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Novel precursors

A compound and general formula technology, applied in the field of synthesis of peripheral inhibitors, can solve the problems of liver damage, short half-life in vivo, side effects of central nervous system, etc.

Inactive Publication Date: 2011-02-02
BIAL PORTELA & CA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Well-known COMT inhibitors such as tolcapone and entacapone show some disadvantages such as liver damage, short half-life in vivo or undesired central nervous system side effects

Method used

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Examples

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Embodiment 1

[0059] Embodiment 1: Preparation of ethyl 5-(dimethylamino)-2-(2,2,2-trifluoroacetyl)-penta-2,4-dienoate

[0060] equipped with a mechanical stirrer, thermometer, dropping funnel and N 2 In an inlet 5L three-neck round bottom flask, 51.60g (0.706mol) of N,N-dimethylformamide was dissolved in 2L of DCM. in N 2 The clear solution was cooled to 0° C. under 0°C, and oxalyl chloride (89.7 g, 61.7 ml, 0.707 mol) was added dropwise over 30 minutes. During the addition, a white precipitate formed. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Cool to 0°C again and add 1-(ethyleneoxy)butane (141.20 g, 182 ml) dropwise keeping the internal temperature below 5°C. Addition continued for 45 minutes. Then remove the cooling bath and react under N 2 Stir for 2 hours. Once again the light yellow homogeneous solution was cooled to -5°C and ethyl trifluoro-acetoacetic acid (99.97 g, 0.543 mol) was added rapidly followed by triethylamine (157 g, 217...

Embodiment 2

[0062] Example 2: Preparation of ethyl 5-(dimethylamino)-2-(2,2,2-trifluoroacetyl)penta-2,4-dienoate

[0063] In a 20ml pear-shaped flask, ethyl 4,4,4-trifluoro-3-oxobutanoate (oxobutanoate) (3.00g, 16.29mmol), 3-(dimethylamino)acrolein (2.63g, 26.6 mmol) was taken up in acetic anhydride (5.8 ml) to give a brown solution. The reaction mixture was stirred for 10 minutes. Thin layer chromatography (TLC) showed the reaction was complete. The reaction mixture was dissolved in DCM. The organic phase was washed with 1N HCl solution, water, and then with MgSO 4 dry. After filtration and evaporation, the resulting dark red oil crystallized from a mixture of petroleum ether and diethyl ether.

[0064] Yield: 3.56g (83%), mp: 70°C

Embodiment 3

[0065] Example 3: Preparation of 5-(dimethylamino)-2-(2,2,2-trifluoroacetyl)penta-2,4-dienenitrile (dienenitrile)

[0066] equipped with a magnetic stirrer, thermometer, dropping funnel and N 2 In an inlet 500ml three-neck round bottom flask, 8.88g (121.6mmol) of N,N-dimethylformamide was dissolved in 350ml of DCM. in N 2 The clear solution was cooled to 0° C. and oxalyl chloride (10.6 ml, 15.43 g, 121.6 mmol) was added dropwise over 30 minutes. During the addition, a white precipitate formed. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Cool to 0°C again and add 1-(ethyleneoxy)butane (24.32g, 31.4ml) dropwise keeping the internal temperature below 5°C. Addition continued for 30 minutes. Then, remove the cooling bath and react under N 2 Stir for 2 hours. Once again the pale yellow homogeneous solution was cooled to -5°C, and 4,4,4-trifluoro-3-oxobutyronitrile (12.82 g, 93.57 mol) was added rapidly, followed by triethylamine (30.7...

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Abstract

The present invention relates to a compound of the formula (I), wherein X represents CN, COOR, wherein R represents hydrogen or a carboxyl protecting group, CONR'2, wherein R' represents hydrogen or a carboxyl protecting group, or nitro,R1, R2, R3, R4, R5 independently of each other represent hydrogen, C1-C6 alkyl, halogen, trifluoromethyl, cyano, nitro, substituted aryl or substituted heteroaryl group,Y represents hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C7-C13 alkaryl, trifluoromethyl, cyano, nitro, substituted aryl or substituted heteroaryl group,and wherein the stereochemically unspecified double bonds in the above formula (I) represent either the E,E,E,Z,Z,E or Z,Z configuration.

Description

technical field [0001] The present invention relates to novel precursors of amidoxime building blocks for efficient, long-acting catechol-O-methyltransferase (COMT) and processes for their preparation Synthesis of peripheral inhibitors. Background technique [0002] COMT inhibitors are used as adjuncts to L-dopa (DOPA) / peripheral amino acid decarboxylase (AADC) inhibitor therapy in patients afflicted with Parkinson's disease. The use of COMT inhibitors is based on their ability to reduce the O-methylation of L-dopa metabolized to 3-O-methyl-L-dopa (3-OMD). Thus, L-dopa is protected from metabolic losses, increasing its mean plasma concentration and enhancing its bioavailability. Well-known COMT inhibitors such as tolcapone, entacapone show some disadvantages such as liver damage, short half-life in vivo or undesired central nervous system side effects. [0003] Potent new peripheral COMT inhibitors based on nitrocatechol derivatives are described in International Patent A...

Claims

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Application Information

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IPC IPC(8): C07D213/89C07D213/82C07D213/81C07D213/803
CPCC07D213/80C07D213/85C07D213/89Y02P20/55A61P25/28
Inventor D·A·利尔蒙斯L·E·基什
Owner BIAL PORTELA & CA SA
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