Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-08-02
2001-06-26
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S620000, C514S657000, C514S658000, C514S921000
Reexamination Certificate
active
06251943
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method of treating or preventing septic shock in a patient by administering to the patient a compound that is a MEK inhibitor.
BACKGROUND OF THE INVENTION
Septic shock is a serious medical condition that is caused by invasion of the circulatory system by bacteria. Septic shock is characterized by acute circulatory failure, usually with hypotension, followed by multiple organ failure and acute renal failure. The mortality rate of patients having septic shock is in the range of 25% to 90%. It is estimated that up to 500,000 people a year in both the United States and Europe develop septic shock.
The human immune system has many dedicated receptor systems that detect common pathogens, especially bacteria, and these receptor systems are distinct from the specific antibody and T-cell receptor systems, because they are permanently present, and are not tailored to meet a particular threat. Many of the dedicated receptor systems recognize the structural components of bacteria, such as lipopolysaccharide (LPS) lipoteichoic acid and peptidoglycan, and lead to activation of the immune system when these receptors bind structural components of bacteria.
LPS, a major component of the outer cell membrane of gram-negative bacteria, appears to be a major factor in the progression of a bacterial infection to septic shock. The principal mechanism for recognition by the human immune system of LPS is by binding of the CD14 receptor on macrophages to LPS. This binding requires LPS Binding Protein (LBP), an inducible protein made in the liver. Once macrophages have bound and recognized LPS, the macrophages produce massive amounts of inflammatory cytokines, especially tumor necrosis factor-&agr;(TNF &agr;), Interleukin 1 &bgr;(IL- 1&bgr;), and Interleukin 6 (IL-6).
Three of the transcription factors important in inducing LBP production in the liver are AP-1, C/EBP and STAT-3. All of these can be stimulated through the IL-6 signaling pathway, which is produced locally in the liver by Kuppfer cells. IL-6 stimulates the MAP kinases Mitogen-Activated Protein Kinases, also known as Extracellular Signal-Regulated Kinase or ERK, of which there are two isoforms (also called ERK1 and ERK2) through MEK, (the name given to MAP-kinase, namely Mitogen-Activated Protein Kinase Kinase), and these MAP kinases can activate the three transcription factors mentioned above by phosphorylation. Thus, an inhibitor of MEK can decrease the stimulation of LBP gene transcription, and attenuate the strength of the macrophage response to LPS.
In macrophages, LPS signaling appears to activate all three of the known MAP kinase pathways, including the MEK/ERK cascade, and LPS stimulation of macrophages leads to rapid and major activation of ERKs. ERK is believed to be one of the kinases that phosphorylates I&kgr;B, a prerequisite for the liberation of the transcription factor NF &kgr;B. NF &kgr;B, once liberated, enters the nucleus, and is probably the single most important transcriptional activator for production of TNF &agr;. Thus, an inhibitor of MEK or ERK activity could also decrease the stimulation of TNF-&agr; gene transcription, leading to a greatly decreased physiological response to LPS.
In cells that contain the TNF receptor, activation of that receptor leads to turning on of many pathways that lead to toxicity in the target cell, and which culminate in apoptosis (regulated self-destruction of the cell). Multiple organ failure is more likely caused by TNF-&agr; induced toxicity than by any other single cause. Neutral sphingomyelinase has been shown to be activated by the TNF receptor, and this, in turn, activates ceramide-activated protein kinase, which then activates the MEK/MAP kinase pathway in the target cells, probably adding to the overall toxic effects of TNF.
Thus, the MEK/MAP kinase pathway is important in septic shock, and is involved at several vital points in the progression of septic shock.
SUMMARY OF THE INVENTION
The present invention provides a method of treating or preventing septic shock, the method comprising administering to a patient having septic shock or at risk of having septic shock a therapeutically acceptable amount of a compound that is a MEK inhibitor.
In a preferred embodiment of the invention the MEK inhibitor is 2-(2-amino-3-methoxyphenyl)4-oxo-4H-[1]benzopyran.
In another preferred embodiment of the invention, the patient has septic shock.
In another preferred embodiment of the invention, the patient is at risk of having septic shock.
In a more preferred embodiment the invention provides a method of treating or preventing septic shock, the method comprising administering to a patient having septic shock or at risk of having septic shock a therapeutically acceptable amount of 2-(2-amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran.
In a preferred embodiment of the invention, the MEK inhibitor is a compound of 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, COOH, or NR
10
R
11
;
n is0-4;
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 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,
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;
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, esters, amides, or prodrugs thereof.
In a more preferred embodiment, the MEK inhibitor is
[4-Chloro-2-(1H-tetrazol-5-yl)-(4iodo-2-methyl-phenyl)-amine;
(4-iodo-2-methyl-phenyl)-[2-(1H-tetrazol-5-yl)-phenyl]amine;
[4-nitro-2-(1H-tetrazol-5-yl)-(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-benzoic acid;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-benzoic acid;
5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide;
N-Ethyl4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1H-tetrazol-5-yl)-benzamide;
5-Bromo
Barrett Stephen Douglas
Bridges Alexander James
Cody Donna Reynolds
Doherty Annette Marian
Dudley David Thomas
Ashbrook Charles W.
Jagoe Donna
Krass Frederick
Warner-Lambert & Company
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