Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-02
2003-07-01
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S369000
Reexamination Certificate
active
06586453
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is in the field of inhibitors of plasminogen activator inhibitor-1 (PAI-1) activity. More particularly, the invention relates to the use of substituted thiazoles as inhibitors of PAI-1, and to novel classes of 2-substituted thiazole derivatives, their synthesis and their use as inhibitors of PAI-1.
2. Related Art
PAI-1 is a naturally occurring serine protease inhibitor, or serpin, that rapidly inhibits the activity of several proteases, including tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), by forming equimolar, irreversible complexes that are internalized and degraded. In this capacity, PAI-1 plays a major role in preventing fibrinolysis by decreasing the level of tPA and/or uPA, and consequently, the level of plasminogen converted to plasmin. Plasmin is an enzyme critical to the lysis of fibrin clots and works by cleaving fibrin to small soluble products.
PAI-1 can contribute to a variety of coronary diseases by retarding the clearance of thrombi. Elevated levels of PAI-1 have been described to correlate with an increased risk of atherosclerosis (Lupu, F., et al., Arteriosclerosis and Thrombosis 13:1090-1100 (1993)), deep vein thrombosis (Patrassi, G. M., et al., Fibrinolysis 6:99-102 (1992)) and of thrombosis during sepsis, surgery and trauma (Kluft, C., et al., Scand. J. Clin. Lab. Invest. 45:605-610 (1985)). Elevated PAI-1 levels are also thought to contribute to the high incidence of coronary disease in individuals with Type 2 diabetes (Sobel, B. E., et al., Circulation 97(22):2213-2221 (1998)), obese individuals (Lundgren, C. H., et al., Circulation 93(1):106-110 (1996)), and the elderly (Lupu, F., et al., Arteriosclerosis and Thrombosis 13:1090-1100 (1993)).
Increased PAI-1 has been demonstrated in human atherosclerotic vessel walls and may contribute to the impaired plasma fibrinolytic capacity in patients at high risk of atherothrombotic events. The atherosclerotic process begins with an injury to the inner lining of the blood vessel, the endothelium. Smooth muscle cells migrate from their normal location in the media to the intima, where they divide and make up a bulk lesion.
Immunohistochemical analyses have revealed that most of the PAI-1 in the thickened intima of early lesions is located in and around neointimal smooth muscle cells and possibly macrophages. Both of these cell types can become lipid-laden foam cells that form fatty streaks, another hallmark feature of atherosclerosis.
In advanced lesions, larger amounts of PAI-1 are expressed by smooth muscle cells and macrophages in the necrotic core. Most of the PAI-1 of this advanced stage is in complex tPA, suggesting that PAI-1 has an important function in modulating mural tPA activity (Padro, T., et al., Arterioscler. Thromb. Vasc. Biol. 15:893-902 (1995) and Saweh, H., et al., Circ. Res. 73:671-680 (1993)). These findings have been supported with experimental work in rabbits that demonstrated an increase in PAI-1 expression in activated endothelial cells, macrophages and smooth muscle cells in response to sustained mechanical injury. The increase in PAI-1 transcription paralleled the severity of vascular lesions induced and was increased in hypercholesterolemic rabbits (Kruithof, E. K. O., et al., Blood 70:1645-1653 (1987)). These results suggest that enhanced PAI-1 expression is a feature of early atherosclerosis and that a PAI-1 inhibitor may be effective preventive therapeutics for high risk patients.
A PAI-1 inhibitor may also serve as an anticancer agent. An antibody to PAI-1 has been shown to suppress metastasis in several cancer models (Tsuchiya, H., et al., Gen. Diag., Pathol. 141:41-48 (1995)). In cultured lung cancer cells, PAI-1 is necessary for optimum invasion (Liu, G., et al., Int. J. Cancer 60:501-506 (1995)). Further, cancer invasion and tumor vascularization have been prevented in PAI-1 knockout mice implanted with malignant murine keratinocytes (Bajou, K., et al., Nature Med. 4(8):923-928 (1998)). This indicates that PAI-1 plays an integral role in tumor progression.
PAI-1 is also expressed at high levels by smooth muscle and endothelial cells, and it regulates the proteolytic activity surrounding the formation of blood vessels. A PAI-1 inhibitor may be suitable as an anti-angiogenic agent by hindering proper vessel formation around tumor. In fact, transduced endothelial cells that express decreased PAI-1 activity compared with normal endothelial cells were found to form large ectactic sac-like structures resembling haemangiomas when cultured in fibrin gels, suggesting abnormal vessel formation (Lawrence, D. A., et al., J. Biol. Chem. 269(21):15223-15229 (1994)).
U.S. Pat. No. 4,942,242 discloses compounds of the following Formula:
wherein n is 3 or 4. These compounds are disclosed to be useful as inhibitors of blood platelet aggregation.
JP 61016274 describes, for example, the following thiazole derivatives that are stated to have platelet aggregation inhibitory activity:
wherein R
1
is CH
2
COOH or CHMeCOOH and R
2
, R
3
and R
4
are independently selected from the group consisting of H, CH
3
, OCH
3
and Cl, and
A need exists in the art for compounds that are potent and/or selective inhibitors of PAI-1.
SUMMARY OF THE INVENTION
It has now been discovered that thiazole derivatives of Formula I:
or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein
Y is —N—, —C(R
3
)— or —CH(R
3
)—, wherein
R
3
is selected from the group consisting of hydrogen, cyano, C(CN)
3
, N(CN)
2
, trifluoromethyl, halogen, alkyl, cycloalkyl, aryl and heteroaryl radical, all of which can be optionally substituted;
Ar
1
and Ar
2
, which can be the same or different, are an optionally substituted aryl or an optionally substituted heteroaryl radical;
m is 0 or 1, provided that when Y is —N— or —C(R
3
)—, then m is 1, and when Y is —CH(R
3
)—, then m is 0;
R
1
is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl or heteroaryl radical, all of which can be optionally substituted; and
R
2
is hydrogen, or an optionally substituted aryl or an optionally substituted heteroaryl radical; with the provisos that
when Y is N, R
1
and R
2
are hydrogen and Ar
2
is an optionally substituted phenyl, then Ar
1
is other than a phenyl group substituted with carboxyalkyl or an alkyl ester of carboxyalkyloxy;
when Y is N, R
1
is hydrogen, and Ar
2
and R
2
are both a phenyl group, then Ar
1
is other than a phenyl group substituted with carboxyalkyl; or
when Y is N, R
1
and R
2
are hydrogen and Ar
2
is naphthyl, then Ar
1
is other than a phenyl group substituted with carboxyalkyl,
inhibit plasminogen activator inhibitor-1 (PAI-1). These compounds can be used in the prophylaxis or for the treatment of thrombosis, angina pectoris, cerebral infarction, myocardial infarction, pulmonary infarction, intra-atrial thrombus in atrial fibrillation, deep venous thrombus, disseminated intravascular coagulation syndrome, diabetic complications, restenosis and stroke.
Accordingly, the present invention provides a method of inhibiting plasminogen activator inhibitor-1. The method comprises administering to a mammal in need thereof an effective amount of a compound of Formula I.
Also, the present invention provides a method for preventing or treating one or more of thrombosis, angina pectoris, cerebral infarction, myocardial infarction, pulmonary infarction, intra-atrial thrombus in atrial fibrillation, deep venous thrombus, disseminated intravascular coagulation syndrome, diabetic complications, restenosis, for example, after percutaneous transluminal coronary angioplasty, or stroke by administering to a mammal in need thereof an effective amount of a compound of Formula I.
A number of compounds useful in the present invention have not been heretofor reported. Thus, the present invention also provides novel thiazole derivatives included in Formula I. Also, the present invention provides a method for preparing the novel compounds included in Formula I.
Further, the present inven
Deckman Ingrid
Dhanoa Dale S.
Ryan Declan E.
Sapienza Anthony
3-Dimensional Pharmaceuticals Inc.
Hui San-ming
Padmanabhan Sreeni
Sterne Kessler Goldstein & Fox P.L.L.C.
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