Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-04-03
2003-12-09
Aulakh, Charanjit S. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C546S022000
Reexamination Certificate
active
06660724
ABSTRACT:
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-&bgr; 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. Aronovitz, 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 within 3-6 months of the intervention. The main cause for restenosis is believed to be abnormal vascular smooth muscle cell activation and proliferation. The proof that high plasma Lp(a) levels are associated with smooth muscle cell proliferation and activation was established in vitro and in vivo by the two following studies:
“Proliferation of Human Smooth Muscle Cells Promoted by Lipoprotein(a)” D. J. Grainger, H. L. Kirschenlohr, J. C. Metcalfe, P. L. Weissberg, D. P. Wade and R. M. Lawn; Science, Vol 260, p.1655-1658 (1993); and
“Activation of Transforming Growth Factor-&bgr; is Inhibited by Apolipoprotein (a) in vivo”, D. J. Grainger, P. R. Kemp, A. C. Liu, R. M. Lawn and J. C. Metcalfe; Circulation, Vol 90, No. 4, Part 2, p. I-623 (1994).
This observation has led to a hypothesis that associates elevated plasma Lp(a) levels with an increased incidence of restenosis. The hypothesis was confirmed by the results of a recent clinical study showing that, in patients with high plasma Lp(a) levels, a reduction of Lp(a) levels by more than 50% by LDL-apheresis significantly reduced the restenosis rate; see for instance:
“Effectiveness of LDL-Apheresis in Preventing Restenosis After Percutaneous Transluminal Coronary Angioplasty (PTCA): LDL-Apheresis Angioplasty Restenosis Trial (L-ART)” H. Yamaguchi, Y. J. Lee, H. Daida, H. Yokoi, H. Miyano, T. Kanoh, S. Ishiwata, K. Kato, H. Nishikawa, F. Takatsu, Y. Kutsumi, H. Mokuno, N. Yamada and A. Noma; Chemistry and Physics of Lipids, Vol 67/68, p. 399-403(1994).
The above discussion has established the rationale for decreasing plasma Lp(a) in patients at risk with elevated levels (>20-30 mg/dl). The Lp(a) concentration in individuals appears to be highly determined by inheritance and is hardly influenced by dietary regimes. Various hormones (i.e. steroid hormones, growth hormones, thyroid hormones) have been shown to regulate plasma levels of Lp(a) in man. Of particular interest, drugs which effectively lower LDL such as the bile acid sequestrant cholestyramine or the HMGCoA reductase inhibitors lovastatin or pravastatin do not affect Lp(a) levels. The drugs of the fibrate family: clofibrate or bezafibrate and the antioxidant drug probucol are equally ineffective. The only drug reported to lower Lp(a) is nicotinic acid. However at the high doses necessary for efficacy (4 g/day) nicotinic acid has several serious side-effects which preclude its wide use: flushing, vasodilation and hepatotoxicity. Therefore the medical need to lower elevated Lp(a) plasma levels, an independent risk factor for cardiovascular disease, is still unmet.
In contrast to LDL, Lp(a) exists only in mammals high in the evolutionary scale (humans and non human primates) and is exclusively synthesized by the liver cells. Cynomolgus monkeys possess Lp(a) that is similar to human Lp(a), including possession of the unique apolipoprotein apo(a). This primate offers an experimental opportunity for studying the synthesis of Lp(a) and the role of Lp(a) in atherosclerosis and thrombosis. Primary cultures of cynomolgus monkey hepatocytes have been selected as the in vitro test for screening aminophosphonate derivatives of formula (I) for their ability to modulate Lp(a) levels. Prior to screening, this assay system had been validated by testing as reference products nicotinic acid and steroid hormones which are known to lower Lp(a) in man.
The present invention relates to the unexpected discovery that aminophosphonate derivatives are effective for lowering plasma and tissue lipoprotein(a). Accordingly, in a first aspect, the present invention provides for the use of a compound of formula (I):
where:
X
1
, X
2
, which may be identical or different, are H, a straight or branched alkyl or alkoxy group having from 1 to 8 carbon atoms, a hydroxy group or a nitro group,
X
3
is H, an alkyl group from 1 to 4 carbon atoms, X
3
O and one of the two other substituents X
1
or X
2
may form an alkylidene dioxy ring having from 1 to 4 carbon atoms,
R
1
, R
2
, identical or different, are H, a straight or branched alkyl group having from 1 to 6 carbon atom
Azoulay Raymond
Bentzen Craig Leigh
Bulla Alexandre
Diep Vinh Van
Floret Simon
Aulakh Charanjit S.
ILEX Products, Inc.
Jecminer Al A.
Moloney Stephen J.
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