U.S. patent application number 10/753170 was filed with the patent office on 2004-07-22 for treatment of asthma with mek inhibitors.
Invention is credited to Bridges, Alexander James, Dudley, David Thomas, Mobley, James Leslie, Saltiel, Alan Robert.
Application Number | 20040141924 10/753170 |
Document ID | / |
Family ID | 22359251 |
Filed Date | 2004-07-22 |
United States Patent
Application |
20040141924 |
Kind Code |
A1 |
Bridges, Alexander James ;
et al. |
July 22, 2004 |
Treatment of asthma with MEK inhibitors
Abstract
This invention provides a method of preventing or treating
asthma by administering to a patient in need of treatment an
effective amount of a selective MEK inhibitor, especially a phenyl
amine of Formula I and II: 1
Inventors: |
Bridges, Alexander James;
(Saline, MI) ; Dudley, David Thomas; (Ann Arbor,
MI) ; Mobley, James Leslie; (Brighton, MI) ;
Saltiel, Alan Robert; (Ann Arbor, MI) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Family ID: |
22359251 |
Appl. No.: |
10/753170 |
Filed: |
January 7, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10753170 |
Jan 7, 2004 |
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09889091 |
Jul 11, 2001 |
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6696440 |
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09889091 |
Jul 11, 2001 |
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PCT/US99/30419 |
Dec 21, 1999 |
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60115086 |
Jan 7, 1999 |
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Current U.S.
Class: |
424/45 |
Current CPC
Class: |
A61K 31/166 20130101;
A61K 31/196 20130101; A61P 11/06 20180101 |
Class at
Publication: |
424/045 |
International
Class: |
A61L 009/04 |
Claims
What is claimed is:
1. A method for preventing or treating asthma in patients, said
method comprising the step of administering an
antiasthmatic-effective amount of a MEK inhibitor to a patient in
need of treatment, or to a patient suspected of developing asthma
and in need of prophylactic treatment.
2. A method according to claim 1 wherein the patient being treated
has been diagnosed as having asthma and is in need of
treatment.
3. A method according to claim 1, wherein the MEK inhibitor is a
selective MEK inhibitor.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 09/889,091 filed on Jul. 11, 2001, which is a
371 application of PCT/US99/30419 filed on Dec. 21, 1999, which
claims the benefit of priority to U.S. Provisional Application
Serial No. 60/115086 filed on Jan. 7, 1999.
FIELD OF THE INVENTION
[0002] 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 MAP (mitogen-associated protein
kinase) and Erk (extracellular signal-regulated) Kinases. These are
enzymes that regulate phosphorylation of substrates in mammals.
BACKGROUND OF THE INVENTION
[0003] 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.
[0004] 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.
[0005] Because asthma is so prevalent in both children and adults,
there is an on-going 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
[0006] 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.
[0007] In another preferred embodiment, the MEK inhibitor to be
administered is a phenyl amine derivative of Formula I: 2
[0008] In Formula (I), R.sub.1 is hydrogen, hydroxy,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, halo,
trifluoromethyl, or CN. R.sub.2 is hydrogen. R.sub.3, R.sub.4, and
R.sub.5 are independently selected from hydrogen, hydroxy, halo,
trifluoromethyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy,
nitro, CN, and --(O or NH).sub.m--(CH.sub.2).sub.- n--R.sub.9.
R.sub.9 is hydrogen, hydroxy, COOH, or NR.sub.10R.sub.11; n is 0-4;
m is 0 or 1. Each of R.sub.10 and R.sub.11 is independently
selected from hydrogen and C.sub.1-C.sub.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.sub.1-C.sub.8 alkyl).
Z is COOR.sub.7, tetrazolyl, CONR.sub.6R.sub.7,
CONHNR.sub.10R.sub.11, or CH.sub.2OR.sub.7. R.sub.6 and R.sub.7
independently are hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, (CO)--C.sub.1-C.sub.8 alkyl,
aryl, heteroaryl, C.sub.3-C.sub.10 cycloalkyl, or C.sub.3-C.sub.10
(cycloalkyl optionally containing one, two, or three heteroatoms
selected from O, S, NH, or N alkyl); or R.sub.6 and R.sub.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.sub.1-C.sub.6 alkoxy, amino, nitro, C.sub.1-C.sub.4
alkylamino, di(C.sub.1-C.sub.4)alkylamino, C.sub.3-C.sub.6
cycloalkyl, phenyl, phenoxy, C.sub.3-C.sub.5 heteroaryl or
heterocyclic radical, or C.sub.3-C.sub.5 heteroaryloxy or
heterocyclic radical-oxy. The invention also provides a
pharmaceutically acceptable salt, ester, amide, or prodrug of each
of the disclosed MEK inhibitors.
[0009] Preferred embodiments of Formula (I) have a structure
wherein: (a) R.sub.1 is hydrogen, methyl, methoxy, fluoro, chloro,
or bromo; (b) R.sub.2 is hydrogen; (c) R.sub.3, R.sub.4, and
R.sub.5 independently are hydrogen, fluoro, chloro, bromo, iodo,
methyl, methoxy, or nitro; (d) R.sub.10 and R.sub.11 independently
are hydrogen or methyl; (e) Z is COOR.sub.7, tetrazolyl,
CONR.sub.6R.sub.7, CONHNR.sub.10R.sub.11, or CH.sub.2OR.sub.7;
R.sub.6 and R.sub.7 independently are hydrogen, C.sub.1-4 alkyl,
heteroaryl, or C.sub.3-5 cycloalkyl optionally containing one or
two heteroatoms selected from O, S, or NH; or R.sub.6 and R.sub.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.sub.7; (g) R.sub.7 is
H, pentafluorophenyl, or tetrazolyl; (h) R.sub.3, R.sub.4, and
R.sub.5 are independently H, fluoro, or chloro; (i) R.sub.4 is
fluoro; (j) two of R.sub.3, R.sub.4, and R.sub.5 are fluoro; or (k)
or combinations of the above. In another preferred embodiment of
Formula (I), R.sub.1 is methyl, fluoro, chloro, or bromo.
[0010] In a more preferred embodiment, the MEK inhibitor is
selected from a compound in Formula (I) Compound Table below.
Formula (I) Compound Table (Page 1 of 10)
[0011]
[4-Chloro-2-(1H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amin-
e
[0012]
(4-iodo-2-methyl-phenyl)-[2-(1H-tetrazol-5-yl)-phenyl]amine
[0013]
[4-nitro-2-(1H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine
[0014] 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid
[0015] 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic
acid
[0016] 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic
acid
[0017] 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic
acid
[0018] 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
[0019] Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate
[0020] 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
[0021] 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid
[0022] 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
[0023] 2-(4-Iodo-2-methyl-phenylamino)-benzoic acid
[0024] 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
[0025] 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
[0026] 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic
acid
[0027] 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid
[0028] 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
[0029] 2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid
[0030] 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid
[0031] 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid
[0032] 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-benzoic
acid
[0033]
5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzami-
de
[0034] 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0035]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide
[0036]
N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0037]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide
[0038]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1H-tetrazol-5-yl)-benza-
mide
Formula (I) Compound Table (Continued, Page 2 of 10)
[0039] 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0040]
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide
[0041]
[5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic
acid
[0042]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide
[0043]
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzami-
de
[0044]
N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0045]
4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iod-
o-2-methyl-phenylamino)-benzamide
[0046]
N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
[0047]
N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0048]
5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0049]
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide
[0050]
5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenyla-
mino)-benzamide
[0051]
N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamin-
o)-benzamide
[0052]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-
-1-yl-ethyl)-benzamide
[0053]
3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-be-
nzamide
[0054]
N-(2,3-Dihydroxy-propyl)4-fluoro-2-(4-iodo-2-methyl-phenylamino)-be-
nzamide
[0055]
3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-b-
enzamide
[0056]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidi-
n-1-yl-ethyl)-benzamide
[0057]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin4--
yl-ethyl)-benzamide
Formula (I) Compound Table (Continued, Page 3 of 10)
[0058]
4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzam-
ide
[0059]
5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methylp-
henylamino)-benzamide
[0060]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-
-4-yl-ethyl)-benzamide
[0061]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-et-
hyl)-benzamide
[0062]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-e-
thyl)-benzamide
[0063]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethy-
l)-benzamide
[0064]
N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylam-
ino)-benzamide
[0065]
N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0066]
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethyl)-b-
enzamide
[0067]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)-
-benzamide
[0068]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl-
)-benzamide
[0069]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-pr-
opyl)-benzamide
[0070]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl-ethyl)--
benzamide
[0071]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl-
)-benzamide
[0072]
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin4-yl-et-
hyl)-benzamide
Formula (I) Compound Table (Continued, Page 4 of 10)
[0073]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-yl-
methyl-benzamide
[0074]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl-b-
enzamide
[0075]
2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino-propyl)-3,4-dif-
luoro-benzamide
[0076]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl-enzam-
ide
[0077]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)-b-
enzamide
[0078]
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin-4-yl-eth-
yl)-benzamide
[0079]
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy-propyl)--
benzamide
[0080]
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin-1-yl--
ethyl)-benzamide
[0081]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl-benzamide
[0082]
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen-2-yl-et-
hyl)-benzamide
[0083]
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin-4-ylmethyl--
benzamide
[0084]
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl-benzamide
[0085]
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin-1-yl-e-
thyl)-benzamide
[0086]
5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iod-
o-2-methyl-phenylamino)-benzamide
[0087]
5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iod-
o-2-methyl-phenylamino)-benzamide
[0088] 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl
methyl-benzamide
Formula (I) Compound Table (Continued, Page 5 of 10)
[0089] 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl
-propyl}-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0090]
5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)-b-
enzamide
[0091]
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)-
-benzamide
[0092]
(3-Hydroxy-pyrrolidin-1-yl)-[5-nitro-2-(4-iodo-2-methyl-phenylamino-
)-phenyl}-methanone
[0093]
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl-
)-benzamide
[0094]
5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)-be-
nzamide
[0095]
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo-2-meth-
yl-phenylamino)-benzamide
[0096]
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo-2-methy-
l-phenylamino)-benzamide
[0097]
N-{3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-2-methy-
l-phenylamino)-benzamide
[0098]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl-benza-
mide
[0099]
5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)--
benzamide
[0100]
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)--
benzamide
[0101]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl-
)-benzamide
[0102]
5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)-
-benzamide
[0103]
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo-2-meth-
yl-phenylamino)-benzamide
Formula (I) Compound Table (Continued, Page 6 of 10)
[0104]
5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-benza-
mide
[0105]
5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo-2-methyl-phe-
nylamino)-benzamide
[0106]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)-
-benzamide
[0107]
5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-benzam-
ide
[0108]
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)-
-benzamide
[0109]
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl-phenyl-
amino)-5-nitro-benzamide
[0110]
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)-
-benzamide
[0111]
5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)--
benzamide
[0112]
5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamin-
o)-benzamide
[0113]
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl-
)-benzamide
[0114]
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-1-yl-ethyl)--
benzamide
[0115]
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin-1-yl-ethyl)--
benzamide
[0116]
N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-b-
enzamide
[0117]
5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)--
benzamide
[0118]
N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzam-
ide
Formula (I) Compound Table (Continued, Page 7 of 10)
[0119]
5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-benza-
mide
[0120]
N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)--
benzamide
[0121]
N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-b-
enzamide
[0122]
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)--
benzamide
[0123]
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-1-yl-propyl)-
-benzamide
[0124] [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(2 or
3-hydroxy-pyrrolidin-1-yl)-methanone
[0125]
5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino-
)-benzamide
[0126]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)-
-benzamide
[0127]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl-
)-benzamide
[0128]
[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-(2-hydroxy-ethy-
l)-piperazin-1-yl)-methanone
[0129]
N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo-2-methyl-phe-
nylamino)-benzamide
[0130]
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0131]
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzam-
ide
[0132]
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzam-
ide
[0133]
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0134]
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
Formula (I) Compound Table (Continued, Page 8 of 10)
[0135]
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)-benz-
amide
[0136]
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzami-
de
[0137]
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamid-
e
[0138]
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro-benzamid-
e
[0139]
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide
[0140]
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0141]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamid-
e
[0142]
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0143]
N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0144]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)-ben-
zamide
[0145]
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0146]
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
[0147]
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0148]
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamid-
e
[0149]
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)-benza-
mide
[0150]
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)-benz-
amide
[0151]
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
[0152]
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)-benz-
amide
[0153]
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0154]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzam-
ide
[0155]
N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
Formula (I) Compound Table (Continued, Page 9 of 10)
[0156]
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
[0157]
N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
[0158]
N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0159] N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0160]
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamid-
e
[0161]
2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro-benzami-
de
[0162]
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
[0163]
N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0164]
5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0165]
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzami-
de
[0166]
5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0167]
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzam-
ide
[0168]
N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
[0169]
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0170]
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0171]
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzam-
ide
[0172]
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzami-
de
[0173]
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide
[0174]
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamid-
e
[0175]
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamid-
e
[0176]
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0177]
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0178]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamid-
e
Formula (I) Compound Table (Continued, Page 10 of 10)
[0179]
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzami-
de
[0180]
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzam-
ide
[0181]
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0182]
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0183]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)-ben-
zamide
[0184]
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
[0185]
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0186]
N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0187]
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0188]
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)-benz-
amide
[0189]
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
[0190] 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol
[0191]
[5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol
[0192]
[2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol
[0193]
[5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol
[0194]
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
[0195] In another preferred embodiment, the MEK inhibitor is a
compound of Formula II 3
[0196] In Formula (II), R.sub.1a is hydrogen, hydroxy,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, halo,
trifluoromethyl, or CN. R.sub.2a is hydrogen. Each of R.sub.3a,
R.sub.4a, and R.sub.5a is independently selected from hydrogen,
hydroxy, halo, trifluoromethyl, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 alkoxy, nitro, CN, and (O or
NH).sub.m--(CH.sub.2).sub.n--R.sub.9a. R.sub.9a is hydrogen,
hydroxy, CO.sub.2H or NR.sub.10aR.sub.11a; n is 0-4; and m is 0 or
1. Each of R.sub.10a and R.sub.11a is independently hydrogen or
C.sub.1-C.sub.8 alkyl, or taken together with the nitrogen to which
they are attached can complete a 3- to 10-member cyclic ring
optionally containing one, two, or three additional heteroatoms
selected from O, S, NH, or N--(C.sub.1-C.sub.8 alkyl). R.sub.6a is
hydrogen, C.sub.1-C.sub.8 alkyl, (CO)--(C.sub.1-C.sub.8 alkyl),
aryl, aralkyl, or C.sub.3-C.sub.10 cycloalkyl. R.sub.7a is
hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.10 (cycloalkyl or cycloalkyl
optionally containing a heteroatom selected from O, S, or
NR.sub.9a). In Formula (II), any of the foregoingany of the
foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and
alkynyl groups can be unsubstituted or substituted by halo,
hydroxy, C.sub.1-C.sub.6 alkoxy, amino, nitro, C.sub.1-C.sub.4
alkylamino, di(C.sub.1-C.sub.4)alkylamino, C.sub.3-C.sub.6
cycloalkyl, phenyl, phenoxy, C.sub.3-C.sub.5 heteroaryl or
heterocyclic radical, or C.sub.3-C.sub.5 heteroaryloxy or
heterocyclic radical-oxy; or R.sub.6a and R.sub.7a taken together
with the N to which they are attached can complete a 5- to
10-membered cyclic ring, optionally containing one, two, or three
additional heteroatoms selected from O, S, or NR.sub.10aR.sub.11a.
The invention also encompasses pharmaceutically acceptable salts,
esters, amides or prodrugs of each of the disclosed compounds.
[0197] Preferred embodiments of Formula (II) are those structures
wherein: (a) R.sub.1a is H, methyl, fluoro, or chloro; (b) R.sub.2a
is H; R.sub.3a, R.sub.4a and R.sub.5a are each H, Cl, nitro, or F;
(c) R.sub.6a is H; (d) R.sub.7a is methyl, ethyl, 2-propenyl,
propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl methyl,
cyclopropylmethyl, or cyclopropylethyl; (e) the 4' position is I,
rather than Br; (f) R.sub.4a is F at the 4 position, para to the
CO--N--R.sub.6a--OR.sub.7a group and meta to the bridging nitrogen;
(f) R.sub.3a or R.sub.5a is F; (g) at least one of R.sub.3a,
R.sub.4a and R.sub.5a is F; (h) R.sub.1a is methyl or chloro; or
(i) or a combination of the above.
[0198] In a more preferred embodiment the MEK inhibitor is a
compound selected from Formula (II) Compound Table below.
Formula (II) Compound Table (Page 1 of 7)
[0199]
4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0200]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(methoxy)-benzamide
[0201]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)-benzami-
de
[0202]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)-benzam-
ide
[0203]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)-benza-
mide
[0204]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)-benzami-
de
[0205]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)-ben-
zamide
[0206]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentoxy)-benzamide
[0207]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-furylmethoxy)-ben-
zamide
[0208]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-ethoxy-benzamide
[0209]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benz-
amide
[0210]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)-
-benzamide
[0211]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1-methylprop-2-ynyl-
oxy)-benzamide
[0212]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-phenylprop-2-ynyl-
oxy)-benzamide
[0213]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-5-phenylpe-
nt-2-en-4-ynyloxy)-benzamide
[0214]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)-ben-
zamide
[0215]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)-benzamide
Formula (II) Compound Table (Continued, Page 2 of 7)
[0216]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclobutyloxy)-benz-
amide
[0217]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)-b-
enzamide
[0218]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-methyl-prop-2-eny-
loxy)-benzamide
[0219]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)-be-
nzamide
[0220]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benz-
amide
[0221]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-3-ynyloxy)-benz-
amide
[0222]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentyloxy)-ben-
zamide
[0223]
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-(2-fluorophenyl)--
prop-2-ynyloxy)-benzamide
[0224]
5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benz-
amide
[0225]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(n-propoxy)--
benzamide
[0226]
5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo-2-methyl-pheny-
lamino)-benzamide
[0227]
5-Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyl-phenylami-
no)-benzamide
[0228]
5-Bromo-N-butoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benza-
mide
[0229]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-bu-
t-2-enyloxy)-benzamide
[0230]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-pe-
nt-2-en-4-ynyloxy)-benzamide
Formula (II) Compound Table (Continued, Page 3 of 7)
[0231]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N-[5-(3-methoxy-phe-
nyl)-3-methyl-pent-2-en-4-ynyloxy]-benzamide
[0232]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyl-
oxy)-benzamide
[0233]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-[3-(3-methox-
y-phenyl)-prop-2-ynyloxy]-benzamide
[0234]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(thiopen-2-y-
lmethoxy)-benzamide
[0235]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(pyridin-3-y-
lmethoxy)-benzamide
[0236]
5-Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-(2-fluoro-
phenyl)-prop-2-ynyloxy)-benzamide
[0237]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(ethoxy)-ben-
zamide
[0238]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropyl-
methoxy)-benzamide
[0239]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(isopropoxy)-
-benzamide
[0240]
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but-3-ynylox-
y)-benzamide
[0241]
5-Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0242]
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran-2-ylox-
y)-benzamide
[0243]
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy-benzamide
[0244]
4-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide
[0245]
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide
[0246]
5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0247]
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide
[0248]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran-2-yloxy-
)-benzamide
Formula (II) Compound Table (Continued, Page 4 of 7)
[0249]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-phenylprop-2-yny-
loxy)-benzamide
[0250]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-furylmethoxy)-be-
nzamide
[0251]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-thienylmethoxy)--
benzamide
[0252]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-3-ynyloxy)-ben-
zamide
[0253]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl-prop-2-en-
yloxy)-benzamide
[0254]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-2-enyloxy)-ben-
zamide
[0255]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)-benzamide
[0256]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)-benzamide
[0257]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclobutoxy)-benza-
mide
[0258]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)-benzam-
ide
[0259]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)-b-
enzamide
[0260]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropylmethoxy-
)-benzamide
[0261]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)-benzami-
de
[0262]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(1-methyl-prop-2-yn-
yloxy)-benzamide
[0263]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-(3-fluorophenyl)-
-prop-2-ynyloxy)-benzamide
[0264]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(4,4-dimethylpent-2-
-ynyloxy)-benzamide
Formula (II) Compound Table (Continued, Page 5 of 7)
[0265]
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopentoxy)-benz-
amide
[0266]
3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0267]
5-Chloro-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-ben-
zamide
[0268]
5-Bromo-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benz-
amide
[0269]
N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide
[0270]
3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide
[0271]
5-Chloro-3,4-difluoro-2-(2-fluoro4-iodo-phenylamino)-N-hydroxy-benz-
amide
[0272]
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benz-
amide
[0273]
2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide
[0274]
2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benzamide
[0275]
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-ben-
zamide
[0276]
5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benza-
mide
[0277]
2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl-benzamide
[0278]
2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benzamide
[0279]
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difluoro-N-hydroxy-benz-
amide
[0280]
2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide
[0281]
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide
[0282]
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide
[0283]
2-(2-Chloro4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide
[0284]
2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide
[0285]
2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide
[0286]
2-(2-Bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide
Formula (II) Compound Table (Continued, Page 6 of 7)
[0287]
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino-
)-benzamide
[0288]
5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-pheny-
lamino)-benzamide
[0289]
5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl-
amino)-benzamide
[0290]
N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzam-
ide
[0291]
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo-phenylamino-
)-benzamide
[0292]
5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-pheny-
lamino)-benzamide
[0293]
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-di-
fluoro-benzamide
[0294]
N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro-benzam-
ide
[0295]
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluor-
o-benzamide
[0296]
5-Chloro-2-(2-chloro4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-di-
fluoro-benzamide
[0297]
5-Bromo-2-(2-bromo4-iodo-phenylamino)-N-ethoxy-3,4-difluoro-benzami-
de
[0298]
2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide
[0299]
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro-
-benzamide
[0300]
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N-cyclopropylmethoxy-3,4-di-
fluoro-benzamide
[0301]
2-(2-Bromo4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro-benzamid-
e
Formula (II) Compound Table (Continued, Page 7 of 7)
[0302]
N-Cyclopropylmethoxy-4-fluoro-2-(2-fluoro4-iodo-phenylamino)-benzam-
ide
[0303]
N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-b-
enzamide
[0304]
2-(2-Chloro4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro-benzam-
ide
[0305]
2-(2-Chloro4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-be-
nzamide
[0306]
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy4-fluoro-benzami-
de
[0307]
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-be-
nzamide.
[0308] In the most preferred embodiment of this invention, a
compound selected from the following is administered to a patient
(ie, a mammal) in an amount that is effective to prevent or treat
rheumatoid arthritis or osteoarthritis:
[0309]
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoroben-
zamide (PD184352);
2-(2-Methyl4-iodophenylamino)-N-hydroxy-4-fluorobenzami- de
(PD170611);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5-bro-
mobenzamide (PD171984);
2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethox-
y-3,4-difluoro-5-bromobenzamide (PD177168);
2-(2-Methyl-4-iodophenylamino)-
-N-cyclobutylmethoxy-3,4-difluoro-5-bromobenzamide (PD 180841);
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromob-
enzamide (PD 184161);
2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluor-
o-5-bromobenzamide (PD184386);
2-(2-Chloro-4-iodophenylamino)-N-cyclobutyl-
methoxy-3,4-difluorobenzamide (PD 185625);
2-(2-Chloro-4-iodophenylamino)-- N-hydroxy-4-fluorobenzamide (PD
185848); 2-(2-Methyl-4-iodophenylamino)-N--
hydroxy-3,4-difluorobenzamide (PD 188563);
2-(2-Methyl4-iodophenylamino)-N-
-cyclopropylmethoxy-3,4,5-trifluorobenzamide (PD 198306); and
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide
(PD 203311); and the benzoic acid derivatives thereof. For example,
the benzoic acid derivative of PD 198306 is
2-(2-Methyl-4-iodophenylamino)-3,- 4,5-trifluorobenzoic acid.
[0310] Additional preferred compounds include
2-(2-chloro-4-iodophenylamin-
o)-5-chloro-N-cyclopropylmethoxy-3,4-difluorobenzamide (PD 297189),
2-(4-iodophenylamino)-N-cyclopropylmethoxy-5-chloro-3,4-difluorobenzamide
(PD 297190), 2-(4-iodophenylamino)-5-chloro-3,4-difluorobenzoic
acid (PD 296771),
2-(2-chloro4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD
296770),
5-chloro-3,4-difluoro-2-(4-iodo-2-methylphenylamino)-benzoic acid
(PD 296767); and
5-chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iod-
o-2-methylphenylamino)-benzamide (PD 298127).
[0311] The invention further provides methods of synthesis and
synthetic intermediates.
[0312] Other features and advantages of the invention are apparent
from the detailed description, examples, and claims set forth.
[0313] In a further preferred embodiment of this invention, a
mitotic inhibitor is administered to a patient suffering from
cancer and in need of treatment in combination with a selective MEK
inhibitor selected from:
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
(PD184352);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide
(PD170611);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5-bromo-
benzamide (PD171984), a more preferred compound;
2-(2-Methyl-4-iodophenyla-
mino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide
(PD177168);
2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy-3,4-difluoro-5-bromobe-
nzamide (PD 180841);
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3-
,4-difluoro-5-bromobenzamide (PD 184161);
2-(2-Chloro-4-iodophenylamino)-N-
-hydroxy-3,4-difluoro-5-bromobenzamide (PD184386);
2-(2-Chloro-4-iodopheny-
lamino)-N-cyclobutylmethoxy-3,4-difluorobenzamide (PD 185625);
2-(2-Chloro4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD
185848);
2-(2-Methyl4-iodophenylamino)-N-hydroxy-3,4-difluorobenzamide
(PD188563);
2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3,4,5-trifluorobenzam-
ide (PD 198306); and
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-4-
-fluorobenzamide (PD 203311); and the benzoic acid derivatives
thereof. For example, the benzoic acid derivative of PD 198306 is
2-(2-Methyl-4-iodophenylamino)-3,4,5-trifluorobenzoic acid.
DETAILED DESCRIPTION OF THE INVENTION
[0314] This invention provides a method of preventing or treating
asthma in a patient which comprises administering to a patient
suffering from asthma and in need of treatment, or to a patient at
risk for developing an asthmatic attack, an anti-asthmatic
effective amount of a MEK inhibitor. The invention provides a
method of preventing and treating all forms of asthma and relieving
the symptoms that accompany the disease. The invention is
preferably practiced by administering a phenyl amine MEK inhibitor
of Formula I or Formula II. Such MEK phenyl amine compounds are
specific MEK 1 and MEK 2 inhibitors, meaning that they inhibit
these enzymes without inhibiting other enzymes to a great
extent.
[0315] The compounds of the present invention, which can be used to
treat septic shock, are MEK inhibitors. A MEK inhibitor is a
compound that shows MEK inhibition when tested in the assays titled
"Enzyme Assays" in U.S. Pat. No. 5,525,625, column 6, beginning at
line 35. The complete disclosure of U.S. Pat. No. 5,525,625 is
hereby incorporated by reference. An example of a MEK inhibitor is
2-(2-amino-3-methoxyphenyl)-4- -oxo-4H-[1]benzopyran. Specifically,
a compound is a MEK inhibitor if a compound shows activity in the
assay titled "Cascade Assay for Inhibitors of the MAP Kinase
Pathway," column 6, line 36 to column 7, line 4 of the U.S. Pat.
No. 5,525,625 and/or shows activity in the assay titled "In Vitro
MEK Assay" at column 7, lines 4 to 27 of the above-referenced
patent.
[0316] A. Terms
[0317] Some of the terms used herein are defined below and by their
usage throughout this disclosure.
[0318] The term "patient" means all animals including humans.
Examples of patients include humans, cows, dogs, cats, goats,
sheep, horses, and pigs. The mammals to be treated according to
this invention are patients who have developed asthma and are
suffering from the symptoms associated with disease, or who are at
risk for developing the disease, for example having a family
history of asthma. Those skilled in the medical art are readily
able to identify individual patients, particularly children, who
are afflicted with asthma, as well as those who are susceptible to
developing the disease.
[0319] As used herein, the term "aryl" means a cyclic, bicyclic, or
tricyclic aromatic ring moiety having from five to twelve carbon
atoms. Examples of typical aryl groups include phenyl, naphthyl,
and fluorenyl. The aryl may be substituted by one, two, or three
groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy,
alkoxy, nitro, amino, alkylamino, or dialkylamino. Typical
substituted aryl groups include 3-fluorophenyl,
3,5-dimethoxyphenyl, 4-nitronaphthyl,
2-methyl-4-chloro-7-aminofluorenyl, and the like.
[0320] The term "aryloxy" means an aryl group bonded through an
oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and
4-methyl-1-fluorenyloxy.
[0321] "Heteroaryl" means a cyclic, bicyclic, or tricyclic aromatic
ring moiety having from four to eleven carbon atoms and one, two,
or three heteroatoms selected from O, S, or N. Examples include
furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,
thiazolyl, oxazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl,
naphthyridyl, pyridyl, benzinnidazolyl, and triazinyl. The
heteroaryl groups can be unsubstituted or substituted by one, two,
or three groups selected from fluoro, chloro, bromo, iodo, alkyl,
hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino.
Examples of substituted heteroaryl groups include chloropyranyl,
methylthienyl, fluoropyridyl, amino-1,4-benzisoxazinyl,
nitroisoquinolinyl, and hydroxyindolyl.
[0322] The heteroaryl groups can be bonded through oxygen to make
heteroaryloxy groups, for example thienyloxy, isothiazolyloxy,
benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.
[0323] The term "alkyl" means straight and branched chain aliphatic
groups. Typical alkyl groups include methyl, ethyl, isopropyl,
tert.-butyl, 2,3-dimethylhexyl, and 1,1-dimethylpentyl. The alkyl
groups can be unsubstituted or substituted by halo, hydroxy,
alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy,
heteroaryl, or heteroaryloxy, as those terms are defined herein.
Typical substituted alkyl groups include chloromethyl,
3-hydroxypropyl, 2-dimethylaminobutyl, and
2-(hydroxymethylamino)ethyl. Examples of aryl and aryloxy
substituted alkyl groups include phenylmethyl, 2-phenylethyl,
3-chlorophenylmethyl, 1,1-dimethyl-3-(2-nitrophenoxy)butyl, and
3,4,5-trifluoronaphthylmethyl. Examples of alkyl groups substituted
by a heteroaryl or heteroaryloxy group include thienylmethyl,
2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and
6-isothiazolylhexyl. Cycloalkyl substituted alkyl groups include
cyclopropylmethyl, 2-cyclohexyethyl, piperidyl-2-methyl,
2-(piperidin-1-yl)-ethyl, 3-(morpholin-4-yl)propyl.
[0324] "Alkenyl" means a straight or branched carbon chain having
one or more double bonds. Examples include but-2-enyl,
2-methyl-prop-2-enyl, 1,1-dimethyl-hex-4-enyl,
3-ethyl-4-methyl-pent-2-enyl, and 3-isopropyl-pent-4-enyl. The
alkenyl groups can be substituted with halo, hydroxy, alkoxy,
amino, alkylamino, dialkylamino, aryl, aryloxy, heteroaryl, or
heteroyloxy, for example 2-bromoethenyl, 3-hydroxy-2-butenyl,
1-aminoethenyl, 3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl,
2-furyloxy-but-2-enyl, and 4-naphthyloxy-hex-2-enyl- .
[0325] "Alkynyl" means a straight or branched carbon chain having
at least one triple bond. Typical alkynyl groups include
prop-2-ynyl, 2-methyl-hex-5-ynyl, 3,4-dimethyl-hex-5-ynyl, and
2-ethyl-but-3-ynyl. The alkynyl groups can be substituted as the
alkyl and alkenyl groups, for example, by aryl, aryloxy,
heteroaryl, or heteroaryloxy, for example
4-(2-fluorophenyl)-but-3-ynyl, 3-methyl-5-thienylpent-4-ynyl,
3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl-hex-4-ynyl.
[0326] The alkenyl and alkynyl groups can have one or more double
bonds or triple bonds, respectively, or a combination of double and
triple bonds. For example, typical groups having both double and
triple bonds include hex-2-en-4-ynyl,
3-methyl-5-phenylpent-2-en-4-ynyl, and
3-thienyloxy-hex-3-en-5-ynyl.
[0327] The term "cycloalkyl" means a nonaromatic ring or fused
rings. Examples include cyclopropyl, cyclobutyl, cyclopenyl,
cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl. The ring can
optionally contain one, two, or three heteroatoms selected from O,
S, or N. Such groups include tetrahydrofuryl, tetrahydropyrrolyl,
octahydrobenzofuranyl, morpholinyl, piperazinyl, pyrrolidinyl,
piperidinyl, octahydroindolyl, and octahydrobenzothiofuranyl. The
cycloalkyl groups can be substituted with the same substituents as
an alkyl and alkenyl groups, for example, halo, hydroxy, aryl, and
heteroaryloxy. Examples include 3-hydroxycyclohexyl,
2-aminocyclopropyl, 2-phenylpyrrolidinyl, and
3-thienylmorpholine-1-yl.
[0328] Selective MEK 1 or MEK 2 inhibitors are those compounds
which inhibit the MEK 1 or MEK 2 enzymes, respectively, without
substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A,
phosphorylase kinase, EGF, and PDGF receptor kinases, and C-src. In
general, a selective MEK 1 or MEK 2 inhibitor has an IC.sub.50 for
MEK 1 or MEK 2 that is at least one-fiftieth ({fraction (1/50)})
that of its IC.sub.50 for one of the above-named other enzymes.
Preferably, a selective inhibitor has an IC.sub.50 that is at least
{fraction (1/100)}, more preferably {fraction (1/500)}, and even
more preferably {fraction (1/1000)}, {fraction (1/5000)}, or less
than that of its IC.sub.50 or one or more of the above-named
enzymes.
[0329] B. Administration and Formulation
[0330] The MEK inhibitors of the present method can be administered
to a patient as part of a pharmaceutically acceptable composition.
The compositions can be administered to humans and animals either
orally, rectally, parenterally (intravenously, intramuscularly,or
subcutaneously), intracisternally, intravaginally,
intraperitoneally, intravesically, locally (powders, ointments, or
drops), or as a buccal or nasal spray.
[0331] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or vehicles include water, ethanol, polyols
(propyleneglycol, polyethyleneglycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil), and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions and by the use of surfactants.
[0332] These compositions may also contain adjuvants such as
preserving, wetting, emulsifying, and dispensing agents. Prevention
of the action of microorganisms can be ensured by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example sugars, sodium
chloride, and the like. Prolonged absorption of the injectable
pharmaceutical form can be brought about by the use of agents
delaying absorption, for example, aluminum monostearate and
gelatin.
[0333] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is admixed with at least one inert customary
excipient (or carrier) such as sodium citrate or dicalcium
phosphate or (a) fillers or extenders, as for example, starches,
lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders,
as for example, carboxymethylcellulose, alignates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for
example, glycerol, (d) disintegrating agents, as for example,
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain complex silicates, and sodium carbonate, (e) solution
retarders, as for example paraffin, (f) absorption accelerators, as
for example, quaternary ammonium compounds, (g) wetting agents, as
for example, cetyl alcohol and glycerol monostearate, (h)
adsorbents, as for example, kaolin and bentonite, and (i)
lubricants, as for example, talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, or
mixtures thereof. In the case of capsules, tablets, and pills, the
dosage forms may also comprise buffering agents.
[0334] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethyleneglycols, and the like.
[0335] Solid dosage forms such as tablets, dragees, capsules,
pills, and granules can be prepared with coatings and shells, such
as enteric coatings and others well-known in the art. They may
contain opacifying agents, and can also be of such composition that
they release the active compound or compounds in a certain part of
the intestinal tract in a delayed manner. Examples of embedding
compositions which can be used are polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned
excipients.
[0336] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to the active compounds, the
liquid dosage forms may contain inert diluents commonly used in the
art, such as water or other solvents, solubilizing agents and
emulsifiers, as for example, ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in
particular, cottonseed oil, groundnut oil, corn germ oil, olive
oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl
alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or
mixtures of these substances, and the like.
[0337] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0338] Suspensions, in addition to the active compounds, may
contain suspending agents, as for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, or mixtures of these substances, and the
like.
[0339] Compositions for rectal administrations are preferably
suppositories which can be prepared by mixing the compounds of the
present invention with suitable non-irritating excipients or
carriers such as cocoa butter, polyethyleneglycol, or a suppository
wax, which are solid at ordinary temperatures but liquid at body
temperature and therefore, melt in the rectum or vaginal cavity and
release the active component.
[0340] Dosage forms for topical administration of a compound of
this invention include ointments, powders, sprays, and inhalants.
The active component is admixed under sterile conditions with a
physiologically acceptable carrier and any preservatives, buffers,
or propellants as may be required. Ophthalamic formulations, eye
ointments, powders, and solutions are also contemplated as being
within the scope of this invention.
[0341] The compounds of the present method can be administered to a
patient at dosage levels in the range of about 0.1 to about 1000 mg
per day. For a normal human adult having a body weight of about 70
kg, a dosage in the range of about 0.01 to about 100 mg per kg of
body weight per day is preferable. The specific dosage used,
however, can vary. For example, the dosage can depend on a numbers
of factors including the requirements of the patient, the severity
of the condition being treated, and the pharmacological activity of
the compound being used. The determination of optimum dosages for a
particular patient is well-known to those skilled in the art.
[0342] The compounds of the present method can be administered as
pharmaceutically acceptable salts, esters, amides, or prodrugs. The
term "pharmaceutically acceptable salts, esters, amides, and
prodrugs" as used herein refers to those carboxylate salts, amino
acid addition salts, esters, amides, and prodrugs of the compounds
of the present invention which are, within the scope of sound
medical judgment, suitable for contact with the tissues of patients
without undue toxicity, irritation, allergic response, and the
like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the invention.
[0343] The term "salts" refers to the relatively non-toxic,
inorganic and organic acid addition salts of compounds of the
present invention. These salts can be prepared in situ during the
final isolation and purification of the compounds or by separately
reacting the purified compound in its free base form with a
suitable organic or inorganic acid and isolating the salt thus
formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate,
valerate, oleate, palmitate, stearate, laurate, borate, benzoate,
lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate, mesylate, glucoheptonate,
lactiobionate and laurylsulphonate salts, and the like. These may
include cations based on the alkali and alkaline earth metals, such
as sodium, lithium, potassium, calcium, magnesium and the like, as
well as nontoxic ammonium, quaternary ammonium, and amine cations
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. (See, for example, S. M.
Berge, et al., "Pharmaceutical Salts," J. Pham. Sci., 1977;66:1-19
which is incorporated herein by reference.) Examples of
pharmaceutically acceptable, non-toxic esters of the compounds of
this invention include C.sub.1-C.sub.6 alkyl esters wherein the
alkyl group is a straight or branched chain. Acceptable esters also
include C.sub.5-C.sub.7 cycloalkyl esters as well as arylalkyl
esters such as, but not limited to benzyl. C.sub.1-C.sub.4 alkyl
esters are preferred. Esters of the compounds of the present
invention may be prepared according to conventional methods.
[0344] Examples of pharmaceutically acceptable, non-toxic amides of
the compounds of this invention include amides derived from
ammonia, primary C.sub.1-C.sub.6 alkyl amines and secondary
C.sub.1-C.sub.6 dialkyl amines wherein the alkyl groups are
straight or branched chain. In the case of secondary amines the
amine may also be in the form of a 5 or 6 membered heterocycle
containing one nitrogen atom. Amides derived from ammonia,
C.sub.1-C.sub.3 alkyl primary amines and C.sub.1-C.sub.2 dialkyl
secondary amines are preferred. Amides of the compounds of the
invention may be prepared according to conventional methods.
[0345] The term "prodrug" refers to compounds that are rapidly
transformed in vivo to yield the parent compound of the above
formula, for example, by hydrolysis in blood. A thorough discussion
is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel
Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987, both
of which are incorporated herein by reference.
[0346] In addition, the compounds of the present method can exist
in unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. In
general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of the present invention.
[0347] Some of the compounds of the present method can exist in
different stereoisometric forms by virtue of the presence of chiral
centers. It is contemplated that all stereoisometric forms of the
compounds as well as mixtures thereof, including racemic mixtures,
form part of this invention.
[0348] C. Synthesis
[0349] The examples presented below are intended to illustrate
particular embodiments of the invention and are not intended to
limit the scope of the specification, including the claims, in any
way. After the priority date of the present disclosure, related
syntheses and MEK inhibition data were also published in WO
99/01421 and WO 99/01426, hereby incorporated by reference.
[0350] The 2-(4-bromo and 4-iodo phenylamino)-benzoic acid
derivatives of Formula I can be prepared from commercially
available starting materials utilizing synthetic methodologies
well-known to those skilled in organic chemistry. A typical
synthesis is carried out by reacting a 4-bromo or 4-iodo aniline
with a benzoic acid having a leaving group at the 2-position to
give a 2-(phenylamino)-benzoic acid. This process is depicted in
Scheme 1. 4
[0351] where L is a leaving group, for example halo such as
fluoro.
[0352] The reaction of aniline and the benzoic acid derivative
generally is accomplished by mixing the benzoic acid with an
equimolar quantity or excess of the aniline in an unreactive
organic solvent such as tetrahydrofuran or toluene, in the presence
of a base such as lithium diisopropylamide, n-butyl lithium, sodium
hydride, triethylamine, and Hunig's base. The reaction generally is
carried out at a temperature of about -78.degree. C. to about
100.degree. C., and normally is complete within about 2 hours to
about 4 days. The product can be isolated by removing the solvent,
for example by evaporation under reduced pressure, and further
purified, if desired, by standard methods such as chromatography,
crystallization, or distillation.
[0353] The 2-(phenylamino)-benzoic acid (e.g., Formula I, where
R.sub.7 is hydrogen) can be reacted with an organic or inorganic
base such as pyridine, triethylamine, calcium carbonate, or sodium
hydroxide to produce a pharmaceutically acceptable salt. The free
acids can also be reacted with an alcohol of the formula HOR.sub.7
(where R.sub.7 is other than hydrogen, for example methyl) to
produce the corresponding ester. Reaction of the benzoic acid with
an alcohol can be carried out in the presence of a coupling agent.
Typical coupling reagents include
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
1,3-dicyclohexylcarbodiimide (DCC),
bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP),
and (benzotriazolyloxy) tripyrrolidino phosphonium
hexafluorophosphate (PyBOP). The phenylamino benzoic acid and
alcohol derivative normally are mixed in approximately equimolar
quantities in an unreactive organic solvent such as
dichloromethane, tetrahydrofuran, chloroform, or xylene, and an
equimolar quantity of the coupling reagent is added. A base such as
triethylamine or diisopropylethylamine can be added to act as an
acid scavenger if desired. The coupling reaction generally is
complete after about 10 minutes to 2 hours, and the product is
readily isolated by removing the reaction solvent, for instance by
evaporation under reduced pressure, and purifying the product by
standard methods such as chromatography or crystallizations from
solvents such as acetone, diethyl ether, or ethanol.
[0354] The benzamides of the invention, Formula I where Z is
CONR.sub.6R.sub.7, are readily prepared by reacting the foregoing
benzoic acids with an amine of the formula HNR.sub.6R.sub.7. The
reaction is carried out by reacting approximately equimolar
quantities of the benzoic acid and amine in an unreactive organic
solvent in the presence of a coupling reagent. Typical solvents are
chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and
xylene. Typical coupling reagents include DCC, EEDQ, PyBrOP, and
PyBOP. The reaction is generally complete after about 10 minutes to
about 2 hours when carried out at a temperature of about 0.degree.
C. to about 60.degree. C. The product amide is readily isolated by
removing the reaction solvent, for instance by evaporation, and
further purification can be accomplished by normal methods such as
chromatography, crystallization, or distillation. The hydrazides
(z=CONHNR.sub.10R.sub.11) are similarly prepared by coupling a
benzoic acid with a hydrazine of the formula
H.sub.2HNR.sub.10R.sub.11.
[0355] The benzyl alcohols of the invention, compounds of Formula I
where Z is CH.sub.2OR.sub.6 and R.sub.6 is hydrogen, are readily
prepared by reduction of the corresponding benzoic acid according
to the following Scheme 2. 5
[0356] Typical reducing agents commonly employed include borane in
tetrahydrofuran. The reduction normally is carried out in an
unreactive organic solvent such as tetrahydrofuran, and generally
is complete within about 2 hours to about 24 hours when conducted
at a temperature of about 0.degree. C. to about 40.degree. C.
[0357] The following detailed examples illustrate specific
compounds provided by this invention.
EXAMPLE 1
4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid
[0358] To a stirring solution comprised of 3.16 g (0.0133 mol) of
2-amino-5-iodotoluene in 5 mL of tetrahydrofuran at -78.degree. C.
was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in
tetrahydrofuran/heptane/ethenylbenzene (Aldrich) solution. The
resulting green suspension was stirred vigorously for 15 minutes,
after which time a solution of 1.00 g (0.00632 mol) of
2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The
reaction temperature was allowed to increase slowly to room
temperature, at which temperature it was stirred for 2 days. The
reaction mixture was concentrated. Aqueous HCl (10%) was added to
the concentrate, and the solution was extracted with
dichloromethane. The organic phase was dried (MgSO.sub.4) and then
boiled over a steambath to low volume and cooled to room
temperature. The off-white fibers were collected by vacuum
filtration, rinsed with hexanes, and vacuum-oven dried. (76.degree.
C.; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired
material;
[0359] mp 224-229.5.degree. C.; .sup.1H NMR (400 MHz; DMSO):
.delta. 9.72 (s, 1H), 7.97 (dd, 1H, J=7.0, 8.7 Hz), 7.70 (d, 1H,
J=1.5 Hz), 7.57 (dd, 1H, J=8.4, 1.9 Hz), 7.17 (d, 1H, J=8.2 Hz),
6.61-6.53 (m, 2H), 2.18 (s, 3H); .sup.13C NMR (100 MHz; DMSO):
.delta. 169.87, 167.60, 165.12, 150.17, 150.05, 139.83, 138.49,
136.07, 135.31, 135.20, 135.07, 125.60, 109.32, 105.09, 104.87,
99.72, 99.46, 89.43, 17.52; .sup.19F NMR (376 MHz; DMSO): .delta.
-104.00 to -104.07 (m); IR (KBr) 1670 (C.dbd.O stretch) cm.sup.-1;
MS (CI) M+1=372. Analysis calculated for
C.sub.14H.sub.11FINO.sub.2: C, 45.31; H, 2.99; N, 3.77. Found: C,
45.21; H, 2.77; N, 3.64.
EXAMPLES 2-30
[0360] By following the general procedure of Example 1, the
following benzoic acids and salts of Formula (I) were prepared.
1 Example No. Compound MP.degree. C. 2
3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)- 206-210 benzoic
acid 3 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benz- oic
240.5-244.5 acid 4 5-Bromo-3,4-difluoro-2-(4-iodo-2-met- hyl-
259.5-262 phenylamino)-benzoic acid 5
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-benzoic acid 255-260 6
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 234-238 7
Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 310-320 benzoate
DEC 8 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
239.5-240 9 2-(2-Chloro-4-iodo-phenylamino)-5-nitro-benzoic acid
289-293 10 4-Fluoro-2-(3-fluoro-4-iodo-2-methyl-phenylamino)-
233-235 benzoic acid 11 2-(4-Iodo-2-methyl-phenylamino)-5--
nitro-benzoic acid 264-267 12
2-(2-Fluoro-4-iodo-phenylamino)-5-nit- ro-benzoic acid 256-258 13
2-(4-Bromo-2-methyl-phenylamino)-4-fluor- o-benzoic 218.5-220 acid
14 2-(2-Bromo-4-iodo-phenylamino- )-5-nitro-benzoic acid 285-288
DEC 15 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro- 230-234
benzoic acid 16 3-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic
acid 218-221 17 3,4-Difluoro-2-(4-iodo-2-methoxy-phenylamino)-
230-233 benzoic acid 18 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-b-
enzoic acid 245-255 DEC 19 2-(4-Iodo-2-methyl-phenylamino)-
-benzoic acid 218-223 20
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-b- enzoic acid 243-46 21
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzo- ic acid 241-245 22
2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)- 218-222 benzoic
acid 23 4-Fluoro-2-(3-chloro-4-iodo-2-meth- yl-phenylamino)-
248-252.5 benzoic acid 24 2-(4-Iodo-phenylamino)-5-methoxy-benzoic
acid 208-211 25 3-Chloro-2-(2-chloro-4-iodo-phenylamino)-benzoic
acid 232-233 26 2-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoic
acid 179-182 27 4-Fluoro2-(2,3-dimethyl-4-iodo-2-methyl- 258-261
phenylamino)benzoic acid 28 5-Methyl-2-(4-iodo-2-methyl-phenylamin-
o)-benzoic 209.5-211 acid 29 2-Chloro-6-(4-iodo-2-methyl--
phenylamino)-benzoic acid 171-175 30
2-(4-Iodo-2-methyl-phenylamino- )-4-nitro-benzoic acid 251-263
EXAMPLE 31
5Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide
[0361] To a stirring solution comprised of 0.1020 g (0.2632 mmol)
of 5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid, 0.1 mL
(1.7 mmol) of ethanolamine, and 0.05 mL (0.29 mmol) of
diisopropylethylamine in 5 mL of a 1:1 (v/v)
tetrahydrofuran-dichloromethane solution was added 0.15 g (0.29
mmol) of solid PyBOP powder directly. The reaction mixture was
stirred at room temperture overnight. The solvent was removed in
vacuo. The crude residue was partitioned between ether (50 mL) and
10% aqueous hydrochloric acid (50 mL). The organic phase was washed
with 10% aqueous sodium hydroxide (50 mL), dried SO.sub.4) and
concentrated in vacuo to afford a yellow-brown oil which was
crystallized from hexanes-ether to afford 0.0831 g (73%) of a
green-yellow power; mp 120-121.degree. C.;
[0362] .sup.1H NMR (400 MHz; CDCl.sub.3): .delta. 9.11 (s, 1H),
7.56 (d, 1H, J=1.4 Hz), 7.46-7.41 (m, 2H), 7.20 (dd, 1H, J=8.9, 2.4
Hz), 7.00 (t, 2H, J=9.6 Hz), 6.55 (broad t, 1H), 3.86 (t, 2H, J=5.0
Hz), 3.61 (dd, 2H, J=10.1, 5.5 Hz), 2.23 (s, 3H), 1.56 (broad s,
1H); IR (KBr) 3297 (O--H stretch), 1627 (C.dbd.O stretch)
cm.sup.-1; MS (CI) M+1=431. Analysis calculated for
C.sub.16H.sub.16ClIN.sub.2O.sub.2: C, 44.62; H, 3.74; N, 6.50.
Found: 44.63; H, 3.67; N, 6.30.
EXAMPLES 32-48
[0363] By following the general procedure of Example 31, the
following benzamides were prepared by reacting the corresponding
benzoic acid with the corresponding amine.
2 Example No. Compound MP.degree. C. 32
4-Methoxy-N-(4-methoxy-phenyl)-3-nitro- 153.5-156 benzamide 33
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 158 benzamide 34
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 102.5-104.5
methyl-benzamide 35 N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamin-
o)- 90-91 benzamide 36 4-Fluoro-2-(4-iodo-2-methyl-phenylam-
ino)-N,N- oil dimethyl-benzamide 37 4-Fluoro-2-(4-iodo-2-me-
thyl-phenylamino)-N-(1H- 285-288 tetrazol-5-yl)-benzamide DEC 38
5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 180-182 benzamide 39
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N- 137-138
dimethyl-benzamide 40 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-
170-173 benzoylamino]-acetic acid 41
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 69-71 propyl-benzamide
42 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- - 132-133.4
phenylamino)-benzamide 43 N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-
oil phenylamino)-benzamide 44
4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piper- azin-1-yl]- 122-124
propyl}-2-(4-iodo-2-methyl-phenylamino)- benzamide 45
N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5- 91-93
nitro-benzamide 46 N-Butyl-4-fluoro-2-(4-iodo-2-meth-
yl-phenylamino)- 97-99 benzamide 47 5-Chloro-N,N-diethyl-2--
(4-iodo-2-methyl- 118-120 phenylamino)-benzamide 48
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N- 142.5-144
dimethyl-benzamide
EXAMPLE 49
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol
[0364] 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (0.50
g, 1.35 mmol) was dissolved in 6 mL (6 mmol) of cold 1.0 M
borane-tetrahydrofuran complex in tetrahydrofuran solution. The
reaction mixture was stirred under nitrogen atmosphere at room
temperature overnight. The reaction was quenched with 80 mL of
methanol. Concentration in vacuo produced a clear tan oil which was
purified by MPLC. Elution with dichloromethane afforded 0.4285 g
89%) of a white solid; mp 99-100.5.degree. C.;
[0365] .sup.1H NMR (400 MHz; DMSO): .delta. 7.57 (d, 1H, J=1.7 Hz),
7.45 (dd, 1H, J=8.4, 1.9 Hz), 7.39 (s, 1H), 7.29 (t, 1H, J=7.5 Hz),
6.89 (d, 1H, J=8.4 Hz), 6.67-6.60 (m, 1H), 5.47 (t,1H, J=5.5 Hz),
4.49 (d, 2H, 5.1 Hz), 2.14 (s, 3H); IR (KBr) 3372 (O--H stretch)
cm.sup.-1; MS (CI) M+1=358. Analysis calculated for
C.sub.14H.sub.13FINO: C, 47.08; H, 3.67; N, 3.92. Found: C, 47.17;
H, 3.75; N, 3.72.
EXAMPLE 50-52
[0366] The following benzyl alcohols were prepared by the general
procedure of Example 49.
3 Example No. Compound MP.degree. C. 50
[5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 82-85 phenyl]-methanol
51 [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-pheny- l]- 126.5-128.5
methanol 52 [5-Bromo-2-(4-iodo-2-methyl-phe- nylamino)- 60.5-63.5
phenyl]-methanol
[0367] Several invention compounds of Formula I were prepared
utilizing combinatorial synthetic techniques. The general procedure
is as follows:
[0368] To a 0.8-mL autosampler vial in a metal block was added 40
.mu.L of a 0.5 M solution of the acid in DMF and 40 .mu.L of the
reagent amine (2 M solution in Hunig's base and 1 M in amine in
DMF). A 0.5 M solution of PyBrop was freshly prepared and 50 .mu.L
were added to the autosampler vial. The reaction was allowed to
stand for 24 hours.
[0369] The reaction mixture was transferred to a 2-dram vial and
diluted with 2 mL of ethyl acetate. The organic layer was washed
with 3 mL of distilled water and the water layer washed again with
2 mL of ethyl acetate. The combined organic layers were allowed to
evaporate to dryness in an open fume hood.
[0370] The residue was taken up in 2 mL of 50% acetonitrile in
water and injected on a semi-prep reversed phase column (10
mm.times.25 cm, 5 .mu.M spherical silica, pore size 115 A
derivatized with C-18, the sample was eluted at 4.7 mL/min with a
linear ramp to 100% acetonitrile over 8.5 minutes. Elution with
100% acetonitrile continued for 8 minutes). Fractions were
collected by monitoring at 214 nM. The residue was dissolved in
chloroform and transferred to a preweighed vial, evaporated, and
weighed again to determine the yield.
EXAMPLES 53-206
[0371] The following compounds of Formula I were prepared by
combinatorial methodology:
4 Example MS No. Compound M - H 53
5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 510
phenylamino)-benzamide 54 N-(2,3-Dihydroxy-propyl)-3,4-difluo-
ro-2-(4-iodo-2-methyl- 462 phenylamino)-benzamide 55
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- 577
piperidin-1-yl-ethyl)-benzamide 56 3,4-Difluoro-N-(2-hydroxy-ethyl-
)-2-(4-iodo-2-methyl- 432 phenylamino)-benzamide 57
N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- 444
phenylamino)-benzamide 58 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-i-
odo-2-methyl- 446 phenylamino)-benzamide 59
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 564
(2-pyrrolidin-1-yl-ethyl)-benzamide 60 5-Bromo-3,4-difluoro-2-(4-i-
odo-2-methyl-phenylamino)-N- 571 (2-pyridin-4-yl-ethyl)-benzamide
61 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-
414 benzamide 62 5-Bromo-N-(3-dimethylamino-propyl)-3,4-di-
fluoro-2-(4-iodo- 551 2-methyl-phenylamino)-benzamide 63
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 580
(2-morpholin-4-yl-ethyl)-benzamide 64 3,4-Difluoro-2-(4-iodo-2-met-
hyl-phenylamino)-N-(2-morpholin- 501 4-yl-ethyl)-benzamide 65
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 485
1-yl-ethyl)-benzamide 66 3,4-Difluoro-2-(4-iodo-2-methyl-phenyl-
amino)-N-(2-pyridin-4-yl- 493 ethyl)-benzamide 67
N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- 473
phenylamino)-benzamide 68 N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phe-
nylamino)-benzamide 460 69
2-(4-Bromo-2-methyl-phenylamino)-3,4-dif- luoro-N-(2-hydroxy- 384
ethyl)-benzamide 70
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- 483
ethyl)-benzamide 71 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3--
piperidin-1-yl- 495 propyl)-benzamide 72
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 513
1-yl-propyl)-benzamide 73 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-
-N-(2-thiophen-2-yl- 480 ethyl)-benzamide 74
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl- 467
ethyl)-benzamide 75 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-
-N-(2-morpholin- 453 4-yl-ethyl)-benzamide 76
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 557
pyridin-4-ylmethyl-benzamide 77 3,4-Difluoro-2-(4-iodo-2-methyl-ph-
enylamino)-N-pyridin- 479 4-ylmethyl-benzamide 78
2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino-propyl)- 425
3,4-difluoro-benzamide 79 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-
-N-pyridin-4-ylmethyl- 461 benzamide 80
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- 475
ethyl)-benzamide 81 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro--
N-(2-pyridin- 445 4-yl-ethyl)-benzamide 82
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy- 400
propyl)-benzamide 83 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-
-N-(2-pyrrolidin- 437 1-yl-ethyl)-benzamide 84
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- 474 benzamide
85 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-th- iophen-
450 2-yl-ethyl)-benzamide 86
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin- 431
4-ylmethyl-benzamide 87 2-(4-Bromo-2-methyl-phenylamino)-3,4-diflu-
oro-N-phenethyl- 444 benzamide 88 2-(4-Bromo-2-methyl-pheny-
lamino)-3,4-difluoro-N-(2-piperidin- 451 1-yl-ethyl)-benzamide 89
5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}- 557*
2-(4-iodo-2-methyl-phenylamino)- benzamide 90
5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}- 541*
2-(4-iodo-2-methyl- phenylamino)- benzamide 91
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- 487
benzamide 92 5-Bromo-N-{ 3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-p-
ropyl}- 601* 2-(4-iodo-2-methyl- phenylamino)- benzamide 93
5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 486*
phenylamino)- benzamide 94 5-Chloro-2-(4-iodo-2-methyl-phenylamino-
)-N-(2-piperidin-1-yl- 497* ethyl)-benzamide 95
(3-Hydroxy-pyrrolidin-1-yl)-[2-(4-iodo-2-methyl-phenylamino)- 466
5-nitro-phenyl]-methanone 96 5-Chloro-2-(4-iodo-2-methyl-phenylami-
no)-N-(2-pyrrolidin-1-yl- 484* ethyl)-benzamide 97
5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 530*
phenylamino)- benzamide 98 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethy-
l}-5-chloro-2-(4-iodo- 518* 2-methyl- phenylamino)- benzamide 99
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo- 562*
2-methyl- phenylamino)- benzamide 100 [5-Bromo-2-(4-iodo-2-me-
thyl-phenylamino)-phenyl]-(3-hydroxy- 499 pyrrolidin-1-yl)-methano-
ne 101 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid
phenethyl 501 ester 102 N-{3-[4-(2-Hydroxy-ethyl)-piperazi-
n-1-yl]-propyl }-2-(4-iodo- 568* 2-methyl-phenylamino)- benzamide
103 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy-
455 pyrrolidin-1-yl)-methanone 104 5-Fluoro-2-(4-iodo-2-me-
thyl-phenylamino)-N-pyridin-4-ylmethyl- 460 benzamide 105
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl- 528*
ethyl)-benzamide 106 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-
-piperidin-1-yl- 542* ethyl)-benzamide 107
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl- 468*
ethyl)-benzamide 108 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-io-
do-2-methyl- 472* phenylamino)-benzamide 109
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo- 502*
2-methyl- phenylamino)- benzamide 110 5-Chloro-N-(3-hydroxy-propy-
l)-2-(4-iodo-2-methyl- 445* phenylamino)-benzamide 111
5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo- 516*
2-methyl-phenylamino)- benzamide 112 5-Fluoro-2-(4-iodo-2-methyl-p-
henylamino)-N-(2-piperidin-1-yl- 482* ethyl)-benzamide 113
5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 489*
phenylamino)-benzamide 114 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-
-N-(3-piperidin-1-yl- 556* propyl)-benzamide 115
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl- 529*
phenylamino)-5-nitro-benzamide 116 5-Chloro-2-(4-iodo-2-methyl-ph-
enylamino)-N-(2-morpholin-4-yl- 500* ethyl)-benzamide 117
5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl- 500*
phenylamino)-benzamide 118 5-Chloro-N-(2-diisopropylamino-ethyl)-2-
-(4-iodo-2-methyl- 514* phenylamino)-benzamide 119
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl- 512*
propyl)-benzamide 120 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(-
2-piperidin-1-yl- 509* ethyl)-benzamide 121
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin-1-yl- 544*
ethyl)-benzamide 122 N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-
-methyl- 470* phenylamino)-benzamide 123
5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- 516*
phenylamino)-benzamide 124 N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-
-phenylamino)-5-nitro- 456* benzamide 125
5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 429*
phenylamino)-benzamide 126 N-(3-Diethylamino-propyl)-5-fluoro-2-(4-
-iodo-2-methyl- 484* phenylamino)-benzamide 127
N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 511*
5-nitro-benzamide 128 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-
-morpholin-4-yl- 544* ethyl)-benzamide 129
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-1-yl- 523*
propyl)-benzamide 130 [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-ph-
enyl]-(3-hydroxy- 439 pyrrolidin-1-yl)-methanone 131
5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- 558*
phenylamino)-benzamide 132 5-Fluoro-2-(4-iodo-2-methyl-phenylamino-
)-N-(2-morpholin-4-yl- 484* ethyl)-benzamide 133
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl- 496*
propyl)-benzamide 134 [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-p-
henyl]- 482 [4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone 135
N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo- 500*
2-methyl-phenylamino)-benzamide 136 [5-Chloro-2-(4-iodo-2-methyl-p-
henylamino)-benzoylamino]- 443 acetic acid 137
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-pyrrolidin-1-yl- 495*
ethyl)-benzamide 138 N-(3-Dimethylamino-propyl)-2-(4-iodo-2-methy-
l-phenylamino)- 483* 5-nitro-benzamide 139
N-(2-Diisopropylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- 498*
phenylamino)- benzamide 140 5-Fluoro-2-(4-iodo-2-methyl-phenylamin-
o)-thiobenzoic acid S- 490 phenethyl ester 141
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 506
phenethyl ester 142 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-thiobe-
nzoic acid S- 536 benzyl ester 143 2-(4-Iodo-2-methyl-pheny-
lamino)-5-nitro-thiobenzoic acid S- 503 benzyl ester 144
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 476
benzyl ester 145 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenz-
oic acid S- 492 benzyl ester 146 N-Cyclopropyl-5-fluoro-2-(-
4-iodo-2-methyl-phenylamino)- 409 benzamide 147
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 429
benzamide 148 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phen-
ylamino)- 413 benzamide 149 N-Benzyloxy-5-fluoro-2-(4-iodo--
2-methyl-phenylamino)- 475 benzamide 150
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 593* benzamide
151 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamo- yl- 567
benzyl)-benzamide 152 5-Bromo-N-(2-hydroxy-ethyl)-2-
-(4-iodo-2-methyl-phenylamino)- 473 benzamide 153
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 521
benzamide 154 N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)--
5-nitro- 440 benzamide 155 2-(4-Iodo-2-methyl-phenylamino)--
N-methyl-5-nitro-N-phenyl- 486 benzamide 156
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 425
benzamide 157 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N--
phenyl- 459 benzamide 158 N-Allyl-5-fluoro-2-(4-iodo-2-meth-
yl-phenylamino)-benzamide 409 159
N-Benzyloxy-5-iodo-2-(4-iodo-2-me- thyl-phenylamino)- 583 benzamide
160 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 538
benzyl)-benzamide 161 N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylam-
ino)-benzamide 425 162
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino- )-5-nitro- 436
benzamide 163 5-Bromo-N-cyclopropyl-2-(4-iod-
o-2-methyl-phenylamino)- 469 benzamide 164
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 475
benzamide 165 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoy-
l-benzyl)- 646 benzamide 166 5-Bromo-2-(4-iodo-2-methyl-phe-
nylamino)-N-(4-sulfamoyl- 598 benzyl)-benzamide 167
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 436 168
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl- 565
benzyl)-benzamide 169 N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylami-
no)-benzamide 469 170
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3- -methyl-benzyl)- 473
benzamide 171 N-Cyclopropyl-5-iodo-2-(-
4-iodo-2-methyl-phenylamino)- 517 benzamide 172
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 519
benzamide 173 N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro-
502 benzamide 174 N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-p-
henylamino)- 559 benzamide 175 N-Allyl-5-iodo-2-(4-iodo-2-m-
ethyl-phenylamino)-benzamide 517 176
5-Iodo-2-(4-iodo-2-methyl-phen- ylamino)-N-(3-methyl-benzyl)- 581
benzamide 177
2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro- 500
benzamide 178 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-ph-
enyl- 567 benzamide 179 N-Cyclohexyl-5-fluoro-2-(4-iodo-2-m-
ethyl-phenylamino)- 451 benzamide 180
5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- 467
benzamide 181 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl--
benzyl)- 533 benzamide 182 5-Bromo-N-cyclohexyl-2-(4-iodo-2-
-methyl-phenylamino)- 511 benzamide 183
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- 489
benzamide 184 N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-
- 478 benzamide 185 N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl--
phenylamino)- 538 benzamine 186 N-Benzyloxy-5-fluoro-2-(4-i-
odo-2-methyl-phenylamino)- 477 benzamide 187
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 431
benzamide 188 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-pheny-
lamino)- 475 benzamide 189 2-(4-Iodo-2-methyl-phenylamino)--
N-methyl-5-nitro-N-phenyl- 488 benzamide 190
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 477
benzamide 191 N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenyl-
amino)- 523 benzamide 192 5-Chloro-N-cyclopropyl-2-(4-iodo--
2-methyl-phenylamino)- 425 benzamide 193
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 427 194
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 461
benzamide 195 N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)--
5-nitro- 442 benzamide 196 5-Fluoro-N-(2-hydroxy-ethyl)-2-(-
4-iodo-2-methyl-phenylamino)- 415 benzamide 197
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 472
benzamide 198 N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamin-
o)- 411 benzamide 199 5-Fluoro-2-(4-iodo-2-methyl-phenylami-
no)-N-(4-sulfamoyl- 540 benzyl)-benzamide 200
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 438
benzamide 201 N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-ben-
zamide 411 202 N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-
585 benzamide 203 N-Allyl-5-bromo-2-(4-iodo-2-methyl-pheny-
lamino)-benzamide 472 204
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N- -(4-sulfamoyl- 601
benzyl)-benzamide 205
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 522
benzamide 206 N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benz-
amide 438 *M + H
EXAMPLE 207
Preparation of
[4-Chloro-2-(1H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-ami- ne
Step a: Preparation of 5-chloro-2-fluoro-benzaldehyde
[0372] To a solution of 1-chloro-4-fluorobenzne (13.06 g, 0.1 mol)
in THF (180 mL), at -78.degree. C., LDA (2M solution in THF, 50 mL,
0.1 mol) was added drop wise. After stirring at -78.degree. C. for
1.5 hours, DMF (8 mL) was added to the reaction mixture and allowed
to warm up to room temperature overnight. The reaction mixture was
partitioned between water and Et.sub.2O. The Et.sub.2O layer was
dried (MgSO.sub.4) and the solvent removed in vacuum to give 14.95
g (94%) yield of crude dehyde: .sup.1H NMR (CDCl.sub.3): .delta.
10.3 (s, --C(.dbd.O)H).
Step b: Preparation of 5-chloro-2-fluoro-benzaldehyde oxime
[0373] A solution of 5-chloro-2-fluoro-benzaldehyde (10 g, 0.0631
mol), hydroxylamine hydrochloride (6.57 g, 0.0946 mol) and pyridine
(8.3 mL, 0.1010 mol) in EtOH (100 mL) was heated at 75.degree. C.
(oil bath temperature) for 1 hour and the solvent removed under
vacuum to give an oil. The oil was partitioned between water and
CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 layer was dried (MgSO.sub.4)
and the solvent removed under vacuum to give crude aldoxime as a
solid. The solid was purified by medium pressure liquid
chromatography on silica. Elution with CH.sub.2Cl.sub.2 gave 4.87 g
(28%) of the aldoxime as white solid: mp 95-97.degree. C.;
[0374] Analysis calculated for C.sub.7H.sub.5NOFCl: C, 48.44; H,
2.90; N, 8.07. Found: C, 48.55; H, 2.69, N, 7.90.
Step c: Preparation of 5-chloro-2-fluoro-benzonirile
[0375] A solution of the 5-chloro-2-fluoro-benzaldehyde oxime (3.15
g, 0.0182 mol) in acetic anhydride (150 mL) was refluxed for 16
hours. The reaction mixture was cooled to room temperature and
poured into saturated aqueous NaHCO.sub.3 (200 mL) solution. The
mixture was extracted with Et.sub.2O. The Et.sub.2O layer was dried
(K.sub.2CO.sub.3) and the solvent removed to give the product as an
oily solid. The product was used without further purification in
the next step.
Step d: Preparation of
5-(5-chloro-2-fluoro-phenyl)-1H-tetrazole
[0376] A mixture of 5-chloro-2-fluoro-benzonitrile (2.84 g, 0.01823
mol), butanol (15 mL), sodium azide (1.543 g, 0.0237 mol), acetic
acid (1.36 mL, 0.0237 mol) was refluxed for 24 hours. The reaction
mixture was cooled to room temperature, additional 1.543 g sodium
azide added, and the reaction mixture refluxed for additional 24
hours. After cooling to room temperature, Et.sub.2O (100 mL) and
10% aqueous NaOH (200 mL) were added sequentially. The mixture was
vigorously stirred. The aqueous layer was separated, cooled with
ice-methanol bath (-15.degree. C.) and acidified to pH 1 with conc.
HCl. A gray solid precipitated. The solid was dried in vacuum at
50.degree. C. to give 1.76 g (49%) of
5-(5-chloro-2-fluoro-phenyl)-1H-tetrazole: mp partial melt at
110.degree. C., complete melting at 124.degree. C.);
[0377] .sup.1H (400 Mz, CDCl.sub.3): .delta. 8.19-8.08 (m, 1H),
7.77-7.71 (m, 1H), 7.61-7.52 (m, 1H); .sup.13C (100 Mz,
CDCl.sub.3): .delta. 159.00, 156.49, 140.88, 133.02, 132.93,
130.73, 129.23, 129.21, 129.08, 126.05, 118.96, 118.73, 114.50; MS
(CI) M+1=199 (100), M=198 (6).
Step e: Preparation of
[4-Chloro-2-(1H-tetrazol-5-yl)-(4-iodo-2-methyl-phe- nyl)-amine
[0378] To a solution of 2-methyl-4-iodoaniline (3.52 g, 0.0151 mol)
in THF (25 mL) at -78.degree. C., LDA (2 molar solution in THF,
11.33 mL, 0.02267 mol) was added dropwise. After stirring for 0.5
hours, a solution of 1-(tetrazol-5-yl)-2-fluoro-5-chlorobenzene
(1.5 g, 0.00756 mol) in THF (15 mL) was added dropwise. The
reaction was stirred for 16 hours as it warmed up to room
temperature. The reaction mixture was quenched with aqueous conc.
NH.sub.4Cl solution and extracted with CH.sub.2Cl.sub.2. The
organic layer was dried (MgSO.sub.4) and the solvent removed giving
a crude product as an oil. The oil with
CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.- sub.2:MeOH (9.7:0.3) gave 1.5
g (48%) of the desired product:
[0379] mp 205-208.degree. C.; .sup.1H (400 Mz, DMSO): .delta. 9.13
(s, 1H), 8.00-7.99 (s, 1H), 7.69 (s, 1H), 7.55-7.52 (m, 1H),
7.43-7.40 (m, 1H), 7.12-7.05 (m, 1H), 2.24 (s, 3H); .sup.13C (100
Mz, CDCl.sub.3): .delta. 141.87, 139.28, 138.88, 135.47, 133.71,
131.65, 128.15, 123.69, 121.94, 116.68, 87.79, 17.22; MS (CI)
M+2=413 (44), M+1=412 (85), M=411 (100). Analysis calculated for
C.sub.14H.sub.11N.sub.5ClI.0.5H.sub.2O: C, 39.97; H, 2.87; N,
16.65. Found: C, 38.87, H, 2.77; N, 16.47.
[0380] The following tetrazole substituted phenylamines were
prepared by following the general procedure of Example 207.
EXAMPLE 208
(4-iodo-2-methyl-phenyl)-[2-(1H-tetrazol-5-yl)-phenyl]amine, mp
231.degree. C. (dec)
EXAMPLE 209
[4-nitro-2-(1H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine, mp
205-208.degree. C.
[0381] The 4-bromo and 4-iodo phenylamino benzhydroxamic acid
derivatives of Formula II can be prepared from commercially
available starting materials utilizing synthetic methodologies
well-known to those skilled in organic chemistry. A typical
synthesis is carried out by reacting a 4-bromo or 4-iodo aniline
with a benzoic acid having a leaving group at the 2-position to
give a phenylamino benzoic acid, and then reacting the benzoic acid
phenylamino derivative with a hydroxylamine derivative (Scheme 3),
where L is a leaving group, for example halo such as fluoro,
chloro, bromo or iodo, or an activated hydroxy group such as a
diethylphosphate, trimethylsilyloxy, p-nitrophenoxy, or
phenylsulfonoxy.
[0382] The reaction of aniline and the benzoic acid derivative
generally is accomplished by mixing the benzoic acid with an
equimolar quantity or excess of the aniline in an unreactive
organic solvent such as tetrahydrofuran, or toluene, in the
presence of a base such as lithium diisopropylamide, n-butyl
lithium, sodium hydride, and sodium amide. The reaction generally
is carried out at a temperature of about -78.degree. C. to about
25.degree. C., and normally is complete within about 2 hours to
about 4 days. The product can be isolated by removing the solvent,
for example by evaporation under reduced pressure, and further
purified, if desired, by standard methods such as chromatography,
crystallization, or distillation. 6
[0383] The phenylamino benzoic acid next is reacted with a
hydroxylamine derivative HNR.sub.6aOR.sub.7a in the presence of a
peptide coupling reagent. Hydroxylamine derivatives that can be
employed include methoxylamine, N-ethyl-isopropoxy amine, and
tetrahydro-oxazine. Typical coupling reagents include
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
1,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)-phosp-
honium hexafluorophosphate (PyBrOP) and
(benzotriazolyloxy)tripyrrolidino phosphonium hexafluorophosphate
(PyBOP). The phenylamino benzoic acid and hydroxylamino derivative
normally are mixed in approximately equimolar quantities in an
unreactive organic solvent such as dichloromethane,
tetrahydrofuran, chloroform, or xylene, and an equimolar quantity
of the coupling reagent is added. A base such as triethylamine or
diisopropylethylamine can be added to act as an acid scavenger if
desired. The coupling reaction generally is complete after about 10
minutes to 2 hours, and the product is readily isolated by removing
the reaction solvent, for instance by evaporation under reduced
pressure, and purifying the product by standard methods such as
chromatography or crystallizations from solvents such as acetone,
diethyl ether, or ethanol. An alternative method for making the
invention compounds involves first converting a benzoic acid to a
hydroxamic acid derivative, and then reacting the hydroxamic acid
derivative with an aniline. This synthetic sequence is depicted in
Scheme 4, where L is a leaving group. The general reaction
conditions for both of the steps in Scheme 4 are the same as those
described above for Scheme 3. 7
[0384] Yet another method for making invention compounds comprises
reacting a phenylamino benzhydroxamic acid with an ester forming
group as depicted in Scheme 5, where L is a leaving group such as
halo, and a base is triethylamine or diisopropylamine. 8
[0385] The synthesis of compounds of Formula (II) is further
illustrated by the following detailed examples.
EXAMPLE 1a
4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide
(a) Preparation of 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic
acid
[0386] To a stirred solution containing 3.16 g (0.0133 mol) of
2-amino-5-iodotoluene in 5 mL of tetrahydrofuran at -78.degree. C.
was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in
tetrahydrofuran/heptane/ethylbenzene (Aldrich) solution. The
resulting green suspension was stirred vigorously for 15 minutes,
after which time a solution of 1.00 g (0.00632 mol) of
2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The
reaction temperature was allowed to increase slowly to room
temperature, at which temperature the mixture was stirred for 2
days. The reaction mixture was concentrated by evaporation of the
solvent under reduced pressure. Aqueous HCl (10%) was added to the
concentrate, and the solution was extracted with dichloromethane.
The organic phase was dried (MgSO.sub.4) and then concentrated over
a steambath to low volume (10 mL) and cooled to room temperature.
The off-white fibers which formed were collected by vacuum
filtration, rinsed with hexane, and dried in a vacuum-oven
(76.degree. C.; ca. 10 mm of Hg) to afford 1.10 g (47%) of the
desired material; mp 224-229.5.degree. C.;
[0387] .sup.1H NMR (400 MHz, DMSO): .delta. 9.72 (s, 1H), 7.97 (dd,
1H, J=7.0, 8.7 Hz), 7.70 (d, 1H, J=1.5 Hz), 7.57 (dd, 1H, J=8.4,
1.9 Hz), 7.17 (d, 1H, J=8.2 Hz), 6.61-6.53 (m, 2H), 2.18 (s, 3H);
.sup.13C NMR (100 MHz, DMSO): .delta. 169.87, 166.36 (d,
J.sub.C--F=249.4 Hz), 150.11 (d, J.sub.C--F=11.4 Hz), 139.83,
138.49, 136.07, 135.26 (d, J.sub.C--F=1.5 Hz), 135.07, 125.60,
109.32, 104.98 (d, J.sub.C--F=21.1 Hz), 99.54 (d, J.sub.C--F=26.0
Hz), 89.43, 17.52; .sup.19F NMR (376 MHz, DMSO): .delta. -104.00 to
-104.07 (m); IR (KBr) 1670 (C.dbd.O stretch)cm.sup.-1; MS (CI)
M+1=372. Analysis calculated for C.sub.14H.sub.11FINO.sub.2: C,
45.31; H, 2.99; N, 3.77. Found: C, 45.21; H, 2.77; N, 3.64.
(b) Preparation of
4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benz- amide
[0388] To a stirred solution of
4-fluoro-2-(4-iodo-2-methyl-phenylamino)-b- enzoic acid (0.6495 g,
0.001750 mol), O-(tetrahydro-2H-pyran-2-yl)-hydroxy- lamine (0.2590
g, 0.002211 mol), and diisopropylethylamine (0.40 mL, 0.0023 mol)
in 31 mL of an equivolume tetrahydrofuran-dichloromethane solution
was added 1.18 g (0.00227 mol) of solid PyBOP
([benzotriazolyloxy]tripyrrolidino phosphonium hexafluorophosphate,
Advanced ChemTech) directly. The reaction mixture was stirred for
30 minutes after which time it was concentrated in vacuo. The brown
oil was treated with 10% aqueous hydrochloric acid. The suspension
was extracted with ether. The organic extraction was washed with
10% sodium hydroxide followed by another 10% hydrochloric acid
wash, was dried (MgSO.sub.4) and concentrated in vacuo to afford
1.0 g of a light-brown foam. This intermediate was dissolved in 25
mL of ethanolic hydrogen chloride, and the solution was allowed to
stand at room temperature for 15 minutes. The reaction mixture was
concentrated in vacuo to a brown oil that was purified by flash
silica chromatography. Elution with a gradient (100%
dichloromethane to 0.6% methanol in dichloromethane) afforded
0.2284 g of a light-brown viscous oil. Scratching with
pentane-hexanes and drying under high vacuum afforded 0.1541 g
(23%) of an off-white foam; mp 61-75.degree. C.;
[0389] .sup.1H NMR (400 MHz, DMSO): .delta. 11.34 (s, 1H), 9.68 (s,
1H), 9.18 (s, 1H), 7.65 (d, 1H, J=1.5 Hz), 7.58 (dd, 1H, J=8.7, 6.8
Hz), 7.52 (dd, 1H, J=8.4, 1.9 Hz), 7.15 (d, 1H, J=8.4 Hz), 6.74
(dd, 1H, J=11.8, 2.4 Hz), 6.62 (ddd, 1H, J=8.4, 8.4, 2.7 Hz), 2.18
(s, 3H); .sup.13C NMR (100 MHz, DMSO): .delta. 165.91, 164.36 (d,
J.sub.C--F=247.1 Hz), 146.78, 139.18, 138.77, 135.43, 132.64,
130.60 (d, J.sub.C--F=11.5 Hz), 122.23, 112.52, 104.72 (d, J=22.1
Hz), 100.45 (d, J.sub.C--F=25.2 Hz), 86.77, 17.03; .sup.19F NMR
(376 MHz, DMSO): .delta. -107.20 to -107.27 (m); IR (KBr) 3307
(broad, O--H stretch), 1636 (C.dbd.O stretch) cm.sup.-1; MS (CI)
M+1=387. Analysis calculated for C.sub.14H.sub.12FIN.sub.2O.sub.2:
C, 43.54; H, 3.13; N, 7.25. Found: C, 43.62; H, 3.24; N, 6.98.
EXAMPLE 2a
5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide
(a) Preparation of 5-Bromo-2,3,4-trifluorobenzoic acid
[0390] To a stirred solution comprised of
1-bromo-2,3,4-trifluorobenzene (Aldrich, 99%; 5.30 g, 0.0249 mol)
in 95 mL of anhydrous tetrahydrofuran cooled to -78.degree. C. was
slowly added 12.5 mL of 2.0 M lithium diisopropylamide in
heptane/tetrahydrofuran/ethylbenzene solution (Aldrich). The
mixture was stirred for 1 hour and transferred by canula into 700
mL of a stirred saturated ethereal carbon dioxide solution cooled
to -78.degree. C. The cold bath was removed, and the reaction
mixture was stirred for 18 hours at ambient temperature. Dilute
(10%) aqueous hydrochloric acid (ca. 500 mL) was poured into the
reaction mixture, and the mixture was subsequently concentrated on
a rotary evaporator to a crude solid. The solid product was
partitioned between diethyl ether (150 mL) and aq. HCl (330 mL, pH
0). The aqueous phase was extracted with a second portion (100 mL)
of diethyl ether, and the combined ethereal extracts were washed
with 5% aqueous sodium hydroxide (200 mL) and water (100 mL, pH
12). These combined alkaline aqueous extractions were acidified to
pH 0 with concentrated aqueous hydrochloric acid. The resulting
suspension was extracted with ether (2.times.200 mL). The combined
organic extracts were dried (MgSO.sub.4), concentrated in vacuo,
and subjected to high vacuum until constant mass was achieved to
afford 5.60 g (88% yield) of an off-white powder; mp
139-142.5.degree. C.;
[0391] .sup.1H NMR (400 MHz, DMSO): .delta. 13.97 (broad s, 1H,
8.00-7.96 (m, 1H); .sup.13C NMR (100 MHz, DMSO): .delta. 162.96,
129.34, 118.47, 104.54 (d, J.sub.C--F=22.9 Hz); .sup.19F NMR (376
MHz, DMSO): .delta. -120.20 to -120.31 (m), -131.75 to -131.86 (m),
-154.95 to -155.07 (m); IR (KBr) 1696 (C.dbd.O stretch)cm.sup.-1;
MS (CI) M+1=255. Analysis calculated for
C.sub.74H.sub.21BrF.sub.3O.sub.2: C, 32.97; H, 0.79; N, 0.00; Br,
31.34; F, 22.35. Found: C, 33.18; H, 0.64; N, 0.01; Br, 30.14; F,
22.75.
(b) Preparation of
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-be- nzoic
acid
[0392] To a stirred solution comprised of 1.88 g (0.00791 mol) of
2-amino-5-iodotoluene in 10 mL of tetrahydrofuran at -78.degree. C.
was added 6 mL (0.012 mol) of a 2.0 M lithium diisopropylamide in
tetrahydrofuran/heptane/ethylbenzene (Aldrich) solution. The
resulting green suspension was stirred vigorously for 10 minutes,
after which time a solution of 1.00 g (0.00392 mol) of
5-bromo-2,3,4-trifluorobenzoic acid in 15 mL of tetrahydrofuran was
added. The cold bath was subsequently removed, and the reaction
mixture stirred for 18 hours. The mixture was concentrated, and the
concentrate was treated with 100 mL of dilute (10%) aqueous
hydrochloric acid. The resulting suspension was extracted with
ether (2.times.150 mL), and the combined organic extractions were
dried (MgSO.sub.4) and concentrated in vacuo to give an orange
solid. The solid was triturated with boiling dichloromethane,
cooled to ambient temperature, and collected by filtration. The
solid was rinsed with dichloromethane, and dried in the vacuum-oven
(80.degree. C.) to afford 1.39 g (76%) of a yellow-green powder; mp
259.5-262.degree. C.;
[0393] .sup.1H NMR (400 MHz, DMSO): .delta. 9.03 (s, 1H), 7.99 (dd,
1H, J=7.5, 1.9 Hz), 7.57 (dd, 1H, J=1.5 Hz), 7.42 (dd, 1H, J=8.4,
1.9 Hz), 6.70 (dd, 1H, J=8.4, 6.0 Hz), 2.24 (s, 3H); .sup.19F NMR
(376 MHz, DMSO): .delta. -123.40 to -123.47 (m); -139.00 to -139.14
(m); IR (KBr) 1667 (C.dbd.O stretch)cm.sup.-1; MS (CI) M+1=469.
Analysis calculated for C.sub.14H.sub.9BrF.sub.2INO.sub.2: C,
35.93; H, 1.94; N, 2.99; Br, 17.07; F, 8.12; I, 27.11. Found: C,
36.15; H, 1.91; N, 2.70; Br, 16.40; F, 8.46; I, 26.05.
(c) Preparation of
5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-pheny-
lamino)-benzamide
[0394] To a stirred solution comprised of
5-bromo-3,4-difluoro-2-(4-iodo-2- -methyl-phenylamino)-benzoic acid
(0.51 g, 0.0011 mol), O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine
(0.15 g, 0.0013 mol), and diisopropylethylamine (0.25 mL, 0.0014
mol) in 20 mL of an equivolume tetrahydrofuran-dichloromethane
solution was added 0.6794 g (0.001306 mol) of solid PyBOP (Advanced
ChemTech) directly. The reaction mixture was stirred at 24.degree.
C. for 10 minutes, and then was concentrated to dryness in vacuo.
The concentrate was suspended in 100 mL of 10% aqueous hydrochloric
acid. The suspension was extracted with 125 mL of diethyl ether.
The ether layer was separated, washed with 75 mL of 10% aqueous
sodium hydroxide, and then with 100 mL of dilute acid. The ether
solution was dried (MgSO.sub.4) and concentrated in vacuo to afford
0.62 g (100%) of an off-white foam. The foam was dissolved in ca.
15 mL of methanolic hydrogen chloride. After 5 minutes, the
solution was concentrated in vacuo to an oil, and the oil was
purified by flash silica chromatography. Elution with
dichloromethane: dichloromethane-methanol (99:1) afforded 0.2233 g
(42%) of a yellow powder. The powder was dissolved in diethyl ether
and washed with dilute hydrochloric acid. The organic phase was
dried (MgSO.sub.4) and concentrated in vacuo to afford 0.200 g of a
foam. This product was triturated with pentane to afford 0.1525 g
of a powder that was repurified by flash silica chromatography.
Elution with dichloromethane afforded 0.0783 g (15%) of an
analytically pure title compound, mp 80-90.degree. C.;
[0395] .sup.1H NMR (400 MHz, DMSO): .delta. 11.53 (s, 1H), 9.38 (s,
1H), 8.82 (s, 1H), 7.70 (dd, 1H, J=7.0, 1.9 Hz), 7.53 (s, 1H), 7.37
(dd, 1H, J=8.4, 1.9 Hz), 6.55 (dd, 1H, J=8.2, 6.5 Hz), 2.22 (s,
3H); .sup.19F NMR (376 MHz, DMSO): .delta. -126.24 to -126.29 (m),
-137.71 to -137.77 (m); IR (KBr) 3346 (broad, O--H stretch), 1651
(C.dbd.O stretch)cm.sup.-1; MS (CI) M+1=484. Analysis calculated
for C.sub.14H.sub.10BrF.sub.2IN.sub.2O.- sub.2: C, 34.81; H, 2.09;
N, 5.80. Found: C, 34.53; H, 1.73; N, 5.52.
[0396] Examples 3a to 12a in the table below were prepared by the
general procedure of Examples 1a and 2a.
EXAMPLES 13a-77a
[0397] Examples 13a to 77a were prepared utilizing combinatorial
synthetic methodology by reacting appropriately substituted
phenylamino benzoic acids (e.g., as shown in Scheme 1) and
hydroxylamines (e.g., (NHR.sub.6a)--O--R.sub.7a). A general method
is given below:
[0398] To a 0.8-mL autosampler vial in a metal block was added 40
.mu.L of a 0.5 M solution of the acid in DMF and 40 .mu.L of the
hydroxylamine (2 M solution in Hunig's base and 1 M in amine in
DMF). A 0.5 M solution of PyBrOP was freshly prepared, and 50 .mu.L
were added to the autosampler vial. The reaction was allowed to
stand for 24 hours.
[0399] The reaction mixture was transferred to a 2-dram vial and
diluted with 2 mL of ethyl acetate. The organic layer was washed
with 3 mL of distilled water and the water layer washed again with
2 mL of ethyl acetate. The combined organic layers were allowed to
evaporate to dryness in an open fume hood.
[0400] The residue was taken up in 2 mL of 50% acetonitrile in
water and injected on a semi-prep reversed phase column (10
mm.times.25 cm, 5 .mu.M spherical silica, pore Size 115 A
derivatized with C-18, the sample was eluted at 4.7 mL/min with a
linear ramp to 100% acetonitrile over 8.5 minutes. Elution with
100% acetonitrile continued for 8 minutes.) Fractions were
collected by monitoring at 214 nM. The desired fractions were
evaporated using a Zymark Turbovap. The product was dissolved in
chloroform and transferred to a preweighed vial, evaporated, and
weighed again to determine the yield. The structure was confirmed
by mass spectroscopy.
EXAMPLES 3a-77a
[0401]
5 Example Melting MS No. Compound Point (.degree. C.) (M - H.sup.+)
3a 2-(4-bromo-2-methyl-phenylamino)-4-f- luoro-N- 56-75 523
hydroxy-benzamide dec 4a 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 65
phenylamino)-benzamide dec 5a
5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 62-67
phenylamino)-N-methyl-benzamide 6a 5-Chloro-2-(4-iodo-2-methyl-ph-
enylamino)-N- 105-108 (terahydropyran-2-yloxy)benzamide 7a
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N- 64-68 methoxybenzamide
8a 4-Fluoro-N-hydroxy-2-(4-fluoro-2-methyl- 119-135
phenylamino)-benzamide 9a 4-Fluoro-N-hydroxy-2-(2- -methyl
phenylamino)- 101-103 benzamide 10a
4-Fluoro-2-(4-fluor-2-methyl-phenylamino)-N- 142-146
(terahydropyran-2-yloxy)benzamide 11a 4-Fluoro-N-hydroxy-2-(4-cluo-
ro-2-methyl- 133.5-135 phenylamino)-benzamide 12a
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 107-109.5
phenylmethoxy-benzamide 13a 4-Fluoro-2-(4-iodo-2-methyl-phenylamin-
o)-N- 399 methoxy-benzamide 14a 3,4-Difluoro-2-(4-iodo-2-m-
ethyl-phenylamino)- 417 N-methoxy-benzamide 15a
2-(4-Bromo-2-methyl-phenylamino)- 369 3,4-difluoro-N-methoxy-ben-
zamide 16a 2-(4-Bromo-2-methyl-phenylamino)-N-ethoxy- 342*
3,4-difluoro-benzamide (M - EtO) 17a 5-Bromo-N-ethoxy-3,4-difluor-
o-2-(4-iodo- 509 2-methyl-phenylamino)-benzamide 18a
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 445
N-isopropoxy-benzamide 19a 2-(4-Bromo-2-methyl-phenylamino)- 397
3,4-difluoro-N-isopropoxy-benzamide 20a
4-Fluoro-N-(furan-3-ylmethoxy)-2-(4-iodo- 465
2-methyl-phenylamino)-benzamide 21a 3,4-Difluoro-N-(furan-3-ylmeth-
oxy)-2-(4-iodo- 483 2-methyl-phenyIamino)-benzamide 22a
2-(4-Bromo-2-methyl-phenylamino)- 435 3,4-difluoro-N-(furan-3-yl-
methoxy)-benzamide 23a 5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)-
561 2-(4-iodo-2-methyl-phenylamino)-benzamide 24a
5-Bromo-N-(but-2-enyloxy)-3,4-difluoro- 536
2-(4-iodo-2-methyl-phenylamino)-benzamide 25a
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 423
(prop-2-ynyloxy)-benzamide 26a 3,4-Difluoro-2-(4-iodo-2-methyl-phe-
nylamino)- 441 N-(prop-2-ynyloxy)-benzamide 27a
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 455
N-(1-methyl-prop-2-ynyloxy)-benzamide 28a 2-(4-Bromo-2-methyl-phen-
ylamino)- 407 3,4-difluoro-N-(1-methyl-prop-2-ynyloxy)- benzamide
29a N-(But-3-ynyloxy)-3,4-difluoro-2-(4-iodo- 455
2-methyl-phenylamino)-benzamide 30a 2-(4-Bromo-2-methyl-phenylam-
ino)-N-(but- 407 3-ynyloxy)-3,4-difluoro-benzamide 31a
5-Bromo-N-(but-3-ynyloxy)-3,4-difluoro- 533
2-(4-iodo-2-methyl-phenylamino)-benzamide 32a
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 517
N-(3-phenyl-prop-2-ynyloxy)-benzamide 33a 3,4-Difluoro-2-(4-bromo--
2-methyl- 469 phenylamino)-N-(3-phenyl-prop-2-ynyloxy)- benzamide
34a 3,4-Difluoro-N-[3-(3-fluoro-phenyl)-prop- 535
2-ynyloxy]-2-(4-iodo-2-methyl-phenylamino)- benzamide 35a
2-(4-Bromo-2-methyl-phenylamino)- 487
3,4-difluoro-N-[3-(3-fluoro-phenyl)-prop- 2-ynyloxy]-benzamide 36a
3,4-Difluoro-N-[3-(2-fluoro-phenyl)-prop- 535
2-ynyloxy]-2-(4-iodo-2-methyl-phenylamino)- benzamide 37a
5-Bromo-3,4-difluoro-N-[3-(2-fluoro-phenyl)- 613
prop-2-ynyloxy]-2-(4-iodo-2-methyl- phenylamino)-benzamide 38a
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 557*
N-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)- *(M + H) benzamide 39a
2-(4-Bromo-2-methyl-phenylamino)- 510
3,4-difluoro-N-(3-methyl-5-phenyl-pent-2-en- 4-ynyloxy)-benzamide
40a N-Ethoxy-3,4-difluoro-2-(4-iodo-2-methyl- 431
phenylamino)-benzamide 41a 2-(4-Bromo-2-methyl-phenylamino)-N-etho-
xy- 383 3,4-difluoro-benzamide 42a 4-Fluoro-2-(4-iodo-2-me-
thyl-phenylamino)-N- 427 propoxy-benzamide 43a
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 445
N-propoxy-benzamide 44a 2-(4-Bromo-2-methyl-phenylamino)- 397
3,4-difluoro-N-propoxy-benzamide 45a 5-Bromo-3,4-difluoro-2-(4-
-iodo-2-methyl- 523 phenylamino)-N-propoxy-benzamide 46a
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 427
isopropoxy-benzamide 47a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylami-
no)- 445 N-isopropoxy-benzamide 48a
2-(4-Bromo-2-methyl-phenylamino)- 397 3,4-difluoro-N-isopropoxy--
benzamide 49a 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 523
phenylamino)-N-isopropoxy-benzamide 50a N-Cyclobutyloxy-3,4-difluo-
ro-2-(4-iodo- 457 2-methyl-phenylamino)-benzamide 51a
2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclobutyloxy-3,4-difluo-
ro-benzamide 52a N-Cyclopentyloxy-4-fluoro-2-(4-iodo-2-methyl- 453
phenylamino)-benzamide 53a N-Cyclopentyloxy-3,4-difluoro-2-
-(4-iodo- 471 2-methyl-phenylamino)-benzamide 54a
2-(4-Bromo-2-methyl-phenylamino)-N- 423 cyclopentyloxy-3,4-diflu-
oro-benzamide 55a N-Cyclopropylmethoxy-4-fluoro-2-(4-iodo- 439
2-methyl-phenylamino)-benzamide 56a N-Cyclopropylmethoxy-3,4-d-
ifluoro-2-(4-iodo- 457 2-methyl-phenylamino)-benzamide 57a
2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclopropylmethoxy-3,4-d-
ifluoro-benzamide 58a 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-
435 2-(4-iodo-2-methyl-phenylamino) 59a
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 505
(2-phenoxy-ethoxy)-benzamide 60a 3,4-Difluoro-2-(4-iodo-2-methyl-p-
henylamino)- 523 N-(2-phenoxy-ethoxy)-benzamide 61a
2-(4-Bromo-2-methyl-phenylamino)- 475 3,4-difluoro-N-(2-phenoxy--
ethoxy)-benzamide 62a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-
481 (thiophen-2-ylmethoxy)-benzamide 63a
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 499
N-(thiophen-2-ylmethoxy)-benzamide 64a 2-(4-Bromo-2-methyl-phenyla-
mino)- 451 3,4-difluoro-N-(thiophen-2-ylmethoxy)- benzamide 65a
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 439
(2-methyl-allyloxy)-benzamide 66a 3,4-Difluoro-2-(4-iodo-2-met-
hyl-phenylamino)- 457 N-(2-methyl-allyloxy)-benzamide 67a
2-(4-Bromo-2-methyl-phenylamino)- 410 3,4-difluoro-N-(2-methyl-a-
llyloxy)-benzamide 68a
N-(But-2-enyloxy)-4-fluoro-2-(4-iodo-2-methy- l- 439
phenylamino)-benzamide 69a N-(But-2-enyloxy)-3,4-di-
fluoro-2-(4-iodo- 457 2-methyl-phenylamino)-benzamide 70a
2-(4-Bromo-2-methyl-phenylarnino)-N-(but- 410
2-enyloxy)-3,4-difluoro-benzamide 71a 3,4-Difluoro-2-(4-iodo-2-met-
hyl-phenylamino)- 441 N-(prop-2-ynyloxy)-benzamide 72a
N-(But-3-ynyloxy)-3,4-difluoro-2-(4-iodo- 455
2-methyl-phenylamino)-benzamide 73a 2-(4-Bromo-2-methyl-phenylamin-
o)-N- 449 (4,4-dimethyl-pent-2-ynyloxy)-3,4-difluoro- benzamide 74a
N-(But-2-enyloxy)-3,4-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide 75a 2-(4-Bromo-2-methyl-phenylam-
ino)-N-(but- 410 2-enyloxy)-3,4-difluoro-benzamide 76a
N-(3-tert-butyl-propyn-2-yl)oxy-4-fluoro- 479
2-(4-iodo-2-methyl-phenylamino)-benzamide 77a
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 577
phenylmethoxy-benzamide
[0402]
6 PHYSICAL DATA FOR SELECTED COMPOUNDS PD 0171984 mp 80-90.degree.
C. PD 0184161 mp 174-175.degree. C. PD 0203311 mp 141-144.degree.
C. PD 0297189 mp 167-169.degree. C. .sup.1H--NMR (400 MHz; DMSO)
.delta. 11.70 (s, 1H), 8.59 (s, 1H), 7.55 (s, 1H), 7.43 (d, 1H,
J=6.5 Hz), 7.27 (d, 1H, J=8.7 Hz), 6.46 (m, 1H), 3.42 (d, 2H, J=7.0
Hz), 0.84 (m, 1H), 0.27 (m, 2H), 0.00 (m, 2H) PD 0297190 mp
125.5-133.degree. C. .sup.1H--NMR (400 MHz; DMSO) .delta. 11.48 (s,
1H), 8.32 (s, 1H), 7.34 (d, 1H, J=7.5 Hz), 7.28 (d, 2H, J=8.2 Hz),
6.48 (d, 2H, J=7.7 Hz), 3.32 (d, 2H, J=6.8 Hz), 0.81 (m, 1H), 0.28
(m, 2H), 0.00 (m, 2H) PD 0296771 mp 266.7-268.9.degree. C.
.sup.1H--NMR (400 MHz; DMSO) .delta. 13.85 (broad s, 1H), 8.99 (s,
1H), 7.87 (dd, 1H, J=7.9, 2.1 Hz), 7.55 (d, 2H, J=8.6 Hz), 6.82
(dd, 2H, J=8.7, 2.8 Hz) PD 0296770 mp 293.2-296.3.degree. C.
.sup.1H--NMR (400 MHz; DMSO) .delta. 14.05 (broad s, 1H), 9.21 (s,
1H), 7.93 (dd, 1H, J=7.8, 2.2 Hz), 7.82 (d, 1H, J=1.9 Hz), 7.54
(dd, 1H, J=8.6, 1.9 Hz), 6.82 (dd, 1H, J=8.6, 6.7 Hz) PD 0296767 mp
249-251.degree. C. .sup.1H--NMR (400 MHz; DMSO) .delta. 13.99
(broad s, 1H), 9.01 (s, 1H), 7.90 (dd, 1H, J=7.9, 2.3 Hz), 7.58 (d,
1H, J=1.6 Hz), 7.42 (dd, 1H, J=8.4, 1.9 Hz), 6.69 (dd, 1H, J=8.4,
6.0 Hz), 2.24 (s, 3H) PD298127 mp 127-135.degree. C.
5-chloro-N-cyclopropyl methoxy-3,4-difluoro-2-[4-iodo-2-methyl
phenylamino]benzamide Proton NMR (440 MHz; DMSO) .delta. 11.64 (s,
1H), 8.28 (s, 1H), 7.38 (dd, 1H, J=7.6, 1.7 Hz), 7.31 (d, 1H, J=1.2
Hz), 7.15 (dd, 1H, J=8.5, 1.7 Hz), 3.35 (d, 2H, J=7.3 Hz), 2.01 (s,
3H), 0.83 (m, 1H), 0.28 (m, 2H), 0.01 (m,2H)
Biological Assays
[0403] The ability of MEK inhibitors described above to prevent and
treat asthma has been demonstrated in three different assays: (1)
inhibition of antigen-induced interleukin-5 (IL-5) production in
vitro, (2) inhibition of the passive-transfer of eosinophilic lung
inflammation in vivo, and (3) inhibition of active eosinophilic
lung inflammation in vivo. For each of these assays, female C57BL/6
mice obtained from the Jackson Laboratory (Bar Harbor, Me.) were
given an intraperitoneal (i.p.) injection of ovalbumin (OVA, Grade
V, Sigma Chemical Company, St. Louis, Mo.) adsorbed to aluminum
hydroxide (10 .mu.g OVA+9 mg aluminum hydroxide in 200 .mu.L
saline). This sensitizes OVA-specific lymphocytes for subsequent
restimulation either in vivo or in vitro.
[0404] The first set of experiments was designed to determine
whether the MEK inhibitors could prevent antigen-induced production
of IL-5 by the OVA-primed splenocytes in vitro. IL-5 is required
for the differentiation, migration, and survival of pulmonary
eosinophils, which are thought to be responsible for much of the
pathology associated with human asthma. In order to examine the
effects of MEK inhibitors on IL-5 production, OVA-sensitized mice
were sacrificed by cervical dislocation 14 days after sensitization
(Day 14), the spleens were excised and disaggregated, and the
erythrocytes were lysed. The splenocytes were washed and
resuspended at 5.times.10.sup.6 cells/mL in complete medium
consisting of RPMI 1640 (Gibco BRL, Gaithersburg, Md.) with 10%
heat-inactivated fetal calf serum (Hyclone, Logan, Utah), 55 .mu.M
2-mercaptoethanol, 50 U/mL penicillin G, 50 .mu.g/mL streptomycin
sulfate, and 2 mM L-glutamine (Gibco BRL). The splenocytes were
then cultured at 37.degree. C. in the presence of 200 .mu.g/mL OVA.
MEK inhibitors were also added to the cultures from sterile 10 mM
stock solutions (in DMSO). After 3 days, the culture medium was
recovered and assayed for IL-5 by specific ELISA. The results of
the analysis of IL-5 inhibition are presented in Table 1. All MEK
inhibitors tested were found to potently inhibit antigen-induced
IL-5 production.
7TABLE 1 The Effects of MEK Inhibitors on Antigen- Induced IL-5
Production MEK Inhibitor IC.sub.50 (nM) PD 184386 23 PD 171984 117
PD 170611 1,121 PD 184161 1,147 PD 177168 1,205 PD 184352 1,622 PD
098059 17,440
[0405] When OVA-sensitized spleen cells are restimulated with OVA
in vitro for 3 days, as described above, the spleen cells not only
produce IL-5, but also acquire the ability to induce eosinophilic
lung inflammation when transferred into nave recipient mice. The
critical cell type responsible for this adoptively-transferred
activity is thought to be IL-5-producing T lymphocytes. Because the
results of the first set of experiments indicated that the MEK
inhibitors inhibited IL-5 production by cultured splenocytes, a
second set of experiments was initiated to determine whether the
MEK inhibitor-treated cells were capable of transferring
eosinophilic lung inflammation to nave mice. Splenocytes from OVA
restimulation cultures, with or without the addition of MEK
inhibitors were harvested after 3 days of culture, washed three
times, and resuspended at 1.times.10.sup.8 cells/mL in sterile
saline. Groups of five nave (unsensitized) C57BL/c mice were
injected i.p. with 200 .mu.L of the cell suspension
(2.times.10.sup.7 cells). Three days after transfer of cells, the
recipient mice were challenged with a 12-minute inhalation of an
aerosol formulation of 1.5% OVA in saline (weight/volume), the mist
being produced by a nebulizer (small particle generator model
SPAG-2, ICN Pharmaceuticals, Costa Mesa, Calif.). Three days after
aerosol challenge, the mice were anesthetized with an i.p.
injection of an anesthetic mixture comprising Ketamine,
acepromazine, and xylazine. The trachea of each mouse was exposed
and cannulated. The lungs and upper airways were lavaged with 0.5
mL of cold (5.degree. C.) phosphate buffered saline (PBS). The
cells within a 200 .mu.L portion of the bronchoalveolar lavage
(BAL) fluid were enumerated using a Coulter counter (Model ZB 1,
Coulter Electronics, Hialeah, Fla.). The remaining BAL fluid was
then centrifuged at 300.times.g for 5 minutes, and the cells
resuspended in 1 mL of Hank's balanced salt solution (HBSS, Gibco
BRL), containing 0.5% fetal calf serum, and 10 mM of
N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES, Gibco
BRL). The cell suspension (100 .mu.L) was centrifuged in a cytospin
(Shandon Southern Instruments, Sewickley, Pa.) and stained with
Diff Quick to distinguish neutrophil, eosinophil, monocyte, and
lymphocyte subsets. The number of eosinophils in the BAL fluid was
determined by multiplying the percentage of eosinophils by the
total cell count.
[0406] As shown in Table 2, OVA-sensitized splenocytes cultured in
the absence of MEK inhibitor, when transferred to nave recipient
mice, were able to promote eosinophilic lung inflammation in
response to an aerosol challenge with OVA. In contrast, splenocytes
cultured in the presence of the MEK inhibitors PD 171984, PD
184352, and PD 184386 (10 .mu.M each) did not promote eosinophilic
lung inflammation (>99% inhibition). For each of the MEK
inhibitors used, a 10 .mu.M concentration was previously found to
inhibit IL-5 production by over 75% (Table 1). These results
suggest that the MEK inhibitors inhibit the IL-5-producing T
lymphocytes that are required to support asthma-like eosinophilic
lung inflammation in mice.
8TABLE 2 The Effects of MEK Inhibitors on the Adoptive-Transfer of
Eosinophilic Lung Inflammation Treatment of Spleen Cell Culture %
Inhibition of Compound Dose (.mu.M) BAL Eosinophils None 0 PD
171984 10 99.82 PD 184386 10 99.78 PD 184352 10 99.46
[0407] The final set of experiments was designed to test whether
MEK inhibitors could inhibit active OVA-induced eosinophilic lung
inflammation in mice. Mice were sensitized with OVA/aluminum
hydroxide on Day 0 as described above. On Day 14, the mice were
challenged by aerosol with 1.5% OVA, as described above for the
adoptive-transfer recipients. One group of eight sensitized mice
was dosed orally with vehicle (0.5%
hydroxypropylmethylcellulose/0.25% TWEEN-80). Other groups of
sensitized mice (8 mice per group) were given oral doses of a MEK
inhibitor. The test compound was dissolved in the vehicle, and the
volume for each dosage was adjusted to 200 .mu.L, so that each test
animal received the same oral volume. In experiments reported in
Table 3 and Table 4, the MEK inhibitor was administered starting on
Day 13 (ie, 13 days after initial sensitization and 1 day prior to
aerosol challenge), and continued daily through Day 16 (4 days
total). In experiments reported in Table 5, the MEK inhibitor was
administered starting on Day 7 (ie, 7 days after initial
sensitization and 7 days prior to aerosol challenge), and continued
daily through Day 16 (9 days total). On Day 17 of each experiment
(17 days following the initial OVA challenge, and 3 days after the
OVA aerosol challenge), all animals including controls were
anesthetized, cannulated, and ravaged as previously described. The
number of BAL eosinophils was determined as described above.
[0408] In the initial analysis of active OVA-induced lung
inflammation, multiple MEK inhibitors (PD 171984, PD 177168, PD
184161, PD 184386, and PD 184352) were dosed orally for 4 days.
Only one compound, PD 171984, demonstrated any inhibition of
pulmonary eosinophilia (Table 3). PD 171984, along with PD 184352,
were tested again at multiple doses, again dosing for only 4 days.
The results in Table 4 essentially parallel those in Table 3 for
these compounds; PD 171984 appears active, whereas PD 184352 does
not. As reported in Table 5, increasing the oral dosing schedule
from 4 days to 9 days (7 days prior to aerosol challenge, 2 days
after) resulted in a degree of inhibitory activity for PD 184352 at
100 mg/kg (59.85% inhibition, p=0.11). PD 171984 continued to
demonstrate statistically significant inhibitory activity under
this dosing regimen.
[0409] In total, these results indicate that MEK inhibitors, when
used in vitro, are potent inhibitors of IL-5 production, and
completely inhibit the ability of antigen-stimulated cells to
adoptively transfer asthma-like symptoms to nave recipient mice.
When used in vivo, some MEK inhibitors are more active than others.
However, a less potent compound (PD 184352) was shown to inhibit
the asthma-like response in mice under a more rigorous dosing
regimen. Thus, the foregoing data establish that the selective MEK
inhibitors are active in inhibiting a model of asthma in mice. The
compounds have little or no toxic effects, and accordingly are
particularly well-suited for treating and controlling asthma in
children, as well as adults. The compounds will be formulated for
convenient oral or parenteral administration, including by aerosol
delivery, transdermal delivery, or even suppositories, and will be
administered in an antiasthmatic effective dose, which is that
amount that is effective to treat the particular asthma severity
for which treatment is needed or otherwise desired.
9TABLE 3 The Effect of MEK Inhibitors on Eosinophilic Lung
Inflammation in Mice MEK Inhibitor Dose (.mu.M) % Inhibition of BAL
Eosinophilia PD 171984 100 55.26* PD 177168 100 -123.38 PD 184161
100 -32.53 PD 184386 100 -33.24 PD 184352 150 -5.41 *p = 0.08
[0410]
10TABLE 4 Inhibition of BAL Eosinophils With 4-Day Compound Dosing
% Inhibition of BAL Eosinophils by: Dose (mg/kg) PD 184352 PD
171984 0 0 0 10 -22.7 38.4* 30 -153.8 46.6* 100 -8.2 58.4*
*Significantly different from control (p < 0.05)
[0411]
11TABLE 5 Inhibition of BAL Eosinophils With 9-Day Compound Dosing
% Inhibition of BAL Eosinophils by: PD 171984 Dose (mg/kg) PD
184352 Experiment 1 Experiment 2 0 0 0 0 10 -42.99 -13.74 50.15* 30
1.83 80.64* 37.23* 100 59.85 88.40* 54.77* *Significantly different
from control (p < 0.05)
[0412] The foregoing data establish that the selective MEK
inhibitors are active in both inhibiting and controlling the
asthmatic disease, for example, prior to actual challenge and
following challenge. The compounds are therefore useful in the
prophylaxis of asthma, and also in treating and alleviating the
symptoms that accompany the disease during its active stage. The
compounds have little or no toxic effects, and accordingly are
particularly well-suited for treating and controlling asthma in
children, as well as adults. The compounds will be formulated for
convenient oral or parenteral administration, including by aerosol
delivery, transdermal delivery, or even suppositories, and will be
administered in an antiasthmatic effective dose, which is that
amount that is effective to treat the particular asthma severity
for which treatment is needed or otherwise desired.
[0413] D. Other Embodiments
[0414] From the above disclosure and examples, and from the claims
below, the essential features of the invention are readily
apparent. The scope of the invention also encompasses various
modifications and adaptations within the knowledge of a person of
ordinary skill. Examples include a disclosed compound modified by
addition or removal of a protecting group, or an ester,
pharmaceutical salt, hydrate, acid, or amide of a disclosed
compound. Publications cited herein are hereby incorporated by
reference in their entirety.
* * * * *