Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-05-25
2001-12-18
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S130000, C549S218000, C568S009000, C568S016000, C568S017000
Reexamination Certificate
active
06331532
ABSTRACT:
TECHNICAL FIELD
The invention relates to antioxidants having a lipophilic cationic group and to uses of these antioxidants, for example, as pharmaceuticals.
BACKGROUND OF THE INVENTION
Oxidative stress contributes to a number of human degenerative diseases associated with aging, such as Parkinson's disease, and Alzheimer's disease, as well as to Huntington's Chorea, diabetes and Friedreich's Ataxia, and to non-specific damage that accumulates with aging. It also contributes to inflammation and ischemic-reperfusion tissue injury in stroke and heart attack, and also during organ transplantation and surgery. To prevent the damage caused by oxidative stress a number of antioxidant therapies have been developed. However, most of these are not targeted within cells and are therefore less than optimally effective.
Mitochondria are intracellular organelles responsible for energy metabolism. Consequently, mitochondrial defects are damaging, particularly to neural and muscle tissues which have high energy demands. They are also the major source of the free radicals and reactive oxygen species that cause oxidative stress inside most cells. Therefore, the applicants believe delivering antioxidants selectively to mitochondria will be more effective than using non-targeted antioxidants. Accordingly, it is towards the provision of antioxidants which may be targeted to mitochondria that the present invention is directed.
Lipophilic cations may be accumulated in the mitochondrial matrix because of their positive charge (Rottenberg, (1979)
Methods Enzymol
, 55, 547-560; Chen, (1988)
Annu Rev Cell Biol
4, 155-181). Such ions are accumulated provided they are sufficiently lipophilic to screen the positive charge or delocalise it over a large surface area, also provided that there is no active efflux pathway and the cation is not metabolized or immediately toxic to a cell.
The focus of the invention is therefore on an approach by which it is possible to use the ability of mitochondria to concentrate specific lipophilic cations to take up linked antioxidants so as to target the antioxidant to the major source of free radicals and reactive oxygen species causing the oxidative stress.
SUMMARY OF THE INVENTION
In its broadest aspect, the invention provides a mitochondrially-targeted antioxidant which comprises a lipophilic cation covalently coupled to an antioxidant moiety, wherein the antioxidant moiety is capable of being transported through the mitochondrial membrane and accumulated within the mitochondria of intact cells, with the proviso that the compound is not thiobutyltriphenylphosphonium bromide.
Preferably, the lipophilic cation is the triphenylphosphonium cation.
Preferably, the mitochondrially-targeted antioxidant has the formula
wherein Z is an anion, X is a linking group and R is an antioxidant moiety.
Preferably, X is a C
1
-C
30
, more preferably C
1
-C
20
, carbon chain, optionally including one or more double or triple bonds, and optionally including one or more substituents (such as hydroxyl, carboxylic acid or amide groups) and/or unsubstituted or substituted alky, alkenyl or alkynyl side chains.
Preferably, X is (CH
2
)
n
, where n is an integer of from 1 to 20,more preferably of from about 1 to 15.
More preferably, X is an ethylene, propylene, butylene, pentylene or decylene group.
Preferably, Z is a pharmaceutically acceptable anion.
In one particularly preferred embodiment, the mitochondrially-targeted anti-oxidant of the invention has the formula
including all stereoisomers thereof.
Preferably, Z is Br. The above compound is referred to herein as “compound 1”.
In another preferred embodiment, the mitochondrially-targeted antioxidant has the general formula:
wherein:
Z is a pharmaceutically acceptable anion, preferably a halogen,
m is an integer from 0 to 3,
each Y is independently selected from groups, chains and aliphatic and aromatic rings having electron donating and accepting properties,
(C)
n
, represents a carbon chain optionally including one or more double or triple bonds, and optionally including one or more substituents and/or unsubstituted or substituted alkyl, alkenyl or alkynyl side chains, and
n is an integer of from 1 to 20.
Preferably, each Y is independently selected from the group consisting of alkoxy, thioalkyl, alkyl, haloalkyl, halo, amino, nitro, optionally substituted aryl, or, when m is 2 or 3, two Y groups, together with the carbon atoms to which they are attached, form an aliphatic or aromatic carbocyclic or heterocyclic ring fused to the aryl ring. More preferably, each Y is independently selected from methoxy and methyl.
Preferably, (C)
n
, is an alkyl chain of the formula (CH
2
)
n
.
In a particularly preferred embodiment, the mitochondrially-targeted antioxidant of the invention has the formula
Preferably, Z is Br. The above compound is referred to herein as “mitoquinol”. The oxidized form of the compound is referred to as “mitoquinone”.
In a further aspect, the present invention provides a pharmaceutical composition suitable for treatment of a patient who would benefit from reduced oxidative stress which comprises an effective amount of a mitochondrially-targeted antioxidant of the present invention in combination with one or more pharmaceutically acceptable carriers or diluents.
In a further aspect, the invention provides a method of reducing oxidative stress in a cell which comprises the step of administering to said cell a mitochondrially targeted antioxidant as defined above.
In still a further aspect, the invention provides a method of therapy or prophylaxis of a patient who would benefit from reduced oxidative stress which comprises the step of administering to said patient a mitochondrially-targeted antioxidant as defined above.
Although broadly as defined above, the invention is not limited thereto but also consists of embodiments of which the following description provides examples.
REFERENCES:
patent: 3532667 (1970-10-01), Singh
Burns et al, “Synthesis and Characterization of Thiobutyltriphenylphosphonium . . . ,” Archives of Biochemistry and Biophysics, vol. 322, No. 1, pp. 60-68 (1995).
Masaki et al, “Mitochondrial Damage as a Mechanism of Cell Injury . . . ,” Archives of Biochemistry and Biophysics, vol. 270, No. 2, pp. 672-680 (1989).
McKittrick et al, “Synthesis of the Yeast Anitoxidant . . . ” J. Chem. Soc. Perkin Trans I, pp. 709-712 (1984).
Burns et al, “Labeling of Mitochondrial Proteins in Living Cells by the Thiol Probe,” Archives of Biochemistry and Biophysics, vol. 339, No. 1, pp. 33-39 (1997).
Everett et al, “Scavenging of Nitrogen Dioxide, Thiyl, and Sulfonyl Free . . . ,” J. Bio. Chem., vol. 271, No. 8, pp. 3988-3994 (1996).
Murphy Michael P.
Smith Robin A. J.
Nixon & Vanderhye
Owens Amelia
University of Otago
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