Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-16
2002-10-08
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S364000, C514S385000, C514S359000, C548S127000, C548S257000, C548S259000, C548S260000, C548S301700
Reexamination Certificate
active
06462060
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to compounds with heterocyclic-hydroxyimino-fluorene nuclei that mediate and/or inhibit the activity of certain protein kinases, 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
Protein kinases are a family of enzymes that catalyze phosphorylation of the hydroxyl group of specific tyrosine, serine, or threonine residues in proteins. Typically, such phosphorylation dramatically alters the function of the protein, and thus protein kinases are pivotal in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell differentiation, and cell survival. Of the many different cellular functions in which the activity of protein kinases is known to be required, some processes represent attractive targets for therapeutic intervention for certain disease states. Two examples are cell-cycle control and angiogenesis, in which protein kinases play a pivotal role; these processes are essential for the growth of solid tumors as well as for other diseases.
Uncontrolled cell proliferation is the insignia of cancer. Cell proliferation in response to various stimuli is manifested by a de-regulation 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.
Cyclin-dependent kinases (CDKs) are serine-threonine protein kinases 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 occurs. See, e.g., the articles compiled in
Science,
274, 1643-1677 (1996); and
Ann. Rev. Cell Dev. Biol.,
13, 261-291 (1997). 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 phases of the cell-cycle.
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.,
29, 91-107 (1997). Aberrations in this control system, particularly those that affect the function of CDK4 and CDK2, have been implicated in the advancement of cells to the highly proliferative state characteristic of malignancies, particularly familial melanomas, esophageal carcinomas, and pancreatic cancers. See, e.g., Hall et al.,
Adv. Cancer Res.,
68, 67-108 (1996); Kamb,
Trends in Genetics,
11, 136-140 (1995); Kamb et al.,
Science,
264, 436-440 (1994).
Over-expression of cyclin D1 is linked to esophageal, breast, and squamous cell carcinomas (see, e.g., DelSal et al.,
Critical Rev. Oncogenesis,
71, 127-142 (1996)). 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,
368, 753-756 (1994)). 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,
3, 231-234 (1997)). Recently there is evidence that CDK4/cyclin D might sequester p27, as reviewed in Sherr et al.,
Genes Dev.,
13, 1501-1512 (1999). The p21 proteins also appear to transmit the p53 tumor-suppression signal to the CDKs (see El-Deiry et al.,
Cell,
75, 817-825 (1993)); thus, the mutation of p53 in approximately 50% of all human cancers may indirectly result in deregulation of CDK activity.
The use of compounds as anti-proliferative therapeutic agents that inhibit protein kinase activity is the subject of several patents and publications. For example, WIPO International Publication No. WO 97/45397 discloses certain alkyloxyamino-substituted fluorenones that control protein kinase C activity (e.g., CDC2 kinase activity) in mammals. WIPO International Publication No. WO 99/21845 discloses 4-aminothiazoles as CDK inhibitors. Isothiazole derivatives useful as anticancer agents are disclosed in WIPO International Publication No. WO 99/62890. U.S. Pat. No. 5,621,082 to Xiong et al. discloses nucleic acid derivatives that encode inhibitors of CDK6. Peptides and peptidomimetic inhibitors, including substrate site antagonists, are described in European Patent Publication No. 0 666 270 A2, Bandara et al.,
Nature Biotechnology,
15, 896-901 (1997), and Chen et al.,
Proc. Natl. Acad. Sci., USA,
96, 4325-4329 (1999). Peptide aptamers are identified in Cohen et al.,
Proc. Natl. Acad. Sci., U.S A.,
95, 14272-14277 (1998). Other small molecules have been identified as CDK inhibitors (for recent reviews, see Webster,
Exp. Opin. Invest. Drugs,
7, 865-887 (1998), Stover et al.,
Current Opinion in Drug Discovery and Development,
2, 274-285 (1999), and Rosania et al.,
Exp. Opin. Ther. Patents,
10, 215-230 (2000)). 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 (Stadler et al.,
J. Clin. Oncol.,
18, 371-375 (2000) and Sedlacek et al.,
Int. J. Oncol.,
9, 1143-1168 (1996)). Analogs of flavopiridol are the subject of other publications, for example, U.S. Pat. No. 5,733,920 to Mansuri et al. (WIPO International Publication No. WO 97/16447) and WIPO 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.,
7, 2697-2702 (1997); Grant et al.,
Proc. Amer. Assoc. Cancer Res,.
39, Abst. 1207 (1998); Legraverend et al.,
Bioorg. Med. Chem. Lett.,
8, 793-798 (1998); Legraverend et al.,
J. Med. Chem.,
43, 1282-1292 (2000); Gray et al.,
Science,
281, 533-538 (1998); Chang et al.,
Chemistry
&
Biology,
6, 361-375 (1999); and WIPO 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: WIPO International Publication Nos. WO 00/12485, WO 00/12486, and WO 98/33798; Ruetz et al.,
Proc. Amer. Assoc. Cancer Res.,
39, Abst. 3796 (1998); and Meyer et al.,
Proc. Amer. Assoc. Cancer Res.,
39, Abst. 3794 (1998). Benzensulfonamides that block cells in G1 are in development by Eisai, see Owa et al.,
J. Med. Chem.
Chong Wesley Kwon Mung
Duvadie Rohit Kumar
Agouron Pharmaceuticals , Inc.
Anderson Rebecca
McKane Joseph K.
Shanks & Herbert
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