Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-08-04
1998-06-30
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544360, 544365, C07D21158, C07D21160, C07D40104, A61K 31495
Patent
active
057734429
DESCRIPTION:
BRIEF SUMMARY
THIS APPLICATION IS A 371 OF PCT/JP96/00244 FILED ON FEB. 8, 1996.
TECHNICAL FIELD
The present invention relates to novel benzamidine derivatives or their salts which are useful as medicines, especially as GPIIb/IIIa antagonists, and to pharmaceutical compositions containing such compounds.
BACKGROUND ART
Blood platelets, since their discovery by Donne in 1842 (see C. R. Acad. Sci. (Paris), 14, 336-368, 1842), have been considered, for a long period of time, as components in blood which are necessary for hemostasis. At present, it has been determined 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, even immunoreactions and others which are clinically important. Therapies for such thrombotic disorders and ischemic disorders are employed to restore the circulation of the blood by the application of medicines or physical means to patients. Recently, however, the occurrence of clinically problematic phenomena has been found after the restoration of the circulation of the blood, which are such that the blood vessel tissue having endothelial cells therein is damaged, the medicines applied make the adenolysis-coagulation equilibrium of the body unbalanced, etc., with the result that the activation, the adhesion and the aggregation of blood platelets are promoted too much. For instance, it has been determined that, after the circulation of the blood has been restored by thrombolytic therapy using t-PA or the like, the adenolytic ability and the coagulating ability of the restored blood are activated to thereby make the systemic adenolysis-coagulation equilibrium of the body unbalanced. Clinically such causes re-obstruction and is therefore seriously problematic in therapy of the disorders (see J. Am. Coll. Cardiol., 12, 616-623, 1988). On the other hand, a PTCA 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 having therein endothelial cells to thereby cause acute coronary obstruction and even re-stenosis in about 30% of cured patients. Blood platelets play the principal part in various thrombotic disorders (e.g., re-obstruction) following such blood circulation-restoring therapy. Therefore, the effectiveness of platelet aggregation inhibitors would be expected for such disorders. However, conventional platelet aggregation inhibitors 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). The integrin bonds to adhesive proteins such as fibrinogen, von Bill Brand factor, etc., while displaying an important function at the terminal in blood platelet aggregation. Monoclonal antibodies to GPIIb/IIIa as well as peptides and others having an RGD sequence have high platelet aggregation inhibiting activity, some of which have already been put into clinical examinations. Non-peptidic, low-molecular GPIIb/IIIa antagonists are described in Japanese Patent Laid-Open Nos. 4-288051 and 6-25227 and are disclosed by Leo et al. (see Journal of Medicinal Chemistry, 35, 4393-4407, 1992). However, these are all for intravenous injection and can be used only at the acute stage of disorders. On the other hand, orally-applicable GPIIb/IIIa antagonists are disclosed in European Patent Laid-Open No. 542363, but their peroral activity cannot be said to be satisfactory. Therefore, peroral GPIIb/IIIa antagonists with definite effect are much desired. The compounds of the present invention are novel benzamidine derivative which are different from the compounds described in the above-mentioned patent specifications in their stru
REFERENCES:
patent: 5442064 (1995-08-01), Pieper et al.
Judkins et al., A Versatile Synthesis of Amidines from nitriles via Amidoximes, Synthetic Communications, 26(23), 4351-4367, 1996.
Eldred et al., Orally Active Non-peptide Fibrinogen Receptor (GPIIb/IIIa) Antagonists, J. Med. Chem., 37(23), 3882-5, 1994.
Akamatsu Seijiro
Ichihara Masato
Kaku Seiji
Kawasaki Tomihisa
Matsumoto Yuzo
Rao Deepak R.
Shah Mukund J.
Yamanouchi Pharmaceutical Co. Ltd.
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