Anticoagulant peptide aldehyde derivatives

Details Anticoagulant peptide aldehyde derivatives Anticoagulant peptide aldehyde derivatives

1999-04-02

2000-09-19

Celsa, Bennett

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 2, 514822, 530331, 548535, A61K 3805, C07K 500

Patent

active

061212415

DESCRIPTION:

BRIEF SUMMARY
This invention relates to new peptide aldehyde derivatives of general formula (I), 2-cyclopentyl-2-hydroxyacetyl group, pharmaceutical compositions containing the same.
The compounds of general formula (I) of the invention have valuable therapeutic, particularly anticoagulant, antiplatelet and antithrombotic, properties.
Particularly preferred representatives of the compounds of general formula (I) of the invention are the following derivatives: and


Definitions

The abbreviations of the hydroxy- and aminoacids, their substituents and peptides built up therefrom are in accordance with the prior art, e.g. Biochem. J. 126, 773 (1972); Biochemistry 14, 449 (1975). [(2R)-2-cycloheptyl-2-hydroxyacetic acid], D-cPga=D-2-cyclopentyl-2-hydroxyacetic acid [(2R)-2-cyclopentyl-2-hydroxyacetic acid], acid], acid], pNA=p-nitrophenylamino, THP=tetrahydropyranyl, Tos=p-toluenesulfonyl, Z=benzyloxycarbonyl.
The abbreviations of amino acids alone represent the respective L-amino acid. The D-amino acid is marked separately, e.g. 3-phenyl-D-alanine=D-Phe. The hyphen before and after the amino acid abbreviation means a missing hydrogen atom from the amino group or a missing hydroxy group from the carboxy group, resp. Accordingly, D-cHga-Pro-Arg-H represents D-cycloheptyl-2-hydroxyacetyl-L-prolyl-L-arginine aldehyde and Bz-Ile-Glu-Gly-Arg-pNA represents benzoyl-L-isoleucyl-L-glutamyl-glycyl-L-arginine p-nitroanilide.


DESCRIPTION OF THE RELATED ART

Blood clotting represents part of the protective mechanism in the organism. Vessel wall injury initiates the cascade, a blood clot is formed to inhibit bleeding to death. In addition, vascular diseases, haemostasis and pathological activation of clotting factors may also induce blood clotting. The vessel is obstructed fully or partially by the intravascular thrombus formed and thrombosis develops. Fibrinolysis represents an other part of the protective mechanism Here excess blood clots are removed by the enzymes participating in thrombolysis and the dissolution of the thrombus, too.
The blood clotting process is a cascade reaction, a series of catalyzed enzyme reactions, where plasma proteins, i.e. the clotting factors, are activated consecutively. The factors are designated by Roman figures, the active form is represented by the letter "a". Trivial names are in rise too, thus fibrinogen=factor I (fI), fibrin=factor Ia (fIa), prothrombin=factor II (fII) and thrombin=factor IIa (fIIa). Serine proteases (fXIIa, fVIIa, fXIa, fIXa, fXa and thrombin), some accelerating co-factors (fVa and fVIIIa) and the clottable molecule itself (fibrin) are all formed during the clotting process fXa and thrombin are the last two factors among the proteases formed. Thrombin, formed upon the action of fXa, initiates the fission of fibrinogen, resulting in the fibrin clot.
According to the earlier concept of blood clotting mechanism [R. G. MacFarlane, Nature 202, 498 (1964); E. W Davie and O. D. Ratnoff, Science 145, 1310 (1964)] fX is activated in two ways by an intrinsic and an extrinsic pathway. In the former case the process is initiated by the surface-activated fXII (fXIIa) with the transformation fXI.fwdarw.fXIa which is followed by the reaction fIX.fwdarw.fIXa; fX is activated by fIXa. In the extrinsic pathway the process is initiated by the appearance of the cellular surface receptor, the tissue factor (TF), and the development of the [fVIIxTF] or [fVIIaxTF] complex. fX is activated by the [fVIIaxTF] complex.
According to recent findings blood clotting in the living organism is a result of both pathways combined [E. W. Davie et al., Biochemistry 43, 10363 (1991)] where the main steps are the following:
1. In the case of vessel wall injury or disease TF migrates to the surface and binds a portion of factor VII circulating in the blood. The [fVII.TF]-complex formed is converted by the action of suitable trace amounts of proteases (e.g. fXIIa, fXa, fIXa and thrombin) into the active enzyme complex [fVIIa.TF] which activates a small portion of plasma factors IX and X (i.e. small amounts of fIXa and

REFERENCES:
patent: 4703036 (1987-10-01), Bajusz et al.
Bajusz et al., Bioorg. & Med. Chem. vol. 3, No. 8, pp. 1079-1089, 1995.
Bajusz et al., J. Med. Chem., 33, 1990. 1729-35.
Shuman et al., J. Med. Chem., 36, 1993, 314-319.

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