Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-21
2002-12-17
Rao, Deepak R. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S321000
Reexamination Certificate
active
06495558
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to inhibitors of kinases, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions. The inhibitors and compositions comprising them are useful for treating or modulating disease in which kinases may be involved, symptoms of such disease, or the effect of other physiological events mediated by kinases. The invention also provides for methods of making kinase inhibitor compounds and methods for treating diseases in which kinase activity is involved.
The protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes within the cell. (See, Hardie, G. and Hanks, S. (1995)
The Protein Kinase Facts Book, I and II
, Academic Press, San Diego, Calif.). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S. K., Hunter, T.,
FASEB J.,
9:576-596 (1995); Knighton et al.,
Science,
253:407-414 (1991); Hiles et al.,
Cell,
70:419-429 (1992); Kunz et al.,
Cell,
73:585-596 (1993); Garcia-Bustos et al.,
EMBO J.,
13:2352-2361 (1994)).
Since the structure of the catalytic subunit of cAMP-dependent protein kinase (cAPK) was elucidated, approximately two dozen additional kinase structures have been solved as either apo enzymes or binary and ternary complexes (with ATP, ATP analogs, metal ions, ADP, ATP competitive inhibitors in the absence or presence of peptide substrate or peptide inhibitors). These proteins share a structurally conserved catalytic domain comprising two lobes that can be further subdivided into twelve subdomains. The N-terminal portion forms the small lobe (including subdomains I-IV) whose architecture is composed of an antiparallel five-strand &bgr;-sheet and one &agr;-helix, while the lower C-terminal domain forms another lobe (including subdomains VIA-XI) containing mostly &agr;-helical architecture. Subdomain V spans the two lobes. The N-terminal domain is thought to participate in orienting the nucleotide (or other binding entity), while the C-terminal domain is thought to be responsible for binding peptide substrate and initiating phosphotransfer to the hydroxyl group of a serine, threonine, or tyrosine residue.
The N- and C-terminal domains are connected through a single peptide strand, to which the adenine moiety of ATP binds via an eleven membered hydrogen bond cycle, involving the N1 and the N6 amino group, and the backbone carbonyl and NH functions of two nonconsecutive residues. This linker acts as a hinge about which the domains can rotate with respect to each other without disruption of the secondary architecture of the kinase. Several torsion angle changes in the linker backbone allow this movement to occur. The ribose group of ATP is anchored to the enzyme via hydrogen bonds with residues within the ribose-binding pocket. The triphosphate group is held in position via various polar interactions with several variable residues form the glycine rich loop, the conserved DFG motive and the catalytic loop.
Protein kinases may be characterized by their regulation mechanisms. It must be noted, however, that an individual protein kinase may be regulated by more than one mechanism. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions.
Kinases regulate many different cell processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. The appropriate protein kinase functions in signaling pathways to activate or inactivate (either directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system, and angiogenesis.
Initial interest in protein kinases as pharmacological targets was stimulated by the findings that many viral oncogenes encode structurally modified cellular protein kinases with constitutive enzyme activity. These findings pointed to the potential involvement of proto-oncogene encoded protein kinases in human proliferative disorders. Subsequently, deregulated protein kinase activity, resulting from a variety of more subtle mechanisms, has been implicated in the pathophysiology of a number of important human disorders including cancer and immunologically related diseases. The development of selective protein kinase inhibitors that can block the disease pathologies and/or symptoms resulting from aberrant protein kinase activity has therefore generated much interest.
SUMMARY OF THE INVENTION
The invention relates to compounds of the formula:
wherein,
R
1
is H; CN; COOR
5
; C(O)NR
5
R
5
; halo; C1-C10 alkyl; C1-C10 alkenyl; C1-C10 alkyl substituted with 1-3 independent NR
5
R
5
, NR
5
R
6
, SR
5
or OR
5
; or C1-C10 alkenyl substituted with 1-3 independent NR
5
R
5
, NR
5
R
6
, SR
5
or OR
5
;
R
2
is NR
5
R
5
; SR
5
; OR
5
; R
8
; aryl; N(R
5
)—N═CH(R
8
); N(R
5
)—N═CH(aryl); NR
5
—NR
5
C(O)NR
5
R
5
; NR
5
—NR
5
R
15
; NR
5
—NR
5
R
6
; C1-C10 alkyl substituted with 1-3 independent aryl, R
8
, halo, CF
3
, SR
5
, OR
5
, OC(O)R
5
, NR
5
R
5
, NR
5
R
6
, COOR
5
, NO
2
, CN, C(O)R
5
, C(O)NR
5
R
5
, or S(O)
2
NR
5
R
5
; or C1-C10 alkenyl substituted with 1-3 independent aryl, R
8
, halo, CF
3
, SR
5
, OR
5
, OC(O)R
5
, NR
5
R
5
, NR
5
R
6
, COOR
5
, NO
2
, CN, C(O)R
5
, C(O)NR
5
R
5
, or S(O)
2
NR
5
R
5
;
R
3
is phenyl substituted with 1-3 independent R
4
; R
8
; COOR
5
; or C1-C10 alkyl substituted with 1-3 independent aryl, R
7
or R
8
;
X is O or S; and
the remaining groups are as defined herein.
The invention also relates to compositions comprising these compounds, methods of making these compounds, methods of inhibiting enzyme activity, particularly kinase activity, through use of these compounds, and methods of treating disease or disease symptoms in a mammal, particularly where modulation of enzyme activity, and more particularly kinase activity, can affect disease outcome.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides compounds useful in inhibiting kinase activity and inhibiting kinases or other polypeptides having sequences or subsequences homologous to kinase sequences or subsequences. In one embodiment, the inhibitory compound has the formula:
wherein,
R
1
is H; CN; COOR
5
; C(O)NR
5
R
5
; halo; C1-C10 alkyl; C1-C10 alkenyl; C1-C10 alkyl substituted with 1-3 independent NR
5
R
5
, NR
5
R
6
, SR
5
or OR
5
; or C1-C10 alkenyl substituted with 1-3 independent NR
5
R
5
, NR
5
R
6
, SR
5
or OR
5
;
R
2
is NR
5
R
5
; SR
5
; OR
5
; R
8
; aryl; N(R
5
)—N═CH(R
8
); N(R
5
)—N═CH(aryl); NR
5
—NR
5
C(O)NR
5
R
5
; NR
5
—NR
5
R
15
; NR
5
—NR
5
R
6
; C1-C10 alkyl substituted with 1-3 independent aryl, R
8
, halo, CF
3
, SR
5
, OR
5
, OC(O)R
5
, NR
5
R
5
, NR
5
R
6
, COOR
5
, NO
2
, CN, C(O)R
5
, C(O)NR
5
R
5
, or S(O)
2
Armistead David M.
Bemis Jean E.
Elbaum Daniel
Habgood Gregory J.
Novak Perry M.
Amgen Inc.
Rao Deepak R.
Ungemach Frank S.
Watt Stuart L.
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