Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-08
2003-05-20
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S367000, C544S367000, C544S368000, C548S153000
Reexamination Certificate
active
06566363
ABSTRACT:
TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION
This invention is directed to 5-amino-3-substituted-pyrazolo[4,5-d]thiazole compounds that mediate and/or inhibit the activity of cyclin-dependent kinases (CDKs), such as CDK1, CDK2, CDK4, and CDK6, and to pharmaceutical compositions containing such compounds. The invention is also directed to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, 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 playing 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.,
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 down regulated 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,
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,
Adv. Cancer Res.,
vol. 68 (1996), pp. 67-108; and Kamb et al.,
Science,
vol. 264 (1994), pp. 436-440). Over-expression of cyclin D1 is linked to esophageal, breast, and squamous cell carcinomas (see, e.g., Del Sal et al.,
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.,
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.,
Nature Medicine,
vol. 3 (1997), pp. 231-234). Recently there is evidence that CDK4/cyclin D might sequester p27, as reviewed in Sherr et al.,
Genes Dev.,
vol. 13 (1999), pp. 1501-1512. The p21 proteins also appear to transmit the p53 tumor-suppression signal to the CDKs; thus, the mutation of p53 in approximately half of all human cancers may indirectly result in deregulation of CDK activity.
Inhibitors of CDKs, and CDK4 and CDK2 in particular, are useful 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 which encode for inhibitors of CDK6, and International Publication No. WO 99/06540 discloses inhibitors for CDKs as well. Peptides and peptidomimetic inhibitors are also described in: European Patent Publication No. 0 666 270 A2; Bandara et al.,
Nature Biotech.,
vol. 15 (1997), pp. 896-901; and Chen et al.,
Proc. Natl. Acad. Sci. USA,
vol. 96 (1999), pp. 4325-4329. Peptide aptamers are identified in Cohen et al.,
Proc. Natl. Acad. Sci. USA,
vol. 95 (1998), pp. 14272-14277, and several small molecules have been recently identified as CDK inhibitors (for recent reviews, see Webster,
Exp. Opin. Invest. Drugs,
vol. 7 (1998), pp. 865-887, and Stover et al.,
Curr. Opin. in Drug Disc. and Devel.,
vol. 2 (1999), pp. 274-285).
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 clinical trials as an oncology chemotherapeutic (Sedlacek et al.,
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. (see also International Publication No. WO 97/16447) and International Publication Nos. WO 97/42949 and WO 98/17662. Results of inhibition of CDKs 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; Chang, et al.,
Chemistry
&
Biology,
vol. 6 (1999), pp. 361-375; and International Publication Nos. WO 99/02162, WO 99/43675, and WO 99/43676.
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. Certain benzensulfonamides that block cells in G1 are described in Owa et al.,
J. Med. Chem.,
vol. 42 (1999), pp. 3789-3799. An oxindole CDK inhibitor is described in Luzzio et al.,
Proc. Amer. Assoc. Cancer Res.
(1999), Abst. 4102, and International Publicati
Chong Wesley Kwan Mung
Duvadie Rohit Kumar
Agouron Pharmaceuticals , Inc.
Hsu Wendy Lei
Reidy Joseph
Stockton Laura L.
Zielinski Bryan C.
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