Serine protease inhibitors

Details Serine protease inhibitors Serine protease inhibitors

1998-08-31

2001-04-17

Davenport, Avis M. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S017400, C514S018700, C514S020800, C530S330000, C530S331000, C530S300000, C530S328000, C530S329000

Reexamination Certificate

active

06218365

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a serine protease inhibitor having a piperidine side chain, a pharmaceutical composition containing the same, as well as the use of said inhibitor 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, XIaa, XIIa, and protein C.
Thrombin is the serine protease which regulates the last step in the coagulation cascade. The prime finction 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 are& 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 bioavailabilirty. 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.
Most of the peptide-like thrombin inhibitors disclosed in prior publications contain side chains of arginine. A problem of the those arginine containing thrombin inhibitors is that they have low oral bioavailabldity. A number of thrombin inhibitors contain lysine side chains instead of arginine have been reported in literature. The lower basicity of lysine, relative to argiine, was expected to result in increased oral bioavailability. Examples of lysine containing thrombin inhibitors are the inhibitor N—Me—D—Cha—Pro—Lys—COOH and derivatives thereof, disclosed by Jones et al., J. Enzyme Inhibition, 9 (1995), 43-60, and the inhibitors N—Me—D—Phe—Pro—Lys—X, X being a carboxamide or carboxylic acid, disclosed by Lewis et al., Thrombosis and Haemostasis, 74(4) (1995), 1107-12. However, the expected improvement was not observed, the oral bioavailabilities of several lysyl thrombin inhibitors being similar to that reported for inhibitors having an arginine side-chain (Lewis et al., Thrombosis and Haemostasis, 74(4) (1995), 1107-12). Other thrombin inhibitors are disclosed in WO 94/25051 wherein the lysine or arginine side chain is replaced by aminocyclohexyl moieties which may be regarded as lysine isosters.
SUMMARY OF THE INVENTION
It has now been found that serine protease inhibitors, and in particular thrombin, Xa and Vila inhibitors, having a piperidine side chain, according to the fornmla I
wherein
A is H, optionally substituted D,L &agr;-hydroxyacetyl, R
1
, R
1
—O—C(O)—, R
1
—C(O)—, R
1
—SO
2
—, R
2
OOC—(CHR
2
)
m
—SO
2
—, R
2
OOC—(CHR
2
)
m
—, H
2
NCO—(CHR
2
)
m
—, or an N-protecting group, wherein R
1
is selected from (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl and (3-8-C)cycloalkyl, which groups may optionally be substituted with (3-8C)cycloalkyl, (1-6C)alkoxy, oxo, OH, COOH, 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; each group R
2
is independently H or has the same meaning as R
1
; m is 1, 2 or 3;
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 with p being 0, 1, 2 or 3, —N((1-12C)alkyl)—CH
2
CO—, —N((2-12C)alkenyl)—CH
2
—CO—, —N((2-12C)alkynyl)—CH
2
—CO—, —N(benzyl)—CH
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
3
R
4
N—CHR
5
—C(O)—, wherein R
3
and R
4
independently are R
1
, R
1
—O—C(O)—, R
1
—C(O)—, R
1
—SO
2
—, R
2
OOC—(CHR
2
)
m
—SO
2
—, R
2
OOC—(CHR
2
)
m
—, H
2
NCO—(CHR
2
)
m
—, or an N-protecting group, or one of R
3
and R
4
is connected with R
5
to form a 5- or 6membered ring together with “N—C” to which they are bound, which ring may be fused with an aliphatic or aromatic 6membered ring; and R
5
is a hydrophobic, basic or neutral side chain;
X is an L-amino acid with a hydrophobic side chain, serine, threonine, a cyclic amino acid optionally containing an additional heteroatom selected from N, 0 or S, and optionally substituted with (1-6C)alkyl, (1-6C)alkoxy, benzyoxy or oxo, or X is —NR
2
—CH
2
—C(O)— or the fragment
wherein n is 2, 3, or 4, and W is CH or N;
Y is H, —CHF
2
, —CF
3
, —CO—NH—(1-6C)alkyleneC
6
H
5
, —COOR
6
with R
6
being H or (1-6C)alkyl, —CONR
7
R
8
and R
7
and R
8
being independently H or (1-6C)alkyl or R
7
and R
8
together being (3-6C)alkylene, or Y is a heterocycle selected from 2-thiazole, 2-thiazoline, 2-benzothiazole, 2-oxazole, 2-oxazoline and 2-benzoxazole, which heterocycles may optionally be substituted with (1-6C)alkyl, phenyl, (1-6C)alkoxy, benzyloxy or oxo; and r is 0, 1, 2 or 3;
or a prodrug thereof or a pharmaceutically acceptable salt thereof are potent and selective inhibitors. In addition, some of the compounds of the invention show good bioavailability after oral administration.
The compounds of the present invention are usefuil 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 wiro anticoagulants.
DETAIL DESCRIPTION OF THE INVENTION
Preferred compounds according to the invention have the formula I, wherein X is an L-amino acid with a hydrophobic side chain, serine, threonine or —NR
2
—CH
2
—C(O)—.
Other preferred compounds of formula I are those wherein A is as previously defined; 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 and p being 0, 1, 2 or 3, —N((1-6C,alkyl)—CH
2
—CO—, —N((2-6C)alkenyl)—CH
2
CO—, —N(benzyl)—CH
2
—CO—, D-1-Tiq, D-3-Tiq, D—Atc, Aic, D-1-Piq, D-3-Piq or a D-anino acid having a hydrophobic side chain, which amino acid may optionally be N—(1-6C)alkyl substituted; or A and B together are the residue R
3
R
4
N—CHR
5
—C(O)—; and X is 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 —NR
2
CH
2
—C(O)— or the fragme

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