N-(4-substituted phenyl)-anthranilic acid hydroxamate esters

Details N-(4-substituted phenyl)-anthranilic acid hydroxamate esters N-(4-substituted phenyl)-anthranilic acid hydroxamate esters

2003-01-23

2004-08-03

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Hydroxamate esters or chalcogen analogues thereof

C560S041000, C562S450000, C564S157000, C564S163000, C564S164000, C564S165000, C564S167000, C556S419000, C514S507000, C514S575000, C514S534000, C514S563000, C514S616000, C514S770000

Reexamination Certificate

active

06770778

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to oxygenated esters of 4-substituted-phenylamino benzhydroxamic acid derivatives, pharmaceutical compositions, and methods of use thereof.
BACKGROUND OF THE INVENTION
MAPK/ERK Kinase (“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 the 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.
It has been found that the compounds of the present invention are inhibitors of MEK and are useful in the treatment of a variety of proliferative disease states, such as conditions related to the hyperactivity of MEK, as well as diseases modulated by the MEK cascade.
SUMMARY OF THE INVENTION
The present invention provides a compound of Formula
wherein
W is
R
2
is hydrogen, methyl, fluorine, or chlorine;
R
3
is hydrogen or fluorine;
R
4
is —CH
2
S(CH
2
)
m
(CH
3
), —C≡C—(CH
2
)
q
NHCH
3
, —C≡C—CH
2
OCH
3
, (Z)—CHCHCH
2
OCH
3
, —(CH
2
)
n
CO
2
R
6
, —(CF
2
)
p
CF
3
, —CH
2
(CF
2
)
q
CF
3
, —(CH
2
)
m
CF(CF
3
)
2
, —CH(CF
3
)
2
, —CF
2
CF(CF
3
)
2
, —C(CF
3
)
3
, —C≡C—(CH
2
)
q
N(CH
3
)
2
, —(Z)—CHCH—(CH
2
)
q
NHCH
3
, (Z)—CHCH—(CH
2
)
q
N(CH
3
)
2
, or C(O)C
1-3
alkyl;
m is 0 to 1;
n is 0 to 2;
p is 1 to 5;
q is 1 to 2;
R
5
is hydrogen, fluorine, bromine, or chlorine;
R
6
is hydrogen, methyl or ethyl;
and pharmaceutically acceptable salts, (C
1-6
) amides and (C
1-6
) esters thereof.
The present invention provides compounds of Formula I wherein W is
R
2
is hydrogen, fluorine, or chlorine; R
3
is fluorine; R
4
is —(CH
2
)
n
CO
2
R
6
where n is 0; R
4
is —C≡C—CH
2
OCH
3
; or R
4
is C(O)C
1-3
alkyl; and R
5
is hydrogen.
The invention also provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.
Additionally, the invention provides a method of treating a proliferative disease in a patient in need thereof comprising administering a therapeutically effective amount of a compound of Formula I.
The invention also provides the use of a compound of Formula I for the manufacture of a medicament for the treatment of a proliferative disease.
Furthermore, the invention provides methods of treating cancer, restenosis, psoriasis, autoimmune disease, atherosclerosis, osteoarthritis, rheumatoid arthritis, heart failure, chronic pain, and neuropathic pain in a patient in need thereof comprising administering a therapeutically effective amount of a compound of Formula I.
The invention also provides the use of a compound of Formula I for the manufacture of a medicament for the treatment of cancer, restenosis, psoriasis, autoimmune disease, atherosclerosis, osteoarthritis, rheumatoid arthritis, heart failure, chronic pain, and neuropathic pain.
In addition, the invention provides a method for treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of a compound of Formula I in combination with radiation therapy or at least one chemotherapeutic agent.
DETAILED DESCRIPTION OF THE INVENTION
Certain terms are defined below and by their usage throughout this disclosure.
The terms “halogen” or “halo” in the present invention refer to a fluorine, bromine, chlorine, and iodine atom or fluoro, bromo, chloro, and iodo. The terms fluorine and fluoro, for example, are understood to be equivalent herein.
Alkyl groups, such as “C
1-6
alkyl”, include aliphatic chains (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, hexyl, and the like. The term “C
1-6
alkyl” includes within its definition the terms “C
1-4
alkyl” and “C
1-2
alkyl”.
Alkenyl groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp
2
carbon atoms). Depending on the placement of a double bond and substituents, if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis, or trans. Similarly, alkynyl groups have at least one triple bond (two adjacent sp carbon atoms). Unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds, respectively, or a mixture thereof. Like alkyl groups, unsatur

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