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4-amino-pyrido[3,2-e]pyrazines, their use as inhibitors of phosphodiesterase 10, and processes for preparing them

An amino, pyrazine technology applied to 4-amino-pyrido[3,2-e]pyrazines

Inactive Publication Date: 2009-06-03
埃尔比昂有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this study, attention deficit was induced by administering phencyclidine for 7 days followed by a washout period

Method used

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  • 4-amino-pyrido[3,2-e]pyrazines, their use as inhibitors of phosphodiesterase 10, and processes for preparing them
  • 4-amino-pyrido[3,2-e]pyrazines, their use as inhibitors of phosphodiesterase 10, and processes for preparing them
  • 4-amino-pyrido[3,2-e]pyrazines, their use as inhibitors of phosphodiesterase 10, and processes for preparing them

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0187] Intermediate A1: 4-Chloro-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine

[0188] 16 g of 8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazin-4-one and 120 ml of POCl 3 Mix and heat to reflux for 8 hours. After cooling to room temperature, the reaction mixture was treated with 1200 ml of crushed ice / water and stirred for a further 1 hour. The product was extracted with 2 x 300ml dichloromethane. The collected organic layer was washed with 2 x 300 ml of water, followed by Na 2 SO 4 dry. The solvent was removed under reduced pressure.

[0189] Yield: 14.5g

[0190] m.p.: 121-123°C

example

[0191] Many other intermediates A of formula (IV) can be prepared according to this procedure. Some examples are as follows:

[0192]

[0193]

[0194] Intermediate A25: 4-Chloro-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazin-8-ol

[0195] Suspend 2 g of 4-chloro-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine in 50 ml of dichloromethane middle. 3ml of bortribromide was added dropwise at 0-5°C, followed by stirring at 0-5°C for 1h, stirring at room temperature for 4h, and standing overnight. The reaction mixture was slowly added to a solution of 10 g potassium carbonate in 100 ml water. After stirring and constant pH >7 (addition of 10% potassium carbonate solution), the precipitate was filtered off and washed with water.

[0196] Yield: 1.87g

[0197] m.p.: 227-234°C (EtOH)

[0198] Other intermediates A of formula (IV) can be prepared according to this procedure. The example of X=Br is obtained by heating to reflux for 6h. Some examples ar...

Embodiment 1

[0205] Example 1: 4-amino-8-methoxy-3-methyl-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazine

[0206] 10g of intermediate A1 and 200ml of NH 3 The aqueous solution (32%) was mixed in the autoclave and heated to 130°C for 8 hours. The reaction mixture was diluted with 200 ml of water. The precipitated reaction product was separated with water and dichloromethane, and dried under reduced pressure.

[0207] Yield: 8.5g

[0208] m.p.: 219-221°C

[0209] The following examples were prepared using the same synthetic route and reaction conditions as described above in Example 1:

[0210]

[0211]

[0212]

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Abstract

The invention relates to 4-amino-pyrido[3,2-e]pyrazines, to processes for preparing them, to pharmaceutical preparations which comprise these compounds and to the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 10, as active compounds for treating diseases of mammals including a human which can be influenced by using the compounds according to the invention to inhibit phosphodiesterase 10 activity in the central nervous system. More particularly, the invention relates to the treatment of neurologic and psychiatric disorders, for example psychosis and disorders comprising cognitive deficits as symptoms.

Description

technical field [0001] The present invention relates to 4-amino-pyrido[3,2-e]pyrazines, processes for their preparation, pharmaceutical formulations containing these compounds, which are phosphodiesters as active compounds, and pharmaceutical uses of these compounds Inhibitors of enzyme 10 for use in the treatment of diseases in mammals, including man, which can be affected by inhibiting the activity of phosphodiesterase 10 in the central nervous system by using the compounds of the present invention. More particularly, the invention relates to the treatment of neurological and psychiatric disorders such as psychosis and disorders that include cognitive impairment as a symptom. Background technique [0002] Mental disorders, especially schizophrenia, are serious mental disorders which impair daily life very seriously. The symptoms of psychosis can be divided into two parts. In the acute phase, it is mainly hallucinations and delusions, which are called positive symptoms. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14A61K31/4985A61P25/18
CPCC07D471/14A61P9/10A61P15/00A61P21/00A61P25/00A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P31/18A61P43/00
Inventor N·霍夫根H·斯坦格B·兰根U·埃格兰德R·欣德勒A·加斯帕里克C·伦德费尔特
Owner 埃尔比昂有限责任公司
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