CFTR regulators and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10604492-B2
Application number	US-201616016290-A
Country	US
Kind code	B2
Filing date	Dec 23, 2016
Priority date	Dec 24, 2015
Publication date	Mar 31, 2020
Grant date	Mar 31, 2020

Abstract

Provided herein are compounds that activate CFTR and methods for treating constipation, dry eye disorders, and other diseases and disorders.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
X is —O—;
R 2 is C 2 -C 4 haloalkyl substituted with at least four fluorines, substituted heteroalkyl, or unsubstituted heteroalkyl;
R 3 is hydrogen;
R 4 is substituted or unsubstituted alkyl;
R 5 is hydrogen; and
R 1 , R 6 , R 7 , R 8 and R 9 are each hydrogen.

2. The compound of claim 1 , wherein R 4 is —CH 3 or —CH 2 CH 3 .

3. The compound of claim 1 , wherein R 2 is C 2 -C 4 haloalkyl substituted with at least four fluorines.

4. The compound of claim 3 , wherein R 2 is —CH(CF 3 ) 2 or —CH 2 —CF 2 —CHF 2 .

5. The compound of claim 1 , wherein the compound of Formula I is:

6. A compound that is:

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 , wherein the compound is:

8. The compound of claim 6 , wherein the compound is a pharmaceutically acceptable salt of:

9. A pharmaceutical composition, comprising a pharmaceutically acceptable excipient, and a compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
X is —O—;
R 2 is C 2 -C 4 haloalkyl substituted with at least four fluorines, substituted heteroalkyl; or unsubstituted heteroalkyl;
R 3 is hydrogen;
R 4 is substituted or unsubstituted alkyl;
R 5 is hydrogen; and
R 1 , R 6 , R 7 , R 8 and R 9 are hydrogen.

10. The pharmaceutical composition of claim 9 , wherein R 4 is —CH 3 or —CH 2 CH 3 .

11. The pharmaceutical composition of claim 9 , wherein R 2 is C 2 -C 4 haloalkyl substituted with at least four fluorines.

12. The pharmaceutical composition of claim 11 , wherein R 2 is —CH(CF 3 ) 2 or —CH 2 —CF 2 —CHF 2 .

13. The pharmaceutical composition of claim 9 , wherein the compound of Formula I is:

14. A pharmaceutical composition comprising a compound that is:

or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of claim 14 , wherein the compound is:

16. The pharmaceutical composition of claim 14 , wherein the compound is a pharmaceutically acceptable salt of:

Assignees

• Univ California
• The Regents Of The Universtiy Of California

Inventors

• Verkman Alan S
• Levin Marc H
• Cil Onur
• Lee Sujin

Classifications

• C07D251/46 Primary

  with oxygen or sulfur atoms attached to the two other ring carbon atoms · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• C07D413/12

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

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P1/10

  Laxatives · CPC title