Oxindole derivatives

Details Oxindole derivatives Oxindole derivatives

2003-02-27

2004-04-13

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S232800, C514S253030, C546S084000, C544S165000, C544S361000

Reexamination Certificate

active

06720332

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to oxindole derivatives, methods for the preparation of such oxindoles, and use of such oxindoles in the treatment of certain diseases or conditions. In particular, the present invention relates to oxindole derivatives useful as cyclin dependent kinase inhibitors and use of the oxindoles in the treatment of disorders mediated by inappropriate cyclin dependent kinase activity.
Protein kinases catalyze the phosphorylation of various residues in proteins including proteins involved in the regulation of cell growth and differentiation. Cell growth, differentiation, metabolism and function are extremely tightly controlled in higher eukaryotes. The ability of a cell to rapidly and appropriately respond to the array of external and internal signals it continually receives is of critical importance in maintaining a balance between these processes (Rozengurt, Current Opinion in Cell Biology 1992, 4, 161-5; Wilks, Progress in Growth Factor Research 1990, 2, 97-111). The loss of control over cellular regulation can often lead to aberrant cell function or death, often resulting in a disease state in the parent organism. Protein kinases play a critical role in the control of cell growth and differentiation and are key mediators of cellular signals leading to the production of growth factors and cytokines. See, for example, Schlessinger and Ullrich,
Neuron
1992, 9, 383. Examples of such kinases include abl, ATK, bcr-abl, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, GSK, Hck, IGF-1R, INS-R, Jak, JNK, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, tie1, tie2, TRK, UL97, VEGF-R1, VEGF-R2, Yes and Zap70.
Inappropriate protein kinase activity has been associated with a wide variety of disease states and accordingly such kinases have been identified as targets in the treatment of the same. For instance, protein kinases have been implicated as targets in central nervous system disorders such as Alzheimer's (Mandelkow, E. M. et al.
FEBS Lett.
1992, 314, 315. Sengupta, A. et al.
Mol. Cell. Biochem.
1997, 167,99), pain sensation (Yashlpal, K.
J. Neurosci.
1995, 15, 3263-72), inflammatory disorders such as arthritis (Badger,
J. Pharm. Exp. Ther.
1996, 279, 1453), psoriasis (Dvir, et al,
J. Cell Biol.
1991, 113, 857), bone diseases such as osteoporosis (Tanaka et al,
Nature,
1996, 383, 528), cancer (Hunter and Pines,
Cell
1994, 79, 573), atherosclerosis (Hajjar and Pomerantz,
FASEB J.
1992, 6, 2933), thrombosis (Salari,
FEBS
1990, 263, 104), metabolic disorders such as diabetes (Borthwick, A. C. et al.
Biochem. Biophys. Res. Commun.
1995, 210, 738), blood vessel proliferative disorders such as angiogenesis (Strawn et al
Cancer Res.
1996, 56, 3540; Jackson et al
J. Pharm. Exp. Ther.
1998, 284, 687), restenosis (Buchdunger et al,
Proc, Nat. Acad. Sci USA
1991, 92, 2258), autoimimune diseases and transplant rejection (Bolen and Brugge,
Ann. Rev. Immunol.
1997, 15, 371) and infectious diseases such as viral (Littler, E.
Nature
1992, 358, 160), and fungal infections (Lum, R. T. PCT Int. Appl., WO 9805335 A1 980212).
The signals mediated by protein kinases have also been shown to control growth, death and differentiation in the cell by regulating the processes of the cell cycle (Massague and Roberts, Current Opinion in Cell Biology 1995, 7, 769-72). Progression through the eukaryotic cell cycle is controlled by a family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins (Myerson, et al., EMBO Journal 1992, 11, 2909-17). The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle (Pines, Trends in Biochemical Sciences 1993, 18, 195-7; Sherr, Cell 1993, 73, 1059-65). Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/CDK activities. In G1, both cyclin D/CDK4 and cyclin E/CDK2 are thought to mediate the onset of S-phase. Controlled progression through the G1 phase of the cell cycle is dependent on the activation of CDK4 by cyclin D. This activation results in the phosphorylation of the retinoblastoma protein (pRb) which then dissociates from its binding partner, E2F. The release of E2F from the inactive pRb-E2F complex allows E2F to regulate the transcription of multiple genes required for DNA synthesis. Under normal physiological conditions the pRb pathway is tightly regulated by proteins (p16
INK4A
, p27, p21) that block the catalytic activity of the CDK4/cyclin D complex. Human genetic evidence supports this p16
INK4A
/CDK4/cyclin D/pRb signal as a tumor suppressor pathway that is frequently de-regulated in many human cancers.
Many mechanisms of de-regulation of pRb have been described. These include gene deletion of the p16
INK4A
locus and down regulation of p16
INK4A
gene expression. The p16
INK4A
protein is a naturally occurring intracellular CDK4 inhibitor that functions as a tumor suppressor gene. An additional mechanism of de-regulation of this pathway is overexpression of cyclin D1, the activation subunit of CDK4. The proposed net effect is an increase in CDK4 activity and hyperphosphorylated pRb.
A method of inhibiting CDK4 activity in a mammal suffering from a susceptible tumor would restore pRb to an active tumor suppressor state. The consequences of restoring pRb function would be to cause cell cycle arrest of normal cells while tumor cells in the mammal would undergo apoptosis. Hypophosphorylated pRb protein positively regulates the apoptotic function of p53 via an interaction with mdm2 (J.-K. Hsieh et al. Molecular Cell 3, 181 1999). Hypophosphorylated pRb prevents mdm2-mediated degradation of p53, resulting in activation of p53 and apoptosis of tumor cells.
A method of inhibiting CDK4 activity would therefore presumably serve to selectively kill human tumors, with wild type Rb status, in which the p161
INK4A
/CDK4/cyclin D/pRb is de-regulated. Administration of an agent capable of selectively inhibiting the activity of CDK4 should provide a treatment of Rb positive human cancers with loss of p16
INK4A
expression and/or overexpression of cyclin D1 protein and therefore block tumor cell survival.
Antisense constructs to cyclin D1 sensitizes human tumor cells to chemotherapy, suggesting CDK4 activity is needed for tumor cell survival in response to DNA damage. (Korman et al. Cancer Research. 59, 3505 1999). In addition, overexpression of p16
INK4A
protein sensitizes tumor cells to radiation (X. Y. Fu et al. J Cancer Res Clin Oncol 124, 621 1998).
There is a continuing need in the oncology field for new and more effective treatments for cancer. Because CDK4 may serve as a general activator of cell division and suppress apoptosis of tumor cells, specific inhibitors of CDK4 may provide an effective treatment for cancer and other hyperproliferative disorders. At present, there is an unmet need for small molecule compounds that may be readily synthesized and are potent inhibitors of CDK4/cyclin complexes. The present inventors have now discovered novel oxindole derivative compounds that selectively inhibit the catalytic activity of CDK4/cyclin D and/or CDK2/cyclin E thereby providing new treatment strategies for those afflicted with cancer and other disorders mediated by inappropriate cyclin dependent kinase activity.
SUMMARY OF THE INVENTION
In one aspect of the present invention, there is provided a compound of
Formula I
or a salt, solvate, or physiologically functional derivative thereof:
wherein:
R
1
is —(CR
4
R
5
)
n
NR
2
R
3
;
n is 1 or 2;
R
2
and R
3
are independently hydrogen, C
1-6
alkyl, C
1-6
alkenyl, C
1-6
alkoxy-C
1-6
alkyl, cycloalkyl, heterocyclyl, benzyl, phenyl, napthyl, heteroaryl, heteroaryl-C
1-6
alkyl, or R
2
and R
3
together with the nitrogen to which they are bound form a 5 or 6 membered heterocyclic or a 5 to 7 membered heteroaryl ring bo

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