Thrombin inhibitors

Details Thrombin inhibitors Thrombin inhibitors

1999-12-29

2002-12-10

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S374000, C514S378000, C514S406000, C514S422000, C548S204000, C548S236000, C548S247000, C548S364100, C548S517000, C548S523000, C548S527000

Reexamination Certificate

active

06492402

ABSTRACT:

FOREIGN PRIORITY CLAIM
This application claims priority under 35 U.S.C. §119 to Korean patent applications KR 1998-0060266 filed Dec. 29, 1998 and KR 1999-0033490 filed Aug. 14, 1999.
FIELD OF THE INVENTION
The present invention relates to thrombin inhibitors that are useful as anticoagulants. In particular, this invention relates to peptide derivatives having high antithrombotic activity and high oral bioavailability.
BACKGROUND OF THE INVENTION
Thrombosis is characterized by excessive blood clotting. The condition plays a significant role in cardiovascular and related diseases, and thrombotic events underlie a significant proportion of the mortality and morbidity associated with cardiovascular disease. Thrombosis can cause a range of disease states which are characterized by the location of the blood vessel in which the clot is formed.
Thrombin is a trypsin-like serine protease that plays a key role in the blood coagulation cascade by catalyzing the conversion of fibrinogen to insoluble fibrin. This enzyme also activates Factor V and Factor VIII for its own production and potently activates platelets as well. Therefore, thrombin has long been recognized as a central regulator in thrombosis and hemostasis, and its inhibition has become a major therapeutic target in the treatment of cardiovascular diseases such as myocardial infarction, unstable angina, deep vein thrombosis and pulmonary embolism. Indirect thrombin inhibitors such as heparin and warfarin (coumarin) have been used as antithrombotic therapies with, however, several limitations. Heparin demonstrates low bioavailability and is associated with side effects such as bleeding problems, moreover, it is not able to inhibit clot-bound thrombin. Warfarin is an effective oral anticoagulant but it has a narrow therapeutic window and also requires patient monitoring. A natural protein inhibitor, hirudin, has been associated with bleeding complications.
Most of the low molecular weight thrombin inhibitors are broadly based upon peptides or peptidomimetic templates which operate by a direct mechanism of action against the target enzyme. Early examples are tripeptidic aldehydes such as D-Phe-Pro-Arg-H and Me-D-Phe-Pro-Arg-H that have been reported to be effective thrombin inhibitors (Bajusz et al. J. Med. Chem. 1990, 33, 1729).
Recently, D-Phe-Pro-Agmatine and its derivatives have been described as thrombin inhibitors in U.S. Pat. No. 4,346,078 and WO93/11152 (agmatine=1-amino-4-guanidinobutane). These compounds are different from the earlier tripeptidic compounds in that the agimatine compounds lack a carbonyl moiety found in similar compounds containing an Arg side chain.
More recently, certain tripeptidic thrombin inhibitors in which 4-amidinobenzylamaine was incorporated at the P1 position in place of agmatine have been disclosed (WO 94/29336). These amidine-based compounds have been reported to possess good antithrombotic activity (WO 95/23609). However, this class of compounds has generally poor or low oral bioavailability.
Certain thrombin inhibitors bearing the unique amino acid D-diphenylalanine at P3 position have been disclosed (WO 93/11152, U.S. Pat. No. 5,510,369, WO 97/15190). These compounds have been reported to have higher potency against thrombin compared to the corresponding D-phenylalanine alalogs (J. Med. Chem. 1992, 35, 3365; J. Med. Chem. 1997, 40, 830). In addition, some of this class of compounds exhibited good oral bioavailability (J. Med. Chem. 1997, 40, 3687; J. Med. Chem. 1997, 40, 3726).
In certain thrombin inhibitors and Factor Xa inhibitors, the amidinothiophene groups have been shown to be better para-benzamidine surrogates (WO 95/23609, WO98/24784, Bioorg. Med. Chem. Lett. 1998, 8,1683). In addition, 2,5-thiophene and other 5-membered heterocyclic moieties have effectively served as a para-phenylene isostere in the inhibitors of other drug-targeting enzymes such as thymidylate synthase and glycinamide riobonuceotide formyltransferase (J. Med. Chem. 1991, 34, 1594; Cancer Research 1994, 54,1021; WO 97/41115).
Therefore, there is a need in the art for thrombin inhibitors which have improved oral bioavailability and stablility as compared to those described supra. We have found that the compounds of the present invention, as defined below, are potent inhibitors of thrombin in vitro and in vivo. In particular, certain compounds of this invention exhibit high bioavailability after oral administration.
SUMMARY OF THE INVENTION
The present invention relates to compounds falling within formula I below which modulate and/or inhibit the serine protease thrombin, as well as to acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts thereof (such compounds, prodrugs, metabolites and salts are collectively referred to as “agents”). The invention is also directed to pharmaceutical compositions containing such agents and their therapeutic use in treating diseases mediated by thrombin, such as myocardial infarction, unstable angina, deep vein thrombosis and pulmonary embolism, as well as other disease states associated with blood clotting and associated clotting factors.
In one general aspect, the invention relates to thrombin inhibitors of the Formula I:
and pharmaceutically acceptable salts thereof
wherein:
n is 1, 2, or 3,
A is hydrogen, alky, C
3-7
cycloalkyl, aryl, —SO
2
R
1
, —SO
3
R
1
, —COR
1
, —CO
2
R
2
, —PO(R
1
)
2
, —PO(OR
1
)
2
, —(CH
2
)
m
CO
2
R
1
, (CH
2
)
m
SO
2
R
1
, —(CH
2
)
m
SO
3
R
1
, or —(CH
2
)
m
PO(OR
1
)
2
,
wherein:
R
1
is hydrogen, C
1-6
alkyl, C
3-7
cycloalkyl, aryl, —(CH
2
)
m
aryl, or —NR
3
R
4
, and
R
2
is C
1-6
alkyl, C
3-7
cycloalkyl, aryl, —(CH
2
)
m
aryl, or alkenyl,
m is 1, 2, or 3,
wherein:
aryl is unsubsituted or substituted phenyl or 5-6 membered aromatic heterocyclic ring,
R
3
and R
4
are independently hydrogen, C
1-6
alkyl, or C
3-7
cycloalkyl;
B is hydrogen or C
1-6
alkyl;
C and D are independently hydrogen, unsubsituted or substituted phenyl with one or two substituents selected from C
1-4
alkyl, C
1-4
alkoxy, CF
3
, methylenedioxy, halogen, hydroxy, or —NR
3
R
4
, C
3-7
cycloalkyl, or a 5-6 membered heterocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and 1-3 heteroatoms selected from the group consisting of N, O, and S;
 wherein
X is S, O, or NR
5
,
Y and Z are independently N or CR
6
,
wherein
R
5
is hydrogen or C
1-4
alkyl and
R
6
is hydrogen, halogen, CF
3
or C
1-4
alkyl; and
F is —C(NH)N(R
7
)
2
, —C(NH
2
)NN(R
7
)
2
, —C(NH
2
)NOH, or —CH
2
NH(R
7
)
2
wherein R
7
is the same or different,
R
7
is hydrogen, C
1-4
perfluoroalkyl or C
1-4
alkyl.
The invention also relates to pharmaceutical compositions each comprising: an effective amount of an agent selected from compounds of Formula I and pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs thereof; and a pharmaceutically acceptable carrier or vehicle for such agent. The invention further provides methods of treating cardiovascular diseases such as myocardial infarction, unstable angina, deep vein thrombosis and pulmonary embolism, as well as other disease states associated with excess thrombin.
DETAILED DESCRIPTION OF THE INVENTION
The inventive compounds of Formula I are useful for mediating the activity of trypsin-like serine proteases. More particularly, the compounds are useful as anti-coagulant agents and as agents for modulating and/or inhibiting the activity of trypsin-like serine proteases, thus providing treatments for thrombosis and other cardiovascular diseases such as myocardial infarction, unstable angina, deep vein thrombosis and pulmonary embolism.
The terms and abbreviations used in the instant disclosure have their normal meanings unless otherwise designated.
As used in the present application, the following definitions apply:
In accordance with a convention used in the art,
is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backb

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