Selective inhibitors of α2 isoform of Na,K-ATPase and use thereof for reduction of intra-ocular pressure and as cardiotonic agents

Patent metadata

Field	Value
Publication number	US-9938316-B2
Application number	US-201414913366-A
Country	US
Kind code	B2
Filing date	Aug 27, 2014
Priority date	Aug 29, 2013
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

The present invention relates to digoxin and digitoxin derivatives that are selective inhibitors of the α2 isoform of Na,K-ATPase, and that reduce intra-ocular pressure. The invention further relates to uses of these derivatives for treating disorders associated with elevated intraocular pressure, such as glaucomas, and/or as cardiotonic agents.

First claim

What is claimed is:

1. A compound represented by the structure of general formula (I):

R is selected from the group consisting of —CH 2 —C(═O)—NH 2 (compound 1), —CH 3 (compound 2), —(CH 2 ) 2 —C(═O)—NH 2 (compound 3), —NHC(═O)—NH 2 (compound 4), —OH (compound 6), —CH(CH 3 )CONH 2 (compound 8), —CH(CH 2 OH)COOH (compound 9), —CH(CH 2 OH)CONH 2 (compound 10), —CH 2 CH 3 (compound 12), —(CH 2 ) 2 CH 3 (compound 13), —CH 2 CH(CH 3 ) 2 (compound 14), —CH 2 CF 3 (compound 15), —CH 2 C(═O)—NHOH (compound 17), —NHCSNH 2 (compound 18), —CH 2 CH 2 F (compound 19),
and
X is OH,
including salts, hydrates, solvates, polymorphs, geometrical isomers, optical isomers, enantiomers, diastereomers, and mixtures thereof.

2. The compound of claim 1 , being selective for α2 isoform of Na,K-ATPase over other isoforms of Na,K-ATPase.

3. The compound of claim 2 , being selective for the α2β1, α2β2 and/or α2β3 isoform of Na,K-ATPase over the α1β1 isoform of Na,K-ATPase.

4. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier or excipient.

5. The composition of claim 4 , being an ophthalmic composition suitable for topical application to the eye in the form of an eye-drop solution, an ointment, a suspension, a gel or a cream.

6. The composition of claim 4 , for treating a condition selected from the group consisting of ocular hypertension, glaucoma and heart failure.

7. A method of treating a condition, comprising the step of administering to a subject in need of such a treatment an effective amount of the compound of claim 1
wherein said condition is selected from the group consisting of ocular hypertension, glaucoma and heart failure.

8. The method of claim 7 , wherein the compound is selective for α2 isoform of Na,K-ATPase over other isoforms of Na,K-ATPase.

9. The method of claim 8 , wherein the compound is selective for the α2β1, α2β2 and/or α2β3 isoform of Na,K-ATPase over the α1β1 isoform of Na,K-ATPase.

10. The method of claim 7 , wherein the compound is administered in a pharmaceutical composition comprising said compound, and a pharmaceutically acceptable carrier or excipient.

Assignees

• Yeda Res & Dev

Inventors

• Karlish Steven J D
• Katz Adriana
• Tal Daniel M
• Marcovich Arie

Classifications

• C07J19/005

  Glycosides · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• C07J43/003 Primary

  not condensed · CPC title