Thrombin inhibitors

Details Thrombin inhibitors Thrombin inhibitors

1999-02-10

2000-09-05

Davis, Zinna Northington

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514422, 514374, 514364, 514365, 514378, 514406, 548527, 548517, 548131, 548236, 5483751, 548524, 548518, 548204, 548247, 5462804, A61K 3144, A61K 3140, A61K 3142, A61K 3141, A61K 31415

Patent

active

061143588

DESCRIPTION:

BRIEF SUMMARY
This is a 371 of PCT/EP97/04104, filed Jul. 29, 1997.
The present invention relates to novel five-membered heterocyclic amidines, to their preparation and to their use as competitive inhibitors of trypsin-like serine proteases, especially thrombin and kininogenases such as kallikrein. The invention also relates to pharmaceutical compositions which contain the compounds as active ingredients, and to the use of the compounds as thrombin inhibitors, anticoagulants and antiinflammatory agents.
Thrombin belongs to the group of serine proteases and plays a central part in the blood coagulation cascade as terminal enzyme. Both the intrinsic and the extrinsic coagulation cascade lead via a plurality of amplifying stages to the production of thrombin from prothrombin. Thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates blood coagulation and aggregation of platelets which, in turn, due to the binding of platelet factor 3 and coagulation factor XIII, and a large number of highly active mediators, enhance thrombin formation.
The formation and action of thrombin are central events in the development both of white, arterial and of red, venous thrombi and are therefore potentially effective points of attack for drugs. Thrombin inhibitors are, by contrast with heparin, able independently of cofactors completely to inhibit simultaneously the effects of free thrombin and of that bound to platelets. They are able to prevent in the acute phase thromboembolic events after percutaneous transluminal coronary angioplasty (PTCA) and lysis, and to act as anticoagulants in extracorporeal circulation (heart-lung machine, hemodialysis). They can also be used generally for the prophylaxis of thrombosis, for example after surgical operations.
It is known that synthetic arginine derivatives influence the enzymatic activity of thrombin by interacting with the active serine residue of the protease thrombin. Peptides based on Phe-Pro-Arg in which the N-terminal amino acid is in the D form have proven particularly beneficial. D-Phe-Pro-Arg isopropyl ester is described as a competitive thrombin inhibitor (C. Mattson et al., Folia Haematol, 109 (1983) 43-51).
Derivatization of the arginine at the C terminus to the aldehyde leads to an enhancement of the inhibitory effect. Thus, a large number of arginals able to bind the hydroxyl group of the "active" serine in a hemiacetal have been described (EP 185390, 479489, 526877, 542525; WO 93/15756, 93/18060.
The thrombin-inhibitory activity of peptide ketones, fluorinated alkyl ketones and of keto esters, boric acid derivatives, phosphoric esters and .alpha.-keto carboxamides can likewise be explained by this serine interaction (EP 118280, 195212, 362002, 364344, 410411, 471651, 589741, 293881, 503203, 504064, 530167; WO 92/07869, 94/08941).
The peptide 4-amidinophenylglycinephosphonate diphenyl esters described by J. Oleksyszyn et al. in J. Med. Chem. 37 (1994) 226-231 are irreversible thrombin inhibitors with inadequate selectivity in respect of other serine proteases.
DE 3 108 810, WO 93/11152 and EP 601 459 describe agmatine and hence arginine derivatives which are unable to interact with the active serine in serine proteases.
WO 94/29336, EP 0 601 459 and WO 95/23609 represent a further development in which the agmatine is replaced by an arylamidine residue.
Kininogenases are serine proteases which liberate vasoactive peptides, called kinins (bradykinin, kallidin and Met-Lys-bradykinin), from kininogens. Kininogens are multifunctional proteins which occur in coagulation and inflammation cascade reactions. As inhibitors, they protect cells from damage by cysteine proteases (Muller Esterl, FEBS Lett. 182 (1985) 310-314). Important kininogenases are plasma kallikrein, tissue kallikrein and mast cell tryptase.
Kinins like bradykinin and kallidin are vasoactive peptides which influence a large number of biological processes. They play an essential part in inflammatory processes. By increasing vascular permeability, they lead to hypotension and edema. Furthermore, they are very potent p

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