Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-13
2003-04-22
Trinh, Ba K. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S276000, C549S469000, C549S471000
Reexamination Certificate
active
06552071
ABSTRACT:
BACKGROUND OF THE INVENTION
In general, the invention features methods and compounds for treating or preventing a cell death disease or inflammation.
A feature of many diseases, for example, neurodegenerative diseases, is the occurrence of cell death. While the death of any type of cell in the body as a result of a disease is a medical concern, the effects of the death of certain types of cells, for example neuronal cells, are particularly disturbing, as these cell types do not readily regenerate. Therefore, understanding the mechanisms that regulate cell death is essential to being able to prevent or treat conditions, such as neurodegenerative diseases.
Research has shown that caspases play a central role in the induction of apoptosis. For example, caspase-11 has been shown to modulate both cytokine production and apoptosis, and to be induced upon ischemic brain injury (Wang et al., J. Biol. Chem. 271:20580-20587, 1996; Wang et al., Cell 92:501-509, 1998). These studies suggest that caspase-11 is involved in mediating cell death and inflammatory responses. Discovery of a compound that modulates the expression of caspases and/or the occurrence of inflammation or cell death would provide a useful therapeutic for treating conditions involving inflammation or conditions in which cell death occurs, and also for preventing such conditions.
SUMMARY OF THE INVENTION
The present invention features methods and compounds for treating or preventing inflammation or a cell death disease. The methods involve the use of the plant extract wedelolactone and may be particularly useful for treating neurodegenerative diseases.
Accordingly, in a first aspect, the invention features a method for treating or preventing a cell death disease in a subject, comprising administering wedelolactone, or a derivative or salt thereof, to the subject. The cell death disease of the first aspect of the invention is not caused by hepatotoxicity.
In a second aspect, the invention features a method for treating or preventing inflammation in a subject, comprising administering wedelolactone, or a derivative or salt thereof, to the subject.
In one embodiment of the above aspects of the invention, the wedelolactone is present in an extract from a plant. Preferably the wedelolactone is substantially pure.
In a third aspect, the invention features a method for treating or preventing a cell death disease in a subject, involving administering to the subject a chemical compound in a pharmaceutically acceptable carrier, having the formula:
where R
1
is selected from the group consisting of H, OH, and OCH
3
; and R
2
is selected from the group consisting of H, CH
3
, and (CH
2
)
x
CH
3
, where x is a positive integer. This method is not used to treat a cell death disease caused by hepatotoxicity.
In a fourth aspect, the invention features a method for treating or preventing inflammation in a subject, involving administering to the subject a chemical compound in a pharmaceutically acceptable carrier, having the formula:
where R
1
is selected from the group consisting of H, OH, and OCH
3
; and R
2
is selected from the group consisting of H, CH
3
, and (CH
2
)
x
CH
3
, where x is a positive integer.
In a preferred embodiment of the third or fourth aspects of the invention, in the compound, R
1
is OH and R
2
is CH
3
.
In one embodiment of the first or third aspect of the invention, the cell death disease is a neurodegenerative disease, for example, ischemic brain injury or stroke. In another embodiment of any of the above aspects of the invention, the subject is a mammal, such as a human or a mouse.
In a fifth aspect, the invention features a chemical compound in a pharmaceutically acceptable carrier, having the formula:
where R
1
is selected from the group consisting of H, OH, and OCH
3
; and R
2
is selected from the group consisting of H, CH
3
, and (CH
2
)
x
CH
3
, where x is a positive integer.
In a preferred embodiment of the fifth aspect of the invention, in the compound, R
1
is OH and R
2
is CH
3
.
In a sixth aspect, the invention features a method of synthesizing a 2,3-disubstituted benzo[b]furan, involving subjecting a molecule having the formula:
to carbonylative heteroannulation.
In one embodiment of the sixth aspect of the invention, the molecule is in reaction with CO and CH
3
OH. In another embodiment, the carbonylative heteroannulation occurs in the presence of PdI
2
-thiourea, CBr
4
, and CsCO
3
.
In a seventh aspect, the invention features a method of synthesizing wedelolactone, involving subjecting a molecule having the formula:
to lactonization.
By “treating” is meant to submit or subject an animal, cell, lysate or extract derived from a cell, or a molecule derived from a cell to a compound that decreases cell death or inflammation.
By a “cell death disease” is meant a disease that results in the death of a cell or a population of cells. As used herein, the cell death disease is not caused by hepatotoxicity. The occurrence of cell death can be measured by determining cellular ATP levels, wherein a cell that is undergoing cell death has a decreased level of cellular ATP compared to a control cell. The occurrence of cell death may also be measured by staining with a vital dye, for example, trypan blue, where a cell that is dead will be stained with the vital dye, and a cell that is not dead will not be stained with the dye. The occurrence of cell death can also be measured by contacting a cell with Hoescht stain and viewing it for morphological indications of cell death. Such indications include nuclear fragmentation.
By a “neurodegenerative disease” is meant a disease characterized by neuronal cell death. Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Huntington's disease and related polyglutamine expansion diseases, ischemic brain injury, stroke, amyotropic lateral sclerosis, multiple sclerosis, Lewy body disease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, and Fahr disease.
By a “neuron” is meant a cell of ectodermal embryonic origin derived from any part of the nervous system of an animal. Neurons express well-characterized neuron-specific markers, including neurofilament proteins, MAP2, and class III tubulin. Included as neurons are, for example, hippocampal, cortical, midbrain dopaminergic, motor, sensory, sympathetic, septal cholinergic, and cerebellar neurons.
By a “derivative” is meant a structural derivative having a chemical modification of the compound that does not modify the ultimate level of cell death or inflammation, but that does enhance bioavailability, solubility, or stability in vivo or ex vivo or that reduces the toxicity or dosage required. Such modifications are known to those skilled in the field of medicinal chemistry. As used herein, a derivative of wedelolactone may be synthesized from the purified wedelolactone extract, or may be chemically synthesized using reagents other than the purified wedelolactone extract.
By “substantially pure” is meant a compound that is at least 60%, by weight, free from proteins and naturally-occurring organic molecules with which it is naturally associated. Preferably the preparation is at least 75%, more preferably 90%, and most preferably at least 99%, by weight, chemical compound, e.g., wedelolactone. A purified compound may be obtained, for example, by high pressure liquid chromatograph, thin layer chromatography, or by synthesizing it.
By “preventing a cell death disease” is meant decreasing the number of cells that undergo cell death relative to an untreated control. As used herein, cell death may be inhibited. Preferably cell death is decreased 10% relative to a control compound with no activity in preventing cell death. More preferably cell death is decreased 50% relative to a control. Most preferably cell death is decreased 90% relative to a control.
By a “plant extract” is meant a compound or mixture of compounds that are obtained from a plant. A plant extract may be obtained from a plant, for example, by chopping up the plant into small pieces, tre
Kobori Masuko
Yang Zhen
Yuan Junying
Bieker-Brady Kristina
Clark & Elbing LLP
President and Fellows of Harvard College
Trinh Ba K.
LandOfFree
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