Ophthalmic compositions for treating ocular hypertension

1. A compound selected from the group consisting of:

2. A method for treating ocular hypertension or glaucoma comprising administration to a patient in need of such treatment a therapeutically effective amount of a compound of structural formula I:

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:

wherein,

R and R 2 independently represent C 1-6 alkyl, (CH 2 ) n aryl, (CH 2 ) n heteroaryl, (CH 2 ) n heterocycloalkyl, said alkyl, aryl or heteroaryl optionally substituted with 1-3 groups of R 3 ;

Y represents —(CH 2 ) n SCOR 4 ;

X represents CH 2 , or O (in which m does not exist);

R 3 represents hydrogen, C 1-6 alkoxy, C 1-6 alkyl, CF 3 , nitro, amino, cyano, C 1-6 alkylamino, or halogen and

R 4 represents C 1-6 alkoxy, or C 1-6 alkyl;

R 7 represents H, halo, OH, NO 2 , NH 2 , CN, alkoxy, —COO—, alkoxycarbonyl, haloalkyl, alkoxycarbonylalkyl, or alkylsulphonyl

m represents 1-3;

n represents 0-3.

3. The method according to claim 2 wherein the compound of formula I is applied as a topical formulation.

4. A method according to claim 2 wherein R is C 1-6 alkyl, or (CH 2 ) n aryl, and all other variables are as originally described.

5. A method according to claim 2 wherein R 2 is C 1-6 alkyl, or (CH 2 ) n aryl, and all other variables are as originally described.

6. A method according to claim 2 wherein X is CH 2 and all other variables are as originally described.

7. A method according to claim 2 wherein Y is —(CH 2 ) n SCOR 4 wherein n=0, and all other variables are as originally described.

8. A method according to claim 2 wherein Y is —(CH 2 ) n SCOR 4 , n=1-3, and all other variables are as originally described.

9. A method according to claim 2 wherein R is (CH 2 ) n aryl, R 2 is C 1-6 alkyl, Y is (CH 2 ) n SCOR 4 , X is CH 2 and m=1.

10. A method according to claim 2 wherein R is (CH 2 ) n aryl, R 2 is C 1-6 alkyl, Y is (CH 2 ) n SCOR 4 , X is CH 2 and m=2.

11. A method according to claim 2 wherein R is C 1-6 alkyl, R 2 is (CH 2 ) n aryl, Y is (CH 2 ) n SCOR 4 , X is CH 2 and m=2.

12. A method according to claim 2 wherein R is (CH 2 ) n aryl, R 2 is (CH 2 ) n aryl, Y is (CH 2 ) n SCOR 4 , X is CH 2 and m=2.

13. A method according to claim 3 wherein the topical formulation is a solution or suspension.

14. A method according to claim 3 wherein an active ingredient belonging to the group consisting of: β-adrenergic blocking agent, parasympathomimetic agent, carbonic anhydrase inhibitor, and a prostaglandin or a prostaglandin derivative is optionally added to the formulation.

15. A method according to claim 14 wherein the β-adrenergic blocking agent is timolol; the parasympathomimetic agent is pilocarpine; the carbonic anhydrase inhibitor is dorzolamide, acetazolamide, metazolamide or brinzolamide; the prostaglandin is latanoprost or rescula, and the prostaglandin derivative is a hypotensive lipid derived from PGF2α prostaglandins.

16. A method for treating macular edema or macular degeneration comprising administration to a patient in need of such treatment a pharmaceutically effective amount of a compound of structural formula I:

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:

wherein,

R and R 2 independently represent C 1-6 alkyl, (CH 2 ) n aryl, (CH 2 ) n heteroaryl, (CH 2 ) n heterocycloalkyl, said alkyl, aryl or heteroaryl optionally substituted with 1-3 groups of R 3 ;

Y represents —(CH 2 ) n SCOR 4 ;

X represents CH 2 , or O (in which m does not exist);

R 3 represents hydrogen, C 1-6 alkoxy, C 1-6 alkyl, CF 3 , nitro, amino, cyano, C 1-6 alkylamino, or halogen and

R 4 represents C 1-6 alkoxy, or C 1-6 alkyl;

R 7 represents H, halo, OH, NO 2 , NH 2 , CN, alkoxy, —COO—, alkoxycarbonyl, haloalkyl, alkoxycarbonylalkyl, or alkylsulphonyl;

m represents 1-3; and/or

n represents 0-3.

17. The method according to claim 16 wherein the compound of formula I is applied as a topical formulation.

18. A method according to claim 16 wherein the compound is:

19. A method for increasing retinal and optic nerve head blood velocity or increasing retinal and optic nerve oxygen tension comprising administration to a patient in need of such treatment an effective ocular hypertensive formulation containing a potassium channel blocker of structural formula I:

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:

wherein,

R and R 2 independently represent C 1-6 alkyl, (CH 2 ) n aryl, (CH 2 ) n heteroaryl, (CH 2 ) n heterocycloalkyl, said alkyl, aryl or heteroaryl optionally substituted with 1-3 groups of R 3 ;

Y represents —(CH 2 ) n SCOR 4 ;

X represents CH 2 , or O (in which m does not exist);

R 3 represents hydrogen, C 1-6 alkoxy, C 1-6 alkyl, CF 3 , nitro, amino, cyano, C 1-6 alkylamino, or halogen and

R 4 represents C 1-6 alkoxy, or C 1-6 alkyl;

R 7 represents H, halo, OH, NO 2 , NH 2 , CN, alkoxy, —COO—, alkoxycarbonyl, haloalkyl, alkoxycarbonylalkyl, or alkylsulphonyl;

m represents 1-3; and/or

n represents 0-3.

20. The method according to claim 19 wherein the compound of formula I is applied as a topical formulation.

21. A method according to claim 19 wherein the compound is:

22. A method for providing a neuroprotective effect comprising administration to a patient in need of such treatment a therapeutically effective amount of structural formula I:

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:

wherein,

R and R 2 independently represent C 1-6 alkyl, (CH 2 ) n aryl, (CH 2 ) n heteroaryl, (CH 2 ) n heterocycloalkyl, said alkyl, aryl or heteroaryl optionally substituted with 1-3 groups of R 3 ;

Y represents —(CH 2 ) n SCOR 4 ;

X represents CH 2 , or O (in which m does not exist);

R 3 represents hydrogen, C 1-6 alkoxy, C 1-6 alkyl, CF 3 , nitro, amino, cyano, C 1-6 alkylamino, or halogen and

R 4 represents C 1-6 alkoxy, or C 1-6 alkyl;

R 7 represents H, halo, OH, NO 2 , NH 2 , CN, alkoxy, —COO—, alkoxycarbonyl, haloalkyl, alkoxycarbonylalkyl, or alkylsulphonyl;

m represents 1-3; and/or

n represents 0-3.

23. The method according to claim 22 wherein the compound of formula I is applied as a topical formulation.

24. A method according to claim 22 wherein the compound is:

25. A method according to claim 2 in which the topical formulation optionally contains xanthan gum or gellan gum.

26. A method for treating ocular hypertension or glaucoma comprising administration to a patient in need of such treatment a therapeutically effective amount of structural formula I:

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:

wherein,

R and R 2 independently represent C 1-6 alkyl, (CH 2 ) n aryl, (CH 2 ) n heteroaryl, (CH 2 ) n heterocycloalkyl, said alkyl, aryl or heteroaryl optionally substituted with 1-3 groups of R 3 ;

Y represents —(CH 2 ) n SCOR 4 ;

X represents CH 2 , or O (in which m does not exist);

R 3 represents hydrogen, C 1-6 alkoxy, C 1-6 alkyl, CF 3 , nitro, amino, cyano, C 1-6 alkylamino, or halogen and

R 4 represents C 1-6 alkoxy, or C 1-6 alkyl;

R 7 represents H, halo, OH, NO 2 , NH 2 , CN, alkoxy, —COO—, alkoxycarbonyl, haloalkyl, alkoxycarbonylalkyl, or alkylsulphonyl;

m represents 1-3; and/or

n represents 0-3.

27. A method according to claim 26 wherein the compound is:

28. A method of preventing repolarization or hyperpolarization of a mammalian cell wherein the cell contains a potassium channel comprising the administration to a mammal, including a human, in need thereof, of a pharmacologically effective amount of a potassium channel blocker of structural formula I:

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:

wherein,

R and R 2 independently represent C 1-6 alkyl, (CH 2 ) n aryl, (CH 2 ) n heteroaryl, (CH 2 ) n heterocycloalkyl, said alkyl, aryl or heteroaryl optionally substituted with 1-3 groups of R 3 ;

Y represents —(CH 2 ) n SCOR 4 ;

X represents CH 2 , or O (in which m does not exist);

R 3 represents hydrogen, C 1-6 alkoxy, C 1-6 alkyl, CF 3 , nitro, amino, cyano, C 1-6 alkylamino, or halogen and

R 4 represents C 1-6 alkoxy, or C 1-6 alkyl;

R 7 represents H, halo, OH, NO 2 , NH 2 , CN, alkoxy, —COO—, alkoxycarbonyl, haloalkyl, alkoxycarbonylalkyl, or alkylsulphonyl;

m represents 1-3; and/or(?)

n represents 0-3.

29. A method of treating depression in a patient in need thereof comprising administering a pharmaceutically effective amount of a compound according to claim 28 .

30. A method of treating cognitive disorders in a patient in need thereof comprising administering a pharmaceutically effective amount of a compound according to claim 28 .

31. A method of treating arrhythmia disorders in a patient in need thereof comprising administering a pharmaceutically effective amount of a compound according to claim 28 .

32. A method of treating diabetes in a patient in need thereof comprising administering a pharmaceutically effective amount of a compound according to claim 28 .