Ophthalmic compositions for treating ocular hypertension

A technology of compounds and mixtures, applied in the field of ophthalmic compositions for treating ocular hypertension, can solve problems such as unsatisfactory distribution of effects and side effects

Inactive Publication Date: 2008-06-11
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] There are treatments for glaucoma and elevated intraocular pressure, but these agents have an unfavorable profile of efficacy and side effects

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

[0148]

[0149] 1-(7-methoxy-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-3,3-dimethylbutan-2-one

[0150] Step A. 7-Methoxy-2,3,4,9-tetrahydro-1H-carbazole

[0151] A mixture of 4.04 g of 3-methoxyphenylhydrazine hydrochloride, 2.27 g of cyclohexanone and 1.90 g of sodium acetate was refluxed in 16 ml of acetic acid for 4 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was partitioned between water and EtOAc. The combined EtOAc extracts were washed with 0.1N HCl, 5% NaHCO 3 and saturated brine, washed with anhydrous Na 2 SO 4 Drying and evaporation gave crude product. The latter was repeatedly purified on silica gel using 15-25% EtOAc / hexanes to afford two isomeric products. The slow eluting isomer is the title compound. 1 H NMR (CDCI3, 500MHz) δ7.57(brs, 1NH), 7.35(d, 8.5Hz, 1H), 6.84(d, 2.1Hz, 1H), 6.77(dd, 2.1 & 8.5Hz, 1H), 3.86( s, 3H), 2.67-2.74 (m, 4H), 1.85-1.95 (m, 4H). LC-MS: 3.60 min. (m / Z = 202.2). The faster elutin...

Embodiment 2

[0155]

[0156] N,N-Dibutyl-2-(7-methoxy-1,2,3,4-tetrahydro-9H-carbazol-9-yl)acetamide

[0157] Step A. (7-Methoxy-1,2,3,4-tetrahydro-9H-carbazol-9-yl)acetic acid

[0158] To a solution of 0.25 g of 7-methoxy-2,3,4,9-tetrahydro-1H-carbazole in 10 mL of anhydrous DMF from step A of Example 1 was added 150 mg of NaH (60% oil dispersion). After 10 minutes, 0.21 g of methyl bromoacetate was added and the resulting mixture was stirred at room temperature for 5 hours. 1 mL each of water and 5N NaOH was carefully added to the reaction mixture. After stirring overnight at room temperature, the solvent was removed under reduced pressure. Workup of the residue with water and ether afforded acidic fractions containing the title compound.1 H NMR (CDCl 3 , 500MHz) δ7.37(d, 8.5Hz, 1H), 6.79(dd, 2.3 & 8.6Hz, 1H), 6.70(d, 2.3Hz, 1H), 4.74(s, 2H), 3.87(s, 3H) , 2.70-2.72(m, 2H), 2.63-2.66(m, 2H), 1.93-1.98(m, 2H), 1.84-1.89(m, 2H).LC-MS: 3.29min.(m / Z=260.2 ).

[0159] Step B. N,N-Dibu...

Embodiment 3-17

[0162]

[0163] Examples 3-17 in Table 1 were prepared using the same method as described in Example 3, Step B, from the appropriate amine. The preparation of the amines used in Examples 13-16 has been described in WO2004 / 04354, which is incorporated herein by reference in its entirety.

[0164] Table 1. Tetrahydrocarbazole acetamide

[0165]

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Abstract

This invention relates to potent potassium channel blocker compounds of Formula (I) or a formulation thereof for the treatment of glaucoma and other conditions which leads to elevated intraoccular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans.

Description

[0001] The case claims the benefit of U.S. Provisional Application 60 / 618,541, filed October 13, 2004. Background of the invention [0002] Glaucoma is a degenerative disease of the eye that causes excessive intraocular pressure that affects normal eye function. As a result, damage to the optic nerve head results in irreversible loss of visual function. If left untreated, glaucoma can eventually lead to blindness. Most ophthalmologists currently believe that ocular hypertension, ie elevated intraocular pressure without damage to the optic nerve head or a condition characterized by glaucomatous visual field defect, represents only the earliest stage of glaucoma onset. [0003] There are some treatments for glaucoma and elevated intraocular pressure, but the efficacy and side effect profile of these agents are not ideal. More recently, potassium channel blockers have been found to lower intraocular pressure and thus provide yet another approach to treating ocular hypertension ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/403C07D209/86
CPCC07D401/06C07D417/12C07D403/06C07D209/88A61P3/10A61P9/06A61P9/10A61P25/00A61P25/24A61P25/28A61P27/02A61P27/06A61P43/00
Inventor Y·-D·高D·-M·沈
Owner MERCK & CO INC
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