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Reference compound for use in analysis of levosimendan batches

A kind of reference compound, compound technology, applied in potential genotoxic impurities as a reference compound, the analytical field of determination of potential genotoxic impurities in levosimendan batch samples

Inactive Publication Date: 2003-12-03
ORION CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, synthetic levosimendan samples have occasionally been found to show genotoxic potential in bacterial mutagenicity assays (Ames test method)

Method used

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  • Reference compound for use in analysis of levosimendan batches
  • Reference compound for use in analysis of levosimendan batches
  • Reference compound for use in analysis of levosimendan batches

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1. [[4-(2-Azido-3-methyl-5-oxotetrahydrofuran-2-yl)phenyl]hydrazono]propanedinitrile (mixture of diastereoisomers) preparation

[0019] 6-(4-Aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (153 g, 0.75 mol) was dissolved in acetic acid (750 ml). Solid sodium nitrite (210 g, 3.0 mol) was slowly added to the solution at 10-20°C. After the addition, the mixture was stirred at 10-20°C for 90 minutes. The reaction mixture was quickly poured into a 20°C solution of malononitrile (150 g, 2.3 mol) and water (1500 ml). The resulting mixture was stirred at 20-25°C for 60 minutes and then filtered, washing with water. The wet solid was extracted successively with tetrahydrofuran (300ml) and ethyl acetate (1900ml). The combined extracts were dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was triturated with ethyl acetate (200ml), filtered and the filtrate evaporated in vacuo. The residue (8.0 g) was purified by chromatography o...

Embodiment 2

[0020] Example 2.[[4-(2-Azido-3-methyl-5-oxotetrahydrofuran-2-yl)phenyl]hydrazono]propane dinitrile (I) as a reference compound in HPLC chromatography Applications

[0021] The HPLC (High Pressure Liquid Chromatography) method for the analysis of compound (I) in the levosimendan starting material was based on a C-8 reverse phase HPLC column with UV detection at 360 nm. The mobile phase consisted of acetonitrile and phosphate buffer pH 2.1. Reagents: 1. Methanol, HPLC grade 2. Sodium dihydrogen phosphate, NaH 2 PO 4 x H 2 O, Merck 3. Orthophosphoric acid, H 3 PO 4 , Merck 4. Phosphate buffer pH 2.1:

[0022] 1.8g sodium dihydrogen phosphate (NaH 2 PO 4 ) was dissolved in water and 2.0 ml phosphoric acid was added. If necessary, adjust the pH with 2M sodium hydroxide or 1M phosphoric acid and dilute to 1000.0ml with water. 5. Dimethyl sulfoxide, BDH6. Acetonitrile, HPLC grade 7. Solvent: a mixture of 200ml methanol and 800ml water 8. [[4-(2-azido-3-methyl-5-oxotetrahy...

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PUM

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Abstract

The present invention relates to a pyridazinyl derivative (I) and its use as a reference compound in the determination of potentially genotoxic impurities in levosimendan samples. The invention also relates to an analytic method for the determination of potentially genotoxic impurities in levosimendan samples wherein (I) is used as a reference compound. Levosimendan is a medicament useful in the treatment of heart failure.

Description

technical field [0001] The present invention relates to [[4-(2-azido-3-methyl-5-oxotetrahydrofuran-2-yl)phenyl]hydrazono]propane dinitrile (I) and its synthesis in levosimendan In batch analysis, especially in the determination of potential genotoxic impurities in batch samples of levosimendan as a reference compound. The present invention also relates to an analytical method for determining potential genotoxic impurities in batch samples of levosimendan, wherein [[4-(2-azido-3-methyl-5-oxotetrahydrofuran-2-yl ) phenyl] hydrazono] propane dinitrile (I) as a reference compound. Background technique [0002] Levosimendan, also known as [[4-(1,4,5,6,-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazino] The (-) enantiomer of propanedinitrile and its preparation are disclosed, for example, in EP 565546 B1. Levosimendan is effective in the treatment of heart failure and has significant calcium-dependent binding to troponin. The use of levosimendan for the treatment of myo...

Claims

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Application Information

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IPC IPC(8): G01N30/88B01D15/08C07D237/04C07D307/33G01N30/04
CPCG01N30/04C07D307/33Y10T436/147777Y10T436/142222C07D307/30B01D15/08G01N2030/042
Inventor R·巴克斯特伦T·海因奥恩T·豪塔-阿霍
Owner ORION CORP