Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-24
2001-12-11
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S394000, C514S415000
Reexamination Certificate
active
06329412
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is concerned with a new use for certain known bisamidine compounds. It has been discovered that said known compounds possess biological activity as inhibitors of the DNA methyltransferase enzyme and consequently are useful in the treatment of diseases and conditions which involve unregulated differentiation of cells and cellular proceses. 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 used in the methods of treatment of the present invention hinder the occurrence of the just-described biochemical process and constrain its pathogenic sequelae. As a result, the known compounds of Formula (5.0.0) are useful as chemopreventative and chemotherapeutic agents in the methods of treating cancers, proliferative diseases such as psoriasis, and hyperplasia, which comprise the present invention.
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.,
235:403406 (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 a pharmaceutical composition for use as an antiproliferative agent, comprising a therapeutically effective amount of a bisamidine compound of Formula (5.0.0) as described further below, 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 (5.0.0) as described further below. 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 further relates to a pharmaceutical composition for use as a DNA methyltransferase inhibiting agent, comprising a therapeutically effective amount of a bisamidine compound of Formula (5.0.0) as described further below, 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 (5.0.0) as described further below. 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 antineoplastic and antiproliferative agents used in the methods of treatment of the present invention are useful as well 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 used in the methods of treatment of the present invention are further useful in the treatment of proliferative diseases such as restenosis, in addition to cancer and psoriasis.
The present invention relates to the use of certain bisamidine compounds as antiproliferative agents, wherein said bisamidine comprises a compound of Formula (5.0.0):
and a pharmaceutically acceptable salt thereof, wherein:
—X is —C(R
34
)—; or —N—;
—R
23
, R
24
, R
28
and R
29
are each independently —H; or —CH
2
— where R
23
and R
24
and
R
28
and R
29
are taken together with the nitrogen atoms to which they are attached, to form an imidazolinyl group; and
—R
34
is —H; or —CH
3
.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is concerned with certain known bisamidines which have been discovered to be newly useful as antiproliferative agents. Said bisamidines comprise a compound of Formula (5.0.0):
and a pharmaceutically acceptable salt thereof.
The X moiety of the compounds of Formula (5.0.0) has the meaning —C(R
34
)— or —N—. Accordingly, there results an indolyl-2-phenyl moiety with a 3-position substituent R
34
as the nucleus of the compounds of Formula (5.0.0) when X has the meaning —C(R
34
)—; and a benzimidazolinyl-2-phenyl moiety as the nucleus of the compounds of Formula (5.0.0) when X has the meaning —N—. These basic nuclei may be represented by partial Formulas (5.1.0) and (5.2.0) as follows:
Of the two above-depicted nuclei, the indolyl-2-phenyl moiety of Formula (5.1.0) is preferred.
The 1-position nitrogen atom of either the indolyl-2-phenyl or benzimidazolinyl-2-phenyl nucleus has only a hydrogen attached thereto, i.e., there is no substitution of said nitrogen atom.
Where R
23
, R
24
, R
28
and R
29
all have the meaning —H, the compounds of Formula (5.0.0) are characterized by having a carbamimidoyl group attached to either the indolyl or benzimidazolinyl component of the basic nucleus, as well as to the phenyl component of said nucleus. These carbamimidoyl groups may be attached only to specific carbon atoms of said components. Particularly, the carbamimidoyl group must be attached at the 4-position of the phenyl component of the nucleus, and must be attached at either the 5- or 6-position of the indolyl-2-phenyl or benzimid
Glazer Edward A.
Goldstein Steven W.
Mylari Banauara L.
Perez Jose R.
Ginsburg Paul H.
Goldberg Jerome D.
Pfizer Inc
Richardson Peter C.
Speer Raymond M.
LandOfFree
Bisamidine compounds as antiproliferative agents does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Bisamidine compounds as antiproliferative agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bisamidine compounds as antiproliferative agents will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2571928