Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-08
2003-10-21
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S252110, C514S253120, C544S360000, C544S364000
Reexamination Certificate
active
06635649
ABSTRACT:
BACKGROUND
The treatment of tumor can be approached by several modes of therapy, including surgery, radiation, chemotherapy, or any combination of any of these treatments. Among them, chemotherapy is indispensable for inoperable or metastatic forms of cancer. Considering the diversity of tumors in terms of cell type, morphology, growth rate, and other cellular characteristics, the U.S. National Cancer Institute (NCI) has developed a “disease-oriented” approach to anti-tumor activity screening. Boyd, M. R. (1989) In
Principle of Practice of Oncology Devita
, J. T., Hellman, S., and Rosenberg, S. A. (Eds.) Vol. 3, PPO Update, No. 10. This in vitro screening system is based on human tumor cell line panels consisting of approximately 60 cell lines of major human tumors (e.g., leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer), and serves as a tool for identifying compounds that possess anti-tumor activities.
Of particular interest are the anti-tumor compounds that function via one or more of the following four mechanisms: (1) inhibiting G
2
/M progression of the cell cycle, which might eventually induce the apoptosis in tumor cells (Yeung et al. (1999)
Biochem. Biophys. Res. Com.
263: 398-404); (2) disturbing tubulin assembly/dissembly, which may inhibit the cell mitosis and induce the cell apoptosis (Panda et al. (1997)
Proc. Natl. Acad. Sci. USA
94:10560-10564); (3) inhibiting endothelial cell proliferation and angiogenesis effect (Witte et al. (1998)
Cancer Metastasis Rev.
17: 155-161; Prewett et al. (1999)
Cancer Res.
59:5209-5218); or (4) regulating Ras protein-dependent signal transduction pathway (Hernandez-Alcoceba et al. (2000)
Cell Mol. Life Sci.
57: 65-76; Buolamwini (1999)
Cur. Opin. Che. Biol.
3: 500-509).
SUMMARY
This invention is based in part on the discovery that piperazinedione compounds have anti-tumor activities, identified by NCI screening system, and function via one or more of the above-mentioned four mechanisms.
An aspect of the present invention relates to piperazinedione compounds of formula:
Each of
and
independently, is a single bond or a double bond; A is H or CH(R
a
R
b
) when
is a single bond, or C(R
a
R
b
) when
is a double bond. Z is R
3
O—(Ar)—B, in which B is CH(R
c
) when
is a single bond, or C(R
c
) when
is a double bond; Ar is heteroaryl; R
3
is H, alkyl, aryl, heteroaryl, C(O)R
d
, C(O)OR
d
, C(O)NR
d
R
e
, or SO
2
R
d
; and both B and R
3
O can be substituted at any suitable position on Ar. Each of R
1
and R
2
, independently, is H, C(O)R
d
, C(O)OR
d
, C(O)NR
d
R
e
, or SO
2
R
d
; and each of R
a
, R
b
, R
c
, R
d
, and R
e
, independently, is H, alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl. Optionally, R
a
and R
b
taken together are cyclyl or heterocyclyl; and, also optionally, R
1
and R
a
or R
1
and R
b
taken together are cyclyl or heterocyclyl.
Referring to the above formula, a subset of the piperazinedione compounds of this invention is featured by that both
and
are double bonds. In these compounds, Ar is pyridyl linked to B at position 2, R
c
is H, R
3
O is arylalkoxy linked to position 5 of pyridyl, both R
1
and R
2
are H, one of R
a
and R
b
is aryl or heteroaryl, and the other of R
a
and R
b
is H. Another subset of the piperazinedione compounds of this invention is featured by that both
and
are single bonds. In these compounds, Ar is pyridyl linked to B at position 2, R
c
is H, R
3
O is arylalkoxy linked to position 5 of pyridyl, both R
1
and R
2
are H, one of R
a
and R
b
is H, aryl, or heteroaryl, and the other of R
a
and R
b
is H.
Alkyl, aryl, heteroaryl, cyclyl, and heterocyclyl mentioned herein include both substituted and unsubstituted moieties. The term “substituted” refers to one or more substituents (which may be the same or different), each replacing a hydrogen atom. Examples of substituents include, but are not limited to, halogen, hydroxyl, amino, alkylamino, arylamino, dialkylamino, diarylamino, cyano, nitro, mercapto, carbonyl, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfoamido, C
1
~C
6
alkyl, C
1
~C
6
alkenyl, C
1
~C
6
alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, wherein alkyl, alkenyl, alkoxy, aryl, heteroaryl cyclyl, and heterocyclyl are optionally substituted with C
1
~C
6
alkyl, aryl, heteroaryl, halogen, hydroxyl, amino, mercapto, cyano, or nitro. The term “aryl” refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and pyrenyl. The term “heteroaryl” refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl moieties include, but are not limited to, furyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl.
Another aspect of the present invention relates to a pharmaceutical composition that contains a pharmaceutically acceptable carrier and an effective amount of at least one of the piperazinedione compounds described above.
A further aspect of this invention relates to a method for treating tumor (e.g., leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer). The method includes administering to a subject in need thereof an effective amount of the piperazinedione compound having the formula:
Each of
and
, independently, is a single bond or a double bond; A is H or CH(R
a
R
b
) when
is a single bond, or C(R
a
R
b
) when
is a double bond, Z is CH(R
c
R
d
) when
is a single bond, or C(R
c
R
d
) when
is a double bond; each of R
1 and R
2
, independently, is H, C(O)R
e
, C(O)OR
e
, C(O)NR
e
R
f
, or SO
2
R
e
; and each of R
a
, R
b
, R
c
, R
d
, R
e
, and R
f
, independently, is H, alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl, provided that one of R
c
and R
d
is aryl or heteroaryl. If
is a double bond,
is a single bond, and one of R
c
and R
d
is H, then the other of R
c
and R
d
is heteroaryl. Optionaly, R
a
and R
b
taken together are cyclyl or heterocyclyl; and, also optionally, R
1
and R
a
or R
1
and R
b
taken together are cyclyl or heterocyclyl.
Referring to the above formula, a subset of the just-described piperazinedione compounds is featured by that both
and
are double bonds. In these compounds, one of R
c
and R
d
is 2-pyridyl, the other of R
c
and R
d
is H, both R
1
and R
2
are H, one of R
a
and R
b
is aryl or heteroaryl, and the other of R
a
and R
b
is H. The 2-pyridyl can be further substituted with 5-arylalkoxy. Another subset of the piperazinedione compounds is featured by that both
and
are single bonds. In these compounds, one of R
c
and R
d
is 2-pyridyl, the other of R
c
and R
d
is H, both R
1
and R
2
are H, one of R
a
and R
b
is H, aryl, or heteroaryl, and the other of R
a
and R
b
is H.
Seven exemplary piperazinedione compounds are 3-[(5-benzyloxypyridin-2-yl)methylidene]-6-phenylmethylidene piperazine-2,5-dione, 3-[(5-benzyloxypyridin-2-yl)methylidene]-6-p-hydroxyphenylmethylidenepiperazine-2,5-dione, 3-[(5-benzyloxypyridin-2-yl)methylidene]-6-p-fluorophenylmethylidenepiperazine-2,5-dione, 3-[(5-benzyloxypyridin-2-yl)methylidene]-6-p-chlorophenylmethylidenepiperazine-2,5-dione, 3-[(5-benzyloxypyridin-2-yl)methylidene]-6-p-phenylmethoxy phenylmethylidenepiperazine-2,5-dione, 3-[(5-benzyloxypyridin-2-yl)methylidene]-6-[(thien-2-yl)methylidene]piperazine-2,5-dione, and 3,6-di [(5-benzyloxypyridin-2-yl)methyl]piperazine-2,5-dione. Their structures are shown below:
The piperazinedione compounds described above include the compounds themselves, as well as their salts and their prodrugs, if applicable. Such salts, for example, can be formed between a positively charged substituent (e.g., amino) on a piperazinedione compound and an anion. Suitable anions include, but are not limited to, chloride, bromide, iod
Chen Huei-Ting
Chen Ya-Lan
Fan Ya-Bing
Guh Jih-Hwa
Lee On
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