Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-28
1998-08-18
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514252, 544238, 544239, 544240, A61K 3150, C07D23722, C07D40512, C07D40112
Patent
active
057958920
DESCRIPTION:
BRIEF SUMMARY
The invention concerns new 4-aminopyridazines of the general formula I ##STR2## in which R.sup.1 denotes a R.sup.2 --SO.sub.2 --O-- or R.sup.2 --SO.sub.2 --NR.sup.3 -- group in which or heteroaryl residues can be substituted once or several times by nitro, halogen, nitrile, hydroxy, carboxy, alkoxycarbonyl, phenylalkoxycarbonyl, phenyl, alkyl, trifluoromethyl, alkoxy, alkenyloxy, alkinyloxy, aralkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, aralkylamino, diaralkylamino, alkylsulfonylamino, alkylcarbonylamino, formylamino, carbamoyl, thiocarbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl or alkoxycarbonylalkyloxy, be substituted once or several times by hydroxy groups wherein the hydroxy groups can be substituted by alkyl, hydroxyalkyl, alkyloxyalkyl, hydroxyalkyloxyalkyl or alkylcarbonyl groups and wherein in each case two vicinal hydroxy groups can be linked together by alkylidene groups, The invention also concerns a optically active forms, racemates and mixtures of diastereomers of these compounds.
The invention also concerns processes for the production of the above-mentioned compounds, pharmaceutical agents that contain such compounds as well as the use of these compounds in the production of pharmaceutical agents.
The aminopyridazines of the general formula I, their solvates and their salts inhibit the thrombin-induced coagulation of fibrinogen in blood as well as thrombin-induced aggregation of blood platelets. Thus they prevent formation of hyaline thrombi and platalet-rich thrombi and can be used to combat and prevent diseases such as thrombosis apoplexy, coronary infarction, inflammations and arteriosclerosis. Furthermore these compounds have an effect on tumour cells and prevent formation of metastases. As a result they can be used as anti-tumour agents.
Thrombin, the last enzyme of the coagulation cascade, cleaves fibrinogen to form fibrin which is cross-linked by factor XIIIa and becomes an insoluble gel which forms the matrix for a thrombus. Thrombin activates platelet aggregation by proteolysis of its receptor on the blood platelets and in this way also contributes to thrombus formation. When a blood vessel is damaged these processes are necessary in order to stop bleeding. No measurable thrombin concentrations are present in blood plasma under normal conditions. Increases in the thrombin concentration can lead to the formation of thrombi and hence to thromboembolic diseases which occur very frequently above all in industrial countries.
Thrombin is kept ready in plasma in the form of prothrombin and is released from it by factor Xa. Thrombin activates the factors V, VIII and XI by which means factor X is then converted into factor Xa. By this means thrombin catalyzes its own release which is why very rapid increases in thrombin concentrations can occur.
Thrombin inhibitors can therefore inhibit the release of thrombin, the platelet-induced and plasmatic blood coagulation.
There is a whole series of serine proteases apart from thrombin that cleave peptide substrates next to a basic amino acid. In order to limit side-effects, the thrombin inhibitors should be selective i.e. they should inhibit other serine proteases only slightly or not at all. Trypsin in particular being the least specific serine protease, can be easily inhibited by the various inhibitors. Trypsin inhibition can lead to pancreatic stimulation and to pancreatic hypertrophy (J. D. Geratz, Am. J. Physiol. 216, (1969) p. 812).
Plasma contains the protein plasminogen which is converted into plasmin by activators. Plasmin is a proteolytic enzyme whose activity is similar to that of trypsin. It serves to dissolve thrombi by degrading fibrin. Inhibition of plasmin would thus have the opposite effect to that which one would like to achieve by inhibiting thrombin.
Synthetic thrombin inhibitors have already been known for a long time. Substances of the (D)-Phe-Pro-Arg type were synthesized based on fibrinogen the natural substrate of thrombin. Such tripeptides imitate the amino acid sequence before t
REFERENCES:
Shuman et al, J. Med. Chem. 36 p. 314-319 (1993).
Heck Reinhard
Kucznierz Ralf
Leinert Herbert
Stegmeier Karlheinz
Von Der Saal Wolfgang
Bernhardt Emily
Boehringer Manneim GmbH
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