SELECTIVE INHIBITORS OF ALPHA2 ISOFORM OF Na,K-ATPase AND USE FOR REDUCTION OF INTRA-OCULAR PRESSURE

Patent metadata

Field	Value
Publication number	US-2016244479-A1
Application number	US-201414913366-A
Country	US
Kind code	A1
Filing date	Aug 27, 2014
Priority date	Aug 29, 2013
Publication date	Aug 25, 2016
Grant date	—

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

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

R is selected from the group consisting of OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl,
—(CR b R c ) n Si(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 ; and —NHC(═Y)NR 1 R 2 ;
Y is O or S;
X is H or OH;
R 1 , R 2 and R 3 are each independently H or a C 1 -C 4 alkyl;
R a is a C 1 -C 4 alkyl;
R b , R c and R d are each independently selected from H, a C 1 -C 4 alkyl and a C 1 -C 4 hydroxy alkyl;
R e is selected from a C 1 -C 4 alkyl and a C 1 -C 4 hydroxyalkyl; and
n is 0, 1 or 2;
including salts, hydrates, solvates, polymorphs, geometrical isomers, optical isomers, enantiomers, diastereomers, and mixtures thereof.

2 . The compound of claim 1 , wherein R is selected from the group consisting of CZ 3 , —CZ 2 CZ 3 , —(CH 2 ) 2 CH 3 , —CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 and —C(CH 3 ) 3 , wherein each Z is independently at each occurrence H or halogen.

3 . The compound of claim 2 , wherein each Z is H or F.

4 . The compound of claim 1 , wherein R 1 , R 2 and R 3 are each H.

5 - 6 . (canceled)

7 . The compound of claim 1 , wherein R is selected from the group consisting of —CH 2 —C(═O)—NH 2 , —CH 3 , —(CH 2 ) 2 —C(═O)—NH 2 , NHC(═O)—NH 2 , OH, —CH(CH 3 )CONH 2 , —CH(CH 2 OH)COOH, —CH(CH 2 OH)CONH 2 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 C(CH 3 ) 2 , —CH 2 CF 3 , —CH 2 CONHOH, —NHCSNH 2 , —CH 2 CH 2 F, —CH(CH 2 ) 3 , —C(CH 3 ) 3 , and —CH 2 —Si(CH 3 ) 3 .

8 . The compound of claim 1 , wherein X is OH, and the compound is a digoxin derivative.

9 . The compound of claim 8 , wherein 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), —CH(CH 3 ) 2 (compound 21), —C(CH 3 ) 3 (compound 22), and methyl(trimethylsilyl)(—CH 2 —Si(CH 3 ) 3 ) (compound 23).

10 - 26 . (canceled)

27 . The compound of claim 1 , wherein X is H, and the compound is a digitoxin derivative.

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

29 . The compound of claim 28 , being selective for the α2β1, α2β2 and/or α2β3 isoform of Na,K-ATPase over the α1β1 isoform of Na,K-ATPase.

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

31 . The composition of claim 30 , 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.

32 - 33 . (canceled)

34 . The composition of claim 30 , for treating a condition selected from the group consisting of ocular hypertension, glaucoma and heart failure.

35 . (canceled)

36 . A method of treating a condition, comprising the step of administering to a subject in need of such a treatment an effective amount of a compound represented by the structure of formula (IA):

wherein
R is selected from the group consisting of OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(CR b R c ) n Si(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;
X is H or OH;
R 1 , R 2 and R 3 are each independently H or a C 1 -C 4 alkyl;
R a is a C 1 -C 4 alkyl;
R b , R c , R d and R e are each independently selected from H, a C 1 -C 4 alkyl and a C 1 -C 4 hydroxy alkyl; and
n is 0, 1 or 2;
including salts, hydrates, solvates, polymorphs, geometrical isomers, optical isomers, enantiomers, diastereomers, and mixtures thereof,
wherein said condition is selected from the group consisting of ocular hypertension, glaucoma and heart failure.

37 . The method of claim 36 , wherein R is selected from the group consisting of —CH 2 —C(═O)OH, —CH 2 —C(═O)—OCH 3 and CH 2 —CH 2 —NH 2 .

38 . The method of claim 36 , wherein X is OH, and the compound is a digoxin derivative.

39 . The method of claim 38 , wherein R is selected from the group consisting of —CH 2 —C(═O)OH (compound 5), —CH 2 —C(═O)—OCH 3 (compound 7), and —CH 2 —CH 2 —NH 2 (compound 11).

40 - 42 . (canceled)

43 . The method of claim 36 , wherein the compound is selective for α2 isoform of Na,K-ATPase over other isoforms of Na,K-ATPase.

44 . The method of claim 43 , 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.

45 . The method of claim 36 , wherein the compound of formula (IA) is administered in a pharmaceutical composition comprising said compound, and a pharmaceutically acceptable carrier or excipient.

46 - 50 . (canceled)

Assignees

• Yeda Res & Dev

Inventors

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

Classifications

• C07J43/003 Primary

  not condensed · CPC title

• C07J19/005

  Glycosides · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title