Slc26a3 inhibitors and use thereof

Patent metadata

Field	Value
Publication number	US-2021363123-A1
Application number	US-201917050393-A
Country	US
Kind code	A1
Filing date	Apr 25, 2019
Priority date	Apr 25, 2018
Publication date	Nov 25, 2021
Grant date	—

Abstract

Provided herein are inhibitors of SLC26A3, which is an anion (CV, HCO3, 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

1 . 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,
provided that when R 2 is carboxyethyl, R 1 is substituted benzyl, or when R 2 is carboxymethyl, R 3 and R 4 are each methyl, R 1 is not benzyl.

2 . (canceled)

3 . The pharmaceutical composition of claim 1 , wherein R 1 has the following structure:

wherein:
X is alkyl, C 3 -C 5 cycloalkyl, halo, haloalkyl, alkoxy, NO 2 , or haloalkoxy; and
n is 1, 2, 3, 4 or 5.

4 . The pharmaceutical composition of claim 3 , wherein X is bromo, chloro, fluoro, iodo, cyclopropyl, CF 3 , methyl, NO 2 or methoxy and n is 1 or 2.

5 . The pharmaceutical composition of claim 1 , wherein R 1 has one of the following structures:

6 . The pharmaceutical composition of claim 1 , wherein R 2 has one of the following structures:

7 . (canceled)

8 . The pharmaceutical composition of claim 1 wherein the compound is 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.

9 . The pharmaceutical composition of claim 1 , wherein the compound has one of the following structures:

10 .- 17 . (canceled)

18 . A method for treating or preventing a condition, disease, or disorder associated with SLC26A3-mediated Cl − , HCO 3 − , or oxalate exchange in a subject, 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.

19 . The method of claim 18 wherein the condition, disease, or disorder is constipation or hyperoxaluria.

20 . The method of claim 19 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.

21 . The method of claim 18 , wherein the compound is 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.

22 . The method of claim 21 , wherein the compound is:

23 . The method of claim 18 , wherein the compound of Formula (I) is combined with an NHE3 inhibitor.

24 . The method of claim 23 wherein the NHE3 inhibitor is tenapanor.

25 . 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.

26 . The method of claim 25 , wherein the subject in need of decreasing urinary oxalate excretion suffers from enteric hyperoxaluria, primary hyperoxaluria or calcium oxalate kidney stone disease.

27 . The method of claim 25 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.

28 . The method of claim 25 , wherein the compound is

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

29 . A compound having one of the following structures:

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

30 . (canceled)

Assignees

• Univ California

Inventors

• Verkman Alan S
• Cil Onur
• Haggie Peter M

Classifications

• A61P13/12

  of the kidneys · CPC title

• A61K31/37 Primary

  Coumarins, e.g. psoralen · CPC title

• A61K31/4164

  1,3-Diazoles · CPC title

• C07D311/18 Primary

  substituted otherwise than in position 3 or 7 · CPC title

• A61P13/02

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