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Ophthalmic compositions for treating ocular hypertension

A technology of compounds and mixtures, applied in the field of neuroprotection, treatment of glaucoma and/or ocular hypertension, which can solve the problems of unsatisfactory and elevated efficacy and side effect profiles

Inactive Publication Date: 2005-12-14
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] There are some therapies for glaucoma and elevated intraocular pressure, and the efficacy and side effect profiles of these agents are suboptimal

Method used

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  • Ophthalmic compositions for treating ocular hypertension
  • Ophthalmic compositions for treating ocular hypertension
  • Ophthalmic compositions for treating ocular hypertension

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-3

[0089] plan 1

[0090]

[0091] Nitroanisole was brominated in Scheme 1 using NBS, AIBN and benzoyl peroxide. Treatment of nitroanisole bromide with potassium cyanide yields cyanonitroanisole. The nitro group is converted to an amine by hydrogenation. The amine is then treated with sodium nitrite and hydrochloric acid to afford the indazole ring. In this reaction, once diazonium is generated by nitrosation of aniline moiety, the diazonium is captured intramolecularly with acidic benzyl cyanide. Tautomerization of the resulting derivatives affords the indazole ring. Treatment of the nitrile with Gringard's reagent followed by hydrolysis of the resulting imino-magnesium complex affords the desired alkyl / aryl ketones.

preparation Embodiment 1

[0093]

[0094] A 500 ml flask was charged with 336 mmol (13.44 g; 60%) of sodium hydride. 150 ml of DMSO was added under an argon atmosphere, and then 32 ml of ethyl cyanoacetate (2.2 eq; 352 mmol) were added dropwise at 50°C. After complete addition, the reaction was allowed to warm to room temperature over 1 hour. 30 g of the nitrobenzene derivative (160 mmol) were added in powder form. The reaction mixture was heated at 90° C. for 8 hours in a closed system. Acidification and standard work-up gave a crude oily residue which was purified on a silica gel column to give 39 g of the desired crystalline product, which was decarboxylated to give the following benzonitrile. 38 g of SM obtained above were dissolved in 400 ml of 1N sodium carbonate. The homogeneous solution was stirred at room temperature for two days. Thin layer chromatography analysis indicated that the reaction was complete. The reaction mixture was acidified and extracted with ethyl acetate (100ml×4). ...

preparation Embodiment 2

[0097]

[0098] 10 g of the benzonitrile derivative were dissolved in 20 ml of THF and then diluted with 50 ml of methanol. The reaction mixture was transferred to a pressure tube, palladium-carbon (10% by weight / 10 mol%) was added, and the reaction mixture was hydrogenated at 40 psi. After the amount of hydrogen necessary to reduce the nitro group has been consumed, the reaction is stopped. TLC analysis indicated that the spots had been transformed spots. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to a solid and used directly in the next step. The crude aniline derivative (52 mmol) was dissolved / suspended in 2N hydrochloric acid (150 ml), cooled to 5°C, and then 5.4 g of sodium nitrite in 10 ml of aqueous solution was added. The reaction mixture was stirred for 1 hour and gradually warmed to room temperature. TLC analysis showed that SM had been consumed and a new spot was formed. The reaction mixture was extracted with...

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PUM

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Abstract

The present invention relates to compounds of formula I which are potent potassium channel blockers or their preparations for the treatment of glaucoma and other conditions which lead to increased intraocular pressure in patients. The present invention also relates to the use of such compounds to provide neuroprotection of the eye in mammals, especially humans.

Description

Background technique [0001] Glaucoma is a degenerative disease of the eye in which the intraocular pressure is too high for normal eye function. The result can damage the optic nerve endings and cause irreversible damage to visual function. If left untreated, glaucoma may eventually lead to blindness. Ocular hypertension, or elevated intraocular pressure without damage to the optic nerve endings or characteristic glaucomatous visual field loss, is now considered by most ophthalmologists to be present only in the earliest stages of glaucoma onset. [0002] There are several therapies for glaucoma and elevated intraocular pressure, and the efficacy and side effect profiles of these agents are suboptimal. Potassium channel blockers have recently been found to lower intraocular pressure in the eye and thus may offer another approach to treating ocular hypertension and the corresponding degeneration of the eye condition. Blockage of potassium channels reduces fluid secretion and...

Claims

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Application Information

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IPC IPC(8): C07D231/56
Inventor J·B·多赫尔蒂M·－H·陈L·刘S·R·纳塔拉彦R·M·泰内博尔
Owner SCHERING AG
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