Store overload-induced calcium release inhibitors and methods for producing and using the same

Patent metadata

Field	Value
Publication number	US-12091408-B2
Application number	US-201414915368-A
Country	US
Kind code	B2
Filing date	Sep 27, 2014
Priority date	Aug 30, 2013
Publication date	Sep 17, 2024
Grant date	Sep 17, 2024

Abstract

The present invention provides compounds having store overload-induced Ca2+ release (SOICR) inhibitory activity and methods for producing and using the same. In particular, compounds of the invention is of the formula: R1—X1-L-X2—R2, wherein R1, X1, L, X2, and R2 are those defined herein.

First claim

What is claimed is:

1. A compound of the formula:
R 1 —X 1 -L-X 2 —R 2

wherein
R 1 is selected from the group consisting of: carbazol-2-yl; carbazol-3-yl; and carbazol-4-yl, each of which is optionally substituted;
X 1 is O;
X 2 is O;
R 2 is selected from the group consisting of substituted phenyl; substituted benzyl;
optionally substituted benzo[d]oxazolyl, and optionally substituted benzofuranyl; and
L is a linker selected from the group consisting of:

wherein m is 1 or 2; and n is 1 to 4;
provided
when R 1 is optionally substituted carbazol-4-yl, then R 2 is optionally substituted benzyl;
when R 1 is unsubstituted carbazol-3-yl, then linker L has at least 7 backbone atoms in the chain; and
when R 1 is unsubstituted carbazol-2-yl, then linker L has at least 7 backbone atoms in the chain, and
R 2 is benzo[d]oxazolyl, benzofuranyl, or phenyl substituted with at least one substituent selected from halide and haloalkyl.

2. The compound according to claim 1 , wherein R 1 is selected from the group consisting of carbazol-3-yl and carbazol-4-yl, each of which is optionally substituted.

3. The compound according to claim 1 , wherein L is:

wherein m is 1 or 2; and n is 1 to 4.

4. A method of treating cardiac arrhythmia in a heart failure patient, said method comprising administering to a heart failure patient a therapeutically effective amount of a compound of claim 1 to treat cardiac arrhythmia.

5. The method of claim 4 , wherein said compound of claim 1 inhibits store-overload-induced calcium release (SOICR).

6. The method of claim 5 , wherein SOICR inhibition of the compound of claim 1 is achieved by regulating calcium efflux through the RyR2 channel.

7. The method of claim 4 , wherein calcium ion-induced calcium ion release (CICR) is minimally inhibited or not inhibited.

8. A pharmaceutical composition comprising (i) a compound of claim 1 , or a pharmaceutically acceptable salt or a prodrug thereof; and (ii) a pharmaceutically acceptable carrier.

9. The compound according to claim 1 , wherein the compound is:

Assignees

• Back Tom
• Chen Wayne
• Smith Chris
• Jiang Dawei
• Uti Lp

Inventors

• Back Tom
• Chen Wayne
• Smith Chris
• Jiang Dawei

Classifications

• C07D279/16

  condensed with one six-membered ring · CPC title

• C07D235/08

  Radicals containing only hydrogen and carbon atoms · CPC title

• C07C217/54

  having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton · CPC title

• C07C2603/74

  Adamantanes · CPC title

• C07C2603/18

  Fluorenes; Hydrogenated fluorenes · CPC title