AU776788C - Treatment of arthritis with MEK inhibitors - Google Patents

Treatment of arthritis with MEK inhibitors

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Publication number
AU776788C
AU776788C AU21858/00A AU2185800A AU776788C AU 776788 C AU776788 C AU 776788C AU 21858/00 A AU21858/00 A AU 21858/00A AU 2185800 A AU2185800 A AU 2185800A AU 776788 C AU776788 C AU 776788C
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Prior art keywords
methyl
phenylamino
iodo
benzamide
bromo
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AU21858/00A
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AU776788B2 (en
AU2185800A (en
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David Thomas Dudley
Craig Mason Flory
Alan Robert Saltiel
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Description

TREATMENT OF ARTHRITIS WITH MEK INHIBITORS
FIELD OF THE INVENTION
This invention relates to methods for preventing and treating rheumatoid arthritis or osteoarthritis by administering a compound characterized as an inhibitor of a kinase enzyme known as MEK (MAP kinase or ERK Kinase). MEK phosphorylates and activates MAP kinase (also known as Erk). The method is ideally practiced by administering a phenyl amine MEK inhibitor.
BACKGROUND OF THE INVENTION
Arthritis is a debilitating disease that afflicts millions of people, and for which there currently are no cures. Several forms of arthritis are known.
Rheumatoid arthritis is characterized as a chronic systemic inflammatory disease, primarily of the joints, and generally marked by inflammatory changes in the synovial membranes and articular structures and by atrophy and rarefaction of the bones. Osteoarthritis is a noninflammatory degenerative joint disease occurring most often in older persons. Characterized by degeneration of the articular cartilage, hypertrophy of bone at the margins, and changes in the synovial membrane, osteoarthritis is accompanied by pain and stiffness, particularly after prolonged physical activity. Osteoarthritis is also referred to as degenerative arthritis, hypertrophic arthritis, and degenerative joint disease. The current treatments are designed to relieve the pain, and to diminish the symptoms. Most of the known treatments are anti-inflammatory agents such as NSAIDs and cyclooxygenase inhibitors.
We have now discovered that a series of compounds that are said to be selective MEK inhibitors are useful to prevent and treat arthritis. Many of the compounds are described in WO 98/37881 as being useful to treat septic shock. SUMMARY OF THE INVENTION
This invention provides a method for preventing and treating arthritis, wherein the method comprises the step of administering to a mammal suspected of developing arthritis, or in need of treatment, an effective anti-arthritic amount of a MEK inhibitor, preferably a selective MEK inhibitor. Selective MEK inhibitors are those compounds which inhibit the MEK 1 and MEK 2 enzymes without substantial inhibition of other related enzymes. One aspect of the invention provides a method for treating rheumatoid arthritis, said method comprising the step of administering a MEK inhibitor to a patient. In another aspect, the invention provides a method for treating osteoarthritis, said method comprising administering a MEK inhibitor to a patient. In further embodiments of these aspects, the invention provides a method for preventing and/or treating arthritis comprising the step of administering a therapeutically effective amount of a selective MEK inhibitor described in US 5,525,625, incorporated herein by reference in its entirety. An example of a selective MEK inhibitor is 2-(2-amino-
3 -methoxyphenyl)-4-oxo-4H- [ 1 ] benzopyran.
MEK inhibitors are compounds which inhibit one or more of the family of mammalian enzymes known as MAP kinase kinases, which phosphorylate the MAP kinase subfamily of enzymes (mitogen-associated protein kinase enzymes) referred to as MAP kinases or ERKs (extracellular signal-regulating enzymes such as ERK1 and ERK 2). These enzymes regulate phosphorylation of other enzymes and proteins within the mammalian body. MEK 1 and MEK 2 are dual specificity kinases that are present in all cell types and play a critical role in the regulation of cell proliferation and differentiation in response to mitogens and a wide variety of growth factors and cytokines
In a preferred embodiment, the MEK inhibitor to be administered is a phenyl amine derivative of Formula I
In formula (I), R\ is hydrogen, hydroxy, Cj-Cg alkyl, Ci -Cg alkoxy, halo, trifiuoromethyl, or CN. R2 is hydrogen. R3, R4, and R5 are independently selected from hydrogen, hydroxy, halo, trifiuoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, and -(O or NH)m-(CH2)n-R9. R9 is hydrogen, hydroxy,
COOH, or NRj QRI 1 ; n is 0-4; m is 0 or 1. Each of R\ Q and R\ \ is independently selected from hydrogen and Cj-Cg 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-(Cj-Cg alkyl). Z is COOR7, tetrazolyl, CONR6R7, CONHNRj 0Rι 1 , or CH2OR7.
Rβ and R7 independently are hydrogen, Cj-Cg alkyl, C2-Cg alkenyl,
C2-Cg alkynyl, (CO)-Cj-Cg alkyl, aryl, heteroaryl, C3-C10 cycloalkyl, or
C3-C10 (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or R and R7 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.;-C6 alkoxy, amino, nitro, Ci- C4 alkylamino, di(Cι-C4)alkylamino, C3-C6 cycloalkyl, phenyl,phenoxy, C3-C5 heteroaryl, or C3-C5 heteroaryloxy; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Preferred embodiments of Formula (I) have a structure wherein: (a) Ri is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; (b) R2 is hydrogen; (c) R3, R-t, and R5 independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; (d) Rio and Rn independently are hydrogen or methyl; (e) Z is
COOR7, tetrazolyl, CONReR?, CONHNR10Rn, or CH2OR7; Re and R7 independently are hydrogen, C alkyl, heteroaryl, or C 3.5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or R^ and R 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 the synthetic intermediate 2,3,4,5,6-pentafluorophenyl); (f) Z is COOR7; (g) R7 is H, pentafluorophenyl, or tetrazolyl; (h) R3, R4, and R5 are independently H, fluoro, or chloro; (i) R4 is fluoro; (j) two of R3, Rj, and R are fluoro; (k) or combinations of the above. In another preferred embodiment of Formula (I), R] is methyl, fluoro, chloro, or bromo.
Examples of preferred embodiments include methods comprising a MEK inhibitor selected from Formula (I) Compound Table below.
FORMULA (I) COMPOUND TABLE (page 1 of 10)
[4-Chloro-2-(lH-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine
(4-iodo-2-methyl-phenyl)-[2-( 1 H-tetrazol-5-yl)-phenyl]amine [4-nitro-2-( 1 H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine
4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid
3 ,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
3 ,4-Difiuoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-Iodo-2-methyl-phenylamino)-benzoic acid
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-benzoic acid 5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-( 1 H-tetrazol-5-yl)- benzamide FORMULA (I) COMPOUND TABLE (continued, page 2 of 10) 5 -Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic acid 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-N- { 3 - [4-(2-hydroxy-ethyl)-piperazin- 1 -y 1] -propyl } -2-(4-iodo-
2-methyl-phenylamino)-benzamide N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide N-Butyl-4-fluoro-2-(4-iodo-2 -methyl -phenylamino)-benzamide
5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide N-(2,3 -Dihydroxy-propyl)-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l- yl-ethyl)-benzamide 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-
1 -yl-ethyl)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4- yl-ethyl)-benzamide FORMULA (I) COMPOUND TABLE (continued, page 3 of 10)
4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- 4-yl-ethyl)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-mo holin-4-yl- ethyl)-benzamide 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 -yl- ethyl)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)- benzamide
N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethyl)- benzamide
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- 1 -yl-propyl)- benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- propyl)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl-ethyl)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl-ethyl)- benzamide
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin-4-yl- ethyl)-benzamide FORMULA (I) COMPOUND TABLE (continued, page 4 of 10) -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4- ylmethyl-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide -(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- propyl)-3 ,4-difluoro-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)- benzamide -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin-4-yl-ethyl)- benzamide -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy-propyl)- benzamide -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin-1-yl- ethyl)-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl-benzamide -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen-2-yl- ethyl)-benzamide -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin-4-ylmethyl- benzamide -(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl-benzamide -(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-piperidin- 1 -yl- ethyl)-benzamide -Chloro-N- { 3 - [4-(2-hydroxy-ethyl)-piperazin- 1 -yl] -propyl } -2-(4-iodo-2- methyl- phenylamino)- benzamide -Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}-2-(4-iodo-2- methyl- phenylamino)- benzamide -(4-Iodo-2-methyl-phenylamino)-5 -nitro-N-pyridin-4-yl methyl- benzamide FORMULA (I) COMPOUND TABLE (continued, page 5 of 10)
5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}-2-(4-iodo-2- methyl- phenylamino)- benzamide
5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl-ethyl)- benzamide (3-Hydroxy-pyrrolidin-l-yl)-[5-nitro-2-(4-iodo-2-methyl-phenylamino)- phenyl] -methanone 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl-ethyl)- benzamide 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo-2-methyl- phenylamino)- benzamide N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo-2-methyl- phenylamino)- benzamide N- { 3 - [4-(2-Hydroxy-ethy l)-piperazin- 1 -yl] -propyl } -2-(4-iodo-2-methyl- phenylamino)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide 5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin-l-yl-ethyl)- benzamide
5 -Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl-ethyl)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl-ethyl)- benzamide 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo-2-methyl- phenylamino)- benzamide FORMULA (I) COMPOUND TABLE (continued, page 6 of 10)
5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo-2-methyl- phenylamino)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl-ethyl)- benzamide 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl-propyl)- benzamide N- {2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl} -2-(4-iodo-2-methyl- phenylamino)-5-nitro- benzamide
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl-ethyl)- benzamide 5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl-propyl)- benzamide 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-l-yl-ethyl)- benzamide
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin-l-yl-ethyl)- benzamide N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benz.amide 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide FORMULA (I) COMPOUND TABLE (continued, page 7 of 10)
5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(3-Diethyl,amino-propyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl-ethyl)- benzamide 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-l-yl-propyl)- benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(2 or 3-hydroxy- pyrrolidin-l-yl)-methanone
5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl-ethyl)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl-propyl)- benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[4-(2-hydroxy-ethyl)- piperazin- 1 -yl)-methanone N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)- benzamide
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide FORMULA (I) COMPOUND TABLE (continued, page 8 of 10)
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro-benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide FORMULA (I) COMPOUND TABLE (continued, page 9 of 10)
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide
N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro-benzamide
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide
5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide FORMULA (I) COMPOUND TABLE (continued, page 10 of 10)
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 4-Fiuoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol
[5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol [5 -Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl] -methanol N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
In another preferred embodiment, the MEK inhibitor is a compound of Formula II
In Formula (II), Ri a is hydrogen, hydroxy, Cj-Cg alkyl, Cj-Cg alkoxy, halo, trifiuoromethyl, or CN. R2a is hydrogen. Each ofR3a, R4a, and R5a is independently selected from hydrogen, hydroxy, halo, trifiuoromethyl, Ci-Cg alkyl, C]-Cg alkoxy, nitro, CN, and (O or NH)m-(CH2)n-R9a- R9a is hydrogen, hydroxy, CO2H or NRjOaRl la» n ^s ~^'> an<^ rn is 0 or 1. Each of RjOa md R-l la ^s independently hydrogen or Cj-Cg 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-(Cι-Cg alkyl). R6a is hydrogen, Ci-Cg alkyl, (CO)-(Cι-Cg alkyl), aryl, aralkyl, or C3-C10 cycloalkyl. Rγa is hydrogen, Cj-Cg alkyl,
C2-Cg alkenyl, C2-Cg alkynyl, C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRc^a). In Formula (II), any of the alkyl, alkenyl, aryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, Cι-C6 alkoxy, amino, nitro, Cι-C4 alkylamino, di(Cι- C4)alkylamino, C3-C cycloalkyl, phenyl,phenoxy, C3-C5 heteroaryl, or C3-C5 heteroaryloxy; or R a and Rja 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 NR1 øaRi ia- The invention also encompasses pharmaceutically acceptable salts, esters, amides or prodrugs of each of the disclosed compounds.
Preferred embodiments of Formula (II) are those structures wherein: (a) Rla is H, methyl, fluoro, or chloro; (b) R a is H; R3a, R4a, and R5aare each H, Cl, nitro, or F; (c) R<sa is H; (d) R a is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylmethyl, or cyclopropylethyl; (e) the 4' position is I, rather than Br; (f) R4a is F at the 4 position, para to the CO-
N-Rόa-OR7a group and meta to the bridging nitrogen; (f) R3a or R5a is F; (g) at least one of R3a, Ria, and R5a is F; (h) ιa is methyl or chloro; or (i) or a combination of the above.
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)
-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(methoxy)-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)- benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)- benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentoxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-furylmethoxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-ethoxy-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-( 1 -methylprop- 2-ynyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -phenylprop-
2-ynyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -methyl- 5-phenylpent-2-en-4-ynyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)-benzamide FORMULA (II) COMPOUND TABLE (continued, page 2 of 7) ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino )))-N-(cyclobutyloxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino )))-N-(2-thienylmethoxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino )))-N-(2-methyl-prop-
2-enyloxy)-benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino j))-N-(2-phenoxyethoxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino )))-N-(but-2-enyloxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino )))-N-(but-3-ynyloxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino )))-N-(cyclopentyloxy)- benzamide ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino 3))-N-(3-(2-fluorophenyl)- prop-2-ynyloxy)-benzamide -Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide -Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide -Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide -Bromo-N-butoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-but-
2-enyloxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- pent-2-en-4-ynyloxy)-benzamide FORMULA (II) COMPOUND TABLE (continued, page 3 of 7) -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N-[5-(3-methoxy- phenyl)-3-methyl-pent-2-en-4-ynyloxy]-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-
2-ynyloxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
[3 -(3 -methoxy-phenyl)-prop-2-ynyloxy] -benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(thiopen-
2-ylmethoxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(pyridin-
3 -ylmethoxy)-benzamide -Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3 -(2-fluorophenyl)-prop-2-ynyloxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(ethoxy)- benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(cyclopropylmethoxy)-benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(isopropoxy)- benzamide -Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but-
3 -ynyloxy)-benzamide -Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide -Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran-2-yloxy)- benzamide -Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy-benzamide -Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide -Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide -Iodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran-2-yloxy)- benzamide FORMULA (II) COMPOUND TABLE (continued, page 4 of 7) ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3 -phenylprop- 2-ynyloxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-furylmethoxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide ,4-Difluoro-2-(4-bromo-2 -methyl -phenylamino)-N-(but-3 -ynyloxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl-prop-
2-enyloxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclobutoxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-( 1 -methyl-prop-
2-ynyloxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-(3-fluorophenyl)- prop-2-ynyloxy)-benzamide ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(4,4-dimethylpent-
2-ynyloxy)-benzamide FORMULA (II) COMPOUND TABLE (continued, page 5 of 7)
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopentoxy)- benzamide
3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide
N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide 3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 5-Chloro-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide 2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benzamide 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide
5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl-benzamide 2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difluoro-N-hydroxy- benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide 4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide
2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide
2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide
2-(2-Bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide FORMULA (II) COMPOUND TABLE (continued, page 6 of 7)
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide
5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro- benzamide N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-
3 ,4-difluoro-benzamide N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro- benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro- benzamide 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-
3 ,4-difluoro-benzamide 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro- benzamide
2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro- benzamide 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N-cyclopropylmethoxy- 3,4-difluoro-benzamide
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro- benzamide FORMULA (II) COMPOUND TABLE (continued, page 7 of 7)
N-Cyclopropylmethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide
N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3 ,4-difluoro- benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide.
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:
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluorobenzamide (PD184352); 2-(2-Methyl-4-iodophenylamino)-N- hydroxy-4-fluorobenzamide (PD 170611); 2-(2-Methyl-4-iodophenylamino)-N- hydroxy-3,4-difluoro-5-bromoberizamide (PD171984); 2-(2-Methyl- 4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide
(PD 177168); 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-bromobenzamide (PD 184161); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluoro- 5-bromobenzamide (PD184386); 2-(2-Chloro-4-iodoρhenylamino)-N- cyclobutylmethoxy-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-Methyl-4-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. Additional preferred compounds include 2-(2-chloro-4- iodophenylamino)-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-chloro-4-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-iodo-2-methylphenylamino)-benzamide
(PD ).
The invention further provides methods of synthesis and synthetic intermediates.
Other features and advantages of the invention are apparent from the detailed description, examples, and claims set forth.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a method of preventing or treating arthritis in a patient which comprises the step of administering to a patient suffering from arthritis and in need of treatment, or to a patient at risk for developing arthritis, an effective anti-arthritic amount of a MEK inhibitor. The invention provides a method of preventing and treating both rheumatoid arthritis and osteoarthritis. The invention is preferably practiced by administering a phenyl amine MEK inhibitor of Formula (I) or Formula (II). Many of these MEK-inhibiting phenyl amine compounds are specific or selective MEK 1 and MEK 2 inhibitors.
Selective MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or MEK 2 enzymes without substantially inhibiting other enzymes such as MKK3, ERK, PKC, Cdk2A, phosphorylase kinase, EGF and PDGF receptor kinases, and C-src. In general, a selective MEK 1 or MEK 2 inhibitor has an IC50 for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC50 for one of the above-named other enzymes. Preferably, a selective inhibitor has an IC50 that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000 or less than that of its IC50 for one or more of the above-named enzymes.
The mammals to be treated according to this invention are patients, not only humans but also animals such as horses and dogs, who have developed arthritis and are suffering from the pain and disfiguration associated with arthritis, or who are at risk for developing the disease, for example, those who have a family history of arthritis. Those skilled in the medical art are readily able to identify individual patients who are afflicted with arthritis, as well as those who are susceptible to developing the disease.
The term "patient" means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, horses, and pigs. 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 United States Patent Number 5,525,625, column 6, beginning at line 35. The complete disclosure of United States Patent Number 5,525,625 is hereby incoφorated by reference. An example of a MEK inhibitor is 2-(2-amino-3-methoxyphenyl)-
4-oxo-4H-[l]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 United States Patent Number 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.
A. Terms
Some of the terms used herein are defined below in combination with their usage throughout this disclosure. 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.
The term "aryloxy" means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl-
1 -fluorenyloxy.
"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.
The heteroaryl groups can be bonded through oxygen to make heteroaryloxy groups, for example thienyloxy, isothiazolyloxy, benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy. 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. Ex.amples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, l,l-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-l-yl)-ethyl, 3-(moφholin-4-yl)propyl. "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.
"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. 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.
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 tetrahydrofliryl, tetrahydropyrrolyl, octahydrobenzofuranyl, moφholinyl, 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-thienylmoφholine-l-yl.
B. Administration and Formulation 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.
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.
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 absoφtion of the injectable pharmaceutical form can be brought about by the use of agents delaying absoφtion, for example, aluminum monostearate and gelatin.
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) absoφtion 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.
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.
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.
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.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
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.
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.
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. 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.
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. 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 Pharm. Sci., 1977;66:1-19 which is incoφorated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include Cj-Cg alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary Ci-Cg alkyl amines and secondary Cj-Cg 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, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods. 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 Drus Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incoφorated herein by reference.
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 puφoses of the present invention.
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.
C. Synthesis
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 incoφorated by reference.
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.
Scheme 1
base
where L is a leaving group, for example halo such as fluoro.
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°C to about 100°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.
The 2-(phenylamino)-benzoic acid (e.g., Formula I, where R7 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 HOR7
(where R7 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.
The benzamides of the invention, Formula (I )where Z is CONRgR7, are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNR6R7. 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°C to about 60°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 = CONHNRi QRI l) are similarly prepared by coupling a benzoic acid with a hydrazine of the formula H2HNR10Rn.
The benzyl alcohols of the invention, compounds of Formula (I) where Z is CH2OR6 and R6 is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following Scheme 2.
Scheme 2
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°C to about 40°C.
The following detailed examples illustrate specific compounds provided by this invention. EXAMPLE 1 4-Fluoro-2-f4-iodo-2-methylphenylamino)benzoic acid
To a stirring solution comprised of 3.16 g (0.0133 mol) of 2-amino-5- iodotoluene in 5 mL of tetrahydrofuran at -78°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_ι) 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°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C;
!H NMR (400 MHz; DMSO): δ 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); 13c NMR (100 MHz; DMSO): δ 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;
19F NMR (376 MHz; DMSO): δ -104.00 to -104.07 (m);
IR (KBr) 1670 (C = O stretch) cm"!; MS (Cl) M+l = 372.
Analysis calculated for C14H11FLNO2:
C, 45.31; H, 2.99; N, 3.77. Found: C, 45.21; H, 2.77; N, 3.64.
EXAMPLES 2-30 By following the general procedure of Example 1 , the following benzoic acids and salts of Formula (I) were prepared. Example Compound MP °C No.
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)-benzoic 240.5-244.5 acid
4 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 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 DEC benzoate
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-nitro-benzoic acid 256-258
13 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-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)-benzoic acid 245-255 DEC
Example Compound MP °C
No.
19 2-(4-Iodo-2-methyl-phenylamino)-benzoic acid 218-223
20 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 243-46
21 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic 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-methyl-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-phenylamino)-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 5-Chloro-N-f2-hvdroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide
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 temperature 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 (MgSO.ι) 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 powder; mp 120-121°C; *H NMR (400 MHz; CDCI3): δ 9.11 (s, IH), 7.56 (d, IH, J = 1.4 Hz), 7.46-7.41
(m, 2H), 7.20 (dd, IH, J = 8.9, 2.4 Hz), 7.00 (t, 2H, J = 9.6 Hz), 6.55 (broad t, IH), 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, IH); IR (KBr) 3297 (O-H stretch), 1627 (C - O stretch) cm- 1 ;
MS (CI) M+1 = 431. Analysis calculated for C16H16CHN2O2'.
C, 44.62; H, 3.74; N, 6.50. Found: 44.63; H, 3.67; N, 6.30.
EXAMPLES 32-48
By following the general procedure of Example 31, the following benzamides were prepared by reacting the corresponding benzoic acid with the corresponding amine.
Example Compound MP °C
No.
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-phenylamino)- 90-91 benzamide
36 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N- oil dimethyl-benzamide
37 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(lH- 285-288 DEC tetrazol-5-yl)-benzamide
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 Example Compound MP °C
No.
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)-piperazin-l-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-methyl-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
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°C; IH NMR (400 MHz; DMSO): δ 7.57 (d, IH, J=1.7 Hz), 7.45 (dd, IH, J=8.4,
1.9 Hz), 7.39 (s, IH), 7.29 (t, IH, J=7.5 Hz), 6.89 (d, IH, J=8.4 Hz), 6.67-6.60 (m, IH), 5.47 (t, IH, J=5.5 Hz), 4.49 (d, 2H, 5.1 Hz), 2.14 (s, 3H); IR (KBr) 3372 (O-H stretch) cm"1 ;
MS (Cl) M+l = 358.
Analysis calculated for C14H13FLNO:
C, 47.08; H, 3.67; N, 3.92. Found: C, 47.17; H, 3.75; N, 3.72.
EXAMPLE 50-52 The following benzyl alcohols were prepared by the general procedure of Example 49.
Example No. Compound MP °C
5θ" [5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 82-85 phenyl]-methanol
51 [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]- 126.5-128.5 methanol
52 [5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 60.5-63.5 phenyl]-methanol
Several invention compounds of Formula (I) were prepared utilizing combinatorial synthetic techniques. The general procedure is as follows:
To a 0.8-mL autosampler vial in a metal block was added 40 μL of a 0.5 M solution of the acid in DMF and 40 μL 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 μL were added to the autosampler vial. The reaction was allowed to stand for 24 hours.
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. The residue was taken up in 2 mL of 50% acetonitrile in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 μM 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 The following compounds of Formula I were prepared by combinatorial methodology:
Example Compound MS
No. 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-difluoro-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-iodo-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-iodo-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-difluoro-2-(4-iodo- 551 2-methyl-phenylamino)-benzamide Example Compound MS
No. M-H
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-methyl-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-phenylamino)-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-phenylamino)-benzamide 460
69 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-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-ρhenylamino)-N- 557 pyridin-4-ylmethyl-benzamide
77 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 479 4-ylmethyl-benzamide
78 2-(4-Bromo-2-methyl-pheny lamino)-N-(3 -dimethylamino-propy 1)- 425
3,4-difluoro-benzamide Example Compound MS
No. M-H
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-thiophen- 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-difluoro-N-phenethyl- 444 benzamide
88 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin- 451 1 -yl-ethyl)-benzamide
89 5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 557* 2-(4-iodo-2-methyl- phenylamino)- benzamide
90 5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-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-l-yl]-propyl}- 601 * 2-(4-iodo-2 -methyl- phenylamino)- benzamide
93 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 486* phenylamino)- benzamide Example Compound MS
No. M-H
94 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl- 497* ethyl)-benzamide
95 (3-Hydroxy-pyrrolidin-l -yl)-[2-(4-iodo-2-methyl-phenylamino)- 466 5-nitro-phenyl]-methanone
96 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-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]-ethyl}-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-methyl-phenylamino)-phenyl]-(3-hydroxy- 499 pyrrolidin- 1 -yl)-methanone
101 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid phenethyl 501 ester
102 N-{3-[4-(2-Hydroxy-ethyl)-piperazin-l-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-methyl-phenylamino)-N-pyridin-4-ylmethyl- 460 benzamide
105 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl- 528* ethyl)-benzamide
106 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-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-iodo-2-methyl- 472* phenylamino)-benzamide
109 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo- 502* 2-methyl- phenylamino)- benzamide Example Compound MS
No. M-H
110 5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 445* phenylamino)-benzamide
1 1 1 5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo- 516* 2-methyl-phenylamino)- benzamide
112 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-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-l-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-phenylamino)-N-(2-moφholin-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
1 19 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- 512* propyl)-benzamide
120 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-l-yl- 509* ethyl)-benzamide
121 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin-l-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 Example Compound MS
No. M-H
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-moφholin-4-yl- 544* ethyl)-benzamide
129 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-l-yl- 523* propyl)-benzamide
130 [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(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-moφholin-4-yl- 484* ethyl)-benzamide
133 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- 496* propyl)-benzamide
134 . [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 482
[4-(2-hydroxy-ethyl)-piperazin- 1 -
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-phenylamino)-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-methyl-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-phenylamino)-thiobenzoic acid S- 490 phenethyl ester
141 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 506 phenethyl ester Example Compound MS
No. M-H
142 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 536 benzyl ester
143 2-(4-Iodo-2-methyl-phenylamino)-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)-thiobenzoic 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-phenylamino)- 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-sulfamoyl- 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
Example Compound MS
No. M-H
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-methyl-phenylamino)-benzamide 409
159 N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-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-phenylamino)-benzamide 425
162 N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 436 benzamide
163 5-Bromo-N-cyclopropyl-2-(4-iodo-2-rnethyl-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-sulfamoyl-benzyl)- 646 benzamide
166 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 598 benzyl)-benzamide
167 N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 436
Example Compound MS
No. M-H
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-phenylamino)-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-phenylamino)- 559 benzamide
175 N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 517
176 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-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-phenyl- 567 benzamide
179 N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-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 Example Compound MS
No. M-H
185 N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 538 benzamide
186 N-Benzyloxy-5-fluoro-2-(4-iodo-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-phenylamino)- 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-phenylamino)- 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-phenylamino)- 411 benzamide
199 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-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)-benzamide 411 Example Compound MS
No. M-H
202 N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 585 benzamide
203 N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-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-benzamide 438 * M+H
EXAMPLE 207 Preparation of ^-Chloro^-dH-tetrazol-S-vD-^-iodo^-methyl-phenvπ-amine
Step a: Preparation of 5-chloro-2-fluoro-benzaldehyde To a solution of l-chloro-4-fluorobenzne (13.06 g, 0.1 mol) in THF
(180 mL), at -78°C, LDA (2M solution in THF, 50 mL, 0.1 mol) was added drop wise. After stirring at -78°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 Et2θ. The Et2θ layer was dried (MgSO4) and the solvent removed in vacuum to give 14.95 g (94%) yield of crude aldehyde: H NMR (CDC13): δ, 10.3 (s, -C(O)H).
Step b: Preparation of 5-chloro-2-fluoro-benzaldehyde oxime
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°C (oil bath temperature) for
1 hour and the solvent removed under vacuum to give an oil. The oil was partitioned between water and CH2CI2. The CH2CI2 layer was dried (MgSO4) 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 CH2CI2 gave 4.87 g (28%) of the aldoxime as white solid: mp 95-97°C;
Analysis calculated for C7H5NOFCI:
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
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 NaHCO3 (200 mL) solution. The mixture was extracted with Et2θ. The Et2θ layer was dried (K2CO3) 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-phenyiy lH-tetrazole
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, Et2θ (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°C) and acidified to pH 1 with cone. HCl. A gray solid precipitated. The solid was dried in vacuum at 50°C to give 1.76 g (49%) of 5-(5-chloro-2-fluoro-phenyl)-lH- tetrazole: mp partial melt at 110°C, complete melting at 124°C); H (400 Mz, CDCI3): δ 8.19-8.08 (m, IH), 7.77-7.71 (m, IH), 7.61-7.52 (m, IH);
13C (100 Mz, CDCI3): δ 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 (Cl) M+l = 199 (100), M = 198 (6). Step e: Preparation of [4-Chloro-2-( 1 H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)- amine
To a solution of 2-methyl-4-iodoaniline (3.52 g, 0.0151 mol) in THF (25 mL) at -78°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 l-(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 cone. NH4CI solution and extracted with CH2CI2. The organic layer was dried (MgSO4) and the solvent removed giving a crude product as an oil. The oil with CH2CI2-
>CH2Cl2:MeOH (9.7:0.3) gave 1.5 g (48%) of the desired product: mp 205-208°C; H (400 Mz, DMSO): δ 9.13 (s, IH), 8.00-7.99 (s, IH), 7.69 (s, IH), 7.55-7.52 (m, IH), 7.43-7.40 (m, IH), 7.12-7.05 (m, IH), 2.24 (s, 3H); 1 C (100 Mz, CDCI3): δ 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 C14H1 ιN5CιI-0.5H2θ:
C, 39.97; H, 2.87; N, 16.65. Found: C, 38.87, H, 2.77; N, 16.47.
The following tetrazole substituted phenylamines were prepared by following the general procedure of Example 207.
EXAMPLE 208 (4-iodo-2-methyl-phenyl)-[2-(lH-tetrazol-5-ylVphenyl]amine, mp 231°C (dec)
EXAMPLE 209 r4-nitro-2-(lH-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl -amine. mp 205-208°C.
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).
Scheme 3
base
R6a HN-O— R 7. a
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.
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°C to about 25°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.
The phenylamino benzoic acid next is reacted with a hydroxylamine derivative HNR6aOR7a 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-l-ethoxycarbonyl-l,2-dihydroquinoline (EEDQ), 1 ,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)-phosphonium 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.
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.
Yet another method for making invention compounds comprises reacting a phenylamino benzhydroxamic acid with an ester forming group as depicted in Scheme 5. Scheme 5
base
where L is a leaving group such as halo, and a base is triethylamine or diisopropylamine. The synthesis of compounds of Formula (II) is further illustrated by the following detailed examples.
EXAMPLE la 4-Fluoro-N-hvdroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide (a) Preparation of 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid To a stirred solution containing 3.16 g (0.0133 mol) of 2-amino-
5-iodotoluene in 5 mL of tetrahydrofuran at -78°C was added 10 mL (0.020 mol) of a 2.0 M lithium dusopropylamide 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 (MgSO4) 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°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C;
*H NMR (400 MHz, DMSO): δ 9.72 (s, IH), 7.97 (dd, IH, J=7.0, 8.7 Hz), 7.70 (d, IH, J=1.5 Hz), 7.57 (dd, IH, J=8.4, 1.9 Hz), 7.17 (d, IH, J=8.2 Hz),
6.61-6.53 (m, 2H), 2.18 (s, 3H);
13c NMR (100 MHz, DMSO): δ 169.87, 166.36 (d, JC-F=249.4 Hz), 150.11 (d, Hz), 135.07,
125.60, 109.32, 104.98 (d, Jc-F=2l-1 Hz), 99.54 (d, JC.F=26.0 Hz), 89.43, 17.52; 19F NMR (376 MHz, DMSO): δ -104.00 to -104.07 (m);
IR (KBr) 1670 (C=O stretch)cm'l;
MS (Cl) M+l = 372.
Analysis calculated for Ci 4H1 1 FLNO2:
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)- benzamide
To a stirred solution of 4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (0.6495 g, 0.001750 mol), O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (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 (MgSO4) 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°C; iH NMR (400 MHz, DMSO): δ 11.34 (s, IH), 9.68 (s, IH), 9.18 (s, IH), 7.65 (d, IH, J=1.5 Hz), 7.58 (dd, IH, J=8.7, 6.8 Hz), 7.52 (dd, IH, J=8.4, 1.9 Hz), 7.15 (d, IH, J=8.4 Hz), 6.74 (dd, IH, J=l 1.8, 2.4 Hz), 6.62 (ddd, IH, J=8.4, 8.4, 2.7 Hz), 2.18 (s, 3H); 13c NMR (100 MHz, DMSO): δ 165.91, 164.36 (d, JC-F=247.1 Hz), 146.78,
139.18, 138.77, 135.43, 132.64, 130.60 (d, JC.F=l 1.5 Hz), 122.23, 112.52,
104.72 (d, J=22.1 Hz), 100.45 (d, J -F=25.2 Hz), 86.77, 17.03;
19F NMR (376 MHz, DMSO): δ -107.20 to -107.27 (m);
IR (KBr) 3307 (broad, O-H stretch), 1636 (C=O stretch) cm"1; MS (Cl) M+l = 387.
Analysis calculated for C14H12FLN2O2:
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-hvdroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide
(a) Preparation of 5-Bromo-2,3,4-trifluorobenzoic acid
To a stirred solution comprised of l-bromo-2,3,4-trifluorobenzene (Aldrich, 99%; 5.30 g, 0.0249 mol) in 95 mL of anhydrous tetrahydrofuran cooled to -78°C was slowly added 12.5 mL of 2.0 M lithium dusopropylamide 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°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 x 200 mL). The combined organic extracts were dried (MgSO4), 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°C; IH NMR (400 MHz, DMSO): δ 13.97 (broad s, IH, 8.00-7.96 (m, IH);
13c NMR (100 MHz, DMSO): δ 162.96, 129.34, 118.47, 104.54 (d, JC-F=22.9 Hz);
19F NMR (376 MHz, DMSO): δ -120.20 to -120.31 (m), -131.75 to -131.86 (m), -154.95 to -155.07 (m); IR (KBr) 1696 (C=O stretch)cπr ;
MS (Cl) M+l = 255. Analysis calculated for C74H2iBrF3θ2:
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)- benzoic acid
To a stirred solution comprised of 1.88 g (0.00791 mol) of 2-amino- 5-iodotoluene in 10 mL of tetrahydrofuran at -78°C was added 6 mL (0.012 mol) of a 2.0 M lithium dusopropylamide in tefrahydrofuran/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 x 150 mL), and the combined organic extractions were dried (MgSO4) 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°C) to afford 1.39 g (76%) of a yellow-green powder; mp 259.5-262°C;
IH NMR (400 MHz, DMSO): δ 9.03 (s, IH), 7.99 (dd, IH, J=7.5, 1.9 Hz), 7.57 (dd, IH, J=1.5 Hz), 7.42 (dd, IH, J=8.4, 1.9 Hz), 6.70 (dd, IH, J=8.4, 6.0 Hz), 2.24 (s, 3H);
19F NMR (376 MHz, DMSO): δ -123.40 to -123.47 (m); -139.00 to -139.14 (m); IR (KBr) 1667 (C=O stretch)cm" 1 ;
MS (Cl) M+l = 469. Analysis calculated for Ci4H9BrF2lNO2:
C, 35.93; H, 1.94; N, 2.99; Br, 17.07; F, 8.12; 1, 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-hvdroxy-2-C4-iodo-2-methyl- phenylaminoVbenzamide
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°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 (MgSO4) 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 (MgSO4) 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°C;
IH NMR (400 MHz, DMSO): δ 11.53 (s, IH), 9.38 (s, IH), 8.82 (s, IH), 7.70 (dd, IH, J=7.0, 1.9 Hz), 7.53 (s, IH), 7.37 (dd, IH, J=8.4, 1.9 Hz), 6.55 (dd, IH, J=8.2, 6.5 Hz), 2.22 (s, 3H); 19F NMR (376 MHz, DMSO): δ -126.24 to -126.29 (m), -137.71 to -137.77 (m);
IR (KBr) 3346 (broad, O-H stretch), 1651 (C=O stretch)cm"l;
MS (Cl) M+l = 484.
Analysis calculated for C14H1 oBrF2LN2θ2:
C, 34.81; H, 2.09; N, 5.80. Found: C, 34.53; H, 1.73; N, 5.52.
Examples 3 a to 12a in the table below were prepared by the general procedure of Examples la and 2a.
EXAMPLES 13a-77a 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., (NHR6a )-O-R7a). A general method is given below: To a 0.8-mL autosampler vial in a metal block was added 40 μL of a
0.5 M solution of the acid in DMF and 40 μL 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 μL were added to the autosampler vial. The reaction was allowed to stand for 24 hours.
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.
The residue was taken up in 2 mL of 50% acetonitrile in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 μM 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
Example Compound Melting MS
No. Point (°C) (M-H+)
3a 2-(4-bromo-2-methyl-phenylamino)-4-fluoro-N- 56-75 dec 523 hydroxy-benzamide
4a 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 65 dec phenylamino)-benzamide
5a 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 62-67 phenyl.amino)-N-methyl-benzamide
6a 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-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-cluoro-2-methyl- 133.5-135 phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
Ϊ2a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 107-109.5 phenylmethoxy-benzamide
13a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 399 methoxy-benzamide
14a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 417
N-methoxy-benzamide
15a 2-(4-Bromo-2-methyl-phenylamino)- 369
3 ,4-difluoro-N-methoxy-benzarnide
16a 2-(4-Bromo-2-methyl-phenylamino)-N-ethoxy- 342*
3,4-difluoro-benzamide (M-EtO)
17a 5-Bromo-N-ethoxy-3,4-difluoro-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 Example Compound Melting MS
No. Point (°C) (M-H+)
2Ϊa 3,4-Difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo- 483 2-methyl-phenylamino)-benzamide
22a 2-(4-Bromo-2-methyl-phenylamino)- 435
3,4-difluoro-N-(furan-3-ylmethoxy)-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-phenylamino)- 441
N-(prop-2-ynyloxy)-benzamide
27a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 455
N-( 1 -methyl-prop-2-yny loxy)-benzamide
28a 2-(4-Bromo-2-methyl-phenylamino)- 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 Example Compound Melting MS
No. Point (°C) (M-H+)
30a 2-(4-Bromo-2-methyl-phenylamino)-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-methy 1-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 Example Compound Melting MS
No. Point (°C) (M-H+)
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-pheny lamino)-N-ethoxy- 383 3 ,4-difluoro-benzamide
42a 4-Fluoro-2-(4-iodo-2-methyl-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 Example Compound Melting MS
No. Point (°C) (M-H+)
47a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 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-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide
51a 2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclobutyloxy-3,4-difluoro-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-difluoro-benzamide
55a N-Cyclopropylmethoxy-4-fluoro-2-(4-iodo- 439
2-methyl-phenylamino)-benzamide
56a N-Cyclopropylmethoxy-3,4-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
57a 2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclopropylmethoxy-3,4-difluoro-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-phenylamino)- 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-phenylamino)- 451
3,4-difluoro-N-(thiophen-2-ylmethoxy)- benzamide
65a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 439
(2-methyl-allyloxy)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
66a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 457 N-(2-methyl-allyloxy)-benzamide
67a 2-(4-Bromo-2-methyl-phenylamino)- 410
3,4-difluoro-N-(2-methyl-allyloxy)-benzamide
68a N-(But-2-enyloxy)-4-fluoro-2-(4-iodo-2-methyl- 439 phenylamino)-benzamide
69a N-(But-2-enyloxy)-3,4-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide
70a 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 410
2-enyloxy)-3 ,4-difluoro-benzamide
71a 3, 4-Difluoro-2-(4-iodo-2-methy 1-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-phenylamino)-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 Example Compound Melting MS
No. Point (°C) (M-H+)
75a 2-(4-Bromo-2-methyl-phenylamino)-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 *CI
D. Pharmacological Activity
Several of the compounds described above have been evaluated in both in vitro and in vivo assays which are designed to measure anti-arthritic activity, and are recognized by those skilled in the art to be valid predictors of clinical efficacy.
Type Il-collagen-induced arthritis (CIA) in mice is recognized as an experimental model of arthritis that has a number of pathologic, immunologic, and genetic features in common with rheumatoid arthritis in humans. The disease is induced by immunization of DBA/1 inbred strain of mice with 100 micrograms of type II collagen (C II), which is the major component of joint cartilage. The collagen was delivered to the mice by intradermal injection of a solution made up in Freund's complete adjuvant. A progressive and inflammatory arthritis develops in the majority of the mice immunized, characterized by paw width increases of up to 100%). A clinical scoring index is used to assess disease progression from erythema and edema (stage 1), joint distortion (stage 2), to joint ankylosis (stage 3). The disease is variable in that it can affect one or all of the paws of the animal, resulting in total possible score of 12 for each mouse. Histopathology of arthritic joints revealed synovitis, pannus formation, and cartilage and bone erosions. All mouse strains that are susceptible to CIA are high antibody responders to type II collagen, and there is a marked cellular response to C II. The foregoing assay was carried out to evaluate the anti-arthritic activity of several doses of the compound 2-(2-chloro-4-iodophenylamino)-N- cyclopropylmethoxy-3,4-difluorobenzamide. The compound (also referred to as "PD 184352") was suspended in an aqueous mixture of 0.5% hydroxypropylmethyl cellulose (HPMC) and 0.2% Tween 80. The suspension was administered orally twice daily (once in the morning and once in the evening) in equally divided doses. All animals were fed laboratory chow, and given water ad libitum. The assay was continued for 63 days, with disease scores being taken periodically throughout the study, and on Day 63, and averaged at the end of the study. The results of the assay are presented in Pharmacological Table 1 below:
Pharmacological Table 1 Collagen-Induced Arthritis in Mice
Treatment Number of Percent Average Average No.
Mice Per Arthritis Severity of Arthritic
Group Incidence Score Paws
Vehicle 10 100 6.3 3.5
PD 184352 9 22 0.333 0.333
200 mg/kg/day
PD 184352 10 10 0.6 0.4
60 mg/kg/day
PD 184352 10 60 2.9 2
20 mg/kg/day
The foregoing data establish that the compound is a potent anti-arthritic agent.
In another standard assay, monoarticular arthritis was induced in rats. Rats were given 6 microgram doses of sonicated Streptoccocal cell wall (SCW) ) in 10 microliters of Dulbecco' s phosphate buffered saline (DPBS) by intra-articular injection into the right tibiotalar joint on Day 0. SCW induces paw swelling in the animals. On Day 21, the delayed-type hypersensitivity (DTH) was initiated with 100 micrograms of SCW administered intravenously. Test compounds were suspended in an aqueous mixture of 0.5%> HPMC and 0.2% Tween 80, sonicated, and administered twice daily in equally divided doses (10 mL/kg volume) beginning 1 hour prior to reactivation with SCW. The amount of edema was determined by measuring the baseline volumes of the sensitized hindpaw before reactivation on Day 21, and comparing them with the volumes at subsequent time points. Paw volumes were measured by mercury plethysmography. The antiarthritic activities of several of the phenyl amine compounds described above, when evaluated in the foregoing assay, are presented below in Pharmacological Table 2. In the Table, compound "PD 184352" is 2-(2-chloro- 4-iodophenylamino)-N-cyclopropylmethoxy-3 ,4-difluorobenzamide, and compound "PD 170611" is 2-(2-methyl-4-iodophenylamino)-N-hydroxy- 4-fluorobenzamide.
Pharmacological Table 2 SCW-Induced Monoarticular Arthritis
Percent Inhibition of Paw Swelling at Indicated Time Points
Treatment (n) Day 22 Day 23 Day 24 Day 25
PD 184352 10 59 57 68 53
200 mg/kg/day
PD 184352 10 30 34 40 31
60 mg/kg/day
PD 184352 10 17 17 28 17
20 mg/kg/day
PD 170611 10 40
300 mg/kg/day
PD 170611 10 80 20 32
100 mg/kg/day
The foregoing data establish that the phenyl amine compounds of Formulas I and II are potent anti-arthritic agents, and can be used to prevent and treat various forms of arthritis, including rheumatoid arthritis and osteoarthritis. Several of the phenyl amine MEK inhibitors have been evaluated in an in vitro cell culture assay designed to measure the effect of MEK inhibitors on interleukin-1 (IL- 1 ) induced stromelysin production and phospo-ERK levels in rabbit synovial fibroblasts. The stromelysin is a matrix metalloproteinase enzyme that is a causative factor in arthritis. The phospho-ERK is an enzyme that is phosphorylated by a MEK enzyme, and is thus an indicator of MEK activity in cells.
New England White rabbits were euthanized with B-euthanasia administered IV with a 25 gauge needle in the marginal ear vein. The synovium was immediately removed by the incision of the quadracep tendon and retracting the patella. The synovium, with the infrapellar fat body, was then cut away from the patellar ligament and placed in sterile phosphate buffered saline (PBS) (Gibco BRL, Gaithersberg, MD). The synovium was finely minced with a sterile scalpel and placed in a 50 mL tube containing 6 mL of a solution of 4 mg collagenase type I (Gibco BRL, Gaithersberg, MD)/mL PBS. The mixture was incubated for 3 hours at 37°C. During the incubation, the 50 mL tube was gently swirled 4 to 6 times. The synoviocytes were then washed twice in media (the media composition is described below). Washed cells were seeded into one T-75 plastic cell culture flask and incubated at 37°C in 5% CO2. After reaching
90-100% confluency, the cells were seeded into appropriate containers for the assay. Synovial fibroblasts were allowed to grow in 96 well plates for three days after confluency before testing. Vehicle (0.1% dimethylsulfoxide in media), or a phenyl amine MEK inhibitor test compound dissolved in vehicle, was added to the synovial fibroblasts 30 minutes before addition of IL-lα. Interleukin-1 α
(100 U/mL) (Genzyme, Cambridge, MA) was suspended in media and added in a volume of 10 μL/well. The cells were then incubated for 24 hours before the media was removed and stored at -20°C. Prostromelysin-1 levels were measured using an ELISA from Amersham (Cat. No. RPN2615). Percent inhibition was determined by comparing the stromelysin- 1 concentration of drug-treated cells to that of vehicle-treated controls. The drug concentration at which 50% inhibition of stromelysin- 1 production was measured (IC50) was determined using linear regression analysis.
The media used in the foregoing assay was prepared as follows, utilizing commercial reagents acquired from Gibco BRL (Gaithersberg, MD) unless otherwise stated. To each 500 mL bottle of alpha-modified Eagles medium
(α-MEM, Cat. No. 12561-023) was added 10 mL of 1 Molar N-2- hydroxyethylpiperazine-N-2-ethane sulfonic acid (1 M HEPES, Cat. No. 15630-023), 10 mL of Penicillin/Streptomycin Stock (Cat. No. 15070-030, 5,000 U/mL Pen./5,000 μg/mL Strep), 500 μL Gentamicin Stock (50 mg/mL) (Cat. No. 15750-011), 40 mL Fetal Calf Serum from Hyclone Inc. (Cat.
No. Al 111-L). The results of the foregoing assays are presented in Pharmacological Tables 3 and 4. Pharmacological Table 3 presents the nanomolar dose of test compound required to cause a 50% inhibition of stromelysin expression (IC50).
Pharmacological Table 3 Effect of MEK Inhibitors on IL-1 -induced Stromeylsin Expression in Rabbit Synovial Fibroblast Cell Cultures Compound Tested IC50 (nM)
PD 171984 59
PD 177168 20
PD 180841 61
PD 184161 192
PD 184352 28
PD 184386 18
PD 185625 24
PD 185848 9
PD 188563 11
PD 198306 18
PD 199601 24
PD 203311 20 In addition, a Western blot analysis of phospho-ERK levels in cell cultures was performed. Pharmacological Table 4 presents the % inhibition of ERK 1/2 phosphorylation caused by a phenyl amine MEK inhibitor. Cells were lysed with ImL lysis buffer (containing NaCl (70 mM), B-glycerol phosphate (50 mM), 1M HEPES (10 mM), Triton X-100 (1%)) per T25. The mixture was transferred to microcentrifuge tubes, and spun at 2500 x g for 15 minutes. After removing the supernatant, the protein assay was performed. The samples were run on a 10% Tris-Glycine gel, and transferred to nitrocellulose. The blots were then probed with a phospho-p44/42 MAP kinase antibody followed by the secondary Ab (goat anti rabbit HRP conjugated), coated with the ECL detection reagent, and exposed to film. The amount of phospo-ERK present was determined by relative densitometry.
Pharmacological Table 4 Inhibition of ERK Phosphorylation by PD 184352 in IL-2 Stimulated Rabbit Synovial Fibroblast Cell Cultures PD 184352 (nM) % Inhibition of Phospho-ERK
Ϊ0 22
10 81
1,000 100
10,000 97
The data presented in Pharmacological Tables 3 and 4 establish the phenyl amino MEK inhibitors of Formula I and Formula II are potent inhibitors of cellular enzymes which are causative factors in arthritis.
The method of this invention has also been established in in vivo assays utilizing New Zealand White rabbits in which cartilage degradation was induced by interleukin 1 -alpha injections into the knee joints.. Adult male rabbits weighing about 3 kg were anesthetized with 5 mg/kg of rompun and 10-15 mg/kg of ketamine. Test compounds were suspended in a vehicle of 0.5% aqueous hydroxypropyl methyl cellulose and 0.2% Tween 80. The suspensions were administered by oral gavage to the animals. Thirty minutes following dosing with the MEK inhibitors, human recombinant IL-lα (Genzyme, Cambridge, MA) was injected (25 ng) into one knee joint space through the suprapatella ligament. The contralateral joint received an equal volume of vehicle (phosphate buffered saline/0.2% fetal bovine serum). The animals were euthanized after 24 hours after the IL-1 injection, and the extent of cartilage degradation was determined by measuring the proteoglycan content of the articular cartilage from the femoral condyles with a dimethylene blue dye assay kit. Analysis was done spectrophotometrically, and the percent of inhibition of proteoglycan loss in the treated joint compared to the non-treated joint was determined. The results of this in vivo assay for several of the selective MEK inhibitors of Formulas I and II are presented below in Pharmacological Table 5.
Pharmacological Table 5 Inhibition of Proteoglycan Loss in Rabbits
PD No. Dose Dosed (n) % Inhibition of (mg/kg Proteoglycan Loss
184352 30 2x 6 75
10 2x 6 48
3 2x 6 13
185625 30 lx 6 63
185848 30 lx 6 43
Additional support for the claimed methods was obtained using the SCW model again and also three other in vivo models of inflammation and/or arthritis. The data for each of the additional experiments is shown in Pharmacological Table 6 below. In a carrageenan-induced footpad edema (CFE) model, male outbred Wistar rats (135-150g, Charles River Labs) were dosed orally with lOml/kg vehicle or test compound one hour prior to administration of a sonicated suspension of carrageenan (lmg/0.1 ml saline). Carrageenan was injected into the subplantar region of the right hind paw. Paw volume was determined by mercury plethysmography immediately after injection and again five hours after carrageenan injection. Percent inhibition of edema was determined, and the ID40 calculated by linear regression. Differences in swelling compared to control animals were assessed by a 1-way ANOVA, followed by Dunnett's test.
In another model, rat adjuvant-induced polyarthritis (rat AIP) was induced following published procedures. Outbred male Wistar rats (100-115 gms) were obtained from Charles River Labs 2 - 5 days prior to initiation of the study. Rats were injected subcutaneously in the distal third of the tail with 1 mg Mycobacterium butyricum suspended in paraffin oil using glass tuberculin syringes and 25 gauge needles on day 0. The Mycobacterium butyricum suspension was achieved by sonicating in paraffin oil for 10 minutes with the vessel immersed in an ice bath. After all the rats in the study were immunized, they were randomized into groups. In the therapeutic study, randomization was done on day 14. Dosing started on day 14 and ended on day 27. Vehicle or drug suspended in vehicle was administered orally in 10 ml/kg volume. Hindpaw swelling was assessed by mercury plethysmography, beginning on the 11th day of the study and occurring every third or fourth day subsequently. The change in edema was determined by the difference between hindpaw volume on the day in which it was assessed and the day 14 volume. Percent inhibition was based on a comparison of the treatment group to the vehicle group. The number of animals in a treatment group was 10 while that in the vehicle was 20.
Finally, in a rabbit IL-1 arthritis (IL-1) model, adult male New Zealand White rabbits were anesthetized with rompun (10 mg/kg) and ketamine (50 mg/kg) (im). Twenty-five nanograms IL-1 was injected into one knee joint space through the suprapatella ligament (using sterile techniques). The contralateral joint received an equal volume of vehicle. The knees were first shaved and then swabbed with a surgical disinfectant prior to intraarticular injection. The animals were euthanized after 24 hours, the articular cartilage scraped from the femoral condyles and tibial plateaus and weighed, and the extent of cartilage degradation determined by a standard dimethylene blue assay. Test compound was administered by oral gavage one hour prior to IL-1 administration. Pharmacological Table 6
Activity of MEK Inhibitors in animal models of arthritis and inflammation
Model 184352 198306 203311
Rat carrageenan footpad edema (CFE) (ID40) 75.8 14.7 18.9 tr
Rat SCW arthritis (SCW) (ID50) 10.0 11.2 >100
Rat adjuvant arthritis (AIP) (ID50) 6.9 6.6 > 30
Rabbit IL-1 arthritis (IL-1)
(% Inh proteoglycan loss @ 30mg/kg) 57.9 42.9 29.2

Claims (16)

CLAIMSWhat is claimed is:
1. A method for treating or preventing arthritis in a mammal, said method comprising the step of administering to a patient suffering from arthritis and in need of treatment, or to a patient suspected of developing arthritis, an effective antiarthritic amount of a MEK inhibitor.
2. The method according to Claim 1 wherein the arthritis is rheumatoid arthritis or osteoarthritis.
3. The method according to Claim 2, wherein the arthritis is osteoarthritis.
4. The method according to Claim 2, wherein the arthritis is rheumatoid arthritis.
5. The method according to Claim 1, wherein said MEK inhibitor is a selective MEK1 or MEK 2 inhibitor.
6. The method according to Claim 1 wherein the MEK inhibitor is a compound of Formula I
wherein:
R\ is hydrogen, hydroxy, Cj-Cg alkyl, Ci -Cg alkoxy, halo, trifiuoromethyl, or CN; R2 is hydrogen; R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifiuoromethyl, C1 -Cg alkyl, Cj-Cg alkoxy, nitro, CN, or -(O or NH)m-(CH2)n-R9> where R9 is hydrogen, hydroxy, COOH, or NRioRn; n is 0-4; m is 0 or 1 ;
RjO and R\ \ independently are hydrogen or Cj-Cg 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-C1 -Cg alkyl; Z is COOR7, tetrazolyl, CONR6R7, CONHNR10Rl 1, or CH2OR7; R and R7 independently are hydrogen, C1 -Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, (CO)-Cι -Cg alkyl, aryl, heteroaryl, C3-C10 cycloalkyl, or C3-C 10 (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or Rg and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl; and wherein any of the foregoing alkyl, alkenyl, aryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, Cj-C6 alkoxy, amino, nitro, Cj-C4 alkylamino, di(Cι- C4)alkylamino, C3-C5 cycloalkyl, phenyl,phenoxy, C3-C5 heteroaryl, or C3- C5 heteroaryloxy; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
7. The method according to Claim 6 wherein the MEK inhibitor is a compound selected from:
[4-Chloro-2-(lH-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)- amine;
(4-iodo-2-methyl-phenyl)-[2-(lH-tetrazol-5-yl)-phenyl]amine; [4-nitro-2-( 1 H-tetrazol-5-yl)-phenyl-(4-iodo-2 -methyl -phenyl)- amine;
4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid;
3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 3, 4-Difluoro-2-(4-iodo-2 -methyl -phenylamino)-benzoic acid;
5 -Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid;
4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-Iodo-2-methyl-phenylamino)-benzoic acid;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2,3,5 -Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid;
5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid; 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid;
2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid;
2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-benzoic acid;
5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide;
N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(lH-tetrazol-5-yl)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide;
[5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic acid; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide;
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}-
2-(4-iodo-2-methyl-phenylamino)-benzamide;
N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;
N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide;
5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2 -piperidin- 1 -yl-ethyl)-benzamide;
3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide ;
3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(2 -pyrrolidin- 1 -yl-ethyl)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-pyridin-4-yl-ethyl)-benzamide ; 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide ; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(2-morpholin-4-yl-ethyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- 4-yl-ethyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- l-yl-ethyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide;
N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide ; N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy- ethyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1 -yl- propyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1 -yl-propyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl- ethyl)-benzamide;
4-Fluoro-2-(4-iodo-2 -methyl -phenylamino)-N-(2 -pyrrolidin- 1 -yl- ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin- 4-yl-ethyl)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- pyridin-4-ylmethyl-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 4-ylmethyl-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-N-(3 -dimethylamino- propyl)-3 ,4-difluoro-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 4-yl-ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy- propyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin- 1 -yl-ethyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-thiophen-
2-yl-ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin- 4-ylmethyl-benzamide ;
2-(4-Bromo-2-methyl-phenylarnino)-3 ,4-difluoro-N -phenethyl - benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin- 1 -yl-ethyl)-benzamide;
5 -Chloro-N- { 3 - [4-(2-hydroxy-ethyl)-piperazin- 1 -yl] -propyl } - 2-(4-iodo-2-methyl- phenylamino)- benzamide; 5-Fluoro-N- { 3- [4-(2-hydroxy-ethyl)-piperazin- 1 -yl] -propyl } -
2-(4-iodo-2 -methyl- phenylamino)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- benzamide;
5-Bromo-N- { 3-[4-(2-hydroxy-ethyl)-piperazin- 1 -yl] -propyl } - 2-(4-iodo-2-methyl- phenylamino)- benzamide;
5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l -yl- ethyl)-benzamide;
(3-Hydroxy-pyrrolidin- 1 -yl)-[2-(4-iodo-2-methyl-phenylamino)- 5 -nitro-pheny 1 ] -methanone ; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2 -pyrrolidin- 1 -yl- ethyl)-benzamide;
5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)- benzamide;
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo- 2-methyl- phenylamino)- benzamide;
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo- 2-methyl- phenylamino)- benzamide;
N- { 3 - [4-(2-Hydroxy-ethyl)-piperazin- 1 -yl] -propyl} -2-(4-iodo- 2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide;
5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2 -pyrrolidin- 1 -yl- ethyl)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl- ethyl)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 -yl- ethyl)-benzamide;
5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo-
2-methyl- phenylamino)- benzamide;
5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo- 2-methyl-phenylamino)- benzamide;
5 -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl- ethyl)-benzamide; 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1 -yl- propyl)-benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl- phenylamino)-5-nitro- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide;
5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1 -yl- propyl)-benzamide; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2 -piperidin- 1 -yl- ethyl)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- 1 -yl- ethyl)-benzamide;
N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide ;
N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide ;
N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 5-nitro-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-l-yl- propyl)-benzamide;
[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- pyrrolidin- 1 -yl)-methanone; 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- 1 -yl- propyl)-benzamide ;
[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- [4-(2-hydroxy-ethyl)-piperazin- 1 -yl]-methanone;
N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo- 2-methyl-phenylamino)- benzamide; N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide;
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro- benzamide; 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide;
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide;
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; N- Allyl-5 -iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro- benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- - benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol; [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol; [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; and
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
8. The method of claim 6, wherein the MEK inhibitor is a compound of Formula (I) wherein (a) Ri is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; (b) R2 is hydrogen; (c) R3, R4, and R5 independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; (d) R10 and independently are hydrogen or methyl; (e) Z is COOR , tetrazolyl, CONReR?, CONHNR10Rπ, or CH2OR7; Re and R7 independently are hydrogen, C alkyl, heteroaryl, or C 3-5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or R^ and R7 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; (f) Z is COOR ; (g) R7 is H, pentafluorophenyl, or tetrazolyl; (h) R3, R4, and R5 are independently H, fluoro, or chloro; (i) R4 is fluoro; (j) two of R3, R4, and R5 are fluoro; or (k) or combinations of the above.
9. The method of claim 8, wherein the MEK inhibitor is a compound of Formula (I) wherein: Z is COOR ; R7 is H, pentafluorophenyl, or tetrazolyl; R3 and R5 are independently H, fluoro, or chloro; and R^t is fluoro.
10. The method of Claim 1 wherein the MEK inhibitor is a compound of Formula II
wherein:
Ri a is hydrogen, hydroxy, Cj-Cg alkyl, Cj-Cg alkoxy, halo, trifiuoromethyl, or CN; R2a is hydrogen;
R3a, R4a, and R5a independently are hydrogen, hydroxy, halo, trifiuoromethyl, Ci -Cg alkyl, Ci -Cg alkoxy, nitro, CN, or
(O or NH)m-(CH2)n-R9a, where R9a is hydrogen, hydroxy, CO2H orNR10aRna. n is 0-4; m is 0 or 1 ;
R10 and Rj 1 a independently are hydrogen or Cj-Cg 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-Ci-Cg alkyl;
Rβa is hydrogen, C1 -Cg alkyl, (CO)-Cι -Cg alkyl, aryl, aralkyl, or
C3-C10 cycloalkyl; R7a is hydrogen, Ci -Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl,
C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NR9a); and wherein any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, Cj-C6 alkoxy, amino, nitro, Cι-C alkylamino, di(Q- C4)alkylamino, C -C6 cycloalkyl, phenyl, phenoxy, C3-C5 heteroaryl or heterocyclic radical, or C3-C5 heteroaryloxy or heterocyclic radical-oxy; or Rga and R7a 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 NRiQa^l la' or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
11. The method of Claim 10, comprising a MEK inhibitor having a structure of Formula (II) wherein: (a) Rja is H, methyl, fluoro, or chloro; (b) R2a is H; 3a, R-ta, and R5a are each H, Cl, nitro, or F; (c) R^ is H; (d) R7a is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl methyl, cyclopropylmethyl, or cyclopropylethyl; and (e) the 4' position is I, rather than Br.
12. The method of claim 11 , comprising a MEK inhibitor having a structure of Formula (II) wherein: R4a is F at the 4 position, para to the
CO-N-R a-OR a group and meta to the bridging nitrogen; at least one of R3a and R5a is F or Cl; and Rla is methyl or chloro.
13. The method of Claim 10, comprising a MEK inhibitor having a formula selected from: 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(methoxy)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentoxy)- benzamide; 3 ,4-Difluoro-2-(4-iodo-2 -methyl -phenylamino)-N-
(3 -furylmethoxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-ethoxy- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide;
3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-( 1 -methylprop- 2-ynyloxy)-benzamide ; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-phenylprop-
2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 5-phenylpent-2-en-4-ynyloxy)-benzamide;
3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- 2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclobutyloxy)- benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(2-thienylmethoxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-methyl-prop- 2-enyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-3 -ynyloxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopentyloxy)-benzamide ; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (n-propoxy)-benzamide;
5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide ;
5-Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide 5-Bromo-N-butoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-but-2-enyloxy)-benzamide;
5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3 -methyl-pent-2-en-4-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N- [5-(3-methoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- 2-ynyloxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
[3-(3-methoxy-phenyl)-prop-2-ynyloxy]-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (thiopen-2-ylmethoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (pyridin-3-ylmethoxy)-benzamide;
5-Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (ethoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide; 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(isopropoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but- 3-ynyloxy)-benzamide;
5-Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran- 2-yloxy)-benzamide ;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- benzamide; 4-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide;
5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran- 2-yloxy)-benzamide ;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3-phenylprop-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3 -furylmethoxy)-benzamide ;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-
3 -ynyloxy)-benzamide ;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl- prop-2-enyloxy)-benzamide ; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 2-enyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)- benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (cyclobutoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide ;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide;
3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-( 1 -methyl- prop-2-ynyloxy)-benzamide;
3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3-(3-fluorophenyl)-prop-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (4,4-dimethylpent-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (cyclopentoxy)-benzamide; 3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5 -Chloro-3 ,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide;
N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide; 3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide; 5-Chloro-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; 2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide;
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide ;
2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difluoro-N- hydroxy-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide; 4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide; 3 ,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; 2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide;
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide ;
5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- lphenylamino)-benzamide; N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro- benzamide;
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide ; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide ;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide;
N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluoro-benzamide;
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide; 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3 ,4-difluoro- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluoro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N- cyclopropylmethoxy-3,4-difluoro-benzamide
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro- benzamide;
N-Cyclopropylmethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide;
N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 4-fluoro-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-
3 ,4-difluoro-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 4-fluoro-benzamide; and 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3 ,4-difluoro-benzamide.
14. The method of claim 1 , comprising a MEK inhibitor having a structure selected from: 2-(2-chloro-4-iodophenylamino)-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- chloro-4-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-iodo-2-methylphenylamino)-benzamide (PD ).
15. A method of treating or preventing arthritis in a patient in need of treatment, or suspected of developing arthritis, said method comprising the step of administering an effective antiarthritic amount of a compound selected from:
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluorobenzamide (PD184352);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 170611);
2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro- 5-bromobenzamide (PD171984);
2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy- 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-bromobenzamide (PD 184161);
2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluoro- 5-bromobenzamide (PD184386); 2-(2-Chloro-4-iodophenylamino)-N-cyclobutylmethoxy- 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-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluorobenzamide (PD 198306); and
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 4-fluorobenzamide (PD 203311).
16. The method of Claim 15 wherein said compound is selected from 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluorobenzamide (PD 184352), 2-(2-Methyl-4-iodophenylamino)-N- cyclopropylmethoxy-3,4,5-trifluorobenzamide (PD 198306); and
2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 4-fluorobenzamide (PD 203311).
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