Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1998-08-12
2000-03-07
Russel, Jeffrey E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 20, 514212, 514269, 514315, 514349, 514424, 514563, 530330, 530331, 540527, 544319, 546242, 546297, 548543, 548549, 562433, 562442, 562560, 564 86, 564 95, 564153, 564157, 564159, A61K 3805, A61K 3806, A61K 3807, C07K 502, C07K 506
Patent
active
060340673
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to a serine protease inhibitor having an acylguanidine side chain, a pharmaceutical composition containing the same, as well as the use of said inhibitor for treating and preventing thrombin-related diseases.
BACKGROUND OF THE INVENTION
Serine proteases are enzymes which, amongst other things, play an important role in the blood coagulation cascade. Members of this group of proteases are for example thrombin, trypsin, factors VIIa, IXa, Xa, XIa, XIIa, and protein C.
Thrombin is the serine protease which regulates the last step in the coagulation cascade. The prime function of thrombin is the cleavage of fibrinogen to generate fibrin monomers, which form an insoluble gel by cross-linking. In addition, thrombin regulates its own production by activating 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 haemostasis and thrombus formation. Since inhibitors of thrombin may have a wide range of therapeutical applications, extensive research has been performed in this area.
In the development of synthetic inhibitors of serine proteases, and more specifically of thrombin, the interest in small synthetic peptides that are recognized by proteolytic enzymes in a manner similar to that of natural substrates, has increased. As a result, new peptide-like inhibitors have been prepared, such as the transition state inhibitors of thrombin and the low molecular weight thrombin inhibitor Inogatran (Thromb. Haemostas. 1995, 73:1325 (Abs. 1633); WO 93/11152 (Example 67)), which has been disclosed to be a potent and selective thrombin inhibitor. Related compounds are described in WO 95/23609; in comparison with Inogatran and its analogs, compounds disclosed in this patent application have an aromatic group in the agmatine-like group.
The search for more effective and more selective serine protease inhibitors continues unabated in order to obtain inhibitors which can be administered in lower dosages and which have fewer and less severe side effects.
SUMMARY OF THE INVENTION
A new class of highly potent serine protease inhibitors, in particular being selective thrombin or Xa inhibitors, has now been found, having the formula I ##STR2## wherein A is H, optionally substituted D,L .alpha.-hydroxyacetyl, R.sup.1, R.sup.1 --O--C(O)--, R.sup.1 --C(O)--, R.sup.1 --SO.sub.2 --, R.sup.2 OOC--(CHR.sup.2).sub.m--SO.sub.2 --, R.sup.2 OOC--(CHR.sup.2).sub.m --, H.sub.2 NCO--(CHR.sup.2).sub.m --, or an N-protecting group, wherein R.sup.1 is selected from (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl and (3-8C)cycloalkyl, which groups may optionally be substituted with (3-8C)cycloalkyl, (1-6C)alkoxy, oxo, OH, COOH, CF.sub.3 or halogen, and from (6-14C)aryl, (7-15C)aralkyl and (8-16)aralkenyl, the aryl groups of which may optionally be substituted with (1-6C)alkyl, (3-8C)cycloalkyl, (1-6C)alkoxy, OH, COOH, CF.sub.3 or halogen; each group R.sup.2 is independently H or has the same meaning as R.sup.1 ; m is 1, 2 or 3; C(O)OH]--C(O)-- or an ester derivative thereof and p being 0, 1, 2 or 3, --N((1-12C)alkyl)--CH.sub.2 --CO--, --N((2-12C)alkenyl)--CH.sub.2 --CO--, --N((2-12C)alkynyl)--CH.sub.2 --CO--, --N(benzyl)--CH.sub.2 --CO--, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a L- or D-amino acid having a hydrophobic, basic or neutral side chain, which amino acid may optionally be N--(1-6C)alkyl substituted; or A and B together are the residue R.sup.3 R.sup.4 N--CHR.sup.5 --C(O)--, wherein R.sup.3 and R.sup.4 independently are R.sup.1, R.sup.1 --O--C(O)--, R.sup.1 --C(O)--, R.sup.1 --SO.sub.2 --, R.sup.2 OOC--(CHR.sup.2).sub.m --SO.sub.2 --, R.sup.2 OOC--(CHR.sup.2).sub.m --, H.sub.2 NCO--(CHR.sup.2).sub.m --, or an N-protecting group, or one of R.sup.3 and R.sup.4 is connected with R.sup.5 to form a 5- or 6-membered ring together with "N--C" to which they are bound, which ring may be
REFERENCES:
Database WPI, Week 9613, XP002031054, Jan. 23, 1996.
Costanzo et al., Journal of Medicinal Chemistry, 39:16:3039-3043, 1996.
Jones et al., Letters in Peptide Science, 2:147-154, 1995.
Krug et al., Chemical Abstracts, 80:25:477, Abs. 146496q, 1974.
Adang Anton Egbert Peter
de Man Adrianus Petrus Antonius
Grootenhuis Peter Diederik Jan
Akzo Nobel N.V.
Gormley Mary E.
Russel Jeffrey E.
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