Plasminogen activator inhibitor antagonists

Details Plasminogen activator inhibitor antagonists Plasminogen activator inhibitor antagonists

1999-11-19

2003-10-28

Killos, Paul J. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S532000, C514S543000, C514S570000, C514S571000, C514S544000, C560S009000, C560S015000, C560S018000, C560S024000, C560S030000, C560S055000, C560S064000, C562S426000, C562S452000

Reexamination Certificate

active

06638977

ABSTRACT:

FIELD OF THE INVENTION
Provided herein are compounds and pharmaceutical compositions useful as plasminogen activator inhibitor (PAI) antagonists, particularly PAI type 1 (PAI-1) antagonists. In particular, methods of antagonizing PAI, particularly PAI-1, with substituted and unsubstituted biaryl and benzyl ethers and thioethers 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 which include fibrinolysis, tissue remodelling, tumor growth and metastasis.
The glycoprotein, plasminogen activator inhibitor type 1 (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, eq., 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
37:1 227-1 234) and several diketopiperazines (piperazinediones)(see, e.g., Charlton 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).
Thus, it is an object herein to provide compositions and methods for antagonizing the effects of PAI, particularly PAI-1. 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, 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. The compounds are substituted aryl or heteroaryl ethers and thioethers that possess at least one acidic moiety, including, but not limited to, a carboxylic acid, sulfonic acid, sulfinic acid, phosphonic acid, phosphinic acid or boronic acid group.
The compounds provided herein are ethers and thioethers that have the formula Ar
1
—X′—Ar
2
, wherein X′ is O, S, (CH
2
)
d
O or (CH
2
)
d
S where d is an integer from 1 to 6; and Ar
1
and Ar
2
are each independently selected from monocyclic or fused bicyclic aryl and heteroaryl, preferably aryl, more preferably phenyl, and are substituted with at least one acidic group selected from a carboxylic acid, sulfonic acid, sulfinic acid, phosphonic acid, phosphinic acid or boronic acid group. Preferred acidic groups are carboxylic acid and sulfonic acid groups, more preferably (CH
2
)
a
COOH, (CH
2
)
b
CH(NRR′)COOH and (CH
2
)
c
SO
3
H where R and R′ are each independently hydrogen or an amino acid blocking or protecting group (see, e.g., Greene, T. W.
Protective Groups in Organic Synthesis
(1981) John Wiley & Sons, New York) including, but not limited to, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), para-toluenesulfonyl (tosyl), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, formyl, acetyl, benzyloxymethyl, benzyloxymethoxycarbonyl, unsubstituted or substituted benzoyl, unsubstituted or substituted benzyl, unsubstituted or substituted triphenylmethyl (trityl), or unsubstituted or substituted benzylidene; or R and R′ together form phthaloyl, succinimidyl or maleimidyl; a is an integer from 0 to 6, b is an integer from 1 to 4, preferably 1 or 2; and c is an integer from 0 to 4, preferably 0.
Ar
1
and Ar
2
may be substituted further with one or more groups such as halide, pseudohalide, nitro, hydroxy, alkoxy, aryloxy, cycloalkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl. The aryl, heteroaryl, heterocyclyl and cycloalkyl substituents may be further substituted with C
1-20
alkyl-L-, C
2-20
alkenyl-L-, or C
2-20
alkynyl-L-, where L is a direct link, amido, carboxy, carbonyl, carbamoyl, sulfonyl, carbamide, ur

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