Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-07-30
2000-02-29
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514269, 544242, 544319, 544326, 544334, 544335, A61K 31505, C07D23942
Patent
active
060309725
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel carbo- and heterocyclic amidines, the preparation thereof and the use thereof as thrombin inhibitors.
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 cascades lead via several amplification stages to the production of thrombin from prothrombin. The thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates the coagulation of blood and the aggregation of the platelets which in turn enhance, owing to the binding of platelet factor 3 and coagulation factor XIII and a whole series of highly active mediators, the formation of thrombin.
The formation and action of thrombin are central events in the production both of white, arterial and of red, venous thrombi and therefore potentially effective points of attack for drugs. Thrombin inhibitors are, in contrast to heparin, able to inhibit completely, independently of cofactors, simultaneously the actions of free thrombin and 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 generally used 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 proved to be particularly beneficial. D--Phe--Pro--Arg isopropyl ester has been described as a competitive thrombin inhibitor (C. Mattson et al., Folia Haematol, 109 (1983) 43-51).
Derivatization of the C-terminal arginine 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 the form of a hemiacetal have been described (EP 185 390, 479 489, 526 877, 542 525; 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 interaction with serine (EP 118 280, 195 212, 362 002, 364 344, 410 411, 471 651, 589 741, 293 881, 503 203, 504 064, 530 167; WO 92/07869, 94/08941).
DE 31 08 810 and WO 93/11152 describe .omega.-aminoalkylguanidine dipeptides.
The diphenyl 4-amidinophenylglycinephosphonate peptides described by J. Oleksyszyn et al. in J. Med. Chem. 37 (1994) 226-231 are irreversible thrombin inhibitors with inadequate selectivity with respect to other serine proteases.
WO 94/29336 and WO 95/23609 describe benzylamidines as thrombin inhibitors.
The invention relates to compounds of the formula I ##STR2## and the salts thereof with physiologically tolerated acids and the stereoisomers thereof, in which the substituents have the following meanings: O--CH.sub.2 --, R.sup.18 --CO--, R.sup.18 --O--CH.sub.2 --CO--, R.sup.18 O--CO--CO--, R.sup.18 --H--CO--CO--, where R.sup.18 is H, C.sub.1-4 -alkyl, phenyl-C.sub.1-4 -alkyl or phenyl, or CF.sub.3 --CO--, C.sub.2 F.sub.5 --CO-- or C.sub.1-4 -alkyl-O--CO--, ##STR3## in which the substituents have the following meanings: m: 0 or 1, OOC--C.sub.1-6 -alkyl (R.sup.19 .dbd.H, C.sub.1-4 -alkyl, benzyl), HO.sub.3 S--C.sub.1-3 -alkyl, C.sub.1-12 -alkyl-CO--, aryl-CO--, aryl-C.sub.1-4 -alkyl-CO--, R.sup.19 OOC-C.sub.1-6 -alkyl-CO--, HO.sub.3 S--C.sub.1-3 -alkyl-CO--, C.sub.1-7 -alkyl-OOC--, benzyl-OOC--, or different and are H, C.sub.1-6 -alkyl, aryl, aryl-C.sub.1-4 -alkyl, R.sup.19 OOC--C.sub.1-4 -alkyl and R.sup.19 --NH--CO--C.sub.1- -alkyl, where R.sup.20 and R.sup.21 may also together be a --(CH.sub.2).sub.3-6 -- group), or R.sup.19 --O-- OOC--C.sub.1-4 -alkyl (R.sup.19 .dbd.H, C.sub.1-4 -alkyl, benzyl), with up to 4 C.sub.1-4 -alkyl and/or CH.sub.3 O groups, and one o
REFERENCES:
patent: 4346078 (1982-08-01), Bajusz et al.
Klimkowski et al., Chemical Abstracts, vol. 128, abstract 102395, 1998.
Folia Haematologica, 109 Band, 1982, 42-51.
J. Med Chem 1994, 37, 266-231.
Database crossfire 4328-4331, 1900.
Database crossfire, BRN 2716610 & BRN 3030402, 1975.
Chem. Abst. DE 4421052, 1995.
Bohm Hans-Joachim
Hoffken Hans Wolfgang
Hornberger Wilfried
Koser Stefan
Mack Helmut
BASF - Aktiengesellschaft
Raymond Richard L.
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