Anticoagulant peptidyl-arginine aldehyde derivatives

Details Anticoagulant peptidyl-arginine aldehyde derivatives Anticoagulant peptidyl-arginine aldehyde derivatives

1998-11-23

2001-05-22

Celsa, Bennett (Department: 1627)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S008100, C514S019300, C514S022000, C530S331000

Reexamination Certificate

active

06235707

ABSTRACT:

This application is a national stage application under 35 U.S.C. §371 of International Application PCT/HU 97/00,028, filed Jun. 5, 1997.
This invention relates to new peptidyl-arginine aldehyde derivatives of general formula (I),
Q-D-Xaa-Pro-Arg-H  (I)
wherein
Q represents an acyl group of formula Q′—O—CO—, wherein Q′ represents an alkyl group with 1-3 carbon atoms,
D-Xaa represents a 3-cyclobutyl-D-alanyl or 3-cyclopentyl-D-alanyl group,
Pro stands for an L-prolyl residue, and
Arg stands for an L-arginyl residue,
and their acid-addition salts formed with an organic or inorganic acids and pharmaceutical compositions containing the same.
The new compounds of general formula (I) have valuable therapeutic, particularly anticoagulant, anti-platelet and antithrombotic properties.
Particularly preferred representatives of the compounds of general formula (I) of the invention are the following derivatives:
ethoxycarbonyl-3-cyclobutyl-D-alanyl-L-prolyl-L-arginine aldehyde,
methoxycarbonyl-3-cyclobutyl-D-alanyl-L-prolyl-L-arginine aldehyde,
ethoxycarbonyl-3-cyclopentyl-D-alanyl-L-prolyl-L-arginine aldehyde,
methoxycarbonyl-3-cyclopentyl-D-alanyl-L-prolyl-L-arginine aldehyde,
and their acid-addition salts with organic and inorganic acids, preferably the hemisulfate salts.
Definitions
The abbreviations of the amino acids, 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).
Amino acids:
Arg=L-arginine[(2R)-2-amino-5-guanidino-pentanoic acid],
Asp=L-aspartic acid[(2S)-2-amino-3-carboxypropionic acid],
boroArg=L-boroarginine[(1R)-1-amino-4-guanidinobutylboric acid],
D-Cba=3-cyclobutyl-D-alanine[(2R)-2-amino-3-cyclobutylpropionic acid],
DL-Cbg=DL-cyclobutyl-glycine[(2RS)-2-amino-2-cyclobutylacetic acid],
D-Chg=D-2-cyclohexyl-glycine[(2R)-2-amino-cyclohexylacetic acid],
D-Cpa=3-cyclopentyl-D-alanine[(2R)-2-amino-3-cyclopentylpropionic acid],
Gla=gamma-carboxy-L-glutamic acid[(2S)-2-amino-4,4-dicarboxybutyric acid],
Glu=L-glutamic acid[(2S)-2-amino-4-carboxybutyric acid],
Glp=L-pyroglutamic acid[(5S)-2-pyrrolidone-5-carboxylic acid],
Gly=glycine (2-aminoacetic acid),
D-MePhe=N-methyl-3-phenyl-D-alanine[(2R)-2-methylamino-3-phenylpropionic acid],
D-MePhg=D-N-methyl-phenylglycine[(2R)-2-amino-2 phenylacetic acid],
Nal(1)=3-(naphth-1-yl)-L-alanine[(2S)-2-amino-3-(naphth-1-yl)-propionic acid],
D-Phe=3-phenyl-D-alanine[(2R)-2-amino-3-phenylpropionic acid],
Pro=L-proline[(2S)-pyrrolidine-2-carboxylic acid].
Substituents:
Ac=acetyl, Boc=t-butoxycarbonyl, Bz=benzoyl, Eoc=ethoxycarbonyl, Et=ethyl, iPoc=isopropoxycarbonyl, Me=methyl, 4MeP=4-methyl-pentanoyl, Moc=methoxycarbonyl, pNA=p-nitrophenylamino, Poc=propoxycarbonyl, Tos=p-toluene-sulfonyl, Z=benzyloxycarbonyl.
TECHNICAL FIELD
The abbreviations of amino acids alone represent the respective L-amino acid. The D-amino acid is marked separately, i.e. 3-phenyl-D-alanine=D-Phe. The hyphen before and after the amino acid abbreviation designates a missing hydrogen atom from the amino group or a missing hydroxy group from the carboxy group, resp. Accordingly, Eoc-D-Cba-Pro-Arg-H represents ethoxycarbonyl-3-cyclobutyl-D-alanyl-L-prolyl-L-arginine aldehyde, while Bz-Ile-Glu-Gly-Arg-pNA represents benzoyl-Lisoleucyl-L-glutamyl-glycyl-L-arginine p-nitroanilide.
BACKGROUND ART
Blood clotting represents part of the protective mechanism in the organism. Induced by a vessel will injury a blood clot is formed to prevent bleeding to death. In addition, vascular diseases, haemostasis and pathological activation of clotting factors may also induce blood clotting. In this case 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 catalysed enzyme reactions, where plasma proteins, the so-called clotting factors, are activated consecutively. The factors are marked by Roman numerals, the active form is represented by the letter “a”. Trivial names are in use 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, 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 fib-rinogen, 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→fXIa which is followed by the reaction fIX→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 [fVII+TF] or [fVIIa+TF] complex. fX is activated by the [fVIIa+TF] 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 (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 fXa are formed), then it is inactivated by the action of TFPI (Tissue Factor Pathway Inhibitor, earlier name Lipoprotein-Associated Coagulation Inhibitor), the common inhibitor of both fXa and [fVIIa+TF] [T. J. Girard et al., Nature 338, 518-520 (1989)].
2. The fIXa generated together with factor X and cofactor VIIIa produces, in the presence of CA
++
ions, on a phospholipid surface (PL) the “tenase” complex, [fIXa+fVIIIa+fX+PL+CA
++
], wherein fX is activated to fXa.
3. The fXa generated up to this point, together with prothrombin (fII) and cofactor Va, produces the “prothrombinase complex” [fXa+fVa+fII+PL+CA
++
], which has a structure similar to that of “tenase”. Inside this complex prothrombin is converted to thrombin. The fV→fVa and fVIII→fVIIIa conversions can be performed either by fXa or thrombin.
4. The small amount of thrombin generated converts a portion of fXI to the enzyme fXIa and activates some factors VIII and V, to produce further amounts of fVIIIa and fVa, resp. By now fXIa can carry out the conversion of factor IX to the enzyme fIXa. With this step the chain reaction starting with the Xase-complex and terminated with thrombin formation is resumed. With the repetition of the process increasing amounts of thrombin are formed.
5. At a suitable high thrombin concentration the fibrinogen dissolved in the plasma undergoes partial proteolysis, a fibrin-monomer is generated which is first associated to a soluble fibrin polymer, then it is converted to insoluble fibrin polymer. He

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