Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-11-22
1996-04-30
Jordan, Kimberly
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 3150
Patent
active
055125727
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FI93/00191, filed May 5, 1993.
The present invention relates to the use of 4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl!hydrazono!prop anedinitrile (I) or its enantiomers or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment or prevention of myocardial ischemia.
4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl!hydrazono!propa nedinitrile (I) has been earlier described in European patent application EP 383449. It has been shown that compound (I) may be potent in the treatment of congestive heart failure. The optically pure enantiomers of this compound has previously been described in the patent application PCT/FI92/00003. It has now been revealed that compound (I) and its optically active enantiomers also have significant anti-ischemic properties.
The method for the preparation of compound (I) and the resolution of its optically active (-) and (+) enantiomers are described in the patent applications mentioned above. Salts of these compounds may be prepared by known methods. Pharmaceutically acceptable salts are useful as active medicaments, however, preferred salts are the salts with alkali or alkaline earth metals.
In EP 383449 it was shown that compound (I) has significant calcium dependent binding to troponin and is a potent inhibitor of PDE III enzyme. Like other PDE III inhibitors, such as pimobendan and milrinone, compound (I) increases contractility of the cardiac muscle and produces vasodilatation and has therefore utility in the treatment of congestive heart failure. The anti-ischemic utility of positive inotropic compound (I) which is a potent PDE III inhibitor was unexpected because arrhythmic effects have often been observed in connection with PDE III inhibitors. We have found that, unlike pimobendan or milrinone, compound (I) can decrease calcium influx. This may play some role in the observed new effect of compound (I) and its enantiomers.
BRIEF DESCRIPTION OF DRAWING
FIG 1 shows the dose dependent effect of compound (I) on infarct size.
The anti-ischemic compound according to the invention is formulated into dosage forms using the principles known in the art. It is given to mammalian organisms, i.e., humans, a patient as such or in combination with suitable pharmaceutical excipients in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions whereby the contents of the active compound is in the formulation from about 0.5 to 100% per weight. In general, the compound of the invention may be administered to man in oral doses ranging from about 1 to 100 mg per day once a day or divided into several doses. Choosing suitable ingredients for the composition is a routine for those of ordinary skill in the art. It is evident that suitable carriers, solvents, gel forming ingredients, dispersion forming ingredients, antioxidants, colours, sweeteners, wetting compounds and other ingredients normally used in this field of technology may be also used. The compositions of the present invention have anti-ischemic activity and are of use in the treatment and prevention of myocardial ischemia. Such conditions can be treated by administration of the compounds according to the invention for example orally, rectally or parenterally.
The anti-ischemic properties of the compounds according to the invention are demonstrated below.
The effects of 4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl!hydrazono!prop anedinitrile on ventricular arrhytmias, survival rate and infarct size after coronary artery ligation were studied in conscious rats (male Sprague-Dawley rats). Anesthetized rats were opened at the fourth intercostal space and a silk loop was placed around the left main coronary artery, about 3 mm from its origin. After complete recovery (7-10 days) from this preliminary surgery, the coronary ligature was tightened in the conscious rats to produce acute coronary artery occlusion. 4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl!hydrazono!prop anedinitrile in do
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patent: 4766123 (1988-08-01), Coates
patent: 4962110 (1990-10-01), Emmett et al.
patent: 5109575 (1991-05-01), Haikala et al.
patent: 5122524 (1992-06-01), Haikala et al.
Backstrom Reijo J.
Haikala Heimo O.
Honkanen Erkki J.
Levijoki Juoko M.
Nore Pentti T.
Jordan Kimberly
Orion-yhtyma Oy
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