Fused azepinone cyclin dependent kinase inhibitors

Details Fused azepinone cyclin dependent kinase inhibitors Fused azepinone cyclin dependent kinase inhibitors

2000-12-14

2003-08-26

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S521000

Reexamination Certificate

active

06610684

ABSTRACT:

FIELD
This invention concerns fused azepinone cyclin dependent kinase inhibitors, compositions comprising these compounds, and methods for administering such compounds for diseases of cellular proliferation and/or abnormal protein phosphorylation.
BACKGROUND
A major advance in the understanding of the control of the cell cycle has been the discovery of a family of enzymes called cyclin dependent kinases (cdk). Structurally they consist of a catalytic subunit and a regulatory subunit. The catalytic subunit is similar to the catalytic region in a number of serine/threonine kinases and at least eight distinct subunits have been described (cdk1(=cdc2)-cdk8). The regulatory subunit is necessary for activity and a number of proteins in this family have been described (cyclin A-cyclin H). Most cyclins can interact with more than one cdk and each known cyclin-cdk pair seems to have a distinct role in regulating the cell cycle. These activities are regulated not only through transcriptional and translational control of the subunits, but also through phosphorylation and dephosphorylation of the subunits. In addition, negative regulatory proteins have been discovered (p15, p16
INK4
, p21
cip1
and p27
Kip1
) which bind to the cyclin-cdk complex and inhibit activity. Structural understanding of the cdks and their regulation has been advanced by the solution of crystal structures for cdk2, cyclin A, cdk2-cyclin A, and cdk2-cyclin A-p2
7
Kip1
. [Russo et al., “Crystal Structure of the P
27
Kip1
Cyclin-Dependent Kinase-4 Bound to the Cyclin-A-Cdk2 Complex,”
Nature,
382(6589):325-331 (1996).]
It is clear then that the cdks are important in the control of the cell cycle. As a result, it appears that alterations in cdk expression, function or regulation are associated with diseases of cellular proliferation. Alterations that would increase cdk activity (overexpression of the catalytic and/or positive regulatory subunit, or underexpression or deletion of negative regulatory proteins) have been reported in many cancers. The most common observation has been the deletion of the pl6 (also called MTS1, CDKN2, p16
INK
) gene. This gene codes for a protein that inhibits the activity of cdk4 and cdk6. This loss of inhibitory activity has been observed in a wide variety of primary human tumors and human tumor-derived cell lines, including lung, breast, brain, bone, skin, bladder, kidney, ovary, liver, colon, pancreas and leukemias. Overexpression of cdk1 in ovarian carcinoma and overexpression of cyclin D in non-small cell lung cancer also has been observed.
Clinical studies have shown that alterations in cdk pathways have prognostic significance. Deletion of the p 16 gene has shown to be associated with poor prognosis in B cell lymphomas [R. Garcia-Sanz et al., “Deletions and Rearrangement of Cyclin-Dependent Kinase 4 Inhibitor Gene p16 are Associated with Poor Prognosis in B cell Non-Hodgkin's Lymphomas,”
Leukemia,
11(11):1915-20 (1997)], and pediatric acute lymphoblastic leukemia [e.g., U. R. Kees et al. “Homozygous Deletion of the p16/MTS1 Gene in Pediatric Acute Lymphoblastic Leukemia is Associated with Unfavorable Clinical Outcome,”
Blood,
89(11):4161-6 (1997)]. High expression of cyclin D1 has also been shown to predict early relapse in pediatric ALL. [U. R. Kees et al., “Deletions of the p16 Gene in Pediatric Leukemia and Corresponding Cell Lines,”
Oncogene,
12(10):2235-9 (1996).] High expression of cdk1 predicts disease recurrence in prostate adenocarcinoma. [B. V. Kallakury et al., “The Prognostic Significance of p34
cdc2
and Cyclin D1 Protein Expression in Prostate Adenocarcinoma,” Cancer, 80(4):753-63 (1997). Loss of p21 expression resulted in a significantly higher risk of recurrence following surgery for gastric carcinoma. M. Ogawa et al., “Loss of p21
WAF1/CIP1
Expression Correlates with Disease Progression in Gastric Carcinoma,”
Br. J Cancer,
75(11):1617-20 (1997).] Higher p27 expression has correlated with longer survival times in breast [e.g., C. Catzavelos et al., “Decreased Levels of the Cell-Cycle Inhibitor of p27
KIP1
Protein: Prognostic Implications in Primary Breast Cancer,”
Nat. Med.,
3(2):227-30 (1997)], and non-small cell lung cancer [V. Esposito, “Prognostic Role of the Cyclin-Dependent Kinase Inhibitor p27 in Non-Small Lung Cancer,”
Cancer Res.,
57(16):3381-5 (1997)].
Atherosclerosis is another disease associated with excessive cellular proliferation. An important signal for proliferation of vascular smooth muscle cells is increased expression of cdk2 and associated regulatory subunits, cyclin E and cyclin A. [E.g., C. Ihling, et al., “Topographical Association Between the Cyclin-Dependent Kinases Inhibitor P21, p53 Accumulation, and Cellular Proliferation in Human Atherosclerotic Tissue,”
Arterioscler. Thromb. Vasc. Biol.,
17(10):2218-24 (1997).] This is consistent with the observation that high levels of homocysteine, known to cause occlusive arterial disease, causes increases in aortic cdk activity. [B. Lubec et al., “Homocysteine Increases Cyclin-dependent Kinase in Aortic Rat Tissue,”
Circulation,
94(10):2620-5 (1996).] The involvement of cdk2 also is consistent with the report that an antisense cdk2 oligonucleotide can prevent graft coronary arteriosclerosis. [J. Suzuki et al., “Prevention of Graft Coronary Arteriosclerosis by Antisense cdk2 Kinase
Oligonucleotide,” Nat. Med.,
3(8):900-3 (1997).]
Other diseases in which there is evidence that inhibitors of cdks may be of therapeutic use include mesangial proliferative glomerulonephritis [J. W. Pippin et al., “Direct in vivo Inhibition of the Nuclear Cell Cycle Cascade in Experimental Mesangial Proliferative Glomerulonephritis with Roscovitine, a Novel Cyclin-Dependent Kinase Antagonist,”
J. Clin. Invest.,
1900(9):2512-20 (1997)], infection with human cytomegalo-virus [W. A. Bresnahan et al., “Inhibition of Cellular cdk2 Activity Blocks Human Cytomegalovirus Replication,”
Virology,
231(2):239-47 (1997)], and malaria [R. Graeser et al., “Plasmodium Falciparum Protein Kinase 5 and the Malarial Nuclear Division Cycles,”
Mol. Biochem. Parasitol,
82(1):37-49 (1996)]. Abnormal phosphorylation of tau protein is a characteristic of Alzheimer's disease. Recent reports have shown that this phosphorylation is carried out, at least in part, by brain cdk5 [e.g., A. Sengupta et al., “Potentiation of GSK-3-Catalyzed Alzheimer-like Phosphorylation of Human tau by cdk5,”
Mol Cell. Biochem.,
167(1-2):99-105 (1997)]. Inhibitors of cdk5 should be useful in the treatment of the disease.
The potential role of cdk inhibitors in therapy of numerous diseases has led to efforts to find small molecules that inhibit all or some of the cdks. Several small molecules have been discovered that inhibit cdks specifically. These include the purine analogs, olomoucine, roscovitine, and CVT-313; the flavonoid, flavopiridol; and butyrolactone I. Other potent inhibitors of cdks are known, including staurosporine, UCN-01, and suramin, but these compounds also are potent inhibitors of other protein kinases. Crystal structures for several specific cdk inhibitors in complex with cdk2 have been determined, including olomoucine, roscovitine, and flavopiridol. One specific inhibitor of cdks has reached clinical trials, flavopiridol [H. H. Sadlacek et al., “Flavopiridol (186-8275, NSC-649890), a New Kinase Inhibitor for Tumor Therapy,”
International Journal of Oncology,
9:1143 (1996)], which has shown antitumor activity in Phase I trials in a number of tumor types and is progressing to Phase II trials. All other known cdk inhibitors have been shown to inhibit the growth of tumor cells in culture, although none are as potent as flavopiridol. No in vivo anti-tumor studies have been reported for these compounds, although there is an anecdotal report of a response to olomoucine in a spontaneous dog melanoma.
Several cdk inhibitors have shown activity in models for other di

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