Substituted naphthyl indole derivatives as inhibitors of...

Details Substituted naphthyl indole derivatives as inhibitors of... Substituted naphthyl indole derivatives as inhibitors of...

2002-06-13

2004-10-05

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S252000, C548S243000, C548S413000, C548S414000, C548S491000, C549S356000, C549S414000, C514S414000, C514S415000

Reexamination Certificate

active

06800654

ABSTRACT:

This invention relates to the composition and utility of substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) and as therapeutic compositions for treating conditions resulting from fibrinolytic disorders such as deep vein thrombosis and coronary heart disease, and pulmonary fibrosis.
BACKGROUND OF INVENTION
Plasminogen activator inhibitor-1 (PAI-1) is a major regulatory component of the plasminogen-plasmin system. PAI-1 is the principal physiologic inhibitor of both tissue type plasminogen activator (tPA) and urokinase type plasminogen activator (uPA). Elevated plasma levels of PAI-1 have been associated with thrombotic events as indicated by animal experiments (Krishnamurti,
Blood,
69, 798 (1987); Reilly,
Arteriosclerosis and Thrombosis,
11, 1276 (1991); Carmeliet,
Journal of Clinical Investigation,
92, 2756 (1993)) and clinical studies (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 of women such as polycystic ovary syndrome (Nordt,
Journal of clinical Endocrinology and Metabolism,
85, 4, 1563 (2000)) and bone loss induced by estrogen deficiency (Daci,
Journal of Bone and Mineral Research,
15, 8, 1510 (2000)). Accordingly, agents that inhibit PAI-1 would be of utility in treating conditions originating from fibrinolytic disorder such as deep vein thrombosis, coronary heart disease, pulmonary embolism, polycystic ovary syndrome, etc.
WO 98/08818 discloses substituted indoles and benzimidazoles of Formulas I, II, & III which are chemical inhibitors of various phospholipase enzymes (such as PLA
2
) useful in the treatment of inflammation.
WO 96/21656 discloses compounds of Formula I which are useful for treating or preventing obesity, breast cancer, osteoporosis, endometriosis, cardiovascular disease and prostatic disease.
In addition, the utilities of the current invention are different.
EP 0 655 439 (Eli Lilly and Company) relates to 5,6 fused ring bicyclic compounds inclusive of indoles, benzofurans, and benzothiophenes corresponding to the general Formula I as platelet aggregation inhibitors.
WO 95/10513 (Pfizer, Inc.) discloses substituted indoles, benzofurans, and benzthiophenes of Formula I as estrogen agonists which are useful for treating syndromes and diseases caused by estrogen deficiency.
WO 94/26738 and EP 0 512 570 (Fujisawa Pharmaceutical Co., Ltd.) disclose the preparation of substituted indoles, benzofurans, and benzthiophenes (Formula I) which possess an inhibitory activity against ACAT (cholesterol acyltransferase enzyme) and are useful for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby.
U.S. Pat. No. 5,151,435 discloses substituted imidazolo/benzimidazolo-indoles and dihydroindoles of Formula I which are useful as angiotensin II antagonists in the treatment of hypertension.
EP 0 416 609 discloses indole-, benzofuran-, and benzothiophene-containing lipoxygenase-inhibiting compounds (Formula I) as well as pro-drugs of these compounds having metabolically cleavable groups.


REFERENCES:
patent: 5151435 (1992-09-01), Bagley et al.
patent: 0 416 609 (1991-03-01), None
patent: 0 508 723 (1992-10-01), None
patent: 0 512 570 (1992-11-01), None
patent: 0 655 439 (1995-05-01), None
patent: WO 94/26738 (1994-11-01), None
patent: WO 95/10513 (1995-04-01), None
patent: WO 96/21656 (1996-07-01), None
patent: WO 97/09308 (1997-03-01), None
patent: WO 98/08818 (1998-03-01), None
Guzzo, P.R. et al., Tetrahedron Letters, 43(1), 41-42 (2002).
Nordt et al., The Journal of Clinical Endocrinology & Metabolism, 85(4), 1563-1568 (2000).
Aznar et al., Haemostasis, 24, 243-251 (1994).
Carmeliet et al., Journal of Clinical Invest., 92, 2756-2760 (1993).
Daci et al., Journal of Bone & Mineral Research, 15(8), 1510-1516 (2000).
Biemond et al., Circulation, 91(4), 1175-1181 (1995).
Levi, et al., Circulation, 85(1), 305-312 (1992).
Rocha, et al., Fibrinolysis, 8, 294-303 (1994).
Reilly et al., Arteriosclerosis & Thrombosis 11, 1276-1286 (1991).
Krishnamurti et al., Blood, 69(3), 798-803 (1987).

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