Prostaglandin conjugates and derivatives for treating glaucoma and ocular hypertension

Patent metadata

Field	Value
Publication number	US-2016108012-A1
Application number	US-201514884074-A
Country	US
Kind code	A1
Filing date	Oct 15, 2015
Priority date	Oct 15, 2014
Publication date	Apr 21, 2016
Grant date	—

Abstract

Prostaglandin conjugates and derivatives and methods for their use to treat glaucoma and/or lower intraocular pressure are disclosed. Additionally, ophthalmic pharmaceutical compositions useful in the treatment of eye diseases such as glaucoma and elevated intraocular pressure are disclosed. Such compositions comprise an effective amount of prostaglandin conjugates or derivatives of the present invention.

First claim

What is claimed is:

1 . An ophthalmic pharmaceutical composition useful in the treatment of glaucoma and control of intraocular pressure, comprising an effective amount of a compound (I) of the following formula:

in which A is selected from the following:

where:
n is 1-6;
R 1 , R 2 , R 3 independently=OH or O—NO 2 ;
R 4 , R 5 independently=H, alkyl, or heteroalkyl; or R 4 and R 5 can combine to form cyclic alkyl or cyclic heteroalkyl; and
R 6 independently=H, NO 2 , organic nitrate, organic nitrite, metal —NO complex, sodium nitroprusside (SNP), dinitrosyl iron thiol complex (DNICs), N-nitrosamine, N-hydroxy-N-nitrosamine, N-nitrosimine, nitrosimine, C-nitroso, diazetine dioxide, furoxan, benzofuroxan, oxatriazole-5-imine, sydnonimine, oxime, hydroxylamine, N-hydroxyguanidine, or hydroxyurea; and

a pharmaceutically acceptable vehicle therefor.

2 . The composition of claim 1 comprising a pharmaceutically acceptable salt of compound (I).

3 . The composition of claim 1 further comprising a compound selected from the group consisting of:
ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, gelling agents, hydrophobic bases, vehicles, buffers, sodium chloride, and water.

4 . The composition of claim 1 wherein said composition comprises a plurality of glaucoma treatment agents.

5 . The composition of claim 4 wherein at least one glaucoma treatment agent is selected from the group consisting of:
β-blockers, prostaglandin analogs, carbonic anhydrase inhibitors, α 2 agonists, miotics, rho kinase inhibitors, serotonergic agonists, and neuroprotectants.

6 . The composition of claim 1 wherein said composition comprises from about 0.01 percent weight/volume to about 5 percent weight/volume of said compound.

7 . The composition of claim 1 wherein said composition comprises from about 0.05 percent weight/volume to about 2 percent weight/volume of said compound.

8 . The composition of claim 1 wherein said compound is selected from: Isopropyl (Z)-7-((1R,2R,3R,5S)-3,5-bis(nitrooxy)-2-((R,E)-3-(nitrooxy)-4-(3-(trifluoromethyl)phenoxy)but-1-en-1-yl)cyclopentyl)hept-5-enoate and (Z)-2-((((Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1-en-1-yl)cyclopentyl)hept-5-enoyl)oxy)methoxy)-1-(pyrrolidin-1-yl)diazene 1-oxide.

9 . A method for lowering intraocular pressure comprising:
applying a therapeutically effective amount of an ophthalmic pharmaceutical composition to the affected eye of a human or other mammal, the composition comprising an effective amount of a compound of the following formula:

in which A is selected from the following:

where:
n is 1-6;
R 1 , R 2 , R 3 independently=OH or O—NO 2 ;
R 4 , R 5 independently=H, alkyl, or heteroalkyl; or R 4 and R 5 can combine to form cyclic alkyl or cyclic heteroalkyl; and
R 6 independently=H, NO 2 , organic nitrate, organic nitrite, metal —NO complex, sodium nitroprusside (SNP), dinitrosyl iron thiol complex (DNICs), N-nitrosamine, N-hydroxy-N-nitrosamine, N-nitrosimine, nitrosimine, C-nitroso, diazetine dioxide, furoxan, benzofuroxan, oxatriazole-5-imine, sydnonimine, oxime, hydroxylamine, N-hydroxyguanidine, or hydroxyurea; and

a pharmaceutically acceptable vehicle therefor.

10 . The method of claim 9 wherein said applying comprises applying 1 to 2 drops of a composition comprising from about 0.01 percent weight/volume to about 5 percent weight/volume of compound (I) 1 to 4 times daily.

11 . The method of claim 9 wherein said composition comprises a plurality of glaucoma treatment agents.

12 . The method of claim 11 wherein at least one glaucoma treatment agent is selected from the group consisting of:
β-blockers, prostaglandin analog, carbonic anhydrase inhibitors, α 2 agonists, miotics, rho kinase inhibitors, serotonergic agonists, and neuroprotectants.

13 . A compound represented by Formula (I):

in which A is selected from the following:

where:
n is 1-6;
R 1 , R 2 , R 3 independently=OH or O—NO 2 ;
R 4 , R 5 independently=H, alkyl, or heteroalkyl; or R 4 and R 5 can combine to form cyclic alkyl or cyclic heteroalkyl; and
R 6 independently=H, NO 2 , organic nitrate, organic nitrite, metal —NO complex, sodium nitroprusside (SNP), dinitrosyl iron thiol complex (DNICs), N-nitrosamine, N-hydroxy-N-nitrosamine, N-nitrosimine, nitrosimine, C-nitroso, diazetine dioxide, furoxan, benzofuroxan, oxatriazole-5-imine, sydnonimine, oxime, hydroxylamine, N-hydroxyguanidine, or hydroxyurea.

14 . The compound of claim 13 wherein the compound is a pharmaceutically acceptable salt of a compound according to Formula (I).

15 . The compound of claim 11 which is selected from: Isopropyl (Z)-7-((1R,2R,3R,5S)-3,5-bis(nitrooxy)-2-((R,E)-3-(nitrooxy)-4-(3-(trifluoromethyl)phenoxy)but-1-en-1-yl)cyclopentyl)hept-5-enoate and (Z)-2-((((Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1-en-1-yl)cyclopentyl)hept-5-enoyl)oxy)methoxy)-1-(pyrrolidin-1-yl)diazene 1-oxide.

Assignees

• Novartis Ag

Inventors

• Ellis David
• Scheibler Lukas
• Sharif Najam A

Classifications

• A61P27/02

  Ophthalmic agents · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• C07D295/28 Primary

  Nitrogen atoms · CPC title

• A61K9/08

  Solutions {(composition of solutions A61K47/00)} · CPC title

• A61K31/559

  having heterocyclic rings containing hetero atoms other than oxygen · CPC title