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Nitrocatechol derivatives as COMT inhibitors

A nitro and methyl technology, applied in the field of novel substituted nitrocatechols, can solve the problem of low activity

Active Publication Date: 2008-08-20
BIAL PORTELA & CA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Regioisomeric 1,3,4-oxadiazoles in which the nitrocatechol pharmacophore is attached to the C-2 position of the oxadiazole central ring are also generally less active in terms of COMT inhibition

Method used

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  • Nitrocatechol derivatives as COMT inhibitors
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  • Nitrocatechol derivatives as COMT inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] 3-nitro-5-[3-(1-oxo-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol (compound 4, Table 1)

[0119] a) To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid (0.5 g, 1.32 mmol) in dimethylformamide (5 mL) was added 1 portion of 1 at room temperature, 1-Carbonyldiimidazole (0.246 g, 1.52 mmol). After stirring for 1 hour, 1 part of N'-hydroxypyridine-4-carboximidamide (0.208 g, 1.52 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was then stirred at 110° C. for three hours and then allowed to cool to room temperature. The mixture was poured onto an ice-water bath (100 mL), and extracted with 20% isopropanol / dichloromethane. The organic extract was washed with water and brine, then dried (Na 2 SO 4 ), filtered and evaporated to leave a solid residue which was recrystallized from ethanol. 4-[5-(3,4-Dibenzyloxy-5-nitrophenyl)-[1,2,4]oxadiazol-3-yl]-pyridine was obtained as a beige solid (0.395 g, 62% ).

[...

Embodiment 2

[0123] 3-nitro-5-[3-(1-oxo-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol (compound 5, Table 1)

[0124] a) To a stirred solution of 3,4-dimethoxy-5-nitrobenzoic acid (0.232 g, 1.022 mmol) in dimethylformamide (5 mL) was added 1 part of 1,1-carbonyl at room temperature Diimidazole (0.174 g, 1.073 mmol). The resulting mixture was stirred for ninety minutes, whereupon 1 part of N'-hydroxypyridine-3-carboximidamide 1-oxide (0.156 g, 1.022 mmol) was added. The resulting mixture was stirred at room temperature for two hours and then allowed to stand overnight at 75°C. After cooling to room temperature, the mixture was poured into water (100 mL), and the precipitate was filtered off, washed with water, then dried in air, and recrystallized from diethyl ether. 3-[5-(3,4-Dimethoxy-5-nitrophenyl)-[1,2,4]oxadiazol-3-yl]-pyridine 1-oxide (0.162 g, 46%).

[0125] b) Under argon protection, to a stirred solution of the above dimethyl ether (0.153 g, 0.445 mmol) in dichloromethane...

Embodiment 3

[0128] 3-nitro-5-[3-(1-oxo-pyridin-2-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol (compound 6, Table 1)

[0129] a) To a stirred solution of 3,4-dimethoxy-10-nitrobenzoic acid (1.0 g, 4.40 mmol) in dimethylformamide (10 mL) was added 1 part of 1,1-carbonyl at room temperature Diimidazole (0.821 g, 5.06 mmol). The resulting mixture was stirred for ninety minutes before adding 1 part of N'-hydroxypyridine-2-carboximidamide 1-oxide (0.775 g, 5.06 mmol). The resulting mixture was stirred overnight at room temperature, then poured into water (100 mL). The resulting precipitate was filtered off, washed with water, and added to dichloromethane (30 mL). The organic layer was washed with water and brine, dried (Na 2 SO 4 ), filtered, and evaporated to leave a white solid (1.37 g, 86%).

[0130] b) Under argon protection, to a stirred suspension of the above obtained solid (1.365 g, 3.77 mmol) in tetrahydrofuran (14 mL) was added a 1N solution of tetrabutylammonium fluoride in tetr...

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Abstract

Novel compounds of general formula I are described which have potentially valuable pharmaceutical properties in the treatment of several central and peripheral nervous system dysfunctions.

Description

technical field [0001] The present invention relates to novel substituted nitrocatechols, their use in the treatment of certain central and peripheral nervous system dysfunctions, and pharmaceutical compositions comprising them. Background technique [0002] Although used in clinical practice for decades, levodopa (L-DOPA) remains the standard drug of choice for the symptomatic treatment of Parkinson's disease. This has led to continued strong interest in the development of catechol-O-methyltransferase (COMT) inhibitors, based on the hypothesis that inhibition of this enzyme could provide a pathological benefit for those suffering from Parkinson's disease. Patients treated with L-DOPA and peripheral amino acid decarboxylase (AADC) inhibitors provided clinical improvement. The rationale for using COMT inhibitors as adjuncts to L-DOPA / AADC therapy is based on their ability to reduce the oxomethylation of metabolized L-DOPA to 3-O-methyl-levodopa (3-OMD). The duration of clin...

Claims

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Application Information

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IPC IPC(8): C07D413/04C07D413/14A61K31/421A61K31/4425A61K31/4439A61K31/506A61P25/00C07D417/14C07D413/06C07D401/04C07D213/89C07D407/04C07D271/06C07D271/10
Inventor D·A·利尔蒙斯L·E·基什P·N·莱亚尔·帕尔马H·多斯·桑托斯·费雷拉P·M·V·阿劳若·苏亚雷斯·达·西尔瓦
Owner BIAL PORTELA & CA SA
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