ZA200104000B - Antiviral method using MEK inhibitors. - Google Patents

Antiviral method using MEK inhibitors. Download PDF

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ZA200104000B
ZA200104000B ZA200104000A ZA200104000A ZA200104000B ZA 200104000 B ZA200104000 B ZA 200104000B ZA 200104000 A ZA200104000 A ZA 200104000A ZA 200104000 A ZA200104000 A ZA 200104000A ZA 200104000 B ZA200104000 B ZA 200104000B
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South Africa
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methyl
phenylamino
iodo
benzamide
difluoro
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ZA200104000A
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Alexander James Bridges
Stephen Joseph Gracheck
Alan Robert Saltiel
David Thomas Dudley
Annette Lynn Meyer
Judith Sebolt-Leopold
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Warner Lambert Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
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Description

ANTIVIRAL METHOD USING MEK INHIBITORS
FIELD OF THE INVENTION
This invention relates to a method for preventing and treating viral diseases in mammals comprising administering a compound characterized as an inhibitor of a family of enzymes known as MEK kinases, which are groups of
MAP (mitogen-associated protein kinase) and ERK (extracellular signal-regulated kinase) enzymes which regulate phosphorylation of substrates.
BACKGROUND OF THE INVENTION
Some diseases caused by viruses are relatively mild and do not lead to major health problems. For example, rhinoviruses, of which there are over 40 strains, are the cause of the common cold. Although generally not considered life threatening, there still are no agents effective in preventing, or even inhibiting, rhinoviruses. Furthermore, not all viruses are as innocuous, and indeed some viruses lead to dreaded diseases which result in substantial suffering and eventual death.
HIV is a member of the class of viruses known as retroviruses. The retrovirus genome is composed of RNA which can be converted to DNA by reverse transcription. This retroviral DNA is integrated into a host cell’s chromosome. Produced via the replicative processes of the host cells, retroviral particles propagate the infection to other cells. HIV appears to have a particular affinity for the human T-4 lymphocyte which plays a vital role in the body’s immune system. HIV infection of these lymphocytes depletes this white cell population. Eventually, the immune system is rendered inoperative or ineffective against various opportunistic diseases such as pneynocystic carini pneumonia,
Karposi’s sarcoma, and cancer of the lymph system.
Another type of virus resistant to treatment is herpesvirus. Herpesvirus includes a large group of DNA viruses found in many animal species. The nucleic acid is a single molecule of double-stranded DNA and consists of about
152,000 base pairs. These viruses mature in the nucleus of an infected cell, where they induce formation of cytoplasmic inclusion bodies. Herpesviruses cause oral . herpes simplex, genital herpes simplex, varicella, herpes zoster, and cytomegalic inclusion disease in humans, and cause pseudorabies and other diseases in animals. Cytomegalovirus is one member of the group of highly host-specific herpesviruses that infect humans, monkeys, and rodents, and generally leads to a syndrome resembling infectious mononucleosis.
Viruses also produce epidermal tumors caused by papillomavirus, commonly referred to as warts. While warts on most skin are not of great concern, genital warts have become a significant health problem.
Because viruses are virtually immune to total destruction, and because the diseases caused by viruses are so devastating, both in health care costs and human suffering, the need continues to find new and better medicines to not only treat the diseases caused by viruses, but to actually prevent the disease. We have now discovered that a new class of MEK inhibitors are particularly well-suited to preventing and treating a wide range of viral diseases and infections in mammals.
Most of these MEK inhibitors are known to be useful for treating septic shock, for instance as described in WO 98/37881. - .
SUMMARY OF THE INVENTION }
This invention provides a method for preventing and treating viral infections in mammals. The method includes the step of administering to a mammal infected with a virus and in need of treatment, or to a mammal at risk of developing a viral infection or disease, an anti-viral effective amount of a MEK inhibitor. In a preferred embodiment, the invention provides a method for preventing or treating viral infections in mammals by administering a selective
MEK inhibitor. Selective MEK inhibitors are those compounds which inhibit the
MEK 1 and MEK 2 enzymes without substantial inhibition of other such enzymes.
In a further embodiment, the invention provides a method for preventing and/or treating viral infections comprising administering an effective amount of the selective MEK inhibitor described in US 5,525,625, incorporated herein by reference, which selective MEK inhibitor is 2-(2-amino-3-methoxyphenyl)-4-oxo- 4H-[1]benzopyran. :
In another preferred embodiment, the MEK inhibitor to be administered is a phenyl amine derivative of Formula I i. 2 z 1 N
TE
Brorl R} R,
In Formula (I), Rj is hydrogen, hydroxy, C1-Cg alkyl, C1-Cg alkoxy, halo, trifluoromethyl, or CN. Rj is hydrogen. R3, R4, and Rg are independently selected from hydrogen, hydroxy, halo, trifluoromethyl, C1-Cg alkyl,
C1-Cg alkoxy, nitro, CN, and -(O or NH)y,-(CH2)n-Ro. Rg is hydrogen, hydroxy,
COOH, or NRjgR|1; nis 0-4; mis 0 or 1. Each of Rjg and Ry] is independently . selected from hydrogen and C;-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally . containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N-(C1-Cg alkyl). Z is COOR7, tetrazolyl, CONRgR7, CONHNR1gR 11, or CH2OR7. Rg and R7 independently are hydrogen, C1-Cg alkyl, C»-Cg alkenyl, C2-Cg alkynyl, (CO)-C-Cg alkyl, aryl, heteroaryl, C3-C1g cycloalkyl, or C3-Cj¢ (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or Rg and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl. In formula (I), any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C,-Cs alkoxy, amino, nitro, C,-C4 alkylamino, di(C,-Cy)alkylamino, C3-C¢ cycloalkyl, phenyl, phenoxy, C3-Cs heteroaryl or heterocyclic radical, or C3-Cs heteroaryloxy or heterocyclic radical-
oxy. The invention also provides a pharmaceutically acceptable salt, ester, amide, or prodrug of each of the disclosed MEK inhibitors.
B Preferred embodiments of Formula (I) have a structure wherein: (a) R; is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; (b) R; is hydrogen; (c) Ra,
Rs, and Rs independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; (d) Ryo and R;) independently are hydrogen or methyl; (e) Z is
COOR;, tetrazolyl, CONRgR7, CONHNR¢R;, or CH;OR7; Rg and Ry independently are hydrogen, C ;.4 alkyl, heteroaryl, or C 3.5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or Rg and R, together with the nitrogen to which they are attached complete a 5-6 member cyclic ring optionally containing 1 or 2 additional heteroatoms selected from O,
NH or N-alkyl; and wherein any of the foregoing alkyl or aryl groups can be unsubstituted or substituted by halo, hydroxy, methoxy, ethoxy, or heteroaryloxy (such as 2,3,4,5,6-pentafluorophenyl); (f) Z is COOR;7; (g) R7is H, pentafluorophenyl, or tetrazolyl; (h) Rs, Rs, and Rs are independently H, fluoro, or chloro; (1) Ry is fluoro; (j) two of Rs, Ry, and Rs are fluoro; or (k) combinations of the above. In another preferred embodiment of Formula (I), R; is methyl, fluoro, chloro, or bromo. :
In a more preferred embodiment, the MEK inhibitor is selected from a compound in Formula (I) Compound Table below. - .
FORMULA (I) COMPOUND TABLE (page 1 of 10) [4-Chloro-2-(1H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine (4-iodo-2-methyl-phenyl)-[2-(1H-tetrazol-5-yl)-phenyl]Jamine [4-nitro-2-(1H-tetrazol-5-y1)-phenyl-(4-iodo-2-methyl-phenyl)-amine 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-lodo-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-phenylamino)-benzoic acid 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid ’ 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-benzoic acid 5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide
N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1H-tetrazol-5-yl)-benzamide
FORMULA (I) COMPOUND TABLE (continued, page 2 of 10) : 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide ~~ “ 5 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide . [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic acid 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide 5-Bromo-N-(2-hydroxy-ethyl)~2-(4-iodo-2-methyl-phenylamino)- benzamide
N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-y1}-propyl} -2-(4-iodo- 2-methyl-phenylamino)-benzamide
N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide
N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- : benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1- . yl-ethyl)-benzamide 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1- yl-ethyl)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide
FORMULA (I) COMPOUND TABLE (continued, page 3 of 10) 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 2-methylphenylamino)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4- yl-ethyl)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)- benzamide
N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide
N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethyl)- : benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- . benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1-yl-propyl)- benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl-ethyl)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1-yl-ethyl)- benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin-4-yl- ethyl)-benzamide
FORMULA (I) COMPOUND TABLE (continued, page 4 of 10) ylmethyl-benzamide am 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- . benzamide 2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- propyl) a -3,4-difluoro-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl-enzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)- benzamide ; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin-4-yl-ethyl)- benzamide . 15 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy-propyl)- benzamide < 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin-1-yl- ethyl)-benzamide : 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl-benzamide : 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen-2-yl- ethyl)- benzamide ; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin-4-ylmethyl- benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl-benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin-1-yl- ethyl)- benzamide 5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl])-propyl}-2-(4-iodo-2- methyl- phenylamino)- benzamide 5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-2- methyl- phenylamino)- benzamide 2-(4-Todo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl-benzamide
FORMULA (I) COMPOUND TABLE (continued, page 5 of 10) 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-2- methyl- phenylamino)- benzamide 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)- benzamide (3-Hydroxy-pyrrolidin-1-yl)-[5-nitro-2-(4-iodo-2-methyl-phenylamino)-phenyl}- methanone 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl }-S-chloro-2-(4-iodo-2-methyl- phenylamino)- benzamide
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl } -5-bromo-2-(4-iodo-2-methyl- phenylamino)- benzamide ’ N-{3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-2-methyl- phenylamino)- benzamide : 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide 5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1-yl-ethyl)- benzamide 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo-2-methyl- phenylamino)- benzamide
FORMULA (I) COMPOUND TABLE (continued, page 6 of 10) benzamide a 5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo-2-methyl- phenylamino)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)- benzamide an 10 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)- ’ benzamide
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl }-2-(4-iodo-2-methyl- 15 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 : 20 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide . 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)- benzamide 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-1-yl-ethyl)- 25 benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin-1-yl-ethyl)- benzamide
N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide 30 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
: FORMULA (I) COMPOUND TABLE (continued, page 7 of 10) 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-1-yl-propyl)- benzamide : [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(2 or 3-hydroxy- pyrrolidin- 1-yl)-methanone 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- ’ benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)- . benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-(2-hydroxy-ethyl)- piperazin-1-yl)-methanone
N-(3-Diethylamino-2-hydroxy-propy!)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)- benzamide
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
FORMULA (I) COMPOUND TABLE (continued, page 8 of 10) 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)}- benzamide 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
Bg N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro-benzamide
N 10 2-(4-1odo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide = N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide : 5-Chloro-2-(4-iodo-2~methyl-phenylamino)-N-methyl-N-phenyl-benzamide 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- ; benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide
N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
FORMULA (I) COMPOUND TABLE (continued, page 9 of 10) 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide 2-(4-Todo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro-benzamide 5-Iodo-2-(4~iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide
N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-fluoro-2-(4-iodo-~2-methyl-phenylamino)-benzamide ’ 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide : N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
FORMULA (I) COMPOUND TABLE {continued, page 10 of 10)
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methy)-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide : 10 N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- : 15 benzamide 5 N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide £5 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol - [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol - [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol : [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl] -methanol
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide. . —
In another preferred embodiment, the MEK inhibitor is a compound of Formula II ite
Ry, 2a C—N—O0—R,
N
II jogs
Brorl rR), Ry,
In Formula (II), Rj, is hydrogen, hydroxy, C1-Cg alkyl, C1-Cg alkoxy, halo, trifluoromethyl, or CN. Rp, is hydrogen. Each of R35, R4a, and Rs, 1s independently selected from hydrogen, hydroxy, halo, trifluoromethyl,
C1-Cg alkyl, C1-Cg alkoxy, nitro, CN, and (O or NH),-(CH2)p-Ro,. Ro, is hydrogen, hydroxy, COoH or NR1(aR11a; nis 0-4; and mis 0 or 1. Each of
R10a and Ry, is independently hydrogen or C1-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from 0, S, NH, or N-(C1-Cg alkyl). Rg, is hydrogen, C-Cg alkyl, (CO)-(C1-Cg alkyl), aryl, aralkyl, or C3-C1 cycloalkyl. R7, is hydrogen, C;-Cg alkyl,
C»-Cg alkenyl, Co-Cg alkynyl, C3-Cyq (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg,). In Formula (II), any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C,-Ce alkoxy, amino, nitro, C,-C4 alkylamino, di(C-Cs)alkylamino, C3-Cs cycloalkyl, phenyl, phenoxy, C3-Cs heteroaryl or heterocyclic radical, or C3-Cs heteroaryloxy or heterocyclic radical- oxy; or Rgg and R7, 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 NR1gaR 11a. The invention also encompasses pharmaceutically acceptable salts, esters, amides or prodrugs of each of the disclosed compounds.
Preferred embodiments of Formula (II) are those structures wherein: (a) Ry, is H, methyl, fluoro, or chloro; (b) Ra, is H; Rig, Raa, and Rs are each H,
Cl, nitro, or F; (¢) Rea is H; (d) R7, is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl methyl, cyclopropylmethyl, or cyclopropylethyl; (e) the 4° position is I, rather than Br; (f) Ra, is F at the 4 position, para to the CO-N-Rg,-OR7, group and meta to the bridging nitrogen; (f) Rs, or Rs, is F; (g) at least one of R3,, Rua, and Rs, is F; (h) Ria is methyl or chloro; or (i) or a combination of the above.
In a more preferred embodiment the MEK inhibitor is a compound selected from Formula (II) Compound Table below.
FORMULA (II) COMPOUND TABLE (pagel of7) . 5 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide
B 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(methoxy)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)-benzamide } 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)-benzamide . 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)-benzamide ) 10 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentoxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-furylmethoxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-ethoxy-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)- benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1-methylprop-2-ynyloxy)- ; benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-phenylprop-2-ynyloxy)- benzamide ] 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-5-phenylpent-2-en- 4-ynyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)-benzamide
FORMULA (II) COMPOUND TABLE (continued, page 2 of 7) 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclobutyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-methyl-prop-2-enyloxy)- benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-3-ynyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-(2-fluorophenyl)-prop- 2-ynyloxy)-benzamide 5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide 5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide } 5-Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide : 5-Bromo-N-butoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-but- 2-enyloxy)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-pent-2-en- 4-ynyloxy)-benzamide
FORMULA (II) COMPOUND TABLE (continued, page 3 of 7) . 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N-[5-(3-methoxy-phenyl)- 3-methyl-pent-2-en-4-ynyloxy]-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-[3-(3-methoxy- phenyl)-prop-2-ynyloxy]-benzamide : 10 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(thiopen- 2-ylmethoxy)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(pyridin- 3-ylmethoxy)-benzamide 5-Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-(2-fluorophenyl)- prop-2-ynyloxy)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(ethoxy)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(isopropoxy)- : benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but-3-ynyloxy)- . benzamide 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran-2-yloxy)- benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy-benzamide 4-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide 5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran-2-yloxy)- benzamide
I ——
FORMULA (II) COMPOUND TABLE (continued, page 4 of 7) 3 4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-phenylprop-2-ynyloxy)- benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-furylmethoxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-3-ynyloxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl-prop-2-enyloxy)- benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclobutoxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide } 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)- benzamide : 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(1-methyl-prop-2-ynyloxy)- benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-(3-fluorophenyl)-prop- 2-ynyloxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(4,4-dimethylpent- 2-ynyloxy)-benzamide
FORMULA (II) COMPOUND TABLE (continued, page 5 of 7) 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopentoxy)-benzamide 3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-3 ,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-3 4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide
N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide 34,5 _Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 5-Chloro-3,4-difluoro-2-(2 -fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3 ,4-difluoro-N-hydroxy-benzamide 2-2-F luoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-3 [4 5-trifluoro-N-hydroxy-benzamide 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3 ,4-difluoro-N-hydroxy-benzamide 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl-benzamide 2-(2-Bromo-4-iodo-phenylamino)-3 ,4,5-triftluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3 JA-difluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide - 4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 3 4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide } 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide 2-(2-Chloro-4-iodo-phenylamino)-3 ,4-difluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-3 ,4-difluoro-N-hydroxy-benzamide
I
FORMULA (Il) COMPOUND TABLE (continued, page 6 of 7)
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-
S benzamide 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide
N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide
N-Cyclopropylmethoxy-3.4,5-trifluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide
N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro- benzamide 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- : benzamide 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro- benzamide 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N-cyclopropylmethoxy-3,4-difluoro- benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro-benzamide
FORMULA (II) COMPOUND TABLE (continued, page 7 of 7) y N-Cyclopropylmethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide
N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropyimethoxy-4-fluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide. ee
In the most preferred embodiment of this invention, a compound selected from the following is administered to a patient (ie, a mammal) in an amount that is effective to prevent or treat rheumatoid arthritis or osteoarthritis: 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3 4-difluorobenzamide (PD184352); 2-(2-Methyl-4-iodophenylamino)-N- : hydroxy-4-fluorobenzamide (PD170611); 2-(2-Methyl-4-iodophenylamino)-N- . hydroxy-3,4-difluoro-5-bromobenzamide (PD171984); 2-(2-Methyl- 4-jodophenylamino)-N-cyclopropylmethoxy-3 ,4-difluoro-5-bromobenzamide (PD177168); 2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy- 3,4-difluoro-5-bromobenzamide (PD 180841), 2-(2-Chloro-4-iodophenylamino)-
N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide (PD 184161); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5-bromobenzamide (PD184386); 2-(2-Chloro-4-iodophenylamino)-N-cyclobutylmethoxy- 3 4-difluorobenzamide (PD 185625); 2~(2-Chloro-4-iodophenylamino)-N- hydroxy-4-fluorobenzamide (PD 185848); 2-(2-Methyl-4-iodophenylamino)-N- hydroxy-3,4-difluorobenzamide (PD 188563); 2-(2-Methyl-4-iodophenylamino)-
N-cyclopropylmethoxy-3,4,5-trifluorobenzamide (PD 198306); and 2-(2-Chloro- 4-iodophenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide (PD 203311); and the benzoic acid derivatives thereof. For example, the benzoic acid derivative of PD 198306 is 2-(2-Methyl-4-iodophenylamino)-3,4,5-trifluorobenzoic acid.
Additional preferred compounds include 2-(2-chloro-4-iodophenylamino)-5- chloro-N-cyclopropylmethoxy -3,4-diflucrobenzamide (PD 297189), 2-(4- iodophenylamino)-N-cyclopropylmethoxy-5-chloro-3,4-difluorobenzamide (PD 297190), 2-(4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD 296771), 2-(2-chloro-4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD 296770), 5-chloro-3,4-difluoro-2-(4-iodo-2-methylphenylamino)-benzoic acid (PD 296767); and 5-chloro-N-cyclopropylmethoxy -3,4-difluoro-2-(4-iodo-2- methylphenylamino)-benzamide (PD 298127).
The invention further provides methods of synthesis and synthetic intermediates as disclosed below.
Other features and advantages of the invention are apparent from the detailed description, examples, and claims set forth.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a method of preventing or treating viral infections in a patient which comprises administering to a patient suffering from a viral infection and in need of treatment, or to a patient at risk for developing a viral disease, an antiviral effective amount of a MEK inhibitor. The invention provides : 20 a method of preventing and treating all forms of viral disease, and relieving the symptoms and degeneration that accompany the disease. The invention is preferably directed to treatment of HIV infections, and is preferably practiced by administering a phenyl amine MEK inhibitor of Formula I or Formula II.
Preferably, such MEK phenyl amine compounds are selective MEK 1 and MEK 2 inhibitors. These MEK inhibitors are described in WO 98/37881, which is incorporated herein by reference.
The mammals to be treated according to this invention are patients who have developed a viral disease and are suffering from the symptoms associated with disease, or who are at risk for developing a viral infection, for example, : 30 having a life style that subjects the patient to substantial risk of contacting a viral disease. Those skilled in the medical art are readily able to identify individual patients, particularly children and young adults who are afflicted with viral infections, as well as those who are susceptible to developing disease which is
- caused by a virus.
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)- 4-0x0-4H-[1]benzopyran. Specifically, a compound is a MEK inhibitor if a compound shows activity in the assay titled “Cascade Assay for Inhibitors of the
MAP Kinase Pathway,” column 6, line 36 to column 7, line 4 of the 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 and by their usage throughout this disclosure.
The term “patient” means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, horses, and pigs. :
As used herein, the term “aryl” means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from five to twelve carbon atoms. Examples of : typical aryl groups include phenyl, naphthyl, and fluorenyl. The aryl may be substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Typical substituted aryl groups include 3-fluorophenyl, 3,5-dimethoxyphenyl, 4-pitronaphthyl, 2-methyl-4-chloro-7-aminofluorenyl, and the like.
The term “aryloxy” means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl- 1-fluorenyloxy. “Heteroaryl” means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, benzinnidazolyl, and triazinyl. The heteroaryl groups can be unsubstituted or substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Examples of substituted heteroaryl groups include chloropyranyl, methylthienyl, fluoropyridyl, amino-1,4-benzisoxazinyl, nitroisoquinolinyl, and hydroxyindolyl.
The heteroaryl groups can be bonded through oxygen to make heteroaryloxy groups, for example thienyloxy, isothiazolyloxy, benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.
The term “alkyl” means straight and branched chain aliphatic groups.
Typical alkyl groups include methyl, ethyl, isopropyl, tert.-butyl, 2,3-dimethylhexyl, and 1,1-dimethylpentyl. The alkyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined herein. Typical substituted alkyl groups include chloromethyl, 3-hydroxypropyl, 2-dimethylaminobutyl, and 2-(hydroxymethylamino)ethyl. Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl. Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, ) 20 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. “Alkenyl” means a straight or branched carbon chain having one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1,1-dimethyl- hex-4-enyl, 3-ethyl-4-methyl-pent-2-enyl, and 3-isopropyl-pent-4-enyl. The alkenyl groups can be substituted with halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy, heteroaryl, or heteroyloxy, for example 2-bromoethenyl, 3-hydroxy-2-butenyl, 1-aminoethenyl, 3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy-but-2-enyl, and 4-naphthyloxy-hex-2-enyl. “Alkynyl” means a straight or branched carbon chain having at least one triple bond. Typical alkynyl groups include prop-2-ynyl, 2-methyl-hex-5-ynyl, 3,4-dimethyl-hex-5-ynyl, and 2-ethyl-but-3-ynyl. The alkynyl groups can be substituted as the alkyl and alkenyl groups, for example, by aryl, aryloxy,
heteroaryl, or heteroaryloxy, for example 4-(2-fluorophenyl)-but-3-ynyl, 3-methyl-5-thienylpent-4-ynyl, 3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl- hex-4-ynyl. ” The alkenyl and alkynyl groups can have one or more double bonds or triple bonds, respectively, or a combination of double and triple bonds. For example, typical groups having both double and triple bonds include hex-2-en- 4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and 3-thienyloxy-hex-3-en-5-ynyl.
The term “cycloalkyl” means a nonaromatic ring or fused rings. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl. The ring can optionally contain one, two, or three heteroatoms selected from O, S, or N. Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, ) octahydroindolyl, and octahydrobenzothiofuranyl. The cycloalkyl groups can be substituted with the same substituents as an alkyl and alkenyl groups, for example, halo, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl, 2-aminocyclopropyl, 2-phenylpyrrolidinyl, and 3-thienylmorpholine-1-yl.
Selective MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or MEK 2 enzymes, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and
PDGF receptor kinases, and C-src. In general, a selective MEK 1 or MEK 2 inhibitor has an ICs for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its ICs, for one of the above-named other enzymes. Preferably, a selective inhibitor has an ICs that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its ICs or one or more of the above- name enzymes.
B. Administration and Formulation
The MEK inhibitors of the present method are administered to a patient as part of a pharmaceutically acceptable composition. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly,or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a } coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged 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 (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (€) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and : (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well- known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds : can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. . : Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isosteary! alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalamic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The compounds of the present method can be administered to a patient at dosage levels in the range of about 0.1 to about 1000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about : 20 0.01 to about 100 mg per kg of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well- known to those skilled in the art.
The compounds of the present method can be administered as pharmaceutically acceptable salts, esters, amides, or prodrugs. The term “pharmaceutically acceptable salts, esters, amides, and prodrugs” as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the
: zwitterionic forms, where possible, of the compounds of the invention. : The term “salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts : include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, and the like.
These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic oo ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetracthylammonium, 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 C1-Cg alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl . esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary
C1-Cg alkyl amines and secondary Cj-Cg dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term “prodrug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and
V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.
Symposium Series, and in Bioreversible Carriers in 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 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.
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 : 20 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 I can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a 2-(phenylamino)- benzoic acid. This process is depicted in Scheme 1.
Scheme 1 i 2 C—OH
Ry
NH L
+ Rs
Brorl
Rg Ry base i 2 C—OH
N
Brorl
Ry Ry where L is a leaving group, for example halo such as fluoro.
The reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran or toluene, in : the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, triethylamine, and Hunig’s base. The reaction generally is carried out at a temperature of about -78°C to about 100°C, and normally is complete within about 2 hours to about 4 days. The product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
The 2-(phenylamino)-benzoic acid (e.g., Formula I, where R7 is hydrogen) can be reacted with an organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide to produce a pharmaceutically acceptable salt. The free acids can also be reacted with an alcohol of the formula HOR?
(where R7 is other than hydrogen, for example methyl) to produce the corresponding ester. Reaction of the benzoic acid with an alcohol can be carried out in the presence of a coupling agent. Typical coupling reagents include 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 1,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)- phosphonium hexafluorophosphate (PyBrOP), and (benzotriazolyloxy) tripyrrolidino phosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acid and alcohol derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired. The coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
The benzamides of the invention, Formula I where Z is CONRgR7, are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNRgR7. The reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic solvent in the presence of a coupling reagent. Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene. Typical coupling reagents include DCC, EEDQ, PyBrOP, and PyBOP. The reaction is generally complete after about 10 minutes to about 2 hours when carried out ata temperature of about 0°C to about 60°C. The product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation. The hydrazides (z= CONHNR{gR 1) are similarly prepared by coupling a benzoic acid with a hydrazine of the formula
HoHNR0R{1.
g The benzyl alcohols of the invention, compounds of Formula I where Z is : CH,ORg and Rg is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following Scheme 2.
Scheme 2 i
Ie wf
N reducing N
Tr = TY
Brorl Rr; R, Brorl RK R,
Typical reducing agents commonly employed include borane in tetrahydrofuran.
The reduction normally is carried out in an unreactive organic solvent such as tetrahydrofuran, and generally is complete within about 2 hours to about 24 hours when conducted at a temperature of about 0°C to about 40°C.
The following detailed examples illustrate specific compounds provided by this invention.
EXAMPLE 1 ; 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid
To a stirring solution comprised of 3.16 g (0.0133 mol) of 2-amino-5- iodotoluene in 5 mL of tetrahydrofuran at -78°C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethenylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 15 minutes, after which time a solution of 1.00 g (0.00632 mol) of 2 4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to increase slowly to room temperature, at which temperature it was stirred for 2 days. The reaction mixture was concentrated.
Aqueous HCI (10%) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSO4) and then boiled over a steambath to low volume and cooled to room temperature. The off-white fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C; 1H NMR (400 MHz; DMSO): § 9.72 (s, 1H), 7.97 (dd, 1H, J = 7.0, 8.7 Hz), 7.70 (d, 1H,J=1.5Hz), 7.57 (dd, 1H, J = 8.4, 1.9 Hz), 7.17 (d, 1H, J = 8.2 Hz), 6.61-6.53 (m, 2H), 2.18 (s, 3H); 13C NMR (100 MHz; DMSO): 5 169.87, 167.60, 165.12, 150.17, 150.05, 139.83, 138.49, 136.07, 135.31, 135.20, 135.07, 125.60, 109.32, 105.09, 104.87, 99.72, 99.46, 89.43, 17.52; 19F NMR (376 MHz; DMSO): § -104.00 to -104.07 (m);
IR (KBr) 1670 (C = O stretch) cm-1;
MS (CI) M+1 =372,
Analysis calculated for C{4H;1FINOj: C, 45.31; H, 2.99; N, 3.77.
Found: C, 45.21; H, 2.77; N, 3.64.
EXAMPLES 2-30
By following the general procedure of Example 1, the following benzoic . acids and salts of Formula (I) were prepared.
) “Example Compound MPC
No. "2 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)- 206-210 : benzoic acid 3 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic =~ 240.5-244.5 acid 4 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 259.5-262 phenylamino)-benzoic acid 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-benzoic acid 255-260 6 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid ~~ 234-238 7 Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 310-320 DEC benzoate 8 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 239.5-240 9 2-(2-Chloro-4-iodo-phenylamino)-5-nitro-benzoic acid 289-293 4.Fluoro-2-(3-fluoro-4-iodo-2-methyl-phenylamino)- 233-235 benzoic acid it 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid 264-267 : 12 2-(2-Fluoro-4-iodo-phenylamino)-5-nitro-benzoic acid 256-258 . 13 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic 218.5-220 acid 14 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid ~~ 285-288 DEC 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro- 230-234 ’ benzoic acid 16 3-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid ~~ 218-221 17 3,4-Difluoro-2-(4-iodo-2-methoxy-phenylamino)- 230-233 benzoic acid 18 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 245-255 DEC
“Example Compound ________________ MP°C
No.
TT 19 2-(4-lodo-2-methyl-phenylamino)-benzoic acid 218-223 20 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 243-46 21 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 241-245 22 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)- 218-222 benzoic acid 23 4-Fluoro-2-(3-chloro-4-iodo-2-methyl-phenylamino)- 248-252.5 benzoic acid 24 2-(4-lodo-phenylamino)-5-methoxy-benzoic acid 208-211 25 3-Chloro-2-(2-chloro-4-iodo-phenylamino)-benzoic acid 232-233 26 2-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoic acid 179-182 27 4-Fluoro2-(2,3-dimethyl-4-iodo-2-methyl- 258-261 phenylamino)benzoic acid 28 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic 209.5-211 acid 29 2-Chloro-6-(4-iodo-2-methyl-phenylamino)-benzoic acid ~~ 171-175 30 2-(4-lodo-2-methyl-phenylamino)-4-nitro-benzoic acid 251-263
EXAMPLE 31 5-Chloro-N-(2-hydroxyethy!)-2-(4-iodo-2-methyl-phenylamino)-benzamide
To a stirring solution comprised of 0.1020 g (0.2632 mmol) of 5-chloro- 2-(4-iodo-2-methyl-phenylamino)-benzoic acid, 0.1 mL (1.7 mmol) of ethanolamine, and 0.05 mL (0.29 mmol) of diisopropylethylamine in 5 mL of a 1:1 (v/v) tetrahydrofuran-dichloromethane solution was added 0.15 g (0.29 mmol) of solid PyBOP powder directly. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The crude residue was partitioned between ether (50 mL) and 10% aqueous hydrochloric acid (50 mL).
The organic phase was washed with 10% aqueous sodium hydroxide (50 mL), dried (MgSO04) and concentrated in vacuo to afford a yellow-brown oil which was crystallized from hexanes-ether to afford 0.0831 g (73%) of a green-yellow powder; mp 120-121°C;
: TH NMR (400 MHz; CDCl3): 8 9.11 (s, 1H), 7.56 (d, 1H, J = 1.4 Hz), 7.46-7.41 (m, 2H), 7.20 (dd, 1H, J = 8.9, 2.4 Hz), 7.00 (t, 2H, J = 9.6 Hz), 6.55 (broad t, 1H), 3.86 (t, 2H, J = 5.0 Hz), 3.61 (dd, 2H, J = 10.1, 5.5 Hz), 2.23 (s, 3H), 1.56 (broad s, 1H);
IR (KBr) 3297 (O-H stretch), 1627 (C = O stretch) cm™1;
MS (CI) M+1 = 431.
Analysis calculated for C1gH1¢ClIN2O2:
C,44.62; H, 3.74; N, 6.50.
Found: 44.63; H, 3.67; N, 6.30.
EXAMPLES 32-48
By following the general procedure of Example 31, the following benzamides were prepared by reacting the corresponding benzoic acid with the corresponding amine. "Example Compound MP°C
No. "32 4Methoxy-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-phenylamino)- 90-91 benzamide 36 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N- oil dimethyl-benzamide 37 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1H- 285-288 DEC tetrazol-5-yl)-benzamide 38 5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 180-182 benzamide 39 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N- 137-138 dimethyl-benzamide
“Example Compound MP°C
No. 40 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 170-173 benzoylamino}-acetic acid 41 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 69-71 propyl-benzamide 42 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 132-1334 phenylamino)-benzamide 43 N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl- oil phenylamino)-benzamide 44 4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]- 122-124 propyl}-2-(4-iodo-2-methyl-phenylamino)- benzamide 45 N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5- 91-93 nitro-benzamide 46 N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- 97-99 benzamide 47 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl- 118-120 ) phenylamino)-benzamide 48 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N- 142.5-144 dimethyl-benzamide
EXAMPLE 49 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (0.50 g, 1.35 mmol) was dissolved in 6 mL (6 mmol) of cold 1.0 M borane- tetrahydrofuran complex in tetrahydrofuran solution. The reaction mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction was quenched with 80 mL of methanol. Concentration in vacuo produced a clear tan oil which was purified by MPLC. Elution with dichloromethane afforded 0.4285 g (89%) of a white solid; mp 99-100.5°C; 1H NMR (400 MHz; DMSO): § 7.57 (d, 1H, J=1.7 Hz), 7.45 (dd, 1H, J=8.4, 1.9 Hz), 7.39 (s, 1H), 7.29 (t, 1H, J=7.5 Hz), 6.89 (d, 1H, J=8.4 Hz), 6.67-6.60 (m, 1H), 5.47 (1, 1H, J=5.5 Hz), 4.49 (d, 2H, 5.1 Hz), 2.14 (5, 3H),
: : IR (KBr) 3372 (O-H stretch) cm-l;
MS (CI) M+1 = 358. : Analysis calculated for C14H(3FINO:
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. “ExampleNo. ~~ Compound ~~ MP°C 50 [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 I were prepared utilizing combinatorial synthetic techniques. The general procedure is as follows:
To a 0.8-mL autosampler vial in a metal block was added 40 pL of a 0.5 M solution of the acid in DMF and 40 pL 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% acetonitrile in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 pM spherical silica, pore size 115 A derivatized with C-18, the sample was eluted at 4.7 mL/min with a linear ramp to 100% acetonitrile over 8.5 minutes. Elution with 100% acetonitrile continued for 8 minutes). Fractions were collected by monitoring at 214 nM. The residue was dissolved in chloroform and transferred to a preweighed vial, evaporated, and weighed again to determine the yield.
EXAMPLES 53-206
The following compounds of Formula I were prepared by combinatorial methodology: “Example Compound MS
No. M-H 53 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 510 phenylamino)-benzamide 54 N+(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- 462 phenylamino)-benzamide 55 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- 577 piperidin-1-yl-ethyl)-benzamide 56 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 432 ) phenylamino)-benzamide 57 N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- 444 phenylamino)-benzamide ) 58 3,4-Difluoro-N-(3-hydroxy-propy!)-2-(4-iodo-2-methyl- 446 phenylamino)-benzamide 59 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 564 (2-pyrrolidin-1-yl-ethyl)-benzamide 60 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 571 (2-pyridin-4-yl-ethyl)-benzamide 61 4-Fluoro-N~(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 414 benzamide
“Example ~~ Compound MS
No. ~~ M-H 62 5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 551 : 2-methyl-phenylamino)-benzamide 63 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 580 (2-morpholin-4-yl-ethyl)-benzamide 64 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- ~~ 501 4-yl-ethyl)-benzamide 65 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- ~~ 485 1-yl-ethyl)-benzamide 66 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- 493 ethyl)-benzamide 67 N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- 473 phenylamino)-benzamide 68 N-Benzy!-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide ~~ 460 69 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy- ~~ 384 ethyl)-benzamide 70 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- 483 ethyl)-benzamide . 71 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl- 495 propyl)-benzamide 72 3 4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 513 1-yl-propyl)-benzamide 73 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl- 480 ethyl)-benzamide 74 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl- ~~ 467 ethyl)-benzamide : 75 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin- 453 4-yl-ethyl)-benzamide 76 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-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-difluoro-benzamide

Claims (48)

PCT/US99/30484 CLAIMS
1. A method for preventing viral infections in mammals, said method comprising the step of administering to a mammal an anti-viral effective amount of a MEK inhibitor.
2. A method according to Claim 1 wherein the MEK inhibitor is 2-(2-amino-3- methoxyphenyl)-4-oxo-4H-[1]benzopyran.
3. A method for preventing viral infections in mammals, said method comprising the step of administering to a mammal an anti-viral effective amount of a phenyl amine compound of Formula I: r2 z Ry N Brorl R, Ry. wherein: R is hydrogen, hydroxy, C-Cg alkyl, C;-Cg alkoxy, halo, trifuoromethyl, or CN; R, is hydrogen; Rj, Ry, and Rg independently are hydrogen, hydroxy, halo, trifluoromethyl, C,-Cg alkyl, C;-Cg alkoxy, nitro, CN or -(O-NH),-(CH9)y-Rg, where Rg is hydrogen, hydroxy, COOH, or NRgR11; n is 0-4; AMENDED SHEET
; misQorl; R10 and Rj independently are hydrogen or C1-Cg alkyl, or taken together with the nitrogen to which they are attached can complete : a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N-C1-Cg alkyl; Z is COOR7, tetrazolyl, CONRgR7, CONHNR; oR11, or CHpOR7; Rg and R7 independently are hydrogen, C-Cg alkyl, C>-Cg alkenyl, Cy-Cg alkynyl, (CO)-Cy-Cg alkyl, aryl, heteroaryl, C3-C1 cycloalkyl, or C3-Cyq (cycloalkyl optionally containing 1, 2, or 3 heteroatoms selected from O, S, NH, or N alkyl); or Rg and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl; and wherein any of the foregoing alkyl, alkenyl, aryl, heteroaryl,
a. heterocyclic, and alkynyl groups can be unsubstituted or : substituted by halo, hydroxy, C;-Cs alkoxy, amino, nitro, C;-C, ) alkylamino, di(C,;~C4)alkylamino, C;3-C¢ cycloalkyl, phenyl, phenoxy, Cs-Cs heteroaryl or heterocyclic radical, or C3-Cs : heteroaryloxy or heterocyclic radical-oxy; : or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
4. The method of claim 3, wherein the compound of Formula (I) has a structure wherein (a) R; is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; (b) R; is hydrogen; (c) R3, Ry, and Rs independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; (d) R;¢ and Ry; independently are hydrogen or methyl; (¢) Z is COORy, tetrazolyl, CONRgR7, CONHNR oR 1, or CH;0OR37; Rg and R, independently are hydrogen, C ;4 alkyl, heteroaryl, or C 3.5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or Rs and R; together with the nitrogen to which they are attached complete a 5-6 member cyclic
: ring optionally containing 1 or 2 additional heteroatoms selected from O, NH or N-alkyl; and wherein any of the foregoing alkyl or aryl groups can be unsubstituted or substituted by halo, hydroxy, methoxy, ethoxy, or heteroaryloxy; (f) Z is COORy; (g) Ry is H, pentafluorophenyl, or tetrazolyl; (h) Rj, Ry, and Rs are independently H, fluoro, or chloro; (i) R4 is fluoro; (j) two of Ry, Ry, and Rs are fluoro; (k) or combinations of the above.
5. The method according to claim 3 wherein the phenyl amine is selected from: [4-Chloro-2-(1H-tetrazol-5-yl)-phenyl(4-iodo-2-methyl-phenyl)- amine; (4-Iodo-2-methyl-phenyl)-[2-(1 H-tetrazol-5-yl)-phenyl]amine; [4-Nitro-2-(1H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)- amine; 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid; 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; : 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic i 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-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-phenylamino)-benzoic acid; 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid; 5-Methyl-2-(4-i0do-2-methyl-phenylamino)-benzoic acid; 2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid; 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid;
co 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-benzoic acid, . 5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide; N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-
benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1H-tetrazol-5-yl)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide; [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic acid; : 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- : benzamide; N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-
: benzamide;
4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl}-propyl}- 2-(4-iodo-2-methyl-phenylamino)-benzamide; N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide; 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-piperidin-1-yl-ethyl)-benzamide; : 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin-1-yl-ethyl)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-pyridin-4-yl-ethyl)-benzamide; 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- : (2-morpholin-4-yl-ethyl)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- } 20 4-yl-ethyl)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1-yl-ethyl)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide; N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy- ethyl)-benzamide; 4-Fluoro-2-(4-10do-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl- propyl)-benzamide;
Lo 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1-yl-propyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl- ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl- ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin- 4-yl-ethyl)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- pyridin-4-ylmethyl-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 4-ylmethyl-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- propyl)-3,4-difluoro-benzamide; oo 15 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide; co 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide; ) 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 4-yl-ethyl)-benzamide; : : 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy- propyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin- 1-yl-ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen- 2-yl-ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin- 4-ylmethyl-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl- benzamide;
: 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin- 1-yl-ethyl)-benzamide; 5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}- 2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl } - 2-(4-i0do-2-methyl-phenylamino)-benzamide; 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- benzamide; 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}- 2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl- _ ethyl)-benzamide; (3-Hydroxy-pyrrolidin-1-yl)-[2-(4-iodo-2-methyl-phenylamino)- 5-nitro-phenyl]; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl- ethyl)-benzamide; 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl} -5-chloro-2-(4-iodo- 2-methyl-phenylamino)-benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo- 2-methyl-phenylamino)-benzamide; N-{3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo- 2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide; 5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin-1-yl- ethyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl- ethyl)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yi- ethyl)-benzamide; . 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide; 5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; - 5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo- 2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl- ethyl)-benzamide; 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl- propyl)-benzamide; ” N-{2-[Bis-(2-hydroxy-ethyl)-amino}-ethyl } -2-(4-iodo-2-methyl- phenylamino)-S5-nitro-benzamide; : 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide; : 5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl- propyl)-benzamide; 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-1-yl- ethyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin-1-yl- ethyl)-benzamide; N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 5-nitro-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-1-yl- propyl)-benzamide; [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- pyrrolidin-1-yl)-methanone 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- . 20 ethyl)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl- propyl)-benzamide; [S-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- [4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone; N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide; N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
: N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; ; N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(2-Hydroxy-ethyl)-5-iodo-2-(4-i0do-2-methyl-phenylamino)- benzamide; ; N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro- benzamide; 2-(4-lodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide; 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; . 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; : N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; ~ 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide; N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methy]-phenylamino)-5-nitro- benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide; N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; : 20 2-(4-lodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro- benzamide; 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; ) N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- : benzamide; : N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5 N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 10: benzamide; 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; B 15 N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; BH 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- - : benzamide; N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 20° 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- . benzamide; N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Fluoro-N-~(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
PCT/US99/30484 N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol, [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-methanol, [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol; [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; and N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
6. A method for preventing viral infections in mammals, said method comprising the step of administering to a mammal an anti-viral effective amount of phenyl amine of Formula II: 0 Rea ],, 2a C—N—O0—R., N I Jule Brorl Ry, Ry, wherein: Ry, is hydrogen, hydroxy, C;-Cg alkyl, C-Cg alkoxy, halo, trifuoromethyl, or CN; R,, is hydrogen; AMENDED SHEET
: R34, R44, and Rg, independently are hydrogen, hydroxy, halo, trifluoromethyl, C1-Cg alkyl, C1-Cg alkoxy, nitro, CN, or (O or NH),-(CH2)p-Rg,, where Rg is hydrogen, hydroxy, COoH orNRj0aR11a: nis 0-4; misOorl; R10a and R11, independently are hydrogen or C1-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-C1-Cg alkyl; Rg is hydrogen, C1-Cg alkyl, (CO)-C1-Cg alkyl, aryl, aralkyl, or C3-Cq cycloalkyl; R75 is hydrogen, C1-Cg alkyl, Co-Cg alkenyl, C»-Cg alkynyl, C3-C1 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg,); and wherein any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C;-Ce alkoxy, amino, nitro, C,-C4 alkylamino, di(C;- Cs)alkylamino, C;-C¢ cycloalkyl, phenyl, phenoxy, C3-Cs heteroaryl or heterocyclic radical, or C;-Cs heteroaryloxy or heterocyclic radical-oxy; or Rga and R7, 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 NR10aR 11a; or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
7. The method of claim 6, comprising a compound having a structure of Formula (II) wherein: (a) Ry, is H, methyl, fluoro, or chloro; (b) Ry, is H; Ria, Raa, and Rs, are each H, Cl, nitro, or F; (¢) Rea is H; (d) Ry, is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl,
cyclobutyl methyl, cyclopropylmethyl, or cyclopropylethyl; and (e) the 4’ position is I, rather than Br. :
8. The method of claim 6, comprising a compound of Formula (II) having a structure wherein: Ry, is F at the 4 position, para to the CO-N-Rgs-OR7, group and meta to the bridging nitrogen; at least one of Rj, and Rs, is F or Cl; and Rjais methyl or chloro.
9. The method of claim 6, comprising a MEK inhibitor having a formula selected from: 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(methoxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide; : 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentoxy)- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-furylmethoxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-ethoxy- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide;
F 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1-methylprop- 2-ynyloxy)-benzamide; : : 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-phenylprop- 2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 5-phenylpent-2-en-4-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- 2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)- benzamide; y 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclobutyloxy)- benzamide; ; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-methyl-prop- 2-enyloxy)-benzamide; = 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide; : 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-3-ynyloxy)- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopentyloxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide; 5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methy!l- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (n-propoxy)-benzamide; 5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide 5-Bromo-N-butoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-but-2-enyloxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-pent-2-en-4-ynyloxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N- [5-(3-methoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- 2-ynyloxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- [3-(3-methoxy-phenyl)-prop-2-ynyloxy]-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (thiopen-2-ylmethoxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- : (pyridin-3-ylmethoxy)-benzamide; 5-Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (ethoxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (isopropoxy)-benzamide; 5-Bromo-3 4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but- 3-ynyloxy)-benzamide; 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran- 2-yloxy)-benzamide;
"g 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- benzamide; : 4-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; 5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran- 2-yloxy)-benzamide; 3 4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- : (3-phenylprop-2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- : 15 (3-furylmethoxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 3-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl- prop-2-enyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 2-enyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)- benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)- benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (cyclobutoxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)- benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide; : 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(1-methyl- prop-2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3-(3-fluorophenyl)-prop-2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (4,4-dimethylpent-2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (cyclopentoxy)-benzamide; 3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- ‘ hydroxy-benzamide; N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide; 3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide; 5-Chloro-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; 2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide; 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide;
= 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl- benzamide; 2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide; 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difluoro-N- hydroxy-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide; 4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide; 3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-
benzamide; 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-
benzamide; 2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-
= benzamide; N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; : 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-
phenylamino)-benzamide;
5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro- benzamide;
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo-
phenylamino)-benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-
cyclopropylmethoxy-3,4-difluoro-benzamide;
N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluoro-benzamide; 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide; 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluoro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N- cyclopropylmethoxy-3,4-difluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro- benzamide; N-Cyclopropylmethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide; N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; : 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 4-fluoro-benzamide; . 20 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 4-fluoro-benzamide; and 2~(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide.
10. The method of claim 1, comprising a MEK inhibitor having a structure selected from: 2-(2-chloro-4-iodophenylamino)-5-chloro-N-cyclopropylmethoxy -3,4- difluorobenzamide (PD 297189); 2-(4-iodophenylamino)-N- cyclopropylmethoxy-5-chloro-3,4-difluorobenzamide (PD 297190); 2-(4- iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD 296771); 2-(2- chloro-4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD
PCT/US99/30484 296770); 5-chloro-3,4-difluoro-2-(4-iodo-2-methylphenylamino)-benzoic acid (PD 296767); and 5-chloro-N-cyclopropylmethoxy -3,4-difluoro-2-(4- iodo-2-methylphenylamino)-benzamide (PD 298127).
11. A method for preventing viral infections in mammals, said method comprising the step of administering to a mammal an anti-viral effective amount of a compound selected from: 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4- difluorobenzamide (PD 184352); 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 170611); 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5- bromobenzamide (PD 171984); 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro- 5-bromobenzamide (PD 177168); 2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy-3,4-difluoro-5- bromobenzamide (PD 180841); 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro- 5-bromobenzamide (PD 184161); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5- bromobenzamide (PD 184386); 2-(2-Chloro-4-iodophenylamino)-N-cyclobutylmethoxy-3,4- difluorobenzamide (PD 185625); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 185848); 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluorobenzamide (PD 188563); 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3,4,5- ’ triffuorobenzamide (PD 198306); and AMENDED SHEET
PCT/US99/30484 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-4- fluorobenzamide (PD 203311).
12. A method according to Claim 1, 3, or 6 wherein the viral infection to be prevented is HIV.
13. A method according to Claim 1, 3, or 6 wherein the viral infection to be prevented is Hepatitis B.
14. A method according to Claim 1, wherein said MEK inhibitor is selected from: 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4- difluorobenzamide (PD 184352); 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 170611); 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5- bromobenzamide (PD 171984); 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro- 5-bromobenzamide (PD 177168); 2-(2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy-3,4-difluoro-5- bromobenzamide (PD 180841); 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro- 5-bromobenzamide (PD 184161); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5- bromobenzamide (PD 184386); 2-(2-Chloro-4-iodophenylamino)-N-cyclobutylmethoxy-3,4- ’ difluorobenzamide (PD 185625); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 185848); AMENDED SHEET
PCT/US99/30484 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluorobenzamide (PD 188563); 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy-3,4,5- trifluorobenzamide (PD 198306); and 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy-4- fluorobenzamide (PD 203311); and the benzoic acid derivatives thereof.
15. A pharmaceutical composition according to Claim 1, 3, or 6 formulated for the treatment of viral infection.
16. Use of a MEK inhibitor in the manufacture of a preparation for preventing and treating viral infections in mammals.
17. Use according to Claim 16, wherein the MEK inhibitor is 2-(2-amino-3- methoxyphenyl)-4-oxo-4H-[1]benzopyran.
18. Use of a phenyl amine compound of Formula (I) as defined in Claim 3 in the manufacture of a preparation for preventing and treating viral infections in mammals.
19. Use according to Claim 18, wherein the compound of Formula (I) has a structure as defined in Claim 4.
20. Use according to Claim 18, wherein the phenyl amine is a compound as defined in Claim 5.
21. Use of a phenyl amine of Formula (II) as defined in Claim 6 in the ) manufacture of a preparation for preventing and treating viral infections in AMENDED SHEET
PCT/US99/30484 mammals.
22. Use according to Claim 21, wherein the compound has a structure of Formula (II) as defined in Claim 7.
23. Use according to Claim 21, wherein the phenyl amine is a compound of Formula (II) as defined in Claim 8.
24. Use according to Claim 21, wherein the phenyl amine is a MEK inhibitor as defined in Claim 9.
25. Use according to Claim 16, wherein the MEK inhibitor has a structure as defined in Claim 10.
26. Use of a compound as defined in Claim 11 in the manufacture of a preparation for preventing and treating viral infections in mammals.
27. Use according to Claim 16, 18, or 21 wherein the viral infection to be prevented or treated is HIV.
28. Use according to Claim 16, 18, or 21 wherein the viral infection to be prevented or treated is Hepatitis B.
29. Use according to Claim 16, wherein said MEK inhibitor is a compound as defined in Claim 14.
30. A substance or composition for use in a method for preventing and treating viral infections in mammals, said substance or composition comprising a MEK inhibitor, and said method comprising the step of administering an anti- AMENDED SHEET
PCT/US99/30484 viral effective amount of said substance or composition to a mammal.
31. A substance or composition for use in a method of treatment according to Claim 30, wherein the MEK inhibitor is 2-(2-amino-3-methoxyphenyl)-4-oxo- 4H [1]benzopyran.
32. A substance or composition for use in a method for preventing and treating viral infections in mammals, said substance or composition comprising a phenyl amine compound of Formula (I) as defined in Claim 3, and said method comprising the step of administering an anti-viral effective amount of said substance or composition to a mammal.
33. A substance or composition for use in a method of treatment according to Claim 32, wherein the compound of Formula (I) has a structure as defined in Claim 4.
34. A substance or composition for use in a method of treatment according to Claim 32, wherein the phenyl amine is a compound as defined in Claim 5.
35. A substance or composition for use in a method for preventing and treating viral infections in mammals, said substance or composition comprising a phenyl amine of Formula (II) as defined in Claim 6, and said method comprising the step of administering an anti-viral effective amount of said substance or composition to a mammal.
36. A substance or composition for use in a method of treatment according to Claim 35, wherein the compound has a structure of Formula (II) as defined in Claim 7. AMENDED SHEET
PCT/US99/30484
37. A substance or composition for use in a method of treatment according to Claim 35, wherein the phenyl amine is a compound of Formula (II) as defined in Claim 8.
38. A substance or composition for use in a method of treatment according to Claim 35, wherein the phenyl is a MEK inhibitor as defined in Claim 9.
39. A substance or composition for use in a method of treatment according to Claim 30, wherein the MEK inhibitor has a structure as defined in Claim 10.
40. A substance or composition for use in a method for preventing and treating viral infections in mammals, said substance or composition comprising a compound as defined in Claim 11, and said method comprising the step of administering an anti-viral effective amount of said substance or composition to a mammal.
41. A substance or composition for use in a method of treatment according to Claim 30, 32, or 35 wherein the viral infection to be prevented or treated is
HIV.
42. A substance or composition for use in a method of treatment according to Claim 30, 32, or 35 wherein the viral infection to be prevented or treated is Hepatitis B.
43. A substance or composition for use in a method of treatment according to Claim 30, wherein said MEK inhibitor is a compound as defined in Claim
14. AMENDED SHEET
PCT/US99/30484
44. A method according to any one of Claims 1, 3, 6, or 11, substantially as herein described and illustrated.
45. A composition according to Claim 15, substantially as herein described and illustrated.
46. Use according to any one of Claims 16, 18, 21, or 26, substantially as herein described and illustrated.
47. A substance or composition for use in a method of treatment according to any one of Claims 30, 32, 35, or 40, substantially as herein described and illustrated.
48. A new non-therapeutic method of treatment; a new composition; a new use of a MEK inhibitor, of a phenyl amine compound of Formula (I) as defined in Claim 3, of a phenyl amine compound of Formula (II) as defined in Claim 6, or of a compound as defined in Claim 11; or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
ZA200104000A 1999-01-07 2001-05-16 Antiviral method using MEK inhibitors. ZA200104000B (en)

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Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100514236B1 (en) 1999-02-24 2005-09-13 에프. 호프만-라 로슈 아게 Phenyl- and pyridinyl derivatives
DE10017480A1 (en) * 2000-04-07 2001-10-11 Transmit Technologietransfer Use of substances that act as MEK inhibitors for the manufacture of a medicament against DNA and RNA viruses
GEP20053496B (en) * 2000-07-19 2005-04-25 Warner Lambert Co Oxygenated Esters of 4-Iodo Phenylamino Benzhydroxamic Acids
EP1201765A3 (en) * 2000-10-16 2003-08-27 Axxima Pharmaceuticals Aktiengesellschaft Cellular kinases involved in cytomegalovirus infection and their inhibition
AU2002249261A1 (en) * 2001-03-06 2002-09-19 Axxima Pharmaceuticals Ag Use of mek inhibitors for treating inflammation and virus induced hemorrhagic shock
NZ518726A (en) 2001-05-09 2004-06-25 Warner Lambert Co Method of treating or inhibiting neutrophil chemotaxis by administering a mek inhibitor
DE10138912A1 (en) * 2001-08-08 2003-02-27 Medinnova Ges Med Innovationen Use of active substances for the prophylaxis and / or therapy of viral diseases as well as test system for finding such active substances
US7235537B2 (en) 2002-03-13 2007-06-26 Array Biopharma, Inc. N3 alkylated benzimidazole derivatives as MEK inhibitors
NZ535158A (en) 2002-03-13 2007-06-29 Array Biopharma Inc N3 alkylated benzimidazole derivatives as MEK inhibitors
DOP2003000641A (en) * 2002-05-10 2003-11-15 Pfizer INHIBITORS OF RNA-DEPENDENT RNA POLYMERASE OF HEPATITIS C VIRUSES AND COMPOSITIONS AND TREATMENT USED
US7538120B2 (en) 2003-09-03 2009-05-26 Array Biopharma Inc. Method of treating inflammatory diseases
US7144907B2 (en) 2003-09-03 2006-12-05 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
AU2004283148A1 (en) 2003-10-21 2005-05-06 Warner-Lambert Company Llc Polymorphic form of N-[(R)-2,3-Dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
US7732616B2 (en) 2003-11-19 2010-06-08 Array Biopharma Inc. Dihydropyridine and dihydropyridazine derivatives as inhibitors of MEK and methods of use thereof
WO2005051906A2 (en) 2003-11-19 2005-06-09 Array Biopharma Inc. Heterocyclic inhibitors of mek and methods of use thereof
US7517994B2 (en) 2003-11-19 2009-04-14 Array Biopharma Inc. Heterocyclic inhibitors of MEK and methods of use thereof
CN1882347A (en) 2003-11-21 2006-12-20 阿雷生物药品公司 AKT protein kinase inhibitors
US7378423B2 (en) 2004-06-11 2008-05-27 Japan Tobacco Inc. Pyrimidine compound and medical use thereof
PL2298768T3 (en) 2004-06-11 2013-03-29 Japan Tobacco Inc 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine derivatives and related compounds for the treatment of cancer
SE0401969D0 (en) * 2004-08-02 2004-08-02 Astrazeneca Ab Piperidine derivatives
US8299076B2 (en) 2005-05-18 2012-10-30 Array Biopharma Inc. Crystalline forms of 2-(2-flouro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide
JP5129143B2 (en) 2005-10-07 2013-01-23 エグゼリクシス， インコーポレイテッド MEK inhibitor and method of use thereof
US8063050B2 (en) 2006-07-06 2011-11-22 Array Biopharma Inc. Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors
CN101511842B (en) 2006-07-06 2012-10-31 阵列生物制药公司 Dihydrofuro pyrimidines as AKT protein kinase inhibitors
CA2656618C (en) 2006-07-06 2014-08-26 Array Biopharma Inc. Cyclopenta [d] pyrimidines as akt protein kinase inhibitors
EP2054418B1 (en) 2006-07-06 2011-11-09 Array Biopharma Inc. Dihydrothieno pyrimidines as akt protein kinase inhibitors
CN101605540A (en) 2006-12-14 2009-12-16 埃克塞利希斯股份有限公司 Use the method for mek inhibitor
US8846683B2 (en) 2007-07-05 2014-09-30 Array Biopharma, Inc. Pyrimidyl cyclopentanes as Akt protein kinase inhibitors
ES2551352T3 (en) 2007-07-05 2015-11-18 Array Biopharma, Inc. Pyrimido cyclopentanes useful for the treatment of inflammatory or hyperproliferative diseases
US9409886B2 (en) 2007-07-05 2016-08-09 Array Biopharma Inc. Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
KR20150091196A (en) 2007-07-05 2015-08-07 어레이 바이오파마 인크. Pyrimidyl cyclopentanes as akt protein kinase inhibitors
MX2010007546A (en) 2008-01-09 2010-09-30 Array Biopharma Inc Hydroxylated pyrimidyl cyclopentane as akt protein kinase inhibitor.
CN101932564B (en) 2008-01-09 2012-12-26 阵列生物制药公司 Hydroxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors
EP2346818B1 (en) 2008-11-10 2012-12-05 Bayer Intellectual Property GmbH Substituted sulphonamido phenoxybenzamides
WO2011047788A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
US20120269803A1 (en) 2009-10-21 2012-10-25 Bayer Intellectual Property Gmbh Substituted benzosulphonamides
CN102574782B (en) 2009-10-21 2014-10-08 拜耳知识产权有限责任公司 Substituted halophenoxybenzamide derivatives
US8993622B2 (en) 2010-06-11 2015-03-31 Eirium Ab Antiviral compounds
EP2632899A1 (en) 2010-10-29 2013-09-04 Bayer Intellectual Property GmbH Substituted phenoxypyridines
CN103635192B (en) 2011-04-01 2017-07-04 基因泰克公司 The combination of AKT inhibitor compounds and chemotherapeutics and application method
JP6147246B2 (en) 2011-04-01 2017-06-14 ジェネンテック， インコーポレイテッド Combinations of AKT and MEK inhibitor compounds and methods of use
EP2903649A1 (en) * 2012-10-08 2015-08-12 Westfälische Wilhelms-Universität Münster Mek inhibitors in the treatment of virus diseases
SI2909188T1 (en) 2012-10-12 2018-07-31 Exelixis, Inc. Novel process for making compounds for use in the treatment of cancer
EP3043790B1 (en) 2013-09-11 2021-05-26 The Administrators of the Tulane Educational Fund Novel anthranilic amides and the use thereof
BR112020007442A2 (en) * 2017-10-17 2020-10-27 Atriva Therapeutics Gmbh mek inhibitor for the treatment of viral and bacterial infections

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6420338B1 (en) * 1997-06-13 2002-07-16 New York University Medical Center Inhibition of the Src kinase family pathway as a method of treating HBV infection and hepatocellular carcinoma
EP0993437B1 (en) * 1997-07-01 2006-11-08 Warner-Lambert Company Llc 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as mek inhibitors
WO1999001426A1 (en) * 1997-07-01 1999-01-14 Warner-Lambert Company 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as mek inhibitors

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