Prodrugs of thrombin inhibitors

Details Prodrugs of thrombin inhibitors Prodrugs of thrombin inhibitors

1997-01-31

1999-10-12

Davenport, Avis M.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

530331, 514 18, 514 19, 548535, A61K 3800, A61K 3806, C07K 500, C07K 700

Patent

active

059656921

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to pharmaceutically useful prodrugs of pharmaceutically active compounds, which active compounds are, in particular, competitive inhibitors of trypsin-like serine proteases, especially thrombin, the use of the prodrugs as medicaments, pharmaceutical compositions containing them and synthetic routes to their production.


BACKGROUND

Blood coagulation is the key process involved in both haemostasis (ie the prevention of blood loss from a damaged vessel) and thrombosis (ie the formation of a blood clot in a blood vessel, sometimes leading to vessel obstruction).
Coagulation is the result of a complex series of enzymatic reactions. One of the ultimate steps in this series of reactions is the conversion of the proenzyme prothrombin to the active enzyme thrombin.
Thrombin is known to play a central role in coagulation. It activates platelets, leading to platelet aggregation, converts fibrinogen into fibrin monomers, which polymerise spontaneously into fibrin polymers, and activates factor XIII, which in turn crosslinks the polymers to form insoluble fibrin. Furthermore, thrombin activates factor V and factor VIII leading to a "positive feedback" generation of thrombin from prothrombin.
By inhibiting the aggregation of platelets and the formation and crosslinking of fibrin, effective inhibitors of thrombin would therefore be expected to exhibit antithrombotic activity. In addition, antithrombotic activity would be expected to be enhanced by effective inhibition of the positive feedback mechanism.


PRIOR ART

The development of low molecular weight inhibitors of thrombin has been described by Claesson in Blood Coagul. Fibrin. (1994) 5, 411.
Blomback et al (in J. Clin. Lab. Invest. 24, suppl. 107, 59, (1969)) reported thrombin inhibitors based on the amino acid sequence situated around the cleavage site for the fibrinogen A.alpha. chain. Of the amino acid sequences discussed, these authors suggested the tripeptide sequence Phe-Val-Arg would be the most effective inhibitor.
Low molecular weight peptide-based thrombin inhibitors have subsequently been disclosed in, for example, U.S. Pat. No. 4,346,078; International Patent Applications WO 93/11152, WO 94/29336, WO 93/18060 and WO 95/01168; and European Patent Applications 648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686 642 and 601 459.
More recently, thrombin inhibitors based on peptide derivatives have been disclosed in European Patent Application 0 669 317 and International Patent Applications WO 95/23609, WO 95/35309, WO 96/25426 and WO 94/29336.
In particular, the latter application discloses the peptide derivatives R.sup.a OOC--CH.sub.2 --(R)Cgl-Aze-Pab-H, wherein R.sup.a represents H, benzyl or C.sub.1-6 alkyl.
Although these active compounds are known to exhibit significant antithrombin activity, it would be beneficial to improve their pharmacokinetic properties both after oral and parenteral administration. Examples of pharmacokinetic properties which it is desirable to improve include: a view to reducing intra- and/or inter-individual variability in relation to the bioavailability of the active compounds; peak/trough ratio in the plasma concentration over the dosing interval), with a view to reducing the risk of falling outside the therapeutic interval and the side effects caused by a concentration peak which is too high (eg bleeding), and those caused by one which is too low (eg thrombus formation); and
Moreover, oral and parenteral administration of active thrombin inhibitors may lead to undesirable local bleeding (eg in the intestinal lumen or subcutaneously) as a result of a high local concentration,
Finally, orally administered active thrombin inhibitors which also inhibit trypsin and other serine proteases in the gastrointestinal tract may exhibit additional side effects, including indigestion (eg if trypsin is inhibited in the intestinal lumen).
Although certain N-benzyloxycarbonyl derivatives of the aforementioned active compounds are also

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