Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1997-08-07
2001-03-13
Ambrose, Michael G. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C558S177000
Reexamination Certificate
active
06200962
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to novel thionophosphate organic derivatives, their preparation and pharmaceutical compositions containing them, particularly suitable for treating and/or preventing oxidative damage.
BACKGROUND OF THE INVENTION
Reactive Oxygen Species (ROS) have been proposed to cause oxidative damage to biological molecules and to be involved in the development of many severe human disorders i.e., atherosclerosis, cancer, rheumatoid artritis and inflammation [Halliwell, B., and Gunteridge, J. M. C. (eds.) (1989) Free Radical in Biology and Medicine, Clarendon Press, London. Neuzil, J., et al. (1993) Biochem. J. 293:601-606; Sies, H., (ed.) (1985) Oxidative stress, Academic Press, London: Steinberg, D. et al. (1989) New Engl. J. Med. 320:915-923].
The antioxidants defense system is composed of several lines of defense. These lines of defense include macromolecular molecules (mainly enzymes such as superoxide dismutase (SOD), catalase glutathione peroxidase and other protecting enzymes) and low molecular weight antioxidants [Halliwell. B. (1990) Free Rad. Res. Comm. 9:1-327].
Despite intensive clinical trials using antioxidants, only marginal therapeutic and preventive successes have been reported [Rice-Evance. C. A., and Diplock A. T. (1993) Free Radical Biology & Medicine 15:77-96]. There are several reasons for the limited success in the use of antioxidants therapy:
1) Antioxidants can be classified according to their partition between aqueous and lipid compartments (lipoproteins and membranes) [Dean. R. T. et al. (1991) Free Radical Biology &, Medicine 11:161-168; Niki. E. et al. (1984) J. Biol. Chem. 259:4177-4182]. Most of the natural antioxidants cannot cross biological membranes and cannot move freely by spontaneous diffusion between aqueous and lipid environments. Some of them are ionized at natural physiologic pH, a fact that also restricts their movement.
2) Antioxidants should not have any pro-oxidative effects, i.e. thiols group produced superoxide radicals causing LDL oxidation and NO. radical distraction or ascorbic acid that induced free radical production when coupled with a transition metal [Heinecke, J. et al. (1993) J. Lipid Res. 34:2051-2061; Jackson, R. L., et al. (1993) Medicinal Research Reviews 13:161-182; Ingold, K. U., et al. (1993) Proc. Natl. Acad. Sci. USA 90:45-49];
3) Halliwell (ibid.) clarified that essential antioxidants should possess a broad spectrum of ROS scavenging capacities and should be in close proximity to the biological target and at relatively high concentrations.
N,N′-dimethyl thiourea (DMTU) is a well known antioxidant and a potent hydroxyl radical scavenger, also capable of removing hydrogen peroxide and superoxide radicals [Kelner. M. J., et al. (1990) J. Biol. Chem. 265:1306-1311; Dey, G. R., et al. (1994) J. Chem. Soc. Perkin Trans 2:1625-1629]. Notwithstanding their antioxidative properties, various DMTU-derived compounds are relatively highly toxic (e.g., lung, liver and thyroid toxicity) and considered carcinogenic substances.
Thus, antioxidants which can fulfill the requirements mentioned above may serve as efficient molecules capable of coping with oxidative stress and may thus be good candidates for antioxidative therapy. There is a basic need for better antioxidants in order to prevent the tissues natural deterioration and to prevent inflammatory and other tissue damage caused by reactive oxygen species.
The present invention thus relates to novel compounds which are efficient, non-toxic, therapeutic antioxidants.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the general formula:
in which X
1
and X
2
each independently represents an oxygen or nitrogen atom; p, m and n are each independently an integer of at least 2; R, R
1
and R
2
each independently represents a hydrogen atom; a halogen atom; an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group R
3
O in which R
3
is a hydrogen atom, an optionally substituted acyl group or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; optionally substituted aryl or heteroaryl; a group R
4
O(O)C in which R
4
is a hydrogen atom or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group —SR
5
in which R
5
is a hydrogen atom or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group —NR
6
R
7
in which R
6
and R
7
each independently represents a hydrogen atom, an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; optionally substituted acyl; or an optionally substituted phosphate ester group.
The invention also relates to a process for the preparation of a compound of formula I comprising reacting a dialkyl halothiophosphate of the formula
in which A is a halogen atom selected from chlorine, bromine and iodine and X
1
, X
2
, R
1
, R
2
, m and n are as defined above with an amine of the formula
in which R and p are as defined above.
The invention further relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula I in a suitable pharmaceutically acceptable carrier or diluent. The pharmaceutical compositions of the invention are particularly suitable for preventing and/or treating oxidative damage associated with inflammatory disorders, atherosclerosis, ischemia, traumatic shock, degenerative brain disease, skin disorders, septic shock, lung disease, malignant disease, damages caused by ionizing or non-ionizing radiation and poisonings by xanobiotics which generates reactive oxygen species.
In a further embodiment the invention relates to methods of preventing and/or treating oxidative damage in a patient in need of such treatment by administering to said patient a therapeutically effective amount of at least one compound of formula I or of a pharmaceutical composition according to the invention
In yet a further aspect the invention relates to antioxidative additives comprising as active ingredient at least one compound of formula I in a suitable carrier or diluent.
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Chemical Abstracts vol. 53, No. 14937a; DE 964678, abstract, 1959.
Dean et al., 1991, Free radical damage to proteins: the influence of the relative localization of radical generation, antioxidants, and target proteins.Free Radical Biol Med.11:161-168.
Ginsburg et al., 1993. Chemiluminescience in activated human neutrophils.Inflammation17:227-243.
Ginsburg et al., 1992, Synergism among oxidants, proteinases, phospholipases, micobial hemolysins, cationic proteins, and cytokinesInflammation16:519-538.
Halliwell, 1990. How to characterize a biological antioxidant.Free Radl Res. Comm.9:1-21.
Halliwell et al., 1987. Deoxyribose method: a simple “test-tube” assay for determination of rate constants for reactions of hydroxyl radicals.Analyt. Biochem165:215-219.
Halliwell and Gutteridge, 1989. Free radicals in biology and medicine.Free Radical in Biol. and Med. Clarendon Press(London) 1-5.
Hazell and Stocker, 1993. Oxidation of low-density lipoprotein with hypochlorite causes transformation of the lipoprotein into a high-uptake form for macrophages.Biochem J.290:165-172.
Heinecke et al., 1993. Oxidation of low density lipoprotein by thiols: superoxide-dependent and -independent mechanisms.J. Lipid Res.34:2051-2061.
Ingold et al., 1993. Autoxidation of lipids and antioxidtion by &agr;-tocopherol and ubiquinol in homogeneous solution and in aqueous dispersions . . .Proc. Natl. Acad. Sci. USA90:45-49.
Jackson et al., 1993. Antioxidants: a bilogical defense mechanism for the prevention of
Barenholz Yehezkel
Ginsburg Isaac
Katzhendler Joshua
Kohen Ron
Tirosh Oren
Ambrose Michael G.
Kohn & Associates
Yissum Research Development Company of the Hebrew University of
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