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Novel substituted pyrazinone derivatives for use in MCH-1 mediated diseases

A technology of pyrazinone and derivatives, applied in the field of pyrazinone derivatives

Active Publication Date: 2009-01-07
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it has been found that MCH also induces the release of corticotropin-releasing factor (CRF) from hypothalamic explants, this effect can be sensitively blocked by MCH-1 receptor antagonists (J. Neuroendrocrinol. (2003) 15, 268- 2729), but there is no direct evidence that the compounds of WO 98 / 11075 also have this effect, so this should not be taken as a starting point for the development of MCH-1 antagonists

Method used

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  • Novel substituted pyrazinone derivatives for use in MCH-1 mediated diseases
  • Novel substituted pyrazinone derivatives for use in MCH-1 mediated diseases
  • Novel substituted pyrazinone derivatives for use in MCH-1 mediated diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A1

[0178] a) Preparation of intermediate compound 1

[0179]

[0180] React in the microwave. 2-phenoxyethylamine (0.010mol), 2,3 dichloropyrazine (0.012mol) and 1,8-diazabicyclo(5.4.0.)undec-7-ene (DBU)(0.012 mol) in CH 3 The mixture in CN (20ml) was heated at 180°C for 20 minutes. The solvent was evaporated. The residue was purified by an open silica gel short column (eluent: CH 2 Cl 2 ). The product fractions were collected and the solvent was evaporated. Obtained: 2.5 g of intermediate compound 1 (quantitative yield; used in the next reaction step without further purification).

[0181] b) Preparation of intermediate compound 2

[0182]

[0183] React in the microwave. A mixture of intermediate compound 1 (0.0092 mol) in NaOH (10 ml; 50%) and DMSO (10 ml) was heated at 150° C. for 30 minutes. The reaction mixture was cooled to 0 °C. EtOAc and water were added at 0 °C. The organic layer was separated and dried (Na 2 SO 4 ), filter Dicalite and evaporate...

Embodiment A2

[0185] Preparation of intermediate compound 3

[0186]

[0187] Stir 4-bromo-2-methoxyphenol (0.0246mol), 2-hydroxyethylpyrrolidine (0.0492mol) and triphenylphosphine (0.0492mol) in THF (50ml; anhydrous) at 0°C in the mixture. In a microwave oven, diethyl azodicarboxylate (0.0492 mol) was added at 0°C. The reaction mixture was stirred at 100°C for 5 minutes. Join Na 2 CO 3 aqueous solution. The mixture was extracted with EtOAc. The separated organic layer was dried (Na 2 SO 4 ), filtered and evaporated the solvent. The residue was captured by adding Amberlyst 15 (0.123 mol) followed by NH 3 / CH 3 OH to release it, followed by purification through an open silica gel short column (eluent: CH 2 CI 2 (CH 3 OH / NH 3 )95 / 5). The product fractions were collected and the solvent was evaporated. Obtained: 6.7 g of intermediate compound 3 (91%).

Embodiment A3

[0189] a) Preparation of intermediate compound 4

[0190]

[0191] A mixture of NaH (0.0049 mol; 60%) in DCE (1.7 ml) was stirred at 0°C. At 0°C, a solution of 2-phenylethanethiol (0.0031 mol) in DCE (5.6 ml) was added in portions. The reaction mixture was stirred at room temperature for 30 min. A solution of 2,3-dichloropyrazine (0.0033 mol) in DCE (1.7 ml) was added and the resulting reaction mixture was heated in a microwave oven at 80° C. for 10 minutes. The mixture was filtered through Celite and the residue on the filter was washed with CH 2 Cl 2 . The solvent of the filtrate was evaporated. The residue was purified by an open silica gel short column (eluent: CH 2 Cl 2 / Hexane 1 / 1, then CH 2 Cl 2 ). The product fractions were collected and the solvent was evaporated. Obtained: 0.5 g of intermediate compound 4 (72%).

[0192] b) Preparation of intermediate compound 5

[0193]

[0194] React in the microwave. A mixture of intermediate compound 4 (0....

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Abstract

The present invention concerns aryl and heteroaryl substituted pyrazinone derivatives having antagonistic melanin-concentrating hormone (MCH) activity, in particular MCH-I activity according to the general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereo chemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, whereinthe variables are defined in Claim 1. It further relates to their preparation, compositions comprising them and their use as a medicine. The compounds according to the invention are useful for the prevention and / or treatment of psychiatric disorders, including but not limited to anxiety, eating disorders, mood disorders, such as bipolar disorders and depression, psychoses, such as schizophrenia, and sleeping disorders; obesity; diabetes; sexual disorders and neurological disorders.

Description

technical field [0001] The field of the invention relates to aryl and heteroaryl substituted pyrazinone derivatives having melanin concentrating hormone (MCH) antagonizing activity, particularly MCH-1 antagonizing activity. The invention also relates to formulations, compositions comprising these compounds and their use as medicaments. Background of the invention [0002] Melanin-concentrating hormone (MCH) is a cyclic 19-amino acid polypeptide that is primarily produced by radiation of hypothalamic neurons throughout the central nervous system (CNS) (J. Comp. Neurol. (1992) 319, 218-245 ). MCH mediates its action through two G protein-coupled receptors (GPCRs) called MCH-1 and MCH-2 (reviewed in Doggrell, 2003). While only the MCH-1 receptor is expressed in rodents, both humans and primates express both MCH-1 and MCH-2 receptors (Genomics (2002), 79, 785-792). Initially, the MCH-1 receptor was considered a valuable target for the treatment of obesity because MCH promotes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/20C07D403/10A61K31/497A61P31/18
CPCC07D401/14C07D401/12C07D241/20C07D403/10C07D403/12C07D491/10C07D401/10C07D401/04A61P11/00A61P15/00A61P15/10A61P25/14A61P25/18A61P25/20A61P25/22A61P25/24A61P3/10A61P3/14A61P31/18A61P3/04A61P3/06A61P43/00A61P5/24
Inventor J·I·安德雷斯-吉尔M·J·艾卡扎尔-瓦卡R·M·艾瓦雷茨-埃施科巴J·奥亚扎巴尔桑塔马里纳F·M·多特詹伯格J·马克里特基D·辛普森S·马蒂尼茨冈扎尔茨
Owner JANSSEN PHARMA NV
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