Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-15
2001-04-24
Shah, Mukund J. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S343000, C544S345000
Reexamination Certificate
active
06221867
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to novel 4,5-pyrazinoxindoles which inhibit or modulate protein kinases, in particular JNK protein kinases. These compounds and their pharmaceutically acceptable salts, and prodrugs of said compounds, are useful as anti-inflammatory agents, particularly useful in the treatment of rheumatoid arthritis. The invention is also directed to pharmaceutical compositions containing such compounds, and to methods for the treatment and/or control of inflammation, particularly in the treatment or control of rheumatoid arthritis. This invention is further directed to intermediates useful in the preparation of the foregoing compounds.
BACKGROUND OF THE INVENTION
Protein kinases are a class of proteins that regulate a variety of cellular functions. This is accomplished by the phosphorylation of specific amino acids on protein substrates resulting in conformational alteration of the substrate protein. The conformational change modulates the activity of the substrate or its ability to interact with other binding partners. The enzyme activity of the protein kinase refers to the rate at which the kinase adds phosphate groups to a substrate. It can be measured, for example, by determining the amount of a substrate that is converted to a product as a function of time. Phosphorylation of a substrate occurs at the active-site of a protein kinase.
The JNK (Jun N-terminal kinase) protein kinases (also know as “stress-activated protein kinases” or “SAPK”) are members of the mitogen-activated protein (MAP) kinases. See, e.g., S. Gupta et al., EMBO J., vol. 15 no. 11 (1996) pp. 2760-2770; and Yang et al., Nature, vol. 289 (Oct 23, 1997) pp. 865-870. At least ten JNK isoforms are currently known. See, Gupta, id. As its name indicates, one of the substrates for JNK is c-Jun. JNK phosphorylates the NH
2
-terminal activation domain of c-Jun on Ser63 and Ser73, causing increased c-Jun transcriptional activity. See Gupta, id. In turn, c-Jun is an AP-1 transcription factor that mediates immediate-early gene expression. See, e.g., A. Minden et al., Biochimica et Biophysica Acta 1333 (1997) F85-F104; and A. Karin, Biochimica et Biophysica Acta, vol. 172 (1991) pp. 129-157.
The JNK protein kinase is markedly activated in response to treatment of cells with pro-inflammatory cytokines or exposure to environmental stress. JNK thus mediates the effect of extracellular stimuli on c-Jun. See Gupta, supra; and Minden, supra. Accordingly, JNK is a physiological regulator of AP-1 transcriptional activity. Thus, inhibition of JNK activity will inhibit AP-1-dependent transcription of inflammatory and immune mediators which are implicated in pathological proliferative conditions, for example inflammatory diseases and neuro-degenerative diseases, in particular, rheumatoid arthritis. See, eg. Swantek et al., Molecular and Cellular Biology, vol. 17 (1997) pp. 6274-6282; Maroney et al., J. Neuroscience, vol. 18 (Jan. 1, 1998) pp. 104-111; and Minden, supra, at F92.
The rat homologue of JNK is also called SAPK (stress-activated protein kinase). SAPK isoforms share significant (>90%) sequence identity with the corresponding JNK isoforms [compare Kyriakis et al., Nature, Vol. 369 (May 12, 1994) pp. 156-160 and Gupta et al., supra]. Both JNK and SAPK are capable of phosphorylation of the cJun substrate and thus have very similar enzyme activity. JNK and SAPK are part of a protein kinase cascade that is activated by various extracellular stimuli. See e.g. Minden supra; and Kyriakis et al., BioEssays Vol. 18 (1996) pp. 567-577. JNK and SAPK each can be activated by phosphorylation on specific threonine and tyrosine residues by dual specificity MAP kinase kinases such as MKK4, SEK-1, or MKK7. See Kyriakis et al., supra; and Tournier et al., Proceedings of the National Academy of Sciences USA Vol. 94 (July 1997), pp. 5 7337-7342). The dual specificity MAP kinase kinases can be activated by phosphorylation on serine and/or threonine residues by MAP kinase kinases such as MEKK-1. Thus, measurement of JNK or SAPK enzyme activity may be enhanced by activation by the upstream or preceding kinases. Moreover, measurement of SAPK inhibition is closely correlated with JNK inhibition.
Inhibitors of protein kinase catalytic activity are known in the art. See WO 98124432 (indoline compounds that inhibit FLK protein kinase); WO 97/45409 (substituted tetralylmethylene-oxindole analogues that inhibit tyrosine kinase). In particular, small molecule inhibitors typically block the binding of substrates by tightly interacting with the protein kinase ATP binding site (or “active site”). See WO 98/24432. It is desirable to identify small-molecule compounds that may be readily synthesized and are effective in inhibiting the catalytic activity of protein kinases, in particular of the JNK protein kinases.
Indolinone (also known as oxindole) compounds asserted to be useful in the regulating abnormal cell proliferation through tyrosine kinase inhibition are disclosed for example in WO 96/40116, WO 98/07695, WO 95/01349, WO 96/32380, WO 96/22976, WO 96/16964 and WO 98/50356 (2-indolinone derivatives as modulators of protein kinase activity); Mohammadi et. al, Science, Vol. 276, May 9, 1997, pp. 955-960. Oxindole derivatives have also been described for various other therapeutic uses: 5,206,261 (improvement of cerebral function); WO 92/07830 (peptide antagonists); EP 580 502 A1 (antioxidants).
There continues to be a need for easily synthesized, small molecule compounds effective in inhibiting JNK protein kinase and thus useful in the treatment or control of pathological proliferative conditions, for example inflammatory diseases and neuro-degenerafive diseases, in particular, rheumatoid arthritis. It is thus an object of this invention to provide such compounds and compositions containing such compounds.
SUMMARY OF THE INVENTION
The present invention relates to 4,5-pyrazinoxindoles capable of inhibiting the activity of one or more JNK protein kinases. Such compounds are useful for the treatment of inflammatory diseases and neuro-degenerative diseases. In particular, the compounds of the present invention are especially useful in the treatment or control of rheumatoid arthritis.
The compounds of the present invention are 4,5-pyrazinoxindoles having the following formula:
and prodrugs and pharmaceutically active metabolites of compounds of Formula I; and the pharmaceutically acceptable salts of the foregoing compounds, wherein:
R
1
and R
2
are independently selected from the group consisting of
—H,
—OR
4
,
—COR
4
,
COOR
4
,
—CONR
5
R
8
,
—NR
5
R
6
,
lower alkyl which optionally may be substituted by the group consisting of —OR
4
, —NR
5
R
6
, halogen, —COR
4
, —COOR
4
, —OCOR
4
, —CONR
5
R
6
, —CN, —SO
2
R
4
, —SO
2
NR
5
R
6
, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the cycloalkyl and heterocycle each may be optionally substituted by the group R
11
and the aryl and heteroaryl each may be optionally substituted by the group R
12
,
cycloalkyl which optionally may be substituted by the group consisting of —OR
4
, —NR
5
R
6
halogen, —COR
4
, —COOR
4
, —OCOR
4
, —CONR
5
R
6
, —CN, —SO
2
R
4
, —SO
2
NR
5
R
6
, lower alkyl, heterocycle, aryl, and heteroaryl, wherein the lower alkyl and heterocycle each may be optionally substituted by the group R
11
and the aryl and heteroaryl each may be optionally substituted by the group R
12
,
heterocycle which optionally may be substituted by the group consisting of —OR
4
, —NR
5
R
6
, halogen, —COR
4
, —COOR
4
, —OCOR
4
, —CONR
5
R
6
, —CN, —SO
2
R
4
, —SO
2
NR
5
R
6
, lower alkyl, cycloalkyl, aryl, and heteroaryl, wherein the lower alkyl and cycloalkyl each may be optionally substituted by the group R
11
and the aryl and heteroaryl each may be optionally substituted by the group R
12
,
aryl which optionally may be substituted by the group consisting of —OR
4
, —NR
5
R
6
, halogen, —NO
2
, perfluoroalkyl, —COR
4
, —COOR
4
, —OCOR
4
, —CONR
5
R
6
, —CN, —SO
2
R
4
, —SO
2
NR
5
R
6
, lower alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, an
Luk Kin-Chun
Michoud Christophe
Hoffmann-La Roche Inc.
Johnston George W.
Liu Hong
Rocha-Tramaloni Patricia S.
Shah Mukund J.
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