Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-20
2002-01-22
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S473000, C552S001000, C436S098000, C436S093000
Reexamination Certificate
active
06340764
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to [[4-(2-azido-3-methyl-5-oxotetrahydrofuran-2-yl)phenyl]hydrazono]propanedinitrile (I) and its use as a reference compound in the analysis of batches of levosimendan synthesis, particularly in the determination of potentially genotoxic impurities in samples of a levosimendan batch. The present invention also relates to an analytic method for the determination of potentially genotoxic impurities in samples of a levosimendan batch wherein [[4-(2-azido-3-methyl-5-oxotetrahydrofuran-2-yl)phenyl]hydrazono]propanedinitrile (I) is used as a reference compound.
Levosimendan, which is the (−)-enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, and the method for its preparation is described e.g. in EP 565546 B1. Levosimendan is potent in the treatment of heart failure and has significant calcium dependent binding to troponin. The use of levosimendan in the treatment of myocardial ischemia is described in WO 93/21921. The hemodynamic effects of levosimendan in man are described in Sundberg, S. et al., Am. J. Cardiol., 1995; 75: 1061-1066. Levosimendan is represented by the formula:
Clinical studies have confirmed the beneficial effects of levosimendan in heart failure patients.
Levosimendan can be prepared in high purity and in nearly quantitative yields by treating (−)-6-(4-aminophenyl)-5-methyl-4,5dihydro-3(2H)pyridazinone with sodium nitrite and malononitrile as described in EP 565546 B1. However, it has been found that samples of levosimendan as synthesized show potential genotoxic properties occasionally in the bacterial mutagenity,test (Ames test).
SUMMARY OF THE INVENTION
It has now been found that the potential genotoxic properties of levosimendan samples are caused by an azido derivative impurity of formula (I)
This azido derivative is a potent mutagen which can be formed during levosimendan synthesis in an amount sufficient to give a positive result in the bacterial mutagenity test. This compound named [[4-(2-azido-3-methyl-5-oxotetrahydrofuran-2-yl)phenyl]hydrazono]propanedinitrile (I) is therefore useful as a reference compound in the routine analysis of batches of levosimendan synthesis, particularly in the determination of potentially genotoxic impurities in levosimendan batches. The presence of (I) in a levosimendan batch indicates that further recrystallization is necessary for obtaining levosimendan material suitable for use as a medicine.
REFERENCES:
patent: 6183771 (2001-02-01), Urtti et al.
patent: 0 359 439 (1990-03-01), None
patent: 0 383 449 (1990-08-01), None
patent: 383449 (1990-08-01), None
patent: 383449 (1990-08-01), None
patent: 0565546 (1993-10-01), None
patent: WO 97/35841 (1997-10-01), None
patent: WO-97/35841 (1997-10-01), None
patent: WO-01/00211 (2001-01-01), None
Bäckström Reijo
Hauta-Aho Tuula
Heinonen Tuula
Higel Floyd D.
Orion Corporation
Saeed Kamal
LandOfFree
Reference compound for use in the analysis of levosimendan... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Reference compound for use in the analysis of levosimendan..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Reference compound for use in the analysis of levosimendan... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2854168