Preparations comprising arylazine substituted with a carbonylic moiety to increase the activity of Gelatinase A in ocular cells

• US 20070049559A1
• Filed: 06/28/2006
• Published: 03/01/2007
• Est. Priority Date: 06/28/2005
• Status: Abandoned Application

• Current Assignee: Bausch & Lomb Incorporated (Bausch Health Cos., Inc.)
• Original Assignee: Bausch & Lomb Incorporated (Bausch Health Cos., Inc.)
• Inventors: Bartels, Stephen, Flick, Rosemarie, Pfeffer, Bruce
• Application Number:
  US11/476,496
• Publication Number:
  US 20070049559A1
• Time in Patent Office: Days
• US Class Current: 514/150
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Preparations for controlling intraocular pressure in the eye comprise as an active compound, arylazine substituted with a carbonylic moiety, which compound is capable of effecting a “pharmacological trabeculocanalotomy” in an eye by means of reducing juxtacanalicular meshwork to promote outflow of aqueous. The organic active compound increases Gelatinase A activity in ocular cells by increasing cell membrane expression of membrane-type matrix metalloproteinases (MT-MMPs) to increase aqueous outflow as a treatment for glaucoma, e.g., primary open angle glaucoma.

Claims

1. A preparation for controlling intraocular pressure in the eye that comprises as an active compound, arylazine substituted with a carbonylic moiety.

2. The preparation of claim 1 wherein said active compound comprises an aryl group selected from homocyclic aryl and heterocyclic aryl.

3. The preparation of claim 1 wherein said active compound comprises an azinyl moiety selected from the group consisting of monoazinyl and diazinyl.

4. The preparation of claim 3 wherein said diazinyl is selected from the group consisting of 1,3-azinyl, 1,4-diazinyl and 2,3-diazinyl.

5. The preparation of claim 1 wherein said active compound is selected from the following general formulae [1-6]:

6. The preparation of claim 5 wherein for A, said homoaryl is phenyl, said heteroaryl is pyridinyl, said halo is selected from fluoro, chloro, bromo and iodo.

7. The preparation of claim 5 wherein said halo C₁-C₈ alkyl is trifluoromethyl.

8. The preparation of claim 5 wherein said active compound is kynurenic acid (hydroxyquinoline carboxylic acid).

9. The preparation of claim 5 wherein said active compound is a derivative of kynurenic acid.

10. The preparation of claim 9 wherein said active compound is selected from the group consisting of 5,7-dichloro kynurenic acid and 3-hydroxy-2-methyl4-quinoline carboxylic acid.

11. The preparation of claim 5 which further comprises a counterion for balancing said active compound, said counterion being selected from:

a) A′

-L₁-NH -L₃-NH-L₂-B, wherein

L₁ and L₂ are independently selected from methylene, ethylene, propylene, isopropylene, and cyclopropylene;

L₃ is alkyl C₁-C₆, linear or branched, and can be replaced in part or entirety with cycloalkyl C₃-C₆, or the alkyl component of L₃ can be substituted with cycloalkyl C₃-C₆ in a spiro configuration such that the maximum total number of carbon atoms in L₃ is 6; and

A′ and

B are independently phenyl, naphthyl, or heteroaryl;

b) A′

-L₁-NH-L₂-B, wherein A′

, B, L₁, L₂ are as described above;

wherein

A′

, B, and M are independently phenyl, naphthyl, or heteroaryl;

L₂ is as described above;

L₄, L₅, L₆ are independently C_n, where n=0, 1, or 2;

L₇ is selected from —

H, alkyl C₁-C₆, linear or branched which may be replaced, in part or in its entirety, with cycloalkyl C₃-C₆;

wherein

A′

, B, M, and Q are independently phenyl, naphthyl, or heteroaryl;

L₂ is as described above;

L₄, L₅, L₆, L₈ are independently C_n, where n=0, 1, or 2;

further providing that for a) through d) above;

1) where allowed, the hydrogens on all alkyl or cycloalkyl groups can be substituted with i) straight or branched C₁-C₆ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, or combinations thereof;

or ii) straight or branched C₁-C₆ alkoxy, C₂-C₈ alkenoxy, C₂-C₈ alkynoxy, or C₃-C₈ cycloalkoxy, whose aliphatic groups are straight or branched;

2) where allowed, the hydrogens on all aromatic rings can be substituted with a group selected from i) C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C₁-C₈ alkoxy, C₂-C₈ alkenoxy, C₂-C₈ alkynoxy, C₂-C₈ thioalkyl, C₂-C₈ thioalkenyl, and C₂-C₈ thioalkynyl, whose aliphatic groups are straight or branched; and

ii) hydroxy, halo, nitro, cyano, and halomethyl; and

3) all optical isomers are permitted.

12. The preparation of claim 11 wherein said counterion is benzathine (Ph-CH₂—

NH—

(CH₂)₂—

NH—

CH₂-Ph, where Ph=phenyl), either as a base or as a salt with an acceptable anion.

13. The preparation of claim 12 wherein said active compound is kynurenic acid.

14. The preparation of claim 12 wherein said active compound is a derivative of kynurenic acid.

15. The preparation of claim 12 wherein said anion is selected from chloride, propionate, and acetate.

16. The preparation of claim 11 wherein the molar ratio of active compound to counterion is no greater than about 3:

1.

17. The preparation of claim 16 wherein the molar ratio of active compound to counterion ranges between about 1:

1 and about 2;

1.

18. The preparation of claim 5 wherein said active compound is useful to increase the activity of Gelatinase A in ocular cells.

19. The preparation of claim 18 wherein said active compound is selected from kynurenic acid.

20. The preparation of claim 18 wherein said active compound is selected from a derivative of kynurenic acid.

21. The preparation of claim 5 wherein said active compound is useful to increase the activity of Gelatinase A in ocular cells.

22. The preparation of claim 11 wherein said active compound is useful to increase the activity of Gelatinase A in ocular cells.

23. The preparation of claim 13 wherein said active compound is useful to increase the activity of Gelatinase A in ocular cells.

24. A pharmaceutically acceptable composition comprising:

the preparation of claim 5 containing said active compound in a therapeutically effective amount to increase the activity of Gelatinase A in ocular cells.

25. A pharmaceutically acceptable composition comprising:

the preparation of claim 11 containing said active compound in a therapeutically effective amount to increase the activity of Gelatinase A in ocular cells.

26. A pharmaceutically acceptable composition comprising:

the preparation of claim 13 containing said active compound in a therapeutically effective amount to increase the activity of Gelatinase A in ocular cells.

27. A method of administering the pharmaceutically acceptable composition of claim 24 comprising:

formulating said composition as a sterile aqueous or non-aqueous solution; and

applying said solution on or within an eye.

28. A method of administering the pharmaceutically acceptable composition of claim 25 comprising:

formulating said composition as a sterile aqueous or non-aqueous solution; and

applying said solution on or within an eye.

29. A method of administering the pharmaceutically acceptable composition of claim 26 comprising:

formulating said composition as a sterile aqueous or non-aqueous solution; and

applying said solution on or within an eye.

30. A method of administering the pharmaceutically acceptable composition of claim 24 comprising:

providing said composition in the form of an ocular implant; and

implanting said ocular implant within an eye.

31. The method of claim 30 wherein said implant comprises a biodegradable matrix.

32. The method of claim 30 wherein said implant comprises a drug-eluting reservoir.

33. A method of administering the pharmaceutically acceptable composition of claim 25 comprising:

providing said composition in the form of an ocular implant; and

implanting said ocular implant within an eye.

34. The method of claim 33 wherein said implant comprises a biodegradable matrix.

35. The method of claim 33 wherein said implant comprises a drug-eluting reservoir.

36. A method of administering the pharmaceutically acceptable composition of claim 26 comprising:

providing said composition in the form of an ocular implant; and

implanting said ocular implant within an eye.

37. The method of claim 36 wherein said implant comprises a biodegradable matrix.

38. The method of claim 36 wherein said implant comprises a drug-eluting reservoir.

39. A method of administering the pharmaceutically acceptable composition of claim 24 comprising:

formulating said composition as a sterile ointment; and

applying said ointment on or near an eye.

40. A method of administering the pharmaceutically acceptable composition of claim 25 comprising:

formulating said composition as a sterile ointment; and

applying said ointment on or near an eye.

41. A method of administering the pharmaceutically acceptable composition of claim 26 comprising:

formulating said composition as a sterile ointment; and

applying said ointment on or near an eye.

42. A method of administering the pharmaceutically acceptable composition of claim 24 comprising:

formulating said composition as a sterile gel; and

applying said gel on or near an eye.

43. A method of administering the pharmaceutically acceptable composition of claim 25 comprising:

formulating said composition as a sterile gel; and

applying said gel on or near an eye.

44. A method of administering the pharmaceutically acceptable composition of claim 26 comprising:

formulating said composition as a sterile gel; and

applying said gel on or near an eye.

45. A method of administering the pharmaceutically acceptable composition of claim 24 comprising:

providing said composition combined with biodegradable polymer matrix, as particles whose largest dimension is less than 10 microns; and

applying said particles on or near an eye.

46. A method of administering the pharmaceutically acceptable composition of claim 25 comprising:

providing said composition combined with biodegradable polymer matrix, as particles whose largest dimension is less than 10 microns; and

applying said particles on or near an eye.

47. A method of administering the pharmaceutically acceptable composition of claim 26 comprising:

providing said composition combined with biodegradable polymer matrix, as particles whose largest dimension is less than 10 microns; and

applying said particles on or near an eye.