Benzoheterocycles and their uses as MEK inhibitors

Details Benzoheterocycles and their uses as MEK inhibitors Benzoheterocycles and their uses as MEK inhibitors

2001-07-11

2002-10-22

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S353000, C548S126000, C548S178000, C548S217000, C548S261000, C548S309700, C514S248000, C514S359000, C514S361000, C514S362000, C514S367000, C514S375000, C514S387000

Reexamination Certificate

active

06469004

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 a compound having the formula (1) below:
In formula (I), W is OR
1
, NR
2
OR
1
, NR
A
R
B
, NR
2
NR
A
R
B
, O(CH
2
)
2-4
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
C
R
D
. R
2
is H, C
1-4
alkyl, phenyl, C
3-6
cycloalkyl, C
3-6
heterocyclic radical, or (C
3-6
cycloalkyl)methyl. 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, [(aminosulfonyl)C
3-6
cycloalkyl]C
1-4
alkyl, or (CH
2
)
2-4
NR
C
R
D
. R
B
is H, C
1-8
alkyl, C
3-8
alkenyl, C
3-8
alkynyl, C
3-8
cycloalkyl, or phenyl.
Q is one of the following formulae (i)-(iii):
R
3
is H or F; R
4
is halo, NO
2
, SO
2
NR
O
(CH
2
)
2-4
NR
E
R
F
, SO
2
NR
E
R
F
or (CO)T. T is C
1-8
alkyl, C
3-8
cycloalkyl, (NR
E
R
F
)C
1-4
alkyl, OR
F
, —NR
O
(CH
2
)
2-4
NR
E
R
F
, or NR
E
R
F
; Z is one of the following formulae (iv)-(viii):
One of R
5
and R
6
is H or methyl and the other of R
5
and R
6
is H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, phenyl, benzyl, or —M—E—G. M is O, CO, SO
2
, NR
J
, (CO)NR
H
, NR
H
(CO), NR
H
(SO
2
), (SO
2
)NR
H
, or CH
2
. E is (CH
2
)
1-4
or (CH
2
)
m
O(CH
2
)
p
where 1≦(each of m and p)≦3 and 2≦(m+p)≦4; or E is absent. G is R
K
, OR
I
, or NR
J
R
K
, provided that if p=1, then G is H. R
7
is H, C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
3-6
cycloalkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH
2
)
1-2
Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, SO
2
NR
H
(CH
2
)
2-4
NR
J
R
K
, (CO)(CH
2
)
2-4
NR
J
R
K
or (CO)NR
H
(CH
2
)
2-4
NR
J
R
K
. X
1
is O, S, NR
8
, or CHR
9
; X
2
is O, S, or CHR
9
; and X
3
is O or S. In one embodiment, if X
1
or X
2
is CHR
9
, the disclosed compound may also be a tautomerized indole. R
8
is H, C
1-4
alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH
2
)
1-2
Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, C
2-4
alkenyl, C
2-4
alkynyl, C
3-6
cycloalkyl, or (C
2-4
alkyl)NR
L
R
M
provided R
7
and R
8
together have no more than 14 carbon atoms, exclusive of R
L
, R
M
, R
J
and R
K
. R
G
is C
1-4
alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
3-4
alkenyl, C
3-4
alkynyl, C
3-6
cycloalkyl, (CO)OR
P
, (C
2-4
alkyl)NR
L
R
M
, (CO)NR
N
(CH
2
)
2-4
NR
L
R
M
, (CO)NR
L
R
M
, (CO)(CH
2
)
2-4
-NR
L
R
M
, or (CH
2
)
1-2
Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. R
9
is C
1-4
alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-4
alkenyl, C
2-4
alkynyl, C
3-6
cycloalkyl, (CO)OR
P
, (C
2-4
alkyl)NR
L
R
M
, (CO)NR
N
(CH
2
)
2-4
NR
L
R
M
, (CO)NR
L
R
M
, (CO)(CH
2
)
2-4
—NR
L
R
M
, or (CH
2
)
1-2
Ar′, where Ar′ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. R
P
is H, C
1-6
alkyl, phenyl, C
3-4
alkenyl, C
3-4
alkynyl, C
3-6
cycloalkyl, or (CH
2
)
2-4
NR
L
R
M
; R
10
is H, methyl, halo, or NO
2
; R
11
is H, methyl, halo, or NO
2
. Each of R
C
, R
D
, R
E
, R
F
, R
I
, R
J
, R
K
, R
L
and R
M
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
, NR
J
R
K
, and NR
L
R
M
can also independently be morpholinyl, piperazinyl, pyrrolidinyl, or piperadinyl. Each of R
H
, R
N
, and R
O
is independently H, methyl, or ethyl. 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
2-4
alkenyl, C
2-4
alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO
2
, wherein e

Affiliated with

Also associated with

Rating

Benzoheterocycles and their uses as MEK inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Benzoheterocycles and their uses as MEK inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzoheterocycles and their uses as MEK inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2970615