Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-10-27
2003-05-27
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S218000, C514S255030, C514S326000, C544S360000, C544S367000, C546S208000, C546S209000, C548S191000, C548S194000, C540S575000
Reexamination Certificate
active
06569878
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to pharmaceutical compositions containing aminothiazole compounds for inhibiting cyclin-dependent kinases (CDKs), such as CDK1, CDK2, CDK4, and CDK6. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds and to methods of treating malignancies and other disorders by administering effective amounts of such compounds.
BACKGROUND OF THE INVENTION
Uncontrolled cell proliferation is the insignia of cancer. Cell proliferation in response to various stimuli is manifested by a deregulation of the cell division cycle, the process by which cells multiply and divide. Tumor cells typically have damage to the genes that directly or indirectly regulate progression through the cell division cycle.
CDKs constitute a class of enzymes that play critical roles in regulating the transitions between different phases of the cell cycle, such as the progression from a quiescent stage in G
1
(the gap between mitosis and the onset of DNA replication for a new round of cell division) to S (the period of active DNA synthesis), or the progression from G
2
to M phase, in which active mitosis and cell-division occur. See, e.g., the articles compiled in
Science
, vol. 274 (1996), pp. 1643-1677; and
Ann. Rev. Cell Dev. Biol
., vol. 13 (1997), pp. 261-291. CDK complexes are formed through association of a regulatory cyclin subunit (e.g., cyclin A, B1, B2, D1, D2, D3, and E) and a catalytic kinase subunit (e.g., cdc2 (CDK1), CDK2, CDK4, CDK5, and CDK6). As the name implies, the CDKs display an absolute dependence on the cyclin subunit in order to phosphorylate their target substrates, and different kinase/cyclin pairs function to regulate progression through specific portions of the cell cycle.
The D cyclins are sensitive to extracellular growth signals and become activated in response to mitogens during the G
1
phase of the cell cycle. CDK4/cyclin D plays an important role in cell cycle progression by phosphorylating, and thereby inactivating, the retinoblastoma protein (Rb). Hypophosphorylated Rb binds to a family of transcriptional regulators, but upon hyperphosphorylation of Rb by CDK4/cyclin D, these transcription factors are released to activate genes whose products are responsible for S phase progression. Rb phosphorylation and inactivation by CDK4/cyclin D permit passage of the cell beyond the restriction point of the G
1
phase, whereupon sensitivity to extracellular growth or inhibitory signals is lost and the cell is committed to cell division. During late G
1
, Rb is also phosphorylated and inactivated by CDK2/cyclin E, and recent evidence indicates that CDK2/cyclin E can also regulate progression into S phase through a parallel pathway that is independent of Rb phosphorylation (see Lukas et al., “Cyclin E-induced S Phase Without Activation of the pRb/E2F Pathway,”
Genes and Dev
., vol. 11 (1997), pp. 1479-1492).
The progression from G
1
to S phase, accomplished by the action of CDK4/cyclin D and CDK2/cyclin E, is subject to a variety of growth regulatory mechanisms, both negative and positive. Growth stimuli, such as mitogens, cause increased synthesis of cyclin D1 and thus increased functional CDK4. By contrast, cell growth can be “reined in,” in response to DNA damage or negative growth stimuli, by the induction of endogenous inhibitory proteins. These naturally occurring protein inhibitors include p21
WAF1/CIP1
, p27
KIP1
, and the p16
INK4
family, the latter of which inhibit CDK4 exclusively (see Harper, “Cyclin Dependent Kinase Inhibitors,”
Cancer Surv
., vol. 29 (1997), pp. 91-107). Aberrations in this control system, particularly those that affect the function of CDK4 and CDK2, are implicated in the advancement of cells to the highly proliferative state characteristic of malignancies, such as familial melanomas, esophageal carcinomas, and pancreatic cancers (see, e.g., Hall and Peters, “Genetic Alterations of Cyclins, Cyclin-Dependent Kinases, and CDK Inhibitors in Human Cancer,”
Adv. Cancer Res
., vol. 68 (1996), pp. 67-108; and Kamb et al., “A Cell Cycle Regulator Potentially Involved in Genesis of Many Tumor Types,”
Science
, vol. 264 (1994), pp. 436-440). Over-expression of cyclin D1 is linked to esophageal, breast, and squamous cell carcinomas (see, e.g., DelSal et al., “Cell Cycle and Cancer: Critical Events at the G
1
Restriction Point,”
Critical Rev. Oncogenesis
, vol. 71 (1996), pp. 127-142). Genes encoding the CDK4-specific inhibitors of the p16 family frequently have deletions and mutations in familial melanoma, gliomas, leukemias, sarcomas, and pancreatic, non-small cell lung, and head and neck carcinomas (see Nobori et al., “Deletions of the Cyclin-Dependent Kinase-4 Inhibitor Gene in Multiple Human Cancers,”
Nature
, vol. 368 (1994), pp. 753-756). Amplification and/or overexpression of cyclin E has also been observed in a wide variety of solid tumors, and elevated cyclin E levels have been correlated with poor prognosis. In addition, the cellular levels of the CDK inhibitor p27, which acts as both a substrate and inhibitor of CDK2/cyclin E, are abnormally low in breast, colon, and prostate cancers, and the expression levels of p27 are inversely correlated with the stage of disease (see Loda et al., “Increased Proteasome-dependent Degradation of the Cyclin-Dependent Kinase Inhibitor p27 in Aggressive Colorectal Carcinomas,”
Nature Medicine
, vol. 3 (1997), pp. 231-234). The p21 proteins also appear to transmit the p53 tumor-suppression signal to the CDKs; thus, the mutation of p53 in approximately 50% of all human cancers may indirectly result in deregulation of CDK activity.
The emerging data provide strong validation for the use of compounds inhibiting CDKs, and CDK4 and CDK2 in particular, as anti-proliferative therapeutic agents. Certain biomolecules have been proposed for this purpose. For example, U.S. Pat. No. 5,621,082 to Xiong et al. discloses nucleic acid encoding an inhibitor of CDK6, and European Patent Publication No. 0 666 270 A2 describes peptides and peptide mimetics that act as inhibitors of CDK1 and CDK2. Several small molecules have been identified as CDK inhibitors (for a recent review, see Webster, “The Therapeutic Potential of Targeting the Cell Cycle,”
Exp. Opin. Invest, Drugs
, vol. 7 (1998), pp. 865-887). The flavone flavopiridol displays modest selectivity for inhibition of CDKs over other kinases, but inhibits CDK4, CDK2, and CDK1 equipotently, with IC
50
s in the 0.1-0.3 &mgr;M range. Flavopiridol is currently in Phase II clinical trials as an oncology chemotherapeutic (Sedlacek et al., “Flavopiridol (L86-8275; NSC 649890), A New Kinase Inhibitor for Tumor Therapy,”
Int. J. Oncol
., vol. 9 (1996), pp. 1143-1168). Analogs of flavopiridol are the subject of other publications, for example, U.S. Pat. No. 5,733,920 to Mansuri et al. (International Publication No. WO 97/16447) and International Publication Nos. WO 97/42949, and WO 98/17662. Results with purine-based derivatives are described in Schow et al.,
Bioorg. Med. Chem. Lett
., vol. 7 (1997), pp. 2697-2702; Grant et al.,
Proc. Amer. Assoc. Cancer Res
,. vol. 39 (1998), Abst. 1207; Legravend et al.,
Bioorg. Med. Chem. Lett
., vol. 8 (1998), pp. 793-798; Gray et al.,
Science
, vol. 281 (1998), pp. 533-538; and Furet et al., 216
th ACS Natl. Mtg
. (Aug. 23-27, 1998, Boston), Abst MEDI-218. In addition, the following publications disclose certain pyrimidines that inhibit cyclin-dependent kinases and growth-factor mediated kinases: International Publication No. WO 98/33798; Ruetz et al.,
Proc. Amer. Assoc. Cancer Res
,. vol. 39 (1998), Abst. 3796; and Meyer et al.,
Proc. Amer. Assoc. Cancer Res
., vol. 39 (1998), Abst. 3794.
There is still a need, however, for small-molecule compounds that may be readily synthesized and are potent inhibitors of one or more CDKs or CDK/cyclin complexes. Because CDK4 may serve as a general activator of cell division in most cells, and because complexes of CDK4/cyclin D and CDK2/cyclin E govern the early G
1
phase of the cell cy
Chong Wesley K. M.
Chu Shao Song
Duvadie Rohit K.
Li Lin
Xiao Wei
Agouron Pharmaceuticals , Inc.
Hsu Wendy Lei
Raymond Richard L.
Reidy Joseph F.
Troung Tamthom N.
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