Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-07-11
2003-01-14
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S535000, C514S603000, C514S618000, C514S619000, C514S621000, C560S048000, C562S435000
Reexamination Certificate
active
06506798
ABSTRACT:
BACKGROUND
MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis.
Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade. The cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP. The above-mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP-bound state. This signal is an absolute prerequisite for proliferation in most cell types. Defects in this signaling system, especially in the deactivation of the Ras-GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated. Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEK
1
and MEK
2
) which then activates MAP kinase, ERK (ERK
1
and ERK
2
). Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. Although Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, S
218
and S
222
in the case of MEK-1, which are the prerequisite for activation of MEK as a kinase. MEK in turn phosphorylates MAP kinase on both a tyrosine, y
185
, and a threonine residue, T
183
, separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase. In fact, no substrate for MEK other than the MAP kinase, ERK, has been demonstrated to date and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it may have enough difference in its mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP binding site, may be found.
SUMMARY
The invention features compounds of formulae (II) below, such as formula(I):
In formulae (I) and (II), W is OR
1
, NR
2
OR
1
, NR
A
R
B
, NR
2
NR
A
R
B
, or NR
2
(CH
2
)
2-4
NR
A
R
B
. R
1
is H, C
1-8
alkyl, C
3-8
alkenyl, C
3-8
alkynyl, C
3-8
cycloalkyl, phenyl, (phenyl)C
1-4
alkyl, (phenyl)C
3-4
alkenyl, (phenyl)C
3-4
alkynyl, (C
3-8
cycloalkyl)C
1-4
alkyl, (C
3-8
cycloalkyl)C
3-4
alkenyl, (C
3-8
cycloalkyl)C
3-4
alkynyl, C
3-8
heterocyclic radical, (C
3-8
heterocyclic radical)C
1-4
alkyl, (C
3-8
heterocyclic radical)C
3-4
alkenyl, (C
3-8
heterocyclic radical)C
3-4
alkynyl, or (CH
2
)
2-4
NR
A
R
B
. R
2
is H, phenyl, C
1-4
alkyl, C
3-4
alkenyl C
3-8
alkynyl, C
3-8
cycloalkyl, or (C
3-8
cycloalkyl)C
1-4
alkyl. R
A
is H, C
1-6
alkyl, C
3-8
alkenyl, C
3-8
alkynyl, C
3-8
cycloalkyl, phenyl, (C
3-8
cycloalkyl)C
1-4
alkyl, (C
3-8
cycloalkyl)C
3-4
alkenyl, (C
3-8
cycloalkyl)C
3-4
alkynyl, C
3-8
heterocyclic radical, (C
3-8
heterocyclic radical)C
1-4
alkyl, (aminosulfonyl)phenyl, [(aminosulfonyl)phenyl]C
1-4
alkyl, (aminosulfonyl)C
1-6
alkyl, (aminosulfonyl)C
3-6
cycloalkyl, or [(aminosulfonyl)C
3-6
cycloalkyl]C
1-4
alkyl. R
B
is H, C
1-8
alkyl, C
3-8
alkenyl, C
3-8
alkynyl, C
3-8
cycloalkyl, or C
6-8
aryl. R
3
is halo, NO
2
, SO
2
NR
I
(CH
2
)
2-4
NR
E
R
F
, SO
2
NR
I
R
K
or (CO)T. T is C
1-8
alkyl, C
3-8
cycloalkyl, (NR
E
R
F
)C
1-4
alkyl, OR
F
, NR
I
(CH
2
)
2-4
NR
E
R
F
, or NR
E
R
F
. R
4
is H or F; R
5
is H, methyl, halo, or NO
2
; and R
6
is H, methyl, halo, or NO
2
. In formula (II), Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. Each of R
7
and R
8
is independently selected from H, halo, C
1-4
alkyl, SO
2
NR
J
(CH
2
)
2-4
NR
G
R
H
, (CO)(CH
2
)
2-4
NR
G
R
H
, (CO)NR
J
(CH
2
)
2-4
NR
G
R
H
, (CO)O(CH
2
)
2-4
NR
G
R
H
, SO
2
NR
G
R
H
, and (CO)NR
G
R
H
. However, where Ar is a pyridyl, each of R
7
and R
8
is H. Each of R
C
, R
D
, R
E
, R
F
, R
G
, and R
H
is independently selected from H, C
1-4
alkyl, C
3-4
alkenyl, C
3-4
alkynyl, C
3-6
cycloalkyl, and phenyl. Each of NR
C
R
D
, NR
E
R
F
, and NR
G
R
H
can also be independently morpholinyl, piperazinyl, pyrrolidinyl, or piperadinyl. Each of R
I
and R
J
is independently H. methyl, or ethyl. R
K
is C
1-4
alkyl, C
3-4
alkenyl, C
3-4
alkynyl, C
3-6
cycloalkyl, or phenyl. X is O, S, or NH. Finally, each hydrocarbon radical or heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C
1-4
alkyl, C
3-6
cycloalkyl, C
1-4
alkenyl, C
1-4
alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO
2
, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 substituents independently selected from halo, C
1-2
alkyl, hydroxyl, amino, and NO
2
. In addition to the above compounds, the invention also provides a pharmaceutically acceptable salt or C
1-7
ester thereof.
The invention also relates to a pharmaceutical composition including (a) a diarylamine (e.g., of formula I) and (b) a pharmaceutically acceptable carrier.
The invention further relates to a method for treating proliferative diseases, such as cancer, restenosis, psoriasis, autoimmune disease, and atherosclerosis. Other aspects of the invention include methods for treating MEK-related cancer, tumors of the breast, lung, colorectal, pancreas, prostate, brain, kidney, or ovary, and other solid or hematopoietic cancers. Further aspects of the invention include methods for treating or reducing the symptoms of xenograft (organ, cell(s), limb, skin, or bone marrow transplant) rejection, osteoarthritis, rheumatoid arthritis, cystic fibrosis, hepatomegaly, cardiomegaly, complications of diabetes (including diabetic nephropathy and diabetic retinopathy), stroke, heart failure, septic shock, asthma, and Alzheimer's disease. Compounds of the invention are also useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). The methods include administering to a patient in need of such treatment, or suffering from such a disease or condition, a pharmaceutically
Barrett Stephen
Tecle Haile
Harvey Suzanne M.
Richter Johann
Shen Evelyn D.
Warner-Lambert & Company
Zucker Paul A.
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