Heterocyclic derivatives and their use as antithrombotic agents

Details Heterocyclic derivatives and their use as antithrombotic agents Heterocyclic derivatives and their use as antithrombotic agents

2000-10-04

2002-08-13

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S248000, C514S258100, C514S260100, C514S301000, C514S302000, C514S310000, C544S183000, C544S184000, C544S235000, C544S237000, C544S253000, C544S293000, C546S114000, C546S115000, C546S143000

Reexamination Certificate

active

06432955

ABSTRACT:

The invention relates to new therapeutic compounds, in particular to 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.
In therapy, a multiplicity of active compounds is used for the treatment and prophylaxis of all sorts of diseases. Drugs differ widely in their pharmacodynamic effects and clinical application, in penetrance, absorption and usual route of administration, in distribution among the body tissues and in disposition and mode of action. Apart from the type of patient and the type of disease to be treated or to be prevented, the physicochemical properties of therapeutically active compounds determine to a great extent the preferred route of their admistration. In the development of drugs, the oral applicability thereof is usually an important selection criterium For the majority of patients this is obviously the most convenient route for access of the drug to the systemic circulation. In order for a drug—administered via oral route—to act, it must first be absorbed before it is transported to the appropriate tissue or organ, where it may penetrate to the responding subcellular structure and may subsequently be metabolized, or where it may be bound, stored, or whatever is necessary to elicit a response or to alter ongoing processes. However, not always compounds which have been found to possess an advantageous therapeutic activity are also sufficiently absorbed in the gastrointestinal tract to display effective oral bioavailability. Thus, one of the pivotal issues in drug design is to develop compounds which both show activity and good absorptive properties. An important area in which is actively sought for oral biavailability is the area of antithrombotic agents.
The present invention relates to antithrombotic compounds comprising the group Q, Q having the formula
wherein the substructure
is a structure selected from
wherein
X is O or S;
X′ being independently CH or N,
and m is 0, 1, 2 or 3;
wherein the group Q is bound through an oxygen atom or an optionally substituted nitrogen or carbon atom,
or a pharmaceutically acceptable salt thereof or a prodrug thereof The compounds of the invention are active antithrombotic agents having an improved pharmacological profile, in particular with regard to properties like their absorptive properties and their toxicity.
The term “antithrombotic compound” means any compound having antithrombotic activity. Examples of such compounds are inhibitors of serine proteases that play a role in the blood coagulation cascade or GpIIb/IIIa antagonists. The group Q is bound to the molecule through an oxygen atom or an optionally substituted nitrogen or carbon atom. “Optionally substituted” in this respect means any suitable substituent, such as, but not limited to, oxo, alkyl, alkenyl, alkoxy, aryl, halogen and the like. The term “prodrug” means a compound of the invention in which (an) amino group(s) is (are) protected, e.g. by (a) hydroxy or (1-6C)alkoxycarbonyl group(s), or a compound wherein—if present—(a) carboxylate group(s) is (are) esterified. The present invention relates to the surprising finding that the presence of the group Q in antithrombotic compounds gives rise to favourable properties of the compounds. Especially when Q is used to replace a basic moiety in compounds of which is known that they require such a moiety for their activity, an improvement of the pharmacological properties is realized, and in particular when that basic moiety is a (hetero)arylguanidino or (hetero)arylamidino moiety. In particular an improvement of the absorptive properties of those compounds is observed. Also a reduction of the toxicity of compounds of this invention is observed.
Preferably the group Q has the formula
m being as previously defined.
An established in vitro model for the determination of the absorptive properties of drugs is the Caco-2 model (Artursson, P., S.T.P. Pharma Sciences 3(1), 5-10, 1993; Walter, E., et al. Pharmaceutical Research, 3, 360-365, 1995). In this in vitro model the transepithelial transport properties of a compound are determined in monolayers of a human intestinal cell-line (Caco-2) in terms of a permeability coefficient (apparent permeability). This model is useful for the prediction of in vivo absorption of compounds in the gastrointestinal tract. Preferably the antithrombotic compounds of the invention have a Caco-2 permeability of 8 nm/s or higher.
As noted above, amongst the compounds of the present invention are inhibitors of serine proteases of the blood coagulation cascade, and in particular inhibitors of thrombin and/or factor Xa. Preferred compounds inhibit thrombin more effectively than other serine proteases. More preferred compounds are thrombin inhibitors having, in addition, an IC
50
value of less than 1 &mgr;M. The compounds 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. Compounds of the invention may also be used as in vitro anticoagulants or as anticoagulants in extracorporeal blood circuits, such as those necessary in dialysis and surgery.
Serine proteases are enzymes which play an important role in the blood coagulation cascade. Apart from thrombin and factor Xa, other examples of this group of proteases comprise the factors VIIa, IXa, 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 homeostasis and thrombus formation. Since inhibitors of thrombin may have a wide range of therapeutical applications, extensive research is done in this area. 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-amidinophenylalanin-piperidide (NAPAP) (Stürzebecher, J. et al., Thromb. Res. 29, 635-642, 1983). However, the pharmacological profile of NAPAP is unattractive for therapeutical applications: the compound shows toxic effects after intravenous administration and, in addition, poor oral bioavailability after oral administration. Up until now, the NAPAP-like benzamidine derivatives which have been investigated for use as thrombin inhibitors show these unfavourable pharmacological and pharmacokinetic properties. It was assumed that these properties are due to the strong basicity of the amidino functionality of these compounds (Kaiser, et al., Pharmazie 42, 119-121, 1987; Stürzebecher, J. et al., Biol. Chem. Hoppe-Seyler, 373, 491-496, 1992). Several studies have been performed on variations of this basic structure (see for example Stürzebecher, J. et al., Pharmazie 43, 782-783, 1988; Stürzebecher, J. et al. (1993), DIC-Pathogenesis, Diagnosis and

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