Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-05
2004-04-13
Rotman, Alan L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S191000, C548S194000
Reexamination Certificate
active
06720346
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds with {4-aminothiazol-2-ylamino}-benzamide nuclei that demonstrate anti-proliferative activity such as antitumor activity, to processes for preparing these compounds and to pharmaceutical compositions containing such compounds. The invention also relates to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating cancer, viral, microbial, and/or parasitic colonization/infection, as well as other disease states associated with unwanted cellular proliferation, by administering effective amounts of such compounds.
BACKGROUND OF THE INVENTION
Cell proliferation occurs in response to various stimuli and may stem from deregulation of the cell division cycle (or cell cycle), the process by which cells multiply and divide. Hyperproliferative disease states, including cancer, are characterized by cells rampantly winding through the cell cycle with uncontrolled vigor due to, for example, damage to the genes that directly or indirectly regulate progression through the cycle. Thus, agents that modulate the cell cycle, and thus hyperproliferation, could be used to treat various disease states associated with uncontrolled or unwanted cell proliferation. In addition to cancer chemotherapeutic agents, cell cycle inhibitors are also proposed as antiparasitics (see Gray et al.,
Curr. Med. Chem
., 6, 859-875 (1999)) and recently demonstrated as potential antivirals (see Schang et al.,
J. Virol
., 74, 2107-2120 (2000)). Moreover, the applicability of antiproliferative agents may be expanded to treating cardiovascular maladies such as arteriosclerosis or restenosis (see Braun-Dullaeus et al.,
Circulation
, 98, 82-89 (1998)), and states of inflammation, such as arthritis (see Taniguchi et al.,
Nature Med
., 5, 760-767(1999)) or psoriasis.
Mechanisms of cell proliferation are under active investigation at cellular and molecular levels. At the cellular level, deregulation of signaling pathways, loss of cell cycle controls, unbridled angiogenesis and stimulation of inflammatory pathways are under scrutiny, while at the molecular level, these processes are modulated by various proteins, among which protein kinases are prominent suspects. Overall abatement of proliferation may also result from programmed cell death, or apoptosis, which is also regulated via multiple pathways, some involving proteolytic enzyme proteins.
Among the candidate regulatory proteins, 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 perturbs the function of the protein, and thus protein kinases are pivotal in the regulation of a wide variety of cellular processes.
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., 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.
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)).
Because CDK4 may serve as a general activator of cell division in most cells and complexes of CDK4/cyclin D and CDK2/cyclin E govern the early G1 phase of the cell cycle, CDK4 or CDK2 inhibitors may be used as anti-proliferative agents. Also, the pivotal roles of cyclin E/CDK2 and cyclin B/CDK1 in the G1/S phase and G2/M transitions, respectively, offer additional targets for therapeutic intervention in suppressing deregulated cell cycle progression.
A large number of small molecule ATP-site antagonists have been identified as CDK inhibitors (see, Webster,
Exp. Opin. Invest. Drugs
, 7, 865-887 (1998); Stover et al.,
Curr. Opin. Drug Disc. Dev
., 2, 274-285(1999); Gray et al.,
Curr. Med. Chem
., 6, 859-875 (1999); Sielecki et al.,
J. Med. Chem
., 43, 1-18 (2000); Crews et al.,
Curr. Opin. Chem. Biol
., 4, 47-53 (2000); Buolamwini,
Curr. Pharm. Des
., 6, 379-392 (2000); and Rosania et al.,
Exp. Opin. Ther. Pat
., 10, 215-230 (2000)).
In addition to the protein kinases identified above, many other protein kinases have been considered to be therapeutic targets, and numerous publications disclose inhibitors of kinase activity, as reviewed in the following: McMahon et al.,
Curr. Opin. Drug Disc. Dev
., 1, 131-146 (1998); Strawn et al.,
Exp. Opin. Invest Drugs
, 7, 553-573 (1998); Adams et al.,
Curr. Opin. Drug Disc. Dev
., 2, 96-109 (1999); Stover et al.,
Curr. Opin. Drug Disc. Dev
., 2, 274-285 (1999); Toledo et al.,
Curr. Med Chem
., 6, 775-805 (1999); and Garcia-Echeverria et al.,
Med. Res. Rev
., 20, 28-57 (2000).
Among others, the following patent publications disclose thiazole compounds: International Publication No. WO 99/21845 discloses certain 2,4-diaminothiazoles as CDK inhibitors; International Publication No. WO 99/62890 discloses certain isothiazoles as anticancer agents; International Publication No. WO 98/04536 describes certain thiazoles as protein kinase C inhibitors; and European Publication No. EP 816362A(1998) discloses certain thiazoles useful as dopamine D4 receptor antagonists. Certain aminothiazoles are reported in International Publication No. WO 99/65844 and International Publication No. WO 99/24416, and certain aminobenzothiazoles are disclosed in International Publication No. WO 99/24035. International Publication No. WO 00/17175 describes certain other aminothiazoles as p38 mitogen-activated protein (MAP) kinase inhibitors, and International Publication No. WO 00/26202, International Publication No. WO 00/26203, and U.S. Pat. No. 6,114,365 describe certain aminothiazoles and certain ureidothiazoles as anti-tumor agents. International Publication No. WO 99/21845 discloses certain 4-aminothiazole derivatives containing unsubstituted nitrogen or primary benzamides.
There is still a need, however, for more potent inhibitors of protein kinases. Moreover, as is understood by those skilled in the art, it is desirable for kinase inhibitors to possess both high affinity for the target kinase as well as high selectivity versus other protein kinases.
SUMMARY OF THE INVENTION
An object of the invention is to discover potent anti-proliferative agents. Another object of the invention is to discover effective inhibitors of protein kinases.
These and other objects of the invention, which will become apparent from the following description, have been achieved through the discovery of 4-aminothiazole compounds with mono- or di-N-substituted benzamides. The invention also relates to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds (such compounds, prodrugs, metabolites and salts are collectively referred to as “agents”) which modulate and/or inhibit cell growth.
Thus, the inventive agents and pharmaceutical compositions containing such agents are useful in treating various dise
Alegria Larry Andrew
Bleckman Ted Michael
Chong Wesley Kwan Mung
Chu Shao Song
Duvadie Rohit K.
Agouron Pharmaceuticals , Inc.
Hsu Wendy Lei
Reidy Joseph F.
Rotman Alan L.
Shiao Rei Tsang
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