Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-13
2004-06-29
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06756394
ABSTRACT:
BACKGROUND OF THE INVENTION
In general, the invention relates to methods and compounds used to decrease necrosis.
In many diseases, cell death is mediated through apoptotic and/or necrotic pathways. While much is known about the mechanisms of action that control apoptosis, control of necrosis is not as well understood. Understanding the mechanisms regulating both necrosis and apoptosis in cells is essential to being able to treat conditions, such as neurodegenerative diseases, stroke, coronary heart disease, kidney disease, and liver disease. A thorough understanding of necrotic and apoptotic cell death pathways is also crucial to treating AIDS and the conditions associated with AIDS, such as retinal necrosis.
Research has shown that caspases play a central role in the induction of apoptosis. Peptide based inhibitors of caspases, such as zVAD-fmk are useful in preventing activation of the apoptotic cell death pathway in cells stimulated to undergo apoptosis by compounds such as TNF&agr;. However, cells treated with zVAD-fmk and these cell death stimuli still die through a caspase-independent form of necrosis.
Discovery of a compound which prevents caspase-independent cell death (necrosis) would provide a useful therapeutic for treating conditions in which necrosis occurs, and for preventing the onset of necrosis. These compounds and methods may be particularly useful for treating ischemic brain and heart injuries and head traumas.
SUMMARY OF THE INVENTION
The present invention features methods and compounds for decreasing necrosis. The compounds of the present invention may be used as therapeutics to decrease necrosis in a desired cell, such as a neuron. These compounds are characterized by their ability to decrease necrosis in response to modulation of intracellular signaling pathways, such as those activated by TNF&agr;. By also treating the cells with zVAD-fmk, we have inhibited the apoptotic pathway. Accordingly, we have been able to determine that the compounds of the invention specifically decrease necrosis. In addition, we have shown that the identified compounds that decrease necrosis in response to a necrotic pathway activated by zVAD-fmk and TNF&agr;, also decrease necrosis in response to a necrotic pathway activated by zVAD-fmk and dimethyl sulfoxide (DMSO).
Accordingly, in a first aspect, the invention features a chemical compound in a pharmaceutically acceptable carrier, having the formula:
wherein each R
1
is independently selected from the group consisting of hydrogen, carboxy, methyl, hydroxyl, methoxyl, amino, and nitro; R
2
is selected from the group consisting of hydrogen, alkyl, and acyl; R
3
is selected from the group consisting of alkyl, acyl, halogen, hydrogen, or hydroxyl; R
4
is selected from the group consisting of methyl, hydroxyl, carboxyl, and linear and branching alkyl groups; X is selected from the group consisting of ═O, —OH and —H; Y is selected from the group consisting of ═S and —SR
5
, where R
5
is either hydrogen or an alkyl group; and each of the bonds (a), (b), and (c) independently is either a double or single bond, provided, however, that bond (a) and bond (b) are not both double bonds.
In a preferred embodiment of the first aspect of the invention, in the compound each R
1
is hydrogen; R
2
and R
3
are each hydrogen; R
4
is a methyl group; X is ═O; Y is ═S; bond (a) is a double bond; and bonds (b) and (c) are each single bonds.
In another embodiment, the acyl group of R
1
or R
3
is selected from the group consisting of:
In other embodiments, in the compound if R
1
is a hydrogen, then R
2
and R
3
are not each hydrogen; or R
4
is not a methyl group; or X is not ═O; or Y is not ═S; or bond (a) is not a double bond; or bonds (b) and (c) are not each single bonds. If R
2
is a hydrogen, then R
1
is a not a hydrogen, or R
3
is not a hydrogen; or R
4
is not a methyl group; or X is not ═O; or Y is not ═S; or bond (a) is not a double bond; or bonds (b) and (c) are not each single bonds. If R
3
is a hydrogen, then R
1
is a not a hydrogen, or R
2
is not a hydrogen; or R
4
is not a methyl group; or X is not ═O; or Y is not ═S; or bond (a) is not a double bond; or bonds (b) and (c) are not each single bonds. If R
4
is a methyl group, then R
1
is a not a hydrogen, or R
2
and R
3
are not each not a hydrogen; or X is not ═O; or Y is not ═S; or bond (a) is not a double bond; or bonds (b) and (c) are not each single bonds.
In other embodiments, if X is ═O, then R
1
is a not a hydrogen, or R
2
and R
3
are not each not a hydrogen; or R
4
is not a methyl group; or Y is not ═S; or bond (a) is not a double bond; or bonds (b) and (c) are not each single bonds. If Y is ═S, then R
1
is a not a hydrogen, or R
2
and R
3
are not each not a hydrogen; or R
4
is not a methyl group; or X is not ═O; or bond (a) is not a double bond; or bonds (b) and (c) are not each single bonds.
In yet other embodiments, if bond (a) is a double bond, then R
1
is a not a hydrogen, or R
2
and R
3
are not each not a hydrogen; or R
4
is not a methyl group; or X is not ═O; or Y is not ═S; or bonds (b) and (c) are not each single bonds. If bond (b) is a single bond, then R
1
is a not a hydrogen, or R
2
and R
3
are not each not a hydrogen; or R
4
is not a methyl group; or X is not ═O; or Y is not ═S; bond (a) is not a double bond or bond (c) is not a single bond. If bond (c) is a single bond, then R
1
is a not a hydrogen, or R
2
and R
3
are not each not a hydrogen; or R
4
is not a methyl group; or X is not ═O; or Y is not ═S; bond (a) is not a double bond or bond (b) is not a single bond.
In a second aspect, the invention features a compound in a pharmaceutically acceptable carrier, having the formula:
wherein each of X
1
and X
2
is independently selected from the group consisting of ═O, —OH and —H; R
1
is selected from the group consisting of hydrogen and hydroxyl; R
2
is selected from the group consisting of hydrogen, sulfate, nitro, and halide; and the bond (a) is either a single or double bond.
In a preferred embodiment of the second aspect of the invention, in the compound each of X
1
and X
2
is ═O; R
1
is a hydroxyl group; R
2
is a nitro group; and the bond (a) is a double bond.
In other embodiments, if X
1
is ═O, then X
2
is not ═O; or R
1
is not a hydroxyl group; or R
2
is a not a nitro group; or the bond (a) is not a double bond. If X
2
is ═O, then X
1
is not ═; or R
1
is not a hydroxyl group; or R
2
is not a nitro group; or the bond (a) is not a double bond. If R
1
is a hydroxyl group, then each of X
1
and X
2
are not ═O; or R
2
is a not a nitro group; or the bond (a) is not a double bond. If R
2
is a nitro group, then each of X
1
and X
2
are not ═O; or R
1
is not a hydroxyl group; or the bond (a) is not a double bond. If the bond (a) is a double bond, then each of X
1
and X
2
are not ═O; or R
1
is not a hydroxyl group; or R
2
is a not a nitro group; or the bond (a) is not a double bond.
In a third aspect, the invention features a chemical compound in a pharmaceutically acceptable carrier, having the formula:
wherein each R
1
and R
2
is independently selected from the group consisting of hydrogen, amino, halide, and hydroxyl; R
3
is selected from the group consisting of hydrogen and methyl; and the bond (a) is either a single or double bond.
In a preferred embodiment of the third aspect of the invention, in the compound each R
1
is hydrogen; R
2
is fluorine; R
3
is a methyl group; and the bond (a) is a double bond.
In other embodiments of the third aspect of the invention, if R
1
is a hydrogen, then R
2
is not fluorine; or R
3
is not a methyl group; or the bond (a) is not a double bond. If R
2
is a fluorine, then R
1
is not hydrogen; or R
3
is a not a methyl group; or the bond (a) is not a double bond. If R
3
is a methyl group, then R
1
is not hydrogen, or R
2
is not fluorine; or the bond (a) is not a double bond. If the bond (a) is a dou
Degterev Alexei
Mitchison Timothy J.
Yuan Junying
Bieker-Brady Kirstina
Clark & Elbing LLP
President and Fellow of Harvard College
Ramsuer Robert W.
Small Andrea D.
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