Small molecule activators of calcium-activated chloride channels and methods of use

Patent metadata

Field	Value
Publication number	US-9790218-B2
Application number	US-201214237079-A
Country	US
Kind code	B2
Filing date	Aug 3, 2012
Priority date	Aug 5, 2011
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

Provided herein are small molecule activators of calcium-activated chloride channels. These small molecules may be used for treatment of diseases and disorders that are treatable by activating calcium-activated chloride channels, such as cystic fibrosis, disorders related to salivary gland dysfunction (for example, Sjogren's syndrome and dysfunction following radiation injury), dry eye syndrome, and intestinal hypomotility.

First claim

We claim the following:

1. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of structure (I):

or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein
R 1 , R 2 and R 3 are each independently alkoxy;
R 4 is heteroaralkyl, or heterocyclylalkyl; and
R 5 and R 6 are each independently hydrogen, alkoxy or halo,
wherein the pharmaceutical composition is inhalable and the pharmaceutically acceptable excipient is not dimethyl sulfoxide (DMSO).

2. The pharmaceutical composition of claim 1 , wherein the compound has one of the following structures (Ia), (Ib) or (Ic):

3. The pharmaceutical composition of claim 1 , wherein at least one of R 1 , R 2 or R 3 is methoxy.

4. The pharmaceutical composition of claim 1 , wherein R 4 is tetrahydrofuran-2-yl-methyl, furan-2-yl-methyl, tetrahydropyran-2-yl-methyl, pyrid-4-yl-methyl or pyrid-2-yl-methyl.

5. The pharmaceutical composition of claim 1 , wherein at least one of R 5 or R 6 is hydrogen.

6. The pharmaceutical composition of claim 1 , wherein at least one of R 5 or R 6 is methoxy, chloro, or fluoro.

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

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

Assignees

• Verkman Alan S
• Namkung Wan
• Univ California

Inventors

• Verkman Alan S
• Namkung Wan

Classifications

• A61K31/41

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/426

  1,3-Thiazoles · CPC title

• C07D277/46

  by carboxylic acids, or sulfur or nitrogen analogues thereof · CPC title

• C07D417/12 Primary

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