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.