Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-24
2004-03-02
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254090, C514S256000, C514S402000, C514S415000, C544S143000, C544S296000, C544S333000, C548S312100, C548S505000
Reexamination Certificate
active
06699862
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is concerned with novel compounds which are biologically active as inhibitors of the DNA methyltransferase enzyme and consequently useful in the treatment of diseases and conditions which involve unregulated differentiation of cells and cellular processes. The DNA methyltransferase enzyme (EC 2.1.1.37) catalyzes the covalent methylation of the DNA base cytosine at the C5 position of that base. This modification of the base cytosine in a DNA molecule has been shown to play a vital role in the transcriptional inactivation, i.e., silencing of the chromatin as well as in the development and differentiation of cells. The resulting unregulated differentiation of cells and cellular processes is found to be a contributing factor in the development via transformation, and growth of particular cancers and malignancies. The compounds of the present invention hinder the occurrence of the just-described biochemical process and constrain its pathogenic sequelae. As a result, the compounds of Formula (1.0.0) are useful as chemopreventative and chemotherapeutic agents for treating cancers, proliferative diseases such as psoriasis, and hyperplasia.
DESCRIPTION OF THE STATE OF THE ART
The DNA methyltransferase enzyme (EC 2.1.1.37), which has been identified as a single gene product of 190 Kd, catalyzes the cofactor S-adenosylmethionine (SAM) dependent methylation of the cytosine base at the C5 carbon of the pyrimidine base. See, e.g., T. H. Bestor and V. M. Ingram,
Proc. Nat. Acad. Sci
., 80:5559-5563 (1983). This DNA modification has been shown to play a vital role in the transcriptional inactivation, i.e., silencing of the chromatin, as well as in the development and differentiation of cells, as described in more detail in E. Li, T. H. Bestor and R. Jaenisch,
Cell
, 69:915-926 (1992).
It is important to point out that aberrant changes in DNA methylation patterns as well as DNA methyltransferase activity itself have been implicated in the progression of cancer. There are two proposed mechanisms by which DNA methyltransferase has been correlated with this progression. (A) The first proposed mechanism is the hypermethylation/hypomethylation of key cell cycle regulatory genes and oncogenes including P16, P15, c-myc and P53. See, e.g., M. Schroeder and Mass, M. J., Biochem.&
Biophys. Res. Comm
., 235:403-406 (1997). (B) The second proposed mechanism is the low frequency DNA methyltransferase mediated deamination of the cytosine base causing a cytosine to thymine point mutation in the DNA sequence. See, e.g., J. -C. Shen, W. M. Rideout III and P. A. Jones,
Cell
, 71:1073-1080 (1992).
Further work in the art also supports the correlation between DNA methyltransferase activity and the transformation and progression of colon cells to malignant carcinomas in min-/APC (−/−) knock-out mice, as described in more detail in P. W. Laird, L. Jackson-Grusby, A. Fazell, S. L. Dickinson, W. E. Jung,. E. Li, R. A. Wienberg and R. Jaenisch,
Cell,
81
:
197
-
205
(1995).
SUMMARY OF THE INVENTION
The present invention relates to heterocyclic bisamidines useful as antiproliferative agents, comprising a compound of Formula (1.0.0):
and a pharmaceutically acceptable salt thereof, wherein:
x is —C(R
14
)—; or —N—;
R
1
is independently selected from the group consisting of hydrogen; and (C
1
-C
3
)alkyl;
R
3
, R
4
, R
5
, R
8
, R
9
, and R
10
are each independently selected from the group consisting of hydrogen; and (C
1
-C
3
)alkyl;
—or—
R
3
and R
4
may be taken together, or R
8
and R
9
may be taken together with the nitrogen atoms to which they are attached, to form an imidazolinyl group; or further together with an additional ring carbon, —CH
2
—, to form a 1 ,4,5,6-tetrahydropyrimidinyl group;
R
14
is independently selected from the group consisting of —H; —NHC(═O)(CH
2
)
m
R
20
; —(CH
2
)
m
R
20
; —CH(CH
3
)R
20
; —(CH
2
)
m
(C
6
H
3
)—R
17
; —(CH
2
)
m
(C
6
H
3
)—R
20
; —(CH
2
)
m
(heterocyclyl)—R
17
; —(CH
2
)
m
(heterocyclyl)—R
20
; —CH
2
CH═CHR
20
; —(CH
2
)
m
C(═O)NHCHR
20
R
21
; and —(CH
2
)
m
C(═O)NH—CH
2
—C(═O)NHCHR
20
R
21
;
R
15
is independently selected from the group consisting of hydrogen; —OR
1
; —O—(C
1
-C
3
) alkylenyl-R
20
; and —OR
20
;
R
17
is independently selected from the group consisting of hydrogen; halogen; (C
1
-C
3
)alkyl; —CF
3
; —CN; —NO
2
; —N(R
1
)
2
; —OH; and (C
1
-C
3
) alkyl(C
1
-C
3
)alkoxy;
R
20
is independently selected from the group consisting of —C(═O)OR
1
; CH(OH)CH
2
OH; —C(═O)NH
2
; and —C(═O)H;
R
21
is independently selected from the group consisting of hydrogen; (C
1
-C
6
)alkyl; —(CH
2
)
n
R
22
; —CH(CH
3
)CH
2
C(═O)OR
1
; and —CH
2
—(C
6
H
5
);
R
22
is independently selected from the group consisting of —H; —NH
2
; —OR
1
; —SR
1
; —CN; —OCH
2
—(C
6
H
5
); —O(CH
2
)
m
—OR
1
; —C(═O)OR
1
; thienyl; tetrahydropyranyl; —CH(OH)CH
2
OH; —C(═O)C(CH
3
)═CH
2
; —NHC(═O)OCH
2
—(C
6
H
5
); and —S(═O)
2
R
1
;
m is an integer independently selected from 1, 2, and 3; and
n is an integer independently selected from 1 through 5, inclusive.
The present invention further relates to a pharmaceutical composition for use as an antiproliferative agent, comprising a therapeutically effective amount of a heterocyclic bisamidine compound of Formula (1.0.0) as above described, together with a pharmaceutically acceptable carrier for said compound. The present invention relates as well to a corresponding method of treating a neoplastic or a non-neoplastic disease characterized by abnormally rapid proliferation of tissue involved in said disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula (1.0.0) as above described. Said patient is a mammal, including especially a human. Said neoplastic disease includes but is not limited to melanoma, colon cancer; bladder cancer, non-small cell lung cancer, gliomas, head and neck squamous cell carcinoma, breast cancer, prostate cancer, renal cancer, and nasopharyngeal carcinoma. Said non-neoplastic disease includes but is not limited to psoriasis,
Pneumocystis carinii
infection, and restenosis.
The present invention still further relates to a pharmaceutical composition for use as a DNA methyltransferase inhibiting agent, comprising a therapeutically effective amount of a heterocyclic bisamidine compound of Formula (1.0.0) as above described, together with a pharmaceutically acceptable carrier for said compound. The present invention relates as well to a corresponding method of treating a neoplastic or a non-neoplastic disease characterized by abnormally rapid proliferation of tissue involved in said disease which is mediated by or associated with abnormally increased levels of DNA methylation, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula (1.0.0) as above described. Said patient is a mammal, including especially a human. Said neoplastic disease includes but is not limited to melanoma, colon cancer; bladder cancer, non-small cell lung cancer, gliomas, head and neck squamous cell carcinoma, breast cancer, prostate cancer, renal cancer, and nasopharyngeal carcinoma. Said non-neoplastic disease includes but is not limited to psoriasis,
Pneumocystis carinii
infection, and restenosis.
Antineoplastic and antiproliferative agents of the present invention may also be used in the therapy of psoriasis, a non-neoplastic disease of the skin characterized by abnormally rapid proliferation of epidermal cells, as well as for the beneficial treatment of
Pneumocystis carinii
. Therapeutic agents of the present invention are useful in the treatment of proliferative diseases such as restenosis, in addition to cancer and psoriasis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is concerned with novel compositions of matter which are heterocyclic bisamidines useful as antiproliferative agents, comprising a compound of Formula (1.0.0):
and a pharmaceutically acc
Glazer Edward A.
Goldstein Steven W.
Mylari Banauara L.
Perez Jose R.
Banerjee Krishna G.
Ginsburg Paul H.
McKenzie Thomas
Pfizer Inc.
Shah Mukund J.
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