Pyrazine derivatives and pharmaceutical use thereof

A compound and low-level technology, applied in the direction of organic chemistry, can solve problems such as the selective synthesis of irrelevant compounds and pyrazine compounds that do not show

Inactive Publication Date: 2006-11-29
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] R, R' and M are independently hydrogen or suitable substituents (such as (1) J.Org.Chem., 40 , 2341(1975)., (2) J.Heterocyclic Chem., 15 , 665(1978), (3) J.Chem.Soc., Perkin Trans.1, 885(1994)., (4) Synthesis, 931(1994)., (5) WO-02 / 088084, etc.), however , whose Ar and Ar' are the same and as far as we know, did not show the selective synthesis of pyrazine compound A whose Ar and Ar' are different, and 2-amino-6-aryl-5-aryl-5- (6-Oxo-1,6-dihydro-pyridin-3-yl)-pyrazine compounds and their derivatives are novel, so as yet nothing is known about these compounds
Moreover, both adenosine A 1 and A 2a Any pyrazine derivatives that inhibit activity are unknown

Method used

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  • Pyrazine derivatives and pharmaceutical use thereof
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  • Pyrazine derivatives and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0383] 3-Amino-5-chloro-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile (1.35 g) was dissolved in dioxane (135 ml). To this solution was added phenylboronic acid (1.89 g) in water (27 ml) and Pd(PPh 3 ) 4 (179mg) and Na 2 CO 3 (2.19g). The reaction mixture was heated at 80°C for 2 hours and then at ambient temperature for 3 hours. The above mixture was partitioned between EtOAc and water. Separate the organic layer with aq.Na 2 CO 3 and brine, washed with MgSO 4 dry. The solvent was evaporated in vacuo to give an oily residue, which was purified by silica gel chromatography (EtOAc:n-Hexane=1:1, v / v) to give 3-amino-6-(6-methoxy-3-pyridyl)-5 -Phenyl-2-pyrazinecarbonitrile as a yellow powder which was crystallized from EtOAc (1.15 g).

[0384] 1 H-NMR (DMSO-d 6 δ): 3.81 (3H, s), 6.73 (1H, d, J = 8.6Hz), 7.35 (5H, s), 7.51 (2H, s), 7.54 (1H, dd, J = 2.4, 8.6Hz), 7.99 (1H, d, J = 2.4Hz)

[0385] MS (ESI + ): 304[M+H] + , 326[M+Na] +

[0386] IR(KBr): 3357, 3183, 2...

Embodiment 2

[0389] 3-Amino-6-(6-methoxy-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile (500 mg) was dissolved in dioxane (10 ml) and conc. HCl (5 ml). The solution was stirred at 80°C for 5 hours. The reaction mixture was cooled to 25-30°C and concentrated in vacuo to obtain a residue. Water was added to the residue and the pH of the aqueous mixture was adjusted to 6-7 with 1N NaOH. The precipitated crystals were collected by filtration and dried in vacuo to obtain 3-amino-6-(6-oxo-1,6-di-hydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (390 mg) .

[0390] 1 H-NMR (DMSO-d 6 δ): 6.16 (1H, d, J=9.4Hz), 7.26-7.70 (10H, m), 8.23 ​​(1H, s), 11.66 (1H, s)

[0391] MS (ESI + ): 330[M+Na] +

[0392] MS (ESI - ): 306[M-H] -

[0393] IR (KBr): 3309, 1656, 1610, 1544, 1201cm -1

[0394] m.p.: 215-220°C (H 2 O)

Embodiment 3

[0396] 3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (61.4 mg) was dissolved in DMF (1 ml). To this solution was added a solution of 1M MeI in DMF (0.22ml) and a solution of 0.1M t-BuOK in DMF (2.2ml). The mixture was stirred at 20-30°C for 2 hours. The reaction mixture was partitioned between EtOAc and water. Separate the organic layer. The aqueous layer was extracted with EtOAc. The combined organic solutions were washed with brine, washed with MgSO 4 dry. The solvent was evaporated to obtain an oily residue. The residue was purified by silica gel chromatography (EtOAc-EtOAc:MeOH=93:7 alone, v / v) to give 3-amino-6-(1-methyl-6-oxo-1,6-dihydro- 3-pyridyl)-5-phenyl-2-pyrazinecarboxamide which was crystallized from EtOAc (20 mg).

[0397] 1 H-NMR (DMSO-d 6 δ): 3.45 (3H, s), 6.12 (1H, d, J=9.4Hz), 6.97 (1H, dd, J=2.4, 9.4Hz), 7.41-7.62 (8H, m), 8.14 (1H, d , J=2.4Hz), 8.29(1H, s)

[0398] MS (ESI + ): 344[M+Na] +

[0399] IR (KBr): 3353, 166...

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Abstract

A pyrazine derivative of the following formula (I): or a salt thereof. The pyrazine compound (I) and a salt thereof of the present invention are adenosine antagonists and are useful for the prevention and/or treatment of depression, dementia (e.g. Alzheimer's disease, cerebrovascular dementia, dementia accompanying Parkinson's, disease, etc.), Parkinson's disease, anxiety, pain, cerebrovascular disease (e.g. stroke), etc.), heart failure and the like.

Description

technical field [0001] The present invention relates to a novel pyrazine derivative and its salt, which can be used as medicine. Background technique [0002] Adenosine is a ubiquitous biochemical messenger. Adenosine binds and activates seven transmembrane G-protein coupled receptors, triggering a variety of physiological responses. Adenosine receptors are divided into four known subtypes (i.e. A 1 , A 2a , A 2b and A 3 ). These receptor subtypes convey different, sometimes opposing effects. For example, adenosine A 1 Activation of the receptor increases renovascular resistance, while adenosine A 2a Activation of the receptor leads to a decrease in renovascular resistance. Therefore, adenosine antagonists can be used to prevent and / or treat various diseases, including cardiovascular diseases, degenerative diseases of the central nervous system, respiratory diseases, and various diseases suitable for diuretic therapy. [0003] Some 2-aminopyridine compounds showing...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14C07D409/14C07D405/14A61K31/4965
CPCY02E10/549
Inventor 余西敏青木敏松岛雄司赤羽厚
Owner ASTELLAS PHARMA INC
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