Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1998-04-03
2000-05-09
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
546 22, A61K 31675, C07F 958
Patent
active
060604646
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a new therapeutic use of aminophosphonate compounds for lowering plasma and tissue levels of lipoprotein(a). In particular, this invention provides a new use of aminophosphonate derivatives, for the preparation of pharmaceutical compositions useful in the treatment of diseases or disorders associated with high plasma and tissue concentrations of lipoprotein(a); such as, for instance artherosclerosis, thrombosis, restenosis after angioplasty and stroke. This invention also provides a method for increasing thrombolysis and preventing thrombosis and a method of treatment of restenosis after angioplasty by administering to a patient in need thereof an aminophosphonate compound at a dose effective for lowering plasma and tissue lipoprotein(a) levels. In addition, this invention also provides a group of new aminophosphonate compounds for use in the above mentioned uses and compositions.
Recent epidemiologic studies have shown a strong association between elevated lipoprotein(a) [Lp(a)] plasma levels and the occurrence of coronary heart disease, stroke and peripheral artery disease. Lp(a) is now recognized as an independent risk factor for cardiovascular diseases; in addition its role in promoting thrombosis by decreasing thrombolysis is increasingly acknowledged, see for instance "Lipoprotein(a) as A Risk Factor for Preclinical Atherosclerosis" P. J. Schreiner, J. D. Morrisett, A. R. Sharrett, W. Patsch, H. A. Tyroler, K. Wu and G. Heiss; Arteriosclerosis and Thrombosis 13, p. 826-833 (1993); "Detection and Quantification of Lipoprotein(a) in the Arterial Wall of 107 Coronary Bypass Patients" M. Rath, A. Niendorf, T. Reblin, M. Dietel, H. J. Krebber and U. Beisiegel; Arteriosclerosis 9, p. 579-592 (1989); and "Lipoprotein(a): Structure, Properties and Possible Involvement in Thrombogenesis and Atherogenesis" A. D. MBewu and P. N. Durrington; Atherosclerosis 85, p. 1-14 (1990).
The potential of thrombosis involvement in vessel occlusion and acute cardiovascular syndrome is being increasingly recognized. One of the mechanisms that mediate thrombosis associated with atherosclerotic plaque rupture involves elevated levels of lipoprotein(a). The structure of Lp(a) consists of a low-density lipoprotein (LDL)-like particle with a glycoprotein, apolipoprotein(a) [apo(a)] that is linked via a disulfide bridge to the apo B-100 moiety of the LDL. Structurally there is striking analogy between apo(a) and plasminogen, the precursor of plasmin which cleaves fibrin to dissolve blood clots. However, unlike plasminogen apo(a) is not a substrate for plasminogen activators. This structural resemblance has led researchers to postulate and later demonstrate that apo(a) interferes with the normal physiological function of plasminogen, leading to a potential thrombogenic activity of Lp(a) see for instance:
"Activation of Transforming Growth Factor-.beta. is Inversely Correlated with Three Major Risk Factors for Coronary Artery Disease: Lipoprotein(a), LDL-Cholesterol and Plasminogen Activator Inhibitor-1", A. Chauhan, N. R. Williams, J. C. Metcalfe, A. A. Grace, A. C. Liu, R. M. Lawn, P. R. Kemp, P. M. Schofield and D. J. Grainger; Circulation, Vol 90, No. 4, Part 2, p. I-623 (1994); and "Influence of Human Apo(a) Expression on Fibrinolysis in vivo in Trangenic Mice" T. M. Palabrica, A. C. Liu, M. J. Aronvitz, B. Furie, B. C. Furie and R. Lawn; Circulation, Vol 90, No. 4, Part 2, p. I-623 (1994).
On the basis of its suspected thrombogenic activity, Lp(a) has also been implicated in peripheral artery disease, in particular stroke. Recently clinicians have shown that serum Lp(a) levels were significantly higher in stroke patients than in a reference normal population:
"Lp(a) Lipoprotein in Patients with Acute Stroke" K. Asplund, T. Olsson, M. Viitanen and G. Dahlen; Cerebrovasc. Diseases 1, p. 90-96 (1991).
Restenosis following percutaneous transluminal angioplasty is a common complication occurring in up to 40% of cases with 3-6 months of the intervention. The main cause for restenosis is believed to be abnorm
REFERENCES:
Chemical Abstracts, vol. 95, No. 17, 1981, Abstract No. 150763b.
Azoulay Raymond
Bentzen Craig Leigh
Bulla Alexandre
Diep Vinh Van
Floret Simon
Dustman Wayne J.
King William T.
Kinzig Charles M.
Rotman Alan L.
SmithKline Beecham p.l.c.
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