AU776788B2 - Treatment of arthritis with MEK inhibitors - Google Patents
Treatment of arthritis with MEK inhibitors Download PDFInfo
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- AU776788B2 AU776788B2 AU21858/00A AU2185800A AU776788B2 AU 776788 B2 AU776788 B2 AU 776788B2 AU 21858/00 A AU21858/00 A AU 21858/00A AU 2185800 A AU2185800 A AU 2185800A AU 776788 B2 AU776788 B2 AU 776788B2
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- 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
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- 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
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- 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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- A61K31/435—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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- 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
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- 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
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- 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
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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Description
-1- 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 Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
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 15 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 nonflammatory degenerative joint disease occurring most often in older persons.
Characterized by degeneration of the articular cartilage, hypertrophy of bone at the 20 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-inglammatory agents such as NSAIDs and cyclooxygenase inhibitors.
500382663 .DOC/BSW Ia- 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 98/3788 1 as being useful to treat septic shock.
500382663 I .DOCIBSWi WO 00/35436 PCT/US99/29783 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 ERKI and ERK 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 WO 00/35436 PCT/US99/29783 Br or I-z R5 I R3 R4 In formula R 1 is hydrogen, hydroxy, CI-C 8 alkyl, C 1
-C
8 alkoxy, halo, trifluoromethyl, or CN. R 2 is hydrogen. R 3
R
4 and R 5 are independently selected from hydrogen, hydroxy, halo, trifluoromethyl, C 1
-C
8 alkyl, C1-C8 alkoxy, nitro, CN, and or NH)m-(CH2)n-R9. R 9 is hydrogen, hydroxy, COOH, or NRIOR 1 1; n is 0-4; m is 0 or 1. Each of R10 and R 1 1 is independently selected from hydrogen and C -C 8 alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N-(C 1-C 8 alkyl). Z is COOR 7 tetrazolyl, CONR 6
R
7 CONHNRIORI or CH20R 7
R
6 and R 7 independently are hydrogen, C 1
-C
8 alkyl, C 2
-C
8 alkenyl,
C
2
-C
8 alkynyl, (CO)-C -Cg alkyl, aryl, heteroaryl, C 3
-C
10 cycloalkyl, or
C
3
-C
10 (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or R 6 and R 7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl. In formula any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, CI-C 6 alkoxy, amino, nitro, Ci-
C
4 alkylamino, di(CI-C 4 )alkylamino, C 3
-C
6 cycloalkyl, phenyl,phenoxy, C 3
-C
heteroaryl, or C 3
-C
5 heteroaryloxy; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Preferred embodiments of Formula have a structure wherein: Ri is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; R 2 is hydrogen; R 3
R
4 and Rs independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; Rio and RI independently are hydrogen or methyl; Z is
COOR
7 tetrazolyl, CONR 6
R
7 CONHNRIoR, 1 or CH 2 0R 7
R
6 and R 7 WO 00/35436 PCT/US99/29783 independently are hydrogen, C 14 alkyl, heteroaryl, or C 3-5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or R 6 and R 7 together with the nitrogen to which they are attached complete a 5-6 member cyclic ring optionally containing 1 or 2 additional heteroatoms selected from O, NH or N-alkyl; and wherein any of the foregoing alkyl or aryl groups can be unsubstituted or substituted by halo, hydroxy, methoxy, ethoxy, or heteroaryloxy (such as the synthetic intermediate 2,3,4,5,6-pentafluorophenyl); Z is COOR 7 R7 is H, pentafluorophenyl, or tetrazolyl; R 3
R
4 and Rs are independently H, fluoro, or chloro; R 4 is fluoro; two of R 3
R
4 and Rs are fluoro; or combinations of the above. In another preferred embodiment of Formula Ri is methyl, fluoro, chloro, or bromo.
Examples of preferred embodiments include methods comprising a MEK inhibitor selected from Formula Compound Table below.
WO 00/35436 PCT[US99/29783 FORMULA COMPOUND TABLE (page 1 of [4-Chloro-2-( H-tetrazol-5-yI)-phenyl-(4-iodo-2-methyl-phenyl)-amine (4-iodo-2-methyl-phenyl)- I [4-nitro-2-( 1 H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl -phenyl)-amine 4-Fluoro-2-(4-iodo-2-methylphenylaniino)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-lodo-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-lodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-lodo-phenylamino)-5-methoxy-benzoic acid 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-Iodo-2-methyl-phenylaxnino)-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-phenylwnino)-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)-benzarnide 4-Fiuoro-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 'i-r iuoro-2-(4-iodo-2-methyi-phenylamino)-N-( benzamide WO 00/35436 WO 0035436PCTIUS99/29783 FORMULA COMPOUND TABLE (continued, page 2 of 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)benzamnide N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-N- {3-[4-(2-hydroxy-ethyl)-piperazin- 1-yI] -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-methylphenylamino)-benzamide N-(2,3-Dihydroxy-propyl)-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamnino)benzamnide 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 yi-ethyl)-benzamide 3 ,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzamnide N-(2,3 -Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl-phenylamino)benzamnide 3 ,4-Difluoro-N-(3 -hvdroxy-propyl)-2-(4-iodo-2-mrreth-!-phenylar-nino)benzamnide 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl -phenylamino)-N-(2-pyrrolidin- 1 -yI-ethyl)-benzamide 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4yI-ethyl)-benzamide WO 00/35436 PCTIUS99/29783 FORMULA COMPOUND TABLE (continued, page 3 of 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzamnide 5-Bromo-N-(3-dimethylamino-propyl)-3 ,4-difluoro-2-(4-iodo-2-methylphenylamino)-benzamide 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamnino)-N-(2-morpholin- 4-yI-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- Il-ylethyl)-benzamide 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yI -ethyl)benzamnide N-(3-Dimethylamino-propyl)-3 ,4-difluoro-2-(4-iodo-2-methylphenylamino)-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)- .benzamnide 4-Fluoro-2 -(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl -ethyl)benzamnide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- I -yl-propyl)benzamnide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- I1-ylpropyl)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylanino)-N -(2-thiophen-2-yl -ethyl)benzarmide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 -yl-ethyl)benzamnide 2-(4-Bromo-2-methvl-tDhenvlamino)-3 :4-di fli1ArA-N-(9)-mnrnhnl I -,ti ethyl)-benzamide WO 00/35436 PCTIUS99/29783 FORMULA COMPOUND TABLE (continued, page 4 of 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4ylmethyl-benzamnide 3,4-Difluoro-2-(4.-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethylbenzamide 2-(4-Bromo-2-methyl -phenyl amino)-N-(3-dimethylarninopropyl)-3 ,4-difluoro-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethylbenzamnide 4-Fluoro-2-(4-i odo-2 -methyl -phenylamino)-N-(2-pyridin-4-yI -ethyl benzamnide 2-(4-Bromo-2-methyl-phenylaniino)-3 ,4-difluoro-N-(2-pyridin-4-yl -ethyl)benzamnide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3 -hydroxy-propyl)benzamnide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin- Il-ylethyl)-benzamnide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl-benzamide 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-thiophen-2-ylethyl)-benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin-4-ylmethylbenzamnide 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-phenethyl-benzamide 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-piperidin- Il-yl ethyl)-benzamide t 3- [4-(2-hvdroxy-ethvl )-piperazin- l -propyl 1 methyl- phenylamino)- benzamnide 5-Fluoro-N- {3-[4-(2-hydroxy-ethyl)-piperazin-I -yl] -propyl)}-2-(4-iodo-2methyl- phenylamino)- benzamnide 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methylbenzamnide WO 00/35436 PCTIUS99/29783 FORMULA COMPOUND TABLE (continued, page 5 of 5-Bromo-N-({3-[4-(2-hydroxy-ethyl)-piperazin-1I-yl]-propyl)}-2-(4-iodo-2methyl- phenylamino)- benzamnide 5-Chloro-N-(2-diethylainino-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzamnide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- Il-yl -ethyl)benzarnide (3-Hydroxy-pyrrolidin- I -yI)-[5-nitro-2-(4-iodo-2-methyl-phenylamino)phenyl] -methanone 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 -yI -ethyl)benzamnide 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzamnide N- 2- [Bis-(2-hydroxy-ethyl)-amino] -ethyl)} -5-chloro-2-(4-iodo-2-methylphenylamino)- benzamnide N- 2- [Bis-(2-hydroxy-ethyl)-amino] -ethyl)} -5-bromo-2-(4-iodo-2-methylphenylamino)- benzamnide N- {3-[4-(2-Hydroxy-ethyl)-piperazin-I -yI] -propyl)}-2-(4-iodo-2-methylphenylamino)- benzamnide 5-Fluoro-2-(4-iodo-2-methyl-phenylaniino)-N-pyridin-4-ylmethylbenzamnide 5-Bronio-2-(4-iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin- 1 -yl-ethyl)benzamnide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl-ethyl)benzamnide -Fl uoro-2-(4-iodo-2-methyl -vhenvlamino)-N-(2-npyrro i din- I -yl-ethyl)benzamnide 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)benzamnide N- 2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl -5-fluoro-2-(4-iodo-2-methylphenylamino)- benzamide WO 00/35436 PCTIUS99/29783 FORMULA COMPOUND TABLE (continued, page 6 of 5-Chloro-N-(3 -hydroxy-propyl)-2-(4-iodo-2-methyl -phenylamino)benzamnide -Chl oro-N-(3 -di ethyl amino-2-hydroxy-propyl)-2 -(4-iodo-2-methyl phenylamino)- benzamnide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- I -yI -ethyl)benzamnide 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylaniino)benzamnide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin-1I-yl-propyl)benzamnide N- 2- [Bis-(2-hydroxy-ethyl)-amnino] -ethyl)} -2-(4-iodo-2-methyl phenylamino)-5-nitro- benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yI -ethyl)benzamnide -Chloro-N-(3 -diethylamino-propyl)-2-(4-iodo-2-methyl-phenyl amino)benzarnide 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzamnide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1 -yl-propyl)benzamnide 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin- 1 -yl-ethyl)benzamnide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- Il-yl -ethyl)benzarnide N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl-nhenylanino)benzamnide 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)benzarnide N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitrobenzamnide WO 00/35436 WO 0035436PCT/US99/29783 FORMULA COMPOUND TABLE (continued, page 7 of -Fluoro-N-(3 -hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)benzaniide N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)benzaniide N-(3 -Diethylamino-propyl)-2-(4-iodo-2-methyl -phenylamino)-5 -nitrobenzamide 5-Bromo-2-(4-iodo-2-methyl -phenylaniino)-N-(2 -morpholin-4-y -ethyl)benzamide 2-(4-Iodo-2-methyl-phenylamnino)-5-nitro-N-(3-piperidin- I -yl-propyl)benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] or 3 -hydroxypyrrolidin- I -yi)-methanone 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzamide -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl -ethyl)benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylanino)-N-(3 -piperidin- I -yl-propyl)benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] -[4-(2-hydroxy-ethyl)piperazin- 1 -yi)-methanone N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo-2-methylphenylamino)- benzamide N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamnino)benzamide 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzamide N-Benzyloxy-5-fluoro-2-(4-iodo-2-methvI-phenvlamino)-ht-n7nMidiP -bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide WO 00/35436 PCTIUS99/29783 FORMULA COMPOUND TABLE (continued, page 8 of 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)benzamnide 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzarnide 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-phenylarnino)-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-phenylbenzamnide N-AllyI-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamnide N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamiio)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfainoyl-benzyl)benzamnide 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-phenylbenzamnide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)benzamnide 5-Bromo-2-(4-iodo-2-methyl-phenylamnino)-N-(4-sulfamoyl-benzyl)benzamnide N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 2-(4-lodo-2-methyl-phenylamino)-5-iitro-N-(4-sulfamoyl-benzyI>) benzamide N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylanino)-benzamnide 5-Fluoro-2-(4-iodo-2-methvl-Dhenvlamino)-N-(3 -mi~thvl-1 nvl benzamnide N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide WO 00/35436 PCT/US99/29783 FORMULA COMPOUND TABLE (continued, page 9 of 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenylbenzamnide N-Benzyloxy-2-(4-iodo-2-methyl-phenylarnino)-5 -nitro-benzamide N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-AllyI-5-iodo-2-(4-iodo-2-metliyl-phenylamino)-benzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-(3 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 -Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3 -methyl-benzyl)benzamnide 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -methyl-benzyl)benzamnide 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)benzamnide 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzamnide 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenylbenzamnide N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamnino)-benzamide N-Allyl-5-chloro-2-(4-iodo-2-methyl -phenyl ami no)-hi-n7,qMidef 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenylbenzamnide WO 00/35436 PCTIUS99/29783 FORMULA COMPOUND TABLE (continued, page 10 of 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)benzamnide 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)benzamnide N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide N-Al Iyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-AIlyl-5-bromo-2-(4-iodo-2-methyl -phenylan-ino)-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-phenylbenzamnide N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzarmide 4-Fluoro-2-(4-iodo-2-methyl-phenylamnino)-benzyl alcohol [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl] -methanol [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl] -methanol -Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl] -methanol N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
WO 00/35436 PCT/US99/29783 In another preferred embodiment, the MEK inhibitor is a compound of Formula II O f6a Ra 2a C-N-O-
R
7 a I I R II Br or I R3a R4a In Formula Rla is hydrogen, hydroxy, C 1 -Cg alkyl, CI-C 8 alkoxy, halo, trifluoromethyl, or CN. R2a is hydrogen. Each of R3a, R4a, and R5a is independently selected from hydrogen, hydroxy, halo, trifluoromethyl, C -C 8 alkyl, C -C 8 alkoxy, nitro, CN, and (O or NH)m-(CH2)n-R9a. R9a is hydrogen, hydroxy, CO 2 H or NR0aRl la; n is 0-4; and m is 0 or 1. Each of RlOa and R lla is independently hydrogen or C 1
-C
8 alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-(CI-C 8 alkyl). R6a is hydrogen, Cl-C 8 alkyl, (CO)-(Ci-C 8 alkyl), aryl, aralkyl, or C 3
-C
10 cycloalkyl. R7a is hydrogen, C 1 -Cg alkyl,
C
2
-C
8 alkenyl, C 2 -Cg alkynyl, C 3
-C
10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from 0, S, or NR9a). In Formula any of the alkyl, alkenyl, aryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, CI-C 6 alkoxy, amino, nitro, CI-C 4 alkylamino, di(Ci-
C
4 )alkylamino, C 3
-C
6 cycloalkyl, phenyl,phenoxy, C 3 -C5 heteroaryl, or C 3 -Cs heteroaryloxy; or R6a 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 NR10aR1 la. 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: WO 00/35436 PCT/US99/29783 Ria is H, methyl, fluoro, or chloro; R2a is H; R3a, R4a, and Rsaare each H, Cl, nitro, or F; R 6 a is H; R 7 a is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylmethyl, or cyclopropylethyl; the 4' position is I, rather than Br; R 4 a is F at the 4 position, para to the CO-
N-R
6 a-OR 7 a group and meta to the bridging nitrogen; R 3 a or Rsa is F; at least one of R3a, R4a, and R 5 a is F; Ria is methyl or chloro; or or a combination of the above.
In a more preferred embodiment the MEK inhibitor is a compound selected from Formula (II) Compound Table below.
WO 00/35436 PCTIUS99/29783 FORMULA (11) COMPOUND TABLE (page 1 of 7) 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)benzamnide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)benzamnide 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)-benzaniide 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-furylmethoxy)benzarnide 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylarnino)-N-ethoxy-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)benzamnide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)benzamnide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamnino)-N-( I -methyiprop- 2-ynyloxy)-benzamide 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylainino)-N-(3 -phenyiprop- 2-ynyloxy)-benzamide 3.4-Difluoro-2-(4-inodo-2-rnethyl-phenyl am-.ino)-N -(3-mreth'yl- 5-phenylpent-2-en-4-ynyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamnino)-N-(prop-2-ynyloxy)benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)-benzamide WO 00/35436 PCTIUS99/29783 FORMULA (II) COMPOUND TABLE (continued, page 2 of 7) 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylam-ino)-N-(cyclobutyloxy)benzamnide 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)benzamnide 3 ,4-Difl uoro-2-(4-iodo-2-methyl-phenylam ino)-N-(2-methyl -prop- 2-enyloxy)-benzamide 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)benzamnide 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)benzamnide 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)beazamnide 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)benzamnide 5-Bromo-3 ,4-difluoro-N-(furan-3 -ylmethoxy)-2-(4-iodo-2-methylphenylamino)-benzamide 5-Bromo-N-(but-2-enyloxy)-3 ,4-difluoro-2-(4-iodo-2-methylphenylamnino)-benzamide 5-Bromo-N-butoxy-3 ,4-difluoro-2-(4-iodo-2-rnethyl-phenylam-ino)benzamnide 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 -methylpent-2-en-4-ynyloxy)-benzamide WO 00/35436 PCTIUS99/29783 FORMULA (11) COMPOUND TABLE (continued, page 3 of 7) 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N- [5-(3-methoxyphenyl)-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-di fluoro-2-(4-iodo-2-methyl-phenylam'ino)-N- [3-(3-methoxy-phenyl)-prop-2-ynyloxyl-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)benzamnide 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamnide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(isopropoxy)benzaniide 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)benzamnide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy-benzamide 4-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzaniide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide 5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylarnino)-benzamide 5-oo2(-oo2mty-~evaio--h~vm- y-P7m'' 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran-2-yloxy)benzarmide WO 00/35436 WO 0035436PCT/US99/29783 FORMULA (II) COMPOUND TABLE (continued, page 4 of 7) 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3 -phenyiprop- 2-ynyloxy)-benzamide 3 ,4-Difl uoro-2-(4-bromo-2-methyl-phenylamino)-N-(3 -furylmethoxy)benzamnide 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-thienymethoxy)benzamnide 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-3 -ynyloxy)benzamnide 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)benzamnide 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-phenylamnino)-N-(cyclobutoxy)benzamnide 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)benzamnide 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)benzamnide 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)-benzamide 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)benzamnide 3 ,4-Difluoro-2-(4-bromo-2-methyl-Dhenylamino)-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 WO 00/35436 WO 0035436PCT/US99/29783 FORMULA (11) COMPOUND TABLE (continued, page 5 of 7) 3 ,4-Di fluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopentoxy)benzamnide 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)benzamnide 5-Bromo-3 ,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxybenzamide 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-hydroxybenzamnide 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3 ,4-difluoro-N-hydroxybenzamnide 2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-3 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3 ,4-difluoro-N-hydroxybenzamide 5-Bromo-2-(2-bromo-4-iodo-phenylamnino)-3,4-difluoro-N-hydroxybenzamide 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl-benzamide 2-(2-Bromo-4-iodo-phenylamino)-3 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difluoro-N-hydroxybenzarnide 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide 4-Fluoro-2-(2-fluoro-4-iodo-phenvlamino)-N-hydroxy-ben-zamide 3 ,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzarnide 2-(2-Chloro-4-iodo-phenylamino)-3 4dfur-Nhcry-h-~Mr, 2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-3 ,4-difluoro-N-hydroxy-benzamide WO 00/35436 WO 0035436PCTIUS99/29783 FORMULA (11) COMPOUND TABLE (continued, page 6 of 7) N-Cyclopropylmethoxy-3 ,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)benzamnide 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-iodophenylamino)-benzamide N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylaniino)-4-nitrobenzarnide N-Cyclopropylmethoxy-3 ,4,5-tri fluoro-2-(2-fluoro-4-iodo-phenylamino)benzamnide 5-Chloro-N-cyclopropylmethoxy-3 ,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamnide 5-Bromo-2-(2-chloro-4-iodo-phenylarnino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitrobenzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3 benzamnide 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide -Bromo-2-(2-bromo-4-iodo-phenylamnino)-N-ethoxy-3 ,4-difluorobenzamnide 2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluorobenzamnide 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N-cyclopropylmethoxy- 3,4-difluoro-benzamide 2-(2-Bromo-4-iodo-Dhenvlaniino)-N-cycfl~opropyvimet'- 6y-A benzamnide WO 00/35436 PCT/US99/29783 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-fl uoro-4-iodo-phenylamino)benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3 ,4-difluorobenzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluorobenzamnide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3 ,4-difluorobenzamide.
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 (PD 184352); 2-(2-Methyl-4-iodophenylamino)-Nhydroxy-4-fluorobenzamide (PD 17061 2-(2-Methyl-4-iodophenylamnino)-Nhydroxy-3 ,4-difluoro-5-bromobenzamide (PD 171984); 2-(2-Methyl- 4-iodophenylamino)-N-cyclopropylmethoxy-3 (PD 177168); 2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy- 3,4-difluoro-5-bromobenzamide (PD 180841); 2-(2-Chloro- 4-iodophenylamino)-N-cyclopropylmethoxy-3 (PD 184161); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluoro- 5-bromobenzarnide (PD 184386); 2-(2-Chloro-4-iodophenylamino)-Ncyclobutylmethoxy-3 ,4-difluorobenzamide (PD 185625); 2-(2-Chloro- 4-iodophenylamino)-N-hydroxy-4-fluorobenzamnide (PD 185848); 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3 ,4-difluorobenzamide (PD 188563); 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy- 24 3 ,4,5-trifluorobenzamnide (PD 198306); and 2-(2-Chloro-4-iodophenylamino)-Ncyclopropylmethoxy-4-fluorobenzamide (PD 203311); and the benzoic acid derivatives thereof. For example, the benzoic acid derivative of PD 198306 is 2-(2-Methyl-4iodophenylamino)-3 ,4,5-trifluorobenzoic acid.
Additional preferred compounds include 2-(2-chloro-4-iodophenylamino)-5chloro-N-cyclopropylmethoxy -3,4-difluorobenzamnide (PD 297189), 2-(4iodophenylamino)-N-cyclopropylmethoxy)-5-chloro-3 ,4-difluorobenzamide (PD 2971 90),2-(2-chloro-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-di fluoro-(4-iodo-2-methylphenylamino)-benzoic acid (PD 296767); and 5-chloro-N-cyclopropylmethoxy-3 ,4-di fluoro-2-(4-iodo-2methylphenylamnino)-benzamide (PDJ In a first aspect, the invention provides a method for treating or preventing arthritis in a mammal, said method comprising the step of administering to patients suffering from arthritis and in need of treatment, or to a patient suspected of developing arthritis, an effective antiarthritic amount of a MEK inhibitor.
In a second aspect, the invention provides 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 20 compound selected from: 0 0.
2-(2-Cehl-4-iodophenylamino)-N-cyclorpmhoxy-3,4r-5-rmbnwie 500382663_i.Doc/BSWV 24a 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3 ,4-di bromobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy-3 ,4-difluoro-5 bromobenzamide; 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3 ,4-di fluoro-5 bromobenzamide; 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3 2-(2-Chloro-4-iodophenylaniino)-N-cyclobutylmethoxy-3 ,4-di fluorobenzamide; 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide; 2-(2-Methyl-4.-iodophenylamnino)-N-hydroxy-3 ,4-difluorobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3 ,4,5 trifluorobenzamnide; and 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide.
a third aspect, the invention provides use of an effective antiarthritic amount of a MEK inhibitor, for the manufacture of a medicament for treating or preventing arthritis in a mammal.
a fourth aspect, the invention provides use of an effective antiarthritic amount of a compound selected from: 2-(2-chloro-4-iodophenylamnino)-N-cyclopropylmethoxy-3 ,4-di fluorobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3 ,4-di fluoro-5 -bromobenzamnide; 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3 bromobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy-3 ,4-difluoro-5 bromobenzamide; 500382663 i. Doc/B SX 24b 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5bromobenzamide; 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5-bromobenzamide; 2-(2-Chloro-4-iodophenylamino)-N-cyclobutylmethoxy-3,4-difluorobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluorobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3,4,5trifluorobenzamide; and 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide for treating or preventing arthritis in a patient.
Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".
15 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 20 both rheumatoid arthritis and osteoarthritis. The invention is preferably practiced by i administering a phenyl amine MEK inhibitor of Formula or Formula 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 500382663 DO/BSW 24c MIKK3, ERK, PKC, Cdk2A, phosphorylase kinase, EGF and PDGF receptor kinases, and C-src. In general, a selective MEKi or MEK 2 inhibitor h~s
B
B.
B
B
B
B *e
B
500382663 l.Doc/BSWt WO 00/35436 PCT/US99/29783 an ICso for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its ICso for one of the above-named other enzymes. Preferably, a selective inhibitor has an ICso that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000 or less than that of its ICso 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 incorporated by reference. An example of a MEK inhibitor is 2-(2-amino-3-methoxyphenyl)- 4-oxo-4H-[ ]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, WO 00/35436 PCT/US99/29783 alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Typical substituted aryl groups include 3-fluorophenyl, 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- I -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-I ,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. Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl. Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethvy!, -frylthy, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl. Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl, piperidyl- 2-methyl, 2-(piperidin-1-yl)-ethyl, 3-(morpholin-4-yl)propyl.
WO 00/35436 PCTIUS99/29783 "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 -dimethylhex-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, 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-methylhex-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 tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl, and octahydrobenzothiofuranyl. The cycloalkyl groups can be substituted with the same substituents as an alkyl and alkenyl groups, for example, halo, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl, 2-aminocyclopropyl, 2-phenylpyrrolidinyl, and 3-thieny!morpholine- 1-yl.
B. Administration and Formulation The MEK inhibitors of the present method an be adminirstered 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, WO 00/35436 PCT/US99/29783 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 absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, 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 fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, humectants, as for example, glycerol, disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, solution retarders, as for example paraffin, absorption accelerators, as for example, quaternary ammonium compounds, wetting agents, as for example, cetyl alcohol and glycerol monostearate, adsorbents, as for example, kaolin and bentonite, and lubricants, as for example, talc, calcium stearate, magnesium stearate, solid WO 00/35436 PCT/US99/29783 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 wellknown 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, aear-agar and tragacanth, or mixtures of these sbstnes, and thc 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 WO 00/35436 PCT/US99/29783 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 wellknown 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, WO 00/35436 PCT/US99/29783 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 incorporated herein by reference.) Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C -C 6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C 5
-C
7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C -C 4 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
C
1
-C
6 alkyl amines and secondary C -C 6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1
-C
3 alkyl primary amines and C
I
-C
2 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 Drug Design, ed. Edward B.
Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
In addition, the compounds of the present method can exist in unsolvated WO 00/35436 PCT/US99/29783 as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
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.
WO 00/35436 PCT/US99/29783 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 incorporated by reference.
The 2-(4-bromo and 4-iodo phenylamino)-benzoic acid derivatives of Formula 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 0
II
P
2
C-OH
NH
L
R
Br or I R3 R4 base 0 11 r2 C-OH RI N R Br or I R3 R 4 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 WO 00/35436 PCT/US99/29783 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 0 C to about 100 0 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 Formula I, where R 7 is hydrogen) can be reacted with an organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide to produce a pharmaceutically acceptable salt. The free acids can also be reacted with an alcohol of the formula HOR 7 (where R 7 is other than hydrogen, for example methyl) to produce the corresponding ester. Reaction of the benzoic acid with an alcohol can be carried out in the presence of a coupling agent. Typical coupling reagents include 2-ethoxy- -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 CONR 6
R
7 are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNR 6
R
7 The reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic WO 00/35436 PCT/US99/29783 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 0 C. The product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation. The hydrazides (z CONHNR 0
R
1 l) are similarly prepared by coupling a benzoic acid with a hydrazine of the formula
H
2
HNRIORI
1 The benzyl alcohols of the invention, compounds of Formula where Z is CH2OR 6 and R 6 is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following Scheme 2.
Scheme 2 0 R2 C-OH 2 H2 0
H
R
1 N reducing N N I -R5 agent Br or I R3 R Br or I R
R
3 R4 R3 R4 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 0
C.
The following detailed examples illustrate specific compounds provided by this invention.
WO 00/35436 PCT/US99/29783 EXAMPLE 1 4-Fluoro-2-(4-iodo-2-methvlphenvlamino)benzoic acid To a stirring solution comprised of 3.16 g (0.0133 mol) of iodotoluene in 5 mL of tetrahydrofuran at -78 0 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 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 HCI was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSO 4 and then boiled over a steambath to low volume and cooled to room temperature. The off-white fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76 0 C; ca. 10 mm of Hg) to afford 1.10 g of the desired material; mp 224-229.5 0
C;
1 H NMR (400 MHz; DMSO): 6 9.72 1H), 7.97 (dd, 1H, J 7.0, 8.7 Hz), 7.70 1H, J 1.5 Hz), 7.57 (dd, 1H, J 8.4, 1.9 Hz), 7.17 1H, J 8.2 Hz), 6.61-6.53 2H), 2.18 3H); 13 C NMR (100 MHz; DMSO): 8 169.87, 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; 19 F NMR (376 MHz; DMSO): 8 -104.00 to -104.07 IR (KBr) 1670 (C O stretch) cm-1; MS (CI) M+1 372.
Analysis calculated for C 1 4 H 1
FINO
2 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 were prepared.
WO 00/35436 PCTIUS99/29783 Example Compound MIP 0
C
No.
2 3,4,5-Trifluoro-2-(4-iodo-2-methyl-pheny lam ino)benzoic acid 3 3 ,4-Di fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 4 5-Bromo-3,4-difluoro-2-(4-iodo-2-methylphenylamnino)-benzoic acid 5-Ch Ioro-2-(2-chloro-4-iodo-phenylamino)-benzoic acid 6 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 7 Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)benzoate 8 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 9 2-(2-Chloro-4-iodo-phenylamino)-5-nitro-benzoic acid 4-Fluoro-2-(3-fluoro-4-iodo-2-methyl-phenylamino)benzoic acid I1I 2-(4-lodo-2-methyl-phenylamino)-5-nitro-benzoic acid 12 2-(2-Fluoro-4-iodo-phenylamino)-5-nitro-benzoic acid 13 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid 14 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluorobenzoic acid 16 3-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 17 3 ,4-Difluoro-2-(4-iodo-2-methoxy-phenylamino)benzoic acid 18 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 206-2 240.5-244.5 259.5-262 255-260 234-238 3 10-320 DEC 239.5-240 289-293 233-235 264-267 256-258 218.5-220 285-288 DEC 230-234 218-221 230-233 245-255 DEC WO OM/55436 :ample No.
PCT1US99/29783 NIP C Compound 19 2-(4-Iodo-2-methyl-phenylamino)-benzoic acid 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 21 5-lodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 22 2,3 ,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)benzoic acid 23 4-Fluoro-2-(3 -chloro-4-iodo-2-methyl-phenylamino)benzoic acid 24 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid 3-Chloro-2-(2-chloro-4-iodo-phenylam ino)-benzoic acid 26 2-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoic acid 27 4-Fluoro2-(2,3-dimethyl-iodo-2-methylphenylamino)benzoic acid 28 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 29 2-Chloro-6-(4-iodo-2-methyl-pbenylamino)-benzoic acid 2-(4-lodo-2-methyl-phenylamino)-4-nitro-benzoic acid 2 18-223 243-46 24 1-245 2 18-222 248-252.5 208-211 232-233 179-182 25 8-26 1 209.5-211 171-175 251-263 EXAMPLE 31 5-Chloro-N-(2-hydroxyethvl)-2-(4-iodo-2-methyl-phenylamino)-benzamide To a stirring solution comprised of 0.1020 g (0.263 2 mmol) of 2-(4-iodo-2-methyl-phenylamino)-benzoic acid, 0.1 mL (1.7 mmol) of ethanolamine, and 0.05 mL (0.29 mmol) of diisopropylethylamnine in 5 mL of a 1: 1 (vlv) tetrahydrofuran-dichioromethane 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 (5 0 mL) and 10% aqueous hydrochloric acid (50 mL).
The organic phase was washed with 10% aqueous sodium hydroxide (50 mL), dried (MgSO 4 and concentrated in vacuo to afford a yellow-brown oil which was crystallized from hexanes-ether to afford 0.0831 g of a green-yellow powder; mp 120-12]'C; WO 00/35436 WO 0035436PCT/US99/29783 I H NMR (400 MHz; CDCI 3 8 9.11 I 7.56 I1H, J 1.4 Hz), 7.46-7.41 (in, 2H), 7.20 (dd, I H, J 8.9, 2.4 Hz), 7.00 2H, J 9.6 Hz), 6.55 (broad t, I 3.86 2H, J =5.0 Hz). 3.61 (dd, 2H1, J 10. 1, 5.5 Hz), 2.23 3H), 1.56 (broad s, IH); IR (K-Br) 3297 (0-H stretch), 1627 (C =0 stretch) cm- I; MIS (CI) M+I 43 1.
Analysis calculated for C 1 I 6 H I 6 C11N2)0 2 C, 44.62; H, 3.74; N, 6.50.
Found: 44.63; H, 3.67; N, 6.30.
0 EXAMPLES 32-48 By following the general procedure of Example 3 1, the following benzamides were prepared by reacting the corresponding benzoic acid with the corresponding amine.
Example Compound MIP 0
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 N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylainino)- 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-( 1 H- 285-288 DEC ide 38 5-Bromo-2-(4-iodo-2-methyl-pbenylamino)- 180-182 henznmidfi- 39 5-Chloro-2-(4-iodo-2-methyl-pbenylamino)-N,N- 137-138 dimethyl-benzamide WO 00/35436 PCT/US99/29783 Example Compound MP 11C No.
[5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 170-173 benzoy lam ino] -acetic acid 41 4-Fluoro-2-(4-iodo-2-methyl-phenylam ino)-N- 69-71 propyl-benzamide 42 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 132-133.4 pheny lam ino)-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-I -yl- 122-124 propyl)}-2-(4-iodo-2-methyl-phenylamino)benzamide N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5- 91-93 nitro-benzamide 46 N-Butyl-4-fluoro-2-(4-iodo-2-m ethyl -phenylam ino)- 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 minol) was dissolved in 6 mL (6 mmol) of cold 1.0 M boranetetrahydrofuran 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 of a white solid; mp 99-100.5'C; 1 H NMR (400 MHz; DMSO): 5 7.57 lH, J=1.7 Hz), 7.45 (dd, 1H, J=8.4, 1.9 Hz), 7.39 IH), 7.29 I H, J=7.5 Hz), 6.89 I1H, J=8.4 Hz), 6.67-6.60 (in, I 5.47 I1H, J=5.5 Hz), 4.49 2H, 5.1 Hz), 2.14 3 H); WO 00/35436 PCTIUS99/29783 IR (KBr) 3372 (O-H stretch) cm- 1 MS (CI) M+1 358.
Analysis calculated for C 14
H
13
FINO:
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 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 82-85 phenyl]-methanol 51 [2-(4-lodo-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 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 utL of a M solution of the acid in DMF and 40 uL 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 pL 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% acetontiile in water and injected A I V/O _T tu olttc in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 .M spherical silica, pore size 115 A derivatized with C-18, the sample was eluted at 4.7 mL/min with WO 00/35436 PCT/US99/29783 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-d ifluoro-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 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- 577 piperidin- I -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- I -yl-ethyl)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-metbyl-phenylamino)-N- 571 (2-pyridin-4-yi-ethyl)-benzamide 61 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 414 benzam ide 62 5-Bromo-N-(3 -dimethylamino-propyl)-3 ,4-difluoro-2-(4-iodo- 551 2-methyl-phenylamino)-benzamide WO 00/35436 WO 0035436PCT/US99/29783 Example Compound MVS No. M-H 63 5-Bromo-3,4-difluoro-2-(4-iodo-2-methy I-phenylamino)-N- 580 (2-morpholin-4-yI-ethyl)-benzamide 64 3,4-Difl uoro-2-(4- iodo-2-methylI-pheny lam ino)-N-(2-morpholI in- 501 4-yi-ethyl)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenyiamino)-N-(2-pyrrolidin- 485 1 -yl-ethyl)-benzamide 66 3,4-Difluoro-2-(4-iodo-2-methyl-phenylam ino)-N-(2-pyridin-4-yI- 493 ethyl)-benzam ide 67 N-(3-Dimethylamino-propyl)-3 ,4-difluoro-2-(4-iodo-2-methyl- 473 phenylamino)-benzamide 68 N-Benzyl-4-fI uoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 460 69 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-hydroxy- 384 ethyl)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-y- 483 ethyl)-benzamide 71 4-Fluoro-2-(4-iodo-2-methyl-pbenylamino)-N-(3-piperidin- I -yl- 495 propyl)-benzamide 72 3 ,4-Difluoro-2-(4-iodo-2-metbyl-phenylamino)-N-(3-piperidin- 513 1 -yi-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-py-rolidin- I -yI- 467 ethyl)-benzamide 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-morpholin- 453 4-yi-ethyl)-benzamide 76 5 -Bromo-3,4I-dfl,,uoro-2-(4-iodo-2-methyi-phenylamino)-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-phenylamino)-N-(3-dimethylamino-propyl)- 425 3 ,4-d ifluoro-benzamide WO 00/35436 WO 0035436PCT/US99/29783 Example Compound MS No. M-H- 79 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- 461 benzamide 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-yi-ethyl)-benzamide 82 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(3 -hydroxy- 400 propyl)-benzamide 83 2-(4-Bromo-2-metbyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin- 437 1 -yi-ethyl)-benzamide 84 4-Fluoro-2-(4-iodo-2-methy-phenylamino)-N-phenethyl- 474 benzamide 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-thiophen- 450 2-yi-ethyl)-benzamide 86 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-pyridin- 431 4-ylmethyl-benzamide 87 2-(4-Bromo-2-metbyl-phenylamino)-3,4-difluoro-N-phenethyl- 444 benzamide 88 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin- 451 1 -yI-ethyl)-benzamide 89 5-Chloro-N- 3-[4-(2-hydroxy-ethyl)-piperazin- I -yI] -propyl 557* 2-(4-iodo-2-methyl- phenylamino)- benzamide 5-Fluoro-N- 3 -[4-(2-hydroxy-ethyl)-piperazin- I -yi]-propyl 541* 2-(4-iodo-2-methyl- phenylamino)- benzamide 91 2-(4-Iodo-2-methyl-pbenylamino)-5-nitro-N-pyridin-4-yI methyl- 487 benzarnide 92 5-Bromo-N- {3-[4-(2-hydroxy-ethyl)-piperazin- 1-yII-propyl)}- 601* 2-(4-iodo-2-methyl- phenylamino)- benzamide 93 5-Cbioro-N-(2-diethvIamino-ethvi)-244-ioin-2?-mi-thvI- 4 86* phenylaniino)- benzamide WO 00/35436 WO 0035436PCT/US99/29783 Example Compound MS No.
M-H
94 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- Il-yl- 497* ethyl)-benzamide (3-Hydroxy-pyrrolidin- I -yl)-[2-(4-iodo-2-methyl-phenylamino)- 466 96 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- I -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- phenylamnino)- benzamide 99 N- 2-[B is-(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- I -yl)-methanone 101 2-(4-lodo -2-methyl-phenylamino)-5-nitro-benzoic acid phenetbyl 501 ester 102 N- 3-[4-(2-Hydroxy-ethyl)-piperazin- I -yl]-propyl -2-(4-iodo- 568 2-methyl-phenylamino)- benzamide 103 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3 -hydroxy- 455 pyrrolidin- I -yI)-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-pyrrol idin- I-yl- 528 ethyl)-benzamide 106 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- I -yI- 542 cthyl)-benizam nide 107 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- Il-yl- 468* ethyl)-benzamide 108 5-Chloro-N-(3-dimethvlamino-prop) 1-2-4-indn-2-mpthvl_ phenylamino)-benzamide 109 N- {2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl)}-5-fluoro-2-(4-iodo- 502 2-methyl- phenylamnino)- benzamide WO 00/35436 WO 0035436PCTIUS99/29783 Example Compound MS No. M-H 110 5-Ch Ioro-N-(3 -hydroxy-propyl)-2-(4-iodo-2-methyl- 445 phenylam ino)-benzam ide III 5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo- 516* 2-methyl-phenylamino)- benzamide 112 S-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- I1-yl- 556* propyl)-benzamide 115 N- {2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl)}-2-(4-iodo-2-methyl- 529* benzamide 116 5-Cbloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morphol in-4-yI- 500* ethyl)-benzamide 117 5-Cbloro-N-(3 -diethylamino-propyl)-2-(4-iodo-2-methyl- 500* pheny lam ino)-benzamide 118 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- 514* phenylamino)-benzamide 119 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- Il-yI- 512 propyl)-benzamide 120 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin- I -yI- 509* ethyl)-benzamide 121 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- Il-yl- 544 ethyl)-benzamide 122 N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- 470* phenylarnino)-benzamide 123 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- 516* phenylamino)-benzam ide 124 N-(3-Hydroxy-propyl)-2-(4-iodo-2-methvl-phenvlamino)-5-n itrn- 45 6* benzamide 125 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 429* phenylamino)-benzamide WO 00/35436 Example No.
126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 Compound
PCTIL
N-(3 -Diethylamnino-propyl)-5 -fl uoro-2-(4-iodo-2 -m ethyl phenylamino)-benzamide N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-ylethyl)-benzamide 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin- Il-ylpropyl)-benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylam ino)-phenyl]-(3-hydroxypyrrolidin- I -yl)-methanone 5-Bromo-N-(2-diisopropylam ino-ethyl)-2-(4-iodo-2-methylphenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-ylethyl)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-I -ylpropyl)-benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- [4-(2-bydroxy-ethyl)-piperazin- I N-(3-Dietbylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo- 2-methyl-phenylamino)- benzamide [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]acetic acid 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-pyrrolidin- I-yI ethyl)-benzamide N-(3 -Dimethylarnino-propyl)-2-(4-iodo-2-methyl-pbenylamino)- N-(2-Di isopropyiamino-ethyl)-5-fluoro-2-(4-iodo-2-methylphenylamino)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid Sphenethyl ester 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid 5phenethyl ester 1S99/29783
MIS
M-H
484 511 544 523 439 558* 484 496* 482 500* 443 495 483 498 490 506 WO 00/35436 Example No.
142 143 144 145 146 147 148 149 150 151 152 153 Compound
PCT/U
5 -Bromo-2-(4-iodo-2-methyl-pheny lam ino)-th iobenzoic acid Sbenzyl ester 2-(4-Iodo-2-methyl-phenylam ino)-5-nitro-th iobenzoic acid Sbenzyl ester 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid Sbenzy) ester 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid Sbenzyl ester N-Cyc lopropyl-5-fl uoro-2-(4-iodo-2-methyl -pheny lam ino)benzamide 5-Cbloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzamide 5-Fluoro-N-(2-bydroxy-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-metbyl-phenylamino)-5-nitro-N-(4-sulfamoylbenzyl)-benzamide 5-Bromo-N-(2-bydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzamide N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)benzamide S99/29783
MS
M-H
536 503 476 492 409 429 413 475 593 567 473 521 WO 00/35436 Example No.
154 155 156 157 158 159 160 161 162 163 164 165 166 167 Compound PcT/U N -(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenvlamino)-5-nitrobenzamide 2-(4-Iodo-2-methyl-phenylam ino)-N-methyl-5-nitro-N-phenylbenzamide 5-Chloro-N-cyclopropyl-2-(4-iodo-2-metbyl-phenylamino)benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenylbenzamide N-Al lyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)benzam ide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoylbenzyl)-benzamide N-Alyl-5-ch loro-2-(4-iodo-2-methyl-phenylamino)-benzamide N -Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5 -nitrobenzamide S-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)benzamide 5-Chloro-2-(4-iodo-2-metbyl-phenylamino)-N-methyl-N-phenylbenzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoylbenzyl)-benzamide N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide S99/29783
NIS
M-H
440 486 425 459 409 583 538 425 436 469 475 646 598 436 WO 00/35436 Example No.
168 169 170 171 172 173 174 175 176 177 178 179 180 181 1 82 183 184 Compound
PCTIU:
2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(4-su Ifamoylbenzyl)-benzamide N-Al Iyl1-5 -bromo-2-(4-iodo-2-methyl-pheny lam ino)-benzamide 5-Fl uoro-2-(4-iodo-2-m ethyl -phenylam ino)-N -methylI-benzylI)benzamide N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)benzamide 5 -Bromo-2-(4-iodo-2-methyl -phenylamnino)-N-m ethyl -N-phenylbenzamide N-Benzyioxy-2-(4-iodo-2-methyl-phenylamino)-5 -nitrobenzamide N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)benzamide N-Al Iyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzy)benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-(3 -methyl-benzyl)-5-nitrobenzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenylbenzamide N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)benzamide 5-Ch Ioro-N-cyclobexyl-2-(4-iodo-2-methyl-phenylamino)benzam ide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-metiyl-benzyl)benzamide 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-metiyl-benzyl)- N-Cyclohexyl-2-(4-iodo-2-metbyl-pheny lam ino)-5 -n itrobenzamide S99/29783
MS
M-H
565 469 473 517 519 502 559 517 581 500 567 451 467 533 511 489 478 WO 00/35436 Example No.
185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 201 Compound
PCT/L
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)benzamide N-Benzyloxy-5-fluoro-2-(4-iodo-2-methy..phenylamino)benzamide 5-Ch Ioro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)benzamide 5 -Bromo-N-(2-hydroxy-ethylI)-2-(4-iodo-2-methyl-pheny lam ino)benzamide 2-(4-Ilodo-2-methyl -pheny lam ino)-N-m ethyl -5 -n itro-N-phenyl benzamide 5 -Gb Ioro-2-(4-iodo-2-m ethyl -phenyiam ino)-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)benzam ide N-Al lyI-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenylbenzamide N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitrobenzamide 5-Fluoro-N-(2-hydroxy-etbyl)-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-phenylam ino)-N-(4-sulfamoylbenzyl)-benzamide N-Cyu kpropyi-2-4-iodo-2-methyl-pheny lam ino)-5-n itrobenzamide N-Al lyI-5 -fluoro-2-(4-iodo-2-methyl-pheny lam ino)-benzamide 1S99/29783
MS
M-H
538 477 431 475 488 477 523 425 427 461 442 415 472 411 540 438 411 WO 00/35436 PCTIUS99/29783 Example Compound MS No. M-H 202 N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 585 benzamide 203 N-Al lyI-5 -bromo-2-(4-iodo-2-methyl-phenylam ino)-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-Al lyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 438
*M+H
EXAMPLE 207 Preparation of [4-Chloro-2-( IH-tetrazol-5-yi )-(4-iodo-2-methvl -phenyl)-amine Step a: Preparation of 5-chloro-2-fluoro-benzaldehyde To a solution of I1-chloro-4-fluorobenzne (13.06 g, 0. 1 mol) in THIF (180 mL), at -78*C, LDA (2M solution in TI-F, 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 Et 2 O. The Et 2 O layer was dried (MgSO 4 and the solvent removed in vacuum to give 14.95 g yield of crude aldehyde: I H NMR (CDCl 3 8, 10.3 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 m.L, 0. 10 10 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 CH 2
CI
2 The CH 2
CI
2 layer was dried (MgSO 4 and the solvent removed under vacuum to give crude aldoxime as a solid. The solid was purified by medium pressure liquid chromatography on silica. Elution WO 00/35436 PCT/US99/29783 with CH 2 C1 2 gave 4.87 g of the aldoxime as white solid: mp 95-97 0
C;
Analysis calculated for C 7
H
5 NOFCl: 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 NaHCO 3 (200 mL) solution. The mixture was extracted with Et20. The layer was dried (K 2 CO3) 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-phenvl)-I H-tetrazole A mixture of 5-chloro-2-fluoro-benzonitrile (2.84 g, 0.01823 mol), butanol mL), sodium azide (1.543 g, 0.0237 mol), acetic acid (1.36 mL, 0.0237 mol) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, additional 1.543 g sodium azide added, and the reaction mixture refluxed for additional 24 hours. After cooling to room temperature, Et 2 0 (100 mL) and 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. HC1. A gray solid precipitated. The solid was dried in vacuum at 50°C to give 1.76 g of 5-(5-chloro-2-fluoro-phenyl)-1Htetrazole: mp partial melt at 110°C, complete melting at 124 0
C);
1H (400 Mz, CDC1 3 8 8.19-8.08 1H), 7.77-7.71 1H), 7.61-7.52 1H); 13 C (100 Mz, CDC1 3 8 159.00, 156.49, 140.88, 133.02, 132.93, 130.73, 129.23, 129.21, 129.08, 126.05, 118.96, 118.73, 114.50; MS (CI) M+1 199 (100), M 198 WO 00/35436 PCTIUS99/29783 Step e: Preparation of [4-Chloro-24( H-tetrazol-5-yl)-(4-iodo-2-methvl-nhenyl)amine To a solution of 2-methyl-4-iodoani line (3.52 g, 0.0151 mol) in THF 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 I1-(tetrazol-5-yl)-2- (1.5 g, 0.0075 6 mol) in THF (15 mL) was added dropwise. The reaction was stirred for 16 hours as it warmned up to room temperature. The reaction mixture was quenched with aqueous conc. NH 4 Cl solution and extracted with CH 2 Cl 2 The organic layer was dried (MgSO 4 and the solvent removed giving a crude product as an oil. The oil with CH 2
CI
2
>CH
2 Cl 2 :MeOH gave 1.5 g of the desired product: mp 205-208'C; 1 H (400 Mz, DM50): 8 9.13 1H), 8.00-7.99 1H), 7.69 (s, I1H), 7.55-7.52 (in, 1IH), 7.43-7.40 (in, I1H), 7.12-7.05 (mn, I 2.24 3H); 13 C (100 Mz, CDCl 3 8 141.87, 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 M+l 412 M =411 (100).
Analysis calculated for C 14 HI 1
N
5 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 O4-odo-2-methyl-phenyl)- H-tetrazol-5-yl )-phenyllamine, mp 23 1 'C (dec) EXAMPLE 209 r4-nitro-2-( IH-tetrazol-5-vl)-(4-iodo-2-inethyl-phenyl)-amine, mp 205-208'C.
The 4-bromo and 4-iodo phenylamino benzhydroxamic acid derivatives of Formula 11 can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic WO 00/35436 PCT/US99/29783 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 0 I I
C-OH
Br or 4a I base Rla- Br or I -Ra R4a R3a R6a HN-O- R7a C 6a C-N-O- R7a Br or 3a R4a WO 00/35436 PCT/US99/29783 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 0 C to about 25 0 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-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 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 diisopropylethyiamine 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.
A teative method for making the ietin compounds involves first converting a benzoic acid to a hydroxamic acid derivative, and then reacting the WO 00/35436 PCT/US99/29783 hydroxamic acid derivative with an aniline. This synthetic sequence is depicted in Scheme 4.
Scheme 4 0
C-OH
f6a HN-O- R7a 0 f6a
C-N-O-R
7 R4a
NHR
2 I Rla I Br or I Rla Br or I R7a
R
3 a R4a 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 WO 00/35436 PCTIUS99/29783 Scheme 0 6a RlP r2a
C-N-OH
Ria N BroI1::
R
5 a L -R 7 a R3a R4a jbase O R4 Rla 2a C-N-0O R 7 a Ria N Br or I a R3a R4a 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 Ila 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 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-aminoin 5 mL of tetrahydrofuran at -78'C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydroftiranlheptane/ethylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 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 WO 00/35436 PCT/US99/29783 temperature the mixture was stirred for 2 days. The reaction mixture was concentrated by evaporation of the solvent under reduced pressure. Aqueous HCI 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 0 C; ca. 10 mm of Hg) to afford 1.10 g of the desired material; mp 224-229.5 0
C;
1 H NMR (400 MHz, DMSO): 8 9.72 1H), 7.97 (dd, 1H, J=7.0, 8.7 Hz), 7.70 1H, J=1.5 Hz), 7.57 (dd, 1H, J=8.4, 1.9 Hz), 7.17 1H, J=8.2 Hz), 6.61-6.53 2H), 2.18 3H); 13 C NMR (100 MHz, DMSO): 5 169.87, 166.36 JC-F= 2 4 9 4 Hz), 150.11 (d, JC-F=I1.4 Hz), 139.83, 138.49, 136.07, 135.26 JC-F= 1.5 Hz), 135.07, 125.60, 109.32, 104.98 JC-F= 2 1 .1 Hz), 99.54 JC-F= 2 6 .0 Hz), 89.43, 17.52; 19 F NMR (376 MHz, DMSO): 8 -104.00 to -104.07 IR (KBr) 1670 (C=O stretch)cm-1; MS (CI) M+1 372.
Analysis calculated for C 14
H
1 1
FINO
2 C, 45.31; H, 2.99; N, 3.77.
Found: C, 45.21; H, 2.77; N, 3.64.
Preparation of 4-Fluoro-N-hvdroxv-2-(4-iodo-2-methyl-phenvlamino)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, 0.00221 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 hexafiuorophosphate, 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 WO 00/35436 PCT/US99/29783 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 of an off-white foam; mp 61-75 0
C;
1H NMR (400 MHz, DMSO): 6 11.34 1H), 9.68 1H), 9.18 1H), 7.65 (d, 1H, J=1.5 Hz), 7.58 (dd, 1H, J=8.7, 6.8 Hz), 7.52 (dd, 1H, J=8.4, 1.9 Hz), 7.15 (d, 1H, J=8.4 Hz), 6.74 (dd, 1H, J=1 1.8, 2.4 Hz), 6.62 (ddd, 1H, J=8.4, 8.4, 2.7 Hz), 2.18 3H); 13 C NMR (100 MHz, DMSO): 6 165.91,164.36 JC-F= 2 4 7 1 Hz), 146.78, 139.18, 138.77, 135.43, 132.64, 130.60 JC-F= 1.5 Hz), 122.23, 112.52, 104.72 J=22.1 Hz), 100.45 JCF=25.
2 Hz), 86.77, 17.03; 19 F NMR (376 MHz, DMSO): 6 -107.20 to -107.27 IR (KBr) 3307 (broad, O-H stretch), 1636 (C=0 stretch) cm- 1 MS (CI) M+1 387.
Analysis calculated for C1 4
H
12 FIN20 2 C, 43.54; H, 3.13; N, 7.25.
Found: C, 43.62; H, 3.24; N, 6.98.
EXAMPLE 2a 5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide Preparation of 5-Bromo-2,3,4-trifluorobenzoic acid To a stirred solution comprised of 1-bromo-2,3,4-trifluorobenzene 5.30 g, 0.09 molU in 95 mL of anhydrous tetrahydrofuran cooled to -78 0 C was slowly added 12.5 mL of 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene solution (Aldrich). The mixture was stirred WO 00/35436 PCT/US99/29783 for 1 hour and transferred by canula into 700 mL of a stirred saturated ethereal carbon dioxide solution cooled to -78 0 C. The cold bath was removed, and the reaction mixture was stirred for 18 hours at ambient temperature. Dilute 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. HCI (330 mL, pH 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 (MgSO 4 concentrated in vacuo, and subjected to high vacuum until constant mass was achieved to afford 5.60 g (88% yield) of an off-white powder; mp 139-142.5 0
C;
1 H NMR (400 MHz, DMSO): 6 13.97 (broad s, 1H, 8.00-7.96 1H); 13 C NMR (100 MHz, DMSO): 8 162.96, 129.34, 118.47, 104.54 (d,
JC-F=
2 2 .9 Hz); 19 F NMR (376 MHz, DMSO): 8 -120.20 to -120.31 -131.75 to -131.86 -154.95 to -155.07 IR (KBr) 1696 (C=O stretch)cm-1; MS (CI) M+1 255.
Analysis calculated for C 74
H
2 1 BrF 3 0 2 C, 32.97; H, 0.79; N, 0.00; Br, 31.34; F, 22.35.
Found: C, 33.18; H, 0.64; N, 0.01; Br, 30.14; F, 22.75.
Preparation of 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenviamino)benzoic acid To a stirred solution comprised of 1.88 g (0.00791 mol) of 2-aminoin 10 mL ofu tetrahyduiuran at -78'C was added 6 mL (0.012 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for WO 00/35436 PCT/US99/29783 minutes, after which time a solution of 1.00 g (0.00392 mol) of 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 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 vacuumoven (80 0 C) to afford 1.39 g of a yellow-green powder; mp 259.5-262 0
C;
IH NMR (400 MHz, DMSO): 6 9.03 1H), 7.99 (dd, 1H, J=7.5, 1.9 Hz), 7.57 (dd, 1H, J=1.5 Hz), 7.42 (dd, 1H, J=8.4, 1.9 Hz), 6.70 (dd, 1H, J=8.4, Hz), 2.24 3H); 19 F NMR (376 MHz, DMSO): 6 -123.40 to -123.47 -139.00 to -139.14 IR (KBr) 1667 (C=0 stretch)cm- 1 MS (CI) M+1 469.
Analysis calculated for Cl 4
H
9 BrF 2
INO
2 C, 35.93; H, 1.94; N, 2.99; Br, 17.07; F, 8.12; I, 27.11.
Found: C, 36.15; H, 1.91; N, 2.70; Br, 16.40; F, 8.46; I, 26.05.
Preparation of 5-Bromo-3,4-difluoro-N-hvdroxv-2-(4-iodo-2-methvlphenvlamino)-benzamide 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-2Hpyran-2-yl)-hydroxylamine (0.15 g, 0.0013 mol), and diisopropylethylamine (0.25 mL, 0.0014 mol) in 20 mL of an equivolume tetrahydrofurandichloromethane solution was added 0.6794 g (0.001306 mol) of solid PyBOP (Advanced ChemTech) directly. The reaction mixture was stirred at 24 0 C for 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 WO 00/35436 PCT/US99/29783 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 of an analytically pure title compound, mp 80-90 0
C;
IH NMR (400 MHz, DMSO): 6 11.53 1H), 9.38 1H), 8.82 1H), 7.70 (dd, 1H, J=7.0, 1.9 Hz), 7.53 1H), 7.37 (dd, 1H, J=8.4, 1.9 Hz), 6.55 (dd, 1H, J=8.2, Hz), 2.22 3H); 19 F NMR (376 MHz, DMSO): 6 -126.24 to -126.29 -137.71 to -137.77 IR (KBr) 3346 (broad, O-H stretch), 1651 (C=O stretch)cm-1; MS (CI) M+1 484.
Analysis calculated for C 1 4
H
10 BrF 2
IN
2 0 2 C, 34.81; H, 2.09; N, 5.80.
Found: C, 34.53; H, 1.73; N, 5.52.
Examples 3a to 12a in the table below were prepared by the general procedure of Examples 1 a and 2a.
EXAMPLES 13a-77a Examples 13a to 77a were prepared utilizing combinatorial synthetic methodology by reacting appropriately substituted phenylamino benzoic acids as shown in Scheme 1) and hydroxylamines (NHR6a)-O-R7a). A general method is given below; To a 0.8-mL autosampler vial in a metal block was added 40 uL of a M solution of the acid in DMF and 40 pL of the hydroxylamine (2 M solution WO 00/35436 PCT/US99/29783 in Hunig's base and 1 M in amine in DMF). A 0.5 M solution of PyBrOP was freshly prepared, and 50 -tL 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 tM 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.
WO 00/35436 PCTIUS99/29783 EXAMPLES 3a-77a Example Compound Melting MS No. Point 0 C) 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 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl 62-67 phenylamino)-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 methoxybenzaniide 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 benzamnide 4-Fluoro-2-(4-fluor-2-methyl-phenylamino)-N- 142-146 (terahydropyran-2-yloxy)benzamide 1Ila 4-Fluoro-N-hydroxy-2-(4-cluoro-2-methyl- 133.5-135 phenylamino)-benzamide WO 00/35436 WO 0035436PCTIUS99/29783 Example Compound Melting MS No. Point (OC) 1 2a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 107-109.5 phenylmethoxy-benzamide 1 3a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-Nmethoxy-benzamnide 1 4a 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- N-methoxy-benzamnide 2-(4-Bromo-2-methyl-phenylaniino)- 3 ,4-difluoro-N-methoxy-benzamide 1 6a 2-(4-Bromo-2-methyl-phenylamino)-N-ethoxy- 3 ,4-difluoro-benzamnide 1 7a 5-Bromo-N-ethoxy-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide 1 8a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamnino)- N-isopropoxy-benzamide 1 9a 2-(4-Bromo-2-methyl-phenylamino)- 3 ,4-difluoro-N-isopropoxy-benzamide 4-Fluoro-N-(furan-3-ylmethoxy)-2-(4-iodo- 2-methyl-phenylamino)-benzamide 399 417 369 342* (M-EtO) 509 445 397 WO 00/35436 PCT/US99/29783 Example Compound Melting MIS No. Point 0 C) 21 a 3 ,4-Difluoro-N-(fuiran-3-ylmethoxy)-2-(4-iodo- 483 2-methyl-phenylamino)-benzamide 22a 2-(4-Bromo-2-methyl-phenylamino)- 3 ,4-difluoro-N-(fuiran-3-ylmethoxy)-benzamide 23 a 5-Bromo-3 ,4-difluoro-N-(furan-3-ylmethoxy)- 2-(4-iodo-2-methyl-phenylamino)-benzamide 24a 5-Bromo-N-(but-2-enyloxy)-3,4-difluoro- 2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- (prop-2-ynyloxy)-benzanide 26a 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- N-(prop-2-ynyloxy)-benzamide 27a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- I -methyl-prop-2-ynyloxy)-benzamide 28a 2-(4-Bromo-2-methvl-phenylaniino)- 3,4-difluoro-N-( 1 -methyl-prop-2-ynyloxy)benzamide 29a N-(But-3-ynyloxy)-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide 435 536 423 441 455 407 455 WO 00/35436 PCTIUS99/29783 Example Compound Melting MS No. Point 0 C) 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 407 3-ynyloxy)-3 ,4-difluoro-benzamide 31Ia 5-Bromo-N-(but-3-ynyloxy)-3,4-difluoro- 533 2-(4-iodo-2-methyl-phenylamino)-benzamide 32a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 517 N-(3-phenyl-prop-2-ynyloxy)-benzamide 33a 3,4-Difluoro-2-(4-bromo-2-methyl- 469 phenylamino)-N-(3-phenyl-prop-2-ynyloxy)benzamide 34a 3,4-Difluoro-N-[3-(3-fluoro-phenyl)-prop- 535 2-ynyloxy]-2-(4-iodo-2-methyl-phenylaxnino)benzaniide 2-(4-Bromo-2-methyl-phenylamino)- 487 3 ,4-difluoro-N-[3-(3-fluoro-phenyl)-prop- 2-ynyloxy]-benzamide 36a 3,4-Difluoro-N-113-(2-fluoro-phenyl)-prop- 535 2-ynyloxy]-2-(4-iodo-2-methyl-phenylamino)benzamide 3 7a 5-Bromo-3,4-difluoro-N-13 -(2-fluoro-phenyl)- 613 prop-2-ynyloxy]-2-(4-iodo-2-methylphenylamino)-benzamide WO 00/35436 WO 0035436PCTIUS99/29783 Example Compound Melting MS No. Point 0 C) 3 8a 3 ,4-Di fluoro-2-(4-iodo-2-methyl-phenyl amino)- 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 N-Ethoxy-3,4-difluoro-2-(4-iodo-2-methyl- 431 phenylamnino)-benzamide 41 a 2-(4-Bromo-2-methyl-phenylamino)-N-ethoxy- 383 3,4-difluoro-benzamide 42a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 427 propoxy-benzamnide 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 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 523 phenylamnino)-N-propoxy-benzamide 46a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 427 isopropoxy-benzaniide WO 00/35436 Example No.
Compound Melting Point PCT/US99/29783
MS
445 47a 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- N-isopropoxy-benzamide 48a 2-(4-Bromo-2-methyl-phenylamino)- 3 ,4-difluoro-N-isopropoxy-benzamide 49a 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methylphenylamino)-N-isopropoxy-benzamide N-Cyclobutyloxy-3 ,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide 51 a 2-(4-Bromo-2-methyl-phenylamino)-Ncyclobutyloxy-3 ,4-difluoro-benzamide 52a N-Cyclopentyloxy-4-fluoro-2-(4-iodo-2-methylphenylaniino)-benzamide 53a N-Cyclopentyloxy-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide 54a 2-(4-Bromo-2-methyl-phenylamino)-Ncyclopentyloxy-3 ,4-difluoro-.benzamide N-Cyclopropylmethoxy-4-fluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide 56a N-Cyclopropylmethoxy-3,4-difluoro-2-(4-iodo- 2-methyi-phenyiamino)-benzamide 397 523 457 423 457 WO 00/35436 Example No.
Compound Melting Point PCTIUS99/29783
MS
409 57a 2-(4-Bromo-2-methyl-phenylamino)-N-- cyclopropylmethoxy-3 ,4-difluoro-benzamide 8a 5-Bromo-N-cyclopropylmethoxy-3 ,4-difluoro- 2-(4-iodo-2-methyl-phenylamino) 59a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-phenoxy-ethoxy)-benzaxnide 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylaniino)- N-(2-phenoxy-ethoxy)-benzamide 61 a 2-(4-Bromo-2-methyl-phenylamino)- 3 ,4-difluoro-N-(2-phenoxy-ethoxy)-benzamide 62a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- (thiophen-2-ylmethoxy)-benzamide 63a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- N-(thiophen-2-ylmethoxy)-benzamide 64a 2-(4-Bromo-2-methyl-phenylamino)- 3 ,4-difluoro-N-(thiophen-2-ylmethoxy)benzanidle 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-methyl-allyloxy)-benzamide 435 475 499 451 439 WO 00/35436 PCTIUS99/29783 Example Compound Melting MS No. Point 66a 3,4-Di fl uoro-2-(4- iodo-2-methyl -phenyl amino)- 457 N-(2-methyl-allyloxy)-benzamide 67a 2-(4-Bromo-2-methyl-phenylamino)- 3 ,4-difluoro-N-(2-methyl-allyloxy)-benzamide 68a N-(But-2-enyloxy)-4-fluoro-2-(4-iodo-2-methylphenylamino)-benzamide 69a N-(But-2-enyloxy)-3 ,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzaxnide 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 2-enyloxy)-3 ,4-difluoro-benzamnide 71 a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- N-(prop-2-ynyloxy)-benzamide 72a N-(But-3-ynyloxy)-3 ,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide 73a 2-(4-Bromo-2-methyl-phenylamino)-N- (4,4-dimethyl-pent-2-ynyloxy)-3,4-difluorobenzamide 74a N-(But-2-enyloxy)-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide 410 439 410 455 WO 00/35436 PCT/US99/29783 Example Compound Melting MS No. Point (oC) (M-H 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 II-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/I 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 joint distortion (stage to joint ankylosis (stage 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 thritic joints revealed synovitis, pannus formation, and caaillage 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.
WO 00/35436 PCT/US99/29783 The foregoing assay was carried out to evaluate the anti-arthritic activity of several doses of the compound 2 -(2-chloro-4-iodophenylamino)-Ncyclopropylmethoxy-3,4-difluorobenzamide. The compound (also referred to as "PD 184352") was suspended in an aqueous mixture of 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 Nimher f PerPnt A A NKT- Mice Per Arthritis Severity Group Incidence Score of Arthritic Paws Vehicle 10 100 6.3 PD 184352 9 22 0.333 0.333 200 mg/kg/day PD 184352 10 10 0.6 0.4 mg/kg/day PD 184352 10 60 2.9 2 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, WO 00/35436 PCT/US99/29783 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 Day 22 Day 23 Day 24 D 10 59 57 68 Treatment PD 184352 200 mg/kg/day PD 184352 mg/kg/day PD 184352 mg/kg/day PD 170611 300 mg/kg/day PD 170611 100 mg/kg/day ay 53 31 17 0 32 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 WO 00/35436 PCT/US99/29783 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 0 C in 5% CO 2 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 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-1la. Interleukin-l a (100 U/mL) (Genzyme, Cambridge, MA) was suspended in media and added in a volume of 10 UL/well. The cells were then incubated for 24 hours before the media was removed and stored at -20 0 C. Prostromelysin-1 levels were measured using an ELISA from Amersham (Cat. No. RPN2615). Percent inhibition was determined by comparing the stromeiysin-I concentration of drug-treated cells to that of vehicle-treated controls. The drug concentration at which 50% inhibition of WO 00/35436 PCT/US99/29783 stromelysin-1 production was measured (IC 50 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 (a-MEM, Cat. No. 12561-023) was added 10 mL of 1 Molar N-2hydroxyethylpiperazine-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 pg/mL Strep), 500 p.L Gentamicin Stock (50 mg/mL) (Cat. No. 15750-011), 40 mL Fetal Calf Serum from Hyclone Inc. (Cat.
No. A 111 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
(IC
5 0 Pharmacological Table 3 Effect of MEK Inhibitors on IL-1-induced Stromeylsin Expression in Rabbit Synovial Fibroblast Cell Cultures Compound Tested
IC
50 (nM) PD 171984 59 PD 177168 PD 180841 61 PD 184161 192 PD 184352 28 PD 184386 18 PD 185625 24 PD 185848 9 PD 188563 11 PD 198306 18 r 1 77u I 24 PD 203311 WO 00/35436 PCT/US99/29783 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 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 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 22 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 WO 00/35436 PCT/US99/29783 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-la (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 Pharmacological Table Inhibition of Proteoglycan Loss in Rabbits PD No. Dose Dosed Inhibition of (mg/kg Proteoglycan Loss 184352 30 2x 6 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 1Oml/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 WO 00/35436 PCT/US99/29783 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 ID 40 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 1 1 th 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 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 mg/kg) 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.
WO 00/35436 PCT/US99/29783 Pharmacological Table 6 Activity of MEK Inhibitors in animal models of arthritis and inflammation Model 184352 198306 203311 Rat carrageenan footpad edema (CFE) (ID 4 0 75.8 14.7 18.9 mg/kg Rat SCW arthritis (SCW) (ID 5 0 10.0 11.2 >100 Rat adjuvant arthritis (AIP) (ID 5 0 6.9 6.6 Rabbit IL-1 arthritis (IL-I) Inh proteoglycan loss 30mg/kg) 57.9 42.9 29.2
Claims (20)
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.
The method according to Claim selective MEK1 or MEK 2 inhibitor.
6. The method according to Claim compound of Formula I RI I I Bror I 1, wherein said MEK inhibitor is a I wherein the MEK inhibitor is a R 3 K 4 wherein: R 1 is hydrogen, hydroxy, C 1 -Cg aikyl, C 1 -Cg alkoxy, halo, trifluoromethyl, or CN; R 2 is hydrogen; 83 R 3 R 4 and R 5 independently are hydrogen, hydroxy, halo, trifluoromethyl, C I-C 8 alkyl, C I-C 8 alkoxy, nitro, CN, or or NR)m{,-CH 2 )n-R 9 where R 9 is hydrogen, hydroxy, COOH, or NRIORI 1 n is 0-4; mnis 0ori1; Rio and R, 1 independently are hydrogen or C 1 -C 8 ailkyl, 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 0, S, NH, or N-C I -C 8 alkyl; Z is COOR-,, tetrazolyl, C0NR 6 R7, CONHNRI 0 RII, or CH 2 0R7; R,5 and R7 independently are hydrogen, CI-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CO)-Cl-Cg alkyl, aryl, heteraryl, C 3 -CI 0 cycloalkyl optionally containing one, two, or three heteroatoms selected from 0, S, NH, or N alkyl; or R, 6 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 0, S, NH, or N alkyl; and wherein any of the foregoing alkyl, alkenyl, aryl, heterocyclic, and alcynyl groups can be unsubstituted or substituted by halo, hydroxy, C 1 -C 6 alkoxy, amino, nitro, C 1 -C 4 alkylamino, di(Ci- C 4 )atkylamnino, C 3 -C 6 cycloalkyl, phenyl, phenoxy, C 3 -C5 heteroaryl, or 3C heteraryloxy; 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-( IH-tetrazol-5 -yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine; [4-iodo-2-methyl-phenyl)-[2-(iH-tetrazol-5-yl)-phenyl]amine; 500382663 i.Doc/BSV/ WO 00/35436 PCT/US99/29783 [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)-berizoic 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-lodo-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-phenylamnino)-benzoic acid; 2-(4-lodo-phenylamino)-5-methoxy-benzoic acid; 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-Iodo-2-methyl-phenylamnino)-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-phenylamnino)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamnino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide; N-Ethyl-4-fluoro-2-(4-iodo-2-m ethyl -phenylamnino)-benzarnide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide; 4-Fluoro-2-(4-iodo-2-methv-phenviamino)-N-(lH-tw-trqzo! -5i -VylI- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; WO 00/35436 PCT/US99/29783 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethy- benzamide; [5-Chloro-2-(4-iodo-2-methyl-pheylaio)-bezoylaifo] -acetic acid; 4-Fluoro-2-(4-iodo-2-methy1-phenylamino)-N-propyl-beflzwmide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phelylamilo) benzamide; N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamilo)- benzamide; 4-Fluoro-N- 3-[4-(2-hydroxy-ethyl)-piperazin- I -yI]-propyl I 2-(4-iodo-2-methyl-phenylamino)-benzamide; N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-belzamide; N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamilo)-belzamide; 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamilo)- benzamide; 5-Bromo-2-(4-iodo-2-methy1-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- I -yl-ethyl)-benzamide; 3 ,4-Difluoro-N-(2--hydrox-e-,thy)-2-(4-odo-2-methyl- phenylamino)-benzamide; N-(2,3-Dihydroxy-propy)-4-fluoro-2-(4-iodo-2-methy1- 3 ,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-mlethyl- phenylamino)-benzamide; (2-pyrrolidin- I -yl-ethyl)-benzaxnide; 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamilo)-N- (2-pyridin-4-yi-ethyl)-benzamnide; WO 00/35436 PCT/US99/29783 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; -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-yI-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-phenylarniino)-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- Il-yl- propyl)-benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamnino)-N-(3-piperidin- I -yl-propyl)-benzamide; 4-Fluoro-2-(4-iodo-2--net-hy!-phenyla.mino)-N-(2-thi.ophen-2-yl,- ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- Il-yl- ethfl)-benzamide: 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-morpholin- 4-yI-ethyl)-benzamide; 5-Bromo-3.4-difluoro-2-(4-iodo-2-methy-henvrimnn)-N- pyridin-4-ylmethyl-benznide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 4-ylmethyl-benzamide; WO 00/35436 PCT/US99/29783 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-yi-ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-di fluoro-N-(3-hydroxy- propyl)-benzaniide; 2 4 -Bromo-2-methyl-phenylarnino)-3 ,4-difluoro-N-(2-pyrrolidin- I -yl-ethyl)-benzamide; 4 -Fluoro- 2 -(4-iodo-2-methyl-phenylamino)-N-phenethyl. benzamide; 2 -(4-Bromo-2-methyl-pheiylamino)-3 ,4-difluoro-N-(2-thiophen- 2-yi-ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-pyridin- 4-ylmethyl-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-di fluoro-N-phenethyl- benzaniide; 2-(4-Bromo-2-methyl -phenylamino)-3 ,4-difluoro-N-(2-piperidin- I -yl-ethyl)-benzaniide; 3 -[4-(2-hydroxy-ethyl)-piperazin- 1 -yi]-propyl 2-(4-iodo-2-methyl- phenylamino)- benzamide; 5-Fluoro-N- 3 -[4-(2-hydroxy-ethyl)-piperazin- Il-yl] -propyl 2-(4-iodo-2-methyl- phenylamino)- benzamide; 2 4 -Iodo-2-methyl-phenvlamino)-5-nitro-N-pyridin-4yI methyl- benzamnide; {3-[4-(2-hydroxy-ethyl)-piperazin- l-yI] -propyl 2-(4-iodo-2-methyl- phenylamino)- benzamnide: 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl. phenylamnino)- benzarnide; WO 00/35436 PCT/US99/29783 -Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- Il-yl ethyl)-benzamide; (3-Hydroxy-pyrrolidin-I [2-(4-iodo-2-methyl-phenylamino)- -Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- Il-yl ethyl)-benzamide; 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)- benzamide; [Bis-(2-hydroxy-ethyl)-amino] -ethyl) -5-chloro-2-(4-iodo- 2-methyl- phenylamino)- benzamnide; N- 2- [Bi s-(2-hydroxy-ethyl)-amino] -ethyl)} -5-bromo-2-(4-iodo- 2-methyl- phenylamino)- benzamide; N- 3- [4-(2-Hydroxy-ethyl)-piperazin- I -yl]-propyl I -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- Il-yl- ethyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- Il-yI- ethyl)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- Il-yl ethyl)-benzamnide; 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- phenylaniino)- benzamide; 5-Chloro-N-(3-hydroxy-VroDV1)-2-(4-iodo-2-methyl-phenyla-mino)- benzamide; 5-Chloro-N-(3 -diethylamino-2-hydroxy-propyl)-2-(4-iodo- 2-methyl-phenylamino)- benzaxnide, 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-I -yI- ethyl)-benzaniide; WO 00/35436 PCT/US99/29783 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- Il-yl- propyl)-benzamide; N- f 2-[Bis-(2-hydroxy-ethyl)-amino] -ethyl I -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- I1-yl- propyl)-benzamnide; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin- Il-yl- ethyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamnino)-N-(2-piperazin- I 1 -yi- ethyl)-benzaniide; 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)- benzaxnide; N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-y- ethyl)-benzamide; WO 00/35436 PCT/US99/29783 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3 -piperidin- I1-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; -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholil- 4 -yI- ethyl)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- Il-yI- propyl)-benzamide; [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyll- [4-(2-hydroxy-ethyl)-piperazin- I -ylI-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-phelylamilo)- benzamide; 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamilo)- benzamide; N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamiflo)- benzamide: 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benfl~y)- benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-ethyl-pheylani.-ifo)- benzamnide; N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phelylamilo)- benzamide; N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5 -itro- benzamide; WO 00/35436 PCTIUS99/29783 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phel- benzamide; 5-Chloro-N-cyclopropyl-2 iodo-2-methyl-phenyl amino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phel- benzamide; N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamnino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamilo)- benzamide; 5-Fluoro-2-(4-iodo-2-methy1-phenylamino)-N-(4-sulfamoyI- benzyl)-benzamide; N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-litro- benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamilo)- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyI- benzainide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfaloyl-belzyl)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamnide; N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 2-(4-Iodo-2-methyl-phenviamino)-5-nitro-N-(4-suf qrooyl-be-zyl- benzamide; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-beflzamide; -Fluoro-2-(4-iodo-2-methyI-phenvlanino)-N-(-methy-be-zyl)- benzamnide; N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamilo)- benzarnide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phel- benzamide; WO 00/35436 PCT[US99/29783 N-Benzy Ioxy-2 -(4-iodo-2-methyl -pheny lamino)-5 -nitro- benzaniide; N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino). benzamide; -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)- benzamnide; 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamnino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3 -methyl-benzyl)- benzaniide; 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-rnethy!-phenylamnino)- 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-ethvl)-244-iodo-2-m ethyl-phnv1 Am ino)- benzaniide; 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide; WO 00/35436 PCTIUS99/29783 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylarnino)- benzamide; -Chloro-N--cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamnino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamnide; N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl -phenylamino)- 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-phenylam ino)-5 -nitro- benzamide; N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; -iodo-2-(4-iodo-2-methyl-phenyl amino)- 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-phenylainino)-N-methyl-N-phenyl- benzamide; N-Allyl-2-(4-.iodo-2-methyl-phenylamino)-5-nitro-en7namide;p. 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol; [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl] -methanol; [2-(4-lodo-2-methyl-phenylamino)-5 -nitro-phenyl] -methanol; -94- [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 Ri is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; R 2 is hydrogen; R 3 R4 and R 5 independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; Rio and R 11 independetly are hydrogen or methyl; Z is COOR 7 tetrazolyl, CONR6R 7 CONHNRioR 1 1 or CH20R 7 R 6 and R 7 independently are hydrogen, C1-4 alkyl, heteroaryl, or C 3 -5 cycloalkyl optionally containing one or two heteroatoms selected from 0, S, or NH; or R6 and R 7 together with the nitrogen to which they are attached complete a 5-6 member cyclic ring optionally containing 1 or 2 additional heteroatoms selected from O, NH or N-alkyl; and wherein any of the foregoing alkyl or aryl groups can be unsubstituted or substituted by halo, hydroxy, methoxy, ethoxy, or 15 heteroaryloxy. 0
9. The method of claim 8, wherein the MEK inhibitor is a compound of Formula wherein Z is COOR 7 R 7 is H, pentafluorophenyl or tetrazoly; and R 3 R4 and are independently H, fluoro or chloro.
10. The method of claim 8, wherein the MEK inhibitor is a compound of Formula (I) 20 wherein: Z is COOR 7 R7 is H, pentafluorophenyl, or tetrazolyl; R3 and R5 are independtly H, fluoro, or chloro; and R 4 is fluoro.
11. The method of claim 8, wherein the MEK inhibits a compound of Formula (I) wherein Z is COOR 7 is H, pentafluorophenyl or tetrazolyl; and two of R 3 R4 and are independent fluoro.
12. The method of claim 1, wherein the MEK inhibitor is a compound of Formula II 500382663 1 DOc/BSW WO 00/35436 WO 0035436PCTIUS99/29783 Ra F'a C-N-0-R 7 a N ril y I RI Br or R3a R4a wherein: Ri1a is hydrogen, hydroxy, C 1 I -C 8 alkyl, C 1 I-C 8 alkoxy, halo, trifluoromethyl, or CN; R2a is hydrogen; R3a, R4a, and R5a independently are hydrogen, hydroxy, halo, trifluoromethyl, C 1 I-C 8 alkyl, C I-C 8 alkoxy, nitro, CN, or (0 or NlH)m-(CH2)n-R9a, where R9a is hydrogen, hydroxy, C0 2 H or NRlOaR11a. n is 04; mnis 0 or 1; RI Oa and RI la independently are hydrogen or Cl -C 8 alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 1 0-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from 0, S, NH, or N-C I-C 8 alkyl; R6a is hydrogen, C I-C 8 alkyl, (C0)-C 1 -C 8 alkyl, aryl, aralkyl, or C 3 -C 10 cycloalkyl; R7a is hydrogen, C I-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C8 alkynyl, C 3 -C 10 (cycloalky! or cyclo-alkyl optionally containing a heteroatomn selected from 0, S, or NRqa); and wherein any of the foregoing alkyl, alkenyl, aryl, heteroaryl, 1hetecocyciic, and aikynyl groups can be unsubstituted or substituted by halo, hydroxy, C I-C 6 alkoxy, amino, nitro, C I-C 4 alkylamino, di(C I- C 4 )alkylamino, C 3 -C 6 cycloalkyl, phenyl, phenoxy, C 3 -C 5 heteroaryl or 96 heterocyclic radical, or C 3 -C 5 heteroaryloxy or heterocyclic radical-oxy; or R&a and R7a taken together with the N to which they are attached can complete a 5- to I 0-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from 0, S, or NRI~aRi 1a; or a pharmaceutically acceptable salt, amide or prodrug thereof.
13. The method of claim 12, comprising a MEK inhibitor having a structure of Formula (1I) wherein: Ria is H, methyl, fluoro, or chioro; R 2 a is H; R 3 a, R~a, and R 5 a are each H, Cl, nitro, or F; R 6 a is H; R 7 a is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl, methyl, cyclopropytmethyl, or cyclopropylethyl; and the 4' position is 1, rather then Br.
14. The method of claim 13, comprising a MEK inhibitor having a structure of Formnula (11) wherein: R 4 a is F at the 4 position, para. to the CO-N-R 6 a-OR 7 a, group and meta to the bridging nitrogen; at least one of R 3 a and R 5 a is F or Cl; and Ria is methyl or chloro.
:15. The method of claim 12, comprising a MEK inhibitor having a formula selected from: 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; ao2(4id--ehy-hnlmno--mtoy)bnaie :.4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(meth2-yoxy)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(preo2yryloxy)-benzamide; ~4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(p-henxylmthoxy)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2r-tenyltoxy)-benzaide; 500382663_1.DOC/BSV/ WO 00/35436 PCTIUS99/29783 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-phenylamnino)-N- (3 -ftuylmethoxy)-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-( I -methyiprop- 2-ynyloxy)-benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -phenyiprop- 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-phenylamnino)-N-(cyclobutyloxy)- benzamnide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide; 3 ,4-Difluoro-2 -(4-iodo-2-methVl-Dhenylamino)-N-(2-methyI -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)- benzwnide; 98 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; -Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(n-propoxy)- benzamnide; -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)-benzainide; 15 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -methyl-pent-2-en- 4-ynyloxy)-benzamnide; 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)- benzarnide; *5 -Bromo-3 ,4-di fluoro-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-(thiophen-2- ylmethoxy)-benzamide; 500382663_i.Doc/BSWV 98a 5-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)-benzaniide;
500382663-i.Doc/BS W WO 00/35436 PCT/US99/29783 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)-benzamnide; 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- benzamnide; 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-phenylaniino)-N-(tetrahydropyran- 2-yloxy)-benzamide; 3 ,4-Difluoro-2-(4-bromo-2-rnethyl-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-methv1-nhenvlqmino)-N-(hilt- 3-ynyloxy)-benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl- prop-2-enyloxy)-benzamide; WO 00/35436 PCT/US99/29783 3,.4-Difluoro-2-(4-bromo-2-methyl-phenylamnino)-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-phenylamnino)-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)-benzamnide; 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)- benzarnide; 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-brorno-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-phenylarnino)- benzaniide; 5-Chloro-3,4-difluoro-N-hydroxv-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamnino)-N- hydroxy-benzamnide; N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide; 3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamnino)-N-hydroxy- benzamide; WO 00/35436 PCTIUS99/29783 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-phenylanuino)-N-hydroxy-4-nitro-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3 benzaniide; 5-Chloro-2-(2-chloro-4-iodo-phenylaniino)-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- benzamnide; 2-(2-Bromo-4-iodo-phenylamino)-3 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-benzaniide; 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-cyclopropylmethoxv-3.4-difluoro-2-(4-iodo-2-rne.thy!- phenylamino)-benzamide; 5-Bromo-N-cyclopropylmethoxy-3 ,4-difluoro-2-(2-fluoro-4-iodo- 'phenylamino)-benzamide; WO 00/35436 PCT1US99/29783 N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro- benzamide; N-Cyclopropylmethoxy-3 ,4,5-trifluoro-2-(2-fluoro-4-iodo- phenylamino)-benzarnide; 5-Chloro-N-cyclopropylmethoxy-3 ,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylwmino)-N- cyclopropylmethoxy-3 ,4-difluoro-benzamide; N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro- benzarnide; 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-phenylamnino)-N-cyclopropylmethoxy- 3 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-Cyclopropvlmethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylam-in.-o) benzaniide; N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; 2-(2-Chloro-4-iodo-phenylarmino)-N-cyclopropylmethoxy- 4-fluoro-berizamide; 2-(2-Chloro-4-iodo-nhenvrnminnM-N-cv1 onropylmethoxyi- 3,4-difluoro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 4-fluoro-benzamide; and 103 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3 ,4-difluoro- benzamide.
16. The method of claim 1, comprising a MEK inhibitor having a structure selected from: 2-(2-chloro-4-iodophenylamnino)-5-chloro-N-cyclopropylmethoxy -3,4- difluorobenzamide; 2-(4-iodophenylamino)-N-cyclopropylmethoxy-5 -chloro-3 ,4- difluorobenzamide; 2-(4-iodophenylamino)-5-chloro-3 ,4-di fluorobenzoic acid; 2-(2- chloro-4-iodophenylamino)-5-chloro-3 ,4-difluorobenzoic acid; 5 -chloro-3 ,4-difluoro-2- (4-iodo-2-methylphenylamino)-benzoic acid; and 5 -chloro-N-cyclopropylmethoxy -3,4- difluoro-2-(4-iodo-2-methylphenylamnino)-benzamide.
17. 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; 2-(2-Methyl-4-iodophenylamnino)-N-hydroxy-3 ,4-di fluorobenzaniide; 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3 ,4-di fluoro-5 -bromobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3 bromobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy-3 ,4-di fluoro-5 bromobenzamide; 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3 ,4-difluoro-5 bromobenzamide; 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3 2-(2-Chloro-4-iodophenylamino)-N-cyclobutylmethoxy-3 ,4-di fluorobenzamide; 500382663 I .DOC/B SV -104- 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3 ,4-difluorobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3 ,4,5 trifluorobenzamide; and 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide.
18. The method of claim 17, wherein said compound is selected from 2-(2-chloro-4- iodophenylamnino)-N-cycloproplmethoxy-3 ,4-difluororbenzamide, 2-(2-Methyl-4- iodophenylamino)-N-cyclopropylmethoxy-3,4,5-trifluorobenzamide; and 2-(2-Chloro-4- iodophenylarmino)-N-cyclopropylmethoxy-4-fluorobenzamide;
19. Use of an effective antiarthritic amount of a MEK inhibitor, for the manufacture of a medicament for treating or preventing arthritis in a mammal. Use according to claim 19, wherein the arthritis is rheumatoid arthritis or osteoarthritis. 21 Us codn*ocam*9 hri h rhitsi seatrts 15 21. Use according to claim 29, wherein the arthritis is osuteodarthritis. 23. The method according to claim 19, wherein said MEK inhibitor is a selective MEKi or MEK2 inhibitor. 24. The method according to claim 19, wherein the MEK inhibitor is a compound of Formula I R2* Z Br or I R 3 K wherein: R, is hydrogen, hydroxy, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halo, trifluoromethyl, or CN; 500382663 i.DocIBSqA -105- R 2 is hydrogen; R 3 R 4 and Rs independently are hydrogen, hydroxy, halo, trifluoromethyl, C 1 -C 8 alkyl CI-Cs alkoxy, nitro, CN, or or NH)m-(CH 2 )n-R 9 where R 9 is hydrogen, hydroxy, COOH, or NRioRI 1 n is 0-4; m is 0 or 1; Rio and R 1 1 independently are hydrogen or Ci-C 8 alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1, 2 or 3 additional heteroatoms selected from 0, S, NH, or N-Ci-C 8 alkyl; Z is COOR 7 tetrazolyl, CONR 6 R 7 CONHNRioR 1 1 or CH 2 0R 7 R 6 and R 7 independently are hydrogen, Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CO)-CI-C 8 alkyl, aryl, heteraryl, C 3 -CIO cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl; or R 6 and R 7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl; and wherein any of the foregoing alkyl, alkenyl, aryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C 1 -C 6 alkoxy, amino, nitro, Ci-C 4 alkylamino, di(Ci- C 4 )alkylamino, C 3 -C 6 cycloalkyl, phenyl, phenoxy, C 3 -C 5 heteroaryl, or C 3 -Cs 20 heteraryloxy; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 25. Use according to claim 24, wherein the MEK inhibitor is a compound selected from: [4-Chloro-2-(1H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine; (4-iodo-2-methyl-phenyl)-[2-(iH-tetrazol-5-yl)-phenyl]amine; 500382663_.DOc/BSW 106- [4-nitro-2-( I H-tetrazol-5 -yI)-phenyl -(4-iodo-2-methyl -phenyl)- amine; 4 -Fluoro- 2 4 -iodo-2-methylphenylamino)benzoic acid; 3, 4 5 -Trfluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 3 4 -Difiuoro-2-(4-iodo-2-methyl-phenyamino)-benzoic acid; 5-Bromo-3 4 -difluoro-2-(4-iodo-2-methy-phenylamnino-benzoic acid; 0 4 0 0e 0 S 0 *4 0 S S *0 .0 0 4 S 0 -Chloro-2-(4-iodo-2-methy-phenylanino)-benzoic acid; Sodium 5 -Chloro- 2 4 -iodo-2-methyl-phenyamino-benzoate; 5-Bromo-2-(4-iodo-2-methy-phenyamino)benzoic acid; 2 4 -Iodo- 2 -methyI-phenyamino-5nitrobenzoic acid; 4 -Chloro- 2 -(4-iodo-2-methyl-phenylamino-benzoic acid; 2 4 -Iodo-2-methyl-phenylamino)-benzoic acid; 2 -(4-iodo-2-methyI-phenylamino-benzoic acid; -Iodo- 2 4 -iodo-2-methy1-phenylamino)-benzoic acid; 2,3 5 -Trifluoro-4-(4-iodo-2-methyI-phenyamino)benzoic acid; 2 4 -lodo-phenylamino)-5-methoxy-benzoic acid; -MethyI-2-(4-iodo-2-methyI-phenyamino)benzoic acid; 2 4 -Iodo- 2 -methyl-phenylamino)A-nitro-benzoic acid; 2 4 -Bromo-2-methyI-phenyaino-4fluorobenzoic acid; 2 2 -Bromo-4-iodo-phenylamino)-5-nitrobenzoic acid; 2 4 -Bromo- 2 -methyI-phenyamino-3,4difluorobenzoic acid; 5 -Chloro-N-( 2 -hydroxyethyl)-2-(4-.iodo-2methylphenyamino). benzamide; 4 -Fluoro- 2 4 -iodo-2-methyl-phenylanmino)benzamide; 4 -Fluoro- 2 4 -iodo-2-methy-phenyamino-Nmethy-be~nide; N-Ethyl- 4 -fluoro-2-(4-iodo-2-methy-phenylamino-benamide; 4 -Fluoro- 2 4 -iodo-2-methy1-phenylamino)-N,N-dimety. benzamnide; 4 -Fluoro-2-(4-iodo-2-methyI-phenylamino)-N-(I benzainide; 2 -(4-iodo-2-methyl-phenyamino)benzamide; *000 0*P* 0 0 I *90 S 009.9 *0 S 44 0 30 107 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- beazamide; [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino] -acetic acid; 4-Fluoro-2-(4-iodo-2 -m ethyl -ph enyl ami no)-N-propyl-benzamide; -B romo-N -(2-hydroxy-ethyl)-2-(4-iodo-2-methyl -phenyl amino)- benzamide; N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylainino)- benzamide; 4-Fluoro-N- {3-[4-(2-hydroxy-ethyl)-piperazin-1I-yI]-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-phenylarmino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamnino)-N,N-dimethyl- beazainide; -Bromo-3,4-difiuoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-berizamide;
20 N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamnide; 5-Bromo-3,4-difluoro-2 -(4-iodo-2-inethyl-phenylamino)-N- (2-piperidin- I -yl-ethyl)-benzamide; 3 ,4-Difiuoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(2,3 -Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- phenylamnino)-berizamide; 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- I -yl-ethyl)-benzamide; 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-pyridin-4-yI-ethyl)-benzamide; 108 4 -Fluoro-N-(2-hydroxy,-eth yl)-2-(4-i odo-2-methyI-phenylamino)- benzamide; 5-Bromo-N-(3 -dimethylam-ino-propyI>3 ,4-difluoro-2-(4-iodo- 2 -methyl-phenylamino)-benzamide; 5-Bromo-3 ,4-difluoro-2-(4-i odo-2-methyl -phenylarnino)-N- 2 -morpholin-4-yl-ethyl)-benzamide; 3 ,4-Difluoro-2 -(4-iodo-2-methyl -phenylamino)-N-(2-morpholin- 4 -yl-ethyl)-benzamide; 3,-iloo2(-oo2mty-hnlmn)N(-yrldn 1 -yi-ethyl)-benzamide; 3 4 -Difluoro-2-(4-iodo-2-methyl -phenylamino)-N-(2-pyridin.4-y- ethyl)-benzarnide; N-(3-Dimethylamino-propyl)-3,4-difluoro-2 -(4-iodo-2-methyl- phenylamino)-benzarnide; N-ezl4fur--4id--mty-hnlmn)bnaie 2 4 -Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy- ethyl)-benzarnide; 4 -Fluoro- 2 -(4-iodo-2-methy-phenyamino)N(2-mopholin-4.y ethyl)-benzamide; 4 -Fluoro- 2 4 odo-2 -methy phenyamino)N(3 piperi din- -yi- propyl)-benzamide; *3, 4 -Di fl uoro- 2 4 -odo2methy-ph enyarino)-N.(3 p iperi din- Z ~I -yI-propyl)-benzamnide; ethyl)-benzamide; 4 -Fluoro-2-(4-iodo-2-methy1.phenyamino)-N.(2-pyroidin-1-yl ethyl)-berizamnide; 2 4 -Bromo-2-methyl-phenylamnino-3 ,4-difluoro-N-(2-rnorpholin- 4-yl-ethyl)-benzamide; :>305-Bromo-3 4 -difluoro-2-(4-iodo..2.methyl..phenylamino-N- pyridin-4-ylmethyl-benzamnide; 3 4 -Difluoro- 2 4 -iodo-2-methylbphenylamino).N-pyridin- 4-ylmethyl-benzamide; 109- 2 -(4-Brom o-2 -methyl -pheny] am ino)-N- (3 -di methyl amino- propyl)-3 ,4-di fluoro-benzamide; 4-Fluoro-2 -(-ilodo-2 -methyi-phenylarnino)-N-pyridin-4-ylmethyl. benzarnide; 4-Fluoro-2-(4-iodo-2-methy] -phenylamino)-N-(2-pyridin-4-yl ethyl)-benzarnide; 2-(4-Broino-2 -methyl-phenylamino-3 ,4-difl uoro-N-(2-pyri din- 4-y]-ethyl)-benzamnide; 2 -(4-Bromo-2-m ethyl -phenylamino).3 ,4-difl uoro-N -(3-hydroxy- propyl)-benzamnide; 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-phenylamino)-3,4-difluoro-N-phenethyl- 20 benzamnide; 2-(4-Brorno-2 -methyl -phenylamino)-3 ,4-difluoro-N-(2-piperi din- I-yl-ethyl)-benzamnide; .1 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- I-yl] -propyl)}- 2-(4-iodo-2-methyl phenylamino)- benzamnide; 2 4 -Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin.4yI methyl- benzam-ide; 30 5-Bromo-N- 3 4 -(2-hydroxy-ethyl)-piperazin-l-yl] -propyl 2-(4-iodo-2-methyl- phenylamino)- benzamide; 5-Chloro-N-(2-diethyamino-ethyl)-2(4iodo2mety. phenylamnino)- benzamide; -110 2 4 -iodo-2-methyl-phenylamino)-N-(2-piperidin- I -yl ethyl) -benzami de; (3-Hydroxy-pyi-rolidin- I 2 odo-2 -methyl -phenyl amino)- 5 -Chloro-2-(4-iodo-2-methyl -phenylamino)-N-('?-pyrrolidin- I ethyl)-benzamide; -2dehlmn -eh l--4id-- ehl phenylamino)- beazamide; N- [B is-(2 -hydroxy-ethyl)-am inoj -ethyl)} -5-chl oro-2-(4-i odo- 2-methyl- phenylamino)- benzamide; N- 2- [Bis-(2-hydroxy-ethyl)-ami no] -ethyl)} -5-bromo-2-(4-iodo- 2-methyl.- phenylamino)- benzamide; A [4-(2-Hydroxy-ethyl)-piperazin- I-yI] -propyl }-2-(4-iodo- 2-methyl-phenylamino)- benzamide; 5-Fluoro- 2 4 -iodo-2-methyl-phenylaxnino)-N-pyridin-4-ymethy- benzamide; 2 4 -iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin-l-yl- ethyl)-benzamide; -Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- I -yl- ethyl)-benzamide; 5-Fluoro-2-(4-iodo-2-methy-pheiylaino)-N-(2-pyrolidin-1 -yl :ethyl)-benzamide; 5-Chloro-N-(3 -dimethylamino-propy)-2-(4-iodo-2-methy phenylamino)-benzamide; N- 2- [Bis-(2-hydroxy-ethyl)-a-ino) -ethyl)} -5-fluoro-2-(4-iodo- 2-methyl- phenylamino)- benzarnide; -Chloro-N-(3 -hydroxy-p'ropyl)-2-(4-iodo-2-methyl-phenylamino)- benzanide; 5-Chloro-N-(3 -diethylamino-2-hydroxy-propyl)-2-(4.iodo- :0 302-methyl-phenylamino)- benzamnide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pipeidin-. -yl ethyl)-benzarnide; ill -Bromo-N -hydroxy-propyl)-2-(4-iodo-2 -m ethyl -pheny Iamino)- benzamnicde; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- I yl- propyl)-bexzarriide; N- f{2- [Bi s-(2-hydroxy-ethyl)-amnino] -ethyl)} -2-(4-iodo-2-methyl- phenyl amino)-5 -nitro- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2 -morpholin-4-y] ethyl)-benzamide; 5-Chloro-N-(3 -diethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-berizamide; 5-Chloro-N-(2-diisopropylarnino-ethyl)--2-(4-iodo-2-methyl- phenylamino)-benzamide; -Chiloro-2-(4-iodo-2 -m ethyl -phenylamino)-N-(3 -piperi din-I 1-y] propyl)-benzarnide; 2-(4-lodo-2-methyl -phenylamino)-5-nitro-N-(2-piperidin- I -yl- ethyl)-benzamide; 5-Bromo-2--(4-iodo-2-methyl-phenylamino)-N-(2-piperazin-I -yl- ethyl)-benzamide; -N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; oo 5-.Bromo-N-(3 -dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; -Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamnide; 5-Fluoro-N-{3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- 0000 benzamide; N-(3 -Di ethyl amino-propyl)-5 -fl uoro-2-(4-iodo-2-methyl o~o.phenylamino)-benzamide; 000000 N-(3 -Di ethyl amino-propyl)-2-(4-iodo-2-methyI -phenylamino)- 30 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2 -morpholin-4-yl- ethyl)-benzamide; 112 2-(4-1 odo-2 -methyl-phenylamirio) 5-nitro-N-(3 -p iperi din- I -yI- propyl)-benzamide; -Fluoro-2--(4-iodo-2-methyl-phenyilamino)-phenyi] -(3-hydroxy- pyrrolidin- 1 -yl)-methanone; .5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamnino)-benzamide; -Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yI ethyl)-benzamide; -Fluoro-2 -(44iodo-2 -methyl -pheniyl amino)-N-(3 -piperi din- Il-y] propyl)-benzamide; [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] f [4-(2-hydroxy-ethyl )-piperazin- 1 -yI]-methanone; N-(3 -Diethylarnino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo- 2-methyl-phenylamino)- benzamide; N-Cyclopropyl-5-fl uoro-2-(4-iodo-2-rnethyl-phenyl amino)- benzamnide; -Chl oro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl -phenyl amino)- benzamide; 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- :20 benzamide; N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Benzyloxy-5 -bromo-2-(4-iodo-2-methyl-phenylamino)- benzarnide; 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)- benzamnide; N-(2-Hydroxy-ethyl)-5-odo-2-(4-iodo-2-methyl-phenylamino)- 30 benzamide; .o N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro- benzamide; -113- 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzarnide; -Chi oro-N-cyci opropyl -i odo-2 -methyl -phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2 -methyl -phenyl amino)-N-methyl-N-phenyl- benzamide; N-All yl-5-fluoro- 2 -(4-iodo-2-methyl-phenylamnino)-benzamide; N-B enzyloxy-5-iodo-2-(4-i odo-2 -methyl-phenyl amino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylanino)-N-(4-sulfamoyl- berizyl)-benzamide; -chloro-2-(4-iodo-2-methyl-phenylamnino)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenyla'nino)-5-nitro- benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamnide; 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 bnaie 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzarnide; 2-(4-Iodo-2-methyl-phenylamino)-5-ritro-N-(4-sulfainoyl-benzyl)- benzamride; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide, -Fluoro-2-(4-iodo-2-methyl -phenylamino)-N-(3-metbyl-benzyl)- benzarnide; N-Cyclopropyl-5-odo-2-(4-iodo-2-methyl-phenylamino)- benzamide; -Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl benzamide; 114 N-B enzyl ox y-2-(4i odo2methyl phenyl am benzamide; N-Cycloh exyl-5 -1o do-2.(4i odo2m ethyl phenylamino)- berizarnidle; N-Allyl-5-id--4ioo--ehlpeyamn)bnaie 5-Iodo-2-(4-iodo-2-methyl -phenylamino)-N-(3 -methyl-benzyl)- benzamide; 2 -(4-Iodo-2-methyl-phenyl aino-N-(3 -methyl -benzyl benzamide; 5-Iodo- 2 4 -iodo-2methy-phenyamino-Nmethy-N-phenylI benzamide; N-Cyclohexy1-5-fluoro-2(4-iodo-2-methyl..phenylamino)- benzamide; 5-Chloro-N-cyclohexyl-2-(4-iodo-2methy..phenylamino)- benzamide; 2 4 -iodo-2rethy-phenyamino-N-(3-methy -benzyl)- benzarnide; 5-Bromo-N-cyclohexyl-2-(4iodo2methyl-phenylamino)- benzamide; 20 5-hoo2(-oo2mty-hn~aio--3mty-eiy) 9 9benzamide; 9. 0N-Cyclohexyl-2-(4-iodo2methy1.phenylamino)5nro- benzarnide; 9.N-Benzyloxy-5-bromo-2-(4iodo-2-.methyl-phenylamino)- benzamide; N-Benzyloxy-5-fluoro-2-(4-iodo-2-methy..phenylamino)- benzamide; ~5-Choro-N-(2 -hydroxy-ethyI)-2-(4iodo2methyl-phenylamino)- benzanmide; 30 -Br-omo-N-( 2 -hydroxehylain)-N-meodo.2metro-phenyl-no benzamnide; 115 2 -(4-iodo-2-methyl-phenylamino)-N-methyl-Nphenyl. benzami de; N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5 -Chloro-N-cycl opropy1 odo-2-methyl-phenyl amino)- benzamide; N-Ally]-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-phenylam benzamide; 5-Fluoro-N-(27hydroxy-ethyl)-2-(4-i odo-2 -methyl-phenyl amino)- benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- beazamide; N-Cyclopropyl-5-fluoro-2-(4-odo-2-methyl-phenylamino). benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N..(4.sulfamoyl benzyl)-benzamide; 20 N-Cyclopropyl-2-(4-iodo-2-methyl-phenylaino)-5nitro- benzamide; ***N-AllyI-5-fluoro-2-(4-i odo- 2 -methyl-phenylamnino)-benzamide; N-Benzyloxy-5-iodo-2-(4-i odo-2 -methyl-phenyl amino)- benzamide; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylaminoy..benzamide; 5-Bromo-2-( 4 -iodo-2-methy-phenylanino)-N(4.sulfamoyl.. bezy bezmie 5-Bromo-2-(4-iodo-2-methyl-phenylamino)Nmethyl-N*phenyl. benzamide; 30 N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5nitrobezide; 4 -Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyI alcohol; oro-2-(4-iodo-2-methyl-phenylamino)-phenyl] -methanol; 4 -lodo-2-methyl-phenylarnino)-5-nitro-phenyl] -methanol; -116- [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; and N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide. 26. Use of claim 24, wherein the MEK inhibitor is a compound of Formula (I) wherein R 1 is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; R 2 is hydroden; R 3 R 4 and Rs indendently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; Rio are R 1 1 independently are hydrogen or methyl; Z is COOR 7 tetrazolyl, CONR 6 R 7 CONHNRioRII, or CH 2 OR 7 R 6 and R 7 independently are hydrogen, C 1-4 alkyl, heteroaryl, or C 3-5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or R 6 and R 7 together with the nitrogen to which they are attached complete a 5-6 member cyclic ring optionally containing 1 or 2 additional heteroatoms selected from 0, 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. 15 27. Use of claim 26, wherein the MEK inhibitor is a compound for Formula (I) o wherein Z is COOR 7 R 7 is H, pentafluorophenyl or tetrazolyl; and R 3 R4 and R 5 are independently H, fluoro or chloro. 28. Use of claim 26, wherein the MEK inhibitor is a compound for Formula (I) wherein: Z is COOR 7 R 7 is H, pentafluorophenyl, or terazolyl; R 3 and Rs are 0 20 independently H, fluoro, or chloro; and R 4 is fluoro. 29. Use of claim 26, wherein the MEK inhibitor is a compound of Formula (I) 4 r wherein Z is COOR 7 R 7 is H, pentafluorophenyl or tetrazolyl; and two of R 3 R4 and R are independently fluoro. Use of claim 19, wherein the MEK inhibitor is a compound of Formula II 500382663 _.DOC/BSW 117 Ra f2a C-N-O-R 7 a Ia N Br or It R3a R4a wherein: Ri1a is hydrogen, hydroxy, C I-C 8 alkyl, C I-C 8 alkoxy, halo, trifluoromethyl, or CN; R2a is hydrogen; R3a, R4a, and R5a independently are hydrogen, hydroxy, halo, trifluoromethyl, C I-C 8 alkyl, C I-C8 alkoxy, nitro, CN, or (0 or NH)m-(CH2)n-Rga, where R9a is hydrogen, hydroxy, COH or NRIOaR I a. n is 0-4; mn is 0 or 1; Rj Oa and R 1 I la independently are hydrogen or C 1 -C 8 alkyl, or taken together with the nitrogen to which they are attached can complete -a 3- to 1 0-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from 0, S, NH, or N-C I-C 8 alkyl; 'r,6a is hydrogen, C I-C 8 alkyl, (CO)-I -C 8 alkyl, aryl, aralkyl, or C 3 -C 1 0 cycloalkyl; *R7a is hydrogen, CI-C 8 alkyl, C2-C 8 alkenyl, C 2 -C 8 alKynyl, 20 C 3 -C 1 0 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from 0, S, or NRqa); wherein any of the fnorgongalyl ak1- 1 y1 rl eeorl heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C I-C 6 alkoxy, amino, nitro, CI-C 4 alkylamino, di(Cl- C4)alkylamino,-C 3 -C 6 cycloalkyl., phenyl, phenoxy, C 3 -C 5 heteroaryl or 118- heterocyclic radical, or C 3 -C 5 heteroaryloxy or heterocyclic radical-oxy; or R6a and R7a taken together with the N to which they are attached can complete a 5- to 1 0-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from 0, S, or NRioRi I a; or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. 31. Use of claim 30, comprising a MEK inhibitor having a structure of Formula (11) wherein: RIa, is H, methyl, fluoro, or chloro; R2a is H; R3a, R4a and R5a are each H, Cl, nitro, or F; R 6 a is H; R 7 a is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl. methyl, cyclopropytmethyl, or cycloproplethyl; and the 4' position is I, rather than Br. 32. Use of claim 3 1, comprising a MEK inhibitor having a structure of Formula (1I) wherein: R4a is F at the 4 position, para to the CO-NR 6 a-OR 7 a group and meta to the bridging nitrogen; at least one of R 3 a and R 5 a is F or Cl; and RIa is methyl or chioro. :33. Use of claim 32, 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-(methyoxy)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)-benzanide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamnino)-N-(2-thienylmethoxy)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)-benzamide; 500382663i.DOC/BSVV 119 4-Fl uoro-2-(4-iodo-2-methyl -phenylamino)-N- (cyclopropylmethoxy)-benzamide; 4-Fluoro2?-(4-4odo-2methylphenylamino).N(cyclopentoxy)- benzamnide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-furylmethoxy)-benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-ethoxy- berizamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamnino)-N-(but-2-enyloxy)- benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide; 3 ,4-Difiuoro-2-(4-iodo-2-methyl-phenylanino)-N-( 1 -methylprop- 2-ynyloxy)-benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -phenyiprop- 2-ynyloxy)-benzarnide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 5-phenylpent-2-en-4-ynyl oxy)-benzamide; ::20 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- :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-methy -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; -120 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)-benzamnide; 5-Bromo-3,4-di fluoro-N.-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide; -Bromo-3 ,4-di fluoro-N(furan-3 -ylmethoxy)2-(4-iodo-2-methyl-phenylamnino)- benzamide; 5-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; 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -methyl-but-2- enyloxy)-benzamide; 5 -Bromo-3 ,4-di fluoro- 2-(4-iodo-2-methyl-phenylamino)-N-(3 -methyl-pent-2- en-4-ynyloxy)-benzwmide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-[5 -(3-methoxy- phenyl)-3-methyl-pent-2-en-4-ynyloxy]-benzamnide; 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide; 5 -Bromo-3 ,4-di fluoro-2-(4-iodo-2-methyl-phenylamino)-N13-(3-methoxy- phenyl)-prop-2-ynyloxy] -benzamide; -Bromo-3 ,4-di fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(thiophen-2- ykmethoxy)-benzamide; 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (pyridin-3-ylmethoxy)-benzamide; 5003826631 Doc/BSW -121 5-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; ),4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamnide; -Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylanino)-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)-benzamnide; 5-Chloro-2-(4-iodo-2-methyl-phenylamnino)-N-methoxy- benzamide; 4-Brorno-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-pheznylamino)-N-phenylmethoxy- benzamide; 5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Iodo-2-(4-iodo-2-methvl-phenvlamino)-N-phenylmehoxy- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran- 2-vloxv)-benzamnide- 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3-phenylprop-2-ynyloxy)-benzamide; 3 .4-Difluoro-2-(4-bromo-2-methvl -nhenvlqm innM-N- (3-furylmethoxy)-benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-thienylrnethoxy)-benzamnide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 3-ynyloxy)-benzamnide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl- 50*prop-2-enyloxy)-benzamide; 122 3 ,4-D I fl uoro 2 -(4-bromo-2-m ethyl -phenylamnino)-N-(b ut- 2-enyloxy)-benzamide; 3 A.-Difluoro- 2 -(4-bromo-2-rnethylbphenyIarnino-N(mthx3..)- benzarnide; 3 4 -Difluoro- 2 -(4-bromo-2-methy-phenylamino)N(efioxy)- benzamride; 3 4 -Difluoro-2-(4-bromo-2-methy-phenyamino)-N (cyclobutoxy)-benzarnide; 3 4 -Difluoro- 2 4 -bromo-2methy-phenyaino)N(isopropoxy)- benzamide; 3 4 -Difluoro- 2 -(4-bromo-2-methyl-phenylamino)-N- 2 -phenoxyethoxy)-benzamide; 3 4 -Difluoro- 2 -(4-bromo-2-methyl-phenylaimino)-N(cyclopropy- methoxy)-benzamide; 3 4 -Difluoro- 2 -(4-bromo-2-methy-phenyamino)-N..(npropoxy)- benzamide; 3 4 -Difluoro-2-(4-bromo-2methy-phenyamino)-N.( I -methyl- prop-2-ynyloxy)-benzamide; 3 4 -Difluoro-2-(4-bromo-2-methy1.phenyamino).Nl 3 3 -fluorophenyl)-prop-2-ynyoxy-bezaride; 3 4 -Difluoro-2-(4-bromno-2-methyl-.phenyamino)-N- (cyclopentoxy)-benzamide; 3 ,4,5-Trifluoro-N-hydroxy-2-(4.i odo- 2 -methyl-phenylamino)- benzamide; -Chloro-3 ,4-difl uoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide; .*5-Bromo-3, 4 -difluoro-2-(2-fluoroA-iodo.phenyamino)-N 3 hydroxy-benzamide; 3 4 ,5-Trifluoro-2-(2-fluoro4-odophenyamino)Nhydroxy- benzamide; 123 5-Chloro-3 ,4-difluoro-2-(2-fl uoro-4-iodo-phenylamino)-N- hydroxy-benzamide; 5-Bromo-2-(2-chiloro-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 benzamnide; 5-Chloro-2-(2-chloro-4-iodo-pheriylamnino)-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 benzamide; 2-(2-Bromo-4-iodo-phenylamnino)-5-chloro-3 ,4-difluoro-N- hydroxy-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide; 204-Fluoro-2-(2-fluoro-4-iodo-phenyiamino)-N-hydroxy-benzami de; 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-iocio-phenylamino)-3 ,4-difluoro-N-hydroxy- benzamnide; 25 2-(2-Bromo-4-iodo-phenylamnino)-4-fluoro-N-hydroxy-benzamide; 9 2-(2-Bromo-4-iodo-phenylamino)-3 ,4-difluoro-N-hydroxy- benzamnide; N-Cyclopropylmethoxy-3 ,4 ,5-trifluoro-2-(4-iodo-2-methyl- phenylaniino)-benzamide; 5-Chloro-N-cyclopropylmethoxy-3 ,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; -Bromo-N-cyclopropylmethoxy-3 ,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; 124 :20 N-Cycl opropylmethoxy-2-(4-i od o-2methyl -phenyl am ino)-4-nitro- benzamide; N-Cyclopropylmethoxy-3 ,4,5-trifluoro-2--(2-fluoro-4-iodo- phenylario)-benazamide; 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-4iodo-phenylamino)-4-ito benzarnide; 2 2 -Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3 5-Chloro-2-(2-chloro-4-iodo-phenylaino)N-. cyclopropylmethoxy-3,4-difluoro-benzamide; S-Bromo-2-(2-bromo4-iodo-phenyaino-Nethoxy-3,4-difluoro- benzamide; 2-2Clr--oopeyanno--toy4ntobnaie 2 2 -Bromo- 4 -iodo-phenylamino)-N-cyclopropylmethoxy. 3 2 -(2-Bromo-4-iodo-phenylamnino)-5-chloro-N cyclopropylmethoxy-3 ,4-difluoro-benzamide 2 2 -Bromo-4-iodo-phenylamnino)-N-cyclopropylmethoxy-4nito-. benzamide; N-ylpoymtoy-loo2(2fur--oopeyann) benzamide; N-Cyclopropylmethoxy-3 ,4-difluoro-2-(2-fluoro-4-iodo- phenylamnino)-benzamnide; 2 2 -Chloro-4-iodo-phenylamino)-N-cyclopropylmetioxy. 4-fluoro-benzamide; 2 2 -Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3 ,4-difiuoro-benzamide; 2 2 -Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy. 4-fluoro-benzamide; and 125 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3 ,4-difluoro-benzamnide. 34. Use of claim 19, comprising a MEK inhibitor having a structure selected from: 2-(2-chloro-4-iodophenylamino)-5-chloro-N-cyclopropylmethoxy -3,4- difluorobenzamide; 2-(4-iodophenylamnino)-N-cyclopropylmethoxy-5 -chloro-3 ,4- difluorobenzamide; 2-(4-iodophenylamino)-5-chloro-3 ,4-di fluorobenzoic acid; 2-(2- chloro-4-iodophenylamino)-5-chloro-3 ,4-difluoro-2-(4-iodo-2-methylphenylamnino)- benzoic acid; and 5-chloro-N-cyclopropylmnethoxy-3 ,4-difluoro-2-(4-iodo-2- methylphenylamino)-benzamide. Use of an effective antiarthritic amount of a compound selected from: 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3 ,4-difluorobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide; 2-(2-Methyl-4-iodophenylamnino)-N-hydroxy-3 ,4-di 2-(2-Methyl-4-iodophenylamnino)-N-cyclopropylmethoxy-3 bromobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy-3 ,4-difluoro-5 bromobenzamide; 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3 ,4-difluoro-5 bromobenzamide; 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3 ,4-di fluoro-5 -bromobenzamide; 20 2-(2-Chloro-4-iodophenylamino)-N-cyclobutylmethoxy-3 ,4-di fluorobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3 ,4-di fluorobenzamide; 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3 ,4,5 trifluorobenzamide; and 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide for treating or preventing arthritis in a patient. 500382663_i.Doc/BSVI -126- 36. Use of claim 35, wherein said compound is selected from 2-(2-chloro-4- iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide, 2-(2-Methyl-4- iodophenylamino)-N-cyclopropylmethoxy-3,4,5-trifluorobenzamide; and 2-(2-Chloro-4- iodophenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide. 37. A method for treating or preventing arthritis in a mammal, or patient, substantially as herein described with reference to any one of the Examples. 38. Use of an effective antiarthritic amount of a MEK inhibitor for treating or preventing arthritis in a mammal or patient, substantially as herein described with reference to any one of the Examples. DATED this 27th day of July 2004 Shelston IP Attorneys for: WARNER-LAMBERT COMPANY 500382663 .DOC/BSW
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11254498P | 1998-12-16 | 1998-12-16 | |
| US60/112544 | 1998-12-16 | ||
| US16465199P | 1999-11-10 | 1999-11-10 | |
| US60/164651 | 1999-11-10 | ||
| PCT/US1999/029783 WO2000035436A2 (en) | 1998-12-16 | 1999-12-15 | Treatment of arthritis with mek inhibitors |
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| AU2185800A AU2185800A (en) | 2000-07-03 |
| AU776788B2 true AU776788B2 (en) | 2004-09-23 |
| AU776788C AU776788C (en) | 2005-10-27 |
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| AU21858/00A Ceased AU776788C (en) | 1998-12-16 | 1999-12-15 | Treatment of arthritis with MEK inhibitors |
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| EP (1) | EP1143957A3 (en) |
| JP (1) | JP2002532415A (en) |
| KR (1) | KR100609800B1 (en) |
| AU (1) | AU776788C (en) |
| CA (1) | CA2346448A1 (en) |
| HU (1) | HUP0104693A3 (en) |
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| WO2023214325A1 (en) | 2022-05-05 | 2023-11-09 | Novartis Ag | Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors |
| WO2023225320A1 (en) | 2022-05-20 | 2023-11-23 | Novartis Ag | Epha2 bcl-xl inhibitor antibody-drug conjugates and methods of use thereof |
| WO2023225336A1 (en) | 2022-05-20 | 2023-11-23 | Novartis Ag | Met bcl-xl inhibitor antibody-drug conjugates and methods of use thereof |
| WO2024023666A1 (en) | 2022-07-26 | 2024-02-01 | Novartis Ag | Crystalline forms of an akr1c3 dependent kars inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996000082A1 (en) * | 1994-06-24 | 1996-01-04 | Cortecs Limited | Medical use of bromelain |
| WO1998028292A1 (en) * | 1996-12-23 | 1998-07-02 | Smithkline Beecham Corporation | Novel piperidine containing compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5525625A (en) * | 1995-01-24 | 1996-06-11 | Warner-Lambert Company | 2-(2-Amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran for treating proliferative disorders |
| WO1998037881A1 (en) * | 1997-02-28 | 1998-09-03 | Warner Lambert Company | Method of treating or preventing septic shock by administering a mek inhibitor |
| GB9713726D0 (en) * | 1997-06-30 | 1997-09-03 | Ciba Geigy Ag | Organic compounds |
| AU765030B2 (en) * | 1998-05-05 | 2003-09-04 | F. Hoffmann-La Roche Ag | Pyrazole derivatives as p-38 map kinase inhibitors |
| EP1082320A4 (en) * | 1998-05-26 | 2001-11-21 | Smithkline Beecham Corp | Novel substituted imidazole compounds |
-
1999
- 1999-12-15 HU HU0104693A patent/HUP0104693A3/en unknown
- 1999-12-15 CA CA002346448A patent/CA2346448A1/en not_active Abandoned
- 1999-12-15 WO PCT/US1999/029783 patent/WO2000035436A2/en not_active Application Discontinuation
- 1999-12-15 KR KR1020017007502A patent/KR100609800B1/en not_active IP Right Cessation
- 1999-12-15 JP JP2000587757A patent/JP2002532415A/en active Pending
- 1999-12-15 IL IL14323699A patent/IL143236A0/en unknown
- 1999-12-15 AU AU21858/00A patent/AU776788C/en not_active Ceased
- 1999-12-15 EP EP99966278A patent/EP1143957A3/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996000082A1 (en) * | 1994-06-24 | 1996-01-04 | Cortecs Limited | Medical use of bromelain |
| WO1998028292A1 (en) * | 1996-12-23 | 1998-07-02 | Smithkline Beecham Corporation | Novel piperidine containing compounds |
Non-Patent Citations (1)
| Title |
|---|
| MIYAZAWA ET AL. J. BIOL. CHEM. VOL. 273 (1998) PP24832-24833 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1143957A3 (en) | 2002-02-27 |
| WO2000035436A3 (en) | 2001-10-18 |
| IL143236A0 (en) | 2002-04-21 |
| AU776788C (en) | 2005-10-27 |
| EP1143957A2 (en) | 2001-10-17 |
| KR100609800B1 (en) | 2006-08-09 |
| HUP0104693A2 (en) | 2002-03-28 |
| JP2002532415A (en) | 2002-10-02 |
| HUP0104693A3 (en) | 2003-12-29 |
| KR20010093840A (en) | 2001-10-29 |
| AU2185800A (en) | 2000-07-03 |
| WO2000035436A2 (en) | 2000-06-22 |
| CA2346448A1 (en) | 2000-06-22 |
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