Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-10-20
2000-05-02
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544360, C07D40100, A61K 31495
Patent
active
060573244
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel substituted-amidinobenzene derivatives and their salts which are useful as medicines, especially as GPIIb/IIIa antagonists.
BACKGROUND ART
For a long period of time after the finding by Donne in 1842 (see C.R. Acad. Sci. (Paris), 14, 336-368, 1842); blood platelets have been considered as the component in blood which is necessary for hemostasis. At present, it has been clarified that blood platelets not only play the principal part in the hemostatic mechanism of blood but also are multi-functional as participating in the creation of arteriosclerosis, cardiovascular system disorders including thrombotic disorders, cancer metastases, inflammations, rejections after transplants, and also immunoreactions, etc., which are clinically important. The thrombotic disorders and ischemic disorders are therapeutically treated by restoring the circulation of the blood by the application of medicines or by physical means. However, a clinically problematic phenomena has been found recently that, after the restoration of the blood circulation, the activation, the adhesion and the aggregation of blood platelets are promoted based on the damage of the blood vessel tissue including endothelial cells and the unbalanced systemic fibrinolysis-coagulation equilibrium caused by the medicines itself, and the like. For instance, it has been clarified that, after the circulation of the blood has been restored by thrombolytic therapy using t-PA (tissue Plasminogen Actitor) or the like, the fibrinolytic activity and the coagulating activity are activated to break the systemic fibrinolysis-coagulation equilibrium. Clinically, it causes re-occlusion and is therefore seriously problematic in the therapy (see J. Am. Coll. Cardiol., 12, 616-623, 1988). On the other hand, a PTCA Percutaneous transluminal coronary angioplasty) therapy has been rapidly popularized, with producing good results in some degree, for curing disorders as based on coronary stenosis and aortostenosis, such as stenocardia, myocardial infarction, etc. However, this therapy involves serious problems in that it damages the blood vessel tissue including endothelial cells to cause acute coronary obstruction and even re-stenosis which occurs in about 30% of therapeutical cases. Blood platelets play the principal role in various thrombotic disorders (e.g., re-occlusion) following such blood circulation-restoring therapy. Therefore, the effectiveness of anti-platelet agents would be expected for such disorders. However, conventional anti-platelet agents have not as yet been verified to be satisfactorily effective. GPIIb/IIIa is a platelet membrane glycoprotein which is one of the integrin family (see Blood, 80, 1386-1404, 1992). This integrin binds to adhesive proteins such as fibrinogen, von Willebrand factor, etc., and have an important function at the terminal in blood platelet aggregation. Monoclonal antibodies against GPIIb/IIIa, peptides having an RGD sequence and the like have potent platelet aggregation inhibiting activity, and some of which have already been put into clinical examinations.
Non-peptidic, low molecular weight GPIIb/IIIa antagonists are known in a published Japanese patent application (kokai) 4-288051 (sulfonamide fibrinogen receptor antagonists of the following representative compound, ##STR2## and a published Japanese patent application (kokai) 6-25227 (cyclic imino derivatives of the following representative compound, ##STR3## and are disclosed by Leo et al. (see Journal of Medicinal Chemistry, 35, 4393-4407, 1992) in which the following representative compound is disclosed. ##STR4## The piperizine acetic acid derivatives of the following general formula are disclosed in a published PCT patent application WO093/10091. ##STR5## (in which X.sup.1 and y.sup.1, which may be the same or different, represent CH or N; 2,2,2-trifluoroethyl group; represent CH, may also represent a fluorine, chlorine or bromine atom or a C.sub.1-4 alkyl group; represent N, may also represent a C.sub.1-4 alkyl or hydrox
REFERENCES:
Eldred, C.D. et al., "Orally Active Non-Peptide Fibrinogen Receptor (GpIIb/IIIa) Antagonist: Identification of 4-(4-(4-(Aminominomethyl)phenyl)-1-piperazinyl)-1-piperidineacetic Acid as a Long-Acting, Broad-Spectrum Antithrombotic Agent", 1994, J. Med. Chem., vol. 37, No. 23, pp. 3882-3885.
Stilz H.U. et al., "Discovery of an Orally Active Non-peptide Fibrinogen Receptor Antagonist", May 24, 1996, J. Med. Chem., vol. 39, No. 11, pp. 2118-2122.
Akamatsu Seijiro
Ichihara Masato
Kaku Seiji
Kawasaki Tomihisa
Matsumoto Yuzo
Merck Patent Gesellschaft mit beschrankter Haftung
Patel Sudhaker B.
Raymond Richard L.
Yamanouchi Pharmaceutical Co. Ltd
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