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  Pyrrolo-naphthyl acids and methods for using themUSPTO Application #: 20070123495Title: Pyrrolo-naphthyl acids and methods for using them Abstract: and methods of using them to modulate PAI-1 expression and to treat PAI-1 related disorders. The present invention relates to pyrrolo-naphthyl compounds of the formula (end of abstract) Agent: Woodcock Washburn LLP - Philadelphia, PA, US Inventors: Thomas J. Commons, Douglas John Jenkins USPTO Applicaton #: 20070123495 - Class: 514091000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Phosphorus Containing Other Than Solely As Part Of An Inorganic Ion In An Addition Salt Doai, Nitrogen Containing Hetero Ring, Hetero Ring Is Five-membered The Patent Description & Claims data below is from USPTO Patent Application 20070123495. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional application of U.S. application Ser. No. 11/208,775, filed Aug. 22, 2005, claiming the benefit of provisional application Ser. No. 60/603,766 filed on Aug. 23, 2004, each of which is incorporated herein by reference in its entirety. BACKGROUND [0002] The present invention relates generally to pyrrolo-napthyl acids, such as pyrrolo-5-yl-naphthyl]oxyalkyl-acids, and methods of using them. [0003] The serine protease inhibitor PAI-1 is one of the primary inhibitors of the fibrinolytic system. The fibrinolytic system includes the proenzyme plasminogen, which is converted to the active enzyme, plasmin, by one of two tissue type plasminogen activators, t-PA or u-PA. PAI-1 is the principal physiological inhibitor of t-PA and u-PA. One of plasmin's main functions in the fibrinolytic system is to digest fibrin at the site of vascular injury. The fibrinolytic system, however, is not only responsible for the removal of fibrin from circulation but is also involved in several other biological processes including ovulation, embryogenesis, intima proliferation, angiogenesis, tumorigenesis, and atherosclerosis. [0004] Elevated levels of PAI-1 have been associated with a variety of diseases and conditions including those associated with impairment of the fibrinolytic system. For example, elevated levels of PAI-1 have been implicated in thrombotic diseases, e.g., diseases characterized by formation of a thrombus that obstructs vascular blood flow locally or detaches and embolizes to occlude blood flow downstream. (Krishnamurti, Blood, 69, 798 (1987); Reilly, Arteriosclerosis and Thrombosis, 11, 1276 (1991); Carmeliet, Journal of Clinical Investigation, 92, 2756 (1993), Rocha, Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis 24, 243 (1994)). Antibody neutralization of PAI-1 activity resulted in promotion of endogenous thrombolysis and reperfusion (Biemond, Circulation, 91, 1175 (1995); Levi, Circulation 85, 305, (1992)). Elevated levels of PAI-1 have also been implicated in diseases such as polycystic ovary syndrome (Nordt, Journal of clinical Endocrinology and Metabolism, 85, 4, 1563 (2000)), bone loss induced by estrogen deficiency (Daci, Journal of Bone and Mineral Research, 15, 8, 1510 (2000)), cystic fibrosis, diabetes, chronic periodontitis, lymphomas, diseases associated with extracellular matrix accumulation, malignancies and diseases associated with neoangiogenesis, inflammatory diseases, vascular damage associated with infections, and diseases associated with increased uPA levels such as breast and ovarian cancer. [0005] In view of the foregoing, there exists a need for inhibitors of PAI-1 activity and methods of using them to modulate PAI-1 expression or activity, for example, in treating disorders associated with elevated PAI-1 levels. SUMMARY [0006] In one aspect, the present invention relates to pyrrolo-naphthyl acids of the following formula: or solvates, hydrates or pharmaceutically acceptable salt or ester forms thereof; wherein: [0007] Ar is aryl or heteroaryl; [0008] R.sub.1 is hydrogen, C.sub.1-C.sub.12 alkyl, C.sub.6-14 aryl, C.sub.6-14ar(C.sub.1-6)alkyl, --(CH.sub.2).sub.p-heteroaryl, --(CH.sub.2).sub.p--CO-aryl, --(CH.sub.2).sub.p--CO-heteroaryl, --(CH.sub.2).sub.p--CO--(C.sub.1-C.sub.6)alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl, or C.sub.3-C.sub.8 cycloalkyl. [0009] R.sub.2 and R.sub.3 are independently hydrogen, C.sub.1-C.sub.12 alkyl, C.sub.6-14 aryl, C.sub.6-14ar(C.sub.1-6)alkyl, --(CH.sub.2).sub.p-heteroaryl, halogen, C.sub.1-C.sub.6 alkoxy, aralkyl, alkoxyaryl, nitro, carboxy(C.sub.1-C.sub.6 alkyl), carbamide, carbamate, or C.sub.3-C.sub.8 cycloalkyl; [0010] R.sub.4 is --CH(R.sub.6)(CH.sub.2).sub.nR.sub.5, --C(CH.sub.3).sub.2R.sub.6, --CH(R.sub.5)(CH.sub.2).sub.nR.sub.6, --CH(R.sub.5)C.sub.6H.sub.4R.sub.6, --CH(R.sub.5)C.sub.6H.sub.3(CO.sub.2H).sub.2, CH(R.sub.5)C.sub.6H.sub.2(CO.sub.2H).sub.3, or an acid mimic; [0011] R.sub.5 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.12 aryl, aralkyl, C.sub.3-C.sub.8 cycloalkyl, or --(CH.sub.2).sub.n(R.sub.7); [0012] R.sub.6 is CO.sub.2H, tetrazole, or PO.sub.3H; [0013] R.sub.7 is [0014] n is from 0 to 6; [0015] p is from 0 to 3; [0016] b is from 0 to 6; and [0017] a is from 0 to 6. [0018] The present invention further provides, inter alia, methods of using pyrrolo-napthyl acids to, for example, modulate PAI-1 expression and/or activity. In certain methods, a therapeutically effective amount of one or more compounds of the present invention is administered to a subject to treat a PAI-1 related disorder. Examplary methods are those that involve inhibiting PAI-1 activity in the subject, such as that associated with impairment of the fibrinolytic system. In certain embodiments, one or more compounds of the present invention is administered to a subject to treat thrombosis, e.g., venous thrombosis, arterial thrombosis, cerebral thrombosis, and deep vein thrombosis, atrial fibrillation, pulmonary fibrosis, thromboembolic complications of surgery, cardiovascular disease, e.g., myocardial ischemia, atherosclerotic plaque formation, chronic obstructive pulmonary disease, renal fibrosis, polycystic ovary syndrome, Alzheimer's disease, or cancer. DETAILED DESCRIPTION [0019] A. General Overview [0020] The present invention provides novel compounds that preferably inhibit PAI-1 activity, processes for preparing such compounds, pharmaceutical compositions containing such compounds, and methods for using such compounds, for example, in medical therapies. Preferred compounds have properties that are useful for prevention and/or inhibition of a wide variety of diseases and disorders including those involving the production and/or action of PAI-1. These include disorders resulting from impairment of the fibrinolytic system including, but not limited to, thrombosis, coronary heart disease, renal fibrosis, atherosclerotic plaque formation, pulmonary disease, myocardial ischemia, atrial fibrillation, coagulation syndromes, thromboembolic complications of surgery, peripheral arterial occlusion and pulmonary fibrosis. Other disorders include, but are not limited to, polycystic ovary syndrome, Alzheimer's disease, and cancer. 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