Treatment of asthma with MEK inhibitors

Details Treatment of asthma with MEK inhibitors Treatment of asthma with MEK inhibitors

2001-07-11

2004-02-24

Spivack, Phyllis G. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S277000, C514S315000, C514S408000, C514S438000, C514S532000, C514S534000, C514S535000

Reexamination Certificate

active

06696440

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a method for preventing and treating asthma in mammals comprising administering a compound characterized as an inhibitor of a family of enzymes known as MEK kinases, which are groups of
M
AP (mitogen-associated protein kinase) and
E
rk (extracellular signal-regulated)
K
inases. These are enzymes that regulate phosphorylation of substrates in mammals.
BACKGROUND OF THE INVENTION
Asthma is a heterogeneous disorder of the airways that afflicts millions of people. Airway inflammation, hyperresponsiveness, and obstruction characterize the condition. The disease often causes spasms of the bronchial smooth muscle system, and affects both the upper and lower respiratory tracts. There are several forms of asthma, characterized by varying degrees of severity. Mild asthma, for example, is defined as brief episodes of wheezing, with or without dyspnea or cough. Moderately severe asthma is defined as wheezing and dyspnea, and can be with or without cough and expectoration, but generally interferes with daily activities and/or sleeping. Severe asthma is characterized by incapacitation due to dyspnea, and the afflicted patient typically is unable to eat or sleep normally, is very anxious, and is often exhausted. A condition known as status asthmaticus is the most severe form of asthma, and generally requires intensive hospital care, and may even prove fatal. The disease may occur as a result of both allergic and nonallergic mechanisms.
While there are several treatments available for relieving the symptoms and discomfort associated with asthma, there are no cures. Moreover, the current treatments often cause side effects that exacerbate the discomfort and precipitate other debilitating conditions. Mild asthma generally is treated with beta-adrenergic drugs, as well as antihistamines, especially in the case of children, to prevent or abort sporadic episodes. Moderately severe and severe asthma are generally treated with adrenergic agents and bronchodilators, as well as corticosteroids. Other actions caused by antiasthmatic agents which limit their widespread use include headache, fatigue, dry mouth, nervousness, and in some cases addiction and substance abuse. Recent advances in the understanding of the pathogenesis and treatment of asthma is discussed more fully by Grayson et al.,
The Mount Sinai Journal of Medicine
, September 1998;65(4):246-256.
Because asthma is so prevalent in both children and adults, there is an ongoing need for agents that can treat the disease, or at least relieve the symptoms that accompany the disease, without causing undesirable side effects. We have now discovered that MEK inhibitors are particularly useful for treating asthma and relieving the symptoms that accompany the disease. An object of this invention is therefore to provide a new method for preventing and treating asthmatic conditions.
SUMMARY OF THE INVENTION
This invention provides a method of preventing and treating asthma, said method comprising the step of administering to a patient an antiasthmatic-effective amount of a MEK inhibitor. Selective MEK inhibitors are those compounds which inhibit the MEK 1 and MEK 2 enzymes without substantial inhibition of other such enzymes. In a preferred embodiment, the invention provides a method for preventing or treating asthma by administering a MEK inhibitor. In a further embodiment, the invention provides a method for preventing and/or treating asthma comprising administering an effective amount of the selective MEK inhibitor described in U.S. Pat. No. 5,525,625, incorporated herein by reference, which selective MEK inhibitor is 2-(2-amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran.
In another preferred embodiment, the MEK inhibitor to be administered is a phenyl amine derivative of Formula I:
In Formula (I), 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
are independently selected from hydrogen, hydroxy, halo, trifluoromethyl, C
1
-C
8
alkyl, C
1
-C
8
alkoxy, nitro, CN, and —(O or NH)
m
—(CH
2
)
n
—R
9
. R
9
is hydrogen, hydroxy, COOH, or NR
10
R
11
; n is 0-4; m is 0 or 1. Each of R
10
and R
11
is independently selected from hydrogen and 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 1, 2, or 3 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, C
2
-C
8
alkynyl, (CO)—C
1
-C
8
alkyl, 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. In formula (I), any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C
1
-C
6
alkoxy, amino, nitro, C
1
-C
4
alkylamino, di(C
1
-C
4
)alkylamino, C
3
-C
6
cycloalkyl, phenyl, phenoxy, C
3
-C
5
heteroaryl or heterocyclic radical, or C
3
-C
5
heteroaryloxy or heterocyclic radicaloxy. The invention also provides a pharmaceutically acceptable salt, ester, amide, or prodrug of each of the disclosed MEK inhibitors.
Preferred embodiments of Formula (I) have a structure wherein: (a) R
1
is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; (b) R
2
is hydrogen; (c) R
3
, R
4
, and R
5
independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; (d) R
10
and R
11
independently are hydrogen or methyl; (e) 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
1-4
alkyl, heteroaryl, or C
3-5
cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or R
6
and R
7
together with the nitrogen to which they are attached complete a 5-6 member cyclic ring optionally containing 1 or 2 additional heteroatoms selected from O, NH or N-alkyl; and wherein any of the foregoing alkyl or aryl groups can be unsubstituted or substituted by halo, hydroxy, methoxy, ethoxy, or heteroaryloxy (such as 2,3,4,5,6-pentafluorophenyl); (f) Z is COOR
7
; (g) R
7
is H, pentafluorophenyl, or tetrazolyl; (h) R
3
, R
4
, and R
5
are independently H, fluoro, or chloro; (i) R
4
is fluoro; (j) two of R
3
, R
4
, and R
5
are fluoro; or (k) or combinations of the above. In another preferred embodiment of Formula (I), R
1
is methyl, fluoro, chloro, or bromo.
In a more preferred embodiment, the MEK inhibitor is selected from a compound in Formula (I) Compound Table below.
FORMULA (I) COMPOUND TABLE
[4-Chloro-2-(1H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine
(4-iodo-2-methyl-phenyl)-[2-(1H-tetrazol-5-yl)-phenyl]amine
[4-nitro-2-(1H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine
4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid
3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid
4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
2-(4-Iodo-2-methyl-phenylamino)-benzoic acid
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid
2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid
5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid
2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid
2-(2-Bromo-4-iodo-phenylamino)-5-nitro-b

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