Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-05-11
2001-03-20
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06204295
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a new medical use of, and method of treatment using, halogenated triphenylethylene derivatives of formula (I), for lowering levels of serum lipid peroxides, and for the prevention or treatment of oxidative tissue damage induced by lipid peroxidation. In particular, the present invention provides a new use of compounds of formula (I) for the prevention or treatment of atherosclerosis, ischemic injury, psoriasis, inflammatory diseases such as inflammatory bowel disease, or cardiovascular disorders such as coronary heart disease, cardiac ischemic injury and post-ischemic cardiac arrhythmias, or for the treatment of AIDS.
wherein Hal is halogen, R
1
and R
2
are independently hydrogen or C
1
-C
4
alkyl, and R
3
is hydrogen or hydroxy, or pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Medicinal antioxidants are compounds that may be used for the prevention of tissue damage induced by lipid peroxidation (Halliwell, B., FASEB J. 1:358-364, 1987). During lipid peroxidation free radicals interact with polyunsaturated fatty acids to form lipid peroxyl radicals, which produce lipid hydroperoxides and further lipid peroxyl radicals. This peroxidative cascade may eventually consume an essential part of the membrane lipid, which may lead to changes in membrane permeability and ultimately in cell death. The peroxidative degradation of lipids also leads to the formation of potentially toxic products such as malondialdehyde.
Numerous recent studies indicate that peroxidation of low density lipoproteins contribute to the formation and progression of atherosclerosis. Various antioxidants have been shown to decrease arterial lesions in animal models of atherosclerosis. So it is believed that the reduction of the atherogenic risk is associated with the reduction of atherogenic lipid peroxides which are essentially transported in the LDL fraction in the serum.
There is evidence that free radical induced lipid peroxidation occurs in ischemic injury, e.g. in cardiac ischemic injury following coronary thrombosis or in reperfusion ischemic injury during surgery. The importance of lipid peroxidation in tissue damage associated with ischemia is supported by the protective effect of natural and synthetic antioxidants or antioxidant enzymes in diverse ischemic models. It is believed that reduction of the lipid peroxidation associated with ischemia protects the vital organs, such as the cardiovascular system and cerebral tissue, from oxidative damage, e.g. in patients recovering from myocardial infarction or during surgery.
NADPH oxidase of polymorphonuclear leucocytes (neutrophils) is the source of superoxide radical anion and other reactive oxygen species which are important in the defence against pathogens. Tissue damage due to the uncontrolled production of reactive oxygen species by activated neutrophils is known to occur in connection with diseases like psoriasis or acute or chronic inflammatory diseases, e.g. inflammatory bowel disease. It is believed that compounds which inhibit the oxidative burst of the activated neutrophils can be of therapeutic interest in the prevention and treatment of these diseases. Furthermore, recent studies indicate that increased oxygen radical production by neutrophils (oxidative stress) is present in HIV-infected patients and that the oxygen radical overproduction can increase the expression and replication of HIV-1 (Jarstrand, C. et al., Chemico-Biological Interactions 91, 141-146, 1994; Schreck, R. et al., The EMBO Journal, 10, 8, 2247-2258, 1991; Favier, A. et al., Chemico-Biological Interactions 91, 165-180, 1994 and Fuchs, J. et al., Medical Hypotheses, 36, 60-64, 1991). Therefore it is believed that compounds which inhibit the oxidative burst of the activated neutrophils can be of therapeutic interest also in the treatment of AIDS.
SUMMARY OF THE INVENTION
In a first aspect the present invention provides a new medical use of compounds of formula (I) in the manufacture of medicaments for use in lowering levels of serum lipid peroxides.
In another aspect the present invention provides a new medical use of compounds of formula (I) in the manufacture of medicaments for use in the prevention or treatment of oxidative tissue damage induced by lipid peroxidation. In particular, the present invention provides a new use of compounds of formula (I) in the manufacture of medicaments for use in the prevention or treatment of atherosclerosis, ischemic injury, psoriasis, inflammatory diseases, such as inflammatory bowel disease, or cardiovascular disorders, such as coronary heart disease, cardiac ischemic injury and post-ischemic cardiac arrhythmias, and in the treatment of AIDS.
In another aspect, the present invention provides a new medical use of compounds of formula (I) in the manufacture of medicaments for use in protection of organs, particularly the cardiovascular system and cerebral tissue, from oxidative damage induced by lipid peroxidation associated with ischemia, particularly in patients recovering from myocardial infarction or during surgery.
In another aspect, the present invention provides a method for lowering levels of serum lipid peroxides in patients comprising administering to a patient in need thereof a serum lipid peroxides lowering amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a method for the prevention or treatment of oxidative tissue damage induced by lipid peroxidation in patients comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular, the present invention provides a method for the prevention or treatment of atherosclerosis, ischemic injury, psoriasis, inflammatory diseases, such as inflammatory bowel disease, or cardiovascular disorders, such as coronary heart disease, cardiac ischemic injury and post-ischemic cardiac arrhythmias, or for the treatment of AIDS in patients comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a method for protection of organs, particularly the cardiovascular system and cerebral tissue, from oxidative damage induced by lipid peroxidation associated with ischemia, particularly in patients recovering from myocardial infarction or during surgery, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In yet another aspect, the present invention provides a method for inhibiting the production of reactive oxygen species by activated neutrophils comprising administering to a patient in need thereof a reactive oxygen species production inhibiting amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
REFERENCES:
patent: 5491173 (1996-02-01), Toivola et al.
patent: 5929123 (1999-07-01), Ahotupa et al.
patent: 4320896A1 (1995-01-01), None
patent: WO93/11757 (1993-06-01), None
patent: WO93/19746 (1993-10-01), None
patent: WO96/07402 (1996-03-01), None
“Droloxifene (3-hydroxytamoxifen) has membrane antioxidant ability: potential relevance to its mechanism of therapeutic action in breast cancer”, H. Wiseman et al.,Cancer Letters,vol. 66 (1992) pp. 61-68.
“The antioxidant action of tamoxifen and its metabolites: Inhibition of lipid peroxidation”, H. Wiseman et al.FEBS Letters,vol. 263, No. 2 (Apr. 1990), pp. 192-194.
Ahotupa Markku
Kangas Lauri
Burns Doane , Swecker, Mathis LLP
Henley III Raymond
Orion Corporation
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