Use of cloprostenol and fluprostenol analogues to treat glaucoma and ocular hypertension

• US 6,184,250 B1
• Filed: 03/30/1999
• Issued: 02/06/2001
• Est. Priority Date: 08/03/1993
• Status: Expired due to Term

• Current Assignee: Alcon Research Limited (Nestle SA)
• Original Assignee: Alcon Laboratories Incorporated (Alcon Incorporated)
• Inventors: Dean, Tom R., Klimko, Peter G., Bishop, John E., Zinke, Paul W., Sallee, Verney L., Chandler, Michael L., Barnes, George E.
• Primary Examiner(s): FAY, ZOHREH A
• Application Number:
  US09/281,043
• Time in Patent Office: 679 Days
• Field of Search: 514/530, 514/573, 514/912
• US Class Current: 514/530
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 31/558 having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: C07C 405/00 Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
• CPC Class Codes: C07C 405/0025 containing keto groups

Abstract

Disclosed is the use of cloprostenol and fluprostenol analogues and combinations thereof with other medicaments for the treatment of glaucoma and ocular hypertension and ophthalmic compositions therefor. Also disclosed are methods of treating optic nerve disorders using the cloprostenol and fluprostenol analogues.

Claims

1. A method of treating glaucoma and ocular hypertension which comprises topically administering to the affected eye a composition comprising a therapeutically effective amount of a combination of a first compound selected from the group consisting of beta-blockers, carbonic anhydrase inhibitors, adrenergic agonists, and cholinergic agonists;

together with a second compound having the absolute stereochemical structure of the following formula (IV);

wherein;

R₁=H;

C₁-C₁₂ straight-chain or branched alkyl;

C₁-C₁₂ straight-chain or branched acyl;

C₃-C₈ cycloalkyl;

or a cationic salt moiety;

R₂, R₃=H, or C₁-C₅ straight-chain or branched alkyl;

or R₂ and R₃ taken together may represent O;

X=O, S, or CH₂;

- - - represents any combination of a single bond, or a cis or trans double bond for the alpha (upper) chain; and

a single bond or trans double bond for the omega (lower) chain;

R₉=H, C₁-C₁₀ straight-chain or branched alkyl, or C₁-C₁₀ straight-chain or branched acyl;

R₁₁=H, C₁-C₁₀ straight-chain or branched alkyl, or C₁-C₁₀ straight-chain or branched acyl;

Y=O;

or H and OR₁₅ in either configuration wherein R₁₅=H, C₁—

C₁₀ straight-chain or branched alkyl, or C₁-C₁₀ straight-chain or branched acyl; and

Z=Cl or CF₃;

with the proviso that when R₂ and R₃ taken together represent O, then R₁≠

C₁-C₁₂ straight-chain or branched acyl; and

when R₂=R₃=H, then R₁≠

a cationic salt moiety.

2. The method of claim 1, wherein for the compound (IV):

R₂, R₃ taken together represent O;

X=CH₂;

- - - represents a cis double bond for the alpha (upper) chain and a trans double bond for the omega (lower) chain;

R₉ and R₁₁=H; and

Y=OH in the alpha configuration and H in the beta configuration.

3. The method of claim 2, wherein for the compound (IV):

Z=CF₃.

4. The method of claim 1, wherein:

R₂=R₃=H, or R₂ and R₃ taken together represent O;

X=O or CH₂;

R₉=R₁₁=H;

Y=H and OR₁₅; and

R₁₅=H.

5. The method of claim 4, wherein:

R₁=H, C₁-C₁₂ straight chain or branched alkyl or cationic salt moiety; and

R₂ and R₃ taken together represent O.

6. The method of claim 5, wherein the compound of formula (IV) is selected from the group consisting of cloprostenol, fluprostenol, 3-oxacloprostenol, 13,14-dihydrofluprostenol, and their pharmaceutically acceptable esters and salts.

7. The method of claim 4, wherein the first compound is beta-blocker.

8. The method of claim 7, wherein the beta-blocker is selected from the group consisting of timolol, betaxolol and levobetaxolol.

9. The method of claim 8, wherein the beta-blocker is timolol and the compound of formula (IV) is fluprostenol isopropyl ester.

10. The method of claim 4, wherein the first compound is an adrenergic agonist.

11. The method of claim 10, wherein the adrenergic agonist is selected from the group consisting of apraclonidine and brimonidine.

12. The method of claim 11, wherein the adrenergic agonist is brimonidine and the compound of formula (IV) is fluprostenol isopropyl ester.

13. The method of claim 1, wherein between about 0.01 and about 1000 μ

g/eye of the compounds of formula (IV) is administered.

14. The method of claim 13, wherein between about 0.1 and about 100 μ

g/eye of the compound of formula (IV) is administered.

15. The method of claim 14, wherein between about 0.1 and about 10 μ

g/eye of the compound of formula (IV) is administered.

16. A topical ophthalmic composition for the treatment of glaucoma and ocular hypertension comprising an ophthalmically acceptable carrier and a therapeutically effective amount of a combination of a first compound selected from the group consisting of beta-blockers, carbonic anhydrase inhibitors, adrenergic agonists, and cholinergic agonists;

together with a second compound having the absolute stereochemical structure of the following formula (IV) and being substantially free of the enantiomer of said compound;

wherein;

R₁=H;

C₁-C₁₂ straight-chain or branched alkyl;

C₁-C₁₂ straight-chain or branched acyl;

C₃-C₈ cycloalkyl;

or a cationic salt moiety;

R₂, R₃=H, or C₁-C₅ straight-chain or branched alkyl;

or R₂ and R₃ taken together may represent O;

X=O, S, or CH₂;

- - - represents any combination of a single bond, or a cis or trans double bond for the alpha (upper) chain; and

a single bond or trans double bond for the omega (lower) chain;

R₉=H, C₁-C₁₀ straight-chain or branched alkyl, or C₁-C₁₀ straight-chain or branched acyl;

R₁₁=H, C₁-C₁₀ straight-chain or branched alkyl, or C₁-C₁₀ straight-chain or branched acyl;

Y=O;

or H and OR₁₅ in either configuration wherein R₁₅=H, C₁-C₁₀ straight-chain or branched alkyl, or C₁-C₁₀ straight-chain or branched acyl; and

Z=Cl or CF₃;

with the proviso that when R₂ and R₃ taken together represent O, then R₁≠

C₁-C₁₂ straight-chain or branched acyl; and

when R₂=R₃=H, then R₁≠

a cationic salt moiety; and

with the further proviso that the following compound be excluded;

cyclopentane heptenol-5-cis-2-(3-α

hydroxy-4-m-chlorophenoxy-1-trans-butenyl)-3,5 dihydroxy, [1_α

, 2_β

, 3_α

, 5_α

].

17. The composition of claim 16, wherein for the compound (IV):

R₂, R₃ taken together represent O;

X=CH₂;

- - - represents a cis double bond for the alpha (upper) chain and a trans double bond for the omega (lower) chain;

R₉ and R₁₁=H; and

Y=OH in the alpha configuration and H in the beta configuration.

18. The composition of claim 17, wherein for the compound (IV):

Z=CF₃.

19. A method of treating an optic nerve disorder, which comprises administering to the affected eye a composition comprising a therapeutically effective amount of a compound having the absolute stereochemical structure of the following formula (IV) an being substantially free of the enantiomer of said compound:

wherein;

R₁=H;

C₁-C₁₂ straight-chain or branched alkyl;

C₁-C₁₂ straight-chain or branched acyl;

C₃-C₈ cycloalkyl;

or a cationic salt moiety;

R₂, R₃=H, or C₁-C₅ straight-chain or branched alkyl;

or R₂ and R₃ taken together may represent O;

X=O, S, or CH₂;

- - - represents any combination of a single bond, or a cis or trans double bond for the alpha (upper) chain; and

a single bond or trans double bond for the omega (lower) chain;

R₉=H, C₁-C₁₀ straight-chain or branched alkyl, or C₁-C₁₀ straight-chain or branched acyl;

R₁₁=H, C₁-C₁₀ straight-chain or branched alkyl, or C₁-C₁₀ straight-chain or branched acyl;

Y=O;

or H and OR₁₅ in either configuration wherein R₁₅=H, C₁-C₁₀ straight-chain or branched alkyl, or C₁-C₁₀ straight-chain or branched acyl; and

Z=Cl or CF₃;

with the proviso that when R₂ and R₃ taken together represent O, then R₁≠

C₁-C₁₂ straight-chain or branched acyl; and

when R₂=R₃=H, then R₁≠

a cationic salt moiety; and

with the further proviso that the following compound be excluded;

cyclopentane heptenol-5-cis-2-(3-α

hydroxy-4-m-chlorophenoxy-1-trans-butenyl)-3,5 dihydroxy, [1_α

, 2_β

, 3_α

, 5_α

].

20. The method of claim 19, wherein the compound of formula (IV) is fluprostenol and its pharmaceutically acceptable esters and salts.

21. The method of claim 20, wherein the compound of formula (IV) is fluprostenol isopropyl ester.