2,3-diketopiperazine derivatives or their salts

Details 2,3-diketopiperazine derivatives or their salts 2,3-diketopiperazine derivatives or their salts

1997-05-30

1999-03-02

Bernhardt, Emily

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514253, 514255, 544295, 544360, 544368, 544377, 544379, 544385, 544405, 544408, A61K 31495, C07D40106, C07D40906, C07D24108

Patent

active

058771743

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a non-peptide compound having inhibitory effect on platelet aggregation because of glycoprotein IIb/IIIa receptor antagonism.


BACKGROUND ART

Platelet aggregation plays an important role in thrombosis and blood coagulation. When a blood vessel is injured, platelets are activated, for example, by collagen under the vascular endothelium, so that binding of fibrinogen to the platelets, i.e., platelet aggregation is caused, resulting in thrombosis. As the final step in platelet aggregation, there is a step in which glycoprotein IIb/IIIa receptor on the platelet surface is activated and then bonded to fibrinogen. Therefore, an inhibitor capable of preventing the combination of glycoprotein IIb/IIIa receptor and an adhesion protein such as fibrinogen is considered useful for preventing thrombosis and blood coagulation.
It is considered that in the binding of fibrinogen to glycoprotein IIb/IIIa receptor, the amino acid sequence Arg-Gly-Asp-Ser (hereinafter referred to as RGDS) portion on fibrinogen is an active site. Therefore, RGDS analogues have been developed as antagonist for glycoprotein IIb/IIIa receptor. They are expected as agents for suppressing metastasis of cancerous cells.
As such competitors, peptide derivatives containing an amino acid sequence Arg-Gly-Asp are known. They, however, are not sufficient in ease of oral absorption, etc. when used as a pharmaceutical.


DISCLOSURE OF THE INVENTION

In view of such conditions, the present inventors earnestly investigated and consequently found that a novel 2,3-diketopiperazine derivative effect on platelet aggregation because of glycoprotein IIb/IIIa receptor antagonism and hence is useful as a prophylactic and therapeutic agent for diseases associated with platelet aggregation, for example, an antithrombotic agent, whereby the present invention has been accomplished. The present invention is explained below in detail.
The present invention relates to a novel 2,3-diketopiperazine derivative represented by the following general formula, or its salt: ##STR2## wherein R.sup.1 represents a protected or unprotected amidino group; R.sup.2 represents a hydrogen atom or a carboxyl-protecting group; A represents a substituted or unsubstituted lower alkylene group; B represents --O--, --CONH--, --NHCO--or --SO.sub.2 NH--; Y represents a substituted or unsubstituted lower alkylene group; and the broken line represents a single bond or a double bond.
In the present specification, unless otherwise specified, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the term "lower alkyl group" means a straight chain or branched chain C.sub.1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl or the like; the term "lower alkylene group" means a straight chain or branched chain C.sub.1-6 alkylene group such as methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, 1-methyltrimethylene, 1-ethyltriethylene, 1-isopropyltriethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene or the like; the term "lower alkylenedioxy group" means a C.sub.1-6 alkylenedioxy group such as methylenedioxy, ethylenedioxy or the like; the term "cycloalkyl group" means a C.sub.3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like; the term "aryl group" means, for example, a phenyl, tolyl or naphthyl group; the term "lower alkoxy group" means a lower alkyl --O--group in which the prefix "lower alkyl" means the above-exemplified lower alkyl group; the term "aryloxy group" means an aryl --O--group in which the prefix "aryl" means the above-exemplified aryl group; the term "aralkyl group" means an aryl-lower alkyl group, in which the term "lower alkyl" means the above-exemplified lower alkyl group, such as benzyl, benzhydryl, trityl, phenethyl or the like; and the term "heterocyclic group" means a 5-membered or 6-membered cyclic group containing at least one hetero atom selected from the group consist

REFERENCES:
patent: 4948892 (1990-08-01), Tanabe et al.
Hori et al, Chem. Pharm. Bull. 29, pp. 386-389, 1981.

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