Pyrazolones derivatives

Details Pyrazolones derivatives Pyrazolones derivatives

1998-04-13

1999-10-19

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514252, 514326, 544371, 5462754, 5483697, C07D23122, A61K 31415

Patent

active

059689676

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel pyrazolone derivatives or their salts having an antiplatelet action, for use in the medicinal or veterinary field, especially in prevention or treatment of various thrombotic diseases.


BACKGROUND ART

Platelets play an important role in the normal hemostatic mechanism, and it has turned out that aggregation of platelets plays an important role in thrombogenesis from a pathological aspect. Major thrombotic diseases resulting from thrombogenesis include cerebral thrombosis, pulmonary thrombosis, myocardial infarction, cardiac angina and peripheral arterial obstruction and all of them require development of effective drugs. As preventive and therapeutic agents for these thrombotic diseases, antithrombotic agents having a platelet aggregation inhibitory action are drawing attention. Heretofore effects of aspirin have been studied extensively for a long time, and ticlopidine and cilostazol are used recently. However, the present situation is that drugs stronger in respect of efficacy are demanded.
A platelet has various membrane-binding glycoproteins including adhesive membrane proteins of the integrin super family on the membrane surface. The most plentiful integrin on the cell membrane of a normal platelet is GPIIb/IIIa. The GPIIb/IIIa on activated platelets binds a number of ligand proteins such as fibrinogen, fibronectin, vitronectin and the von Willebrand factor. These various ligands such as fibrinogen have the tripeptide sequence Arg-Gly-Asp (RGD), which is considered to be the most important site recognized for the binding. In recent years, compounds which inhibit GPIIb/IIIa from binding fibrinogen are assumed to be useful as antiplatelet agents, and chemical analogues of RGD have been examined on the usefulness as antiplatelet agents.
In addition to the above-mentioned thrombotic diseases, it is indicated that various diseases including nephritis and cancer cell metastasis are likely to be associated with platelets. Recently, extensive research is conducted on the preventive and therapeutic effects of antiplatelet agents which suppress the platelet function on these diseases.
The relevancy of the novel pyrazolone derivatives represented by general formula (I) and their pharmaceutically acceptable salts of the present invention to some compounds disclosed in the published literature is stated below. reference (a)) and No. 4302051 (hereinafter referred to as reference (a')) disclose pyrazolone derivatives but discloses nothing about their preparation, their specific examples or their medicinal activity. reference (b)) discloses 3-alkoxypyrazole derivatives.


DISCLOSURE OF THE INVENTION

As a result of their extensive research, the present inventors have found unexpectedly that the pyrazolone derivatives of the present invention which are different from any of the compounds disclosed in references (a), (a') and (b) and their pharmaceutically acceptable salts are superior compounds as antiplatelet agents and can be an active ingredient of a preventive or therapeutic agent for the above-mentioned various thrombotic diseases. The present invention has been accomplished on the basis of this finding.
Namely, the present invention relates to a pyrazolone derivative represented by general formula (I) or a salt thereof: ##STR4## [wherein one of X.sup.1 and X.sup.2 is ##STR5## {wherein A is a cyano group, a cyano C.sub.1-4 alkyl group, an amino group, an amino C.sub.1-4 alkyl group, an amidino group or a guanidino group (the amino group, the amino C.sub.1-4 alkyl group, the amidino group and the guanidino group may be substituted at a nitrogen atom with a C.sub.1-6 alkyl group, a C.sub.1-4 alkoxycarbonyl group, an aryl C.sub.1-4 alkyloxycarbonyl group, an aryloxycarbonyl group or an arylcarbonyl group),
R.sup.1 and R.sup.2 are independently hydrogen atoms, halogen atoms, C.sub.1-6 alkyl groups, hydroxyl groups, C.sub.1-4 alkyloxy groups, C.sub.1-4 alkylsulfenyl groups, C.sub.1-4 alkylsulfinyl groups, C.sub.1-4 alkylsulfonyl groups, R.sup.3 R.sup.3' N-- gro

REFERENCES:
patent: 4348528 (1982-09-01), Breda

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