Purine inhibitors of cyclin dependent kinase 2 & IKBA

Details Purine inhibitors of cyclin dependent kinase 2 & IKBA Purine inhibitors of cyclin dependent kinase 2 & IKBA

2001-08-14

2004-09-14

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S265000, C544S264000, C544S276000

Reexamination Certificate

active

06790958

ABSTRACT:

BACKGROUND OF THE INVENTION
(1) Field of the Invention
This invention concerns 2,6,9-trisubstituted purines that have been discovered to be selective inhibitors of cell cycle kinases and, as such, the compounds are inhibitors of cell proliferation. The 2,6,9-trisubstituted purines are useful in for example in—treating autoimmune diseases, e.g. rheumatoid arthritis, lupus, type I diabetes, multiple sclerosis, etc., in treating cancer, cardiovascular disease, such as restenosis, host vs graft disease, gout, polycystic kidney disease and other proliferative diseases whose pathogenesis involves abnormal cell proliferation.
This invention also concerns 2,6,9-trisubstituted purines that have been discovered to be potent and specific inhibitors of I&kgr;B-&agr; kinase which prevents signal induced NF-&kgr;B activation and cytokine synthesis in vitro and in vivo. Such inhibitors are expected to inhibit the synthesis of cytokines and adhesion proteins whose synthesis is transcriptionally regulated by NF-&kgr;B. Proinflammatory cytokines such as IL-1, IL-6, TNF and adhesion proteins (e.g. ICAM, VCAM and selections) belong to this class of molecules and have been implicated in the pathogenesis of inflammatory diseases. Thus a potent inhibitor of I&kgr;B-&agr; kinase is useful in the clinical management of diseases where NF-&kgr;B activation is required for disease induction.
(2) Description of the Art
In the past few years, advances in molecular and cellular biology have contributed to our understanding of the mechanisms of cell proliferation and of specific events that occur during progression of cells through mitosis. E.g., “Progress in Cell Cycle Research” Vol 1, Eds. L. Meijer, S. Guidet and H. Y. L. Tung; Plenum Press, New York, 1995. These studies have shown that progression through the cell cycle is controlled by a family of serine/threonine kinases called cyclin dependent kinases. These enzymes contain (a) a catalytic protein called cyclin dependent kinase (CDK) that uses ATP as a substrate and (b) a regulatory protein called cyclin. Different cyclin-CDK combinations control events such as growth, DNA replication and cell division. One key member of the CDK family of enzymes is CDK2. CDK2 activity has been shown to be essential for mammalian cell cycle progression at the G1/S boundary. Microinjection of antibodies directed against CDK2 blocks the progression of human diploid fibroblasts into the S phase of the cell cycle. Expression of a CDK2 dominant negative mutant in human osteosarcoma cells has a similar effect. Together, these: studies indicate that inhibition of cellular CDK2 activity will prevent progression of cells through the mitotic cycle and induce growth arrest prior to the S phase. Consistent with this view, in vitro studies with olomoucine (2-(hydroxyethylamino)-6-benzylamino-9-methylpurine), have shown that it is a specific inhibitor of CDK2 with an IC
50
of approximately 2.1 &mgr;g/ml J. Vesely, et al.; Eur. J.Biochem 224, 771-786 (1994), L. Meijer “Chemical Inhibitors of Cyclin-Dependent Kinases” pp 351-356 in “Progress in Cell Cycle Research Vol 1, Eds. L. Meijer, S. Guidet and H. Y. L. Tung; Plenum Press, New York, 1995. In vivo studies using mammalian cells in culture have shown that olomoucine inhibits cell proliferation at an approximate concentration of 50 &mgr;g/ml.
In this invention, we have developed several compounds whose biological activity is considerably more potent than olomoucine. In vivo studies using mammalian cells indicate that some of the disclosed compounds inhibit cell proliferation at concentrations that are significantly lower than olomoucine.
Recently an I&kgr;B-&agr; kinase activity has been described in the cytoplasm of stimulated human umbilical vein endothelial cells (Bennett et al (1996) J. Biol. Chem 271, 19680-19688). Some of the compounds of this invention have been identified as potent and specific inhibitors of I&kgr;B-&agr; kinase which prevents signal induced NF-&kgr;B activation and cytokine synthesis in vitro and in vivo. The activation of the heterodimeric transcription factor NF-&kgr;B is a complex process. In unstimulated cells, the NF-&kgr;B (p50/p65) heterodimer is located in the cytosol where it is complexed with an inhibitory subunit I&kgr;B-&agr;, I&kgr;B-&agr;, binds to NF-&kgr;B thus masking its nuclear localization signal and preventing translocation to the nucleus. Upon stimulation of cells with a variety of signals (e.g. lipopolysaccharide) I&kgr;B-&agr; is rapidly phosphorylated, uniquitinated and degraded by the proteasome. Degradation of I&kgr;B-&agr;, allows the translocation of NF-&kgr;B to the nucleus where it activates transcription of a number of inflammatory response genes.
These observations suggest that I&kgr;B-&agr; kinase is an attractive target for the identification of inhibitors that may be useful in the treatment of inflammatory diseases where NF-&kgr;B activation is required for disease induction.
SUMMARY OF THE INVENTION
It is an object of this invention to provide 2,6,9-trisubstituted purine compounds, which inhibit the cyclin dependent kinase 2.
It is another object of this invention to provide 2,6,9-trisubstituted purine compounds which are useful for inhibiting cell proliferation.
This invention also constitutes a pharmaceutical composition, which comprises a 2,6,9-trisubstituted purine compound and a pharmaceutically acceptable carrier.
This invention further constitutes a method for inhibiting cell proliferation, which comprises administering to a mammal in need thereof an effective amount of a 2,6,9-trisubstituted purine compound.
In one embodiment, this invention is A 2,6,9-trisubstituted purine composition of matter having the following formula:
wherein R
1
is halogen or R′
1
—X wherein X=NH, O, S, S(O
2
). In the composition, R′
1
is alkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, and alkynyl, each having one to 20 carbon atoms, which alkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, and alkynyl, are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, aryl, CF
3
, heteroaryl, heterocyclyl, R
22
, SR
20
, S(O)R
21
, SO
2
R
21
, SO
2
NR
20
R
23
, SO
2
NR
20
COR
21
, SO
2
NR
20
CONR
20
R
20
CO
2
R
21
, NR
20
R
23
, NR
20
COR
21
, NR
20
CO
2
R
21
, NR
20
CONR
20
R
23
, N(R
20
)C(NR
20
)NHR
23
, NR
20
SO
2
R
21
, OR
20
, OCONR
20
R
23
, OCONR
20
SO
2
R
21
, OCONR
20
R
23
, CN, CO
2
R
20
, CONR
20
R
23
, CONR
20
SO
2
R
21
and COR
20
. Also in the composition, R
2
is a hydrogen or hydrocarbon selected from the group alkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, and alkynyl, each having one to 20 carbon atoms, which alkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, and alkynyl, are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, aryl, heteroaryl, heterocyclyl, R
22
, SR
20
, S(O)R
21
, SO
2
R
21
, SO
2
NR
20
R
23
, SO
2
NR
20
COR
21
, SO
2
NR
20
CONR
20
R
23
, SO
2
NR
20
CO
2
R
21
, NR
20
CR
23
, NR
20
COR
21
, NR
20
CO
2
R
21
, NR
20
CONR
20
R
23
, N(R
20
)C(NR
20
)NHR
23
, NR
20
SO
2
R
21
, OR
20
, OCONR
20
R
23
, OCONR
20
SO
2
R
21
, OCONR
20
R
23
, CN, CO
2
R
20
, CONR
20
R
23
, CONR
20
SO
2
R
21
and COR
20
. Further, in the compositions, R
3
is a halogen, hydroxyl, thio, alkoxy, alkylthio, alkyl, —NR
4
R
5
or a component having the formula:
where m=1-3, n=1-3, o=1,3, y=carbonyl, —NR
4
R
5
, hydroxyl, thiol, alkoxy, alkylthiol;
R
4
and R
5
are each independently hydrogen, OR
20
, NR
20
R
23
, or a hydrocarbon selected from the group including alkyl, acyl, heterocyclyl, aryl, heteroaryl, aralkyl;, heteroarylalkyl, alkenyl, and alkynyl, each having one to 20 carbon atoms, which alkyl, acyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, and alkynyl, are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, aryl, heteroaryl, heterocyc

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