Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-28
2003-09-30
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S263210, C514S263220, C514S263230, C514S263400, C544S277000
Reexamination Certificate
active
06627633
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds that are shown to be potent cyclin/cyclin dependent kinase (cdk) inhibitors. Compounds with these properties are shown to be potent inhibitors of cell growth and proliferation. Such compounds can be used to treat the following conditions: rheumatoid arthritis, lupus, type 1 diabetes, multiple sclerosis, cancer, restenosis, gout and other proliferative diseases involving abnormal cellular proliferation. Compounds of the present invention which are biaryl substituted purine derivatives are shown to be potent antiproliferative agents against a number of human transformed cell lines, and also inhibitors of human cyclin/cdk kinase complexes.
BACKGROUND OF THE INVENTION
Cellular Proliferation and Cancer
The disruption of external or internal regulation of cellular growth can lead to uncontrolled proliferation and in cancer, tumor formation. This loss of control can occur at many levels and, indeed, does occur at multiple levels in most tumors. Further, although tumor cells can no longer control their own proliferation, they still must use the same basic cellular machinery employed by normal cells to drive their growth and replication.
Cyclin Dependent Kinases and Cell Cycle Regulation
Progression of the normal cell cycle from the G1 to S phase, and from the G2 phase to M phase is dependent on cdks (Sherr, C. J.,
Science
274:1672-1677 (1996)). Like other kinases, cdks regulate molecular events in the cell by facilitating the transfer of the terminal phosphate of adenosine triphosphate (ATP) to a substrate protein. Isolated cdks require association with a second subunit, called cyclins (Desai et al.,
Mol. Cell. Biol.,
15:345-350 (1995)). Cyclins cause conformational changes at the cdk active site, allowing ATP access and interaction with the substrate protein. The balance between its rates of synthesis and degradation controls the level of each cyclin at any point in the cycle (Elledge, S. J., et al.,
Biochim. Biophys. Acta,
1377:M61-M70 (1998)). The influences of cyclin/cdk activity on the cell cycle and cellular transformation are summarized in Table 1.
Abnormal Cyclin/cdk Activity in Cancer
In a normal cell, interlocking pathways respond to the cell's external environment and internal checkpoints monitor conditions within the cell to control the activity of cyclin/cdk complexes. A reasonable hypothesis is that the disruption of normal control of cyclin/cdk activity may result in uncontrolled proliferation. This hypothesis appears to hold in a number of tumor types in which cyclins are expressed at elevated levels (Table 1). Mutations in the genes encoding negative regulators (proteins) of cyclin/cdk activity are also found in tumors (Larsen, C.-J.,
Prog. Cell Cycle Res.,
3:109-124 (1997)); (Kamb, A.,
Trends in Genetics,
11:136-140 (1995)). Members of the Cip family of cdk inhibitors form a ternary complex with the cyclin/cdk and require binding to cyclinA, cyclinE, or cyclinD (Hall, M., et al.,
Oncogene,
11:1581-1588 (1995)). In contrast, Ink family members form a binary complex with cdk4 or cdk6 and prevent binding to cyclinD (Parry, D.; et al.,
EMBO J.,
14:503-511 (1995)).
TABLE 1
Associations Among Cyclins and Cancers
Cell
Cycle
Associated
Cyclin
Role
cdk
Cancer
A
S,
cdk1, cdk2
hepatocellular carcinoma (Wang, J.; et
G2
al., Oncogene, 8:1653-1656 (1992))
to M
B1/B2
G2
cdk1
none yet defined
to M
D1
G1
cdk4, cdk6
parathyroid adenoma (Motokura, T., et
al., Nature, 350:512-515 (1991))
centrocytic B cell lymphoma (Withers,
D.A., et al., Mol. Cell. Biol., :4846-
4853 (1991))
esophageal carcinoma (Jiang, W., et al.
Cancer Res., 52:2980-2983 (1992))
breast cancer (Dickson, C., et al.,
Cancer Lett., 90:43-50 (1995))
squamous cell carcinoma (Bartkova, J.,
et al., Cancer Res., 55:949-956 (1995))
hepatocellular carcinoma (Nishida, N.,
et al., Cancer Res., 54:3107-3110
(1994))
D2
G1
cdk4, cdk6
colorectal carcinoma (Leach, F.S., et
al., Cancer Res., 54:1986--1989 (1993))
E
G1
cdk2
breast cancer (Keytomarsi, K., et al.,
to S
Cancer Res., 54:380-385 (1994))
gastric carcinoma (Akama, Y.; et al.,
Jap. J. Cancer Res., 86:617-621 (1995))
colorectal carcinoma (Kitihara, K.; et
al., Int. J. Cancer, 62:25-28 (1995))
Inhibitors of Cyclin/cdk Complexes as Potential Anticancer Agents
Tumors with elevated cyclin/cdk activity, whether from the over expression of cyclins or the loss of an endogenous cdk inhibitor, are prime targets for potential therapies based on small molecule cyclin/cdk inhibitors. In fact, several small molecule inhibitors of cyclin/cdks are reported (Meijer, L., et al., “Progress in Cell Cycle Research,” Plenum Press: New York, 351-363 (1995)) and appear to bind at the ATP site of the kinase. Some information is known about small molecule inhibitors of other kinases, such as PKC (serine kinase) (Murray, K. J. et al., “Ann. Rep. Med. Chem.,” J. Bristol, Ed., Academic Press, Inc.: New York, Chapter 26 (1994)) and tyrosine kinases (Fatl, W. J., et al.,
Ann. Rev. Biochem.,
62:453 (1993); Burke, T. R.,
Drugs of the Future,
17:119-1131 (1992); Dobrusin, E. M. et al., “Ann. Rep. Med. Chem,” J. Bristol, Ed., Academic Press, Inc.: New York, Chapter 18 (1992); Spence, P.,
Curr. Opin. Ther. Patents,
3:3 (1993)). A number of known inhibitors were obtained from commercial sources or were synthesized by literature procedures.
Purine Compounds as Cyclin/cdk Inhibitors
There are several reports of 2,6-diamino substituted purine derivatives as cyclin/cdk inhibitors and as inhibitors of cellular proliferation. Among those are reports by U.S. Pat. No. 5,583,137 to Coe, et al., olomoucine (Vesely, J., et al.,
Eur. J. Biochem.,
224:771-786 (1994)), roscovitine (Meijer, L.,
Eur. J. Biochem.,
243:527-536 (1997)), WO 97/16452 to Zimmerman, Imbach, P., et al.,
Bioorg. Med. Chem. Lett.,
9:91-96 (1999), Norman, T. C., et al.,
J. Amer. Chem. Soc.,
118:7430-7431 (1996), Gray, N. S., et al.,
Tetrahedron Lett.,
38:1161-1164 (1997), Gray, N. S., et al.,
Science,
281:533-538 (1998), WO 98/05335 to Lum, et al., Schow, S. R., et al.,
Bioorg. Med. Chem. Lett,
7:2697-2702 (1997), U.S. Pat. No., 5,886,702 to Mackman, et al., Nugiel, D. A., et al.,
J. Org. Chem.,
62:201-203 (1997), and Fiorini. M. T. et al.,
Tetrahedron Lett.,
39:1827-1830 (1998). Many of these reported compounds are shown to inhibit cyclin/cdk complexes and have modest cellular proliferation inhibition properties.
The compounds of the present invention are shown to have far superior biological activities as cyclin/cdk complex inhibitors as well as inhibitors of cellular proliferation compared to those previously reported. In fact, the art (e.g., Fiorini, M. T. et al.,
Tetrahedron Lett.,
39:1827-1830 (1998)) teaches away fiom compounds of this invention, claiming lack of cellular proliferation inhibition.
SUMMARY OF THE INVENTION
The compounds of the present invention are 2,6,9-trisubstituted purine derivatives which are inhibitors of cyclin/cdk complexes. The compounds of the current invention also are potent inhibitors of human cellular proliferation. As such. the compounds of the present invention constitute pharmaceutical compositions with a pharmaceutically acceptable carrier. Such compounds are useful in inhibiting cellular proliferation in a mammal by administering to such mammal an effective amount of the compound.
In one embodiment, the compounds of the present invention are represented by the chemical structure found in Formula I
wherein:
R
1
are the same or different and independently selected from:
H;
C
1
-C
4
-straight chain alkyl;
C
3
-C
4
-branched chain alkyl;
X=
N;
CH;
R
2
=
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from R
1
, OR
1
, SR
1
, S(O)R
1
, S(O
2
)R
1
, NHR
1
, NO
2
, OC(O)CH
3
, NHC(O)CH
3
, F, Cl, Br, CF
3
, C(O)R
1
, C(O)NHR
1
, phenyl, C(O)NHCHR
1
CH
2
OH;
1-naphthyl;
2-naphthyl;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
2-benzofuranyl;
benzoth
Albany Molecular Research, Inc.
Berch Mark L.
Nixon & Peabody LLP
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