Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-07-10
1998-09-29
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514316, 544360, 544364, 546187, 546188, 546189, 546190, A61K 31495, A61K 31445, C07D40104, C07D40114
Patent
active
058146369
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to nitrogen-containing heterocyclic derivatives for inhibiting the aggregation of platelets, and pharmaceutical compositions for the treatment and prophylaxis of thrombotic diseases comprising as effective ingredient at least one of these derivatives.
2. Description of Related Art
Cardiovascular diseases are increased along with the change of dietary habits and the increase of advanced ages. Almost fifty percent of these diseases may be caused by thrombus.
Platelets in plasma are mainly associated with the formation of thrombus in organisms. For the purpose of the treatment and prophylaxis of thrombotic diseases in clinical practice, there have been used a medicine which suppresses the functions of platelet or inhibits the aggregation of platelets, for example, aspirin which inhibits cyclooxygenase and ticlopidine which activates adenylcyclase.
In recent years, glycoproteins on platelet membrane have been progressively analyzed. As the results, it has been elucidated that the glycoprotein called GPIIb/IIIa is a receptor of fibrinogen. This has therefore led to the expectation that a GPIIb/IIIa antagonists would become an inhibitor of platelet aggregation having a novel action mechanism effectively used for the treatment and prophylaxis of the thrombotic diseases (Trends in Pharmacological Science, 13, 413, 1992). The compounds as the GPIIb/IIIa antagonist include monoclonal antibodies (Ann. New York Acad. Sci., 614, 193, 1991), tripeptide derivatives comprising arginine-glycine-aspartic acid (J. Med. Chem., 35, 2040, 1992), amidinophenyl derivatives (J. Med. Chem., 35, 4393, 1992; Japanese Patent Laid-Open Publication Nos. 264068/1992, 334351/1992, EP-483667, EP-502536, EP-525629, EP-29858, EP-537980, WO-9307867 and WO-9402472), tyrosine derivatives (J. Med. Chem., 35, 4640, 1992), and piperidine derivatives (EP-512831, EP-540334 and EP-578535).
It is also desired to be developed a drug having no side effects such as hemorrhage and a highly selective function as a therapeutic or prophylactic agent of thrombotic diseases.
SUMMARY OF THE INVENTION
The present inventors have now found that a certain kind of a compound becomes a GPIIb/IIIa antagonist.
Thus, an object of the present invention is to provide novel compounds inhibiting the aggregation of platelets.
Another object of the present invention is to provide a pharmaceutical composition comprising a novel compound having the above effect.
Further object of the present invention is to provide a therapeutic or prophylactic method of thrombotic diseases which comprises administering a novel compound having the above activity.
Further object of the present invention is to provide the use of the novel compound having the above activity for preparing a pharmaceutical composition used for the therapy or prophylaxis of thrombotic disorders.
The compound according to the present invention is represented by the formula (I): ##STR3## or a pharmaceutically acceptable salt and solvate thereof, wherein integer of 1 to 4; and m is an integer of 0 to 3); ##STR4## wherein n is an integer of 1 to 3; and Z is --W--(CH.sub.2).sub.p --COOR.sup.3 (wherein W is --O-- or a bond; p is an integer of 1 to 4; and R.sup.3 is hydrogen, lower alkyl or an ester moiety which can be removed under physiological conditions); be substituted by hydroxyl, halogen, amino, lower alkylamino, or imino, or a lower-alkyl-substituted-2-oxodioxol-4-yl group; substituted by hydroxyl, halogen, amino, carboxyl, lower alkoxy, lower alkylamino or lower alkoxycarbonyl; phenyl in which at least one hydrogen atom may be substituted by hydroxyl, halogen, amino, carboxyl, lower alkoxy, lower alkylamino, lower alkoxycarbonyl or halo-lower alkyl; or phenyl-lower alkyl in which at least one hydrogen atom of this phenyl group may be substituted by hydroxyl, halogen, amino, carboxyl, lower alkoxy, lower alkylamino, lower alkoxycarbonyl or halo-lower alkyl.
DETAILED DESCRIPTION OF THE INVENTION
The term "lower alkyl" as a grou
REFERENCES:
patent: 5225402 (1993-07-01), Ogawa et al.
patent: 5273982 (1993-12-01), Alig et al.
patent: 5442004 (1995-08-01), Pieper et al.
patent: 5700801 (1997-12-01), Pieper et al.
Pieper et al, Chemical Abstracts, vol. 125, No. 142565 (Abstract for DE 4,446,301, Jun. 27, 1996).
Pieper et al, Chemical Abstracts, vol. 125, No. 195688 (Abstract for WO 9620,173, Jul. 4, 1996).
Asai Kenji
Hatsushiba Emiko
Iida Hiroyuki
Ishikawa Midori
Isomura Yasuko
Bernhardt Emily
Meiji Seika Kabushiki Kaisha
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