Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-28
2003-09-23
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S229200, C514S299000, C514S366000, C514S411000, C514S418000, C514S426000, C546S079000, C546S083000, C546S113000, C546S151000, C548S427000, C548S430000, C548S431000, C548S452000, C548S465000, C548S486000, C548S490000, C544S098000, C544S111000, C544S359000, C544S368000, C544S336000, C544S242000, C544S301000, C544S179000, C544S180000, C544S059000, C544S061000
Reexamination Certificate
active
06624171
ABSTRACT:
The present invention provides novel compounds, novel compositions and methods for their use and manufacture. The compounds and compositions of the present invention are generally useful pharmacologically as therapeutic agents in disease states alleviated by the inhibition or antagonism of protein kinase activated signalling pathways in general, and in particular in the pathological processes which involve aberrant cellular proliferation, such disease states including tumor growth, restenosis, atherosclerosis, and thrombosis. In particular, the present invention relates to a series of substituted aza-oxindole compounds, which exhibit protein tyrosine kinase and protein serine/threonine kinase inhibition, and which are useful for the prevention of chemotherapy-induced alopecia.
BACKGROUND OF THE INVENTION
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. A partial, non-limiting, list of such kinases includes abl, ARaf, ATK, ATM, bcr-abl, BIk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, cfms, c-fms, c-kit, c-met, cRaf1, CSF1R, CSK, c-src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, IGF-1R, IKK, IKK1, IKK2, IKK3, INS-R, Integrin-linkedkinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKC&agr;, PKC&bgr;, PKC&dgr;, PKC&egr;, PKC&ggr;, PKC&lgr;, PKC&mgr;, PKC&zgr;, PLK1, Polo-like kinase, PYK2, tie
1
, tie
2
, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70. 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 (Yashpal, 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), autoimmune 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 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 kinases called cyclin dependent kinases (CDKs) (Myerson, et al., EMBO Journal 1992, 11, 2909). 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; Sherr, Cell 1993, 73, 1059). 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 (Matsushime, et al., Molecular & Cellular Biology 1994, 14, 2066; Ohtsubo and Roberts, Science 1993, 259, 1908; Quelle, et al., Genes & Development 1993, 7, 1559; Resnitzky, et al., Molecular & Cellular Biology 1994, 14, 1669). Progression through S-phase requires the activity of cyclin A/CDK2 (Girard, et al., Cell 1991, 67, 1169; Pagano, et al., EMBO Journal 1992, 11, 961; Rosenblatt, et al., Proceedings of the National Academy of Science USA 1992, 89, 2824; Walker and Maller, Nature 1991, 354, 314; Zindy, et al., Biochemical & Biophysical Research Communications 1992, 182, 1144) whereas the activation of cyclin A/cdc2 (CDK1) and cyclin B/cdc2 are required for the onset of metaphase (Draetta, Trends in Cell Biology 1993, 3, 287; Murray and Kirschner, Nature 1989, 339, 275; Solomon, et al., Molecular Biology of the Cell. 1992, 3, 13; Girard, et al., Cell 1991, 67, 1169; Pagano, et al., EMBO Joumal 1992, 11, 961; Rosenblatt, et al., Proceedings of the National Academy of Science USA 1992, 89, 2824; Walker and Maller, Nature 1991, 354, 314; Zindy, et al., Biochemical & Biophysical Research Communications 1992, 182, 1144). It is not surprising, therefore, that the loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer (Pines, Current Opinion in Cell Biology 1992, 4, 144; Lees, Current Opinion in Cell Biology 1995, 7, 773; Hunter and Pines, Cell 1994, 79, 573). The selective inhibition of CDKs is therefore an object of the present invention.
SUMMARY OF THE INVENTION
In brief summary, the invention comprises compounds of the formula (I):
wherein X is selected from the group consisting of: N, CH, CCF
3
, and C(C
1-12
aliphatic);
Y is C or N, with the proviso that when Y is N, R
1
is absent, and Z, A and D are each C;
Z is C or N, with the proviso that when Z is N, R
2
is absent, and Y, A and D are each C;
A is C or N, with the proviso that when A is N, R
3
is absent, and Y, Z and D are each C;
D is C or N, with the proviso that when D is N, then Y, Z and A are each C; with the further proviso that Y, Z, A and D do not simultaneously all represent C;
R
1
is selected from the group consisting of: hydrogen, C
1-12
aliphatic, thiol, hydroxy, hydroxy-C
1-12
aliphatic, Aryl, Aryl-C
1-12
aliphatic, R
6
-Aryl-C
1-12
aliphatic, Cyc, Cyc-C
1-6
aliphatic, Het, Het-C
1-12
aliphatic, C
1-12
alkoxy, Aryloxy, amino, C
1-12
aliphatic amino, di-C
1-12
aliphatic amino, di-C
1-12
aliphatic aminocarbonyl, di-C
1-12
aliphatic aminosulfonyl, C
1-12
alkoxycarbonyl, halogen, cyano, sulfonamide and nitro, where R
6
, Aryl, Cyc and Het are as defined below;
R
2
is selected from the group consisting of: hydrogen, C
1-12
aliphatic, N-hydroxyimino-C
1-12
aliphatic, C
1-12
alkoxy, hydroxy-C
1-12
aliphatic, C
1-12
alkoxycarbonyl, carboxyl C
1-12
aliphatic, Aryl, R
6
-Aryl-oxycarbonyl, R
6
-oxycarbonyl-Aryl, Het, aminocarbonyl, C
1-12
aliphatic-aminocarbonyl, Aryl-C
1-12
aliphatic-aminocarbonyl, R
6
-Aryl-C
1-12
aliphatic-aminocarbonyl, Het-C
1-12
aliphatic-aminocarbonyl, hydroxy-C
1-12
aliphatic-aminocarbonyl, C
1-12
-alkoxy-C
1-12
aliphatic-aminocarbonyl, C
1-12
alkoxy-C
1-12
aliphatic-amino, di-C
1-12
aliphatic amino, di-C
1-12
aliphatic aminocarbonyl, di-C
1-12
aliphatic aminosulfonyl, halogen, hydroxy, nitro, C
1-12
aliphatic-sulfonyl, aminosulfonyl and C
1-12
aliphatic-aminosulfonyl, where R
6
Aryl and Het are as defined below;
R
1
and R
2
are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by one or more substituents selected from the group consisting of: C
1-12
aliphatic, halogen, nitro, cyano, C
1-12
alkoxy, carbonyl-C
1-12
alkoxy and oxo;
R
3
is selected from the group consisting of: hydrogen, C
1-12
aliphatic, hydroxy, hydroxy C
1-12
aliphatic, di-C
1-12
aliphatic amino, di-C
1-12
aliphatic aminocarbonyl, di-C
1-12
aliphatic aminosulfonyl, C
1-12
alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy and halogen, where Aryl and Het are as defined below;
R
2
and R
3
are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by C
1-6
aliphatic and/or C
1-6
alipha
Harris Philip Anthony
Kuyper Lee Frederick
Lackey Karen Elizabeth
Veal James Marvin
Ford John M.
Lemanowicz John L.
Patel Sudhaker B.
SmithKline Beecham Corporation
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