Plasminogen activator inhibitor antagonists

Details Plasminogen activator inhibitor antagonists Plasminogen activator inhibitor antagonists

2000-11-17

2004-01-13

Killos, Paul J. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S009000, C560S011000, C562S426000, C562S429000, C562S460000, C564S162000, C564S163000, C568S332000

Reexamination Certificate

active

06677473

ABSTRACT:

FIELD OF THE INVENTION
Provided herein are compounds and pharmaceutical compositions that are plasminogen activator inhibitor (PAI) antagonists. In particular, methods of antagonizing PAI, particularly plasminogen activator inhibitor type 1 (PAI-1), with substituted and unsubstituted biaryl and benzyl ethers and thioethers, benzils and benzophenones are provided.
BACKGROUND OF THE INVENTION
Plasminogen activators (PA's), such as tissue type plasminogen activator (tPA) and urokinase plasminogen activator (uPA), are serine proteases that control the activation of the zymogen, plasminogen, to the active enzyme plasmin. Plasmin is important in a number of (patho)-physiological processes, including fibrinolysis, tissue remodelling, tumor growth and metastasis. The glycoprotein PAI-1 is an endogenous fast-acting inhibitor of PA activity. PAI-1 is a member of the serpin (serine protease inhibitor) family of protease inhibitors and is synthesized by a variety of cells including endothelial cells. An imbalance between PAs and PAI-1 contributes to several pathological conditions including thrombosis, inflammation, tumor growth and metastasis.
Thrombosis
Elevated circulating levels of PAI-1 can result in a downregulation of fibrinolysis. This condition can contribute to the pathogenesis of various thrombotic disorders, including myocardial infarction, reocclusion following thrombolytic therapy, deep vein thrombosis and disseminated intravascular coagulation. Compounds and pharmaceutical compositions that antagonize PAI-1 can be used in the treatment of certain thrombotic disorders by enhancing the extent of endogenous fibrinolysis by PAs. In addition, PAI-1 antagonists, in this context, may enhance the efficacy of thrombolytic therapy where exogenous PAs such as recombinant tPA (r-tPA) is administered to a patient to reperfuse blood vessels occluded by thrombus as is commonly observed in myocardial infarction (see, e.g., U.S. Pat. Nos. 5,750,530, 5,902,812 and 5,891,877).
Cancer
Current therapies for cancer are generally characterized by limited efficacy, or significant and/or debilitating side effects. In certain solid tumor cancers, malignant tumors invade and disrupt nearby tissues and can also metastasize or spread to other organs and tissues. The impact of these secondary metastatic tumors on vital organs such as the lungs and the liver frequently leads to death. Surgery is used to remove solid tumors that are accessible to the surgeon and can be effective if the cancer has not metastasized. Radiation therapy also can be employed to irradiate a solid tumor and surrounding tissues and is a firstline therapy for inoperable tumors, but side effects are a limiting factor in treatment. Radiation therapy is used frequently in conjunction with surgery either to reduce the tumor mass prior to surgery or to destroy tumor cells that may remain at the tumor site after surgery. However, radiation therapy cannot assure that all tumor cells will be destroyed and has only limited utility for treating widespread metastases. While surgery and radiation therapy are the primary treatments for solid tumors, chemotherapy and hormonal treatments often are used as adjunctive therapies and also are used as primary therapies for inoperable or metastatic cancers. However, the side effects of these therapies can often limit their effectiveness due to patient tolerance and compliance.
Plasminogen Activator Inhibitor (PAI) and Its Role in Solid Tumor Cancer
The role of PAI, particularly PAI-1, in the natural progression of certain solid tumor cancers has been suggested based on the strong correlation of increased levels of this protein and a poor patient survival rates in certain types of cancer, including breast cancer. In addition, recent evidence in animals genetically lacking PAI (PAI knockouts) has demonstrated that the growth and metastasis of certain human tumors is significantly impaired, suggesting that PAI may play a pivotal role in the growth and metastatic migration of certain solid tumors (Bajou et al. (1998)
Nat. Med
. 4(8):923-928).
PAI antagonists that have been reported to date include the anthranilic acid derivative AR-H029953XX (Björquist et al. (1998)
Biochemistry
37:1227-1234) and several diketopiperazines (piperazinediones)(see, e.g., Chariton et al. (1997)
Fibrinolysis
&
Proteolysis
11(1):51-56; Charlton et al. (1996)
Thrombosis and Haemostasis
75(5):808-815; and U.S. Pat. Nos. 5,750,530; 5,902,812; and 5,891,877). See also European Patent Application Publication No. EP 0 819 686. U.S. Pat. No. 3,794,729 discloses compounds for inhibition of blood platelet aggregation. Hence PAI-1 is a target for development of pharmaceuticals. Therefore, it is an object herein to provide compositions and methods for antagonizing the effects of PAI, particularly PAI-1, are provided. It is also an object herein to provide methods of treating, preventing, or ameliorating one or more symptoms of disease states, including, but not limited to, disease states mediated by or in which PAI-1 is implicated. These disease states include unstable angina, thrombotic disorders, such as myocardial infarction, reocclusion following thrombolytic therapy, deep vein thrombosis and disseminated intravascular coagulation, and cancer, particularly solid tumors, that are modulated or otherwise affected by the activity of PAI, particularly PAI-1. A further object herein is to provide methods of attenuating tumor or other cancer metastasis. Finally, it is an object herein to provide methods of modulating the interaction of PAs, particularly tPA and uPA, with PAI, particularly PAI-1.
SUMMARY OF THE INVENTION
Compounds and compositions useful as plasminogen activator inhibitor (PAI) antagonists are provided. The compounds and compositions are useful in the treatment, prevention, or amelioration of one or more symptoms of thrombotic disorders, such as myocardial infarction, reocclusion following thrombolytic therapy, deep vein thrombosis and disseminated intravascular coagulation, and cancer, particularly tumors, solid tumors, metastatic solid tumors and breast cancer. The compositions contain compounds that are active in assays that measure PAI-1 antagonist activity, such as an assay described herein. The compounds contain optionally substituted aryl and/or heteroaryl groups linked via various moieties, including but not limited to, ethers, thioethers, ketones, diketones and esters, and possess at least one acidic moiety, as defined herein, on one of the aryl or heteroaryl groups. An acidic group refers to a molecular fragment that is spatially and/or electronically capable of mimicking a carboxylic acid or that has acidic properties. As used herein, preferred acidic moieties include those that exist in anionic or salt form under physiological conditions. Among the preferred compounds are benzophenones, benzoate esters, benzyl ethers, sulfones and benzils.
In particular, provided herein are compounds and pharmaceutical compositions that contain therapeutically effective amounts of a compound of formula MX′
j
J, or pharmaceutically acceptable derivatives thereof, in a pharmaceutically acceptable carrier. In these embodiments, j is 0 or 1, and the formula MX′
j
J is intended to represent the formulae M-X′-J (when j is 1) or MJ (when j is 0). In the compounds, X′ is a direct link or is any suitable linkage such that the resulting compound has activity as a PAI-1 antagonist, and as noted above, at least one of M and J possesses an acidic group.
In one embodiment, the compounds for use in the compositions and methods provided herein have formula (I): MX′
j
J, or a pharmaceutically acceptable derivative thereof, wherein M, X′, j and J are selected from (i) or (ii) as follows:
(i) j is 1 and the compound has the formula M-X′-J;
X′ is selected from (i) or (ii) as follows:
(i) X′ is a direct link or is a divalent group having any combination of the following groups: arylene, heteroarylene excluding benzo[b]thienylene, cycloalkylene, C(R
15
)
2
, —C(R
15
)═C(

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