Serine protease inhibitors

Details Serine protease inhibitors Serine protease inhibitors

1999-10-26

2003-03-18

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S212080, C514S309000, C514S349000, C514S550000, C540S524000, C540S527000, C546S141000, C546S297000, C560S013000, C560S150000

Reexamination Certificate

active

06534495

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to new serine protease inhibitors, pharmaceutical compositions containing the same, as well as to the use of said inhibitors for the manufacture of a medicament 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 the 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.
The search for more effective and more selective thrombin inhibitors continues unabated in order to obtain thrombin inhibitors which can be administered in lower dosages and which have fewer and less severe side effects. Furthermore, special attention is paid to oral bioavailability. Potent intravenous thrombin inhibitors are clinically effective in acute care settings requiring the treatment of thrombin-related diseases. However, particularly the prevention of thrombin-related diseases such as myocardial infarct, thrombosis and stroke require long-term therapy, preferably by orally dosing an anticoagulant.
Many of the peptide-like serine protease inhibitors, in particular thrombin inhibitors, disclosed in prior publications are based on the sequence -D-Phe-Pro-Arg-, see for example compounds as disclosed by Brady et al. [Bioorganic & Medical Chemistry, 3 (1995), 1063-78] and in U.S. Pat. No. 5,597,804. Thrombin inhibitors may also contain lysine side chains instead of arginine, such as other inhibitors disclosed by Brady et al., and Lewis et al. [Thrombosis and Haemostasis, 74(4) (1995), 1107-12], and further by Jones et al. [J. Enzyme Inhibition, 9 (995), 43-60]. In the latter publication it was reported that tripeptide compounds containing &agr;-keto methyl ester functions are labile compounds and therefore unfavourable for further development as thrombin inhibitors. Also thrombin inhibitors having an aminocyclohexyl moiety instead of lysine or arginine side chain are known [WO 94/25051]. From these and also other references [e.g. U.S. Pat. No. 5,523,308] a number of variations at the C-terminus of these peptide-like thrombin inhibitors is known. The developments in this field have already improved the understanding of how to modulate the biological properties of this type of thrombin inhibitors. However, although great effort is being spend on finding selective thrombin inhibitors having good oral bioavailability there are still few transition state thrombin inhibitors known in the art which fulfill these requirements.
SUMMARY OF THE INVENTION
Surprisingly, it has now been found that compounds of the formula:
R
1
SO
2
—B—X—Z—C(O)—Y  (I)
wherein
R
1
is R
2
OOC—(CHR
2
)
m
— or R
2
NH—CO—(CHR
2
)
m
— or is selected from (1-12C)alkyl, (2-12C)alkenyl, which groups may optionally be substituted with (3-12C)cycloalkyl, (1-6C)alkoxy, OH, COOR
2
, CF
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
3
or halogen;
m is 1, 2 or 3;
each group R
2
is independently H, (1-12C)alkyl, (3-8C)cycloalkyl, (6-14C)aryl or (7-1 5C)aralkyl, the aryl groups of which may be substituted with (1-6C)alkyl, (1-6C)alkoxy or halogen;
B is a bond, an amino-acid of the formula —NH—CH[(CH
2
)
p
C(O)OH]—C(O)— or an ester derivative thereof wherein p is 1, 2 or 3, Gly, D-1-Piq, D-3-Piq, D-1-Tiq, D-3-Tiq, D-Atc, Aic, or a L- or D-amino acid having a hydrophobic, basic or neutral side chain;
X is an amino acid with a hydrophobic side chain, glutamine, serine, threonine, a cyclic amino acid optionally containing an additional heteroatom selected from N, O or S, and optionally substituted with (1-6C)alkyl, (1-6C)alkoxy, benzyloxy or oxo, or X is 2-amino-isobutyric acid, —NR
2
—CH
2
—C(O)— or the fragment
 wherein n is 2, 3, or 4, W is CH or N and R
3
is H, (1-6C)alkyl or phenyl which groups may optionally be substituted with hydroxy, (1-6C)alkoxy, COOH, COO(1-6C)alkyl, CONH
2
, or halogen;
Z is lysine or 4-aminocyclohexylglycine;
Y is —NH-(1-6C)alkylene-C
6
H
5
, the phenyl group of which may be substituted with (1-6C)alkyl, (1-6C)alkoxy or halogen, or Y is —OR
4
or —NR
5
R
6
, wherein R
4
is H, (2-6C)alkyl or benzyl, and R
5
and R
6
are independently H, (1-6C)alkoxy, or (1-6C)alkyl optionally substituted with halogen, or R
5
and R
6
together are (3-6C)alkylene, or R
5
and R
6
together with the nitrogen atom to which they are bonded are
 wherein V is O, S or SO
2
;
or a prodrug thereof or a pharmaceutically acceptable salt thereof, are potent and selective serine protease inhibitors. Specifically, the compounds of the present invention are inhibitors of thrombin, of factor VIIa/tissue factor and of factor Xa. Compounds of the invention show improved pharmacokinetics, and in particular good bioavailability after oral administration. The &agr;-(2-6C)keto ester compounds which are part of the present invention do not show the disadvantages of the previously reported labile &agr;-keto methyl ester compounds.
The compounds of the present invention are useful for treating and preventing thrombin-mediated and thrombin-associated diseases. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated which include, but are not limited to, deep vein thrombosis, pulmonary embolism, thrombophlebitis, arterial occlusion from thrombosis or embolism, arterial reocclusion during or after angioplasty or thrombolysis, restenosis following arterial injury or invasive cardiological procedures, postoperative venous thrombosis or embolism, acute or chronic atherosclerosis, stroke, myocardial infarction, cancer and metastasis, and neurodegenerative diseases. The compounds of the invention may also be used as anticoagulants in extracorporeal blood circuits, as necessary in dialysis and surgery. The compounds of the invention may also be used as in vitro anticoagulants.
DETAILED DESCRIPTION OF THE INVENTION
Preferred serine protease inhibitors according to this invention are the compounds wherein Z is lysine. More preferred are the compounds wherein X is a cyclic amino acid, an amino acid with a hydrophobic side chain, glutamine, serine, threonine, —NR
2
—CH
2
—C(O)—, or the fragment
wherein R
3
is H, (1-6C)alkyl or phenyl.
Particularly preferred are the compounds wherein X is proline, leucine, glutamine, threonine, phenylalanine, —NR
2
—CH
2
—C(O)— wherein R
2
is methyl, cyclopentyl or cyclohexyl, or the fragment
wherein R
3
is H or methyl.
Other preferred compounds are those wherein B is a bond or a D-amino acid having a hydrophobic or neutral side chain. The most preferred compounds of the invention are those wherein R
1
is (1-6C)alkyl or benzyl. Preferably R
4
in the definition of Y is (2-6C)alkyl or benzyl. In particular preferred are the compounds wherein Y is —OC

Affiliated with

Also associated with

Rating

Serine protease inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Serine protease inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Serine protease inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3069962