Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-07-16
2004-03-16
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S622000
Reexamination Certificate
active
06706766
ABSTRACT:
BACKGROUND OF THE INVENTION
In general, the invention features methods and compounds for increasing cell death.
Cell growth is a tightly regulated process. When the body has no need for new cells, but cells nonetheless divide in an unregulated manner, the result is cancer. Cancer therapies are directed at controlling the rapid proliferation of cells and/or controlling the differentiation rate of cells, as an undifferentiated cell is highly proliferative. One way in which the proliferation of cancer cells may be controlled is by killing such unregulated dividing cells.
The family of Bcl-2 proteins plays a central role in the regulation of cell life and death, acting by modulating apoptosis, a specific type of cell death. Some members of this family, for example, Bax, Bad, and Bak promote apoptosis, while other members of the family, for example, Bcl-2, Bcl-xL, Bcl-w, and Mcl-1 inhibit apoptosis. The precise mechanism by which the various Bcl-2 family members promote either cell viability or cell death has not yet been resolved.
One method for treating cancer involves controlling the expression and/or activity of Bcl-2 family member proteins. In particular, methods that decrease the expression or activity of anti-apoptotic Bcl-2 family members or increase the expression or activity of pro-apoptotic Bcl-2 family members would be useful for treating cancer.
SUMMARY OF THE INVENTION
The present invention features methods and compounds for disrupting an interaction between a polypeptide containing a Bcl-2-homology-3 domain and another polypeptide, and for increasing cell death. The compounds of the present invention may be used as therapeutics to increase cell death in a desired cell, such as a cancer cell. These compounds are characterized by their ability to inhibit heterodimerization between pro-apoptotic and anti-apoptotic members of the Bcl-2 family of proteins. Identified compounds may be especially useful in treating cancers that overexpress Bcl-2 protein family members.
Accordingly, in a first aspect, the invention features a chemical compound in a pharmaceutically acceptable carrier having the formula:
where each of R
1
, R
2
, R
4
, and R
5
is independently selected from the group consisting of hydrogen, alkoxyl, hydroxyl, and halogens; R
3
is selected from the group consisting of N(CH
3
)
2
, phenyl, hydroxyl, alkoxyl, and halogens; R
6
is selected from the group consisting of CH(CH
3
)
2
, CH
2
CH(CH
3
)
2
, CH(CH
3
)CH
2
CH
3
, and CH
3
; R
7
is either hydrogen or an alkyl group; and the bond (a) is either a single or double bond.
In a preferred embodiment of the above aspect of the invention, the heterocyclic ring of the compound is substituted with a benzyl ring.
In another preferred embodiment, in the compound, each of R
1
, R
2
, R
4
, and R
5
are hydrogen; R
3
is bromine; R
6
is CH(CH
3
)
2
; R
7
is hydrogen; and the bond (a) is a double bond.
In yet another preferred embodiment, in the compound, each of R
1
, R
2
, R
4
, and R
5
are hydrogen; R
3
is chlorine; R
6
is CH(CH
3
)
2
; R
7
is hydrogen; and the bond (a) is a double bond.
In yet another preferred embodiment, in the compound, each of R
1
, R
2
, R
3
, R
4
, and R
5
are hydrogen; R
6
is CH(CH
3
)
2
; R
7
is hydrogen; and the bond (a) is a double bond.
In still another preferred embodiment, in the compound, each of R
1
, R
2
, R
4
, and R
5
are hydrogen; R
3
is N(CH
3
)
2
; R
6
is CH(CH
3
)
2
; R
7
is hydrogen; and the bond (a) is a double bond.
In other embodiments, the alkoxyl group of R
1
, R
2
, R
4
, R
5
, or R
3
contains 10 or fewer carbons. Preferably the alkoxyl group of R
1
, R
2
, R
4
, R
5
, or R
3
contains 4 or fewer carbons. Most preferably the alkoxyl group of R
1
, R
2
, R
4
, R
5
, or R
3
is a methoxyl group.
In yet other embodiments of the above aspect of the invention, if R
1
is hydrogen, then R
2
, R
4
, or R
5
is not hydrogen; or R
3
is not bromine or chlorine; or R
6
is not CH(CH
3
)
2
; or R
7
is not hydrogen; or the bond (a) is not a double bond. If R
2
is hydrogen, then R
1
, R
4
, or R
5
is not hydrogen; or R
3
is not bromine or chlorine; or R
6
is not CH(CH
3
)
2
; or R
7
is not hydrogen; or the bond (a) is not a double bond. If R
4
is hydrogen, then R
1
, R
2
, or R
5
is not hydrogen; or R
3
is not bromine or chlorine; or R
6
is not CH(CH
3
)
2
; or R
7
is not hydrogen; or the bond (a) is not a double bond. If R
5
is hydrogen, then R
1
, R
2
, or R
4
is not hydrogen; or R
3
is not bromine or chlorine; or R
6
is not CH(CH
3
)
2
; or R
7
is not hydrogen; or the bond (a) is not a double bond. If R
3
is bromine or chlorine, then R
1
, R
2
, R
4
, or R
5
is not hydrogen; or R
6
is not CH(CH
3
)
2
; or R
7
is not hydrogen; or the bond (a) is not a double bond. If R
6
is CH(CH
3
)
2
, then R
1
, R
2
, R
4
, or R
5
is not hydrogen; or R
3
is not chlorine or bromine; or R
7
is not hydrogen; or the bond (a) is not a double bond. If R
7
is hydrogen, then R
1
, R
2
, R
4
, or R
5
is not hydrogen; or R
3
is not chlorine or bromine; or R
6
is not CH(CH
3
)
2
; or the bond (a) is not a double bond. If the bond (a) is a double bond, then R
1
, R
2
, R
4
, or R
5
is not hydrogen; or R
3
is not chlorine or bromine; or R
6
is not CH(CH
3
)
2
; or R
7
is not hydrogen.
In a second aspect, the invention features a chemical compound in a pharmaceutically acceptable carrier having the formula:
where each of R
1
, R
2
, R
4
, and R
5
is, independently, hydrogen, a halogen, or a phenyl group; and R
3
is hydrogen or an alkyl group.
In a preferred embodiment of the second aspect of the invention, in the compound, each of R
1
, R
4
, and R
5
is chlorine; R
2
is bromine; and R
3
is hydrogen.
In another preferred embodiment of the second aspect of the invention, in the compound, each of R
1
, R
4
, and R
5
is chlorine; R
2
is iodine; and R
3
is hydrogen.
In yet another preferred embodiment of the second aspect of the invention, in the compound, R
1
and R
2
are iodine, R
4
, and R
5
are chlorine; and R
3
is hydrogen.
In other embodiments of the second aspect of the invention, if R
1
is chlorine, then R
4
or R
5
is not chlorine; or R
2
is not bromine; or R
3
is not hydrogen. If R
4
is chlorine, then R
1
or R
5
is not chlorine; or R
2
is not bromine; or R
3
is not hydrogen. If R
5
is chlorine, then R
1
or R
4
is not chlorine; or R
2
is not bromine; or R
3
is not hydrogen. If R
2
is bromine, then R
1
, R
4
, or R
5
is not chlorine; or R
3
is not hydrogen. If R
3
is hydrogen, then R
1
, R
4
, or R
5
is not chlorine; or R
2
is not bromine.
In a third aspect, the invention features a method for increasing cell death, involving the steps of:
(a) providing a cell predicted to be resistant to cell death, or to be at risk for resisting cell death; and
(b) contacting the cell with a chemical compound having the formula:
where each of R
1
, R
2
, R
4
, and R
5
is independently selected from the group consisting of hydrogen, alkoxyl, hydroxyl, and halogens; R
3
is selected from the group consisting of N(CH
3
)
2
, phenyl, hydroxyl, methoxyl, and halogens; R
6
is selected from the group consisting of CH(CH
3
)
2
, CH
2
CH(CH
3
)
2
, CH(CH
3
)CH
2
CH
3
, and CH
3
; R
7
is either hydrogen or an alkyl group; and the bond (a) is either a single or double bond.
In a preferred embodiment of the above aspect of the invention, in the compound, the heterocyclic ring of the compound is substituted with a benzyl ring.
In another preferred embodiment, in the compound, each of R
1
, R
2
, R
4
, and R
5
are hydrogen; R
3
is bromine; R
6
is CH(CH
3
)
2
; R
7
is hydrogen; and the bond (a) is a double bond.
In yet another preferred embodiment, in the compound, each of R
1
, R
2
, R
4
, and R
5
are hydrogen; R
3
is chlorine; R
6
is CH(CH
3
)
2
; R
7
is hydrogen; and the bond (a) is a double bond.
In yet another preferred embodiment, in the compound, each of R
1
, R
2
, R
3
, R
4
, and R
5
are hydrogen; R
6
is CH(CH
3
)
2
; R
7
is hydrogen; and the bond (a) is a double bond.
In still another preferred embodiment, in the compound, each o
Degterev Alexei
Mitchison Timothy J.
Yuan Junying
Bieker-Brady Kristina
Clark & Elbing LLP
President and Fellows of Harvard College
Stockton Laura L.
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