Piperazinones, their production and use

Details Piperazinones, their production and use Piperazinones, their production and use

1996-07-10

1999-08-10

Bernhardt, Emily

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514252, 544367, 544384, A61K 31495, C07D24108, C07D41312

Patent

active

059359633

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to novel piperazinones having a platelet aggregation inhibitory action, whose undesirable side effects are slight, or a salt thereof and to a pharmaceutical composition for inhibiting cell-adhesion comprising them as effective components.


BACKGROUND ART

The present invention relates to novel piperazinones having an excellent controlling or inhibiting action cell-adhesion and to the pharmaceutical composition for various diseases.
As the factors participating in adhesion to extracellular substrate of animal cells, there have been known fibronectin, vitronectin, osteopontin, collagen, thrombospondin, fibrinogen and von willebrand factor. These proteins include -Arg-Gly-Asp- as cell recognition site. This tripeptide is recognized by at least one protein belonging to receptors integrins, which are heterodimeric proteins consisting of sub-units combined to two
Structurally related integrin receptors, which recognize the amino acid sequence -Arg-Gly-Asp-, are known to express at extracellular surface glycoprotein of platelets, endothelial cells, leucocyte, lymphocyte, monocyte and granulocyte. Compounds having the amino acid sequence -Arg-Gly-Asp- are competitively bound to the site to be bound with intracellular adhesive factors to thereby inhibit the binding of intracellular adhesive factors. As such substances for inhibiting intracellular adhesion, there has been known, for example, H-Gly-Arg-Gly-Asp-Ser-Pro--OH.
When blood vessels are injured, platelets are activated with, for example, endothelial collagens, which causes binding of fibrinogen to platelets, i.e. platelet aggregation, to form thrombus. The interaction between platelets and fibrinogen takes place through GP IIb/IIIa, this being an important characteristic feature of platelet aggregation. Cell adhesion-inhibiting substances can inhibit platelet aggregation due to substances causing platelet aggregation such as thrombin, epinephrine, ADP and collagen.
Besides, cell-adhesion inhibiting substances are expected as drugs for suppression of metastasis of tumor cells (inhibition of fixed adhesion at the site where the tumor cells are migrated).
Linear or cyclic peptides containing the amino acid sequence, -Arg-Gly-Asp- Biological Chemistry (J. Biol. Chem.), 262, 17294 (1987) and Japanese published unexamined patent application No. 174797/1990, among others!.
And, non-peptide compounds having an antithrombotic action are disclosed in Japanese published unexamined patent application No. 264068/1992 and EPA 505868, in which compounds having 4- to 7-membered cyclic alkyleneimino such as pyrrolidine ring and compounds having e.g. piperidine ring are respectively described. Further, compounds having piperidinone ring, which have cell-adhesion inhibiting action, are disclosed in EPA 529858. And, such drugs as aspirin, heparin and ticlopidine are known to show undesirable side effects such as prolongation of bleeding time. As known platelet aggregation inhibiting substances which are slight in the action of prolonging bleeding time, cyclic peptide derivatives are described in Japanese publication of translations of International patent application No. 509551/1994.


DISCLOUSURE OF INVENTION

These known peptide derivatives mentioned above are not satisfactory in the potency of their activity, and their oral absorbability is not satisfactory from the practical viewpoint. Besides, since these peptide derivatives are hydrolyzed with enzymes including aminopeptidase, carboxypeptidase or various types of endopeptidase, e.g. serineprotease, their stability in a solution containing these enzymes or in a living body is not satisfactory. Therefore, for clinical application of these peptide derivatives, there are problems still to be solved.
And, in the non-peptide compounds having an antithrombotic action, compounds having higher potency durable for a longer period as compared with the above-mentioned known compounds having an antithrombotic action have been sought for.
Further, in the known platelet aggregation inhibiting sub

REFERENCES:
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patent: 5493007 (1996-02-01), Burnier et al.
patent: 5541343 (1996-07-01), Himmelsbach et al.
patent: 5545658 (1996-08-01), Alig et al.
patent: 5550131 (1996-08-01), Sugihara et al.
Takenaka et al Chemical Abstracts, vol. 120, No. 31211v, p. 903, col. 1, Jan. 17, 1994.
Takenaka et al Chemistry Express, vol. 8, No. 9., "Preparation of optically active N,N.sup.1 -ethylene-bridged dipetides as units of pseudopeptides"., pp. 697-700, 1993.
Ruoslahti et al, Science, vol. 238, pp. 491-486 (1987).
Pierschbacher et al Journal of Biological Chemical vol. 262, No. 35, pp. 17294-17297, Dec. 15, 1987.
Receptor Data for Biological Experiments by Doods and van Meel, pp. 112-117 (1991).

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