Selective inhibitors of Alpha2-containing isoforms of Na,K-ATPase and use thereof for reduction of intraocular pressure

Patent metadata

Field	Value
Publication number	US-11077128-B2
Application number	US-202016847737-A
Country	US
Kind code	B2
Filing date	Apr 14, 2020
Priority date	Jul 19, 2015
Publication date	Aug 3, 2021
Grant date	Aug 3, 2021

Abstract

Provided herein are alpha2-selective Na,K-ATPase inhibitors and prodrugs thereof, characterized by having a cyclic moiety attached to a digoxin or digitoxin derivative, as well as uses thereof in lowering intraocular pressure and in treating glaucoma and heart conditions.

First claim

What is claimed is:

1. A pharmaceutical composition comprising as active ingredients:
at least one ingredient selected from the group consisting of a prostaglandin analog, a β-blocker, an adrenergic agent, an α2-adrenergic receptor agonist, a miotic agent, a carbonic anhydrase inhibitor and a cholinergic agonist; and
a compound represented by Formula III:

including any pharmaceutically acceptable salt, hydrate, solvate, enantiomer and diastereomer thereof, and any mixtures thereof, and a pharmaceutically acceptable carrier, wherein:
X is H or OH;
R′ is selected from the group consisting of OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl (C 1 -C 6 alkyl substituted with at least one halo), —(CR b R c )nSi(R a ) 3 , —(CR b R c )n-C(═Y)—NR 1 R 2 , —(CR b R c )n-C(═Y)—NHOH, —(CR d R e )n-C(═Y)—COOR 3 , —NHC(═Y)NR 1 R 2 and —(CR b R c )n-NH 2 ;
Y is O or S;
R1, R2 and R3 are each independently H or a C 1 -C 4 alkyl;
Ra is a C 1 -C 4 alkyl;
Rb, Rc and Rd are each independently selected from H, a C 1 -C 4 alkyl and a C 1 -C 4 hydroxyalkyl;
Re is selected from a C 1 -C 4 alkyl and a C 1 -C 4 hydroxyalkyl; and
n is 0, 1 or 2.

2. The pharmaceutical composition of claim 1 , being packaged in a packaging material and identified in print, or on said packaging material, for use in reducing intraocular pressure (IOP).

3. The pharmaceutical composition of claim 1 , wherein said at least one ingredient is said prostaglandin analog.

4. The pharmaceutical composition of claim 1 , wherein said at least one ingredient is said β-blocker.

5. The pharmaceutical composition of claim 1 , wherein said at least one ingredient is said adrenergic agent.

6. The pharmaceutical composition of claim 1 , wherein said at least one ingredient is said α2-adrenergic receptor agonist.

7. The pharmaceutical composition of claim 1 , wherein said at least one ingredient is said miotic agent.

8. The pharmaceutical composition of claim 1 , wherein said at least one ingredient is said carbonic anhydrase inhibitor.

9. The pharmaceutical composition of claim 1 , wherein said at least one ingredient is said cholinergic agonist.

10. A method of treating a heart condition in a subject in need thereof, comprising co-administering to the subject a therapeutically effective amount of:
an agent selected from the group consisting of a β-blocker, an anticoagulation agent, an angiotensin-converting-enzyme inhibitor and an angiotensin II receptor antagonist; and
a compound represented by Formula III:

including any pharmaceutically acceptable salt, hydrate, solvate, enantiomer and diastereomer thereof, and any mixtures thereof, wherein:
X is H or OH;
R′ is selected from the group consisting of OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl (C 1 -C 6 alkyl substituted with at least one halo), —(CR b R c )nSi(R a ) 3 , —(CR b R c )n-C(═Y)—NR 1 R 2 , —(CR b R c )n-C(═Y)—NHOH, —(CR d R e )n-C(═Y)—COOR 3 , —NHC(═Y)NR 1 R 2 and —(CR b R c )n—NH 2 ;
Y is O or S;
R 1 , R 2 and R 3 are each independently H or a C 1 -C 4 alkyl;
Ra is a C 1 -C 4 alkyl;
Rb, Rc and Rd are each independently selected from H, a C 1 -C 4 alkyl and a C 1 -C 4 hydroxyalkyl;
Re is selected from a C 1 -C 4 alkyl and a C 1 -C 4 hydroxyalkyl; and
n is 0, 1 or 2.

11. The method of claim 10 , wherein said agent is said β-blocker.

12. The method of claim 10 , wherein said agent is said anticoagulation agent.

13. The method of claim 10 , wherein said agent is said angiotensin-converting-enzyme inhibitor.

14. The method of claim 10 , wherein said agent is said angiotensin II receptor antagonist.

Assignees

• Yeda Res & Dev

Inventors

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

Classifications

• C07H17/00

  Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07J43/003

  not condensed · CPC title

• C07J19/005

  Glycosides · CPC title