kidney stone disease, enteric hyperoxaluria and primary hyperoxalurias.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising a physiologically acceptable excipient and a compound having one of the following structures:

2. A pharmaceutical composition comprising a physiologically acceptable excipient and a compound having one of the following structures:

3. A method for treating a condition, disease, or disorder associated with SLC26A3-mediated Cl − , HCO 3 − , or oxalate exchange in a subject, wherein the condition, disease, or disorder is constipation or hyperoxaluria, the method comprising administering to the subject a pharmaceutical composition comprising a physiologically acceptable excipient and a compound of Formula (I):

or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof, wherein:
R 1 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkylalkyl, optionally substituted alkoxyalkyl, carboxyC 1 -C 3 alkyl, optionally substituted heteroarylalkyl, —S(O) 2 aryl (wherein aryl is optionally substituted), or optionally substituted arylalkyl;
R 2 is carboxyC 1 -C 3 alkyl;
R 3 is C 1 -C 4 alkyl; and
R 4 is C 1 -C 4 alkyl.

4. The method of claim 3 wherein the condition, disease, or disorder is chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), constipation-predominant irritable bowel syndrome (IBS-C), kidney stone disease, CF-associated constipation, meconium ileus, distal intestinal obstruction syndrome, calcium oxalate kidney stone disease, enteric hyperoxaluria, or primary hyperoxaluria.

5. A method for decreasing urinary oxalate excretion in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof, wherein:
R 1 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 3 alkenyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 cycloalkylalkyl, optionally substituted alkoxyalkyl, carboxyC 1 -C 3 alkyl, optionally substituted heteroarylalkyl, —S(O) 2 aryl (wherein aryl is optionally substituted) or optionally substituted arylalkyl;
R 2 is carboxyC 1 -C 3 alkyl;
R 3 is C 1 -C 4 alkyl; and
R 4 is C 1 -C 4 alkyl.

6. The method of claim 5 , wherein the subject in need of decreasing urinary oxalate excretion suffers from enteric hyperoxaluria, primary hyperoxaluria or calcium oxalate kidney stone disease.

7. The method of claim 5 wherein the compound has a structure represented by Formula (Ia):

wherein, X is alkyl, C 3 -C 5 cycloalkyl, halo, haloalkyl, alkoxy, NO 2 , or haloalkoxy; and n is 1, 2, or 3.

8. The method of claim 5 , wherein the compound is

or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof.

9. A method for treating a condition, disease, or disorder associated with SLC26A3-mediated Cl − , HCO 3 − , or oxalate exchange in a subject, wherein the condition, disease, or disorder is constipation or hyperoxaluria, the method comprising administering to the subject a pharmaceutical composition comprising a physiologically acceptable excipient and a compound of Formula (II):

or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof, wherein:
R 7 is optionally substituted aryl; and
R 8 is optionally substituted aryl.

10. The method of claim 9 , wherein R 7 has the following structure:

wherein:
X is hydrogen, alkyl, halo, haloalkyl, alkoxy or haloalkoxy; and
n is 0, 1, 2, 3, 4 or 5.

11. The method of claim 9 , wherein R 8 has the following structure:

wherein:
X is alkyl, halo, haloalkyl, alkoxy or haloalkoxy; and
n is 1, 2, 3, 4 or 5.

12. The method of claim 9 , wherein the compound has one of the following structures:

Assignees

• Univ California

Inventors

• Verkman Alan S
• Cil Onur
• Haggie Peter M

Classifications

• A61P13/12

  of the kidneys · CPC title

• A61P13/02

  of urine or of the urinary tract, e.g. urine acidifiers · CPC title

• C07D311/16

  substituted in position 7 · CPC title

• A61K31/4164

  1,3-Diazoles · CPC title

• A61P1/10

  Laxatives · CPC title