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Pyrazolo[3,4-e]benzoxazoles for the treatment of glaucoma

Inactive Publication Date: 2006-03-30
DANTANARAYANA ANURA P +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] Another feature of the present invention is to provide compounds which have increased chemical stability and which are useful in lowering and controlling normal or elevated intraocular pressure and / or treating glaucoma.

Problems solved by technology

Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be at high risk for the eventual development of the visual loss associated with glaucoma.
There are some individuals who do not respond well when treated with certain existing glaucoma therapies.

Method used

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  • Pyrazolo[3,4-e]benzoxazoles for the treatment of glaucoma
  • Pyrazolo[3,4-e]benzoxazoles for the treatment of glaucoma
  • Pyrazolo[3,4-e]benzoxazoles for the treatment of glaucoma

Examples

Experimental program
Comparison scheme
Effect test

example 1

(S)-2-(7-Methoxy-1H-pyrazolo[3,4-e]benzoxazol-1-yl)-1-methylethylamine

Step A. [(S)-2-(6-Hydroxy-indazol-1-yl)-l-methylethyl]-carbamic acid benzyl ester

[0061] 1-((S)-2-Aminopropyl)-1H-indazol-6-ol [prepared in accordance with commonly owned WO 02 / 098862A1, the contents of which are by this reference incorporated herein] (2.00 g, 10.5 mmol) was suspended in THF (20 mL) and saturated aqueous sodium bicarbonate (10 mL) and benzyl chloroformate (1.50 mL, 15 mol) were added. The mixture was stirred at room temperature until the starting amine dissolved. Saturated aqueous sodium bicarbonate (150 mL) was added and the reaction mixture extracted with ethyl acetate (3×150 mL). The combined organic layers were dried (magnesium sulfate), filtered, and evaporated to give a tan foam (2.65 g, 78%) which was pure by LC / MS (+APCI) m / z 326 (M+H+).

Step B: Benzyl (S)-2-(7-bromo-6-hydroxy-1H-indazol- 1-yl)-1-methylethylcarbamate

[0062] A solution of benzyl (S)-2-(6-hydroxy-1H-indazol-1-yl)-1-methyl...

example 2

(S)-2-[7-(Methoxymethyl)-1H-pyrazolo[3,4-e]benzoxazol- 1 -yl]- 1 -methylethylamine

Step A: 1 -[(R)-2-hydroxypropyl]-7-nitroso-1H-indazol-6-ol

[0067] To a solution of 1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol (2.0 g, 1.04 mmol) in acetic acid (20 mL) was added sodium nitrite (0.72 g, 10.4 mol) and the mixture was stirred at room temperature for 1 hour. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2×200 mL). The combined extracts were washed with water (200 mL), and a saturated aqueous solution of sodium bicarbonate (200 mL), dried over magnesium sulfate, filtered and evaporated to a residue which was purified by chromatography (silica gel, hexane / ethyl acetate gradient) to give a red solid (1.07 g, 47%): LC / MS m / z 222.

Step B: (R)-1-[7-(Methoxymethyl)-1H-pyrazolo[3,4-e]benzoxazol-1-yl]propan-2-ol

[0068] A solution of the product from Step A (1.05 g, 4.75 mol) in tetrahydrofuran (50 mL) containing 10% palladium-on-carbon (0.1 g) was stirred under an atmos...

example 3

1-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole -7-carboxylic acid amide

Step A: 7-Bromo-1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol

[0071] A solution of 1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol (4.76 g, 24.8 mmol) in tetrahydrofuran (50 mL), cooled in an ice bath, added small portions of N-bromosuccinimide (4.41 g, 24.8 mmol) and stirred while the reaction warmed to room temperature. The reaction was quenched with aqueous saturated sodium sulfite (100 mL) and extracted with ethyl acetate (100 mL). The combined extracts were dried (magnesium sulfate), filtered and evaporated to a yellow solid (7 g): mp 134-136° C.; LC / MS m / z 271 / 273.

Step B:1-[(R)- 2-Hydroxypropyl]-7-nitro-1-H-indazol-6-ol

[0072] A solution of the product from Step A (6.99 g, 24.8 mmol) in a mixture of tetrahydrofuran (20 mL) and acetic acid (20 mL) was cooled in an ice bath. Sodium nitrite (5.13 g, 74.4 mol) was added and the mixture was stirred for one hour, warmed to room temperature and stirring continued for o...

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Abstract

Pyrazolo[3,4-e]benzoxazoles and analogues thereof for lowering intraocular pressure and treating glaucoma are disclosed.

Description

RELATED APPLICATIONS [0001] This application claims priority form U.S. patent application Ser. No. 60 / 529,531, filed Dec. 15, 2003.BACKGROUND OF THE INVENTION [0002] The present invention relates to the use of pyrazolo[3,4-e]benzoxazoles and analogues thereof for lowering and controlling normal or elevated intraocular pressure (IOP) and for treating glaucoma. [0003] The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be at high risk for the eventual development of the visual loss associated with glaucoma. If glaucoma or ocular hyperte...

Claims

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Application Information

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IPC IPC(8): A61K31/5377A61K31/433A61K31/4245A61K31/424
CPCA61K9/0048Y10S514/913C07D491/04A61K31/424
Inventor DANTANARAYANA, ANURA P.MAY, JESSE A.
Owner DANTANARAYANA ANURA P
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