Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-16
2002-12-10
Tsang, Cecilia (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S381000, C514S428000, C514S650000, C544S165000, C544S241000, C544S334000, C544S335000, C544S376000, C564S149000, C548S250000, C548S252000, C562S463000
Reexamination Certificate
active
06492363
ABSTRACT:
FIELD OF THE INVENTION
This invention provides benzoic acid and amide derivatives of anthranilic acids which inhibit certain dual specificity kinase enzymes involved in proliferative diseases such as cancer and restenosis.
BACKGROUND OF THE INVENTION
Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Cancer, for example, is commonly caused by a series of defects in these signaling proteins, resulting from a change either in their intrinsic activity or in their cellular concentrations. 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, which is 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, (eg, MEK
1
and MEK
2
) which then activates MAP kinase. Activation of MAP kinase by mitogens appears to be essential for proliferation, and 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 tyro sine, Y
185
, and a threonine residue, T
183
, separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100-fold, and it can now 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, whether it be another kinase, a transcription factor, or other cellular protein. MEK is also activated by several kinases other than Raf-1, including MEKK, and itself appears to be a signal integrating kinase. As far as is currently known, MEK is highly specific for the phosphorylation of MAP kinase. In fact, no substrate for MEK other than MAP kinase 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.
This invention provides compounds which are highly specific inhibitors of the kinase activity of MEK. Both in enzyme assays and whole cells, the compounds inhibit the phosphorylation of MAP kinase by MEK, thus preventing the activation of MAP kinase in cells in which the Ras cascade has been activated. The results of this enzyme inhibition include a reversal of transformed phenotype of some cell types, as measured both by the ability of the transformed cells to grow in an anchorage-independent manner and by the ability of some transformed cell lines to proliferate independently of external mitogens.
The compounds provided by this invention are 2-(phenylamino)benzoic acid, tetrazole, ester, amide, and benzyl alcohol derivatives, in which the phenyl ring is substituted at the 4-position with bromo or iodo. U.S. Pat. No. 5,155,110 discloses a wide variety of fenamic acid derivatives, including certain 2-(phenylamino)benzoic acid derivatives, as anti-inflammatory agents. The reference fails to describe the compounds of this invention or their kinase inhibitory activity.
SUMMARY OF THE INVENTION
This invention provides 4-bromo and 4-iodo phenylamino benzoic acid derivatives which are selective MEK kinase inhibitors and as such are useful for treating proliferative diseases such as cancer, psoriasis, and restenosis. The compounds are defined by Formula I
wherein
R
1
is hydrogen, hydroxy, C
1
-C
8
alkyl, C
1
-C
8
alkoxy, halo, trifluoromethyl, or CN;
R
2
is hydrogen;
R
3
, R
4
, and R
5
independently are hydrogen, hydroxy, halo, trifluoromethyl, C
1
-C
8
alkyl C
1
-C
8
alkoxy, nitro, CN, or —(O or NH)
m
—(CH
2
)
n—R
9
, where R
9
is hydrogen, hydroxy, CO
2
H, or NR
10
R
11
;
n is 0-4;
m is 0 or 1;
R
10
and R
11
independently are hydrogen or C
1
-C
8
alkyl, or taken together with the nitrogen to which they are attached, can complete a 3-10 member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N—C
1
-C
8
alkyl;
Z is COOR
7
, tetrazolyl, CONR
6
R
7
, CONHNR
10
R
11
, or CH
2
OR
7
;
R
6
and R
7
independently are hydrogen, C
1
-C
8
alkyl, C
2
-C
8
alkenyl,
aryl, heteroaryl, C
3
-C
10
cycloalkyl, or C
3
-C
10
(cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or R
6
and R
7
together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl;
and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, and the pharmaceutically acceptable salts thereof.
Preferred compounds have Formula II
where R
1
, R
3
, R
4
, R
5
, R
6
, and R
7
are as defined above. Especially preferred are compounds wherein R
1
is methyl or halo, and R
3
, R
4
, and R
5
are halo such as fluoro or bromo.
The compounds of Formula II are carboxylic acids when R
7
is hydrogen, and are esters when R
7
is other than hydrogen. Compounds which are analogous to the acids in physical and biological properties are tetrazolyl derivatives of Formula IIa
Another preferred group of compounds are amides Formula III
and hydrazides of Formula IIIa
The benzyl alcohols of the invention have Formula IV
The most preferred compounds are those wherein R
1
is methyl, R
3
is hydrogen or halo such as fluoro, R
4
is halo such as fluoro, and R
5
is hydrogen or halo such as fluoro, bromo, or chloro. Representative compounds have the formulas
This invention also provides pharmaceutical formulations comprising a compound of Formula I together with a pharmaceutically acceptable excipient, diluent, or carrier. Preferred formulations include any of the foregoing preferred compounds together with an excipient, diluent, or carrier.
The compounds of Formula I are potent and selective inhibitors of MEK
1
and MEK
2
kinase enzymes. They are, therefore, useful to treat subjects suffering from cancer, stroke, diabetes, Alzheimer's disease, cystic fibrosis, viral disease, hea
Barrett Stephen Douglas
Bridges Alexander James
Cody Donna Reynolds
Doherty Annette Marian
Dudley David Thomas
Ashbrook Charles W.
Harvey Suzanne M.
Sackey Ebenezer
Tsang Cecilia
Warner-Lambert & Company
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