Antithrombotic compounds

Details Antithrombotic compounds Antithrombotic compounds

2000-12-18

2002-11-26

O'Sullivan, Peter (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S025000, C514S330000, C514S517000, C536S017100, C536S017400, C536S017600, C536S017900, C546S206000, C562S036000

Reexamination Certificate

active

06486129

ABSTRACT:

The invention relates to new antithrombotic agents, a process for their preparation, pharmaceutical compositions containing the compounds as active ingredients, as well as the use of said compounds for the manufacture of medicaments.
Serine proteases are enzymes which play an important role in the blood coagulation cascade. Members of this group of proteases are for example thrombin, trypsin, factors VIIa, IXa, Xa, XIa, XIIa, and protein C. Thrombin is the final serine protease enzyme in the coagulation cascade. The prime function of thrombin is the cleavage of fibrinogen to generate fibrin monomers, which are cross-linked to form an insoluble gel. In addition, thrombin regulates its own production by activation of factors V and VIII earlier in the cascade. It also has important actions at cellular level, where it acts on specific receptors to cause platelet aggregation, endothelial cell activation and fibroblast proliferation. Thus thrombin has a central regulatory role in haemostasis and thrombus formation. Since inhibitors of thrombin may have a wide range of therapeutical applications, extensive research is done in this area. Another important serine protease, factor Xa, catalyzes the conversion of prothrombin into thrombin.
In the development of synthetic inhibitors of serine proteases, and more specifically of thrombin, the benzamidine moiety is one of the key structures. It mimics the protonated side-chain of the basic amino acids Arg and Lys of its natural substrates. Compounds with this moiety have been studied extensively and repeatedly. A very potent representative of this type of thrombin inhibitors is the amino acid derivative N&agr;-(2-naphthylsulfonyl)-glycyl-4-amidinophenylaianinpiperidide (NAPAP) (Stürzebecher, J. et al., Thromb. Res. 29, 635-642, 1983). However, the profile of NAPAP is unattractive for therapeutical applications: for example, the compound has low thrombin specificity and is poorly soluble. Derivatives of NAPAP were subsequently prepared, such as the N-alkyl substituted derivatives disclosed in EP 0,236,163 or the glycopeptide derivatives described EP 0,558,961, Proc. Am. Pept. Symp., 13th (60LXAW); 94; pp. 643-5 (Stüber, W. et al., Pept.: Chem., Struct. Biol.,), Proc. Int. Symp. Controlled Release Bioact. Mater. (PCRMEY, 10220178); 94;Vol. 21 st; pp. 712-12 (Walter, E. et al.), and EP 0,513,543. However, although these derivatizations may have led to improvements of the pharmacological profile when compared to NAPAP, all such NAPAP-derived compounds are still active only as direct thrombin inhibitors and they have a restricted plasma half-life and a fast clearance (thus displaying their anti-thrombin activity only for a short period of time).
It has now been found that compounds of the formula (I)
wherein
R
1
is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (iso)quinolinyl, tetrahydro(iso)quinolinyl, 3,4-dihydro-1H-isoquinolinyl, chromanyl or the camphor group, which groups may optionally be substituted with one or more substituents selected from (1-8C)alkyl or (1-8C)alkoxy;
R
2
and R
3
are independently H or (1-8C)alkyl;
R
4
is (1-8C)alkyl or (3-8C)cycloalkyl;
or R
3
and R
4
together with the nitrogen atom to which they are bonded are a nonaromatic (4-8)membered ring optionally containing another heteroatom, the ring optionally being substituted with (1-8C)alkyl or SO
2
-(1-8C)alkyl;
Q is a spacer having a chain length of 10 to 70 atoms; and
Z is a negatively charged oligosaccharide residue comprising two to six mionosaccharide units, the charge being compensated by positively charged counterions;
or a pharmaceutically acceptable salt thereof or a prodrug thereof are potent and highly versatile antitbrombotics. The compounds of the invention have antithrombin activity, but also the structure of the compounds may be selectively modified so that they have a tuneable mixed profile of both non-mediated, direct anti-thrombin (factor IIa) activity And antithrombin III (AT-III) mediated anti-Xa activity. The compounds of the invention thus are dual inhibitors. Compounds of the invention have a long plasma half-life and, as a result, they possess prolonged anti-thrombin activity compared to NAPAP or its above reported derivatives. Further, compounds of the invention may escape the neutralizing action of platelet factor 4 (PF4). Low toxicity is also an advantageous aspect of compounds of this invention.
Another type of dual inhibitors is disclosed in EP 0,649,854. Contrary to the compounds of the present invention the conjugated saccharide compounds disclosed in that document display indirect, AT-III mediated anti-thrombin activity, in addition to AT-III mediated anti-Xa activity.
The compounds of the present invention are useful for treating and preventing thrombin-mediated and thrombin-associated diseases. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated which include, but are not limited to, deep vein thrombosis, pulmonary embolism, thrombophlebitis, arterial occlusion from thrombosis or embolism, arterial reocclusion during or after angioplasty or thrombolysis, restenosis following arterial injury or invasive cardiological procedures, postoperative venous thrombosis or embolism, acute or chronic atherosclerosis, stroke, myocardial infarction, cancer and metastasis, and neurodegenerative diseases. The compounds of the invention may also be used as anticoagulants in extracorporeal blood circuits, as necessary in dialysis and surgery. The compounds of the invention may also be used as in vitro anticoagulants.
The mixed profile of the compounds of the invention may be tuned by varying the nature of the oligosaccharide residue Z and the length of the spacer Q. A range of profiles is thereby available.
Any negatively charged oligosaccharide residue of 2 to 6 saccharide units is useable in the compounds of the present invention. Suitable compounds of the invention are compounds wherein Z is a sulfated or phosphorylated oligosaccharide residue. Preferably, the oligosaccharide residue Z is derived from an oligosaccharide which has per se AT-III mediated anti-Xa activity, such as the saccharides disclosed in EP 0,454,220 and EP 0,529,715. Particularly preferred oligosaccharide residues are pentasaccharide residues. Most preferably, Z has the formula (II)
wherein R
5
is independently OSO
3
−
or (1-8C)alkoxy.
Further preferred compounds of the invention are compounds of formula I, wherein R
1
is phenyl, 4-methoxy-2,3,6-trimethylphenyl or naphthyl. In preferred compounds, NR
3
R
4
represents the piperidinyl group. Preferably, R
2
is H.
The chemical structure of the spacer is of minor or no importance for the anti-thrombotic activity of the compounds of the invention, it may however not be completely rigid. Highly flexible spacers are more suitable than others.
Further, for synthetic reasons some spacers are more appropriate than others. Suitable spacers that can easily be used have for example the formula (III):
—[(CH
2
)
2
O]
m
—[(CH
2
)
n
—NR
3
—C(O)]
p
—W—(CH
2
)
s
—  (III),
wherein
W
is —[1,4-phenylene-NR
3
—C(O)]
q
—(CH
2
)
r
—S— or
—(CH
2
)
t
—S—(CH
2
)
u
—[O(CH
2
)
2
]
v
—O—(CH
2
)
w
—C(O)—NR
3
—;
and R
3
is independently H or (1-8C)alkyl;
m=1-12; n=1-8; p=0-4; q=0 or 1; r=1-8; s=1-8; t=1-8; u=1-8; v=1-12; w=1∝8; the total number of atoms is 10-70; and the moiety —[(CH
2
)
2
O]
m
— is the end with which Q is attached to Z.
Preferred spacers are the following:
—[(CH
2
)
2
O]
5
—(CH
2
)
2
—NH—C(O)—CH
2
—S—CH
2
—;
—[(CH
2
)
2
O]
5
—(CH
2
)
2
—NH—C(O)—CH
2
—S—(CH
2
)
2
—[O(CH
2
)2]
3
—O—CH
2
—C(O)—NH—(CH
2
)
4
—; and
—[(CH
2
)
2
O]
3
—(CH
2
)
2
—NH—C(O)-1,4-phenylene-NH—C(O)—CH
2
—S—CH
2
—.
In the description of the compounds of formula (I) the following definitions are used.
The term (1-8C)alkyl means a branched or unbranched alkyl group having 1-8 carbon atoms, for example methyl, ethyl, propyl, isopropy

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